tbuckley/cabot-search huggingface dataset:
Abstract P3-01-24: The cancer-associated TRPC5 opposite strand protein, a novel regulatory factor for cell proliferation in triple negative breast cancer
Authors: Yangyang Cui, Jinghui Peng, Yue Huang, Ziyi Fu, Hui Xie, Shui Wang
Journal: Cancer Research (2020)

Abstract Background: Breast cancer is the most common malignant tumors worldwide and the leading cause of cancer death among female. Microproteins, a kind of protein which is nearly 100 amino acids in length, have been demonstrated to play important roles in biology and disease. Here, we present a potential microprotein TRPC5 opposite strand (TRPC5OS), which may exert function in breast cancer progression. Methods: Differential expression of TRPC5OS in breast cancer was measured via Immunohistochemistry (IHC) in breast cancer samples and quantitative real-time PCR (qRT-PCR) in cell lines. The effects of TRPC5OS on proliferation and cell cycle progression of breast cancer cells were evaluated by using Cell counting kit-8 (CCK-8), colony formation assay and cell cycle analysis by flow cytometry. The tumor growth in vivo was observed in xenograft model. Co-immunoprecipitation (Co-IP), western blot analysis and immunofluorescent staining were performed to validate the interaction between TRPC5OS and ENO1. Glucose uptake was measured by liquid scintillation spectrometry and involvement of the PI3K and AKT pathways was investigated by western blot analysis. Results: TRPC5OS showed an enhanced expression in breast cancer patient samples predominantly in HER-2 negative breast cancer, especially in triple negative breast cancer (TNBC). Overexpression TRPC5OS increased TNBC cell proliferation, promoted cell cycle progression, enhanced xenograft tumor growth, and associated with PI3K-AKT pathway. In addition, TRPC5OS could enhance glucose uptake via interacting with alpha-enolase (ENO1) and increase the protein level of ENO1, and ENO1 was found to be the functional target of TRPC5OS in TNBC cells. Conclusions: This study demonstrates that TRPC5OS promotes proliferation by interacting with ENO1 and may provide a strategy for future diagnosis of human breast cancer, a new potential therapeutic target for TNBC patients as well. Key words: breast cancer, TRPC5OS, proliferation, ENO1, glucose uptake Citation Format: Yangyang Cui, Jinghui Peng, Yue Huang, Ziyi Fu, Hui Xie, Shui Wang. The cancer-associated TRPC5 opposite strand protein, a novel regulatory factor for cell proliferation in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-24.
Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models
Authors: Taiki Kurino, Reiko Matsuda, Ayu Terui, Hiroyuki Suzuki, Tomomi Kokubo, Tomoya Uehara, Yasushi Arano, Akihiro Hisaka, Hiroto Hatakeyama
Journal: Journal for ImmunoTherapy of Cancer (2020)

Recently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models. Herein, murine breast MM48 and colon MC38 xenografts were used to analyze the pharmacological activity of aPD-1 and aPD-L1 mAbs. The PK of the mAbs in the tumor-bearing mice was investigated at low and high doses using two radioisotopes (Indium-111 and Iodine-125) to evaluate the accumulation and degradation of the mAbs. aPD-1 mAb showed antitumor effect in a dose-dependent manner, indicating that the tumor model was sensitive to PD-1/PD-L1 blockade therapy, whereas aPD-L1 mAb failed to suppress tumor growth. The PK study showed that aPD-L1 mAb was accumulated largely in normal organs such as the spleen, liver, and kidney, resulting in low blood concentration and low distributions to tumors at a low dose, even though the tumors expressed PD-L1. Sufficient accumulation of aPD-L1 mAb in tumors was achieved by administration at a high dose owing to the saturation of target-mediated binding in healthy organs. However, degradation of aPD-L1 mAb in tumors was greater than that of aPD-1 mAb, which resulted in poor outcome presumably due to less inhibition of PD-L1 by aPD-L1 mAb than that of PD-1 by aPD-1 mAb. According to the PK studies, aPD-1 mAb showed linear PK, whereas aPD-L1 mAb showed non-linear PK between low and high doses. Collectively, the poor PK characteristics of aPD-L1 mAb caused lower antitumor activity than of aPD-1 mAb. These results clearly indicated that aPD-L1 mAb required higher doses than aPD-1 mAb in clinical setting. Thus, targeting of PD-1 would be more advantageous than PD-L1 in terms of PK.
Evaluation of the Coverage of 3 Antibiotic Regimens for Neonatal Sepsis in the Hospital Setting Across Asian Countries
Authors: Julia A. Bielicki, Mike Sharland, Paul T. Heath, A. Sarah Walker, Ramesh Agarwal, Paul Turner, David A. Cromwell
Journal: JAMA Network Open (2020)

High levels of antimicrobial resistance in neonatal bloodstream isolates are being reported globally, including in Asia. Local hospital antibiogram data may include too few isolates to meaningfully examine the expected coverage of antibiotic regimens.To assess the coverage offered by 3 antibiotic regimens for empirical treatment of neonatal sepsis in Asian countries.A decision analytical model was used to estimate coverage of 3 prespecified antibiotic regimens according to a weighted-incidence syndromic combination antibiogram. Relevant data to parameterize the models were identified from a systematic search of Ovid MEDLINE and Embase. Data from Asian countries published from 2014 onward were of interest. Only data on blood culture isolates from neonates with sepsis, bloodstream infection, or bacteremia reported from the relevant setting were included. Data analysis was performed from April 2019 to July 2019.The prespecified regimens of interest were aminopenicillin-gentamicin, third-generation cephalosporins (cefotaxime or ceftriaxone), and meropenem. The relative incidence of different bacteria and their antimicrobial susceptibility to antibiotics relevant for determining expected concordance with these regimens were extracted.Coverage was calculated on the basis of a decision-tree model incorporating relative bacterial incidence and antimicrobial susceptibility of relevant isolates. Data on 7 bacteria most commonly reported in the included studies were used for estimating coverage, which was reported at the country level.Data from 48 studies reporting on 10 countries and 8376 isolates were used. Individual countries reported 51 (Vietnam) to 6284 (India) isolates. Coverage varied considerably between countries. Meropenem was generally estimated to provide the highest coverage, ranging from 64.0% (95% credible interval [CrI], 62.6%-65.4%) in India to 90.6% (95% CrI, 86.2%-94.4%) in Cambodia, followed by aminopenicillin-gentamicin (from 35.9% [95% CrI, 27.7%-44.0%] in Indonesia to 81.0% [95% CrI, 71.1%-89.7%] in Laos) and cefotaxime or ceftriaxone (from 17.9% [95% CrI, 11.7%-24.7%] in Indonesia to 75.0% [95% CrI, 64.8%-84.1%] in Laos). Aminopenicillin-gentamicin coverage was lower than that of meropenem in all countries except Laos (81.0%; 95% CrI, 71.1%-89.7%) and Nepal (74.3%; 95% CrI, 70.3%-78.2%), where 95% CrIs for aminopenicillin-gentamicin and meropenem were overlapping. Third-generation cephalosporin coverage was lowest of the 3 regimens in all countries. The coverage difference between aminopenicillin-gentamicin and meropenem for countries with nonoverlapping 95% CrIs ranged from -15.9% in China to -52.9% in Indonesia.This study's findings suggest that noncarbapenem antibiotic regimens may provide limited coverage for empirical treatment of neonatal sepsis in many Asian countries. Alternative regimens must be studied to limit carbapenem consumption.
Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition through Patched-Induced Apoptosis
Authors: Pierre-Antoine Bissey, Pauline Mathot, Catherine Guix, Mélissa Jasmin, Isabelle Goddard, Clélia Costechareyre, Nicolas Gadot, Jean-Guy Delcros, Sachitanand M. Mali, Rudi Fasan, André-Patrick Arrigo, Robert Dante, Gabriel Ichim, Patrick Mehlen, Joanna Fombonne
Journal: Cancer Research (2020)

Abstract The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (SMO) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (PTCH) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to PTCH not only activates the SHH canonical pathway but also blocks PTCH-induced apoptosis. Eighty percent, 64%, and 8% of human colon, pancreatic, and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the PTCH-induced apoptotic pathway. Although the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic, and lung cell lines triggered cell death through PTCH proapoptotic signaling. In vivo, SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the antitumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is, at least in part, because of the engagement of PTCH proapoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/PTCH interaction in SHH-overexpressing cancers should be explored. Significance: Sonic Hedgehog–overexpressing tumors express PTCH-induced cell death effectors, suggesting that this death signaling could be activated as an antitumor strategy.
Elimination of the Autopsy Requirement by CMS
Authors: Justin Rueckert
Journal: New England Journal of Medicine (2020)

This final rule reforms Medicare regulations that are identified as unnecessary, obsolete, or excessively burdensome on health care providers and suppliers.This final rule also increases the ability of health care professionals to devote resources to improving patient care by eliminating or reducing requirements that impede quality patient care or that divert resources away from furnishing high quality patient care.Additionally, this rule updates fire safety standards for Medicare and Medicaid participating End-Stage Renal Disease (ESRD) facilities by adopting the 2012 edition of the Life Safety Code and the 2012 edition of the Health Care Facilities Code.Finally, this final rule updates the requirements that hospitals and Critical Access Hospitals (CAHs) must meet to participate in the Medicare and Medicaid programs.These requirements are intended to conform to current standards of practice and support improvements in quality of care, reduce barriers to care, and reduce some issues that may exacerbate workforce shortage concerns.
Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity
Authors: Juan A. Ortega, Elizabeth L. Daley, Sukhleen Kour, Marisa Samani, Liana Tellez, Haley S. Smith, Elizabeth A. Hall, Y. Taylan Esengul, Yung-Hsu Tsai, Tania F. Gendron, Christopher J. Donnelly, Teepu Siddique, Jeffrey N. Savas, Udai B. Pandey, Evangelos Kiskinis
Journal: Neuron (2020)
LRR domain of NLRX1 protein delivery by dNP2 inhibits T cell functions and alleviates autoimmune encephalomyelitis
Authors: Ja-Hyun Koo, Do-Hyun Kim, Donghun Cha, Min-Jong Kang, Je-Min Choi
Journal: Theranostics (2020)

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS), which is a chronic progressive disease and is caused by uncontrolled activation of myelin antigen specific T cells.It has high unmet medical needs due to the difficulty of efficient drug delivery into the CNS to control tissue inflammation.In this study, we demonstrate that a fusion protein of NOD-like receptor family member X1 (NLRX1) and blood brain barrier (BBB)-permeable peptide, dNP2 ameliorates experimental autoimmune encephalomyelitis (EAE).Methods: We purified recombinant LRR or NBD regions of NLRX1 protein conjugated with dNP2.To examine intracellular delivery efficiency of the recombinant protein, we incubated the proteins with Jurkat T cells or murine splenic T cells and their delivery efficiency was analyzed by flow cytometry.To investigate the therapeutic efficacy in an EAE model, we injected the recombinant protein into mice with 3 different treatment schemes e.g., prevention, semitherapeutic, and therapeutic.To analyze their functional roles in T cells, we treated MACS-sorted naïve CD4 T cells with the proteins during their activation and differentiation into Th1, Th17, and Treg cells.Results: dNP2-LRR protein treatment showed significantly higher delivery efficiency than TAT-LRR or LRR alone in Jurkat T cells and mouse splenic T cells.In all three treatment schemes of EAE experiments, dNP2-LRR administration showed ameliorated tissue inflammation and disease severity with reduced number of infiltrating T cells producing inflammatory cytokines such as IFNγ.In addition, dNP2-LRR inhibited T cell activation, cytokine production, and Th1 differentiation.Conclusion: These results suggest that dNP2-LRR is a novel agent, which regulates effector T cell functions and could be a promising molecule for the treatment of CNS autoimmune diseases such as multiple sclerosis.
NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis
Authors: Carlotta Ronchi, Joyce Bernardi, Manuela Mura, Manuela Stefanello, Beatrice Badone, Marcella Rocchetti, Lia Crotti, Paul Brink, Peter J Schwartz, Massimiliano Gnecchi, Antonio Zaza
Journal: Cardiovascular Research (2020)

NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency.In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed 'transient inward current' events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased.The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.
Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade
Authors: Allison Betof Warner, Jessica S. Palmer, Alexander N. Shoushtari, Debra A. Goldman, Katherine S. Panageas, Sara A. Hayes, Raazi Bajwa, Parisa Momtaz, Margaret K. Callahan, Jedd D. Wolchok, Michael A. Postow, Paul B. Chapman
Journal: Journal of Clinical Oncology (2020)

To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients.We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death.CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab.In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.
Prevalence of Electronic Cigarette Use Among Adolescents in New Jersey and Association With Social Factors
Authors: Mary Hrywna, Michelle T. Bover Manderski, Cristine D. Delnevo
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Use of electronic cigarettes (e-cigarettes) is high among adolescents, but the extent to which the JUUL e-cigarette brand accounts for the high prevalence has not been explored using population-based surveys. <h3>Objective</h3> To examine e-cigarette and JUUL use among adolescents in New Jersey. <h3>Design, Setting, and Participants</h3> Survey study using data from the 2018 New Jersey Youth Tobacco Survey, a cross-sectional statewide representative survey of tobacco use. The survey was school based and sampled New Jersey students in grades 9 to 12. <h3>Exposures</h3> Use of tobacco products; JUUL as first tobacco product tried; exposure to JUUL at school; number of friends perceived as JUUL users; liking or following a tobacco brand on social media; and buying or receiving tobacco-branded merchandise. <h3>Main Outcomes and Measures</h3> Prevalence ratio (PR) for current and frequent e-cigarette use, inclusive of JUUL. <h3>Results</h3> In this sample of 4183 adolescents, respondents were 49.6% female and 49.6% non-Hispanic white. Students were evenly distributed across grades 9 through 12. Overall, the estimate for current use of e-cigarettes inclusive of JUUL was higher (24.2%; 95% CI, 22.5%-25.9%) compared with current use assessed by use of e-cigarettes only (17.8%; 95% CI, 16.4%-19.4%) or JUUL use only (21.3%; 95% CI, 19.7%-23.0%). Divergence in e-cigarette use estimates was higher for certain subgroups, including female respondents and non-Hispanic black respondents. Also, 88.8% (95% CI, 86.6%-91.1%) of current e-cigarette users reported JUUL as a brand they used. Hispanic students (PR, 0.78; 95% CI, 0.69-0.89) and non-Hispanic students of other races (PR, 0.64; 95% CI, 0.51-0.81) were significantly less likely than non-Hispanic white students to be current e-cigarette users, and students in 12th grade were more likely than those in 9th grade to be current users (PR, 1.29; 95% CI, 1.11-1.48). Current e-cigarette use was positively associated with current use of other tobacco products (PR, 2.57; 95% CI, 2.24-2.95), endorsing a tobacco brand on social media (PR, 1.43; 95% CI, 1.19-1.72), having tobacco-branded merchandise (PR, 1.70; 95% CI, 1.46-1.97), having close friends who used JUUL (PR, 3.81; 95% CI, 3.17-4.58), and seeing JUUL used on school grounds (PR, 1.43; 95% CI, 1.24-1.65). Estimates of prevalence were greater when modeling frequent use. <h3>Conclusions and Relevance</h3> This study found that prevalence of current and frequent e-cigarette use among adolescents was higher when inclusive of JUUL use, and JUUL was by far the most common e-cigarette brand used, providing support for inclusion of brand-specific questions when assessing e-cigarette use. The results also identify characteristics of adolescents who may be more likely to use e-cigarettes.
Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals
Authors: Isabelle A. van Zeventer, Aniek O. de Graaf, Hanneke JCM Wouters, Bert A. Van der Reijden, Melanie van der Klauw, Theo M de Witte, Marianne A. Jonker, Luca Malcovati, Joop H Jansen, Geert Huls
Journal: Blood (2020)
Abstract P1-20-20: Intraoperative ultrasound localization (IOUS) for non-palpable breast cancer
Authors: Shideh Pour Zahed, Thor Knudsen Andersen
Journal: Cancer Research (2020)

Abstract Background: With the introduction of breast cancer screening the number of non-palpable breast cancers and so the number of breast conserving surgery (BCS) has increased. Wire-guided localization (WGL) is used as invasive standard method for localization. IOUS is an alternative non-invasive, time-sparing and safe localization method with many cost benefits. Patient and methods: A retrospective observational study was performed in a single breast unit where IOUS was used as localization method by two surgeons in the period June 2013 to October2016. The surgeons did not have any special experience with Ultrasound (US) apart from one week of bed-side training. Results: During a 41 months period the two surgeons treated 452 with BCS. Of them 126 were non-palpable and visible by US 28%. The 126 cancers were identified with IOUS at surgery and removed successfully by the surgeons. In the period a total of 156 had a BCS with WGL. These cases had a nonpalpable cancer which were non-visible on US with either calcifications, DCIS or non-specific lesions. In the study we also found that the re-lumpectomy rate for BCS with IOUS was lower than without IOUS. In the entire breast unit, the number of BCS were 848 and number of BCS+WGL were 320 in the same period. Of them 263 (22.5%) had a re-lumpectomy. The number BCS with IOUS were 452 and the number of BCS+WGL with IOUS were 156. Of them 72 (11.8%) had a re-lumpectomy. Conclusion: In our breast unit, IOUS was used after a short bed-side training, with 100% success rate, to remove non-palpable cancers if visible on US. IOUS is easy to learn and easy to use and offers many financial and time-sparing benefits. IOUS has a reasonable learning curve and can reduce the work load on the Radiology Department. Citation Format: Shideh Pour Zahed, Thor Knudsen Andersen. Intraoperative ultrasound localization (IOUS) for non-palpable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-20.