tbuckley/cabot-search huggingface dataset:
Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
Authors: Michael Bockmayr, Kim Harnisch, Lara C Pohl, Leonille Schweizer, Theresa Mohme, Meik Körner, Malik Alawi, Abigail K Suwala, Mario M Dorostkar, Camelia M Monoranu, Martin Hasselblatt, Annika K Wefers, David Capper, Jürgen Hench, Stephan Frank, Timothy E Richardson, Ivy Tran, Elisa Liu, Matija Snuderl, Lara Engertsberger, Martin Benesch, Andreas von Deimling, Denise Obrecht, Martin Mynarek, Stefan Rutkowski, Markus Glatzel, Julia E Neumann, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Background Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients’ clinical course are unknown. Methods We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. Results MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06). Conclusions We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
Cyclin-Dependent Kinase 4/6 Inhibitors: Is a Noncanonical Substrate the Key Target?
Authors: David A. Frank
Journal: Cancer Research (2022)

Cyclin-dependent kinases (CDK), such as CDK4 and CDK6, phosphorylate RB1 to release the transcription factor E2F and drive the transition from G1 to S-phase of the cell cycle. Inhibitors of these kinases thereby block cell-cycle progression and presumably exert their therapeutic effect. While this mechanism is straight forward, several aspects have seemed problematic, not the least of which is that these drugs seem to have therapeutic effects on a relatively small number of human cancers. Tong and colleagues took an open-ended approach to this mechanistic question, and their results raise the possibility that inhibition of phosphorylation of the transcription factor p73 is a key mechanism of action of these drugs. They show that p73 inhibition and the resultant upregulation of the cell surface receptor DR5 are necessary for the anticancer effects of CDK4/6 inhibitors, including enhancement of immune-mediated cell killing, and that therapeutic benefit relies largely on their use in conjunction with other agents. While many questions remain to be answered, these findings demonstrate the importance of keeping an open mind to mechanistic aspects of therapeutic agents already in clinical use and highlight how rigorous mechanistic studies can answer both basic and translational questions. See related article by Tong et al., p. 1340.
Letter to the editor: HBeAg expression suppressing/abolishing mutation elevated HBV DNA level in HBeAg‐negative patients with chronic HBV infection
Authors: Danli Yang, Jun Zou, Leijie Wang, Xiangmei Chen, Fengmin Lu
Journal: Hepatology (2022)

- Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract P066: The 24-hour Movement Guidelines Adherence During The Covid-19 Pandemic In Undergraduate Students From Low-income Region
Authors: Marcus Vinicius Nascimento-Ferreira, Jairon Alves Carvalho, Eduardo Pereira Nascimento, Erika da Silva Maciel, Augusto Cesar Ferreira De Moraes
Journal: Circulation (2022)

Objective: The coronavirus disease 2019 (COVID-19) pandemic continues to pose profound challenges to society. Its spread has been mitigated through strategies including social distancing; however, this may result in adopting an unhealthy lifestyle. This study tested the associations between 24-hour movement guidelines adherence and undergraduate course characteristics in a low-income region during a COVID-19 pandemic. Methods: A sample of 195 undergraduate students (from 18 to 52 years, 68.71% female) was recruited. The data were collected in 2020 in Imperatriz, Maranhão, Brazil, a city with a Gini Index of 0.56. All data were self-reported electronically by Google forms (https://forms.gle/L92wXsVaxxfPNgpE8). The outcomes were the 24-hour movement guidelines: physical activity (≥ 150 min/week), sedentary behavior (≤ 8 h/day), and sleep time (7-9 h/day). The independent variables were undergraduate study courses (health sciences course vs. other undergraduate courses) and time (≤ 3rd semester vs. &gt; 3rd semester). The potential confounding variables were age, biological sex, ethnicity, income (in minimum wages), marital status, and family members living in the house. We tested the associations based on the odds ratio (OR) with a confidence interval (CI) of 95%, obtained by logistic regression. Results: We observed guidelines adherence for physical activity of 48.3%, sedentary behavior of 39.5%, and sleep time of 48.2%. Students from other undergraduate courses (e.g., Business, Law, Social sciences) were more likely to present a low level of physical activity (OR: 2.51 [95%CI: 1.20-4.42]); whereas, non-beginner students were more likely to show a high level of sedentary behavior (OR: 2.00 [95%CI: 1.01-3.99]). Conclusion: Undergraduate students presented low adherence to healthy behaviors during the COVID-19 pandemic in 2020. The adherence to 24-hour movement guidelines (physical activity and sedentary behavior) was related to undergraduate courses and years in a low-income region during a COVID-19 pandemic.
164P Immune modulatory functions of lurbinectedin in small cell lung cancer and malignant pleural mesothelioma patients
Authors: L. Cantini, D. Dumoulin, M. Vink, L. Klaase, K. Slooff, R. Cornelissen, J. Mankor, A-M.C. Dingemans, M. Willemsen, J.G. Aerts
Journal: Annals of Oncology (2022)
Abstract MP42: Physical Activity And Clinical Outcomes Among Older Adults With Atrial Fibrillation
Authors: Jordy Mehawej, Qiying Dai, Jane Saczynski, Khanh-van T Tran, Essa Hariri, Hawa O Abu, Tenes Paul, Andreas Filippaios, Catarina I Kiefe, Mayra Tisminetzky, Weijia Wang, Apurv Soni, Robert Goldberg, David D McManus
Journal: Circulation (2022)

Background: Current guidelines encourage adults with atrial fibrillation (AF) to engage in regular physical activity. However, little is known about the association between meeting the recommended level of regular physical activity and clinical outcomes among older adults with AF. Objective: To examine the association between meeting the recommended level of physical activity and clinical outcomes including mortality, stroke, and major bleeding. Methods: We used data collected from the Systemic Assessment of Geriatrics Elements (SAGE)-AF study which include patients with AF (≥65 years) and a CHA 2 DS 2 -VASc score ≥2. Participants were recruited from several clinics in Massachusetts and Georgia. We used the Minnesota Leisure Time Physical Activity questionnaire to examine if participants met the recommended level of physical activity (i.e. at least 500 metabolic equivalent task (MET)-minutes per week). A multivariable cox regression model was used to examine the association between meeting the recommended level of physical activity and our clinical outcomes while controlling for several potentially confounding variables. Results: A total of 1,244 participants (average age 75 years; 49% male; 85 % non-Hispanic White) were included in this study. Nearly one-half of participants engaged in regular physical activity. Meeting the recommended level of physical activity was associated with improved survival (adjusted HR (aHR) = 0.60, 95% CI = 0.38-0.96). However, engaging in regular physical activity was not significantly associated with reduced risk of stroke or major bleeding ( aHR = 1.37, 95% CI = 0.51-3.69; aHR = 0.86, 95% CI = 0.56-1.33, respectively ), although we may have lacked power for these associations, therefore, these results should be interpreted with caution. Conclusions: Meeting the recommended level of physical activity among older adults with AF significantly reduces the risk of mortality. Clinicians and health care providers should promote and encourage engagement in physical activity and tailor interventions to address barriers of engagement to improve patient survival.
Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
Authors: Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDNeoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined.METHODSUsing barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT.RESULTSWe identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with increased survival and that neoepitope-specific CD8+ T cells shared with the infusion product in posttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product.CONCLUSIONSThese data support previous case studies of neoepitope-specific CD8+ T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.FUNDINGNEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.
Increased Accumulation of 18F-FDG Incidentally Observed in Hyperacute Cerebral Infarction
Authors: Wataru Sotome, Yoshiaki Ito, Nobuya Higuchi, Yuta Asami, Nao Satomi
Journal: Clinical Nuclear Medicine (2022)

A 75-year-old man with lung cancer undertook an 18F-FDG PET/CT for staging. He presented neurological symptoms immediately after the 30-minute scan. An emergent MRI study revealed hyperacute cerebral infarction with occlusion of a left MCA branch. At PET/CT, an increased 18F-FDG uptake was observed in the corresponding areas of infarction. In literature, acceleration of compensatory anaerobic glycolysis has been proposed as 1 of the causes of increased uptake in the penumbra of acute cerebral infarction, and a similar process was hypothesized in this case. In addition, a decreased 18F-FDG uptake in the ipsilateral thalamus was noted on the PET/CT images.
Abstract MP70: Differing Age, Sex, And Ancestry-related Trends In Visceral Fat Between Youth With Healthy Weight, Obesity, And Type 2 Diabetes
Authors: Simon Higgins, Babette S Zemel, Philip R Khoury, Elaine M Urbina, Joseph M Kindler
Journal: Circulation (2022)

Introduction: Excess visceral fat is implicated in obesity-related cardiometabolic disease, but normal age, sex, and ancestry-related trends in visceral fat among youth with varying body size and metabolic health status are unknown. Objective: The objective of this study was to characterize age, sex, and ancestry-related trends in abdominal visceral fat among youth with healthy weight, obesity, and type 2 diabetes. Methods: This cross-sectional sample included youth ages 10 to 23 years (67% female, 56% non-black) with healthy weight (BMI=5 th to 85 th percentile, n=236), obesity (BMI &gt; 95 th percentile, n=224), and type 2 diabetes (BMI &gt; 95 th percentile, n=145). Visceral fat (cm 2 ) was assessed via dual-energy X-ray absorptiometry. Multiple linear regression analyses were performed to examine interaction and main effects of age, sex, and ancestry in relation to visceral fat (log) in the three groups separately. Results: Age was positively associated with visceral fat in the healthy weight (P&lt;0.001), obese (P&lt;0.001), and type 2 diabetes groups (P=0.051), such that visceral fat was greater in later adolescents and young adults compared to younger children. Non-blacks had significantly greater visceral fat compared to blacks in the healthy weight (P=0.003), obesity (P&lt;0.001), and type 2 diabetes groups (P&lt;0.001). Sex differences in visceral fat differed by group. In the healthy weight group, males had significantly greater visceral fat than females, but in the obesity group, females had greater visceral fat than males (both P&lt;0.001). In the type 2 diabetes group, females tended to have greater visceral fat, but this difference did not reach statistical significance (P=0.060). When accounting for BMI, significant sex and ancestry differences were maintained, but age associations were nullified. Conclusions: This study reports novel findings with respect to demographic determinants of visceral fat assessed via DXA in children, adolescents, and young adults. Our findings that sex differences in visceral fat in youth with obesity and type 2 diabetes persisted following control for BMI are novel and of clinical interest. Specifically, that females may accrue greater visceral adiposity with weight gain when compared to their male counterparts might help to explain differing risk for obesity-related chronic disease. Prospective studies of youth during critical periods of growth are needed to define the consequences of excess visceral fat accrual with respect to future cardiometabolic risk.
FDG PET/CT in a Case of Lynch Syndrome With Synchronous Inverted Urothelial Papilloma of the Bladder, Urothelial Carcinoma of the Ureter, and Jejunal Adenocarcinoma
Authors: Qian Zhao, Aisheng Dong, Yang Wang
Journal: Clinical Nuclear Medicine (2021)

Abstract A 64-year-old man was referred because of the right ureteral obstruction. CT urography showed an intraluminal enhancing mass in the right midureter and an enhancing nodule in the bladder wall. FDG PET/CT showed increased FDG uptake of the ureteral mass and an unexpected hypermetabolic lesion in the jejunum. The patient underwent transurethral resection of the bladder tumor, right laparoscopic nephroureterectomy, and partial enterectomy. Inverted urothelial papilloma of the bladder, high-grade urothelial carcinoma of the right ureter, and jejunal adenocarcinoma were confirmed by histopathology. Genetic testing of the jejunal adenocarcinoma revealed MSH2 germline mutation, confirming the diagnosis of Lynch syndrome.
Engineering microparticles based on solidified stem cell secretome with an augmented pro-angiogenic factor portfolio for therapeutic angiogenesis
Authors: Thomas Später, Marisa Assunção, Kwok Keung Lit, Guidong Gong, Xiaoling Wang, Yi-Yun Chen, Ying Rao, Yucong Li, Chi Him Kendrick Yiu, Matthias W. Laschke, Michael D. Menger, Dan Wang, Rocky S. Tuan, Kay-Hooi Khoo, Michael Raghunath, Junling Guo, Anna Blocki
Journal: Bioactive Materials (2022)

Tissue (re)vascularization strategies face various challenges, as therapeutic cells do not survive long enough in situ, while the administration of pro-angiogenic factors is hampered by fast clearance and insufficient ability to emulate complex spatiotemporal signaling. Here, we propose to address these limitations by engineering a functional biomaterial capable of capturing and concentrating the pro-angiogenic activities of mesenchymal stem cells (MSCs). In particular, dextran sulfate, a high molecular weight sulfated glucose polymer, supplemented to MSC cultures, interacts with MSC-derived extracellular matrix (ECM) components and facilitates their co-assembly and accumulation in the pericellular space. Upon decellularization, the resulting dextran sulfate-ECM hybrid material can be processed into MIcroparticles of SOlidified Secretome (MIPSOS). The insoluble format of MIPSOS protects protein components from degradation, while facilitating their sustained release. Proteomic analysis demonstrates that MIPSOS are highly enriched in pro-angiogenic factors, resulting in an enhanced pro-angiogenic bioactivity when compared to naïve MSC-derived ECM (cECM). Consequently, intravital microscopy of full-thickness skin wounds treated with MIPSOS demonstrates accelerated revascularization and healing, far superior to the therapeutic potential of cECM. Hence, the microparticle-based solidified stem cell secretome provides a promising platform to address major limitations of current therapeutic angiogenesis approaches.
24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk
Authors: Yuan Ma, Feng J. He, Qi Sun, Changzheng Yuan, Lyanne M. Kieneker, Gary C. Curhan, Graham A. MacGregor, Stephan J.L. Bakker, Norm R.C. Campbell, Molin Wang, Eric B. Rimm, JoAnn E. Manson, Walter C. Willett, Albert Hofman, Ron T. Gansevoort, Nancy R. Cook, Frank B. Hu
Journal: New England Journal of Medicine (2021)

The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method.We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis.Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94).Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).
Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells
Authors: Zhe Sun, Ziheng Zhang, Qiao-Qi Wang, Ji-Long Liu
Journal: Cancer Research (2022)

The "undruggable" oncogene MYC supports cancer cell proliferation and survival through parallel induction of multiple anabolic processes. Here we find that inhibiting CTP synthase (CTPS) selectively decreases cell viability and induces DNA replication stress in MYC-overexpressing cells. MYC-driven rRNA synthesis caused the selective DNA replication stress upon CTPS inhibition. Combined inhibition of CTPS and ataxia telangiectasia and Rad3-related protein (ATR) is synthetically lethal in MYC-overexpressing cells, promoting cell death in vitro and decreasing tumor growth in vivo. Unexpectedly, interfering with CTPS1 but not CTPS2 is required to induce replication stress in MYC-deregulated cancer cells and consequent cell death in the presence of an ATR inhibitor. These results highlight a specific and key role of CTPS1 in MYC-driven cancer, suggesting that selectively inhibiting CTPS1 in combination with ATR could be a promising strategy to combat disease progression.Inhibition of CTPS in MYC-overexpressing cells blocks pyrimidine synthesis while maintaining ribosome synthesis activity to create an anabolic imbalance that induces replication stress, providing a new approach to selectively target MYC-driven cancer. See related commentary by Chabanon and Postel-Vinay, p. 969.
Abstract P161: Plasma Betaine, But Not Trimethylamine N-oxide Or Choline, Associated With 15-year Incident Diabetes: Coronary Artery Risk Development In Young Adults Study
Authors: Katie Meyer, Annie Green G Howard, Ravi V Shah, Venkatesh L Murthy, David R Jacobs, Penny Gordon-Larsen
Journal: Circulation (2022)

Objective: Data from animal models supports a role for metabolites in the choline pathway in glycemic control and diabetes. Cross-sectional and case-control studies have documented positive associations between trimethylamine N-oxide (TMAO) and prevalent diabetes, but these findings have not been replicated in prospective analysis. Circulating choline has been positively, and betaine negatively, associated with diabetes in some, but not all, prospective data. We tested associations between three metabolites in the choline pathway (TMAO, choline, betaine) and 15-year incident diabetes in a diverse cohort of early-middle-aged adults. Methods: Study participants were from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter cohort of Black and White Americans established in 1985/86 (baseline n=5,115; ages 18-30). Plasma concentrations of TMAO, choline, and betaine were measured from Year 15 (2000-01) stored plasma (-70°C) with liquid chromatography mass spectrometry (LC-MS). Logistic regression was used to quantify associations between plasma metabolites and diabetes, adjusting for sociodemographic, behavioral, and clinical covariates. Results: Among 3,317 participants without diabetes at Year 15, n=373 developed diabetes over 15 years of follow-up (2000-2016). Plasma TMAO and choline were not significantly associated with incident diabetes in all multivariable-adjusted models, while betaine was negatively associated with incident diabetes in all models (Table). Conclusion: In this population-based cohort of early-middle-aged US adults, plasma TMAO and choline were not associated with incident diabetes over 15 years of follow-up, while plasma betaine was negatively associated with incident diabetes.