tbuckley/cabot-search huggingface dataset:
Advances and challenges in the treatment of esophageal cancer
Authors: Shiming He, Jian Xu, Xiujun Liu, Yongsu Zhen
Journal: Acta Pharmaceutica Sinica B (2021)

Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.
Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project
Authors: Stephen P. Finn, Alfredo Addeo, Urania Dafni, Erik Thunnissen, Lukas Bubendorf, Line Bille Madsen, Wojciech Biernat, Eric Verbeken, Javier Hernandez-Losa, Antonio Marchetti, Richard Cheney, Arne Warth, Ernst-Jan M. Speel, Anne Marie Quinn, Kim Monkhorst, Eloisa Jantus-Lewintre, Verena Tischler, Nesa Marti, Georgia Dimopoulou, Miguel A. Molina-Vila, Roswitha Kammler, Keith M. Kerr, Solange Peters, Rolf A. Stahel
Journal: Journal of Thoracic Oncology (2021)
Gene therapy using Aβ variants for amyloid reduction
Authors: Kyung-Won Park, Caleb A. Wood, Jun Li, Bethany C. Taylor, SaeWoong Oh, Nicolas L. Young, Joanna L. Jankowsky
Journal: Molecular Therapy (2021)

Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid β (Aβ) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aβ variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases. Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid β (Aβ) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aβ variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases.
Land use-induced spillover: a call to action to safeguard environmental, animal, and human health
Authors: Raina K Plowright, Jamie K Reaser, Harvey Locke, Stephen J Woodley, Jonathan A Patz, Daniel J Becker, Gabriel Oppler, Peter J Hudson, Gary M Tabor
Journal: The Lancet Planetary Health (2021)

The rapid global spread and human health impacts of SARS-CoV-2, the virus that causes COVID-19, show humanity's vulnerability to zoonotic disease pandemics. Although anthropogenic land use change is known to be the major driver of zoonotic pathogen spillover from wildlife to human populations, the scientific underpinnings of land use-induced zoonotic spillover have rarely been investigated from the landscape perspective. We call for interdisciplinary collaborations to advance knowledge on land use implications for zoonotic disease emergence with a view toward informing the decisions needed to protect human health. In particular, we urge a mechanistic focus on the zoonotic pathogen infect–shed–spill–spread cascade to enable protection of landscape immunity—the ecological conditions that reduce the risk of pathogen spillover from reservoir hosts—as a conservation and biosecurity priority. Results are urgently needed to formulate an integrated, holistic set of science-based policy and management measures that effectively and cost-efficiently minimise zoonotic disease risk. We consider opportunities to better institute the necessary scientific collaboration, address primary technical challenges, and advance policy and management issues that warrant particular attention to effectively address health security from local to global scales.
Biopolymer-nanotube nerve guidance conduit drug delivery for peripheral nerve regeneration: In vivo structural and functional assessment
Authors: Ohan S. Manoukian, Swetha Rudraiah, Michael R. Arul, Jenna M. Bartley, Jiana T. Baker, Xiaojun Yu, Sangamesh G. Kumbar
Journal: Bioactive Materials (2021)

Peripheral nerve injuries account for roughly 3% of all trauma patients with over 900,000 repair procedures annually in the US. Of all extremity peripheral nerve injuries, 51% require nerve repair with a transected gap. The current gold-standard treatment for peripheral nerve injuries, autograft repair, has several shortcomings. Engineered constructs are currently only suitable for short gaps or small diameter nerves. Here, we investigate novel nerve guidance conduits with aligned microchannel porosity that deliver sustained-release of neurogenic 4-aminopyridine (4-AP) for peripheral nerve regeneration in a critical-size (15 mm) rat sciatic nerve transection model. The results of functional walking track analysis, morphometric evaluations of myelin development, and histological assessments of various markers confirmed the equivalency of our drug-conduit with autograft controls. Repaired nerves showed formation of thick myelin, presence of S100 and neurofilament markers, and promising functional recovery. The conduit's aligned microchannel architecture may play a vital role in physically guiding axons for distal target reinnervation, while the sustained release of 4-AP may increase nerve conduction, and in turn synaptic neurotransmitter release and upregulation of critical Schwann cell neurotrophic factors. Overall, our nerve construct design facilitates efficient and efficacious peripheral nerve regeneration via a drug delivery system that is feasible for clinical applications.
Modeling the effect of exposure notification and non-pharmaceutical interventions on COVID-19 transmission in Washington state
Authors: Matthew Abueg, Robert Hinch, Neo Wu, Luyang Liu, William Probert, Austin Wu, Paul Eastham, Yusef Shafi, Matt Rosencrantz, Michael Dikovsky, Zhao Cheng, Anel Nurtay, Lucie Abeler-Dörner, David Bonsall, Michael V. McConnell, Shawn O’Banion, Christophe Fraser
Journal: npj Digital Medicine (2021)

Abstract Contact tracing is increasingly used to combat COVID-19, and digital implementations are now being deployed, many based on Apple and Google’s Exposure Notification System. These systems utilize non-traditional smartphone-based technology, presenting challenges in understanding possible outcomes. In this work, we create individual-based models of three Washington state counties to explore how digital exposure notifications combined with other non-pharmaceutical interventions influence COVID-19 disease spread under various adoption, compliance, and mobility scenarios. In a model with 15% participation, we found that exposure notification could reduce infections and deaths by approximately 8% and 6% and could effectively complement traditional contact tracing. We believe this can provide health authorities in Washington state and beyond with guidance on how exposure notification can complement traditional interventions to suppress the spread of COVID-19.
Network meta-analysis (NMA) comparing the efficacy of enzalutamide versus apalutamide, darolutamide, and bicalutamide for treatment of nonmetastatic (nm) castration-resistant prostate cancer (CRPC).
Authors: Tomasz M. Beer, Fred Saad, Cora N. Sternberg, Maha H. A. Hussain, Arijit Ganguli, Hemant Singh Bhadauria, Mok Oh, Konstantina Skaltsa, Bertrand Tombal
Journal: Journal of Clinical Oncology (2021)

101 Background: Enzalutamide is a potent androgen receptor (AR) inhibitor, targeting multiple steps in AR signaling. In recent years, the EMA and FDA approved enzalutamide for the management of adults with CRPC, irrespective of metastatic status, based on the Phase 3 PROSPER clinical trial results. To provide indirect evidence on the relative efficacy of enzalutamide vs bicalutamide or the second-generation AR antagonists apalutamide and darolutamide for the management of nmCRPC, a NMA was performed using published data from their Phase 3 clinical trials. Methods: NMA enables indirect comparison of ≥3 interventions across a network of studies, identified by systematic literature review and based on a common comparator, to estimate relative effects between interventions. This NMA compared data from PROSPER (enzalutamide vs placebo [PBO]), SPARTAN (apalutamide vs PBO), ARAMIS (darolutamide vs PBO), and STRIVE (enzalutamide vs bicalutamide) studies, following NICE technical support document 2. Four key endpoints (metastasis-free survival [MFS], overall survival [OS], time to prostate-specific antigen progression [TTPP], and time to first use of cytotoxic chemotherapy [TTCH]) were assessed. It was assumed that there was no variation between studies that could influence the size of treatment effect. Fixed-effect models were developed and implemented under a Bayesian framework. Results: MFS, OS, and TTCH outcomes of PROSPER, SPARTAN, and ARAMIS were compared between androgen deprivation treatment alone and in combination with enzalutamide/apalutamide/darolutamide. TTPP of PROSPER, SPARTAN, ARAMIS, and STRIVE was compared between enzalutamide, apalutamide, darolutamide, bicalutamide, and PBO. Enzalutamide showed significant benefit vs PBO for all endpoints measured (median hazard ratio [HR] 0.29, 0.73, 0.54, 0.07 for MFS, OS, TTCH, TTPP respectively, Table), vs darolutamide for MFS HR 0.71, and vs darolutamide HR 0.51 and bicalutamide HR 0.18 for TTPP. OS for enzalutamide vs apalutamide was not statistically different HR 0.94. Conclusions: Enzalutamide showed significant therapeutic benefit; MFS, OS, TTCH, and TTPP were better vs PBO and MFS and/or TTPP were longer compared to darolutamide and bicalutamide. No statistically significant differences were observed between enzalutamide and apalutamide. This NMA may facilitate the development and testing of treatment strategies for nmCRPC. [Table: see text]
Author Correction: BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells
Authors: Chen Yao, Guohua Lou, Hong-Wei Sun, Ziang Zhu, Yi Sun, Zeyu Chen, Daniel Chauss, E. Ashley Moseman, Jun Cheng, Marc A. D’Antonio, Wangke Shi, Junwei Shi, Kohei Kometani, Tomohiro Kurosaki, E. John Wherry, Behdad Afzali, Luca Gattinoni, Yuwen Zhu, Dorian B. McGavern, John J. O’Shea, Pamela L. Schwartzberg, Tuoqi Wu
Journal: Nature Immunology (2021)
Chilblain-like acral lesions in long COVID-19: management and implications for understanding microangiopathy
Authors: Puja Mehta, Christopher B Bunker, Coziana Ciurtin, Joanna C Porter, Rachel C Chambers, Charalampia Papdopoulou, Helen Garthwaite, Toby Hillman, Melissa Heightman, Kevin J Howell, Despina Eleftheriou, Christopher P Denton
Journal: The Lancet Infectious Diseases (2021)
Should We Prioritize Deimplementation of Continuous Pulse Oximetry in Bronchiolitis Care?
Authors: Christine C. Cheston, Ronnye Rutledge, Heather E. Hsu
Journal: JAMA Pediatrics (2021)

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Investigation of a 22-gene genomic classifier (GC) for risk stratification and molecular subtyping in an Asian prostate cancer (PCa) cohort.
Authors: Wei Loong Sherman Yee, Wai Yee Woo, Adelene Sim, Kar Perng Low, Alice Meng, Janice Ser Huey Tan, Jeffrey Tuan, Terence WK Tan, Michael Lian Chek Wang, Kae-Jack Tay, Christopher Cheng, Joe Poh Sheng Yeong, Yang Liu, Lui Shiong Lee, Ravindran Kanesvaran, Michael Chien Sheng Tan, Elai Davicioni, Li Yan Khor, Melvin Lee Kiang Chua
Journal: Journal of Clinical Oncology (2021)

249 Background: A 22-gene GC has been proposed to refine risk stratification of localized PCa by conventional NCCN criteria, and this may potentially influence treatment recommendations. Nonetheless, majority of studies looking at the utility of GC were conducted in White and non-White men from Western cohorts. We therefore investigated the association of GC with NCCN risk groups (RG) in an Asian PCa cohort. Additionally, we examined for inter-racial differences in molecular subtyping between Asian and White/non-White PCa. Methods: GC (Decipher Biosciences Inc., CA) was performed on diagnostic biopsies of men who were treated with radiotherapy +/- hormonal therapy at a single institution (N = 75). ISUP Gleason’s grade (GG) and tumor cellularity were reviewed by an expert GU pathologist. RNA was extracted from 2 x 2.0-mm tumor cores using Qiagen AllPrep DNA/RNA FFPE Kit (Qiagen, Germany) and gene expression was performed on Affymetrix Human Exon 1.0 ST Array (ThermoFischer, CA). PAM50 molecular subtyping was derived using the Decipher GRID database. Results: We profiled 80 tumors from 75 patients, comprising of 18 (24.0%), 9 (12.0%), 21 (28.0%), and 19 (25.3%) NCCN low-/favorable intermediate-, unfavorable intermediate-, high- and very high-RG, respectively; of note, 8 (10.7%) patients had regional/metastatic disease at diagnosis. Using the GC, 27 (33.8%), 14 (17.5%) and 39 (48.8%) were classified as low- (&lt;0.45), intermediate- (0.45-0.6) and high-RG, respectively (&gt;0.6). When stratified using a three-tier clinico-genomic (CG) classification system (Spratt et al. 2017), 6 of 21 (28.6%) NCCN-defined high-risk and 4 of 19 (21.1%) very high-risk patients were downgraded to CG-defined intermediate-/low-risk, while 2 of 27 (7.4%) NCCN low-/intermediate-risk patients were in fact upgraded to CG high-risk. Next, we interrogated the PAM50 basal-luminal signature in our cohort. Interestingly, when matched to White (N = 5762) and non-White (N = 155) for NCCN RG, ISUP GG and age, we observed a high proportion of basal subtype (62.7%) in Asians, which contrasted the prevalence observed in White (16.7%) and non-White (15.9%) North American patients (Chi-sq P &lt;0.001). Conclusions: Here, we demonstrated the utility of the 22-gene GC for refining the NCCN risk stratification in a largest Asian PCa dataset to-date. An unexpectedly high proportion of PAM50 basal-subtype was observed, suggesting race-specific differences of the tumor transcriptome.
Covid-19: Where are we on vaccines and variants?
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: Where are we on vaccines and variants?Nearly a year after WHO declared the covid-19 pandemic, Elisabeth Mahase reports on the latest developments in vaccines, variants, and diplomacy Elisabeth MahaseHave any new variants emerged?We've heard a lot about B.1.1.7 (first detected in the UK), B.1.351(first detected in South Africa), and P.1 (detected in Manaus, Brazil), but other variants have also emerged, including one in New York.Named B.1.526, the variant contains the same E484K mutation that has caused so much concern in B.1.351.This mutation is thought to allow the virus to escape some of the body's immune response.Vaccines developed against the original virus have also been found to be less effective against B.1.351(table 1).In a preprint released on 25 February, 20 researchers said the variant was "surging, alarmingly, in our patient population over the past few weeks" and that patients with this novel variant "were on average older and more frequently hospitalised."They added that further analysis showed that the B.1.526variant was "scattered in the northeast of US, and its unique set of spike mutations may also pose an antigenic challenge for current interventions.
The impact of adjuvant chemotherapy on oncologic outcomes of patients with locally advanced bladder adenocarcinoma: An analysis of the National Cancer Database.
Authors: Akshay G Reddy, Andrew D Sparks, Michael Helbig, Michael Joseph Whalen
Journal: Journal of Clinical Oncology (2021)

495 Background: The relatively poor prognosis associated with locally advanced bladder adenocarcinoma necessitates investigation of the utility of adjuvant chemotherapy (AC) and risk stratification of those who would benefit from such systemic therapy. This study seeks to evaluate the oncologic and surgical outcomes of those with locally advanced disease treated with and without AC. Methods: A retrospective cohort analysis was performed using the National Cancer Database from 2006 to 2016. Patients with non-metastatic locally advanced pT3-4 or pT(any)N1-3 primary bladder adenocarcinoma who received AC only or did not receive AC after radical (RC) or partial cystectomy (PC) were included. The AC cohort was further sub-stratified by surgery type (PC versus RC) and disease origin (urachal versus non-urachal subtypes). Survival, oncologic, and surgical outcomes were compared between cohorts. Results: Inclusion criteria identified 79 AC patients and 251 no AC patients. Of the 79 patients who received AC, 23 had PC procedure, 56 had RC procedure, 10 had urachal origin and 69 had non-urachal origin. Receipt of AC was significantly higher in RC relative to PC (27.6% vs 18.1%; p = 0.049). Urachal vs. non-urachal subtype did not impact receipt of AC (25.3% vs 17.5%; p = 0.214), but urachal subtype was associated with improved overall survival compared to non-urachal (47% vs 18%; HR = 0.37; p = 0.04). Although receipt of AC was significantly associated with higher odds of positive margins (46% vs 23%; odds ratio = 2.85; p &lt; 0.01), no difference in overall survival was detected between the AC and no AC cohorts (23% vs 19%; hazards ratio [HR] = 0.98; p = 0.91). Of note, independent of AC, PC was associated with improved survival compared to RC (51% vs 12%; HR = 0.25; p &lt; 0.01). Conclusions: There is no detected survival benefit to the use of a non-standardized AC regimen in locally advanced bladder adenocarcinoma. Within the AC treated population, survival outcomes suggest that urachal subtype may confer survival advantage and that those patients selected for PC tend to have improved survival. Although employing a national dataset, statistical power was limited given the rarity of this disease. Further investigation is warranted on a larger scale in order to assess the impact of AC regimen, afford proper patient selection, and enhance risk stratification for oncologic outcomes.
Abstract 14145: Frequency Analysis of the Paced QRS Predicts Development of Pacing Induced Left Ventricular Dysfunction
Authors: Ram Amuthan, John Rickard, Patrick J Tchou, Niraj Varma, Daniel Cantillon, Erich Kiehl, Mandeep Bhargava, Bryan Baranowski, Thomas Callahan, Mina Chung, Thomas Dressing, Ayman Hussein, Mohammad Kanj, Bruce Lindsay, Walid Saliba, Khaldoun Tarakji, Ousamma Wazni, Bruce Wilkoff, Christine Tanaka Esposito, Kenneth Mayuga, David Martin, Mark J Niebauer
Journal: Circulation (2018)

Introduction: Single site pacing from the right ventricle (RV) has been identified as a risk factor for the development of left ventricular (LV) dysfunction. To date, there are no definite QRS char...
Regulatory mechanisms, functions, and clinical significance of CircRNAs in triple-negative breast cancer
Authors: Lijuan Lyu, Shizhen Zhang, Yujiao Deng, Meng Wang, Xinyue Deng, Si Yang, Ying Wu, Zhijun Dai
Journal: Journal of Hematology & Oncology (2021)

Abstract Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by covalently closed cyclic structure lacking poly-adenylated tails, and are capable of regulating gene expression at transcription or post-transcription levels. Recently, plentiful circRNAs have been discovered in breast cancer and some circRNAs expression profiles are specifically involved in the triple-negative breast cancer (TNBC). TNBC is a type of malignant tumor defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Considering its clinical characteristics of high invasion, metastasis, poor prognosis, and lack of effective response to conventional chemotherapies or targeted therapies, it could be a promosing option to discover specific circRNAs as new targets for TNBC treatment. Meanwhile, accumulating evidence has demonstrated that circRNAs are dysregulated in TNBC tissues and are correlated with clinicopathological features and prognosis of TNBC patients. Furthermore, looking for circRNAs with high specificity and sensitivity will provide a new opportunity for the early diagnosis, clinical treatment, and prognosis monitoring of TNBC. Herein, we reviewed the biogenesis, regulatory mechanisms, and biological functions of circRNAs in TNBC and summarized the relationship between circRNAs expression and the clinicopathology, diagnosis, and prognosis of patients with TNBC.