tbuckley/cabot-search huggingface dataset:
Reduced Lymphatic Reserve in Heart Failure With Preserved Ejection Fraction
Authors: Giacomo Rossitto, Sheon Mary, Christine McAllister, Karla Bianca Neves, Laura Haddow, John Paul Rocchiccioli, Ninian Nicholas Lang, Clare Louise Murphy, Rhian Merry Touyz, Mark Colquhoun Petrie, Christian Delles
Journal: Journal of the American College of Cardiology (2020)

Microvascular dysfunction plays an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link between systemic microvasculature and congestion, a central feature of the syndrome, has yet been investigated. This study aimed to investigate capillary–interstitium fluid exchange in HFpEF, including lymphatic drainage and the potential osmotic forces exerted by any hypertonic tissue Na+ excess. Patients with HFpEF and healthy control subjects of similar age and sex distributions (n = 16 per group) underwent: 1) a skin biopsy for vascular immunohistochemistry, gene expression, and chemical (water, Na+, and K+) analyses; and 2) venous occlusion plethysmography to assess peripheral microvascular filtration coefficient (measuring capillary fluid extravasation) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation). Skin biopsies in patients with HFpEF showed rarefaction of small blood and lymphatic vessels (p = 0.003 and p = 0.012, respectively); residual skin lymphatics showed a larger diameter (p = 0.007) and lower expression of lymphatic differentiation and function markers (LYVE-1 [lymphatic vessel endothelial hyaluronan receptor 1]: p < 0.05; PROX-1 [prospero homeobox protein 1]: p < 0.001) compared with control subjects. In patients with HFpEF, microvascular filtration coefficient was lower (calf: 3.30 [interquartile range (IQR): 2.33 to 3.88] l × 100 ml of tissue–1 × min–1 × mm Hg–1 vs. 4.66 [IQR: 3.70 to 6.15] μl × 100 ml of tissue–1 × min–1 × mm Hg–1; p < 0.01; forearm: 5.16 [IQR: 3.86 to 5.43] l × 100 ml of tissue–1 × min–1 × mm Hg–1 vs. 5.66 [IQR: 4.69 to 8.38] μl × 100 ml of tissue–1 × min–1 × mm Hg–1; p > 0.05), in keeping with blood vascular rarefaction and the lack of any observed hypertonic skin Na+ excess, but the lymphatic drainage was impaired (isovolumetric pressure in patients with HFpEF vs. control subjects: calf 16 ± 4 mm Hg vs. 22 ± 4 mm Hg; p < 0.005; forearm 17 ± 4 mm Hg vs. 25 ± 5 mm Hg; p < 0.001). Peripheral lymphatic vessels in patients with HFpEF exhibit structural and molecular alterations and cannot effectively compensate for fluid extravasation and interstitial accumulation by commensurate drainage. Reduced lymphatic reserve may represent a novel therapeutic target.
EPCO-19. INTEGRATED ANALYSIS OF INTRA-TUMORAL HETEROGENEITY IN GLIOBLASTOMAS THROUGH SINGLE NUCLEI ATAC-SEQ AND RNA-SEQ
Authors: Ramya Raviram, Anugraha Raman, Sebastian Preissl, Jianfang Ning, Shaoping Wu, Kinsey Deynze, Clark Chen, Bing Ren
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma, the most common form of primary brain cancer in adult, consists of an ecosystem of cancer cells characterized by cell-to-cell variations in genotypes and phenotypes. This intra-tumoral heterogeneity forms the substrate for cancer evolution, which in turn fuels therapeutic failure and resistance. To better define this heterogeneity, we profiled clinical glioblastoma specimens using single nuclei assays for Transposase-Accessible Chromatin with sequencing (snATAC-seq), RNA-Seq (snRNA-Seq), Paired snATAC/snRNA-seq, and whole genome-seq (WGS). We found that snATAC-Seq detected focal amplifications (~40kb-2MB) of genomic regions, revealing magnitudes of intra-tumoral heterogeneity previously unappreciated. snATAC-seq and WGS provided high resolution chromatin-state maps of extrachromosomal DNA (ecDNA), while Paired-seq delineated gene expression patterns associated with these chromatin-states. sn-RNAseq confirmed distinct cell states previously defined by others, including oligodendrocyte progenitor cell (OPC), neural progenitor cell (NPC), astrocyte, and mesenchymal -like glioblastomas. Analysis of snATAC-seq profiles in this context revealed shared dependency of these cell states on the Nuclear Factor 1 complex (NFIA and NFIB). Our results demonstrate the utility of cross-platform integration of single cell genomic technologies and suggest that, despite the overwhelming genotypic and phenotypic heterogeneity, shared vulnerability of predominant glioblastoma cell states can be identified.
Targeting cystic fibrosis inflammation in the age of CFTR modulators: focus on macrophages
Authors: Jonathan L. Gillan, Donald J. Davidson, Robert D. Gray
Journal: European Respiratory Journal (2020)

Cystic fibrosis (CF) is a life-shortening, multi-organ, autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most prominent clinical manifestation in CF is the development of progressive lung disease characterised by an intense, chronic inflammatory airway response that culminates in respiratory failure and, ultimately, death. In recent years, a new class of therapeutics that have the potential to correct the underlying defect in CF, known as CFTR modulators, have revolutionised the field. Despite the exciting success of these drugs, their impact on airway inflammation, and its long-term consequences, remains undetermined. In addition, studies querying the absolute requirement for infection as a driver of CF inflammation have challenged the traditional consensus on CF pathogenesis, and also emphasise the need to prioritise complementary anti-inflammatory treatments in CF. Macrophages, often overlooked in CF research despite their integral role in other chronic inflammatory pathologies, have increasingly become recognised as key players in the initiation, perpetuation and resolution of CF lung inflammation, perhaps as a direct result of CFTR dysfunction. These findings suggest that macrophages may be an important target for novel anti-inflammatory interventional strategies to effectively treat CF lung function decline. This review will consider evidence for the efficacy of anti-inflammatory drugs in the treatment of CF, the potential role of macrophages, and the significance of targeting these pathways at a time when rectifying the basic defect in CF, through use of novel CFTR modulator therapies, is becoming increasingly viable.
Proteasome Inhibition Overcomes ALK-TKI Resistance in <i>ALK</i>-Rearranged/<i>TP53</i>-Mutant NSCLC via Noxa Expression
Authors: Azusa Tanimoto, Shingo Matsumoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Akihiro Nishiyama, Kiyotaka Yoh, Takaya Ikeda, Naoki Furuya, Kazumi Nishino, Yuichiro Ohe, Koichi Goto, Seiji Yano
Journal: Clinical Cancer Research (2020)

In ALK-rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms.We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs.In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); P = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. ALK-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with nonfunctional p53.These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.
QOL-12. CLINICAL SIGNIFICANCE OF RADIATION-INDUCED CEREBROVASULAR DISEASE IN CHILDHOOD BRAIN TUMOR SURVIVORS
Authors: Tiina Remes, Maria Suo-Palosaari, Niina Ritari, Riina Puosi, Päivi Koskenkorva, Anna Sutela, Sanna-Maria Toiviainen-Salo, Pekka Arikoski, Mikko Arola, Emma Hovén, Päivi Lähteenmäki, Tuula Lönnqvist, Pekka Riikonen, Kirsti Sirkiä, Heikki Rantala, Marika Harila, Marja Ojaniemi, Arja Harila-Saari
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Childhood brain tumor survivors have a high risk of early cerebrovascular disease, but currently its clinical significance is unknown. METHODS In a nation-wide study, we investigated 68 childhood brain tumor survivors treated with radiotherapy by using magnetic resonance imaging (MRI) and neuropsychological examination after median follow-up time of 20.6 years (range 5.0 – 33.1 years) since radiotherapy. Associations between imaging markers of cerebrovascular disease, white matter hyperintensities and the results of neuropsychological examination were investigated. RESULTS Majority (65 %) of the survivors was diagnosed with cerebrovascular disease at median age of 27.1 years (range16.2 – 43.8 years). The presence of imaging markers of cerebrovascular disease or white matter hyperintensities was associated with poorer performance in verbal (VIQ) and performance (PIQ) intelligent quotient, working and semantic memory, executive functions, visuospatial ability, and immediate and general auditive memory (P &amp;lt; 0.05). Survivors with microbleeds performed worse in PIQ, processing speed, executive functions, and visuospatial ability (P &amp;lt;0.05). Lacunar infarcts were associated with difficulties in visuospatial ability (P &amp;lt;0.05). Survivors with white matter hyperintensities in MRI had higher impairment of working and semantic memory, visuospatial ability, and general auditive memory (P &amp;lt; 0.05). Cerebrovascular and small-vessel disease burden associated with poorer neurocognitive performance. CONCLUSION The imaging markers of cerebrovascular disease and white matter hyperintensities were related to poorer cognitive performance in radiation-treated long-term survivors of childhood brain tumor. Longitudinal studies are urgently needed to investigate how cerebrovascular disease and related cognitive impairment progress in the survivors.
31. Dystrophin Expression in Muscles of Duchenne Muscular Dystrophy Patients Following High_Density Injections of Normal Myogenic Cells
Authors: Jacques P. Tremblay, Daniel Skuk, Marlyne Goulet, Brigitte Roy, Pierre Chapdelaine, Raynald Roy, Francine Dugré, Jean-Pierre Bouchard, Jean-Guy Lachance, Michel Sylvain, Louise Deschênes, Hélène Senay
Journal: Molecular Therapy (2006)
ATRT-16. MODELLING ATRT THROUGH SWI/SNF COMPLEX DEFICIENCY IN GENETICALLY-ENGINEERED MOUSE MODELS
Authors: Andrew Bondoc, Brian Golbourn, Christian Smith, Annie Huang, James Rutka
Journal: Neuro-Oncology (2020)

Abstract Atypical Teratoid/Rhabdoid Tumours (ATRT) are highly malignant neoplasms arising primarily in the CNS of children. They are defined by loss of function mutations in smarcb1, a gene serving a vital role in neurogenesis and differentiation. In order to recapitulate ATRT in the mouse, we used a Cre-Lox recombination system to conditionally knockout smarcb1 in specific cell compartments. Loss of smarcb1 in BLBP-expressing cells of the developing brain led to severe neurologic defects. Mice exhibited seizures, ataxia, and median 12-day survival. Histological analysis revealed severe thinning of the cerebral cortex and cerebellum. Temporally-targeted smarcb1 loss in BLBP/Nestin-expressing embryonic compartments did not result in tumour formation. Similarly, BLBP-expressing, smarcb1-deficient neural stem/progenitor cells (NSC/NPCs) were isolated and allografted but did not form tumours. These cells demonstrated decreased proliferation, higher apoptosis, and upregulation of p53, CDKN1A, and CDKN2A. In contrast, ubiquitous smarcb1 loss at the earlier embryonic day 6.5 produced widespread tumorigenicity in the forebrain, hindbrain, skullbase, and spine; each with unique phenotypes, survival, and morphology. We employed a clinically-relevant Nanostring gene-panel screen to stratify tumours into genetically distinct subgroups. Our findings indicate that smarcb1 plays an important role in CNS development. Loss of smarcb1 in NSC/NPCs is lethal, and its developmental context influences cell fate. Targeted smarcb1 loss likely plays a tumorigenic role at an earlier developmental stage than previously determined, in a diverse array of primitive stem cells. These data support the generation of a murine ATRT model capable of producing distinct tumour entities that recapitulate the human disease.
Regorafenib-Associated Acute Pancreatitis Diagnosed on 18F-FDG PET/CT
Authors: Melvika Pereira, Anjali Prakash, Ameya D. Puranik, Nilendu Purandare, Sneha Shah, Archi Agrawal, Venkatesh Rangarajan
Journal: Clinical Nuclear Medicine (2020)

A 23-year-old man with metastatic osteosarcoma, with disease progression on conventional chemotherapy, was treated with regorafenib, a multikinase inhibitor. After treatment for 6 months with regorafenib, 18F-FDG PET/CT scan demonstrated FDG uptake in a necrotic space-occupying lesion involving tail of pancreas. After imaging, patient described symptoms of epigastric pain with elevated serum amylase and lipase levels, confirming diagnosis of regorafenib-induced pancreatitis, because patient had no other causative factors of pancreatitis. Physicians should be aware of rare and possibly clinically silent adverse effects of tyrosine kinase inhibitors, like acute pancreatitis, and recognize the 18F-FDG PET/CT findings to guide appropriate clinical management.
Contrast-Induced Acute Kidney Injury: Underappreciated or a New Marker of Cardiovascular Mortality?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Roxana Mehran, Somjot Brar, George Dangas
Journal: Journal of the American College of Cardiology (2010)
EXTH-77. ONC201 EXHIBITS PASSIVE DIFFUSION AND BROAD DISTRIBUTION IN THE CENTRAL NERVOUS SYSTEM
Authors: Sara Morrow, Varun Prabhu, Rohinton S Tarapore, Gina Theerman, Leah Lake, Ailan Guo, Martin Stogniew, Joshua Allen
Journal: Neuro-Oncology (2020)

Abstract Imipridone ONC201 is an investigational agent in phase II clinical trials for H3 K27M-mutant diffuse midline glioma with evidence of durable objective responses and clinical symptom improvements as a single agent. The systemic pharmacokinetics of ONC201 and its ability to achieve target concentrations in supratentorial glioblastoma have been demonstrated in clinical trials; however, its clearance and distribution in midline structures and other areas of the central nervous system (CNS) haven’t been evaluated. A quantitative whole-body autoradiography study was conducted in Long-Evans rats with a single dose of [14C]-ONC201. [14C]-ONC201-related material was rapidly distributed throughout the body, with concentrations peaking at 1h for most tissues. The endocrine, metabolic/excretory, ocular and gastrointestinal tract tissues contained the highest distribution of [14C]-ONC201-derived radioactivity. Importantly, [14C]-ONC201 material was distributed evenly across brain substructures, including the meninges and midline structures of the brain; all tissues had a half-life of 1.4–7.9h, with the exception of the meninges (2397.3h). Given the uniform distribution throughout the CNS, we evaluated the permeability and efflux potential of ONC201 in bidirectional transport assays using human Caco-2 cell monolayers. ONC201 displayed high permeability in the apical to basolateral direction with apparent permeability values of 23–31×10–6 cm/s at 7–700μM. In the basolateral to apical direction, apparent permeability values were 11–24 × 10–6 cm/s. The efflux ratio values were 0.46–0.79 for ONC201, suggesting that ONC201 is not a substrate of efflux transporters. However, ONC201 exerted inhibitory potential on MDR1- (90.6%) and BCRP-mediated (81.6%) transport at 200mM. In summary, ONC201 exhibits passive diffusion without being effluxed, which may enable its rapid and wide distribution throughout the CNS. This distribution profile suggests that the compound may achieve therapeutic concentrations throughout the CNS with oral administration and that investigation of additional CNS tumors will not be hindered by drug delivery to specific anatomic structures.
CTNI-48. NOVEL TREATMENT OF END STAGE RECURRENT GLIOBLASTOMA TREATED WITH A NONINVASIVE ONCOMAGNETIC DEVICE USING OSCILLATING MAGNETIC FIELDS – A NEW AND POWERFUL NONINVASIVE THERAPY
Authors: Santosh Helekar, Martyn Sharpe, Kumar Pichumani, Omkar Ijare, Lisa Nguyen, David Baskin
Journal: Neuro-Oncology (2020)

Abstract Noninvasive treatment with alternating electric fields at 200 kHz (Optune therapy) has been approved for recurrent and newly diagnosed glioblastoma (GBM). We have recently tested and confirmed in vitro, and in patient derived xenografted mouse models, the oncolytic potential of powerful newly developed device generating oscillating magnetic fields (OMF) using rotating magnets. This device is completely different and has different mechanisms of action than Optune therapy. We report the successful treatment of an endstage recurrent GBM in a 53-year-old man. The patient had undergone radical surgical excision and standard of care chemoradiotherapy, as well as experimental gene therapy for a left frontal tumor. 18 months after this treatment, there was recurrence with progressive enlargement and leptomeningeal spread, making the patient’s condition not suitable for further treatment. We conducted a 5-week treatment (followed by a pause of one week) consisting of daily exposure (on weekdays) with intermittent OMF. The patient tolerated the treatment well. At 4 weeks there was a progressive reduction of the contrast-enhanced tumor (CET) volume to less than 60% of the pre-treatment volume on magnetic resonance imaging scans. Caregiver report indicated mild subjective improvement in speech and cognitive function. The daily decrease in volume was correlated with the amount of daily treatment, with longer treatments showing an increase in shrinkage of the CET volume. After the treatment pause in the 6th week, there was an apparent increase in CET volume. However, a marked reduction in the choline peak and an increase in the lipid peak on a proton magnetic resonance spectrogram of the tumor at this timepoint documented that this represented necrotic tissue. We are excited about this new and powerful treatment for glioblastoma and will present the details of treatment and imaging studies during therapy.
NCOG-57. NEUROPSYCHOLOGICAL FUNCTION IN MENINGEAL MELANOCYTOMA: A CASE REPORT
Authors: Brandon Baughman, Kinsey Pebley, Manjari Pandey, Matthew Ballo, Madison Michael
Journal: Neuro-Oncology (2020)

Abstract Meningeal melanocytomas are rare tumors derived from leptomeningeal melanocytes. The aggressive subtype is considered a rare variant of malignant melanoma, carrying a poor prognosis. To date, the extant literature is void of any studies that have systematically assessed cognition or neuropsychological function in these patients. We present a case report of a 61-year-old male, right-hand dominant, Caucasian male with 16 years of formal education. He has an unremarkable medical history, and his presenting symptom were syncopal episodes. An extensive work-up revealed a complex pineal region mass. Serum markers (CEA, AFP, and beta HcG) were negative. The patient continued to deteriorate neurologically and underwent a gross total resection of the mass. At the time of resection, there was evidence of definitive leptomeningeal dissemination. Because of the leptomeningeal spread, he underwent whole brain radiation therapy with a boost to the cerebellum and surgical site. He subsequently required implantation of a ventriculoperitoneal shunt for treatment of communicating hydrocephalus. Prior to WBRT, the patient underwent comprehensive neuropsychological testing. According to the patient and his spouse, they estimated functioning at approximately 50% of normal cognition, with precipitous decline noted prior to resection of the lesion. At the time of the exam, he was dependent in essentially all instrumental activities of daily living. The examination identified a pattern consistent with diffuse subcortical involvement, characterized by impairments in cognitive processing speed, attention, working memory and executive function. Conversely, the patient demonstrated no amnesia or higher cortical dysfunction. Moreover, mood, anxiety, or other psychopathology failed to account for his cognitive impairment. In our review, this is the first case in the literature of a patient with meningeal melanocytoma (with leptomeningeal spread) who has been comprehensively assessed neuropsychologically. Conceptualizations, treatment, and prognosis will be discussed.
Functional roles of antisense enhancer RNA for promoting prostate cancer progression
Authors: Chun-Wu Pan, Simeng Wen, Lei Chen, Yulei Wei, Yuanjie Niu, Yu Zhao
Journal: Theranostics (2020)

Rationale: Enhancer RNA (eRNA) bi-directionally expresses from enhancer region and sense eRNA regulates adjacent mRNA in cis and in trans.However, it has remained unclear whether antisense eRNAs in different direction are functional or merely a reflection of enhancer activation.Methods: Strand-specific, ribosome-minus RNA sequencing (RNA-seq) were performed in AR positive prostate cancer cells.RNA-seq, GRO-seq, ChIP-seq, 4C-seq and DNA-methylation-seq that published in our and other labs were re-analyzed to define bi-directional enhancer RNA and DNA methylation regions.Molecular mechanisms were demonstrated by 3C, ChIP, ChIRP, CLIP, RT-PCR and western blot assays.The biological functions of antisense-eRNA were assessed using mice xenograft model and RT-PCR analysis in human tissues.Results: In this study, we identified that antisense eRNA was regulated by androgen receptor (AR) activity in prostate cancer cells.Antisense eRNA negatively regulated antisense ncRNA in AR-related target genes' loci, through recruiting DNMT1 on the antisense enhancer in the gene-ending regions and elevating DNA methylation.Importantly, the chromatin exhibited a double looping manner that facilitated sense-eRNA to promoter and antisense-eRNA to gene-ending region in cis.Depletion of antisense eRNA impaired its neighbor mRNA expression, cancer growth and invasion.The expressions of antisense eRNA were correlated with biochemical recurrence and clinical marker PSA's levels in patients' tissues.Conclusions: The findings indicated that antisense eRNA was a functional RNA and may be a novel target that when suppressed improved prostate cancer therapy and diagnosis.New chromatin interaction among enhancer, promoter and gene-ending region might provide new insight into the spatiotemporal mechanism of the gene transcription and acting of bi-directional eRNAs.