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The Pivotal Immunoregulatory Functions of Microglia and Macrophages in Glioma Pathogenesis and Therapy.

Gliomas are mixed solid tumors composed of both neoplastic and nonneoplastic cells. In glioma microenvironment, the most common nonneoplastic and infiltrating cells are macrophages and microglia. Microglia are the exact phagocytes of the central nervous system, whereas macrophages are myeloid immune cells that are depicted with ardent phagocytosis. Microglia are heterogeneously located in almost all nonoverlapping sections of the brain as well as the spinal cord, while macrophages are derived from circulating monocytes. Microglia and macrophages utilize a variety of receptors for the detection of molecules, particles, and cells that they engulf. Both microglia and peripheral macrophages interact directly with vessels both in the periphery of and within the tumor. In glioma milieu, normal human astrocytes, glioma cells, and microglia all exhibited the ability of phagocytosing glioma cells and precisely apoptotic tumor cells. Also, microglia and macrophages are robustly triggered by the glioma via the expression of chemoattractants such as monocyte chemoattractant protein, stromal-derived factor-1, and macrophage-colony stimulating factor. Glioma-associated microglia andor macrophages positively correlated with glioma invasiveness, immunosuppression, and patients poor outcome, making these cells a suitable target for immunotherapeutic schemes.

Effect of Early Surgical Intervention for Brain Tumors Associated with Epilepsy on the Improvement in Memory Performance.

We evaluated the effect of early surgical intervention on the change in memory performance of patients with low-grade brain tumors associated with epilepsy. Twenty-three adult patients with low-grade brain tumors and epilepsy who underwent surgery at our institution between 2010 and 2019 were included. The Wechsler Memory Scale-Revised (WMS-R) was used to assess cognitive memory performance. Memory performance before and after surgery was retrospectively evaluated. In addition, the relationships among preoperative memory function, postoperative seizure outcome, preoperative seizure control, temporal lobe lesion, and change in memory function were examined. There were statistically significant improvements from median preoperative to postoperative WMS-R subscale scores for verbal memory, general memory, and delayed recall (p<0.001, p<0.001, and p0.0055, respectively) regardless of preoperative sores and tumor location. Good postsurgical seizure control was associated with significant improvements in postoperative WMS-R performance. Our results indicated that early surgical intervention might improve postoperative memory function in patients with low-grade brain tumors and epilepsy.

TGF-β induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-αNF-κB signal pathway.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. The unregulated expression of Claudin-4 (CLDN4) plays an important role in tumor progression. However, the biological role of CLDN4 in GBM is still unknown. This study aimed to determine whether CLDN4 mediates glioma malignant progression, if so, it would further explore the molecular mechanisms of carcinogenesis. Our results revealed that CLDN4 was significantly upregulated in glioma specimens and cells. The inhibition of CLND4 expression could inhibit mesenchymal transformation, cell invasion, cell migration and tumor growth in vitro and in vivo. Moreover, combined with in vitro analysis, we found that CLDN4 can modulate tumor necrosis factor-α (TNF-α) signal pathway. Meanwhile, we also validated that the transforming growth factor-β (TGF-β) signal pathway can upregulate the expression of CLDN4, and promote the invasion ability of GBM cells. Conversely, TGF-β signal pathway inhibitor ITD-1 can downregulate the expression of CLDN4, and inhibit the invasion ability of GBM cells. Furthermore, we found that TGF-β can promote the nuclear translocation of CLDN4. In summary, our findings indicated that the TGF-βCLDN4TNF-αNF-κB signal axis plays a key role in the biological progression of glioma. Disrupting the function of this signal axis may represent a new treatment strategy for patients with GBM.

Serum-derived extracellular vesicles facilitate temozolomide resistance in glioblastoma through a HOTAIR-dependent mechanism.

Extracellular vesicle (EV)-mediated transfer of long non-coding RNAs (lncRNAs) has been reported to regulate chemoresistance in various cancers. We herein investigate the therapeutic potential of bioinformatically identified HOTAIR transferred by serum-derived EVs (serum-EVs) in temozolomide (TMZ) resistance of glioblastoma (GBM) and the downstream mechanisms. EVs were isolated from the serum of GBM patients. Expression of HOTAIR was examined in the clinical tissue samples and serum-EVs of GBM patients. The downstream miRNAs of HOTAIR and its target genes were predicted in silico. The effects of the HOTAIR transmitted by serum-EVs in malignant phenotypes, tumor growth, and TMZ resistance were assessed in vitro and in vivo. HOTAIR expression was upregulated in clinical tissues, cells, and serum-EVs of GBM. Co-culture data showed that GBM-serum-EVs facilitated GBM cell proliferative and invasive phenotypes and TMZ resistance by elevating HOTAIR. In GBM cells, HOTAIR competitively bound to miR-526b-3p and weakened miR-526b-3ps binding ability to EVA1, thus increasing the expression of EVA1. Furthermore, HOTAIR carried by serum-EVs promoted tumor growth and TMZ resistance in vivo by suppressing miR-526b-3p-mediated EVA1 inhibition. GBM-serum-EV-enclosed HOTAIR may augment GBM progression and chemoresistance through miR-526b-3p downregulation and EVA1 upregulation. These results provide a strategy to reduce TMZ resistance in GBM treatment.

HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.

Assessment and Comparison of Three Dimensional Exoscopes for Near-Infrared Fluorescence-Guided Surgery Using Second-Window Indocyanine-Green.

Compared to microscopes, exoscopes have advantages in field-depth, ergonomics, and educational value. Exoscopes are especially well-poised for adaptation into fluorescence-guided surgery (FGS) due to their excitation source, light path, and image processing capabilities. We evaluated the feasibility of near-infrared FGS using a 3-dimensional (3D), 4 K exoscope with nearinfrared fluorescence imaging capability. We then compared it to the most sensitive, commercially-available near-infrared exoscope system (3D and 960 p). In-vitro and intraoperative comparisons were performed. Serial dilutions of indocyanine-green (1-2000 μgmL) were imaged with the 3D, 4 K Olympus Orbeye (system 1) and the 3D, 960 p VisionSense Iridium (system 2). Near-infrared sensitivity was calculated using signal-to-background ratios (SBRs). In addition, three patients with brain tumors were administered indocyanine-green and imaged with system 1, with two also imaged with system 2 for comparison. Systems 1 and 2 detected near-infrared fluorescence from indocyanine green concentrations of >250 μgL and >31.3 μgL, respectively. Intraoperatively, system 1 visualized strong near-infrared fluorescence from two, strongly gadoliniumenhancing meningiomas (SBR2.4, 1.7). The high-resolution, bright images were sufficient for the surgeon to appreciate the underlying anatomy in the near-infrared mode. However, system 1 was not able to visualize fluorescence from a weakly-enhancing intraparenchymal metastasis. In contrast, system 2 successfully visualized both the meningioma and the metastasis but lacked high resolution stereopsis. Three-dimensional exoscope systems provide an alternative visualization platform for both standard microsurgery and near-infrared fluorescent guided surgery. However, when tumor fluorescence is weak (i.e., low fluorophore uptake, deep tumors), highly sensitive near-infrared visualization systems may be required.

Application of high throughput sequencing in pediatric neurooncology.

Over the past decade, next generation sequencing (NGS) has become the standard method in research of cancer genomics currently NGS is entering a new stage - direct usage in clinical oncology to improve diagnostics and establish personalized tumor treatments. NGS allows to read the genome and it is successfully applied to detect mutations and other somatic changes (translocations, inversions, insertions and deletions, copy number variants) leading to the development of a tumor. With a focus on transcriptome sequencing allows to clearly identify differences in gene expression, improve the classification of tumors and detect somatic chimeras. All these possibilities are especially relevant for pediatric neurooncology filed in view of the existing limitations in treatment and the need for the most accurate identification of the key factors of tumor development. In this article, we describe sequencing technology basis, its application on brain tumor materials to improve diagnostics, and other relevant possibilities that can be considered for direct usage in medicine. Технологии секвенирования нового поколения за последнее 10-летие стали стандартным методом в исследованиях геномики злокачественных опухолей и постепенно выходят на новый этап — применение в клинической онкологии для улучшения диагностики и построения персонализированного лечения опухолей. Секвенирование позволяет прочитать геном и успешно используется для обнаружения мутаций и других соматических изменений — транслокаций, инверсий, вставок и делеций, вариантов числа копий, ведущих к развитию опухоли. При фокусе на транскриптом (систему активных генов) секвенирование позволяет четко определить различия в экспрессии генов, улучшить классификацию опухолей и выявить соматические химеры. Все эти возможности особенно актуальны для педиатрической онкологии ввиду существующих ограничений в лечении и потребности в самом точном выявлении ключевых факторов развития опухоли. В этой статье описаны технология секвенирования, ее применение на материалах опухолей мозга для улучшения диагностики и другие актуальные возможности, которые могут быть рассмотрены для прямого использования в медицине.

The phenomenon of pseudotumorous cross immunohistochemical reactivity of glia in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating brain damage caused by infection of oligodendrocytes and astrocytes with the lytic JC virus on the background of immunosuppression. A case report of PML with a tumor-like course is presented. Morphological diagnostics revealed non-specific staining of antibodies to Ki-67, p53, IDH1, NF and Vim in the nuclei of gliocytes affected by the JC virus. Histological examination and microscopic evaluation of the changes in the brain for the diagnosis of PML is a priority. The recommended intravital biopsy does not always help in clear verification of PML due to the limited volume of tissue fragments presented for research. For the correct interpretation of changes during an intravital pathological examination and verification of PML, it is important to take material during a stereotaxic biopsy, not only from the center, but from the edges and perifocal zone of the altered tissues for the possibility of a spatial histological assessment of the pathological process. Прогрессирующая мультифокальная лейкоэнцефалопатия (ПМЛ) — подострое демиелинизирующее поражение головного мозга, вызванное инфицированием олигодендроцитов и астроцитов литическим вирусом JC на фоне иммуносупрессии. Представлено наблюдение ПМЛ с тумороподобным течением. При морфологической диагностике выявлено неспецифическое окрашивание антителами к Ki-67, p53, IDH1, NF и Vim в ядрах глиоцитов, пораженных JC-вирусом. Гистологическое исследование и микроскопическая оценка изменений головного мозга для постановки диагноза ПМЛ являются приоритетными. Рекомендуемая прижизненная биопсия не всегда помогает в четкой верификации ПМЛ в связи с ограниченным объемом тканевых фрагментов, представляемых для исследования. Для корректной интерпретации изменений при прижизненном патолого-анатомическом исследовании и верификации ПМЛ важно забирать материал во время стереотаксической биопсии не только из центра, но и из краев измененных тканей и перифокальной зоны для возможности пространственной гистологической оценки патологического процесса.

Evaluation of a method to measure fluorescent cell burden in complex culture systems.

Mismatch repair deficiency and MUTYH variants in small intestine-neuroendocrine tumors.

Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology remain to be determined. Interestingly, recent studies linked the development of (SI-)NETs to both Lynch syndrome (LS) and MUTYH variants. If confirmed, these associations would have important consequences for treatment. In this study we therefore investigated the prevalence of mismatch repair (MMR) deficiency and MUTYH variants in 64 primary resected SI-NETs. Immunohistochemistry was used to assess the expression of the MMR genes, and competitive allele-specific PCR (KASPar) targeting two hotspot MUTYH variants p.(Tyr179Cys), p.(Gly396Asp) was performed to determine their prevalence in SI-NETs. Strikingly, all 64 SI-NETs stained positive for MSH6 and PMS2, indicating MMR proficiency. In addition, no MUTYH hotspot variant was found in any of the 64 SI-NETs. As such, these results do not support an association between SI-NET development and LS or MUTYH variants. In order to gain insight into SI-NET pathogenesis and optimally manage patients, future research should therefore focus on other candidate genes.

Microgliamacrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model.

Factors released from glioma-associated microgliamacrophages (GAMs) play a crucial role in glioblastoma multiforme (GBM) progression. Here, we study the importance of CCL18, a cytokine expressed in human but not in rodent GAMs, as a modulator of glioma growth. Since CCL18 signaling could not be studied in classical mouse glioma models, we developed an approach by transplanting induced pluripotent stem cell-derived human microglia and human glioma cells into mouse brain slices depleted of their intrinsic microglia. We observe that CCL18 promotes glioma cell growth and invasion. Chemokine (C-C motif) receptor 8 (CCR8) is identified as a functional receptor for CCL18 on glioma cells, and ACP5 (acid phosphatase 5) is revealed as an important part of the downstream signaling cascade for mediating glioma growth. We conclude, based on the results from an in vitro, ex vivo humanized glioma model and an in vivo GBM model that microgliamacrophage-derived CCL18 promotes glioma growth.

Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC12 in Glioblastoma.

Novel therapeutic targets are critical to unravel for the most common primary brain tumor in adults, glioblastoma (GBM). We have identified a novel synthetic lethal interaction between ClpP activation and HDAC12 inhibition that converges on GBM energy metabolism. Transcriptome, metabolite, and U-13C-glucose tracing analyses were utilized in patient-derived xenograft (PDX) models of GBM. Orthotopic GBM models were used for in vivo studies. We showed that activation of the mitochondrial ClpP protease by mutant ClpP (Y118A) or through utilization of second-generation imipridone compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2 as well as with global (panobinostat) or selective (romidepsin) HDAC inhibitors caused synergistic reduction of viability in GBM model systems, which was mediated by interference with tricarboxylic acid cycle activity and GBM cell respiration. This effect was partially mediated by activation of apoptosis along with activation of caspases regulated chiefly by Bcl-xL and Mcl-1. Knockdown of the ClpP protease or ectopic expression of a ClpP D190A mutant substantially rescued from the inhibition of oxidative energy metabolism as well as from the reduction of cellular viability by ClpP activators and the combination treatment, respectively. Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC inhibitors and imipridones prolonged host survival more potently than single treatments or vehicle in vivo. Collectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.

ATRX-dependent SVCT2 mediates macrophage infiltration in the glioblastoma xenograft model.

The α thalassemiamental retardation syndrome X-linked (ATRX) mutation impairs DNA damage repair in glioblastoma (GBM), making these cells more susceptible to treatment, which may contribute to the survival advantage in patients with GBM containing ATRX mutations. To better understand the role of ATRX in GBM, genes correlated with ATRX expression were screened in the Cancer Genome Atlas (702 cases) and Chinese Glioma Genome Atlas (325 cases) databases. Sodium-vitamin C cotransporter 2 (SVCT2) was the most positively correlated gene with ATRX expression. ATRX (about 1.99-fold) and SVCT2 (about 2.25-fold) were upregulated in GBM tissues from 40 patients compared with normal brain tissues from 23 subjects. ShSVCT2 transfection did not alter the in vitro viability of GL261 cells. At the same time, it could inhibit the proliferation of GL261 cells in the orthotopic transplantation model with diminished infiltrating macrophages (CD45

Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAF

Molecularly targeted therapeutics have revolutionized the treatment of BRAF

ABO blood group type and risk of venous thromboembolism in patients with cancer.

Venous thromboembolism (VTE) is common in patients with cancer. Although in the general population blood type non-O is associated with increased VTE risk, the impact of ABO blood type on risk of cancer-associated VTE has not been clarified. To determine the influence of ABO blood type on cancer-associated VTE risk, we conducted an analysis within the Vienna Cancer and Thrombosis Study, a prospective cohort study including patients with newly diagnosed or recurrent cancer observed for the primary outcome VTE. Restricted cubic spline analysis was performed and specific time-restricted subdistribution hazard ratios (SHR) were calculated to investigate the association between non-O blood type and VTE over time. One thousand, seven hundred and eight patients were included in the analysis (median follow-up time 24 months interquartile range 10-24), and 151 patients developed VTE (8.8%). During the first 3 months of follow-up, there was no association between non-O blood type and VTE risk (SHR 1.00 95% confidence interval CI 0.60-1.67). Thereafter, non-O blood type was associated with a higher VTE risk (SHR 1.79 95% CI 1.12-2.85). Furthermore, non-O blood type was associated with increased VTE risk in patients with intermediate and low thrombotic risk tumor types (SHR 1.73 95% CI 1.09-2.73) but not in very high-risk types (pancreatic, gastroesophageal, and brain cancer SHR 0.94 95% CI 0.55-1.61). This association was weakened after adjustment for factor VIII. Non-O blood type is a time-dependent predictor of VTE in patients with cancer. It is associated with increased VTE risk beyond 3 months of follow-up and in patients with intermediate- and low-risk tumor types.

Diffuse Midline Gliomas With Histone H3 K27M Mutation in Adults and Children A Retrospective Series of 164 Cases.

Diffuse midline glioma, H3 K27M-mutant (H3 K27M-mt DMG), is a rare and highly aggressive tumor that is more common in children than in adults. Few studies have compared the differences between pediatric and adult patients with this rare tumor. We here report our retrospective study of 94 adult and 70 pediatric cases of diffuse midline glioma. Surgical tumor samples were analyzed by routine histopathology and immunohistochemistry for H3 K27M, IDH1 R132H, ATRX, p53, OLIG2, glial fibrillary acidic protein, and Ki-67 Sanger sequencing for hot mutation spots in genes including H3F3A, HIST1H3B, IDH1, IDH2, TERT, and BRAF and methylation-specific polymerase chain reaction for O6-methylguanine DNA methyltransferase promoter methylation. The most frequent anatomic locations in adult and pediatric patients were the thalamus and brainstem, respectively. Molecular profiling revealed higher frequencies of ATRX loss and H3.3 mutation in adult than in pediatric H3 K27M-mt DMGs. TERT promoter mutations and O6-methylguanine DNA methyltransferase promoter methylation were not detected in pediatric patients but were present in a few adult patients. During the follow-up period, 93122 patients (70.1%) died from the disease, with a median survival time of 10.5 months (range 1 to 104 mo). Kaplan-Meier analyses demonstrated that the prognosis was better for adult patients than the pediatric cohort (P0.0003). Multivariate analyses indicated that patient age, primary tumor size, status of ATRX expression, and Ki-67 index were independent prognosticators. The present study showed that there were differences between adult and pediatric H3 K27M-mt DMGs in terms of the anatomic location of tumor, molecular changes, and prognosis.

Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones.

Skeletal muscle plays an integral role in coordinating physiological homeostasis, where signaling to other tissues via myokines allows for coordination of complex processes. Here, we aimed to leverage natural genetic correlation structure of gene expression both within and across tissues to understand how muscle interacts with metabolic tissues. Specifically, we performed a survey of genetic correlations focused on myokine gene regulation, muscle cell composition, cross-tissue signaling, and interactions with genetic sex in humans. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little relative differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion in particular, with estradiol. These sex- and hormone-specific effects were consistent across key metabolic tissues liver, pancreas, hypothalamus, intestine, heart, visceral, and subcutaneous adipose tissue. To characterize the role of estradiol receptor signaling on myokine expression, we generated male and female mice which lack estrogen receptor α specifically in skeletal muscle (MERKO) and integrated with human data. These analyses highlighted potential mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other putative sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived tumor necrosis factor alpha ( The muscles that are responsible for voluntary movements such as exercise are called skeletal muscles. These muscles secrete proteins called myokines, which play roles in a variety of processes by interacting with other tissues. Essentially, myokines allow skeletal muscles to communicate with organs such as the kidneys, the liver or the brain, which is essential for the body to keep its metabolic balance. Some of the process myokines are involved include inflammation, cancer, the changes brought about by exercise, and even cognition. Despite the clear relevance of myokines to so many physiological outcomes, the way these proteins are regulated and their effects are not well understood. Genetic sex – specified by sex chromosomes in mammals – contributes to critical aspects of physiology. Specifically, many of the metabolic traits impacted by myokines show striking differences arising from hormonal or genetic interactions depending on the genetic sex of the subject being studied. It is therefore important to consider genetic sex when studying the effects of myokines on the body. Velez, Van et al. wanted to gain a better understanding of how skeletal muscles interact with metabolic tissues such as pancreas, liver and brain, taking genetic sex into consideration. To do this they surveyed human datasets for the correlations between the activity of genes that code for myokines, the composition of muscle cells, the signaling between muscles and metabolic tissues and genetic sex. Their results showed that, genetic sex and sex hormones predicted most of the effects of skeletal muscle on other tissues. For example, myokines from muscle were predicted to be more impactful on liver or pancreas, depending on whether individuals were male or female, respectively. The results of Velez, Van et al. illustrate the importance of considering the effects of genetic sex and sexual hormones when studying metabolism. In the future, these results will allow other researchers to design sex-specific experiments to be able to gather more accurate information about the mechanisms of myokine signaling.

CircRFX3 Up-regulates Its Host Gene RFX3 to Facilitate Tumorigenesis and Progression of Glioma.

Glioma is classified as one of the most common types of primary brain tumors. The high expression of CircRFX3 has been found in glioma. However, its functional roles in glioma and underlying mechanism remain unknown. Our study aimed to explore the function and specific mechanism of circRFX3 in glioma. RT-qPCR or western blot was applied to examine the expression of RNAs or proteins. Functional assays were carried out to evaluate the influence of circRFX3, RFX3 and PROX1 on glioma cells. In vivo experiments were done to ascertain the impact of circRFX3 on glioma growth. Moreover, mechanism assays were conducted to investigate the molecular relation among circRFX3, RFX3, HNRNPK and PROX1. CircRFX3 was highly expressed in glioma cells. CircRFX3 knockdown led to the suppression of glioma cell and tumor growth. CircRFX3 overexpression resulted in the opposite outcomes. Mechanism analyses suggested that circRFX3 recruited HNRNPK to enhance RFX3 mRNA stability, thereby facilitating glioma cell malignant behaviors. RFX3 was also unveiled to affect glioma cells via stimulating PROX1 transcription. CircRFX3, as a tumor promoter, could recruit HNRNPK to stabilize RFX3 mRNA in glioma cells. Additionally, RFX3 could promote PROX1 transcription to promote glioma progression.

A two-stage combined anterolateral and endoscopic endonasal approach to the petroclival region an anatomical study and clinical application.

The pretemporal transcavernous anterior petrosal (PTAP) approach and the combined petrosal (CP) approach have been used to resect petroclival meningiomas (PCMs). In this cadaveric anatomical study, a two-stage combined PTAP and endoscopic endonasal far medial (EEFM) approach (the PTAPE approach) was compared morphometrically to the CP approach. A case study provides a clinical example of using the PTAPE approach to treat a patient with a PCM. The key elements of the approach selection process are outlined. Five cadaveric specimens underwent a CP approach and 5 underwent a PTAPE approach. The area of drilled clivus, length of multiple cranial nerves (CNs), and the area of brain stem exposure were measured, reported as means (standard deviations) by group, and compared. The total area of the clivus drilled in the PTAPE group (695.3 121.7 mm A combined open-endoscopic paradigm is proposed for managing large PCMs. This approach incorporates the EEFM approach to address the limitations of the PTAP and the CP approach in a systematic fashion. Understanding the anatomical findings of this study will aid in tailoring surgical approaches to patients with these complex lesions.

Body mass index at diagnosis of a childhood brain tumor a reflection of hypothalamic-pituitary dysfunction or lifestyle

Childhood brain tumor survivors (CBTS) are at risk of becoming overweight, which has been shown to be associated with hypothalamic-pituitary (HP) dysfunction during follow-up. Body mass index (BMI) at diagnosis is related to BMI at follow-up. It is uncertain, however, whether aberrant BMI at brain tumor diagnosis reflects early hypothalamic dysfunction or rather reflects genetic and sociodemographic characteristics. We aimed to examine whether BMI at childhood brain tumor diagnosis is associated with HP dysfunction at diagnosis or its development during follow-up. The association of BMI at diagnosis of a childhood brain tumor to HP dysfunction at diagnosis or during follow-up was examined in a Dutch cohort of 685 CBTS, excluding children with craniopharyngioma or a pituitary tumor. Individual patient data were retrospectively extracted from patient charts. Of 685 CTBS, 4.7% were underweight, 14.2% were overweight, and 3.8% were obese at diagnosis. Being overweight or obese at diagnosis was not associated with anterior pituitary deficiency or diabetes insipidus at diagnosis or during follow-up. In children with suprasellar tumors, being obese at diagnosis was associated with central precocious puberty. Overweight or obesity at diagnosis of a childhood brain tumor seems not to be associated with pituitary deficiencies. These results suggest that genetics and lifestyle may be more important etiologic factors for higher BMI at diagnosis in these children than hypothalamic dysfunction. To improve the long-term outcome of CBTS with regards to overweight and obesity, more attention should be given to lifestyle already at the time of brain tumor treatment.

Effects of Baduanjin exercise on cognitive function and cancer-related symptoms in women with breast cancer receiving chemotherapy a randomized controlled trial.

Cognitive decline is one of the main side effects of breast cancer patients after relevant treatment, but there is a lack of clear measures for prevention and management without definite mechanism. Moreover, postoperative patients also have a need for limb rehabilitation. Whether the cognitive benefits of Baduanjin exercise can improve the overall well-being of breast cancer patients remains unknown. This randomized controlled trial was conducted on 70 patients with breast cancer receiving chemotherapy who were randomly assigned and allocated to (11) a supervised Baduanjin intervention group (5 timesweek, 30 min each time) or a control group for 3 months. The effects of Baduanjin exercise intervention were evaluated by outcome measures including subjective cognitive function, symptoms (fatigue, depression, and anxiety), and health-related quality of life at pre-intervention (T0), 4 weeks (T1), 8 weeks (T2), and 12 weeks (T3). The collected data were analyzed by using an intention-to-treat principle and linear mixed-effects modeling. Participants in the Baduanjin intervention group had a significantly greater improvement in terms of FACT-Cog (F 14.511 p < 0.001), PCI (F 15.789 p < 0.001), PCA (F 6.261 p 0.015), and FACT-B scores (F 8.900 p 0.004) compared with the control group over the time. The exercise-cognition relationship was significantly mediated through the reduction of fatigue (indirect effect β 0.132 95% CI 0.046 to 0.237) and the improvement of anxiety (indirect effect β - 0.075 95% CI - 0.165 to -0.004). This pilot study revealed the benefits of Baduanjin exercise for subjective cognition and health-related quality of life of Chinese breast cancer patients receiving chemotherapy and outlined the underlying mediating mechanism of exercise-cognition. The findings provided insights into the development of public health initiatives to promote brain health and improve quality of life among breast cancer patients. ChiCTR 2,000,033,152.

Prediction of H3 K27M-mutant in midline gliomas by magnetic resonance imaging a systematic review and meta-analysis.

To summarize the predictive value of MRI for H3 K27M-mutant in midline gliomas using meta-analysis. Systematic electronic searches of the PubMed, Embase, ISI Web of Science, and Cochrane Library up to Jun 31, 2021, were conducted by two experienced neuroradiologists with the keywords of MRI, Glioma, and H3 K27M. The hierarchical summary receiver-operating characteristic (HSROC) model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (LR ), negative likelihood ratio (LR -), and diagnostic odds ratio (DOR). Coupled forest plots were used to evaluate the heterogeneity of the included studies. Of seven original studies with a total of 593 patients, 240 glioma patients were included, with 45.5-70.6% H3 K27M-mutant gliomas. Using MRI, a pooled sensitivity of 0.78 (95% CI, 0.66-0.87), specificity of 0.85 (95% CI, 0.76-0.91), LR of 5.07 (95% CI, 3.19-8.08), LR - of 0.26 (95% CI, 0.16-0.42), and DOR of 19.80 (95% CI, 9.28-42.28) were achieved for H3 K27M-mutant prediction. Significant heterogeneity was observed among the studies in terms of sensitivity (Q 16.83, df 7, p 0.02 I This meta-analysis demonstrated a clinical value of MRI to predict H3 K27M-mutant in midline gliomas with a pooled sensitivity of 0.78 and specificity of 0.85.

Glioblastoma scRNA-seq shows treatment-induced, immune-dependent increase in mesenchymal cancer cells and structural variants in distal neural stem cells.

Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved. Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ). We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo. These data reveal the dynamic, immune-dependent nature of glioblastomas response to treatments and identify distant NSCs as likely cells of origin.

Comprehensive exploration of long-wave emission carbon dots for brain tumor visualization.

Carbon dot (CD)-based tumor imaging has been proven to be a reliable nanodiagnostic technique. Although abundant types of CDs have been developed, it is still a major challenge to synthesize long-wavelength CDs with high quality and superior repetition due to the complicated synthetic process. Here, stable long-wavelength red-light emission carbon dots (R-CDs) have been synthesized using appropriate carbon sources

Coats plus in prematurity.

Coats plus syndrome or cerebroretinal microangiopathy with calcifications and cysts (CMCC) is an exceedingly rare autosomal recessive disorder that predominantly affects the microvasculature in the retina, brain, bones, and gastrointestinal system. Unlike Coats disease, CMCC is bilateral and affects multiple organ systems. Case report. We report the case of two brothers with Coats Plus syndrome who presented with variable phenotypic expression. One sibling (Patient 1) was thought to have atypical retinopathy of prematurity and was only diagnosed with Coats plus after his older brother (Patient 2) presented with a seizure and a left upper extremity tremor at 4 years of age. The CTC1 mutation was confirmed in both patients. Aggressive treatment with laser photocoagulation and intravitreal bevacizumab dramatically improved the retinal vascular and exudative changes. Coats Plus syndrome can have a variable phenotypic presentation, including retinal vascular findings. This rare genetic disease should be in the differential diagnosis in patients who present with atypical retinal pathology, including Retinopathy of Prematurity, Familial Exudative Vitreoretinopathy, or Coats disease associated with non-specific multiorgan abnormalities.

Advances in Head and Neck Cancer Pain.

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneicimmunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell-derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.

Prostate cancer dural metastasis resembling a meningioma.

CT images of a 56-year-old man with headache showed a meningioma-like mass in the occipital region. The tumor was well-defined and non-uniform with bone thickening and no internal calcification. Eventually, he was diagnosed on the basis of histopathology and immunostaining findings as having a dural metastasis from a prostate cancer.

A weakly supervised deep learning-based method for glioma subtype classification using WSI and mpMRIs.

Accurate glioma subtype classification is critical for the treatment management of patients with brain tumors. Developing an automatically computer-aided algorithm for glioma subtype classification is challenging due to many factors. One of the difficulties is the label constraint. Specifically, each case is simply labeled the glioma subtype without precise annotations of lesion regions information. In this paper, we propose a novel hybrid fully convolutional neural network (CNN)-based method for glioma subtype classification using both whole slide imaging (WSI) and multiparametric magnetic resonance imagings (mpMRIs). It is comprised of two methods a WSI-based method and a mpMRIs-based method. For the WSI-based method, we categorize the glioma subtype using a 2D CNN on WSIs. To overcome the label constraint issue, we extract the truly representative patches for the glioma subtype classification in a weakly supervised fashion. For the mpMRIs-based method, we develop a 3D CNN-based method by analyzing the mpMRIs. The mpMRIs-based method consists of brain tumor segmentation and classification. Finally, to enhance the robustness of the predictions, we fuse the WSI-based and mpMRIs-based results guided by a confidence index. The experimental results on the validation dataset in the competition of CPM-RadPath 2020 show the comprehensive judgments from both two modalities can achieve better performance than the ones by solely using WSI or mpMRIs. Furthermore, our result using the proposed method ranks the third place in the CPM-RadPath 2020 in the testing phase. The proposed method demonstrates a competitive performance, which is creditable to the success of weakly supervised approach and the strategy of label agreement from multi-modality data.

Clinical and genetic predictions of early-onset cardiac toxicity in adjuvant chemotherapy for breast cancer.

Growth factor independence underpins a paroxysmal, aggressive Wnt5a

Glioblastoma multiforme (GBM) is an incurable tumor, with a median survival rate of only 14-15 months. Along with heterogeneity and unregulated growth, a central matter in dealing with GBMs is cell invasiveness. Thus, improving prognosis requires finding new agents to inhibit key multiple pathways, even simultaneously. A subset of GBM stem-like cells (GSCs) may account for tumorigenicity, representing, through their pathways, the proper cellular target in the therapeutics of glioblastomas. GSCs cells are routinely enriched and expanded due to continuous exposure to specific growth factors, which might alter some of their intrinsic characteristic and hide therapeutically relevant traits. By removing exogenous growth factors stimulation, here we isolated and characterized a subset of GSCs with a mitogen-independent phenotype (I-GSCs) from patients tumor specimens. Differential side-by-side comparative functional and molecular analyses were performed either in vitro or in vivo on these cells versus their classical growth factor (GF)-dependent counterpart (D-GSCs) as well as their tissue of origin. This was performed to pinpoint the inherent GSCs critical regulators, with particular emphasis on those involved in spreading and tumorigenic potential. Transcriptomic fingerprints were pointed out by ANOVA with Benjamini-Hochberg False Discovery Rate (FDR) and association of copy number alterations or somatic mutations was determined by comparing each subgroup with a two-tailed Fishers exact test. The combined effects of interacting in vitro and in vivo with two emerging GSCs key regulators, such as Wnt5a and EphA2, were then predicted under in vivo experimental settings that are conducive to clinical applications. In vivo comparisons were carried out in mouse-human xenografts GBM model by a hierarchical linear model for repeated measurements and Dunnetts multiple comparison test with the distribution of survival compared by Kaplan-Meier method. Here, we assessed that a subset of GSCs from high-grade gliomas is self-sufficient in the activation of regulatory growth signaling. Furthermore, while constitutively present within the same GBM tissue, these GF-independent GSCs cells were endowed with a distinctive functional and molecular repertoire, defined by highly aggressive Wnt5a We show how the preservation of a mitogen-independent phenotype in GSCs plays a central role in determining the exacerbated tumorigenic and high mobility features distinctive of GBM. The exploitation of the I-GSCs peculiar features shown here offers new ways to identify novel, GSCs-specific effectors, whose modulation can be used in order to identify novel, potential molecular therapeutic targets. Furthermore, we show how the combined use of PepA, the anti-Wnt5a drug, and of ephrinA1-Fc to can hinder GSCs lethality in a clinically relevant xenogeneic in vivo model thus being conducive to perspective, novel combinatorial clinical application.

Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1.

Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy is linked with morphine-induced immunosuppression in the brain remains unknown. NLRX1 is the only mitochondrially localized NOD family receptor protein which serves as a critical regulator in immunity and mitophagy activation, but it remains an enigma how NLRX1 functions in the crosstalk between microglial inflammatory defense and mitophagy in the presence of morphine. Primary microglia and astrocytes, BV2 and MA cell lines were utilized. Mice were stimulated with repeated morphine treatment to mimic chronic morphine exposure, and activation of mitophagy, lysosomal functions, and inflammation were assayed in specific brain regions and immune organs with or without NLRX1-silencing. Morphine induced microglial mitophagy in a LC3 (microtubule-associated proteins light chain 3)-dependent manner, which was mediated by NLRX1. Contrastingly, morphine impaired lysosomal functions, including generation, acidification and mitophagosome-lysosome fusion, thus leading to insufficient mitophagy activation in microglia. NLRX1-silencing inhibited mitophagy activity and rescued lysosomal functions including generation and acidification in microglia. The NLRX1-mediated incomplete mitophagy in microglial cells contributed to immunosuppression and vulnerability towards pathogenic challenge after morphine treatment. In vivo, NLRX1-mediated microglial mitophagy activation by morphine was mainly located in the murine brain cortex, striatum, and cerebellum, where NLRX1 functioned as a negative immune regulator and facilitated septic shock. Collectively, microglial immune responses to septic shock were amenable to NLRX1 silencing in the brain with morphine treatment. Morphine activated insufficient mitophagy in microglia which was regulated by NLRX1, ultimately leading to host immunosuppression and susceptible conditions in the brain.

Group-level stability but individual variability of neurocognitive status after awake resections of right frontal IDH-mutated glioma.

Awake surgery for low-grade gliomas is currently considered the best procedure to improve the extent of resection and guarantee a worth living life for patients, meaning avoiding not only motor but also cognitive deficits. However, tumors located in the right hemisphere, especially in the right frontal lobe, are still rarely operated on in awake condition one of the reasons possibly being that there is little information in the literature describing the rates and nature of long-lasting neuropsychological deficits following resection of right frontal glioma. To investigate long-term cognitive deficits after awake surgery in right frontal IDH-mutated glioma. We retrospectively analyzed a consecutive series of awake surgical resections between 2012 and 2020 for right frontal IDH-mutated glioma. We studied the patients subjective complaints and objective neuropsychological evaluations, both before and after surgery. Our results were then put in perspective with the literature. Twenty surgical cases (including 5 cases of redo surgery) in eighteen patients (medium age 42.5 range 26-58) were included in the study. The median preoperative volume was 37 cc WHO grading was II, III and IV in 70%, 20%, and 10% of cases, respectively. Preoperatively, few patients had related subjective cognitive or behavioral impairment, while evaluations revealed mild deficits in 45% of cases, most often concerning executive functions, attention, working memory and speed processing. Immediate postoperative evaluations showed severe deficits of executive functions in 75% of cases but also attentional deficits (65%), spatial neglect (60%) and behavioral disturbances (apathy, aprosodiaamimia, emotional sensitivity, anosognosia). Four months after surgery, although psychometric z-scores were unchanged at the group level, individual evaluations showed a slight decrease of performance in 920 cases for at least one of the following domains executive functions, speed processing, attention, semantic cognition, social cognition. Our results are generally consistent with those of the literature, confirming that the right frontal lobe is a highly eloquent area and suggesting the importance of operating these patients in awake conditions.

Microglial cell response in α7 nicotinic acetylcholine receptor-deficient mice after systemic infection with Escherichia coli.

Development of neurodegeneration in older people has been associated with microglial cell activation triggered by systemic infection. We hypothesize that α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulation of this process. 8- to 10-week-old male wild-type (WT) and α7nAChR knock-out (α7nAChR We observed no differences in Iba-1 positive cell number or morphology and flow cytometry (CD11b, CD45 and CD14) of microglial cells between WT and α7nAChR Loss of function of α7nAChR during systemic infection led to an increased expression of TNF-α and IL-6 in brain after systemic infection with E. coli, but not to distinct differences in microglial cell number or morphological activation of microglia.

Effect of neoadjuvant iodine-125 brachytherapy upon resection of glioma.

A more extensive surgical resection of glioma contributes to improved overall survival (OS) and progression-free survival (PFS). However, some patients miss the chance of surgical resection when the tumor involves critical structures. The present study aimed to assess the feasibility of neoadjuvant Six patients diagnosed with inoperable glioma due to invasion of eloquent areas, bihemispheric diffusion, or large tumor volume received Shrinkage of the tumor after adjuvant In the present study, the results demonstrated that

Identification of a key glioblastoma candidate gene, FUBP3, based on weighted gene co-expression network analysis.

Glioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene. Two GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was performed to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was applied for survival analysis to determine the significant gene, FUBP3. OS, DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis. GSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4 T cells, CD8 T cells, and macrophages) and FUBP3. FUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Recent Advances of LncRNA H19 in Diabetes LncRNA H19 in Diabetes.

Diabetes mellitus (DM) causes damage to major organs, including the heart, liver, brain, kidneys, eyes, and blood vessels, threatening the health of the individuals. Emerging evidence has demonstrated that lncRNAs has important functions in the pathogenesis of human diseases, such as cancers, neurodegenerative diseases, cardiac fibroblast phenotypes, hypertension, heart failure, atherosclerosis and diabetes. Recently, H19, a lncRNA, has been reported to shown to participate in the regulatory process of muscle differentiation, glucose metabolism, and tumor metastasis, as well as endometrial development. However, the roles of H19 in DM were still not completely understood. This review was conducted to summarize the functions of H19 in diabetes and discuss the challenges and possible strategies of H19 in DM.

Cancer among Refugees Resettled to Idaho during 2008-2019 A Proof-of-Concept Study.

Disparities in cancer burden and outcomes according to socioeconomic characteristics have been extensively characterized for US populations. The cancer experience of refugees, who may share characteristics of other socioeconomically disadvantaged populations and also experience distinct barriers to care, has not been described previously. We conducted a proof-of-concept study evaluating our ability to characterize cancer incidence in refugees resettled to Idaho via a novel linkage of cancer data and administrative data characterizing refugee arrivals to Idaho. In July 2021, the Cancer Data Registry of Idaho probabilistically linked cancer surveillance data and refugee arrival data (2008- 2019 diagnosis and arrival years) collected through the Centers for Disease Control and Preventions Electronic Disease Notification (EDN) System. We used SEERStat to calculate standardized incidence ratios (SIR) for malignant tumors and benignborderline malignant brain and other nervous system (ONS) tumors using Idaho-specific and Surveillance, Epidemiology, and End Results (SEER) Program referent incidence rates. 60 malignant and 7 benign brain and ONS tumors were diagnosed among 9,499 refugees resettled to Idaho. Refugees had fewer than expected malignant tumors overall (57 observed vs 96.0 expected SIR, 0.60 95% CI, 0.45-0.77). An excess of tumors of the esophagus were diagnosed among Southeast Asian refugees (4 observed vs 0.64 expected SIR, 6.3 95% CI, 1.7-16.0). We also used EDN data to update country of birth for linked persons. Linking EDN refugee data to cancer surveillance data presented unique challenges. However, we used a novel data source to augment cancer data and characterize incidence in refugees, potentially improving our ability to serve this vulnerable population.

Resection of Giant Remote Recurrence of Ependymoma After 41 Years.

Ependymomas are rare primary tumors of the brain and spinal cord that arises from the ependymal cell layer. Cranial ependymomas commonly occur in the posterior fossa however, approximately 30% of all tumors can be found in the supratentorial region. Supratentorial ependymomas have a shorter progression-free and overall survival than their infratentorial counterparts. We present the case of a 47-year-old man who presented with mild left-sided hemiparesis and confusion secondary to a right-sided 8.5 × 6.0 × 6.0 cm frontotemporal neoplasm encasing the ipsilateral internal and middle cerebral arteries. The patient had undergone a suboccipital craniectomy for resection of a posterior fossa ependymoma at 6 years of age (41 years ago). After multidisciplinary discussion, we performed a right frontotemporal craniotomy for tumor resection (Video) using intraoperative navigation, ultrasound, and intraoperative neurophysiological monitoring. While skeletonizing branches of the middle cerebral artery, an M3 branch was injured inadvertently and repaired immediately. Histopathologic specimens were consistent with ependymoma (World Health Organization grade II). A near-total resection was achieved. The patient developed a transient left-sided hemiparesis but improved to full strength on discharge from the hospital.

Recent advances in glioma microenvironment-response nanoplatforms for phototherapy and sonotherapy.

The newly emerging nanotheranostic strategies including photodynamic therapy (PDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) have exhibited their unbeatable advantages in treatment and prognosis of glioma tumors as compared to conventional ones like chemotherapy, radiotherapy and surgery. Meanwhile, the components of glioma microenvironment including blood brain barrier (BBB), oxidative stress, hypoxia and angiogenesis, play essential roles in glioma initiation, progression, invasion, recurrence and drug resistance. More importantly, the nanoparticles can modulate the glioma environments to increase targeting capability, monitor the glioma growth, and enhance therapy outcomes. In this review, we will introduce the basic components of glioma microenvironment, the role that glioma microenvironment played on tumor development and progression, and the key perspectives associated with glioma microenvironment-based multifunctional nanoplatform design. In particular, recent advances in glioma microenvironment-response nanoparticles for phototherapy (PTT and PDT) and sonotherapy will be discussed in detail. Finally, the challenges related to the clinical transition for nanomedicine-based glioma theranostics will be addressed.

Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.

The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSC) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK-BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia toward an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8 T-cell infiltration, activation, and cytotoxicity, and synergizes with anti-programmed cell death protein 1 (anti-PD-1 therapy). In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK-OLFML3-HIF1α-LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for patients with GBM.

Intraoperative brain shift in neuronavigation. Causes, clinical significance and solution of the problem.

Intraoperative brain shift is the main cause of inaccurate navigation. This limits the use of both conventional and functional neuronavigation. Causes of brain shift are divided into surgical, pathophysiological and metabolic ones. Brain shift is usually unidirectional and directed towards gravitation. Brain dislocation depends on lesion size and its location. Shift is minimal in patients with tumors <20 ml and skull base neoplasms. Small craniotomy, retractor-free surgery and no ventriculostomy are valuable to reduce brain shift. Brain dislocation increases during surgery thats why marking of eloquent lesions at the beginning of surgery and primary resection near subcortical tracts minimize the risk of damage to conduction pathways. Augmented reality and manual shift of marked objects are the cornerstones of linear correction of brain shift in modern navigation systems. In case of nonlinear brain shift, sonography and intraoperative magnetic resonance imaging can clarify location of surgical target and cerebral structures. Интраоперационное смещение головного мозга является основной причиной неточности навигационных систем. Это ограничивает применение как обычной, так и функциональной нейронавигации. Причины сдвига мозга разделяют на хирургические, патофизиологические и метаболические. Смещение мозга чаще происходит в направлении гравитации и имеет однонаправленный характер. Дислокация зависит от размера новообразования и его расположения. Она минимальна при опухолях объемом <20 мл и их расположении на основании черепа. Уменьшить сдвиг мозга позволяют минимизация энцефалотомии, отказ от использования ретракторов и выполнения вентрикулостомии. Смещение мозга нарастает на протяжении хирургического вмешательства, поэтому маркировка функционально значимых зон в начале основного этапа операции и начало резекции рядом с проводящими путями (по данным трактографии) до возможного смещения мозга минимизируют риск их повреждения. «Расширенная реальность» и ручной сдвиг оконтуренных навигационных объектов лежат в основе линейной коррекции дислокации мозга в современных навигационных системах. При нелинейном характере интраоперационного смещения мозга расположение хирургической цели и мозговых структур целесообразно уточнять с помощью сонографии и интраоперационной магнитно-резонансной томографии.

Clinical and neuropsychological survey of patients with glioma of the corpus callosum.

We found no reports devoted to a comprehensive analysis of cognitive impairment that can determine the quality of life in patients with glioma of the corpus callosum and topical affiliation of these disorders. Clinical and neuropsychological study of mental disorders in patients with gliomas of the corpus callosum, qualification of topical affiliation of the identified syndromes. We examined 30 patients with gliomas of the corpus callosum using the Lurias approach to clinical and neuropsychological survey. We identified the features of cognitive impairment depending on localization of glioma in the corpus callosum. Non-spontaneity, reduced criticism to own condition up to denial of disease and memory impairment were more common in patients with anterior gliomas of the corpus callosum. These disorders can be associated with tumor spread into medial parts of frontal lobes. Subcortical symptoms including hypomimia, quiet dull voice, involuntary urination, severe disorders of dynamic praxis and memory impairment were more common in patients with glioma of the middle part of the corpus callosum. These disorders can be associated with dorsal tumor spread towards posterior part of the frontal lobe or ventrally towards the basal ganglia. Memory disorders more often manifested by Korsakoff syndrome prevailed in patients with posterior gliomas of the corpus callosum. This finding can be associated with ventral growth of tumor towards the fornix. We identified the features of cognitive impairment depending on localization of glioma in the corpus callosum. Split-brain symptoms were rare in these patients and observed in lesions of middle and posterior parts of the corpus callosum only in 3 patients. В литературе мы не встретили работ с подробным анализом когнитивных нарушений, которые определяют качество жизни больных с глиомами мозолистого тела (МТ), а также нет квалификации топической принадлежности этих нарушений. Клинико-нейропсихологическое исследование нарушений высших психических функций у больных с глиомами разных отделов МТ и квалификация топической принадлежности выявленных синдромов. Проведено клинико-нейропсихологическое исследование 30 больных с глиомами разных отделов МТ по методу А.Р. Лурия. Выявлены особенности когнитивных нарушений в зависимости от локализации глиомы в пределах МТ. У больных с глиомами передних отделов МТ чаще отмечались аспонтанность, снижение критики к своему состоянию вплоть до отрицания болезни и нарушения памяти. Данные расстройства можно связать с распространением опухоли в медиальные отделы лобных долей. У больных с глиомами средних отделов МТ чаще преобладали подкорковые симптомы гипомимия, тихий глухой голос, непроизвольное мочеиспускание, грубые нарушения динамического праксиса и нарушения памяти. Данные расстройства можно связать с распространением опухоли дорсально в задние отделы лобной доли либо вентрально в сторону подкорковых узлов. У больных с глиомами задних отделов МТ на первый план выходили расстройства памяти, чаще проявляющиеся корсаковским синдромом, что можно связать с вентральным ростом опухоли по направлению к своду. Выявлены особенности когнитивных нарушений в зависимости от локализации глиомы в пределах мозолистого тела. Симптомы «расщепленного мозга» при глиомах мозолистого тела были относительно редкими и отмечены при поражении его средних и задних отделов всего у 3 больных.

Anaplastic pleomorphic xanthoastrocytoma - single-center analysis of 42 patients.

Anaplastic pleomorphic xanthoastrocytoma is a rare tumor. There are still no objective data on the incidence of its diagnosis. To study neuroimaging, morphological features of tumors, as well as factors affecting treatment and prognosis. A retrospective study enrolled 42 patients operated on at the Burdenko Neurosurgery Center between 2003 and 2020. MR characteristics of anaplastic pleomorphic xanthoastrocytoma were analyzed. All patients underwent resection of tumor (total resection in 83.3% of cases). Redo surgeries were performed in 13 of patients. Mutational status of BRAF V600E was assessed in all patients. Adjuvant radio- and chemotherapy was performed in more than 80% of cases. Tyrosine kinase inhibitors were administered in 19% of cases. The follow-up period was 152 months (median 34 months). We found no pathognomonic MR signs of this disease. Indeed, anaplastic pleomorphic xanthoastrocytoma have the same signal characteristics as other malignant gliomas. The BRAF V600E mutation status was positive in 54.8% of cases. None patient had IDH-1 mutation. Mean Ki-67 index was 12.5%. The overall survival was 79 months (range 4-152). Seven (17%) patients are alive for more than 90 months. Only Ki-67 index and BRAF mutation significantly influenced the treatment prognosis and overall survival regardless the use of tyrosine kinase inhibitors. Such well-known factors for malignant glioma as patient age, total resection and adjuvant therapy did not significantly affect overall survival. Perhaps, searching for new molecular genetic features will reveal additional significant factors of prognosis in patients with anaplastic pleomorphic xanthoastrocytoma. Анапластическая плеоморфная ксантоастроцитома (аПКСА) — редко выявляемая опухоль, и объективных данных о частоте этой патологии к настоящему времени в литературе нет. Изучить нейровизуализационные и морфологические особенности аПКСА, а также факторы, влияющие на лечение и прогноз. Данное ретроспективное исследование базируется на результатах изучения серии из 42 пациентов, оперированных в ФГАУ «НМИЦ нейрохирургии им. акад. Н.Н. Бурденко» Минздрава России за период 2003—2020 гг. Проанализированы магнитно-резонансные характеристики аПКСА. Всем пациентам проведена операция по удалению опухоли, при этом в 83,3% случаев — радикально. Повторные операции выполнены примерно у 30% больных. Всем больным проведено исследование мутационного статуса При анализе магнитно-резонансных изображений не удалось выявить патогномоничные для этой нозологии особенности, поскольку аПКСА имеют те же сигнальные характеристики, что и другие злокачественные глиомы. Статус мутации V600E Возраст, радикальность резекции и применение адъювантной терапии статистически значимо не влияли на общую выживаемость пациентов со злокачественными глиомами. Возможно, поиск новых молекулярно-генетических особенностей позволит выявить дополнительные значимые факторы, определяющие прогноз лечения пациентов с анапластическими плеоморфными ксантоастроцитомами.

Tubular retractors for transcranial approaches to intraaxial brain tumors in children.

Reduction of surgical trauma associated with approach to deep brain structures including resection of tumors is an urgent direction in development of techniques and technology. To analyze the efficacy and safety of tubular retractors in surgery of deep brain tumors in children. The study included 17 children with deep brain tumors who underwent surgery between 2020 and 2021. Tubular retractors were used in all cases. The control group consisted of 15 children with a similar disease and standard intraoperative tissue traction technique. All patients underwent MRI of the brain on the first postoperative day. We analyzed severity of traction-induced damage to brain tissue in T2 FLAIR and DWI images. Clinical outcomes and structure of surgical complications were similar in both groups. Tubular retractor turned out to be a tool reducing traction injury. In the main group, postoperative MRI revealed significantly less damage to brain tissue along surgical approach in T2 (edema zone) and DWI (ischemic changes) images. Уменьшение объема хирургической травмы при доступах к глубинным структурам головного мозга, в том числе при удалении объемных образований, — актуальное направление развития микрохирургической техники. Проанализировать эффективность и безопасность применения тубулярных ретракторов в хирургии глубинных опухолей головного мозга у детей. В исследование включены 17 детей, прооперированных по поводу глубинных опухолей головного мозга в 2020—2021 гг. с применением тубулярного ретрактора. В контрольную группу вошли 15 детей с аналогичной патологией, оперированных с применением стандартной методики тракции тканей. Всем пациентам в 1-е сутки после операции выполнена магнитно-резонансная томография (МРТ) головного мозга, оценена степень тракционного повреждения ткани головного мозга по ходу доступа по изображениям в режимах T2 FLAIR и DWI. С помощью тубулярного ретрактора можно снизить тракционную травму без значительного различия в клинических исходах и структуре хирургических осложнений. На контрольных МРТ в исследуемой группе менее выражены изменения тканей мозга по ходу доступа в режимах T2 (зона отека) и DWI (ишемические изменения). Выявлено преимущество тубулярного ретрактора в профилактике тракционной травмы тканей головного мозга. Полученные данные позволяют рекомендовать применение методики в детской нейрохирургии.

MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas The HERBY Phase II Trial.

Background Diffuse midline gliomas (DMG) are characterized by a high incidence of

Targeting Angiogenic Factors for the Treatment of Medulloblastoma.

Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.

miR-3184-3p enriched in cerebrospinal fluid exosomes contributes to progression of glioma and promotes M2-like macrophage polarization.

Liquid biopsy is a novel strategy for tumour diagnosis. The contents of cerebrospinal fluid (CSF) exosomes could reflect glioma status, hence sampling exosomes from CSF is a means of liquid biopsy for glioma. However, few studies have focused on the function of microRNAs in CSF exosomes. In this study, we found that miR-3184-3p was enriched in CSF exosomes in glioma patients and was downregulated after tumour resection. We found that miR-3184 facilitates glioma progression in two ways. On the one hand, miR-3184 directly promotes proliferation, migration, and invasion while inhibiting apoptosis in glioma. On the other hand, miR-3184 in glioma-derived exosomes polarizes macrophages to an M2-like phenotype, which further aggravates tumour progression. Overall, the current findings uncovered a new mechanism and highlighted the significant role of miR-3184 in glioma progression. Furthermore, exosomal miR-3184 could be a considerable factor with potential applications in glioma diagnosis and treatment in the future.

A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis.

Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.

Blood biomarkers in epilepsy.

Robust and accessible biomarkers are greatly needed in epilepsy. Diagnostic and prognostic precision in the clinic needs to improve, and there is a need for objective quantification of seizure burden. In recent years, there have been advances in the development of accessible and cost-effective blood-based biomarkers in neurology, and these are increasingly studied in epilepsy. However, the field is in its infancy and specificity and sensitivity for most biomarkers in most clinical situations are not known. This review describes advancements regarding human blood biomarkers in epilepsy. Examples of biochemical markers that have been shown to have higher blood concentrations in study subjects with epilepsy include brain proteins like S100B or neuronal specific enolase, and neuroinflammatory proteins like interleukins, and tumor necrosis factor-alpha. Some of the blood biomarkers also seem to reflect seizure duration or frequency, and levels decrease in response to treatment with antiseizure medication. For most biomarkers, the literature contains seemingly conflicting results. This is to be expected in an emerging field and could reflect different study populations, sampling or analysis techniques, and epilepsy classification. More studies are needed with emphasis put on the classification of epilepsy and seizure types. More standardized reporting could perhaps decrease result heterogeneity and increase the potential for data sharing and subgroup analyses.

Molecular cloning, characterization and expression analysis of P53 from high latitude fish Phoxinus lagowskii and its response to hypoxia.

As an intermediate link between multiple cellular stresses and cellular responses, p53, together with its upstream and downstream regulators and related genes, constitutes a complex network that regulates cellular stresses and cellular responses. However, no studies have investigated p53 in Phoxinus lagowskii, particularly the expression of p53 under different hypoxic conditions. In the present study, the cDNA of p53 from the Phoxinus lagowskii was cloned by the combination of homology cloning and rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of Pl-p53 was 1878 bp, including an open reading frame (ORF) of 1116 bp encoding a polypeptide of 371 amino acids with a predicted molecular weight of 41.22 kDa and a theoretical isoelectric point of 7.38. Quantitative real-time (qRT) PCR assays revealed that Pl-p53 was commonly expressed in all tissues examined, with highest expression in the heart. In addition, we investigated the expression of Pl-p53 in different tissues under different hypoxic conditions. In the short-term hypoxia group, Pl-p53 expression was down-regulated in both the brain and heart. The Pl-p53 expression was significantly elevated at 6 h in the muscle and liver, and was significantly up-regulated at 24 h in spleen. These results suggest that Pl-p53 plays different regulatory roles and provide a theoretical basis for the changes of p53 in fish facing hypoxic environments.

Cellular Conversations in Glioblastoma Progression, Diagnosis and Treatment.

Glioblastoma (GBM) is the most frequent malignancy among primary brain tumors in adults and one of the worst 5-year survival rates (< 7%) among all human cancers. Till now, treatments that target particular cell or intracellular metabolism have not improved patients survival. GBM recruits healthy brain cells and subverts their processes to create a microenvironment that contributes to supporting tumor progression. This microenvironment encompasses a complex network in which malignant cells interact with each other and with normal and immune cells to promote tumor proliferation, angiogenesis, metastasis, immune suppression, and treatment resistance. Communication can be direct via cell-to-cell contact, mainly through adhesion molecules, tunneling nanotubes, gap junctions, or indirect by conventional paracrine signaling by cytokine, neurotransmitter, and extracellular vesicles. Understanding these communication routes could open up new avenues for the treatment of this lethal tumor. Hence, therapeutic approaches based on glioma cells communication have recently drawn attention. This review summarizes recent findings on the crosstalk between glioblastoma cells and their tumor microenvironment, and the impact of this conversation on glioblastoma progression. We also discuss the mechanism of communication of glioma cells and their importance as therapeutic targets and diagnostic and prognostic biomarkers. Overall, understanding the biological mechanism of specific interactions in the tumor microenvironment may help in predicting patient prognosis and developing novel therapeutic strategies to target GBM.

The combination of tumor treating fields and hyperthermia has synergistic therapeutic effects in glioblastoma cells by downregulating STAT3.

Glioblastoma multiforme (GBM), the most common type of brain tumor, is a very aggressive and treatment-refractory cancer, with a 5-year survival rate of approximately 5%. Hyperthermia (HT) and tumor treating fields (TTF) therapy have been used to treat cancer, either alone or in combination with other treatment methods. Both treatments have been reported to increase the efficacy of other treatment techniques and to improve patient prognosis. The present study evaluated the therapeutic effects of combining HT and TTF on GBM cell lines. Cells were subjected to HT, TTF, HTTTF, or neither treatment, followed by comparisons of cell proliferation, apoptosis, migration and invasiveness. Clonogenic assays showed that the two treatments had a synergistic effect. The levels of cleaved PARP and cleaved caspase-3 were higher and apoptosis was increased in cells treated with HTTTF than in cells treated with HT or TTF alone. In addition, HTTTF showed greater inhibition of GBM cell migration and invasiveness and greater downregulation of STAT3 than either HT or TTF alone. The stronger anticancer effect of HTTTF suggested that this combination treatment can increase the survival rate of patients with difficult-to-treat cancers such as GBM.

High-throughput functional evaluation of human cancer-associated mutations using base editors.

Comprehensive phenotypic characterization of the many mutations found in cancer tissues is one of the biggest challenges in cancer genomics. In this study, we evaluated the functional effects of 29,060 cancer-related transition mutations that result in protein variants on the survival and proliferation of non-tumorigenic lung cells using cytosine and adenine base editors and single guide RNA (sgRNA) libraries. By monitoring base editing efficiencies and outcomes using surrogate target sequences paired with sgRNA-encoding sequences on the lentiviral delivery construct, we identified sgRNAs that induced a single primary protein variant per sgRNA, enabling linking those mutations to the cellular phenotypes caused by base editing. The functions of the vast majority of the protein variants (28,458 variants, 98%) were classified as neutral or likely neutral only 18 (0.06%) and 157 (0.5%) variants caused outgrowing and likely outgrowing phenotypes, respectively. We expect that our approach can be extended to more variants of unknown significance and other tumor types.

Stratification of radiosensitive brain metastases based on an actionable S100A9RAGE resistance mechanism.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Distinct phases of adult microglia proliferation a Myc-mediated early phase and a Tnfaip3-mediated late phase.

Microgliosis is a hallmark of many neurological diseases, including Alzheimers disease, stroke, seizure, traumatic brain and spinal cord injuries, and peripheral and optic nerve injuries. Recent studies have shown that the newly self-renewed microglia have specific neurological functions. However, the mechanism of adult microglia proliferation remains largely unclear. Here, with single-cell RNA sequencing, flow cytometry, and immunohistochemistry, we demonstrate that the sciatic nerve injury induced two distinct phases of microglia proliferation in mouse spinal cord, each with different gene expression profiles. We demonstrate that the transcription factor Myc was transiently upregulated in spinal cord microglia after nerve injury to mediate an early phase microglia proliferation. On the other hand, we reveal that the tumor-necrosis factor alpha-induced protein 3 (Tnfaip3) was downregulated to mediate the Myc-independent late-phase microglia proliferation. We show that cyclin dependent kinase 1, a kinase with important function in the M phase of the cell cycle, was involved only in the early phase. We reveal that although the early phase was neither necessary nor sufficient for the late phase proliferation, the late-phase suppressed the early phase microglia proliferation in the spinal cord. Finally, we demonstrate that the termination of spinal cord microglia proliferation required both Myc and Tnfaip3 to resume their baseline expression. Thus, we have delineated an interactive signaling network in the proliferation of differentiated microglia.

P2x4 receptor promotes mammary cancer progression by sustaining autophagy and associated mesenchymal transition.

Metastatic progression is a major burden for breast cancer patients and is associated with the ability of cancer cells to overcome stressful conditions, such as nutrients deprivation and hypoxia, and to gain invasive properties. Autophagy and epithelial-to-mesenchymal transition are critical contributors to these processes. Here, we show that the P2X4 purinergic receptor is upregulated in breast cancer biopsies from patients and it is primarily localised in endolysosomes. We demonstrate that P2X4 enhanced invasion in vitro, as well as mammary tumour growth and metastasis in vivo. The pro-malignant role of P2X4 was mediated by the regulation of lysosome acidity, the promotion of autophagy and cell survival. Furthermore, the autophagic activity was associated with epithelial-to-mesenchymal transition (EMT), and this role of P2X4 was even more pronounced under metabolic challenges. Pharmacological and gene silencing of P2X4 inhibited both autophagy and EMT, whereas its rescue in knocked-down cells led to the restoration of the aggressive phenotype. Together, our results demonstrate a previously unappreciated role for P2X4 in regulating lysosomal functions and fate, promoting breast cancer progression and aggressiveness.

Carbonized paramagnetic complexes of Mn (II) as contrast agents for precise magnetic resonance imaging of sub-millimeter-sized orthotopic tumors.

Paramagnetic complexes containing gadolinium ions have been widely used for magnetic resonance imaging (MRI) in clinic. However, these paramagnetic complexes pose some safety concerns. There is still a demand for the development of stable MRI contrast agents that exhibit higher sensitivity and superior functionality to existing contrast agents. Here, we develop carbonized paramagnetic complexes of manganese (II) (MnCCs) to encapsulate Mn

Stereotactic radiosurgery for hypoglossal schwannoma.

Hypoglossal schwannomas (HS) are extremely rare neoplasms. Surgical resection has historically been the treatment of choice but carries a significant risk of postoperative neurological deficits and mortality. Stereotactic radiosurgery (SRS) is a minimally invasive approach that may afford long-term tumour growth. However, literature to determine the safety and effectiveness of SRS in the treatment of HS is scarce. We report on a patient who presented with progressive headache and dysphagia as well as tongue deviation to the left, due to a space-occupying lesion, consistent on brain MRI with a left HS. Primary SRS using a prescription dose of 12 Gy in a single fraction was used to treat the tumour without complications. By last follow-up, the tumour regressed, and the patients symptoms improved. Our case shows that radiosurgery can be safe and effective for the management of HS.

Factors Associated With Long-term Survival in Women Who Get Pregnant After Surgery for WHO Grade II Glioma.

Women with a World Health Organization grade II glioma (GIIG) often question clinicians about the effects of pregnancy on their disease. Previous reports have indicated a higher risk of glioma progression during and after pregnancy. Here, the aim was to investigate postpregnancy outcomes and predictive factors affecting overall survival in female patients who underwent GIIG surgery. Inclusion criteria were adult women who have been pregnant after a GIIG resection and with a stable oncologic status at the time of pregnancy (no ongoing oncologic treatment, no contrast enhancement, no debilitating clinical condition). Relevant cases were identified from a databank (1998-2021) of patients who underwent surgical resection for a histologically confirmed GIIG in our department. Among 345 women with GIIG in their reproductive years (age <45 years), 16 patients (4.6%, mean age at delivery 30.9 ± 5.1 years) were pregnant (twice in 5 cases). The mean interval between the last oncologic treatment (surgery alone in 11 patients, surgery followed by chemotherapy andor radiotherapy in 5 patients) and pregnancy was 3.5 years (range 0.75-10 years). Two patients experienced seizures during pregnancy. The delivery was vaginal and uneventful in all cases but 1 (1 caesarean). All children had normal mental and physical development. The glioma behavior changed in 7 patients (43.7%), with an acceleration of the velocity of diameter expansion andor the occurrence of a contrast enhancement during or within 3 months after pregnancy, resulting in medical treatment andor reoperation in the early postpartum period in 7 cases. The median clinical follow-up from delivery was 5.3 years (range 1.25-11.6 years). Four other patients received delayed adjuvant therapy for glioma progression. Seven patients (43.7%) died at a median time from delivery of 3.9 years (range 1.25-5.9 years). Overall, the median survival from delivery was 5.75 years. A crucial finding is that patients who underwent a complete surgical resection and patients with stable lesions before pregnancy lived longer (log rank, Tumor residual volume and tumor speed growth are strong predictive factors conditioning postpregnancy long-term survival in patients with GIIG. Identifying patients at risk is critical to provide relevant counsel to women with GIIG with a desire for motherhood.

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer applicability from clinical trials to real-world practice.

Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 PD-(L)1 blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others overall survival (OS), p 0.0105 progression-free survival (PFS), p 0.0167. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p 0.3742 PFS, p 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p 0.0087 PFS, p 0.0290) and in the real-world practice (OS, p 0.0182 PFS, p 0.0045). Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

The side effects of dopamine receptor agonist drugs in Chinese prolactinoma patients a cross sectional study.

Recently, side effects from Dopamine Receptor Agonist Drugs (DAs) in treating pituitary prolactinoma have raised widespread concern. This study explores the incidence and influencing factors of DAs-related side effects in Chinese prolactinoma patients. A cross-sectional study was conducted. 51 prolactinoma patients treated with DAs, 12 prolactinoma or pituitary microadenoma patients without DAs treatment, and 33 healthy controls were included. The Barratt impulsivity scale-11, Patient Health Questionnaire 9, and the ICD screening questionnaire were all used to evaluate the psychological and physical side effects of DAs. Clinical data of all subjects were collected from their electronic medical records. The incidence of ICDs in the treated group, the untreated group, and control group was 9.8% (551), 16.7% (212), and 9.1% (333), respectively. In the treated group in particular, there were 1 patient (2%, 151), 2 patients (3.9%, 251), and 2 patients (3.9%, 251) with positive screening for punding, compulsive shopping, and hypersexuality, respectively. In terms of depression, the incidence of minimal, mild and moderate depression in the treated group was 62.8% (3251), 25.5% (1351), and 5.9% (351), respectively. The incidence of physical symptoms was 51.0% (2651) in the treated group and gastrointestinal symptoms were the most common symptoms (33.3%, 1751). In addition, we found that the various parameters of DAs treatment had no association with the occurrence of physical symptoms or ICDs (all P > 0.05). Chinese prolactinoma patients treated with DAs had a lower incidence of ICDs (9.8%), while gastrointestinal symptoms were common. In this way, more attention should be paid to side effects, especially physical symptoms, in Chinese prolactinoma patients with DAs therapy during follow-up regardless of dose.

Intraoperative rupture of intracerebral aneurysm immediately after meningioma resection a case report.

Meningiomas and unruptured cerebral aneurysms (UCAs) rarely coexist. However, the treatment strategy remains to be fully elucidated. This report is a first report that UCA related to the tumor feeder intraoperatively ruptured when the meningioma was resected. Herein, we present a case of meningioma coexisting with contralateral UCA related to a tumor feeder. Immediately after the meningioma was resected, intraoperative acute brain swelling due to rupture of the contralateral aneurysm appeared. The swollen brain protruding into the epidural space was resected, following contralateral ruptured aneurysm was performed by endovascular surgery. Intensive neurological treatment was administered and the patient gradually recovered. This report highlights the possibility of intraoperative UCA rupture related to the tumor feeder when the meningioma is resected.

Impact of Seismic Activity on Access to Health Care in HispanicLatino Cancer Patients from Puerto Rico.

On 7 January 2020, the southern region of Puerto Rico was struck by a 6.4 magnitude earthquake, followed by continual seismic activity. Our team performed secondary analyses to explore the relationship between exposure to seismic activity, protection (support) received, and barriers to health care access for cancer patients. Methods The research team collected data from the database of a longitudinal case-control cohort parent study concerning the impact of Hurricane Maria in Puerto Rican cancer patients. The participants from the parent study were recruited in community clinics. The extracted data was collected from 51 cancer patients who completed the parent studys interviews from January-July 2020 (seismic activity period). Barriers to health care were assessed using the Barrier to Care Questionaries (BCQ), which is composed of five subscales skills, marginalization, knowledge and beliefs expectations, and pragmatics. Exposure to seismic activity and protection was assessed using their respective subscales from the Scale of Psychosocial Impact of Disasters. Results The results showed a significant relationship between exposure to seismic activity and barriers to health care (

Physical Forces in Glioblastoma Migration A Systematic Review.

The invasive capabilities of glioblastoma (GBM) define the cancers aggressiveness, treatment resistance, and overall mortality. The tumor microenvironment influences the molecular behavior of cells, both epigenetically and genetically. Current forces being studied include properties of the extracellular matrix (ECM), such as stiffness and sensing capabilities. There is currently limited data on the physical forces in GBM-both relating to how they influence their environment and how their environment influences them. This review outlines the advances that have been made in the field. It is our hope that further investigation of the physical forces involved in GBM will highlight new therapeutic options and increase patient survival. A search of the PubMed database was conducted through to 23 March 2022 with the following search terms (glioblastoma) AND (physical forces OR pressure OR shear forces OR compression OR tension OR torsion) AND (migration OR invasion). Our review yielded 11 externalappliedmechanical forces and 2 tumor microenvironment (TME) forces that affect the ability of GBM to locally migrate and invade. Both external forces and forces within the tumor microenvironment have been implicated in GBM migration, invasion, and treatment resistance. We endorse further research in this area to target the physical forces affecting the migration and invasion of GBM.

Synthesis and Biological Evaluation of Novel Bufalin Derivatives.

Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawas reagent resulted in the production of two novel bufalin derivatives bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na

MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53.

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a master regulatory microRNA that could be therapeutically exploited.

The Evidence for Effective Inhibition of

Mirogabalin (MGB, Tarlige

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir.

Children with high-risk SHH

SOAT1 A Suitable Target for Therapy in High-Grade Astrocytic Glioma

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and

Transcription Factors with Targeting Potential in Gliomas.

Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-123, E2F1-8, STAT3, and HIF-12) and tumor suppressor (NFI-AB, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.

Analysis of microRNAs in Exosomes of Breast Cancer Patients in Search of Molecular Prognostic Factors in Brain Metastases.

Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use.

Functional Characterization of the Solute Carrier LAT-1 (SLC7A5SLC2A3) in Human Brain Capillary Endothelial Cells with Rapid UPLC-MSMS Quantification of Intracellular Isotopically Labelled L-Leucine.

The solute carrier L-type amino acid transporter 1 (LAT-1SLC7A5) is a viable target for drug delivery to the central nervous system (CNS) and tumors due to its high abundance at the blood-brain barrier and in tumor tissue. LAT-1 is only localized on the cell surface as a heterodimer with CD98, which is not required for transporter function. To support future CNS drug-delivery development based on LAT-1 targeting, we established an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MSMS) assay for stable isotopically labeled leucine (

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes.

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method of enabling the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

Coated Blade Spray-Mass Spectrometry as a New Approach for the Rapid Characterization of Brain Tumors.

Brain tumors are neoplasms with one of the highest mortality rates. Therefore, the availability of methods that allow for the quick and effective diagnosis of brain tumors and selection of appropriate treatments is of critical importance for patient outcomes. In this study, coated blade spray-mass spectrometry (CBS-MS), which combines the features of microextraction and fast ionization methods, was applied for the analysis of brain tumors. In this approach, a sword-shaped probe is coated with a sorptive material to enable the extraction of analytes from biological samples. The analytes are then desorbed using only a few microliters of solvent, followed by the insertion of the CBS device into the interface on the mass spectrometer source. The results of this proof-of-concept experiment confirmed that CBS coupled to high-resolution mass spectrometry (HRMS) enables the rapid differentiation of two histologically different lesions meningiomas and gliomas. Moreover, quantitative CBS-HRMSMS analysis of carnitine, the endogenous compound, previously identified as a discriminating metabolite, showed good reproducibility with the variation below 10% when using a standard addition calibration strategy and deuterated internal standards for correction. The resultant data show that the proposed CBS-MS technique can be useful for on-site qualitative and quantitative assessments of brain tumor metabolite profiles.

LCESITOF-MS Characterization, Anxiolytic and Antidepressant-like Effects of

In this study, the attenuative effects of the hydro-alcoholic extract from

A New Deep Hybrid Boosted and Ensemble Learning-Based Brain Tumor Analysis Using MRI.

Brain tumor analysis is essential to the timely diagnosis and effective treatment of patients. Tumor analysis is challenging because of tumor morphology factors like size, location, texture, and heteromorphic appearance in medical images. In this regard, a novel two-phase deep learning-based framework is proposed to detect and categorize brain tumors in magnetic resonance images (MRIs). In the first phase, a novel deep-boosted features space and ensemble classifiers (DBFS-EC) scheme is proposed to effectively detect tumor MRI images from healthy individuals. The deep-boosted feature space is achieved through customized and well-performing deep convolutional neural networks (CNNs), and consequently, fed into the ensemble of machine learning (ML) classifiers. While in the second phase, a new hybrid features fusion-based brain-tumor classification approach is proposed, comprised of both static and dynamic features with an ML classifier to categorize different tumor types. The dynamic features are extracted from the proposed brain region-edge net (BRAIN-RENet) CNN, which is able to learn the heteromorphic and inconsistent behavior of various tumors. In contrast, the static features are extracted by using a histogram of gradients (HOG) feature descriptor. The effectiveness of the proposed two-phase brain tumor analysis framework is validated on two standard benchmark datasets, which were collected from Kaggle and Figshare and contain different types of tumors, including glioma, meningioma, pituitary, and normal images. Experimental results suggest that the proposed DBFS-EC detection scheme outperforms the standard and achieved accuracy (99.56%), precision (0.9991), recall (0.9899), F1-Score (0.9945), MCC (0.9892), and AUC-PR (0.9990). The classification scheme, based on the fusion of feature spaces of proposed BRAIN-RENet and HOG, outperform state-of-the-art methods significantly in terms of recall (0.9913), precision (0.9906), accuracy (99.20%), and F1-Score (0.9909) in the CE-MRI dataset.

Assessing Nordihydroguaiaretic Acid Therapeutic Effect for Glioblastoma Multiforme.

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGAs impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGAs beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.

RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways.

RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g.,

A Boronated Derivative of Temozolomide Showing Enhanced Efficacy in Boron Neutron Capture Therapy of Glioblastoma.

There is an incontestable need for improved treatment modality for glioblastoma due to its extraordinary resistance to traditional chemoradiation therapy. Boron neutron capture therapy (BNCT) may play a role in the future. We designed and synthesized a

Single-Cell Molecular Characterization to Partition the Human Glioblastoma Tumor Microenvironment Genetic Background.

Glioblastoma (GB) is a devastating primary brain malignancy. The recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. The barriers to treatment include the complex interactions among the different cellular components inhabiting the tumor microenvironment. The complex heterogeneous nature of GB cells is helped by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. By using fluorescent multiple labeling and a DEPArray cell separator, we recovered several single cells or groups of single cells from populations of different origins from IDH-WT GB samples. From each GB sample, we collected astrocytes-like (GFAP), microglia-like (IBA1), stem-like cells (CD133), and endothelial-like cells (CD105) and performed Copy Number Aberration (CNA) analysis with a low sequencing depth. The same tumors were subjected to a bulk CNA analysis. The tumor partition in its single components allowed single-cell molecular subtyping which revealed new aspects of the GB altered genetic background. Nowadays, single-cell approaches are leading to a new understanding of GB physiology and disease. Moreover, single-cell CNAs resource will permit new insights into genome heterogeneity, mutational processes, and clonal evolution in malignant tissues.

Lichen Secondary Metabolites Inhibit the Wntβ-Catenin Pathway in Glioblastoma Cells and Improve the Anticancer Effects of Temozolomide.

Lichens are a source of secondary metabolites with significant pharmacological potential. Data regarding their possible application in glioblastoma (GBM) treatment are, however, scarce. The study aimed at analyzing the mechanism of action of six lichen secondary metabolites atranorin, caperatic acid, physodic acid, squamatic acid, salazinic acid, and lecanoric acid using two- and three-dimensional GBM cell line models. The parallel artificial membrane permeation assay was used to predict the blood-brain barrier penetration ability of the tested compounds. Their cytotoxicity was analyzed using the MTT test on A-172, T98G, and U-138 MG cells. Flow cytometry was applied to the analysis of oxidative stress, cell cycle distribution, and apoptosis, whereas qPCR and microarrays detected the induced transcriptomic changes. Our data confirm the ability of lichen secondary metabolites to cross the blood-brain barrier and exert cytotoxicity against GBM cells. Moreover, the compounds generated oxidative stress, interfered with the cell cycle, and induced apoptosis in T98G cells. They also inhibited the Wntβ-catenin pathway, and this effect was even stronger in case of a co-treatment with temozolomide. Transcriptomic changes in cancer related genes induced by caperatic acid and temozolomide were the most pronounced. Lichen secondary metabolites, caperatic acid in particular, should be further analyzed as potential anti-GBM agents.

A Prognostic Model Using Post-Steroid Neutrophil-Lymphocyte Ratio Predicts Overall Survival in Primary Central Nervous System Lymphoma.

Ratios of differential blood counts (hematological indices, HIs) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSLs), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HIs could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HIs were calculated at three time-points baseline (pre steroid), pre chemoimmunotherapy (post steroid) and post chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan-Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan-Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR ≥ 4.0, HR 0.42, 95% CI 0.21-0.83, We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed for accurate and well-calibrated stratification into three risk groups.

Quantification of Tissue Compression Identifies High-Grade Glioma Patients with Reduced Survival.

The compression of peritumoral healthy tissue in brain tumor patients is considered a major cause of the life-threatening neurologic symptoms. Although significant deformations caused by the tumor growth can be observed radiologically, the quantification of minor tissue deformations have not been widely investigated. In this study, we propose a method to quantify subtle peritumoral deformations. A total of 127 MRI longitudinal studies from 23 patients with high-grade glioma were included. We estimate longitudinal displacement fields based on a symmetric normalization algorithm and we propose four biomarkers. We assess the interpatient and intrapatient association between proposed biomarkers and the survival based on Cox analyses, and the potential of the biomarkers to stratify patients according to their survival based on Kaplan-Meier analysis. Biomarkers show a significant intrapatient association with survival (

The Extent of Necrosis in Brain Metastases May Predict Subtypes of Primary Cancer and Overall Survival in Patients Receiving Craniotomy.

Although necrosis is common in brain metastasis (BM), its biological and clinical significances remain unknown. We evaluated necrosis extent differences by primary cancer subtype and correlated BM necrosis to overall survival post-craniotomy. We analyzed 145 BMs of patients receiving craniotomy. Necrosis to tumor ratio (NTR) was measured. Patients were divided into two groups by NTR BMs with sparse necrosis and with abundant necrosis. Clinical features were compared. To investigate factor relevance for BM necrosis, multivariate logistic regression, random forests, and gradient boosting machine analyses were performed. Kaplan-Meier analysis and log-rank tests were performed to evaluate the effect of BM necrosis on overall survival. Lung cancer was a more common origin for BMs with abundant necrosis (4272, 58.33%) versus sparse necrosis (2373, 31.51%,

SMYD3 Promotes Cell Cycle Progression by Inducing Cyclin D3 Transcription and Stabilizing the Cyclin D1 Protein in Medulloblastoma.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Maximum safe resection, postoperative craniospinal irradiation, and chemotherapy are the standard of care for MB patients. MB is classified into four subgroups Shh, Wnt, Group 3, and Group 4. Of these subgroups, patients with Myc Group 3 MB have the worst prognosis, necessitating alternative therapies. There is increasing interest in targeting epigenetic modifiers for treating pediatric cancers, including MB. Using an RNAi functional genomic screen, we identified the lysine methyltransferase SMYD3, as a crucial epigenetic regulator that drives the growth of Group 3 Myc MB cells. We demonstrated that SMYD3 directly binds to the cyclin D3 promoter to activate its transcription. Further, SMYD3 depletion significantly reduced MB cell proliferation and led to the downregulation of cyclin D3, cyclin D1, pRBSer795, with concomitant upregulations in RB in vitro. Similar results were obtained following pharmacological inhibition of SMYD3 using BCI-121 ex vivo. SMYD3 knockdown also promoted cyclin D1 ubiquitination, indicating that SMYD3 plays a vital role in stabilizing the cyclin D1 protein. Collectively, our studies demonstrate that SMYD3 drives cell cycle progression in Group 3 Myc MB cells and that targeting SMYD3 has the potential to improve clinical outcomes for high-risk patients.

Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer-From Bench to Bedside.

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their free form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform.

Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor Role of Lipid Metabolism.

Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3KAKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to β-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.

Baseline Objective Malnutritional Indices as Immune-Nutritional Predictors of Long-Term Recurrence in Patients with Acute Ischemic Stroke.

The controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score were designed as indicators of patients immune-nutritional status. This study aimed to investigate the prognostic impact of the CONUT and PNI scores on long-term recurrent ischemic stroke (RIS) and adverse outcomes for adults with acute ischemic stroke (AIS). This retrospective study enrolled 991 AIS patients. Multivariable Cox regression models were used to assess the relationships of the malnutritional indices and RIS and major cardiovascular events (MACEs). During a median follow-up at 44 months (IQR 39-49 months), 203 (19.2%) patients had RIS and 261 (26.3%) had MACEs. Compared with normal nutritional status, moderate to severe malnutrition was significantly related to an increased risk of RIS in the CONUT score (adjusted hazard ratio (HR) 3.472, 95% confidence interval (CI) 2.223-5.432, This study demonstrated that the CONUT and PNI are promising, straightforward screening indicators to identify AIS patients with impaired immune-nutritional status at higher risk of long-term RIS and MACEs.

The significance of nanoparticles in brain cancer diagnosis and treatment modeling and simulation.

A numerical analysis of specific absorption rate (SAR) and temperature distributions in a realistic human head model is presented in this study. The key challenge is to rise cancer temperature to an optimal temperature without heating nearby healthy tissues. The models uniqueness is that it captures the effect of nanoparticles on both brain cancer diagnosis and treatment. A realistic human head model with a cancerous brain segmented from 2D magnetic resonance imaging (MRI) gained from an actual patient using 3D Slicer, modeled, and simulated using CST-Microwave Studio, and illuminated by Archimedes spiral antenna. At frequencies of 2450 MHz and 915 MHz, the model simulated the absence and presence of various nanoparticles. The obtained results suggest that when using nanoparticles, it is possible to achieve sufficient energy deposition and temperature rise to therapeutic values (greater than 42 °C) in brain cancers using the proposed noninvasive hyperthermia system at 915 MHz frequency, especially for gold nanoparticles, without harming surrounding healthy tissue. Our research might pave the way for a clinical applicator prototype that can heat brain cancer.

Short-term or long-term outcomes for stroke patients with cancer according to biological markers.

Although hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer. Consecutive acute ischemic stroke patients with cancer (n 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed. Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio aOR 1.04, 95% confidence interval CI 1.00-1.08, and aOR 0.50, 95% CI 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio aHR 2.65, 95% CI 1.37-5.12, and aHR 2.29, 95% CI 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer. Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

Borrowing strength from adults Transferability of AI algorithms for paediatric brain and tumour segmentation.

AI brain tumour segmentation and brain extraction algorithms promise better diagnostic and follow-up of brain tumours in adults. The development of such tools for paediatric populations is restricted by limited training data but careful adaption of adult algorithms to paediatric population might be a solution. Here, we aim exploring the transferability of algorithms for brain (HD-BET) and tumour segmentation (HD-GLIOMA) in adults to paediatric imaging studies. In a retrospective cohort, we compared automated segmentation with expert masks. We used the dice coefficient for evaluating the similarity and multivariate regressions for the influence of covariates. We explored the feasibility of automatic tumor classification based on diffusion data. In 42 patients (mean age 7 years, 9 below 2 years, 26 males), segmentation was excellent for brain extraction (mean dice 0.99, range 0.85-1), moderate for segmentation of contrast-enhancing tumours (mean dice 0.67, range 0-1), and weak for non-enhancing T2-signal abnormalities (mean dice 0.41). Precision was better for enhancing tumour parts (p < 0.001) and for malignant histology (p 0.006 and p 0.012) but independent from myelinisation as indicated by the age (p 0.472). Automated tumour grading based on mean diffusivity (MD) values from automated masks was good (AUC 0.86) but tended to be less accurate than MD values from expert masks (AUC 1, p 0.208). HD-BET provides a reliable extraction of the paediatric brain. HD-GLIOMA works moderately for contrast-enhancing tumours parts. Without optimization, brain tumor AI algorithms trained on adults and used on paediatric patients may yield acceptable results depending on the clinical scenario.

The human anti-ganglioside GM1 autoantibody response following traumatic and surgical central nervous system insults.

Predictors of the central nervous system (CNS) directed autoantibody response after acute CNS injury are poorly understood. We analyzed titers of IgG and IgM autoantibodies to ganglioside GM1 in serial serum specimens collected from human patients following acute spinal cord injury (SCI), traumatic brain injury (TBI) and brain tumor resection. We also assessed putative predictors of the autoantibody titers. We enrolled 19 patients with acute SCI, 14 patients with acute severe TBI, and 19 patients undergoing brain tumor resection. We also enrolled 25 control subjects. Some SCI, TBI and tumor patients exhibited elevated IgG titers as compared with control values some SCI and TBI patients exhibited an acute peak in IgG titers, most commonly 14 days after insult. Some clinical and radiographic measures of injury severity correlated with IgG titer elevation in SCI and TBI patients but not tumor patients. Our study demonstrates that diverse CNS insults are followed by increased IgG autoimmune antibody titers to the CNS antigen ganglioside GM1, however the response inherent to each insult type is unique. IgG autoimmune antibody titers to GM1 merit further study as a biomarker of traumatic injury severity that can be measured in delayed fashion after CNS insult. These human data help to inform which patients with CNS insults are at risk for CNS-directed autoimmunity as well as the time course of the response.

Tumor suppressor PALB2 maintains redox and mitochondrial homeostasis in the brain and cooperates with ATG7autophagy to suppress neurodegeneration.

The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.

Diffusion tensor imaging-derived biomarkers performance in glioblastoma tumor regions exploratory data analysis using zombie plots and diagnostic tests.

Using diffusion tensor imaging (DTI), 11 biomarkers have been reported in different glioblastoma (GB) regions. To compare the efficacy of GB biomarkers using zombie plots. Retrospective cohort of 29 subjects with GB who underwent 3-Tesla brain magnetic resonance imaging. DTI major, intermediate and minor eigenvalues were used to calculate biomarkers at five tumor regions normal-appearing white matter (NAWM), proximal and distal edema, tumor tissue and necrosis. Contingency tables with true and false positive and negative results allowed the calculation of zombie plots based on the Bayes factor and previously unreported diagnostic tests. The MD, FA, q, L, Cl, Cp and RA biomarkers had a good performance at the optimal zone for NAWM diagnosis. The proximal and distal edema, enhancing rim and necrosis regions do not have biomarkers that identify them with an optimal performance level. Zombie plots allow simultaneous comparison of biomarkers based on likelihood ratios. MD, FA, q, L, Cl, Cp, RA discriminated NAWM normal brain tissue at the optimal zone, but performance for other regions was at the mediocre, diagnostic inclusion and diagnostic exclusion zones. Han sido reportados 11 biomarcadores de imágenes con tensor de difusión (DTI) en las regiones tumorales del glioblastoma. Comparar la eficacia de biomarcadores de glioblastoma mediante gráficos de zombie, que permiten la comparación simultánea en función de razones de verosimilitud. Cohorte retrospectiva de 29 sujetos con glioblastoma a quienes se efectuó resonancia magnética cerebral de 3 T. Los eigenvalores mayor, intermedio y menor de ITD se utilizaron para calcular 11 biomarcadores en cinco regiones tumorales sustancia blanca de apariencia normal (NAWM), edema proximal y distal, tumoral viable y necrosis. Las tablas de contingencia con resultados verdaderos y falsos positivos y negativos permitieron calcular gráficos de zombie basados en el factor de Bayes y pruebas diagnósticas previamente no reportadas. Los biomarcadores DM, AF, q, L, Cl, Cp, AR actúan en la zona óptima para el diagnóstico de NAWM. Las regiones de edema proximal y distal, tejido tumoral que se realza con contraste y necrosis no poseen biomarcadores que las identifiquen en un nivel de rendimiento óptimo. Los biomarcadores DM, AF, q, L, Cl, Cp, AR discriminan el tejido cerebral normal en la zona óptima, pero el rendimiento de otras regiones tumorales se ubica en las zonas de inclusión diagnóstica, exclusión diagnóstica y mediocre.

Factors associated with health-related quality of life (HRQoL) deterioration in glioma patients during the progression-free survival period.

Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled.

Activity of Adagrasib (MRTX849) in Brain Metastases Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-LucH23-LucLU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Axicabtagene Ciloleucel in Patients Ineligible for ZUMA-1 Because of CNS Involvement andor HIV A Multicenter Experience.

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

Advanced Glycosylation End Products Induced Synaptic Deficits and Cognitive Decline Through ROS-JNK-p53miR-34cSYT1 Axis in Diabetic Encephalopathy.

miR-34c has been found to be implicated in the pathological process of Alzheimers disease, diabetes, and its complications. To investigate the underlying mechanisms of miR-34c in the pathogenesis of diabetic encephalopathy (DE). Diabetes mellitus rats were developed by incorporating a high-fat diet and streptozotocin injection. Morris water maze test and novel object recognition test were used to assess the cognitive function of rats. Expression of miR-34c were detected by fluorescence in situ hybridization and qRT-PCR. Immunofluorescence and western blot were used to evaluate synaptotagmin 1 (SYT1) and AdipoR2 or other proteins. Golgi staining was performed to investigate dendritic spine density. The increased miR-34c induced by advanced glycation end-products (AGEs) was mediated by ROS-JNK-p53 pathway, but not ROS-Rb-E2F1 pathway, in hippocampus of DE rats or in HT-22 cells. miR-34c negatively regulated the expression of SYT1, but not AdipoR2, in hippocampal neurons. miR-34c inhibitor rescued the AGE-induced decrease in the density of dendritic spines in primary hippocampal neurons. Administration of AM34c by the intranasal delivery increased the hippocampus levels of SYT1 and ameliorated the cognitive function in DE rats. The serum levels of miR-34c were increased in patients with DE comparing with normal controls. These results demonstrated that AGE-induced oxidative stress mediated increase of miR-34c through ROS-JNK-p53 pathway, resulting in synaptic deficits and cognitive decline by targeting SYT1 in DE, and the miR-34cSYT1 axis could be considered as a novel therapeutic target for DE patients.

Human Norovirus Triggers Primary B Cell Immune Activation

Human norovirus (HNoV) is a global health and socioeconomic burden, estimated to infect every individual at least five times during their lifetime. The underlying mechanism for the potential lack of long-term immune protection from HNoV infections is not understood and prompted us to investigate HNoV susceptibility of primary human B cells and its functional impact. Primary B cells isolated from whole blood were infected with HNoV-positive stool samples and harvested at 3 days postinfection (dpi) to assess the viral RNA yield by reverse transcriptase quantitative PCR (RT-qPCR). A 3- to 18-fold increase in the HNoV RNA yield was observed in 50 to 60% of donors. Infection was further confirmed in B cells derived from splenic and lymph node biopsy specimens. Next, we characterized infection of whole-blood-derived B cells by flow cytometry in specific functional B cell subsets (naive CD27