tbuckley/cabot-search huggingface dataset:
Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921.
Authors: Daniel Peter Petrylak, Neal D. Shore, Mostefa Bennamoun, Raffaele Ratta, Josep M. Piulats, Ben Li, Charles Schloss, Karim Fizazi
Journal: Journal of Clinical Oncology (2020)

TPS262 Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m 2 IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m 2 IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506.
Class A1 scavenger receptor prevents obesity-associated blood pressure elevation through suppressing overproduction of vascular endothelial growth factor B in macrophages
Authors: Xudong Zhu, Yan Wang, Liu Zhu, Ye Zhu, Kun Zhang, Lei Wang, Hui Bai, Qing Yang, Jingjing Ben, Hanwen Zhang, Xiaoyu Li, Yong Xu, Qi Chen
Journal: Cardiovascular Research (2020)

Dysfunctional innate immune function and inflammation contributes to the pathogenesis of obesity-associated hypertension, in which macrophage infiltration in the perivascular adipose tissue (PVAT) plays a key role. However, the mechanisms behind it are not well understood. Class A1 scavenger receptor (SR-A1) is one of the major pattern recognition receptors in modulating macrophage activity, and here, we aimed to investigate its role in obesity-associated hypertension.Both diet-induced and genetic obesity were generated in mice. Deficiency in SR-A1 aggravated the obesity-induced blood pressure (BP) elevation and endothelial dysfunction in mice. The BP-elevating effect of SR-A1 deficiency was blocked by the down-regulation of vascular endothelial growth factor B (VEGF-B) in obese mice. Overexpression of VEGF-B raised BP in the obese mice but not in normal mice. Administration of fucoidan, a ligand of SR-A1, lowered BP, and VEGF-B levels in Sr-a1+/+ but not in Sr-a1-/- obese mice.These results reveal a new link between PVAT and vascular biology in obesity orchestrated by the SR-A1/VEGF-B axis in macrophages. SR-A1 and VEGF-B may be promising therapeutic targets in the treatment of obesity-associated hypertension.
Treatment of coronary microvascular dysfunction
Authors: C Noel Bairey Merz, Carl J Pepine, Hiroki Shimokawa, Colin Berry
Journal: Cardiovascular Research (2020)

Abstract Contemporary data indicate that patients with signs and symptoms of ischaemia and non-obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) with elevated risk for adverse outcomes. Coronary endothelial (constriction with acetylcholine) and/or microvascular (limited coronary flow reserve with adenosine) dysfunction are well-documented, and extensive non-obstructive atherosclerosis is often present. Despite these data, patients with INOCA currently remain under-treated, in part, because existing management guidelines do not address this large, mostly female population due to the absence of evidence-based data. Relatively small sample-sized, short-term pilot studies of symptomatic mostly women, with INOCA, using intense medical therapies targeting endothelial, microvascular, and/or atherosclerosis mechanisms suggest symptom, ischaemia, and coronary vascular functional improvement, however, randomized, controlled outcome trials testing treatment strategies have not been completed. We review evidence regarding CMD pharmacotherapy. Potent statins in combination with angiotensin-converting enzyme inhibitor (ACE-I) or receptor blockers if intolerant, at maximally tolerated doses appear to improve angina, stress testing, myocardial perfusion, coronary endothelial function, and microvascular function. The Coronary Microvascular Angina trial supports invasive diagnostic testing with stratified therapy as an approach to improve symptoms and quality of life. The WARRIOR trial is testing intense medical therapy of high-intensity statin, maximally tolerated ACE-I plus aspirin on longer-term outcomes to provide evidence for guidelines. Novel treatments and those under development appear promising as the basis for future trial planning.
Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts
Authors: Joel Hellewell, Sam Abbott, Amy Gimma, Nikos I Bosse, Christopher I Jarvis, Timothy W Russell, James D Munday, Adam J Kucharski, W John Edmunds, Sebastian Funk, Rosalind M Eggo, Fiona Sun, Stefan Flasche, Billy J Quilty, Nicholas Davies, Yang Liu, Samuel Clifford, Petra Klepac, Mark Jit, Charlie Diamond, Hamish Gibbs, Kevin van Zandvoort
Journal: The Lancet Global Health (2020)
High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
Authors: Hao Xu, Liang Zhong, Jiaxin Deng, Jiakuan Peng, Hongxia Dan, Xin Zeng, Taiwen Li, Qianming Chen
Journal: International Journal of Oral Science (2020)

It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Analysis of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated in-house were used to identify and confirm the ACE2-expressing cell composition and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clinical practice as well as daily life.
Abstract 13447: Prospective Analysis of Utility of Signals From an Ecg-Enabled Stethoscope to Automatically Detect a Low Ejection Fraction Using Neural Network Techniques Trained From the Standard 12-Lead Ecg
Authors: Zachi I Attia, Jennifer Dugan, John Maidens, Adam Rideout, Francisco Lopez-Jimenez, Peter A Noseworthy, Samuel Asirvatham, Patricia A Pellikka, Dorothy J Ladewig, Gaurav Satam, Steve Pham, Subramaniam Venkatraman, Paul Friedman, Suraj Kapa
Journal: Circulation (2019)

Background: ECG-enabled stethoscopes (ECG-steth) can acquire single lead ECGs during cardiac auscultation, and may facilitate real-time screening for pathologies not routinely identified during phy...
Genomic landscape and immune microenvironment features of FH-deficient renal cell carcinoma.
Authors: Guangxi Sun, Xingming Zhang, Xiuyi Pan, Sha Zhu, Zhenhua Liu, Jinge Zhao, Cameron M. Armstrong, Haoran Zhang, Rui Huang, Xiaoxue Yin, Mengni Zhang, Pengfei Shen, Jindong Dai, Yali Shen, Ling Nie, Qiang Wei, Xiang Li, Jin Yao, Ni Chen, Hao Zeng
Journal: Journal of Clinical Oncology (2020)

717 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but aggressive subtype of RCC, and an understanding of their genomic landscape is lacking. Methods: Thirteen FH-deficient RCC and matched normal samples from our medical center were used for whole-exome sequencing and molecular profiling. Transcriptomic sequencing data were analyzed from The Cancer Genome Atlas (TCGA) RCC samples and two independent datasets of FH-mutated RCC. For each patient in our cohort, clinical outcomes were recorded, with median follow-up until March, 2019. Results: We identified FH-deficient RCC had high mutation burden, frequent somatic mutations in MUC4, MUC16, ANKRD6 and PRDM16 and germline pathologic FANCD2 mutation. In contrast to mainly RCC subtypes, FH-deficient RCC exhibited elevated mutational signatures of homologous recombination deficiency (7/13, 53%) and microsatellite instability (4/13, 30%). Moreover, we revealed that FH-deficient RCC was characteristic of an immunogenic tumor type, with high tumor-specific neoantigen burdens, enhanced immune cells infiltration but immunosuppressive microenvironment. In our cohort, 11 patients received systematic treatments; 63% (5/8) responded poorly to antiangiogenic or anti-mammalian target of rapamycin agents, but all (6/6) achieved benefit from immune checkpoint blockade monotherapy or combination with antiangiogenic agents. Conclusions: Our study provides a better understanding of the mutational landscape of FH-deficient RCC, highlighting the potential of immunotherapy for treating this patient populations.
Artificial intelligence for streamlined immunofluorescence-based biomarker discovery in prostate cancer.
Authors: Claire Marie de la Calle, Hao Gia Nguyen, Ehsan Hosseini-Asl, Clarence So, Richard Socher, Caiming Xiong, Lingru Xue, Peter Carroll, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2020)

279 Background: Immunofluorescence (IF) performed on tissue microarrays (TMA) is used for biomarker discovery but is limited by the arduous and subjective human visual assessment with an IF microscope. We aim to implement deep learning-based artificial intelligence (AI) models to automate and speed up the analysis of numerous biomarkers and generate prediction models of recurrence and metastasis after surgery. Methods: A TMA was constructed consisting of 648 samples (424 tumors, 224 normal tissue) generated from prostatectomy specimens. IF staining was performed on the TMA using anti Ki-67, ERG antibodies and analyzed for differential expression using “gold standard” manual microscopy and using an AI algorithm. Analysis was done blinded to any clinicopathological data. For manual microscopy, relative mean fluorescence intensity of cancerous versus normal tissue was determined. The AI algorithm was generated using a training cohort of digitized images. To do so the Otsu method thresholding algorithm combined with mean shift clustering was employed to find cell centers, followed by a level-set algorithm, to compute cell boundaries.These predictions were then combined with pixel predictions of a fully convolutional deep model to refine the regions of overlapping epithelium, stroma, and artifact. The algorithm was then validated using a separate cohort. Results from the algorithm were then compared to the data from manual microscopy. Results: Ki-67 and ERG expression levels generated by the algorithm showed only a 5% variance compared to the manually generated results. The algorithm was able to pick out which tumor were positive for ERG with 100% accuracy in spite of variance from artifacts. The algorithm also had the ability to improve its accuracy after each iteration of modifications and feedback through the training cohort. Conclusions: The AI algorithm produced similar outcomes than manual quantification with high accuracy but with more efficiency, cost effectiveness and objectivity. We are now developing more complex algorithms that will include the differential pattern of expression of PTEN, MYC and others with the objectives of streamlining biomarker discovery.
Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation
Authors: Yong Wang, Yiming Xu, Siyuan Yan, Kaixiang Cao, Xianqiu Zeng, Yaqi Zhou, Zhiping Liu, Qiuhua Yang, Yue Pan, Xiaoling Wang, Detlev Boison, Yunchao Su, Xuejun Jiang, Vijay S Patel, David Fulton, Neal L Weintraub, Yuqing Huo
Journal: Cardiovascular Research (2020)

Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action.
Prehospital Severe Trauma Management in Tactical Medicine
Authors: Simon-Pierre Corcostegui, Julien Galant, Cédric Boutillier du Retail
Journal: JAMA Surgery (2020)

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Blood mass spectrometry detects residual disease better than standard techniques in light-chain amyloidosis
Authors: Angela Dispenzieri, Bonnie Arendt, Surendra Dasari, Mindy Kohlhagen, Taxiarchis Kourelis, Shaji K. Kumar, Nelson Leung, Eli Muchtar, Francis K. Buadi, Rahma Warsame, Robert A. Kyle, Martha Q. Lacy, David Dingli, Prashant Kapoor, Wilson I. Gonsalves, Ronald S. Go, Suzanne R. Hayman, Yi Lisa Hwa, Amy Fonder, Miriam Hobbs, Dragan Jevremovic, John A. Lust, Steven Zeldenrust, Steve J. Russell, S. Vincent Rajkumar, Morie A. Gertz, David Murray
Journal: Blood Cancer Journal (2020)

Abstract In patients with immunoglobulin light-chain (AL) amyloidosis, depth of hematologic response correlates with both organ response and overall survival. Our group has demonstrated that screening with a matrix-assisted laser desorption/ionization-time-of-flight (TOF) mass spectrometry (MS) is a quick, sensitive, and accurate means to diagnose and monitor the serum of patients with plasma cell disorders. Microflow liquid chromatography coupled with electrospray ionization and quadrupole TOF MS adds further sensitivity. We identified 33 patients with AL amyloidosis who achieved amyloid complete hematologic response, who also had negative bone marrow by six-color flow cytometry, and who had paired serum samples to test by MS. These samples were subjected to blood MS. Four patients (12%) were found to have residual disease by these techniques. The presence of residual disease by MS was associated with a poorer time to progression (at 50 months 75% versus 13%, p = 0.003). MS of the blood out-performed serum and urine immunofixation, the serum immunoglobulin free light chain, and six-color flow cytometry of the bone marrow in detecting residual disease. Additional studies that include urine MS and next-generation techniques to detect clonal plasma cells in the bone marrow will further elucidate the full potential of this technique.
Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells
Authors: Tiantian Zhang, Zhuqiang Zhang, Qiang Dong, Jun Xiong, Bing Zhu
Journal: Genome biology (2020)

Abstract H3K27ac is well recognized as a marker for active enhancers and a great indicator of enhancer activity. However, its functional impact on transcription has not been characterized. By substituting lysine 27 in histone variant H3.3 with arginine in mouse embryonic stem cells, we diminish the vast majority of H3K27ac at enhancers. However, the transcriptome is largely undisturbed in these mutant cells, likely because the other enhancer features remain largely unchanged, including chromatin accessibility, H3K4me1, and histone acetylation at other lysine residues. Our results clearly reveal that H3K27ac alone is not capable of functionally determining enhancer activity.
Comprehensive assessment of computational algorithms in predicting cancer driver mutations
Authors: Hu Chen, Jun Li, Yumeng Wang, Patrick Kwok-Shing Ng, Yiu Huen Tsang, Kenna R. Shaw, Gordon B. Mills, Han Liang
Journal: Genome biology (2020)

Abstract Background The initiation and subsequent evolution of cancer are largely driven by a relatively small number of somatic mutations with critical functional impacts, so-called driver mutations. Identifying driver mutations in a patient’s tumor cells is a central task in the era of precision cancer medicine. Over the decade, many computational algorithms have been developed to predict the effects of missense single-nucleotide variants, and they are frequently employed to prioritize mutation candidates. These algorithms employ diverse molecular features to build predictive models, and while some algorithms are cancer-specific, others are not. However, the relative performance of these algorithms has not been rigorously assessed. Results We construct five complementary benchmark datasets: mutation clustering patterns in the protein 3D structures, literature annotation based on OncoKB, TP53 mutations based on their effects on target-gene transactivation, effects of cancer mutations on tumor formation in xenograft experiments, and functional annotation based on in vitro cell viability assays we developed including a new dataset of ~ 200 mutations. We evaluate the performance of 33 algorithms and found that CHASM, CTAT-cancer, DEOGEN2, and PrimateAI show consistently better performance than the other algorithms. Moreover, cancer-specific algorithms show much better performance than those designed for a general purpose. Conclusions Our study is a comprehensive assessment of the performance of different algorithms in predicting cancer driver mutations and provides deep insights into the best practice of computationally prioritizing cancer mutation candidates for end-users and for the future development of new algorithms.
Activity-Dependent Plasticity of Axo-axonic Synapses at the Axon Initial Segment
Authors: Alejandro Pan-Vazquez, Winnie Wefelmeyer, Victoria Gonzalez Sabater, Guilherme Neves, Juan Burrone
Journal: Neuron (2020)

The activity-dependent rules that govern the wiring of GABAergic interneurons are not well understood. Chandelier cells (ChCs) are a type of GABAergic interneuron that control pyramidal cell output through axo-axonic synapses that target the axon initial segment. In vivo imaging of ChCs during development uncovered a narrow window (P12–P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window result in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the axon initial segment (AIS) showed that axo-axonic synapses were depolarizing during this period. Identical manipulations of network activity in older mice (P40–P46), when ChC synapses are inhibitory, resulted instead in an increase in axo-axonic synapses. We propose that the direction of ChC synaptic plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.
Does presence of bone metastases portend worsened prognosis in metastatic renal cell carcinoma? Analysis of the REMARCC (Registry of MetAstatic RCC) database.
Authors: Aaron Bradshaw, Maria Carmen Mir, Ricardo Autorino, Andrea Minervini, Maximilian Kriegmair, Tobias Maurer, Francesco Porpiglia, Siska Van Bruwaene, Estefania Linares Espinos, Vital Hevia, Mireia Musquera, Eduard Rousel, Nicola Pavan, Alessandro Antonelli, Shudong Zhang, Margaret Meagher, Jose Rubio, Maarten Albersen, Maria Furlan, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

655 Background: The presence of brain metastases and bone metastases are generally understood to herald worsened prognosis following nephrectomy in patients with renal cell carcinoma (RCC). However, we sought to determine the effect of bone metastases on outcomes when already present at the time of cytoreductive radical nephrectomy (RN). Methods: Multicenter retrospective analysis of mRCC patients from the REgistry of MetAstatic RCC) REMARCC. Demographics, clinical variables, and outcomes were collected. Patients were stratified into low, medium, and high-risk groups based on Motzer Criteria, and analysis of impact of bone metastases was conducted within each group utilizing Kaplan-Meier analysis (KMA). Multivariable analysis (MVA) was utilized to identify predictors for outcomes. Primary outcome was progression-free survival (PFS) and secondary outcome was overall survival (OS). Results: A total of 447 patients (low- n=30, intermediate- n=208, and high-risk mRCC n=123, median follow-up 14.3 months) were included in the analysis. 124 patients had bone metastases and 323 had mRCC but no bone metastases. No significant demographic differences were noted between groups. KMA (Figure) showed no difference in median PFS for bone metastases vs. non bone metastases groups (6.1 vs. 6.4 months, p=0.973). KMA showed no difference in median OS (25.5 vs. 26.5 months, p=0.958). Similarly, stratification of patients into different Motzer risk categories did not demonstrate difference between bone vs. none bone mRCC for PFS and OS. MVA for PFS demonstrated increasing Motzer risk category (low risk referent vs. intermediate OR 1.89, p=0.006, high risk OR 3.24, p&lt;0.001) as independent predictors. MVA for OS revealed increasing Motzer risk category (low ref, vs. intermediate OR 1.88, p=0.033, high risk 5.17, p&lt;0.001) as being predictive. In neither analysis was presence of bone metastases significant (PFS p=0.690, OS p=0.268). Conclusions: Presence of bone metastases does not independently predict survival or oncologic outcomes in mRCC. While further validation is needed, the prognostic significance of bone metastases may be less than previously thought.