tbuckley/cabot-search huggingface dataset:
EPID-11. A POPULATION STUDY OF CLINICAL TRIAL ACCRUAL FOR WOMEN AND MINORITIES IN NEURO-ONCOLOGY FOLLOWING THE NIH REVITALIZATION ACT
Authors: Sheantel Reihl, Nirav Patil, Ramin Morshed, Mulki Mehari, alexander Aabedi, Ugonma Chukwueke, Alyx Porter, Valy Fontil, Gino Cioffi, Kristin Waite, Carol Kruchko, Quinn Ostrom, Jill Barnholtz-Sloan, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate the progress made in neuro-oncology in all phase therapeutic clinical trials for neuro-epithelial central nervous system tumors in comparison to their demographic-specific age-adjusted disease incidence and mortality. METHODS Registry study of all published clinical trials for World Health Organization (WHO) defined neuro-epithelial CNS tumors between January 2000 and December 2019. Study participants for trials were obtained from PubMed and ClinicalTrials.gov. Population-based data from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and c2 tests were used to analyze the data. RESULTS Among 662 published clinical trial articles representing 49, 907 accrued participants, 62.5% of study participants were men and 37.5% were women (P&amp;lt; 0.0001) representing a mortality specific over-accrual for men (P= 0.001) and under-accrual for women (P= 0.001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with their US cancer mortality, Blacks (47% of expected mortality, P=.008), Hispanics (17% of expected mortality, P&amp;lt; .001) and Asians (33% of expected mortality, P&amp;lt; .001) were underrepresented compared with Whites (114% of expected mortality, P&amp;lt; .001). CONCLUSIONS Nearly 30 years since the Revitalization Act, minorities and women are consistently underrepresented when compared with their demographic-specific incidence and mortality in therapeutic clinical trials for neuroepithelial tumors. This study provides a framework for investigating cancer clinical trial accrual and offers guidance regarding workforce factors associated with enrollment of vulnerable patients.
A Striking Case of Perfusion-Metabolism “Flip-Flop” in a Patient With Left Anterior Descending Artery Total Occlusion
Authors: Malik E. Juweid, Rahma M. Doudeen, Khaled Alkhawaldeh
Journal: Clinical Nuclear Medicine (2021)

A 57-year-old man diagnosed with left anterior descending artery chronic total occlusion underwent rest gated 99mTc-MIBI scan showing moderately to markedly decreased perfusion with abnormal wall motion in the apex, anterior, anteroseptal, and apical anterolateral walls. 18F-FDG PET showed a "flip-flop" phenomenon with markedly increased FDG uptake in the hypoperfused regions and absent/markedly decreased uptake in the normally perfused, normokinetic myocardium, presumably due to the predominant use of free fatty acids under normoxic conditions. After coronary artery bypass grafting, left ventricular motion normalized except for surgery-related paradoxical septal motion and the left ventricular ejection fraction improved from 52% to 68%.
An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages
Authors: Sandro Satta, Zhaojie Meng, Rebecca Hernandez, Susana Cavallero, Tong Zhou, Tzung K. Hsiai, Changcheng Zhou
Journal: Theranostics (2022)

Rationale: Macrophages are the frontline immune cells in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Angiotensin-converting enzyme 2 (ACE2) serves as the binding receptor to SARS-CoV-2 Spike glycoprotein for fusion and internalization into the human host cells.However, the mechanisms underlying SARS-CoV-2-elicited macrophage inflammatory responses remain elusive.Neutralizing SARS-CoV-2 by human ACE2 (hACE2) decoys has been proposed as a therapeutic approach to ameliorate SARS-CoV-2-stimulated inflammation.This study aims to investigate whether an engineered decoy receptor can abrogate SARS-CoV-2-induced macrophage inflammation.Methods: hACE2 was biotinylated to the surface of nano-liposomes (d = 100 nm) to generate Liposome-human ACE2 complex (Lipo-hACE2).Lentivirus expressing Spike protein (D614G) was also created as a pseudo-SARS-CoV-2 (Lenti-Spike).Liposome-hACE2 was used as a decoy receptor or competitive inhibitor to inhibit SARS-CoV-2 or Lenti-Spike-induced macrophage inflammation in vitro and in vivo.Results: Both SARS-CoV-2 and Lenti-Spike stimulated strong inflammatory responses by inducing the expression of key cytokine and chemokines, including IL-1β, IL-6, TNFα, CCL-2, and CXCL-10, in murine and human macrophages in vitro, whereas Lipo-hACE2 decoy abolished these effects in macrophages.Furthermore, intravenous injection of Lenti-Spike led to increased macrophage and tissue inflammation in wild type mice, which was also abolished by Lipo-hACE2 treatment.Mechanistically, Spike protein stimulated macrophage inflammation by activating canonical NF-κB signaling.RNA sequencing analysis revealed that Lenti-Spike induced over 2,000 differentially expressed genes (DEGs) in murine macrophages, but deficiency of IκB kinase β (IKKβ), a key regulator for NF-κB activation, abrogated Lenti-Spike-elicited macrophage inflammatory responses.Conclusions: We demonstrated that the engineered Lipo-hACE2 acts as a molecular decoy to neutralize SARS-CoV-2 or Spike protein-induced inflammation in both murine and human macrophages, and activation of the canonical IKKβ/NF-κB signaling is essential for SARS-CoV-2-elicited macrophage inflammatory responses.
Phase I Clinical Trial of DNA Methyltransferase Inhibitor Decitabine and PARP Inhibitor Talazoparib Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia
Authors: Maria R. Baer, Aksinija A. Kogan, Søren M. Bentzen, Tian Mi, Rena G. Lapidus, Vu H. Duong, Ashkan Emadi, Sandrine Niyongere, Casey L. O'Connell, Benjamin A. Youngblood, Stephen B. Baylin, Feyruz V. Rassool
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here, we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in relapsed/refractory AML. Patients and Methods: Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on cycle 1 days 1 (pretreatment), 5 and 8 blood blasts. Results: Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3–5 events included fever in 19 patients and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) and hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci, and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine. Conclusions: Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial
Authors: Jonathan R Strosberg, Martyn E Caplin, Pamela L Kunz, Philippe B Ruszniewski, Lisa Bodei, Andrew Hendifar, Erik Mittra, Edward M Wolin, James C Yao, Marianne E Pavel, Enrique Grande, Eric Van Cutsem, Ettore Seregni, Hugo Duarte, Germo Gericke, Amy Bartalotta, Maurizio F Mariani, Arnaud Demange, Sakir Mutevelic, Eric P Krenning
Journal: The Lancet Oncology (2021)
ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression
Authors: Cuicui Liu, Jiankun Qiang, Qiaodan Deng, Jie Xia, Lu Deng, Lei Zhou, Dong Wang, Xueyan He, Ying Liu, Botao Zhao, Jinhui Lv, Zuoren Yu, Qun-Ying Lei, Zhi-Ming Shao, Xiao-Yong Zhang, Lixing Zhang, Suling Liu
Journal: Cancer Research (2021)

Abstract Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However, the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of GM-CSF, which led to myeloid-derived suppressor cell expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T-cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlighting new therapeutic strategies for malignant breast cancer. Significance: ALDH1A1 enzyme activity induces MDSC expansion and triggers a procancer immune microenvironment to facilitate breast cancer progression, providing a novel therapeutic vulnerability in this disease.
Artificial intelligence for older people receiving long-term care: a systematic review of acceptability and effectiveness studies
Authors: Kate Loveys, Matthew Prina, Chloe Axford, Òscar Ristol Domènec, William Weng, Elizabeth Broadbent, Sameer Pujari, Hyobum Jang, Zee A Han, Jotheeswaran Amuthavalli Thiyagarajan
Journal: The Lancet Healthy Longevity (2022)

Artificial intelligence (AI)-enhanced interventions show promise for improving the delivery of long-term care (LTC) services for older people. However, the research field is developmental and has yet to be systematically synthesised. This systematic review aimed to synthesise the literature on the acceptability and effectiveness of AI-enhanced interventions for older people receiving LTC services. We conducted a systematic search that identified 2720 records from Embase, Ovid, Global Health, PsycINFO, and Web of Science. 31 articles were included in the review that evaluated AI-enhanced social robots (n=22), environmental sensors (n=6), and wearable sensors (n=5) with older people receiving LTC services across 15 controlled and 14 non-controlled trials in high-income countries. Risk of bias was evaluated using the RoB 2, RoB 2 CRT, and ROBINS-I tools. Overall, AI-enhanced interventions were found to be somewhat acceptable to users with mixed evidence for their effectiveness across different health outcomes. The included studies were found to have high risk of bias which reduced confidence in the results. AI-enhanced interventions are promising innovations that could reshape the landscape of LTC globally. However, more trials are required to support their widespread implementation. Pathways are needed to support more high-quality trials, including in low-income and middle-income countries.
Exploring linkages between drought and HIV treatment adherence in Africa: a systematic review
Authors: Kingsley Stephen Orievulu, Sonja Ayeb-Karlsson, Sthembile Ngema, Kathy Baisley, Frank Tanser, Nothando Ngwenya, Janet Seeley, Willem Hanekom, Kobus Herbst, Dominic Kniveton, Collins C Iwuji
Journal: The Lancet Planetary Health (2022)

Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral therapy (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/MEDLINE, and PsycINFO suggests that livelihoods and economic conditions, comorbidities and ART regimens, human mobility, and psychobehavioural dispositions and support systems interact in complex ways in the drought–ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions, and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and developing interventions.
Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor–positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities
Authors: Maxwell R. Lloyd, Laura M. Spring, Aditya Bardia, Seth A. Wander
Journal: Clinical Cancer Research (2021)

Abstract The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become the standard of care, in combination with antiestrogen therapy, for patients with hormone receptor–positive (HR+)/HER2− advanced breast cancer. Various preclinical and translational research efforts have begun to shed light on the genomic and molecular landscape of resistance to these agents. Drivers of resistance to CDK4/6i therapy can be broadly subdivided into alterations impacting cell-cycle mediators and activation of oncogenic signal transduction pathways. The resistance drivers with the best translational evidence supporting their putative role have been identified via next-generation sequencing of resistant tumor biopsies in the clinic and validated in laboratory models of HR+ breast cancer. Despite the diverse landscape of resistance, several common, therapeutically actionable resistance nodes have been identified, including the mitotic spindle regulator Aurora Kinase A, as well as the AKT and MAPK signaling pathways. Based upon these insights, precision-guided therapeutic strategies are under active clinical development. This review will highlight the emerging evidence, in the clinic and in the laboratory, implicating this diverse spectrum of molecular resistance drivers.
Impact of single-room contact precautions on acquisition and transmission of vancomycin-resistant enterococci on haematological and oncological wards, multicentre cohort-study, Germany, January−December 2016
Authors: Lena M. Biehl, Paul G. Higgins, Jannik Stemler, Meyke Gilles, Silke Peter, Daniela Dörfel, Wichard Vogel, Winfried V. Kern, Hanna Gölz, Hartmut Bertz, Holger Rohde, Eva-Maria Klupp, Philippe Schafhausen, Jon Salmanton-García, Melanie Stecher, Julia Wille, Blasius Liss, Kyriaki Xanthopoulou, Janine Zweigner, Harald Seifert, Maria J.G.T. Vehreschild
Journal: Eurosurveillance (2022)

Background Evidence supporting the effectiveness of single-room contact precautions (SCP) in preventing in-hospital acquisition of vancomycin-resistant enterococci (haVRE) is limited. Aim We assessed the impact of SCP on haVRE and their transmission. Methods We conducted a prospective, multicentre cohort study in German haematological/oncological departments during 2016. Two sites performed SCP for VRE patients and two did not (NCP). We defined a 5% haVRE-risk difference as non-inferiority margin, screened patients for VRE, and characterised isolates by whole genome sequencing and core genome MLST (cgMLST). Potential confounders were assessed by competing risk regression analysis. Results We included 1,397 patients at NCP and 1,531 patients at SCP sites. Not performing SCP was associated with a significantly higher proportion of haVRE; 12.2% (170/1,397) patients at NCP and 7.4% (113/1,531) patients at SCP sites (relative risk (RR) 1.74; 95% confidence interval (CI): 1.35–2.23). The difference (4.8%) was below the non-inferiority margin. Competing risk regression analysis indicated a stronger impact of antimicrobial exposure (subdistribution hazard ratio (SHR) 7.46; 95% CI: 4.59–12.12) and underlying disease (SHR for acute leukaemia 2.34; 95% CI: 1.46–3.75) on haVRE than NCP (SHR 1.60; 95% CI: 1.14–2.25). Based on cgMLST and patient movement data, we observed 131 patient-to-patient VRE transmissions at NCP and 85 at SCP sites (RR 1.76; 95% CI: 1.33–2.34). Conclusions We show a positive impact of SCP on haVRE in a high-risk population, although the observed difference was below the pre-specified non-inferiority margin. Importantly, other factors including antimicrobial exposure seem to be more influential.
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial
Authors: Christian Pfister, Gwenaelle Gravis, Aude Fléchon, Christine Chevreau, Hakim Mahammedi, Brigitte Laguerre, Aline Guillot, Florence Joly, Michel Soulié, Yves Allory, Valentin Harter, Stéphane Culine
Journal: Journal of Clinical Oncology (2022)

The optimal perioperative chemotherapy regimen for patients with nonmetastatic muscle-invasive bladder cancer is not defined.Between February 2013 and March 2018, 500 patients were randomly assigned in 28 French centers and received either six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) once every 2 weeks or four cycles of gemcitabine and cisplatin (GC) once every 3 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the primary end point of the GETUG-AFU V05 VESPER trial (ClinicalTrials.gov identifier: NCT01812369): progression-free survival (PFS) at 3 years. Secondary end points were time to progression and overall survival.Four hundred thirty-seven patients (88%) received neoadjuvant chemotherapy; 60% of patients received the planned six cycles in the dd-MVAC arm, 84% received four cycles in the GC arm, and thereafter, 91% and 90% of patients underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% v 63%, P = .001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm, and 81% of patients received four cycles in the GC arm. For all patients in the clinical trial, 3-year PFS was improved in the dd-MVAC arm, but the study did not meet its primary end point (3-year rate: 64% v 56%, hazard ratio [HR] = 0.77 [95% CI, 0.57 to 1.02], P = .066); nevertheless, the dd-MVAC arm was associated with a significantly longer time to progression (3-year rate: 69% v 58%, HR = 0.68 [95% CI, 0.50 to 0.93], P = .014). In the neoadjuvant group, PFS at 3 years was significantly higher in the dd-MVAC arm (66% v 56%, HR = 0.70 [95% CI, 0.51 to 0.96], P = .025).In the VESPER trial, dd-MVAC improved 3-years PFS over GC. In the neoadjuvant group, a better bladder tumor local control and a significant improvement in 3-year PFS were observed in the dd-MVAC arm.
A Triolet for Newly Hatched Docs
Authors: Rae Varcoe
Journal: Annals of Internal Medicine (2022)

Ad LibitumApril 2022A Triolet for Newly Hatched DocsRae Varcoe, MA, MB ChBRae Varcoe, MA, MB ChBNelson, New ZealandSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4105 Audio Reading - “A Triolet for Newly Hatched Docs” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “A Triolet for Newly Hatched Docs” by Rae Varcoe, MA, MB ChB Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Swot ‘til you drop. Read until your brain bleedsfor the art of medicine's very hard to masterOn nights, the wards are scary dark and deepthough you swot ‘til you drop and read until your brain bleedsyou will have calls to make before you sleepand bookish skills to keep your patients from disasterSwot ‘til you drop. Read until your brain bleedsfor the art of medicine's very hard to master Author, Article, and Disclosure InformationAffiliations: Nelson, New ZealandCorresponding Author: Rae Varcoe, MA, MB ChB; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “A Triolet for Newly Hatched Docs” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “A Triolet for Newly Hatched Docs” by Rae Varcoe, MA, MB ChB Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics April 2022Volume 175, Issue 4Page: 615 ePublished: 19 April 2022 Issue Published: April 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Reply to Jaffuel and Borel: If Oral Breathing Does Not Determine Mask Choice for Continuous Positive Airway Pressure Delivery, What Does?
Authors: Jeane Lima de Andrade Xavier, Fernanda Madeiro Leite Viana Weaver, George Lago Pinheiro, Paulo Henrique Sousa Fernandes, Pedro R. Genta, Geraldo Lorenzi-Filho
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study
Authors: Do-Youn Oh, Kyung-Hun Lee, Dae-Won Lee, Jeesun Yoon, Tae-Yong Kim, Ju-Hee Bang, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Young Lee, Violeta Guthrie, Patricia McCoon, Weimin Li, Song Wu, Qu Zhang, Marlon C Rebelatto, Jin Won Kim
Journal: The Lancet. Gastroenterology & hepatology (2022)