tbuckley/cabot-search huggingface dataset:
Crosstalk between autophagy and microbiota in cancer progression
Authors: Yu Wang, Jiang Du, Xuemei Wu, Ahmed Abdelrehem, Yu Ren, Chao Liu, Xuan Zhou, Sinan Wang
Journal: Molecular Cancer (2021)

Abstract Autophagy is a highly conserved catabolic process seen in eukaryotes and is essentially a lysosome-dependent protein degradation pathway. The dysregulation of autophagy is often associated with the pathogenesis of numerous types of cancers, and can not only promote the survival of cancer but also trigger the tumor cell death. During cancer development, the microbial community might predispose cells to tumorigenesis by promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. The complex relationship between autophagy and microorganisms can protect the body by activating the immune system. In addition, autophagy and microorganisms can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses involved in cancer progression. Various molecular mechanisms, correlating the microbiota disorders and autophagy activation, control the outcomes of protumor or antitumor responses, which depend on the cancer type, tumor microenvironment and disease stage. In this review, we mainly emphasize the leading role of autophagy during the interaction between pathogenic microorganisms and human cancers and investigate the various molecular mechanisms by which autophagy modulates such complicated biological processes. Moreover, we also highlight the possibility of curing cancers with multiple molecular agents targeting the microbiota/autophagy axis. Finally, we summarize the emerging clinical trials investigating the therapeutic potential of targeting either autophagy or microbiota as anticancer strategies, although the crosstalk between them has not been explored thoroughly.
Abstract 16932: Primary Hyperaldosteronism And Resistant Hypertension In Pregnancy
Authors: Agnes Koczo, Malamo E Countouris, Alisse Hauspurg, Kathryn Berlacher
Journal: Circulation (2021)

Case Presentation: A 42-year-old woman with history of primary hyperaldosteronism (PA), IDDM and chronic kidney disease stage 3b (baseline Cr 2.5 mg/dl) presented at 10 weeks gestation with uncontrolled hypertension during pregnancy. Given prior difficulties conceiving and lack of discussions surrounding pregnancy risks, preconception counseling had not been done. She was taking carvedilol, spironolactone, and furosemide at pregnancy diagnosis. Given unclear safety profile in pregnancy, her spironolactone was discontinued. Her regimen was uptitrated to nifedipine 90 mmHg, carvedilol 50mg BID, hydralazine 50mg TID and furosemide 80mg BID. At 18 weeks gestation, she was readmitted with severe range hypertension and fluid overload unresponsive to escalating diuretic dosing. Due to poor urine output and creatinine to 5.5 mg/dl, she was initiated on dialysis. Her fetus was diagnosed with severe intrauterine growth restriction (IUGR) and umbilical doppler noted reversal of umbilical artery end-diastolic flow indicating severely elevated arterial resistance (Figure). During admission, she developed resistant hypertension requiring nicardipine and esmolol drips and severe headache, concerning for superimposed preeclampsia (SIPE). At 25 weeks gestation, she was taken for urgent c-section. Given extreme prematurity and growth restriction, her newborn baby passed away shortly after delivery. Discussion: This case highlights complications which arise from PA and antepartum persistent hypertension including progression of kidney disease, heart failure, IUGR, SIPE, and preterm delivery. It further highlights unique challenges using targeted therapies of mineralocorticoid receptor antagonists in PA in pregnancy. This information is crucial as PA is an increasingly recognized cause of resistant hypertension in young adults. Both PA and preeclampsia involve pathophysiologic mechanisms in the RAAS pathway and deserve further attention and research.
Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells
Authors: Siyuan Huang, Di Liu, Jianhui Sun, Huacai Zhang, Jing Zhang, Qiang Wang, Lebin Gan, Guoxin Qu, Jinchao Qiu, Jin Deng, Jianxin Jiang, Ling Zeng
Journal: Molecular Therapy (2021)

Immunosuppression in response to severe sepsis remains a serious human health concern. Evidence of sepsis-induced immunosuppression includes impaired T lymphocyte function, T lymphocyte depletion or exhaustion, increased susceptibility to opportunistic nosocomial infection, and imbalanced cytokine secretion. CD4 T cells play a critical role in cellular and humoral immune responses during sepsis. Here, using an RNA sequencing assay, we found that the expression of T cell-containing immunoglobulin and mucin domain-3 (Tim-3) on CD4 T cells in sepsis-induced immunosuppression patients was significantly elevated. Furthermore, the percentage of Tim-3+ CD4 T cells from sepsis patients was correlated with the mortality of sepsis-induced immunosuppression. Conditional deletion of Tim-3 in CD4 T cells and systemic Tim-3 deletion both reduced mortality in response to sepsis in mice by preserving organ function. Tim-3+ CD4 T cells exhibited reduced proliferative ability and elevated expression of inhibitory markers compared with Tim-3−CD4 T cells. Colocalization analyses indicated that HMGB1 was a ligand that binds to Tim-3 on CD4 T cells and that its binding inhibited the NF-κB signaling pathway in Tim-3+ CD4 T cells during sepsis-induced immunosuppression. Together, our findings reveal the mechanism of Tim-3 in regulating sepsis-induced immunosuppression and provide a novel therapeutic target for this condition. Immunosuppression in response to severe sepsis remains a serious human health concern. Evidence of sepsis-induced immunosuppression includes impaired T lymphocyte function, T lymphocyte depletion or exhaustion, increased susceptibility to opportunistic nosocomial infection, and imbalanced cytokine secretion. CD4 T cells play a critical role in cellular and humoral immune responses during sepsis. Here, using an RNA sequencing assay, we found that the expression of T cell-containing immunoglobulin and mucin domain-3 (Tim-3) on CD4 T cells in sepsis-induced immunosuppression patients was significantly elevated. Furthermore, the percentage of Tim-3+ CD4 T cells from sepsis patients was correlated with the mortality of sepsis-induced immunosuppression. Conditional deletion of Tim-3 in CD4 T cells and systemic Tim-3 deletion both reduced mortality in response to sepsis in mice by preserving organ function. Tim-3+ CD4 T cells exhibited reduced proliferative ability and elevated expression of inhibitory markers compared with Tim-3−CD4 T cells. Colocalization analyses indicated that HMGB1 was a ligand that binds to Tim-3 on CD4 T cells and that its binding inhibited the NF-κB signaling pathway in Tim-3+ CD4 T cells during sepsis-induced immunosuppression. Together, our findings reveal the mechanism of Tim-3 in regulating sepsis-induced immunosuppression and provide a novel therapeutic target for this condition.
Biopolymer Nano‐Network for Antimicrobial Peptide Protection and Local Delivery
Authors: Natthaporn Klubthawee, Giovanni Bovone, Bruno Marco‐Dufort, Elia A. Guzzi, Ratchaneewan Aunpad, Mark W. Tibbitt
Journal: Advanced Healthcare Materials (2021)

Antimicrobial resistance (AMR) develops when bacteria no longer respond to conventional antimicrobial treatment. The limited treatment options for resistant infections result in a significantly increased medical burden. Antimicrobial peptides offer advantages for treatment of resistant infections, including broad-spectrum activity and lower risk of resistance development. However, sensitivity to proteolytic cleavage often limits their clinical application. Here, a moldable and biodegradable colloidal nano-network is presented that protects bioactive peptides from enzymatic degradation and delivers them locally. An antimicrobial peptide, PA-13, is encapsulated electrostatically into positively and negatively charged nanoparticles made of chitosan and dextran sulfate without requiring chemical modification. Mixing and concentration of oppositely charged particles form a nano-network with the rheological properties of a cream or injectable hydrogel. After exposure to proteolytic enzymes, the formed nano-network loaded with PA-13 eliminates Pseudomonas aeruginosa during in vitro culture and in an ex vivo porcine skin model while the unencapsulated PA-13 shows no antibacterial effect. This demonstrates the ability of the nano-network to protect the antimicrobial peptide in an enzyme-challenged environment, such as a wound bed. Overall, the nano-network presents a useful platform for antimicrobial peptide protection and delivery without impacting peptide bioactivity.
51P Translational analyses of the DeCidE phase II clinical study in advanced ovarian cancer patients reveal a substantial role for B-cells in the clinical benefit derived from maveropepimut-S (MVP-S) treatment
Authors: O. Dorigo, B. Dirk, M. Bydoun, W. Ebrahimizadeh, T. Omar, B. Kennedy, H.T. Torrey, V. Kaliaperumal, E. Kelly, Y. Bramhecha, O. Hrytsenko, S. Fiset, H. Hirsch, J. Graff
Journal: Annals of Oncology (2021)
Abstract 10394: Long-Term Functional and Quality-of-Life Outcomes of Cardiac Arrest Survivors Stratified by Shock Provider: A 10 Year Retrospective Study
Authors: Brian A Haskins, Ziad Nehme, Emily Andrew, Stephen Bernard, Peter Cameron, Karen L Smith
Journal: Circulation (2021)

Introduction: To assess the long-term functional recovery and health related quality-of-life (HRQoL) outcomes for out-of-hospital cardiac arrest (OHCA) survivors stratified by shock provider. Methods: We included adult OHCA in initial shockable rhythms between 2010-2019. Those surviving to 12 months post arrest were invited to participate in telephone interviews to identify functional recovery and HRQoL outcomes, using the following assessment tools, Glasgow Outcome Scale-Extended (GOS-E), EuroQol-5D (EQ-5D), and 12-Item Short Form (SF-12). Results: Of the 1,581 patients surviving to 12 months, 1,325 (85.5%) responded to the interviews, of these, 227 (17.1%) and 144 (10.9%) were initially shocked by bystanders and first responders, respectively. A higher proportion of patients shocked by bystanders were located in public (p&lt;0.001), received bystander CPR (p&lt;0.001) and received initial defibrillation faster from time of collapse (P&lt;0.001). Survivors receiving bystander defibrillation reported higher rates of living at home without care (p=0.004), upper good recovery (GOS-E) (p=0.008) and EQ-5D index score of 1 (perfect health) (p=0.023). After adjustment, bystander defibrillation was associated with a 64% increase in the odds of an EQ-5D current Visual Analogue Scale ≥ 80 (AOR 1.64, 95%CI: 1.17-2.31; p=0.004) and a 45% increase in the odds of a good functional recovery (GOS-E ≥ 7) (AOR 1.45, 95% CI: 1.02-2.06; p=0.037), than those initially shocked by paramedics. No improvement in adjusted outcomes were observed for survivors initially defibrillated by first responders. Conclusion: Patients receiving bystander defibrillation reported better functional recovery and HRQol outcomes at 12 months compared to those defibrillated by first responders and paramedics.
Pandemic heightens the need to combat cardiovascular diseases
Authors: The Lancet Regional Health– Europe
Journal: The Lancet Regional Health - Europe (2021)

Cardiovascular diseases are the most common causes of death globally, and account for more than half of all deaths across the WHO European region—making them the largest disease burden in the EU. As per the Global Burden of Diseases, Injuries, and Risk Factors Study database, it is estimated that more than 60 million people in the EU live with cardiovascular disease, and almost 13 million cases are diagnosed each year. The pandemic has exacerbated cardiovascular disease burden, as acute SARS-CoV-2 infection can lead to or accentuate heart complications including arrhythmia, cardiac injury, heart failure, and pulmonary embolism.
Combination Therapy of Physical Activity and Dexamethasone for Cancer-Related Fatigue: A Phase II Randomized Double-Blind Controlled Trial
Authors: Sriram Yennurajalingam, Vicente Valero, Zhanni Lu, Diane D. Liu, Naifa L. Busaidy, James M. Reuben, Carolina Diaz Fleming, Janet L. Williams, Kenneth R. Hess, Karen Basen-Engquist, Eduardo Bruera
Journal: Journal of the National Comprehensive Cancer Network (2021)

Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF.In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue).A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86).Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified.gov identifier: NCT02491632.
PRMT5 Inhibition Modulates E2F1 and P53 to Restore Cell Cycle Regulation and Drive DNA Damage Response in Ibrutinib-Resistant Mantle Cell Lymphoma
Authors: Shelby Sloan, Fiona Brown, Mackenzie Long, JoBeth Helmig-Mason, Stacey Beck, Ji Hyun Chung, Walter Hanel, Eric Brooks, Haley Klimazewski, Cem Meydan, Jonathan Foox, Daniel Butler, John C. Byrd, Rosa Lapalombella, Maurizio Di Liberto, Christopher Mason, Selina Chen-Kiang, Kris Vaddi, Peggy Scherle, Robert Baiocchi, Lapo Alinari
Journal: Blood (2021)
Conceptualizing ecosystem services using social–ecological networks
Authors: María R. Felipe-Lucia, Angela M. Guerrero, Steven M. Alexander, Jaime Ashander, Jacopo A. Baggio, Michele L. Barnes, Örjan Bodin, Aletta Bonn, Marie-Josée Fortin, Rachel S. Friedman, Jessica A. Gephart, Kate J. Helmstedt, Aislyn A. Keyes, Kailin Kroetz, François Massol, Michael J.O. Pocock, Jesse Sayles, Ross M. Thompson, Spencer A. Wood, Laura E. Dee
Journal: Trends in Ecology & Evolution (2021)
Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation
Authors: Xue Gong, Miao Tian, Nian Cao, Peili Yang, Zaicheng Xu, Shuo Zheng, Qiao Liao, Caiyu Chen, Cindy Zeng, Pedro A. Jose, Da-Zhi Wang, Zhao Jian, Yingbin Xiao, Ding-Sheng Jiang, Xiang Wei, Bing Zhang, Yibin Wang, Ken Chen, Gengze Wu, Chunyu Zeng
Journal: Journal of Clinical Investigation (2021)

Circular RNAs (circRNAs) have been recently recognized as playing a role in the pathogenesis of vascular remodeling–related diseases by modulating the functions of miRNAs. However, the interplay between circRNAs and proteins during vascular remodeling remains poorly understood. Here, we investigated a previously identified circRNA, circEsyt2, whose expression is known to be upregulated during vascular remodeling. Loss- and gain-of‑function mutation analyses in vascular smooth muscle cells (VSMCs) revealed that circEsyt2 enhanced cell proliferation and migration and inhibited apoptosis and differentiation. Furthermore, the silencing of circEsyt2 in vivo reduced neointima formation, while circEsyt2 overexpression enhanced neointimal hyperplasia in the injured carotid artery, confirming its role in vascular remodeling. Using unbiased protein–RNA screening and molecular validation, circEsyt2 was found to directly interact with polyC-binding protein 1 (PCBP1), an RNA splicing factor, and regulate PCBP1 intracellular localization. Additionally, circEsyt2 silencing substantially enhanced p53β splicing via the PCBP1–U2AF65 interaction, leading to the altered expression of p53 target genes (cyclin D1, p21, PUMA, and NOXA) and the decreased proliferation of VSMCs. Thus, we identified a potentially novel circRNA that regulated vascular remodeling, via altered RNA splicing, in atherosclerotic mouse models.
‘Too high, too low’: The complexities of using thresholds in isolation to inform precautionary allergen (‘may contain’) labels
Authors: Paul J. Turner, Joseph L. Baumert, Kirsten Beyer, Simon Brooke‐Taylor, Pasquale Comberiati, René W. R. Crevel, Jennifer D. Gerdts, M. Hazel Gowland, Geert F. Houben, Jonathan O’B. Hourihane, George N. Konstantinou, Sébastien La Vieille, Beatriz Moya, Antonella Muraro, E. N. Clare Mills, Nandinee Patel, Marcia Podestà, Bert Popping, Imke Reese, Graham Roberts, Maria Said, Alexandra F. Santos, Sabine Schnadt, Steve L. Taylor, Berber Vlieg‐Boerstra, Benjamin C. Remington
Journal: Allergy (2021)

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Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Authors: T. Powles, J. Bellmunt, E. Comperat, M. De Santis, R. Huddart, Y. Loriot, A. Necchi, B.P. Valderrama, A. Ravaud, S.F. Shariat, B. Szabados, M.S. van der Heijden, S. Gillessen
Journal: Annals of Oncology (2021)
CBIO-15. LOSS OF WILLIAMS SYNDROME TRANSCRIPTION FACTOR (WSTF) LEADS TO IMPROVED TEMOZOLOMIDE SENSITIVITY IN HUMAN GLIOBLASTOMA CELLS IRRESPECTIVE OF MGMT EXPRESSION
Authors: Katharina Sarnow, Stephanie Schwab, Oline Rio, Joydeep Mukherjee, Rolf Bjerkvig, Tor-Christian Johannessen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The prognosis for glioblastoma multiforme (GBM) patients is poor with a median survival of approximately 15 months. The DNA repair protein O 6-methylguanine-DNA methyltransferase (MGMT) counteracts the effects of temozolomide (TMZ) chemotherapy and is thus associated with poor outcome in GBM patients. Williams Syndrome Transcription Factor (WSTF) has been suggested to regulate the DNA damage response pathway (DDR) in both an indirect (through chromatin remodeling) and direct manner (by phosphorylating H2AX at Tyr142). However, whether WSTF has any role in the development of resistance against chemotherapy through its functions in the DDR in GBMs, is so far unknown. In this study, we investigated whether a loss of WSTF sensitizes different MGMT-proficient and -deficient GBM cell lines to TMZ treatment. METHODS We generated WSTF knockout clones from both MGMT-proficient (LN18, T98G) and -deficient GBM cell lines (U-251) using CRISPR/Cas9 gene-editing technology with lentiviral vectors. The PCR-based screening results combined with the T7 endonuclease mismatch assay for bi-allelic monoclonal knockouts were verified via sequencing and immunoblotting to identify candidate knockout clones. Colony formation assays were performed to determine the survival ability in response to TMZ treatment. Statistical analysis was performed using two-way ANOVA. RESULTS WSTF knockout clones showed a significant decrease in colony formation after TMZ-treatment compared to the corresponding control groups (non-target single guide RNA) (LN18: Clone 59 vs control: p= 0.0456, T98G: All three studied clones vs control: p&amp;lt; 0.0001, U-251: Clone 7/35.1/70.2 vs control: p&amp;lt; 0.0001/p= 0.0107/p= 0.0119). CONCLUSION WSTF is an important factor in both MGMT de- and proficient GBM cell lines for response against TMZ chemotherapy. The loss of WSTF leads to a significantly increased TMZ sensitivity in clinically relevant concentrations for all the studied cell lines. Ongoing studies are investigating the underlying mechanisms and potential alterations in the DDR pathway caused by WSTF loss.
Trends in Buprenorphine Use in US Jails and Prisons From 2016 to 2021
Authors: Ashish P. Thakrar, G. Caleb Alexander, Brendan Saloner
Journal: JAMA Network Open (2021)

Although this study found that buprenorphine use has increased, access in jails and prisons is still inadequate.Extensive efforts remain under way to expand the availability of all medications for OUD in carceral settings.
Loss of Timeless Underlies an Evolutionary Transition within the Circadian Clock
Authors: Joanna Kotwica-Rolinska, Lenka Chodáková, Vlastimil Smýkal, Milena Damulewicz, Jan Provazník, Bulah Chia-Hsiang Wu, Markéta Hejníková, Daniela Chvalová, David Doležel
Journal: Molecular Biology and Evolution (2021)

Abstract Most organisms possess time-keeping devices called circadian clocks. At the molecular level, circadian clocks consist of transcription–translation feedback loops (TTFLs). Although some components of the negative TTFL are conserved across the animals, important differences exist between typical models, such as mouse and the fruit fly. In Drosophila, the key components are PERIOD (PER) and TIMELESS (TIM-d) proteins, whereas the mammalian clock relies on PER and CRYPTOCHROME (CRY-m). Importantly, how the clock has maintained functionality during evolutionary transitions between different states remains elusive. Therefore, we systematically described the circadian clock gene setup in major bilaterian lineages and identified marked lineage-specific differences in their clock constitution. Then we performed a thorough functional analysis of the linden bug Pyrrhocoris apterus, an insect species comprising features characteristic of both the Drosophila and the mammalian clocks. Unexpectedly, the knockout of timeless-d, a gene essential for the clock ticking in Drosophila, did not compromise rhythmicity in P. apterus, it only accelerated its pace. Furthermore, silencing timeless-m, the ancestral timeless type ubiquitously present across animals, resulted in a mild gradual loss of rhythmicity, supporting its possible participation in the linden bug clock, which is consistent with timeless-m role suggested by research on mammalian models. The dispensability of timeless-d in P. apterus allows drawing a scenario in which the clock has remained functional at each step of transition from an ancestral state to the TIM-d-independent PER + CRY-m system operating in extant vertebrates, including humans.