bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytotoxic Effects of Nanoliposomal Cisplatin and Diallyl Disulfide on Breast Cancer and Lung Cancer Cell Lines
Authors: Gunasekaran Kaavya , Vasamsetti Bala Murali Krishna , Thangavelu Priyadharshini , Natesan Karthi , Mujyambere Bonaventure , Sundaram Viswanathan , Jayaraj Rama , Kim Yeon-Jun , Samiappan Suja , Choi Jae-Won
Published: March 2023

Dual drug delivery has become the choice of interest nowadays due to its increased therapeutic efficacy in targeting the tumor site precisely. As quoted in recent literature, it has been known to treat several cancers with an acute course of action. Even so, its use is restricted due to the drug’s low pharmacological activity, which leads to poor bioavailability and increases first-pass metabolism. To overcome these issues, a drug delivery system using nanomaterials which would not only encapsulate the drugs of interest but also carry them to the target site of action is needed. Given all these attributes, we have formulated dual drug-loaded nanoliposomes with cisplatin (cis-diamminedichloroplatinum(II) (CDDP)), an effective anti-cancer drug, and diallyl disulfide (DADS), an organosulfur compound derived from garlic. The CDDP and DADS-loaded nanoliposomes (Lipo-CDDP/DADS) exhibited better physical characteristics such as size, zeta potential, polydispersity index, spherical shape, optimal stability, and satisfactory encapsulation percentage. The in vitro anti-cancer activity against MDA-MB-231 and A549 cell lines revealed that Lipo-CDDP/DADS showed significant efficacy against the cancer cell lines, depicted through cell nucleus staining. We conclude that Lipo-CDDP/DADS hold exceptional pharmacological properties with better anti-cancer activity and would serve as a promising formulation to treat various cancers.
Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review
Authors: Hertelendi Marianna , Belguenani Oulaya , Cherfi Azzeddine , Folitar Ilya , Kollar Gabor , Polack Berna Degirmenci
Published: March 2023

Background: We have performed a systematic review to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Methods: Studies identified in PubMed from inception to 13 May 2021 must have assessed [177Lu]Lu-DOTA-TATE as a single agent and reported outcome data for the specific NET types of interest. Results: Two independent reviewers performed the screening and data extraction, resulting in 16 publications: PPGL (n = 7), bronchial NETs (n = 6; one also included NETs of unknown origin), and MTC (n = 3). Overall, [177Lu]Lu-DOTA-TATE offers encouraging antitumor activity (overall tumor response rates and disease control rates) across NET types. Safety was favorable with most adverse events mild to moderate in severity, transient, and consistent with those seen in patients with gastroenteropancreatic (GEP)-NETs. Conclusions: [177Lu]Lu-DOTA-TATE has been used effectively in clinical practice to treat NETs of non-GEP origin.
Recent Progress in Functional-Nucleic-Acid-Based Fluorescent Fiber-Optic Evanescent Wave Biosensors
Authors: Wang Zheng , Lou Xinhui
Published: March 2023

Biosensors capable of onsite and continuous detection of environmental and food pollutants and biomarkers are highly desired, but only a few sensing platforms meet the “2-SAR” requirements (sensitivity, specificity, affordability, automation, rapidity, and reusability). A fiber optic evanescent wave (FOEW) sensor is an attractive type of portable device that has the advantages of high sensitivity, low cost, good reusability, and long-term stability. By utilizing functional nucleic acids (FNAs) such as aptamers, DNAzymes, and rational designed nucleic acid probes as specific recognition ligands, the FOEW sensor has been demonstrated to be a general sensing platform for the onsite and continuous detection of various targets ranging from small molecules and heavy metal ions to proteins, nucleic acids, and pathogens. In this review, we cover the progress of the fluorescent FNA-based FOEW biosensor since its first report in 1995. We focus on the chemical modification of the optical fiber and the sensing mechanisms for the five above-mentioned types of targets. The challenges and prospects on the isolation of high-quality aptamers, reagent-free detection, long-term stability under application conditions, and high throughput are also included in this review to highlight the future trends for the development of FOEW biosensors capable of onsite and continuous detection.
Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice
Authors: Yu Haiping , Kan Junli , Tang Mingming , Zhu Yanbing , Hu Baoyang
Published: March 2023

Overactive microglia and severe neuroinflammation play crucial roles in the development of major depressive disorder. Preconditioning with lipopolysaccharide (LPS) provides protection against severe neuroinflammation. However, administering high doses of LPS to mice triggers depressive symptoms. Therefore, the optimal dose of LPS preconditioning needs to be determined by further experiments. LPS preconditioning is an effective agent in anti-inflammation and neuroprotection, but the mechanism by which LPS preconditioning acts in depression remain unclear. This study finds that the anti-inflammation mechanism of low-dose LPS preconditioning is mainly dependent on G-protein-coupled receptor 84 (GPR84). We use low-dose LPS for preconditioning and re-challenged mice or BV2 microglia with high-dose LPS. In addition, RNA-seq is used to explore underlying changes with LPS preconditioning. Low-dose LPS preconditioning reduces the expression of pro-inflammatory mediators and inhibits microglial activation, as well as suppresses the depressive-like behavior when the mice are re-challenged with high-dose LPS. Further investigation reveals that the tolerance-like response in microglia is dependent on the GPR84. Here, we show that low-dose LPS preconditioning can exert anti-inflammation effects and alleviates inflammation-induced depressive-like behavior in mice. As a potential therapeutic target for depression, LPS preconditioning needs to be given further attention regarding its effectiveness and safety.
Articulation-Function-Associated Cortical Developmental Changes in Patients with Cleft Lip and Palate
Authors: Zhang Wenjing , Zhao Cui , Sun Liwei , Yang Xintao , Yang Linrui , Liang Ying , Zhang Xu , Du Xiaoxia , Chen Renji , Li Chunlin
Published: March 2023

Cleft lip and palate (CLP) is one of the most common craniofacial malformations. Overall, 40–80% of CLP patients have varying degrees of articulation problems after palatoplasty. Previous studies revealed abnormal articulation-related brain function in CLP patients. However, the association between articulation disorders and cortical structure development in CLP patients remains unclear. Twenty-six CLP adolescents (aged 5–14 years; mean 8.88 years; female/male 8/18), twenty-three CLP adults (aged 18–35 years; mean 23.35 years; female/male 6/17), thirty-seven healthy adolescents (aged 5–16 years; mean 9.89 years; female/male 5/16), and twenty-two healthy adults (aged 19–37 years; mean 24.41 years; female/male 19/37) took part in the experiment. The current study aims to investigate developmental changes in cortical structures in CLP patients with articulation disorders using both structural and functional magnetic resonance imaging (MRI). Our results reveal the distinct distribution of abnormal cortical structures in adolescent and adult CLP patients. We also found that the developmental pattern of cortical structures in CLP patients differed from the pattern in healthy controls (delayed cortical development in the left lingual gyrus (t = 4.02, cluster-wise p < 0.05), inferior temporal cortex (z = −4.36, cluster-wise p < 0.05) and right precentral cortex (t = 4.19, cluster-wise p < 0.05)). Mediation analysis identified the cortical thickness of the left pericalcarine cortex as the mediator between age and articulation function (partial mediation effect (a*b = −0.48), 95% confident interval (−0.75, −0.26)). In conclusion, our results demonstrate an abnormal developmental pattern of cortical structures in CLP patients, which is directly related to their articulation disorders.
Association of Urinary Biomarkers of Renal Tubular Injury with Cognitive Dysfunction in Older Patients with Chronic Kidney Disease: A Cross-Sectional Observational Study
Authors: Wang Yiwei , Hu Ling , Zhou Difei , Chen Xiaolei , Zhou Leting
Published: March 2023

Epidemiological data suggest that individuals in all stages of chronic kidney disease (CKD) have higher risks of developing cognitive impairment. The relationship between CKD and cognition has been assessed exclusively using glomerular function markers; however, kidney tubule injury has not been assessed. We assessed the association between urinary biomarkers of renal tubular injury and cognitive dysfunction in older patients with CKD Stages 3–4. According to the Montreal Cognitive Assessment, participants were divided into cognitive dysfunction and control groups. Compared with the control group, the cognitive dysfunction group had significantly higher percentages of smokers, noticeably lower average education, and higher mitochondrial DNA (mtDNA) levels in the peripheral blood. Spearman correlation analysis showed that higher urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and beta-2 microglobulin (β2M) levels were significantly associated with lower cognitive scores. Multivariate logistic regression analysis showed that only increased urinary β2M levels were independently associated with cognitive worsening in CKD after adjusting for confounders. Logistic regression identified a promising role of urinary β2M combined with smoking and education for predicting cognitive impairment in CKD. Urinary β2M and cognitive function negatively correlated with mtDNA content, suggesting that mitochondrial dysfunction is a common pathophysiological mechanism linking CKD and cognitive dysfunction.
Differentiation of the Contribution of Familiarity and Recollection to the Old/New Effects in Associative Recognition: Insight from Semantic Relation
Authors: Nie Aiqing , Wu Yuanying
Published: March 2023

Previous research has revealed two different old/new effects, the early mid-frontal old/new effect (a.k.a., FN400) and the late parietal old/new effect (a.k.a., LPC), which relate to familiarity and recollection processes, respectively. Although associative recognition is thought to be more based on recollection, recent studies have confirmed that familiarity can make a great contribution when the items of a pair are unitized. However, it remains unclear whether the old/new effects are sensitive to the nature of different semantic relations. The current ERP (event-related potentials) study aimed to address this, where picture pairs of thematic, taxonomic, and unrelated relations served as stimuli and participants were required to discriminate the pair type: intact, rearranged, “old + new”, or new. We confirmed both FN400 and LPC. Our findings, by comparing the occurrence and the amplitudes of these two components, implicate that the neural activity of associative recognition is sensitive to the semantic relation of stimuli and depends more on stimulus properties, that the familiarity of a single item can impact the neural activities in discriminating associative pairs, and that the interval length between encoding and test modulates the familiarity of unrelated pairs. In addition, the dissociation between FN400 and LPC reinforces the dual-process models.
Effects of the Ground Reinforcement on the Dynamic Behaviors of Compacted Loess Embankment with Ballasted Track
Authors: Wei Xinsheng , Wang Rui , Hu Zhiping , Wen Xin
Published: March 2023

An embankment is needed to satisfy the requirements for the longitudinal slope of railway lines, and ground reinforcement is also generally required in loess regions. The present study attempted to understand the effects of different ground reinforcement measures on the dynamic characteristics of a track–embankment–ground system. To this end, the critical speeds and the distributions of dynamic stress and environmental vibration were analyzed using a 2.5D finite element method. Three typical ground reinforcements, including dynamic compaction ground (DCG), soil–cement compacted pile composite ground (SCG) and CFG pile composite ground (CFGG), were used. The results indicate that the train speed (critical speed I) at which the maximum vertical displacement of the track occurs is universally higher than that (critical speed II) at which the wave propagation phenomenon occurs. The lower boundary limit of the peak region in the dispersion relationship can be selected as the reference value of critical speed II. Moreover, the values of critical speed I obtained using the DCG, SCG and CFGG models were around 92, 105 and 127 m/s, respectively. For critical speed II, the values were 75, 80 and 115 m/s. Once the train speed exceeded critical speed II, the vibration was confined to the embankment in the CFGG model, as evidenced by the isolation of the wave propagation from the embankment to the ground as well as the increasing dynamic stress in the embankment. After reinforcement, the dynamic stress, dynamic influence depth (DID), critical speed and resonant frequency increased. Additionally, the DID stayed around the 3–6 m range at all speeds.
Stress–Strain Model of High-Strength Concrete Confined by Lateral Ties under Axial Compression
Authors: Wang Lei , Huang Xiaokun , Xu Fuquan
Published: March 2023

High-strength concrete can effectively reduce the cross-sectional size, increase space usage, and cut material costs. To analyze the mechanical properties of high-strength concrete vertical members, various confinement models have been proposed to define the ties-confined concrete stress–strain relationship. However, most existing models are divided into ascending and descending segments. These are continuous but not derivable at the peak point, which does not facilitate numerical calculations. Moreover, these models have a large number of parameters that are mostly obtained based on the fitting of experimental data, which may also lead to the limited applicability of the models. In this study, existing confinement models for high-strength concrete under axial compression are reviewed, and the differences between the models are discussed. Based on the results of normal triaxial experiments on high-strength concrete and the test data from other studies on ties-confined concrete columns, the effective confinement coefficient and empirical formula of ties strain at the peak stress of confined concrete are proposed. A confinement model is proposed based on the continuous derivable function, and it is validated based on the available experimental data. Results show that the proposed model can reflect the stress–strain relationship of the test specimens more simply while keeping the basic accuracy with other models.
Replacing Lime with Rice Husk Ash to Reduce Carbon Footprint of Bituminous Mixtures
Authors: Mistry Raja , Roy Tapash Kumar , Aldagari Sand , Fini Elham H.
Published: March 2023

There have been several emphasized pathways toward a reduction in carbon footprint in the built environment such as recycling, technologies with lower energy consumption, and alternative materials. Among alternative materials, bio-based materials and nature inspired solutions have been well-received. This study examines the merits of using rice husk ash as a replacement for lime; lime has a high carbon footprint mainly associated with the decomposition of calcium carbonate to calcium oxide to form lime. Lime is commonly used in bituminous composites for roadway construction to mitigate their susceptibility to moisture damage. Replacing lime with a low-carbon alternative could allow a reduction in CO2 equivalent of bituminous composites. This paper studies the merits of using rice husk ash (RHA) as a substitute for conventional hydrated lime (HL) in bituminous composites. It should be noted that rice industries burn rice husks in a boiler as fuel, generating a substantial volume of RHA. The disposal of this ash has major environmental impacts associated with the contamination of air and water. Here, we study physical and chemical characteristics of both HL and RHA for use in bitumen mixtures. This was followed by examining the extent of dispersion of each filler in bitumen via optical microscopy to ensure their uniform dispersion. The properties of the mixtures were further studied using the Marshall mix design method. It was found that a 25.67% increase in Marshall stability and a 5.95% decrease in optimum binder content were achieved when HL was replaced by RHA at 4% filler concentration. In addition, mixtures containing RHA exhibited higher resistance to cracking and permanent deformation compared to mixtures containing HL. Additionally, 4% RHA in the mix showed stripping resistance similar to the conventional mix with HL. The mixture with 4% RHA had a lower carbon footprint with enhanced economic and environmental impacts compared to the conventional mix with HL. The study results provide insights pertaining to the merits of bio-based materials to reduce the carbon footprint of pavements.
Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer
Authors: Saba Nabil F. , Pamulapati Saagar , Patel Bhamini , Mody Mayur , Strojan Primož , Takes Robert , Mäkitie Antti A. , Cohen Oded , Pace-Asciak Pia , Vermorken Jan B. , Bradford Carol , Forastiere Arlene , Teng Yong , Wieland Andreas , Ferlito Alfio
Published: March 2023

Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer.
Targeting HDAC2-Mediated Immune Regulation to Overcome Therapeutic Resistance in Mutant Colorectal Cancer
Authors: Conte Mariarosaria , Di Mauro Annabella , Capasso Lucia , Montella Liliana , De Simone Mariacarla , Nebbioso Angela , Altucci Lucia
Published: March 2023

A large body of clinical and experimental evidence indicates that colorectal cancer is one of the most common multifactorial diseases. Although some useful prognostic biomarkers for clinical therapy have already been identified, it is still difficult to characterize a therapeutic signature that is able to define the most appropriate treatment. Gene expression levels of the epigenetic regulator histone deacetylase 2 (HDAC2) are deregulated in colorectal cancer, and this deregulation is tightly associated with immune dysfunction. By interrogating bioinformatic databases, we identified patients who presented simultaneous alterations in HDAC2, class II major histocompatibility complex transactivator (CIITA), and beta-2 microglobulin (B2M) genes based on mutation levels, structural variants, and RNA expression levels. We found that B2M plays an important role in these alterations and that mutations in this gene are potentially oncogenic. The dysregulated mRNA expression levels of HDAC2 were reported in about 5% of the profiled patients, while other specific alterations were described for CIITA. By analyzing immune infiltrates, we then identified correlations among these three genes in colorectal cancer patients and differential infiltration levels of genetic variants, suggesting that HDAC2 may have an indirect immune-related role in specific subgroups of immune infiltrates. Using this approach to carry out extensive immunological signature studies could provide further clinical information that is relevant to more resistant forms of colorectal cancer.
Radiomics and Delta-Radiomics Signatures to Predict Response and Survival in Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors
Authors: Cousin François , Louis Thomas , Dheur Sophie , Aboubakar Frank , Ghaye Benoit , Occhipinti Mariaelena , Vos Wim , Bottari Fabio , Paulus Astrid , Sibille Anne , Vaillant Frédérique , Duysinx Bernard , Guiot Julien , Hustinx Roland
Published: March 2023

The aim of our study was to determine the potential role of CT-based radiomics in predicting treatment response and survival in patients with advanced NSCLC treated with immune checkpoint inhibitors. We retrospectively included 188 patients with NSCLC treated with PD-1/PD-L1 inhibitors from two independent centers. Radiomics analysis was performed on pre-treatment contrast-enhanced CT. A delta-radiomics analysis was also conducted on a subset of 160 patients who underwent a follow-up contrast-enhanced CT after 2 to 4 treatment cycles. Linear and random forest (RF) models were tested to predict response at 6 months and overall survival. Models based on clinical parameters only and combined clinical and radiomics models were also tested and compared to the radiomics and delta-radiomics models. The RF delta-radiomics model showed the best performance for response prediction with an AUC of 0.8 (95% CI: 0.65−0.95) on the external test dataset. The Cox regression delta-radiomics model was the most accurate at predicting survival with a concordance index of 0.68 (95% CI: 0.56−0.80) (p = 0.02). The baseline CT radiomics signatures did not show any significant results for treatment response prediction or survival. In conclusion, our results demonstrated the ability of a CT-based delta-radiomics signature to identify early on patients with NSCLC who were more likely to benefit from immunotherapy.
Simultaneous Ultra-Sensitive Detection of Structural and Single Nucleotide Variants Using Multiplex Droplet Digital PCR in Liquid Biopsies from Children with Medulloblastoma
Authors: Arthur Cecilia , Jylhä Cecilia , de Ståhl Teresita Díaz , Shamikh Alia , Sandgren Johanna , Rosenquist Richard , Nordenskjöld Magnus , Harila Arja , Barbany Gisela , Sandvik Ulrika , Tham Emma
Published: March 2023

Medulloblastoma is a malignant embryonal tumor of the central nervous system (CNS) that mainly affects infants and children. Prognosis is highly variable, and molecular biomarkers for measurable residual disease (MRD) detection are lacking. Analysis of cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) using broad genomic approaches, such as low-coverage whole-genome sequencing, has shown promising prognostic value. However, more sensitive methods are needed for MRD analysis. Here, we show the technical feasibility of capturing medulloblastoma-associated structural variants and point mutations simultaneously in cfDNA using multiplexed droplet digital PCR (ddPCR). Assay sensitivity was assessed with a dilution series of tumor in normal genomic DNA, and the limit of detection was below 100 pg of input DNA for all assays. False positive rates were zero for structural variant assays. Liquid biopsies (CSF and plasma, n = 47) were analyzed from 12 children with medulloblastoma, all with negative CSF cytology. MRD was detected in 75% (9/12) of patients overall. In CSF samples taken before or within 21 days of surgery, MRD was detected in 88% (7/8) of patients with localized disease and in one patient with the metastasized disease. Our results suggest that this approach could expand the utility of ddPCR and complement broader analyses of cfDNA for MRD detection.
Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact
Authors: Vardas Vasileios , Tolios Anastasios , Christopoulou Athina , Georgoulias Vassilis , Xagara Anastasia , Koinis Filippos , Kotsakis Athanasios , Kallergi Galatea
Published: March 2023

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU+VIM+CK+ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1+CD45−CK+ and CTLA-4+CD45−CK+ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU+VIM+CK+ and PD-L1+CD45−CK+ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype.
Prognostic Relevance and In Vitro Targeting of Concomitant PTEN and p16 Deficiency in Chordomas
Authors: Seeling Carolin , Mosca Elena , Mantel Eva , Möller Peter , Barth Thomas F. E. , Mellert Kevin
Published: March 2023

Chordomas are rare bone tumors arising along the spine. Due to high resistance towards chemotherapy, surgical resection—often followed by radiation therapy—is currently the gold standard of treatment. So far, targeted systemic therapies have not been approved. The most frequent molecular alterations include the loss of PTEN and CDKN2A (encoding p16), being associated with poor prognoses in chordoma patients. Specific inhibitors of the PI3K/AKT/mTOR pathway as well as CDK4/6 have shown antitumor activity in preclinical studies and have recently been under investigation in phase II clinical trials; however, the clinical impacts and therapeutic consequences of concomitant PTEN and p16 deficiency have not yet been investigated in chordomas. In a cohort of 43 chordoma patients, 16% of the cases were immunohistochemically negative for both markers. The simultaneous loss of PTEN and p16 was associated with a higher KI-67 index, a tendency to metastasize, and significantly shorter overall survival. Additionally, 30% of chordoma cell lines (n = 19) were PTEN-/p16-negative. Treating these chordoma cells with palbociclib (CDK4/6 inhibitor), rapamycin (mTOR inhibitor) or the pan-PI3K inhibitor buparlisib significantly reduced cell viability. Synergistic effects were observed when combining palbociclib with rapamycin. In conclusion, we show that patients with PTEN-/p16-negative chordomas have poor prognoses and provide strong preclinical evidence that these patients might benefit from a Palbociclib/rapamycin combination treatment.
Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience
Authors: Trabal Adriana , Gibson Amber , He Jiasen , McCall David , Roth Michael , Nuñez Cesar , Garcia Miriam , Buzbee Meredith , Toepfer Laurie , Bidikian Aram , Daver Naval , Kadia Tapan , Short Nicholas J. , Issa Ghayas C. , Ravandi Farhad , DiNardo Courtney D. , Montalban Bravo Guillermo , Garces Sofia , Marcogliese Andrea , Paek Hana , Dreyer Zoann , Brackett Julienne , Redell Michele , Yi Joanna , Garcia-Manero Guillermo , Konopleva Marina , Stevens Alexandra , Cuglievan Branko
Published: March 2023

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6–21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.
Systemic Anticoagulation and Inpatient Outcomes of Pancreatic Cancer: Real-World Evidence from U.S. Nationwide Inpatient Sample
Authors: Huang Yen-Min , Shih Hsuan-Jen , Chen Yi-Chan , Hsieh Tsan-Yu , Ou Che-Wei , Su Po-Hsu , Chen Shih-Ming , Zheng Yun-Cong , Hsu Li-Sung
Published: March 2023

Background: Pancreatic cancer can induce a hypercoagulable state which may lead to clinically apparent thrombosis. However, the effect of anticoagulants remains ambiguous. This study aimed to investigate the potential effect of long-term systemic anticoagulant usage on hospitalization outcomes of patients with pancreatic cancer. Methods: This retrospective study extracted all data from the U.S. Nationwide Inpatient Sample (NIS) database from 2005 to 2018. We included hospitalized adults ≥18 years old with a pancreatic cancer diagnosis identified by International Classification of Diseases ninth revision (ICD-9) and tenth revision (ICD-10) codes. We utilized diagnostic codes ICD9 V58.61 and ICD10 Z79.01, i.e., ‘long-term use of anticoagulant’, to identify individuals who were on a long-term systemic anticoagulant. The study cohort were then further grouped as being with or without long-term systemic use of an anticoagulant. Propensity score matching was performed to balance the characteristics of the two groups. The risks of life-threatening events, e.g., acute myocardial infarction (AMI), acute heart failure (AHF), sepsis, shock, and acute kidney injury (AKI), in-hospital death, and prolonged length of stay (LOS) in the hospital were compared between the groups by univariable and multivariable logistic regression analyses. Results: The study population consisted of 242,903 hospitalized patients with pancreas cancer, 6.5% (n = 15,719) of whom were on long-term systemic anticoagulants. A multivariable regression analysis showed that long-term systemic anticoagulant use was independently associated with lower odds of sepsis (aOR: 0.81, 95% CI: 0.76–0.85), shock (aOR: 0.59, 95% CI: 0.51–0.68), AKI (aOR: 0.86, 95% CI: 0.81–0.91), in-hospital mortality (aOR: 0.65, 95% CI: 0.60–0.70), and prolonged LOS (aOR: 0.84, 95% CI: 0.80–0.89). Conclusions: Long-term systemic anticoagulant use is associated with better clinical outcomes in terms of decreased risks of some life-threatening events, in-hospital death, and prolonged LOS among hospitalized patients with pancreatic cancer in the U.S.
High Throughput Fluorescence-Based In Vitro Experimental Platform for the Identification of Effective Therapies to Overcome Tumour Microenvironment-Mediated Drug Resistance in AML
Authors: Arroyo-Berdugo Yoana , Sendino Maria , Greaves David , Nojszewska Natalia , Idilli Orest , So Chi Wai , Di Silvio Lucy , Quartey-Papafio Ruby , Farzaneh Farzin , Rodriguez Jose Antonio , Calle Yolanda
Published: March 2023

The interactions between Acute Myeloid Leukaemia (AML) leukemic stem cells and the bone marrow (BM) microenvironment play a critical role during AML progression and resistance to drug treatments. Therefore, the identification of novel therapies requires drug-screening methods using in vitro co-culture models that closely recreate the cytoprotective BM setting. We have developed a new fluorescence-based in vitro co-culture system scalable to high throughput for measuring the concomitant effect of drugs on AML cells and the cytoprotective BM microenvironment. eGFP-expressing AML cells are co-cultured in direct contact with mCherry-expressing BM stromal cells for the accurate assessment of proliferation, viability, and signaling in both cell types. This model identified several efficacious compounds that overcome BM stroma-mediated drug resistance against daunorubicin, including the chromosome region maintenance 1 (CRM1/XPO1) inhibitor KPT-330. In silico analysis of genes co-expressed with CRM1, combined with in vitro experiments using our new methodology, also indicates that the combination of KPT-330 with the AURKA pharmacological inhibitor alisertib circumvents the cytoprotection of AML cells mediated by the BM stroma. This new experimental model and analysis provide a more precise screening method for developing improved therapeutics targeting AML cells within the cytoprotective BM microenvironment.
Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas
Authors: Pilmis Benoît , Kherabi Yousra , Huriez Pauline , Zahar Jean-Ralph , Mokart Djamel
Published: March 2023

Background: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Objectives: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. Sources: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. Content: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton’s tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. Implications: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations.
From Exosome Biogenesis to Absorption: Key Takeaways for Cancer Research
Authors: Lau Nicolas Cheuk Hang , Yam Judy Wai Ping
Published: March 2023

Exosomes are mediators of intercellular communication in normal physiology and diseases. While many studies have emerged on the function of exosomal cargoes, questions remain regarding the origin of these exosomes. The packaging and secretion of exosomes in different contexts modify exosomal composition, which may in turn impact delivery, uptake and cargo function in recipient cells. A mechanistic understanding of exosome biology is therefore crucial to investigating exosomal function in complex biological systems and to the development of novel therapeutic approaches. Here, we outline the steps in exosome biogenesis, including endosome formation, MVB formation, cargo sorting and extracellular release, as well as exosome absorption, including targeting, interaction with recipient cells and the fate of internalized exosomes. In addition to providing a framework of exosome dynamics, we summarize current evidence on major pathways and regulatory mechanisms. We also highlight the various mechanisms observed in cancer and point out directions to improve study design in exosome biology. Further research is needed to illuminate the relationship between exosome biogenesis and function, which will aid the development of translational applications.
Outcomes of Rural Men with Breast Cancer: A Multicenter Population Based Retrospective Cohort Study
Authors: Fisher Lucas A. B. , Ahmed Osama , Chalchal Haji Ibraheem , Deobald Ray , El-Gayed Ali , Graham Peter , Groot Gary , Haider Kamal , Iqbal Nayyer , Johnson Kate , Le Duc , Mahmood Shazia , Manna Mita , Meiers Pamela , Pauls Mehrnoosh , Salim Muhammad , Sami Amer , Wright Philip , Younis Moftah , Ahmed Shahid
Published: March 2023

Background: Breast cancer is rare in men. This population-based study aimed to determine outcomes of male breast cancer in relation to residence and other variables. Methods: In this retrospective cohort study, men diagnosed with breast cancer in Saskatchewan during 2000–2019 were evaluated. Cox proportional multivariable regression analyses were performed to determine the correlation between survival and clinicopathological and contextual factors. Results: One hundred-eight eligible patients with a median age of 69 years were identified. Of them, 16% had WHO performance status ≥ 2 and 61% were rural residents. The stage at diagnosis was as follows: stage 0, 7%; I, 31%; II, 42%; III, 11%; IV, 8%. Ninety-eight percent had hormone receptor-positive breast cancer. The median disease-free survival of urban patients was 97 (95% CI: 50–143) vs. 64 (46–82) months of rural patients (p = 0.29). The median OS of urban patients was 127 (94–159) vs. 93 (32–153) months for rural patients (p = 0.27). On multivariable analysis, performance status ≥ 2, hazard ratio (HR) 2.82 (1.14–6.94), lack of adjuvant systemic therapy, HR 2.47 (1.03–5.92), and node-positive disease, HR 2.32 (1.22–4.40) were significantly correlated with inferior disease-free survival in early-stage invasive breast cancer. Whereas stage IV disease, HR 7.8 (3.1–19.5), performance status ≥ 2, HR 3.25 (1.57–6.71), and age ≥ 65 years, HR 2.37 (1.13–5.0) were correlated with inferior overall survival in all stages. Conclusions: Although residence was not significantly correlated with outcomes, rural men had numerically inferior survival. Poor performance status, node-positive disease, and lack of adjuvant systemic therapy were correlated with inferior disease-free survival.
Photocatalytic Performances and Antifouling Efficacies of Alternative Marine Coatings Derived from Polymer/Metal Oxides (WO3@TiO2)-Based Composites
Authors: Thongjamroon Sunida , Wootthikanokkhan Jatuphorn , Poolthong Nuchthana
Published: March 2023

This work concerns development of alternative antifouling paints for marine applications using composite metal oxides derived from TiO2 and WO3. Composite metal oxides with a variety of tungsten content were prepared via a sol–gel process using titanium isopropoxide and sodium tungstate dihydrate as the precursors. The crystalline phase, bandgap energy, morphology, surface structure, and electronic states of the synthesized products were then characterized and confirmed by XPS, XRD, UV/Vis spectroscopy, SEM-EDX, and TEM techniques. Photocatalytic performance polymer film loaded with composite metal oxides containing 10% by mole of WO3 (10%WO3@TiO2) was confirmed both under UV irradiation and in the dark. The results are discussed in light of oxygen vacancies and the presence of heterojunctions between the TiO2 and WO3 domains in the composites, which eventually lead to suppression of charges recombination. Finally, antifouling and the antimicrobial efficacy of the polymer film loaded with composite metal oxide particles (10%WO3@TiO2) were evaluated under static marine immersion conditions using Zobell Marine agar. After 30 days, the percentage fouling coverage (16.35%), colonies number (CFU value 12 × 103), and percentage reduction of colonies (92.94%), were obtained, which significantly outperformed those of the control (the bare substrate).
Role of Basic Fibroblast Growth Factor in Cancer: Biological Activity, Targeted Therapies, and Prognostic Value
Authors: Ardizzone Alessio , Bova Valentina , Casili Giovanna , Repici Alberto , Lanza Marika , Giuffrida Raffaella , Colarossi Cristina , Mare Marzia , Cuzzocrea Salvatore , Esposito Emanuela , Paterniti Irene
Published: March 2023

Cancer is the leading cause of death worldwide; thus, it is necessary to find successful strategies. Several growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF, FGF2), and transforming growth factor beta (TGF-β), are involved in the main processes that fuel tumor growth, i.e., cell proliferation, angiogenesis, and metastasis, by activating important signaling pathways, including PLC-γ/PI3/Ca2+ signaling, leading to PKC activation. Here, we focused on bFGF, which, when secreted by tumor cells, mediates several signal transductions and plays an influential role in tumor cells and in the development of chemoresistance. The biological mechanism of bFGF is shown by its interaction with its four receptor subtypes: fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3, and FGFR4. The bFGF–FGFR interaction stimulates tumor cell proliferation and invasion, resulting in an upregulation of pro-inflammatory and anti-apoptotic tumor cell proteins. Considering the involvement of the bFGF/FGFR axis in oncogenesis, preclinical and clinical studies have been conducted to develop new therapeutic strategies, alone and/or in combination, aimed at intervening on the bFGF/FGFR axis. Therefore, this review aimed to comprehensively examine the biological mechanisms underlying bFGF in the tumor microenvironment, the different anticancer therapies currently available that target the FGFRs, and the prognostic value of bFGF.
Targeted Demethylation of the TGFβ1 mRNA Promotes Myoblast Proliferation via Activating the SMAD2 Signaling Pathway
Authors: Deng Kaiping , Liu Zhipeng , Li Xiaodan , Zhang Zhen , Fan Yixuan , Huang Qunhao , Zhang Yanli , Wang Feng
Published: March 2023

Recent evidence suggested that N6-methyladenosine (m6A) methylation can determine m6A-modified mRNA fate and play an important role in skeletal muscle development. It was well known that transforming growth factor beta 1 (TGFβ1) is involved in a variety of cellular processes, such as proliferation, differentiation, and apoptosis. However, little is known about the m6A-mediated TGFβ1 regulation in myogenesis. Here, we observed an increase in endogenous TGFβ1 expression and activity during myotube differentiation. However, the knockdown of TGFβ1 inhibits the proliferation and induces cell apoptosis of myoblast. Moreover, we found that m6A in 5′-untranslated regions (5′UTR) of TGFβ1 promote its decay and inhibit its expression, leading to the blockage of the TGFβ1/SMAD2 signaling pathway. Furthermore, the targeted specific demethylation of TGFβ1 m6A using dCas13b-FTO significantly increased the TGFβ1-mediated activity of the SMAD2 signaling pathway, promoting myoblast proliferation. These findings suggest that TGFβ1 is an essential regulator of myoblast growth that is negatively regulated by m6A. Overall, these results highlight the critical role of m6A-mediated post-transcriptional regulation in myogenesis.
Unraveling the Role of Peroxisome Proliferator-Activated Receptor β/Δ (PPAR β/Δ) in Angiogenesis Associated with Multiple Myeloma
Authors: Leone Patrizia , Solimando Antonio Giovanni , Prete Marcella , Malerba Eleonora , Susca Nicola , Derakhshani Afshin , Ditonno Paolo , Terragna Carolina , Cavo Michele , Silvestris Nicola , Racanelli Vito
Published: March 2023

Growing evidence suggests a role for peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR β/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR β/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR β/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR β/δ. We also demonstrated that PPAR β/δ was a strong stimulator of angiogenesis in vitro and that PPAR β/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR β/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR β/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.
Microglia Mediated Neuroinflammation in Parkinson’s Disease
Authors: Isik Sevim , Yeman Kiyak Bercem , Akbayir Rumeysa , Seyhali Rama , Arpaci Tahire
Published: March 2023

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder seen, especially in the elderly. Tremor, shaking, movement problems, and difficulty with balance and coordination are among the hallmarks, and dopaminergic neuronal loss in substantia nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein are the pathological characterizations. Neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. It is a complex network of interactions comprising immune and non-immune cells in addition to mediators of the immune response. Microglia, the resident macrophages in the CNS, take on the leading role in regulating neuroinflammation and maintaining homeostasis. Under normal physiological conditions, they exist as “homeostatic” but upon pathological stimuli, they switch to the “reactive state”. Pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes are used to classify microglial activity with each phenotype having its own markers and released mediators. When M1 microglia are persistent, they will contribute to various inflammatory diseases, including neurodegenerative diseases, such as PD. In this review, we focus on the role of microglia mediated neuroinflammation in PD and also signaling pathways, receptors, and mediators involved in the process, presenting the studies that associate microglia-mediated inflammation with PD. A better understanding of this complex network and interactions is important in seeking new therapies for PD and possibly other neurodegenerative diseases.