tbuckley/cabot-search huggingface dataset:
Very-low-protein diets lead to reduced food intake and weight loss, linked to inhibition of hypothalamic mTOR signaling, in mice
Authors: Yingga Wu, Baoguo Li, Li Li, Sharon E. Mitchell, Cara L. Green, Giuseppe D’Agostino, Guanlin Wang, Lu Wang, Min Li, Jianbo Li, Chaoqun Niu, Zengguang Jin, Anyongqi Wang, Yu Zheng, Alex Douglas, John R. Speakman
Journal: Cell Metabolism (2021)
Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML
Authors: Ilaria Gionfriddo, Lorenzo Brunetti, Federica Mezzasoma, Francesca Milano, Valeria Cardinali, Roberta Ranieri, Alessandra Venanzi, Sara Pierangeli, Calogero Vetro, Giulio Spinozzi, Erica Dorillo, Hsin Chieh Wu, Caroline Berthier, Raffaella Ciurnelli, Melanie J. Griffin, Claire E. Jennings, Enrico Tiacci, Paolo Sportoletti, Franca Falzetti, Hugues de Thé, Gareth J. Veal, Maria Paola Martelli, Brunangelo Falini
Journal: Leukemia (2021)

Abstract Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1 -mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1 -mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1 -mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1 -mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1 -mutated AML that deserves further investigation in larger clinical studies.
Role of free testosterone serum levels during salvage chemotherapy with carboplatin plus weekly docetaxel in patients with docetaxel-refractory, metastatic castration-resistant prostate cancer (mCRPC).
Authors: Stefan Brunotte, Philipp Ivanyi, Paula Kappler, Michael A. Morgan, Christoph W. Reuter
Journal: Journal of Clinical Oncology (2021)

145 Background: Carboplatin plus docetaxel (CD) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis and thus lower testosterone levels . In this study, the impact of CD on free and total testosterone (fT, TT) serum levels and the prognostic role of fT and TT were analyzed in mDRPC patients. Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel (35 mg/m2) iv for one hour on days 1, 8, (15) plus prednisone 2x5 mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Results: Of the 118 pts. treated since February 2005, 95.8% had bone, 47.5% lymph node, 28.0% liver and 20.3% lung metastases. Median follow-up time was 14.4 months at the time of the current analysis. The objective response rate (ORR) was 46.4% in the 69 pts. with measureable disease (58.5%). Response of prostate-specific antigen (PSAR ≥ 50%) was observed in 56 (47.9%) patients. Median progression free survival (PFS) was 7.6 months (CI 95% 6.0, 9.1) and median overall survival (OS) was 15.7 months (CI 95% 12.2, 19.2). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (36.4/28.8%). Median FT serum levels were 0.35 pg/mL before and &lt; 0.18 pg/mL during CD treatment (nadir levels, p &lt; 0.001; detection limit &lt; 0.18 pg/mL). In multivariate analyses, LDH &gt; 2xULN, PSAR≥50% and FT nadir levels below the detection limit ( &lt; 0.18 pg/mL) during CD treatment were associated with longer PFS (p &lt; 0.05). Conclusions: These data suggest that CD may be an important salvage treatment option for mDRPC patients by inhibition of the testosterone biosynthesis.
rMVP: A Memory-Efficient, Visualization-Enhanced, and Parallel-Accelerated Tool for Genome-Wide Association Study
Authors: Lilin Yin, Haohao Zhang, Zhenshuang Tang, Jingya Xu, Dong Yin, Zhiwu Zhang, Xiaohui Yuan, Mengjin Zhu, Shuhong Zhao, Xinyun Li, Xiaolei Liu
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Along with the development of high-throughput sequencing technologies, both sample size and SNP number are increasing rapidly in genome-wide association studies (GWAS), and the associated computation is more challenging than ever. Here, we present a memory-efficient, visualization-enhanced, and parallel-accelerated R package called “rMVP” to address the need for improved GWAS computation. rMVP can 1) effectively process large GWAS data, 2) rapidly evaluate population structure, 3) efficiently estimate variance components by Efficient Mixed-Model Association eXpedited (EMMAX), Factored Spectrally Transformed Linear Mixed Models (FaST-LMM), and Haseman-Elston (HE) regression algorithms, 4) implement parallel-accelerated association tests of markers using general linear model (GLM), mixed linear model (MLM), and fixed and random model circulating probability unification (FarmCPU) methods, 5) compute fast with a globally efficient design in the GWAS processes, and 6) generate various visualizations of GWAS-related information. Accelerated by block matrix multiplication strategy and multiple threads, the association test methods embedded in rMVP are significantly faster than PLINK, GEMMA, and FarmCPU_pkg. rMVP is freely available at https://github.com/xiaolei-lab/rMVP.
Vacuolization of hematopoietic precursors: an enigma with multiple etiologies
Authors: Carmelo Gurnari, Simona Pagliuca, Lisa Durkin, Laila Terkawi, Hassan Awada, Sunisa Kongkiatkamon, Misam Zawit, Eric D. Hsi, Hetty E. Carraway, Heesun J. Rogers, Valeria Visconte, Jaroslaw P. Maciejewski
Journal: Blood (2021)
Saliva Tests Comparable With Nasal Swabs for SARS-CoV-2 Detection
Authors: Jennifer Abbasi
Journal: JAMA (2021)

Guillaume Butler-Laporte, MD; Alexander Lawandi, MD, MSc; Ian Schiller, MSc; Mandy Yao, BSc; Nandini Dendukuri, PhD; Emily G. McDonald, MD, MSc; Todd C. Lee, MD, MPH
Abstract PO-077: Image clustering of brain tumor patients using a deep neural network
Authors: Hadi Hosseini, Cheng Cheng, John Glass, Gene Reddick, Amar Gajjar, Zhaohua Lu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The clustering of pediatric patients based on their unlabeled brain magnetic resonance (MR) images reveal the latent features and group structures. It is an unbiased approach to finding image-based markers and risk-stratification for neurocognitive functions. Analyzing large sets of MR images is time-intensive and challenging due to the MR images' high dimensionality and complexity. The extraction of low-dimension informative feature space instead of high-dimension MR image is an effective and fast solution to cluster images accurately. We aimed at developing a feature extraction method using deep learning. Our long-term research goal is to develop a feature extraction model using deep learning to automatically and accurately identify brain regions in association with neurocognitive outcomes. Methods: We used 124 registered fractional anisotropy (FA)-mapped of diffusion tensor (DT) images of pediatric medulloblastoma patients obtained after tumor surgery and before radiation from the SJMB03 clinical trial. First, we developed a 3D convolutional auto-encoder model based on a deep neural network for the voxel-wise analysis of 3D images to produce low-dimensional features, which can reconstruct input images accurately. Then, we applied the density-based clustering model, named OPTICS (Ordering Points To Identify the Clustering Structure), to the features. To train two models, we used a soft and dynamic algorithm to simultaneously combine two loss functions. Distance measure and CAHL (Cluster Assignment Loss Hardening) are used to measure feature learning and clustering performance. Results: Our experiment demonstrates that the proposed models yield results comparable in quality to manual clustering. The model trained regarding using a sufficient dataset and reducing dynamic loss function. Our model can cluster patients precisely and extract representative hidden features of the images, which is much more time- and labor-efficient compared to manual clustering by experts. Conclusions: In this study, we focused on a new feature extraction method and clustering of brain images. Because of the deep neural networks' unique advantages in image processing, we considered a 3D convolutional auto-encoder for the feature extraction part and OPTICS algorithm for the clustering part of the model. This method is highly useful in neuroimaging and neurocognitive research. Citation Format: Hadi Hosseini, Cheng Cheng, John Glass, Gene Reddick, Amar Gajjar, Zhaohua Lu. Image clustering of brain tumor patients using a deep neural network [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-077.
William Osler's Departure from North America
Authors: W.Bruce Fye
Journal: New England Journal of Medicine (1989)

William Osler was widely acknowledged to be the most influential physician in the English-speaking world at the turn of the century. Born in 1849 in Bond Head, Ontario, he was educated in Canada and Great Britain but emigrated to the United States in 1884 to occupy the chair of clinical medicine at the University of Pennsylvania. Two decades later Osler decided to leave North America to become Regius Professor of Medicine at Oxford. Several considerations influenced his decision to go to Oxford, but the main reason he left America was that his success had made it difficult for him to . . .
Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response <i>In Vivo</i>
Authors: Giorgia Foggetti, Chuan Li, Hongchen Cai, Jessica A. Hellyer, Wen-Yang Lin, Deborah Ayeni, Katherine Hastings, Jungmin Choi, Anna Wurtz, Laura Andrejka, Dylan G. Maghini, Nicholas Rashleigh, Stellar Levy, Robert Homer, Scott N. Gettinger, Maximilian Diehn, Heather A. Wakelee, Dmitri A. Petrov, Monte M. Winslow, Katerina Politi
Journal: Cancer Discovery (2021)

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.
Systematic review of time to definitive treatment for intermediate-risk and high-risk prostate cancer: Are delays associated with worse outcomes?
Authors: David-Dan Nguyen, Lorine Haeuser, Marco Paciotti, Chanan Reitblat, Jacqueline Cellini, Stuart R. Lipsitz, Eugene Blanchard Cone, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2021)

233 Background: Prostate cancer (PCa) is an indolent disease, especially when detected at a localized stage. Unlike other tumors that may benefit from timely receipt of definitive therapy, it is generally accepted that treatment delays for localized PCa are acceptable, especially for low-risk PCa. We sought to determine if treatment delays for intermediate-risk and high-risk PCa negatively impacted oncological outcomes. Methods: We conducted a systematic review of the literature with searches of Medline, EMBASE, and the Cochrane Database of Systematic Reviews, from inception to June 30, 2020. General study characteristics as well as study population and delay information were collected. The outcomes of interest extracted included biochemical recurrence (BCR), pathological features (positive surgical margins, upgrading, extracapsular extension, and other pathological features), cancer-specific survival, and overall survival. Due to significant heterogeneity between studies, a meta-analysis was not possible. Results: After identifying 1793 unique references, 24 manuscripts met criteria for data extraction, 15 of which were published after 2013. Based on our review, delays up to 3 months are safe for all PCa and are not associated with worse oncological outcomes. Some studies identified worse oncological outcomes as a result of delays beyond 6 to 9 months. However, these studies are counterbalanced by others finding no statistically significant association with delays up to 12 months. Studies that did find worse outcomes as a result of delays identified a higher risk of BCR and pathological findings, but not worse survival. Conclusions: Definitive treatment for intermediate-risk and high-risk PCa can be delayed up to 3 months without any oncological consequences. Some evidence suggests that delays beyond 6-9 months are associated with a higher risk of BCR and varying worse pathological findings; as such, care should be given to provide definitive treatment within 9 months. To date, there is no evidence of worse cancer-specific or overall survival as a result of delayed treatment for intermediate-risk and high-risk PCa.
Safety and efficacy of perioperative cisplatin/gemcitabine (cis/gem) and durvalumab (durva) for operable muscle-invasive urothelial carcinoma (MIUC): SAKK 06/17.
Authors: Richard Cathomas, Sacha Rothschild, Stefanie Hayoz, Martin Spahn, Julian Schardt, Roland Seiler, Andreas Erdmann, Stefanie Aeppli, Nicolas Mach, Raeto Strebel, Boris A. Hadaschik, Dominik R. Berthold, Miklos Pless, Deborah Zihler, Mathias Schmid, Martina Schneider, Zuzanna Maniecka, Ulf Petrausch
Journal: Journal of Clinical Oncology (2021)

430 Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: &lt;ypT2N0) but carries the risk of increased perioperative morbidity. Methods: SAKK 06/17 is an open-label single arm phase II trial for pts with operable MIUC cT2-T4a cN0-1. Treatment consists of 4 cycles of neoadjuvant cis/gem q3w in combination with 4 cycles durva 1500mg q3w followed by resection. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival (EFS) at 2 years. 58 pts are needed based on type I error of 10% and a power of 80% for H 1 EFS at 2 years ≥ 65% compared to H 0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.
Trilineage Sequencing Reveals Complex TCRβ Transcriptomes in Neutrophils and Monocytes Alongside T Cells
Authors: Tina Fuchs, Kerstin Puellmann, Chunlin Wang, Jian Han, Alexander W. Beham, Michael Neumaier, Wolfgang E. Kaminski
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Recent findings indicate the presence of T cell receptor (TCR)-based combinatorial immune receptors beyond T cells in neutrophils and monocytes/macrophages. In this study, using a semiquantitative trilineage immune repertoire sequencing approach as well as under rigorous bioinformatic conditions, we identify highly complex TCRβ transcriptomes in human circulating monocytes and neutrophils that separately encode repertoire diversities one and two orders of magnitude smaller than that of T cells. Intraindividual transcriptomic analyses reveal that neutrophils, monocytes, and T cells express distinct TCRβ repertoires with less than 0.1% overall trilineage repertoire sharing. Interindividual comparison shows that in all three leukocyte lineages, the vast majority of the expressed TCRβ variants are private. We also find that differentiation of monocytes into macrophages induces dramatic individual-specific repertoire shifts, revealing a surprising degree of immune repertoire plasticity in the monocyte lineage. These results uncover the remarkable complexity of the two phagocyte-based flexible immune systems which until now has been hidden in the shadow of T cells.
Between-Community Low-Income Status and Inclusion in Mandatory Bundled Payments in Medicare’s Comprehensive Care for Joint Replacement Model
Authors: Joshua M. Liao, Qian Huang, Said A. Ibrahim, John Connolly, Deborah S. Cousins, Jingsan Zhu, Amol S. Navathe
Journal: JAMA Network Open (2021)

This cohort study examines whether communities in Medicare's Comprehensive Care for Joint Replacement (CJR) Model are representative of others nationwide with respect to residents' socioeconomic status.
Efficacy of a Combination of Conservative Therapies vs an Education Comparator on Clinical Outcomes in Thumb Base Osteoarthritis
Authors: Leticia A. Deveza, Sarah R. Robbins, Vicky Duong, Kim L. Bennell, Bill Vicenzino, Paul W. Hodges, Anne Wajon, Ray Jongs, Edward A. Riordan, Kai Fu, Win Min Oo, Rachel L. O’Connell, Jillian P. Eyles, David J. Hunter
Journal: JAMA Internal Medicine (2021)

A combination of conservative treatments is commonly used in clinical practice for thumb base osteoarthritis despite limited evidence for this approach.To determine the efficacy of a 6-week combination of conservative treatments compared with an education comparator.Randomized, parallel trial with 1:1 allocation ratio among people aged 40 years and older with symptomatic and radiographic thumb base osteoarthritis in a community setting in Australia.The intervention group (n = 102) received education on self-management and ergonomic principles, a base-of-thumb splint, hand exercises, and diclofenac sodium, 1%, gel. The comparator group (n = 102) received education on self-management and ergonomic principles alone. Intervention use was at participants' discretion from 6 to 12 weeks.Hand function (Functional Index for Hand Osteoarthritis; 0-30) and pain (visual analog scale; 0-100 mm) were measured at week 6 (primary time point) and week 12. An α of .027 was used at week 6 to account for co-primary outcomes.Of the 204 participants randomized, 195 (96%) and 194 (95%) completed follow-ups at 6 and 12 weeks, respectively; the mean (SD) age of the population was 65.6 (8.1) years, and 155 (76.0%) were female. At week 6, hand function improved significantly more in the intervention group than the comparator (between-group difference, -1.7 units; 97.3% CI, -2.9 to -0.5; P = .002). This trend was sustained at 12 weeks (-2.4 units; 95% CI, -3.5 to -1.3; P < .001). Pain scores improved similarly at week 6 (between-group difference, -4.2 mm; 97.3% CI, -11.3 to 3.0; P = .19). At week 12, pain reduction was significantly greater in the intervention group (-8.6 mm; 95% CI, -15.2 to -2.0; P = .01). There were 34 nonserious adverse events, all in the intervention group-mostly skin reactions and exercise-related pain exacerbations.In this randomized clinical trial of people with thumb base osteoarthritis, combined treatments provided small to medium and potentially clinically beneficial effects on hand function but not pain.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000353493.
Abstract 441: Endogenous MicroRNAs Induced In vivo by Whole Body Heat Shock Limits Myocardial Infarct Size Following Ischemia/Reperfusion Injury in Mouse
Authors: Chang Yin, Xaioyin Wang, Rakesh C Kukreja
Journal: Circulation (2006)

Background: Non-coding microRNAs (miRNAs) have emerged as important gene regulators, rather than “evolutionary transcriptional debris”. They are a large class of endogenous short RNAs that repress ...