tbuckley/cabot-search huggingface dataset:
Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary
Authors: Kanwal Raghav, Hyunsoo Hwang, Alexandre A. Jácome, Eric Bhang, Anneleis Willett, Ryan W. Huey, Nishat P. Dhillon, Jignesh Modha, Brandon Smaglo, Aurelio Matamoros, Jeannelyn S. Estrella, Justin Jao, Michael J. Overman, Xuemei Wang, F. Anthony Greco, Jonathan M. Loree, Gauri R. Varadhachary
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. Experimental Design: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012–2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). Results: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68–0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. Conclusions: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.
Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells
Authors: Nathan Singh, Noelle V. Frey, Boris Engels, David M. Barrett, Olga Shestova, Pranali Ravikumar, Katherine D. Cummins, Yong Gu Lee, Raymone Pajarillo, Inkook Chun, Amy Shyu, Steven L. Highfill, Andrew Price, Linlin Zhao, Liaomin Peng, Brian Granda, Melissa Ramones, Xueqing Maggie Lu, David A. Christian, Jessica Perazzelli, Simon F. Lacey, Nathan H. Roy, Janis K. Burkhardt, Florent Colomb, Mohammad Damra, Mohamed Abdel-Mohsen, Ting Liu, Dongfang Liu, Daron M. Standley, Regina M. Young, Jennifer L. Brogdon, Stephan A. Grupp, Carl H. June, Shannon L. Maude, Saar Gill, Marco Ruella
Journal: Nature Medicine (2021)
Biomechanical sensing of <i>in vivo</i> magnetic nanoparticle hyperthermia-treated melanoma using magnetomotive optical coherence elastography
Authors: Pin-Chieh Huang, Eric J Chaney, Edita Aksamitiene, Ronit Barkalifa, Darold R Spillman, Bethany J Bogan, Stephen A Boppart
Journal: Theranostics (2021)

Magnetic nanoparticle hyperthermia (MH) therapy is capable of thermally damaging tumor cells, yet a biomechanically-sensitive monitoring method for the applied thermal dosage has not been established. Biomechanical changes to tissue are known indicators for tumor diagnosis due to its association with the structural organization and composition of tissues at the cellular and molecular level. Here, by exploiting the theranostic functionality of magnetic nanoparticles (MNPs), we aim to explore the potential of using stiffness-based metrics that reveal the intrinsic biophysical changes of
Vaccination against COVID-19: insight from arterial and venous thrombosis occurrence using data from VigiBase
Authors: David M. Smadja, Qun-Ying Yue, Richard Chocron, Olivier Sanchez, Agnes Lillo-Le Louet
Journal: European Respiratory Journal (2021)

<b>This study observed an imbalance between venous and arterial thrombotic events in mRNA vaccines while with AZ1222 they are evenly shared. Our analysis highlights cerebral vein thrombosis with the three vaccines.</b>https://bit.ly/3mZqguE
Budesonide Oral Suspension Improves Outcomes in Patients With Eosinophilic Esophagitis: Results From a Phase 3 Trial
Authors: Ikuo Hirano, Margaret H. Collins, David A. Katzka, Vincent A. Mukkada, Gary W. Falk, Robin Morey, Nirav K. Desai, Lan Lan, James Williams, Evan S. Dellon
Journal: Clinical Gastroenterology and Hepatology (2021)

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no pharmacologic therapy approved by the US Food and Drug Administration.In this double-blind, placebo-controlled, phase 3 trial, patients 11-55 years of age with EoE and dysphagia were randomized 2:1 to receive budesonide oral suspension (BOS) 2.0 mg twice daily or placebo for 12 weeks at academic or community care practices. Co-primary endpoints were the proportion of stringent histologic responders (≤6 eosinophils/high-power field) or dysphagia symptom responders (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] score) over 12 weeks. Changes in DSQ score (key secondary endpoint) and EoE Endoscopic Reference Score (EREFS) (secondary endpoint) from baseline to week 12, and safety parameters were examined.Overall, 318 patients (BOS, n = 213; placebo, n = 105) were randomized and received ≥1 dose of study treatment. More BOS-treated than placebo-treated patients achieved a stringent histologic response (53.1% vs 1.0%; Δ52% [95% confidence interval (CI), 43.3%-59.1%]; P < .001) or symptom response (52.6% vs 39.1%; Δ13% [95% CI, 1.6%-24.3%]; P = .024) over 12 weeks. BOS-treated patients also had greater improvements in least-squares mean DSQ scores and EREFS over 12 weeks than placebo-treated patients: DSQ, -13.0 (SEM 1.2) vs -9.1 (SEM 1.5) (Δ-3.9 [95% CI, -7.1 to -0.8]; P = .015); EREFS, -4.0 (SEM 0.3) vs -2.2 (SEM 0.4) (Δ-1.8 [95% CI, -2.6 to -1.1]; P < .001). BOS was well tolerated; most adverse events were mild or moderate in severity.In patients with EoE, BOS 2.0 mg twice daily was superior to placebo in improving histologic, symptomatic, and endoscopic outcomes over 12 weeks. BOS 2.0 mg twice daily was well tolerated. ClinicalTrials.gov number: NCT02605837.
NADPHレベルはHDAC3-Ncor複合体の阻害により細胞エピジェネティック状態に影響する【JST・京大機械翻訳】
Authors: Li Wei, Kou Junjie, Qin Junying, Li Li, Zhang Zhenxi, Pan Ying, Xue Yi, Du Wenjing
Journal: Nature Metabolism (2021)
Age Is Just a Number: Considerations for Older Adults in Cancer Clinical Trials
Authors: Dany Habr, Lynn McRoy, Vassiliki A Papadimitrakopoulou
Journal: JNCI Journal of the National Cancer Institute (2021)

Older adults continue to be underrepresented in cancer clinical trials, despite most cancer occurrence peaking in the later decades of life. Consequently, diagnostic and management strategies are commonly extrapolated from data on younger patients, thus challenging the delivery of informed cancer care in this patient population. Several recommendations and calls to action have been released by cancer societies, advocacy organizations, and regulatory agencies to guide inclusion of older adults in clinical trials. Effective implementation, however, requires awareness and close collaboration between all stakeholders involved in the clinical trial journey. We herein provide insights and experience from a drug developer on key considerations to optimize participation and retention of older adults in cancer clinical trials and discuss those under 4 key domains: trial eligibility and design, assessments and endpoints, patients and oncologists, and data reporting.
Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study
Authors: Ajjai S. Alva, Pam K. Mangat, Elizabeth Garrett-Mayer, Susan Halabi, Damien Hansra, Carmen J. Calfa, Maged F. Khalil, Eugene R. Ahn, Timothy L. Cannon, Pamela Crilley, Julie G. Fisher, Derrick S. Haslem, Sagun Shrestha, Kaitlyn R. Antonelli, Nicole L. Butler, Sasha L. Warren, Andrew L. Rygiel, Shamika Ranasinghe, Suanna S. Bruinooge, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2021)

The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported.Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety.Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label.Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.
Artificial intelligence for automating the measurement of histologic image biomarkers
Authors: Toby C. Cornish
Journal: Journal of Clinical Investigation (2021)

Artificial intelligence has been applied to histopathology for decades, but the recent increase in interest is attributable to well-publicized successes in the application of deep-learning techniques, such as convolutional neural networks, for image analysis. Recently, generative adversarial networks (GANs) have provided a method for performing image-to-image translation tasks on histopathology images, including image segmentation. In this issue of the JCI, Koyuncu et al. applied GANs to whole-slide images of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) to automate the calculation of a multinucleation index (MuNI) for prognostication in p16-positive OPSCC. Multivariable analysis showed that the MuNI was prognostic for disease-free survival, overall survival, and metastasis-free survival. These results are promising, as they present a prognostic method for p16-positive OPSCC and highlight methods for using deep learning to measure image biomarkers from histopathologic samples in an inherently explainable manner.
Warfarin use and risk of knee and hip replacements
Authors: Priyanka Ballal, Christine Peloquin, Cindy Germaine Boer, Tuhina Neogi
Journal: Annals of the Rheumatic Diseases (2021)

Identification of modifiable risk factors and treatments for osteoarthritis (OA) are needed. Warfarin, a vitamin K antagonist, causes fetal and animal model skeletal abnormalities. Vitamin K insufficiency has been associated with OA, but whether warfarin is also detrimental to OA is not known.We conducted a nested case-control study using a UK general practitioner electronic medical records database. We identified cases of knee or hip replacement (KR or HR) from among adults with atrial fibrillation newly prescribed either warfarin or direct oral anticoagulants (DOACs). Cases were matched with four controls by age and sex. We assessed the relation of warfarin compared with DOAC use to risk of joint replacement using conditional logistic regression. We also evaluated different durations of warfarin use.We identified 857 subjects with KR or HR (cases), of whom 64.6% were warfarin users, and 3428 matched controls, of whom 56.1% were warfarin users (mean age 75, 47% female). Warfarin users had a 1.59 times higher risk of joint replacement than DOAC users (adjusted OR 1.59, 95% CI 1.31 to 1.92). Longer duration of warfarin use was associated with higher risk of joint replacement in comparison with <1 year of warfarin use.Warfarin, a vitamin K antagonist, was associated with greater risk of KR and HR (an indicator for end-stage knee OA) than DOAC use, supporting the importance of adequate vitamin K functioning in limiting OA progression.
Abstract 13145: Differences of Cancer Types in Hospital Mortality in Patients With Venous Thromboembolism
Authors: Okushi Yuichiro, Kenya Kusunose, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata
Journal: Circulation (2020)

Introduction: We sought to evaluate the clinical characteristics and outcomes of patients with cancer-associated VTE, compared with the matched cohort without cancer using real-world big data of VTE. Background: Cancer is associated with a high incidence of Venous Thromboembolism (VTE) and there are many guidelines/recommendations about VTE. However, the prognosis of cancer-VTE patients is not well known because of a lack of big data. Moreover, there is also no knowledge on how cancer type is related to prognosis. Methods: This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). We identified 28,247 patients who were first hospitalized with VTE from April 2012 to March 2017. 26.0% were cancer patients. Compared with national statistics of cancer incidence in 2015 from National Cancer Center of Japan, the proportion of gynecological cancer patients was higher, but other cancer types had similar prevalence rates. Propensity score (PS) was estimated with logistic regression model, with cancer as the dependent variable and 18 clinically relevant covariates. Results: We included 24,576 patients after exclusion. The median age was 71years (range: 59-80 years), and 42.0% were male. On PS-matched analysis with 12,418 patients, patients with cancer had higher total in-hospital mortality (9.5% vs. 3.8%, P&lt;0.001; OR, 2.72, 95% CI: 2.33-3.19) and in-hospital mortality within 30days (6.8% vs. 3.2%, P&lt;0.001; OR, 2.20, 95% CI: 1.85-2.62). On analysis for each type of cancer, in-hospital mortality in 10 types of cancer was significantly high, especially pancreas (OR: 9.65, 95%CI: 4.31-21.64), biliary tract (OR: 8.36, 95%CI: 2.42-28.89) and liver (OR: 7.33, 95%CI: 1.92-28.02). Conclusions: Patients with cancer had a higher in-hospital mortality for VTE than those without cancer, especially in pancreatic, biliary tract and liver cancers.
Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association
Authors: Tiffany M. Powell-Wiley, Paul Poirier, Lora E. Burke, Jean-Pierre Després, Penny Gordon-Larsen, Carl J. Lavie, Scott A. Lear, Chiadi E. Ndumele, Ian J. Neeland, Prashanthan Sanders, Marie-Pierre St-Onge
Journal: Circulation (2021)

The global obesity epidemic is well established, with increases in obesity prevalence for most countries since the 1980s. Obesity contributes directly to incident cardiovascular risk factors, including dyslipidemia, type 2 diabetes, hypertension, and sleep disorders. Obesity also leads to the development of cardiovascular disease and cardiovascular disease mortality independently of other cardiovascular risk factors. More recent data highlight abdominal obesity, as determined by waist circumference, as a cardiovascular disease risk marker that is independent of body mass index. There have also been significant advances in imaging modalities for characterizing body composition, including visceral adiposity. Studies that quantify fat depots, including ectopic fat, support excess visceral adiposity as an independent indicator of poor cardiovascular outcomes. Lifestyle modification and subsequent weight loss improve both metabolic syndrome and associated systemic inflammation and endothelial dysfunction. However, clinical trials of medical weight loss have not demonstrated a reduction in coronary artery disease rates. In contrast, prospective studies comparing patients undergoing bariatric surgery with nonsurgical patients with obesity have shown reduced coronary artery disease risk with surgery. In this statement, we summarize the impact of obesity on the diagnosis, clinical management, and outcomes of atherosclerotic cardiovascular disease, heart failure, and arrhythmias, especially sudden cardiac death and atrial fibrillation. In particular, we examine the influence of obesity on noninvasive and invasive diagnostic procedures for coronary artery disease. Moreover, we review the impact of obesity on cardiac function and outcomes related to heart failure with reduced and preserved ejection fraction. Finally, we describe the effects of lifestyle and surgical weight loss interventions on outcomes related to coronary artery disease, heart failure, and atrial fibrillation.
Novel Human and Canine Desmin Phosphorylations as Potential Regulators of Oligomer Formation and Disease in Heart Failure
Authors: Giulio Agnetti
Journal: Circulation (2009)

Abstract #1809 Giulio Agnetti, Victoria Halperin-Kuhns, Yurong Guo, Shijun Sheng, Zongming Fu, Johns Hopkins Univ, Baltimore, MD; Francesco Nicolini, Tiziano Gherli, Univ of Parma, Parma, Italy; Carlo Guarnieri, Claudio M Caldarera, Univ of Bologna, Bologna, Italy; David A Kass, Gordon F Tomaselli, Jennifer E Van Eyk, Johns Hopkins Univ, Baltimore, MD Giulio Agnetti, 2009 Finalist and Presenting Author
Photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and synergistic chemo-photodynamic therapy
Authors: Shenwu Zhang, Ziyue Wang, Zhiqiang Kong, Yuequan Wang, Xuanbo Zhang, Bingjun Sun, Haotian Zhang, Qiming Kan, Zhonggui He, Cong Luo, Jin Sun
Journal: Theranostics (2021)

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.
Abstract PO-064: Predicting molecular phenotypes with scRNAseq: An assessment of unsupervised machine learning methods
Authors: Anastasia Dunca, Frederick R. Adler, Mark W. Smithson
Journal: Clinical Cancer Research (2021)

Abstract We evaluated the performance of machine learning models in predicting cell state based on single cell RNA sequencing data (scRNAseq) analysis. scRNAseq quantifies the number of mRNA molecules in individual cells providing information on regulatory relationships between genes and the trajectories of distinct cell lineages in development. Different cells may express different genes at different levels which is key to analyzing the molecular phenotypes of cells. We tested nine machine learning models for their ability to distinguish subclonal cell populations in scRNAseq data by making predictions of cell state. Two scRNAseq datasets were examined: one with cells separated by cell phase: S, G1, or G2/M and one with distinct tumor and non-tumor cells. The pipeline consisted of data filtering, dimensionality reduction with Principal Component Analysis, naive projection with Uniform Manifold Approximation and Projection, and cluster analysis using Ward, BIRCH, Gaussian Mixture Model, DBSCAN, Spectral, Affinity Propagation, Average Linkage Agglomerative Clustering, Mean Shift, and K-Means models. These represent centroid, density, hierarchical, distribution, and graph-based clustering. Models failing to generate the true number of cells of each type were eliminated from further evaluation. The rest were evaluated on accuracy on a true cell type versus predicted cell type basis with a mapping algorithm. The true molecular phenotypes of the plotted cells were annotated onto the data points for a biological examination of the clusters. Six models divided G2 vs. S cells; Spectral and Ward clustering performed best with ~60% accuracy on average. Parallel to that result, seven models divided the total population into the tumorous and non-tumorous subclonal cell populations; Ward and BIRCH clustering performed best with ~80% accuracy on average. Overall, unsupervised machine learning models were effective in predicting molecular phenotypes of cells by accurately identifying subclonal cell populations and analyzing the relationship between gene expression levels and cell state. BIRCH, Ward, and Spectral clustering showed the highest performance. Citation Format: Anastasia Dunca, Frederick R. Adler, Mark W. Smithson. Predicting molecular phenotypes with scRNAseq: An assessment of unsupervised machine learning methods [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-064.
JAAD Game Changers∗: Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: A double-blind randomized controlled trial
Authors: Faramarz H. Samie
Journal: Journal of the American Academy of Dermatology (2021)