tbuckley/cabot-search huggingface dataset:
The athlete’s sleep paradox prompts us to reconsider the dose-response relationship of physical activity and sleep
Authors: Ryan S Falck, Emmanuel Stamatakis, Teresa Liu-Ambrose
Journal: British Journal of Sports Medicine (2021)

Everyone needs good quality sleep. Good sleep is essential for health, while poor sleep increases morbidity and mortality risk.1

Sleep is also crucial for athletic performance and recovery.2 Even though physical activity (PA) and exercise improve sleep,3 poor sleep is prevalent among elite-level athletes.4 We therefore propose a modified, inverted U-shaped, dose-response relationship between PA and sleep (figure 1), and highlight the need for more research on the PA-sleep dose-response relationship. In this editorial, we briefly discuss the current understanding of the dose-response relationship of PA and sleep, describe the paradox of sleep in athletes, illustrate our hypothetical model, and outline where future research is needed.



Figure 1 
The dose-response relationship between physical activity (intensity and/or volume) and sleep quality (ie, duration, efficiency, etc) is dependent on physical fitness level. Low physical activity is associated with poorer sleep quality irrespective of fitness level; however, the benefits of physical activity on sleep quality are positive until acute fatigue or overtraining occurs from too much physical activity (either volume and/or intensity). The ‘tipping point’ for when acute fatigue and overtraining occur is dependent on whether an adult has low physical fitness (red), moderate-to-high physical fitness (green) or has elite athlete physical fitness (yellow). Individual, social and mental health factors may also impact sleep positively or negatively. Individual factors include: age, gender, lifestyle (eg, diet and caffeine intake), body mass, among others. …
TCR β chain–directed bispecific antibodies for the treatment of T cell cancers
Authors: Suman Paul, Alexander H. Pearlman, Jacqueline Douglass, Brian J. Mog, Emily Han-Chung Hsiue, Michael S. Hwang, Sarah R. DiNapoli, Maximilian F. Konig, Patrick A. Brown, Katharine M. Wright, Surojit Sur, Sandra B. Gabelli, Yana Li, Gabriel Ghiaur, Drew M. Pardoll, Nickolas Papadopoulos, Chetan Bettegowda, Kenneth W. Kinzler, Shibin Zhou, Bert Vogelstein
Journal: Science Translational Medicine (2021)

Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen-targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.
Three-dimensional (3D) hydrogel serves as a platform to identify potential markers of chondrocyte dedifferentiation by combining RNA sequencing
Authors: Yang Ling, Weiyuan Zhang, Peiyan Wang, Wanhua Xie, Wei Yang, Dong-An Wang, Changjiang Fan
Journal: Bioactive Materials (2021)

Dedifferentiation of chondrocyte greatly restricts its function and application, however, it is poorly understood except a small number of canonical markers. The non-cell-adhesive property endows polysaccharide hydrogel with the ability to maintain chondrocyte phenotype, which can serve as a platform to identify new molecular markers and therapeutic targets of chondrocyte dedifferentiation. In this study, the high-throughput RNA sequencing (RNA-seq) was first performed on articular chondrocytes at primary (P0) and passage 1 (P1) stages to explore the global alteration of gene expression along with chondrocyte dedifferentiation. Significantly, several potential marker genes, such as PFKFB3, KDM6B, had been identified via comparatively analyzing their expression in P0 and P1 chondrocytes as well as in 3D constructs (i.e. chondrocyte-laden alginate hydrogel and HA-MA hydrogel) at both mRNA and protein level. Besides, the changes in cellular morphology and enriched pathway of differentially expressed genes during chondrocyte dedifferentiation was studied in detail. This study developed the use of hydrogel as a platform to investigate chondrocyte dedifferentiation; the results provided new molecular markers and potential therapeutic targets of chondrocyte dedifferentiation.
Beyond the Glass Ceiling—Do Women in Senior Positions Face a Precarious Glass Cliff?
Authors: Nithya Krishnan, Ala Szczepura
Journal: JAMA Surgery (2021)

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TKI-28, a broad-spectrum tyrosine kinase inhibitor with anti-tumor and anti-angiogenic effects
Authors: Xiao-Ning Guo, Zhong Li, Jingyu Lang, Xiao-Min Luo, Hua-Liang Jiang, Li-Ping Lin, Xiong-Wen Zhang, Jian Ding
Journal: Cancer Research (2005)

5825  Aberrant regulation of tyrosine kinases is often associated with a more aggressive behavior and poor prognosis in many tumor types and also play an important role in angiogenic process essential to carcinogenesis. Recent studies suggested that broad-spectrum tyrosine kinase inhibitors often have greater potentials in preclinical and clinical anti-tumor activities than specific inhibitors for they might overcome redundancies and crosstalk in growth signaling pathways of tumor cells. TKI-28 (6-(2,6-Dichlorophenyl)-8-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one) is a potent inhibitor for a broad range of tyrosine kinases. At the enzyme level, TKI-28 suppressed ErbB-2, KDR, PDGFRβ and c-Src tyrosine kinases activities with IC50 values of 10±5.9, 27±12, 36±17, 11±1.1 nM respectively while it has weak effects on EGFR and Flt-1. In cellular level, TKI-28 inhibited EGF-induced ErbB-2 tyrosine kinase autophosphorylation efficiently in human SK-OV-3 ovarian carcinoma cells. In addition, VEGF-stimulated KDR and PDGF-stimulated PDGFRβ autophosphorylation were also blocked in human microvascular endothelial cells (HMEC) and mouse Swiss 3T3 cells, individually. As a result of inhibition of ErbB-2 in SK-OV-3 cells, EGF-mediated phosphorylation of many downstream signaling proteins including ERK1/2, AKT, mTOR, c-Src, STAT1, STAT3 and PLCγ were also downregulated. TKI-28 was demonstrated a more potent anti-proliferative activity against EGF- and neuregulin-stimulated SK-OV-3 cells than serum-stimulated. In the same way, TKI-28 inhibited EGF-, VEGF-, PDGF-driven proliferation of HMEC cells in the submicromolar range (IC50s: 0.26 ±0.21, 0.35 ±0.12, 0.35 ±0.21 μM, respectively), lower than serum-stimulated (IC50: 3.13 ±0.93 μM). Furthermore, TKI-28 significantly decreased the proliferation of a series of human tumor cells. TUNEL assay and flow cytometry method both indicated TKI-28 could induce SK-OV-3 cells apoptosis in a dose-dependent manner. The effects of TKI-28 on angiogenesis were also investigated using a modified Boyden chamber assay and tube formation assay. It showed that the compound potently inhibited HMEC cells migration and blocked HMEC cells tube formation on Matrigel. These results collectively highlight the biological characteristics of TKI-28 as a broad-spectrum tyrosine kinase inhibitor and indicate its potential to be an anti-cancer agent as well as an angiogenesis inhibitor.
Final results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic castration-resistant prostate cancer (LuPIN trial).
Authors: Sarennya Pathmanandavel, Megan Crumbaker, Andrew On Wah Yam, Christopher Rofe, Bao Ho, Wai Ling Chan, Shikha Sharma, Adam James Hickey, Kamonwan Kongrak, Lalith Ratnayake, Edmond Michael Kwan, Arun Azad, Peter Eu, Andrew Nguyen, Anthony M. Joshua, Louise Emmett
Journal: Journal of Clinical Oncology (2021)

103 Background: 177 LuPSMA – 617 is a promising therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and synergistic combination therapy may improve outcomes. We combined 177 LuPSMA – 617 with idronoxil (NOX66), an inhibitor of external NADH oxidase type 2 with radio-sensitizing properties. We present the final safety and efficacy results. Methods: Men with progressive mCRPC after androgen signalling inhibition (ASI) and taxane chemotherapy were enrolled. Key inclusion criteria were: PSMA PET/CT intensity SUV max &gt; 15 with no discordant disease on FDG PET/CT, haemoglobin &gt; 100g/L, platelets &gt; 100x10 9 /L and eGFR &gt; 40mls/min. Enrolled patients received up to six doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n = 8) received 400mg NOX66. Following safety reviews the doses were escalated in cohorts 2 (n = 24) and 3 (n = 24) to 800mg and 1200mg of NOX66, respectively. Blood samples were prospectively collected for androgen receptor splice variant 7 (ARV7) expression. PSMA and FDG PET/CT were performed at study entry and on progression. The primary outcomes were safety and tolerability; the secondary outcomes evaluated were efficacy, pain scores, and quality of life. Results: Of the 56 men enrolled, all had received prior treatment with ASI and docetaxel, and 95% (53/56) had prior cabazitaxel. 96% (54/56) patients received ≥2 cycles and 46% (26/56) completed six cycles of treatment. Adverse events are summarized in the table below. PSA responses were as follows: 86% (48/56) had any PSA reduction and 61% (34/56) had &gt; 50% PSA reduction. 84% (47/56) have had PSA progression to date with median follow up 18.9 months (95% CI 11.9-25.8). Median PSA PFS was 7.5 months (95% CI 6.0-9.0). 55% (31/56) have died and median overall survival was 19.7 months (95% CI 10.7-28.7). 34/56 men had baseline pain scores ≥3, of whom 53% (18/34) had significant reduction in pain indicators. There was no correlation between quantitative PET results and either PSA &gt; 50% response, PSA PFS or OS. Conclusions: The combination of 177 Lu-PSMA 617 + NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Exploratory analysis of ARV7 expression and quantitative PET imaging markers of treatment response and resistance is in progress. Clinical trial information: ACTRN12618001073291. [Table: see text]
<i>LRP1B</i>mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types
Authors: Landon C Brown, Matthew D Tucker, Ramy Sedhom, Eric B Schwartz, Jason Zhu, Chester Kao, Matthew K Labriola, Rajan T Gupta, Daniele Marin, Yuan Wu, Santosh Gupta, Tian Zhang, Michael R Harrison, Daniel J George, Ajjai Alva, Emmanuel S Antonarakis, Andrew J Armstrong
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B ) is a putative tumor suppressor, and preliminary evidence suggests LRP1B- mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI). Methods We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status. Results We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB). Conclusions This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.
Abstract PO-004: A deep convolutional neural network for segmentation of whole-slide pathology images in glioblastoma
Authors: Amin Zadeh Shirazi, Mark D. McDonnell, Eric Fornaciari, Narjes Sadat Bagherian, Kaitlin G. Scheer, Michael S. Samuel, Mahdi Yaghoobi, Rebecca J. Ormsby, Santosh Poonnoose, Damon Tumes, Guillermo A. Gomez
Journal: Clinical Cancer Research (2021)

Abstract Glioblastoma is the most aggressive type of brain cancer with high-levels of intra- and inter-tumour heterogeneity that contribute to its rapid growth and invasion within the brain. Here, we have used a deep convolutional neural network (DCNN) as a semantic segmentation model to segment seven different tumour regions including leading-edge (LE), infiltrating tumour (IT), cellular tumour (CT), cellular tumour microvascular proliferation (CTmvp), cellular tumour pseudopalisading region around necrosis (CTpan), cellular tumour perinecrotic zones (CTpnz) and cellular tumour necrosis (CTne) in digitised glioblastoma histopathological slides from The Cancer Genome Atlas (TCGA). Analysis of segmentation results from tumour images together with matched RNA expression data identified genetic signatures that are specific to these different tumour regions. We found that spatially resolved gene signatures were strongly correlated with survival in patients with defined genetic mutations. Moreover, in silico cell ontology analysis and single-cell RNA sequencing data from resected glioblastoma tissue samples, showed that these tumour regions had different gene signatures, suggesting they are driven by different cell types in the tumour microenvironment. This points to a key role for interactions between microglia/pericytes/monocytes and tumour cells that occur in the IT and CTmvp regions, which may contribute to poor patient survival. Overall, this work identifies key histopathological features that are indicative of patient survival and detected spatially associated genetic signatures that mediate tumour-stroma interactions that should be investigated as new targets in glioblastoma. Citation Format: Amin Zadeh Shirazi, Mark D. McDonnell, Eric Fornaciari, Narjes Sadat Bagherian, Kaitlin G. Scheer, Michael S. Samuel, Mahdi Yaghoobi, Rebecca J. Ormsby, Santosh Poonnoose, Damon Tumes, Guillermo A. Gomez. A deep convolutional neural network for segmentation of whole-slide pathology images in glioblastoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-004.
Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?
Authors: Anja Rinke, Christoph J Auernhammer, Lisa Bodei, Mark Kidd, Sebastian Krug, Rita Lawlor, Ilaria Marinoni, Aurel Perren, Aldo Scarpa, Halfdan Sorbye, Marianne Ellen Pavel, Matthias M Weber, Irvin Modlin, Thomas M Gress
Journal: Gut (2021)

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options. The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour. This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
Conditional progression-free survival in men on active surveillance for prostate cancer stratified by NCCN risk.
Authors: Andrew Gusev, Florian Rumpf, Keyan Salari, Jeffrey Twum-Ampofo, Matthew F Wszolek, Douglas M. Dahl, Michael L. Blute, Adam S. Feldman
Journal: Journal of Clinical Oncology (2021)

222 Background: Active surveillance (AS) is an accepted management strategy for men with very low, low, and select cases of favorable intermediate National Comprehensive Cancer Network (NCCN) risk prostate cancer (PCa). However, how patients’ risk of disease progression evolves over time during AS has not been well defined. Conditional survival measures the probability a patient will continue to survive some number of years, given that they have already survived a certain number without progression. We evaluated our AS cohort to investigate overall and conditional progression free survival on AS, stratified by the NCCN risk groups. Methods: We reviewed our institutional database of 1254 men enrolled in AS for localized PCa from 1996-2016. Our AS protocol includes prostate specific antigen (PSA) and digital rectal exam (DRE) every 4-6 months for 3 years, then annually. Mandatory confirmatory 12 core biopsy is done at 12-18 months. Multiparametric magnetic resonance imagining (mpMRI) or additional systematic or MRI-fusion biopsies are done at the discretion of physician and patient. Overall freedom from pathologic grade progression on follow-up biopsy and treatment free survival were estimated using the Kaplan-Meier method. Survival curves were compared pairwise using the Log-rank test and adjusted for false discovery rates with the Benjamini-Hochberg procedure. Three-year conditional survival estimates were derived for both outcomes from the Kaplan-Meier estimator. Results: Of 1254 men, 521 (41.6%) met criteria for very low, 606 (48.4%) for low, and 125 (10.0%) for favorable intermediate NCCN risk at diagnosis. Median follow-up time was 6.5 years (IQR 4.1-9.4). Median pathologic grade progression free survival in years was significantly longer for very low risk (7.8, 95% CI 6.8-11.2) compared to low risk men (5.6, 95% CI 4.7-6.9), however neither was significantly different from favorable intermediate risk men (5.9). There was no significant difference in treatment free survival between the three risk groups. At diagnosis, the three-year risk for pathologic grade progression (24%, 95% CI 21-27%) and progression to treatment (22%, 95% CI 20-25%) were similar. However, with increasing time of event-free AS, the conditional probability of pathologic grade progression increased, while that of progression to treatment decreased. Conclusions: Our results demonstrate that despite a mild increase in pathologic progression free survival in very low risk men, there was no clear difference in overall treatment free survival between very low, low, and select favorable intermediate NCCN risk men. Further, with increased time spent on AS, despite elevated rates of pathologic progression, patient progression to treatment decreased. This trend may be indicative of changes in goals of care as men with PCa age and should be closely monitored during AS.
IL‐33 augments the effect of rhinovirus HRV16 on inflammatory activity of human lung vascular endothelium—possible implications for rhinoviral asthma exacerbations
Authors: Adrian Gajewski, Mateusz Gawrysiak, Robert Szewczyk, Izabela Gulbas, Aleksandra Likońska, Sylwia Michlewska, Marek L. Kowalski, Maciej Chałubiński
Journal: Allergy (2021)

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