tbuckley/cabot-search huggingface dataset:
Price Transparency—Promise and Peril
Authors: Sherry Glied
Journal: JAMA (2021)

mid the turmoil of its waning days, 2 Trump administration regulations advancing the goal of price transparency in health care moved forward.On October 26, 2020, the US Department of Labor and the US Department of Health and Human Services finalized a rule mandating insurer price transparency.On December 29, 2020, the District of Columbia Court of Appeals upheld the administration's hospital price transparency rule.The rules both stem from provisions of the Affordable Care Act (ACA) and operate quite similarly.Both require the disclosure of consumer-relevant information in a form intended to make shopping easier and provide information about negotiated rates between clinicians and insurers in a machine-readable file (intended to power apps and research efforts).Given the origins of these rules in the ACA and the near-universal support for the notion of transparency, it is likely that these rules will be maintained by the Biden administration.Although they are unlikely to make much direct difference to US health care costs, these rules are important because they mark the first step along a new path for US health policy.
Hospital Admissions Associated With Noncommunicable Diseases During the COVID-19 Outbreak in Brazil
Authors: Jean Henri Maselli-Schoueri, Luis Eduardo Werneck de Carvalho, Leandro F. M. Rezende, Fernando Luiz Affonso Fonseca, Gerson Ferrari, Fernando Adami
Journal: JAMA Network Open (2021)

This cross-sectional study uses data from the Brazilian Unified Health System to compare the number of hospital admissions for treatment of noncommunicable diseases from January to June 2020 with that during the corresponding period in each of the previous 3 years in São Paulo, Brazil.
Missing Funding Information
Authors: Ezra Golberstein
Journal: JAMA Pediatrics (2020)

Russell M. Viner, PhD; Oliver T. Mytton, PhD; Chris Bonell, PhD; G. J. Melendez-Torres, PhD; Joseph Ward, MBBS; Lee Hudson, PhD; Claire Waddington, DPhil; James Thomas, PhD; Simon Russell, PhD; Fiona van der Klis, PhD; Archana Koirala, MBChB; Shamez Ladhani, MD; Jasmina Panovska-Griffiths, DPhil; Nicholas G. Davies, DPhil; Robert Booy, MD; Rosalind M. Eggo, PhD
Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial
Authors: Richard A. Larson, Sumithra J. Mandrekar, Lucas J. Huebner, Ben L. Sanford, Kristina Laumann, Susan Geyer, Clara D. Bloomfield, Christian Thiede, Thomas W. Prior, Konstanze Döhner, Guido Marcucci, Maria Teresa Voso, Rebecca B. Klisovic, Ilene Galinsky, Andrew H. Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Jürgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Insa Gathmann, Hartmut Döhner, Richard M. Stone
Journal: Leukemia (2021)
Abstract 140: Role of miR-181c in Mitochondrial Matrix Calcium Accumulation During Ischemia/Reperfusion Injury in the Heart
Authors: Soroosh Solhjoo, Sangeetha M Kannan, Deepthi Ashok, Brian O’Rourke, Charles Steenbergen, Samarjit Das
Journal: Circulation Research (2017)

Background: We have identified a microRNA, miR-181c, which can translocate into the mitochondria of cardiomyocytes, and regulate the mitochondrial gene mt-COX1. Recently, we have also demonstrated that miR-181c/d -/- mice are protected against ischemia/reperfusion (I/R) injury by attenuating oxidative stress in the heart. Previous data also suggest that overexpression of miR-181c in the heart can activate Ca 2+ entry into mitochondria. Here, we investigate the mechanism by which miR-181c regulates Ca 2+ influx into the mitochondrial matrix. Methods and Results: We found both Mitochondrial Calcium Uptake 1 (MICU1) and mitochondrial respiratory complex IV (COX IV) expression are markedly higher in the miR-181c/d -/- mouse heart. Immunoprecipitated with MICU1, and then immunoblot for different sub-units of COX IV confirmed a protein-protein interaction between MICU1 and COX IV. We have also found significantly less Pyruvate Dehydrogenase (PDH) activity in neonatal mouse ventricular myocytes (NMVMs) isolated from miR-181c/d -/- mouse compared to C57BL6 (WT), suggesting significantly lower mitochondrial Ca 2+ -concentrations in the miR-181c/d -/- group. Utilizing a coverslip induced I/R-model, we observe that siRNAs against MICU1 (si-MICU1) during the ischemic phase significantly increase Ca 2+ -entry into the mitochondria of the NMVMs. Lowering MICU1 also significantly increases Ca 2+ -entry into the mitochondria after 30 min of ischemia in miR-181c/d -/- NMVMs. Furthermore, 30 min ischemia followed by 30 min reperfusion in NMVM monolayers led to significantly less oscillatory instability in mitochondrial inner membrane potential (ΔΨ m ) in miR-181c/d -/- NMVMs compared with WT NMVMs. However, using si-MICU1 in the miR-181c/d -/- NMVM group attenuated mitochondrial protection against I/R-injury. Conclusions: MICU1 is directly associated with complex IV. Thus, miR-181c can regulate mitochondrial Ca 2+ -entry by targeting mt-COX1 during I/R injury.
1,3‐Diazepine: A privileged scaffold in medicinal chemistry
Authors: Yohan Malki, Jean Martinez, Nicolas Masurier
Journal: Medicinal Research Reviews (2021)

Abstract Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.
Abstract PO-075: Kinotype to phenotype: Perturbed phosphoproteomic state predicts cancer cell growth rates in vitro
Authors: Isaac S. Robson, Matthew E. Berginski, Shawn M. Gomez
Journal: Clinical Cancer Research (2021)

Abstract Numerous aspects of cellular signaling are regulated by the kinome - the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation being a key driver of many diseases, particularly cancer. Linked with their role in disease, the druggability of kinases has led to increased interest in the development of kinase inhibitors, with over fifty now having achieved FDA approval. These and other yet to be approved compounds have been used in a variety of contexts, including in screens to test their efficacy as potential therapeutics. Recent proteomics techniques including Kinobeads and multiplexed inhibitor beads linked with mass spectroscopy (MIB/MS) are a relatively new mechanism which affords the ability to assess the state of the protein kinome en masse. When combined with perturbation with targeted kinase inhibitors, the quantification of the dynamic response of the kinome provides a novel platform for the study of cell signaling and potential design of drug therapies. Here, we describe an approach that links the state of the kinome, or kinotype, with a downstream cancer cell phenotype, in this case, cellular growth. Integrating independent perturbation and growth response data sets, we find that the kinotype of a cell has a significant and predictive relationship with cell growth. More specifically, we characterize kinome response to perturbation via Kinobeads within models aimed at predicting cellular growth inhibition rates. Integrating 82 drugs, 237 kinases, and 380 cell lines (both malignant and nonmalignant) into a sparse GLM predicts growth rate inhibition at multiple doses of an unseen small molecule with an r^2 value of 0.624 (Bonferroni corrected p-value of 5.7 × 10^−69), even with an unmatched dataset. We further explore the use of higher-level kinase relationships, i.e., kinome subnetworks, along with manifold learning approaches as a component of these models to better ascertain the potential impact of kinome architecture in cellular response. Together, this systems view of the kinome presents potential opportunities for improved cancer disease classification, the identification of new drug targets, as well as impacting on the broader design of combination therapies for cancer treatment. Citation Format: Isaac S. Robson, Matthew E. Berginski, Shawn M. Gomez. Kinotype to phenotype: Perturbed phosphoproteomic state predicts cancer cell growth rates in vitro [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-075.
Clinical utility of the AJCC eighth edition pT1 subclassification and impact on practice patterns in stage I seminoma.
Authors: Rohit R Badia, Solomon L. Woldu, Hiten Dilip Patel, Nirmish Singla, Arnav Srivastava, Joseph G Cheaib, Phillip M. Pierorazio, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2021)

377 Background: The American Joint Committee on Cancer 8 th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (&lt;3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns has not been studied. Methods: We retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004-2016. Receiver operating curves (ROC) were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among stage I patients. Results: 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under ROC: 0.546). Surveillance has grown as the preferred treatment after orchiectomy – 32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated. Conclusions: The 3 cm cutoff for subclassification of stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized.
Real-world clinical outcomes study of sequential novel antihormonal therapy (NAH) or radium-223 (Ra-223) treatment of metastatic castration-resistant prostate cancer (mCRPC) that progressed after first-line NAH.
Authors: Oliver A. Sartor, Daniel J. George, Bertrand Tombal, Celestia S. Higano, Cora N. Sternberg, Kurt Miller, Xiaolong Jiao, Helen Guo, Per Sandstrom, Frank Verholen, Fred Saad, Neal D. Shore
Journal: Journal of Clinical Oncology (2021)

48 Background: We assessed real-life clinical outcomes in patients with mCRPC treated in the USA who received sequential first-line (1L)/second-line (2L) NAH (abiraterone/enzalutamide or enzalutamide/abiraterone) or switched to a different mechanism of action (alpha-emitter Ra-223) after progression on 1L NAH. Methods: This was a retrospective study (PHENIX, NCT03896984) of the Flatiron electronic health record database in patients with mCRPC that progressed on 1L NAH and started 2L monotherapy with Ra-223 (n=120) or NAH (n=226) between Jan 2013 and Dec 2018. Patient characteristics, overall survival (OS) from 2L start, and symptomatic skeletal events (SSEs) were analyzed descriptively. Results: The two cohorts were generally similar at 2L start, including similar rates of bone-health agent (BHA) use, but the Ra-223 cohort had a higher incidence of bone-only metastases, shorter duration of 1L NAH, and higher rate of prior SSEs than the 2L NAH cohort (Table). Median treatment duration was 5.6 mo (median 4.5 doses) for Ra-223 and 4.7 mo for 2L NAH. Median OS from 2L start was 10.8 mo for Ra-223 and 11.2 mo for 2L NAH, with 49% and 39%, respectively, receiving subsequent therapy. Among those who received subsequent therapy, the proportion who received subsequent taxane was lower in the Ra-223 cohort (47%) than in the 2L NAH cohort (76%). SSEs were observed after 2L start in 32 patients (27%) on Ra-223 and 49 (22%) on 2L NAH. Conclusions: OS from start of 2L mCRPC treatment was similar for patients who received Ra-223 or alternative NAH in 2L. Slightly more patients received subsequent therapy in the Ra-223 cohort than in the 2L NAH cohort. Patients who received subsequent therapy were more likely to receive chemotherapy in the 2L NAH cohort, which is unsurprising as 2L NAH after 1L NAH is not highly active. Although the prior SSE rate before 2L start was higher in the Ra-223 cohort than in the 2L NAH cohort, and the two cohorts had similar rates of BHA use at 2L start, the rate of SSEs after 2L start was similar in both cohorts. Clinical trial information: NCT03896984. [Table: see text]
Therapy for Alzheimer’s disease: Missing targets and functional markers?
Authors: Milan Stoiljkovic, Tamas L Horvath, Mihály Hajós
Journal: Ageing Research Reviews (2021)

The development of the next generation therapy for Alzheimer's disease (AD) presents a huge challenge given the number of promising treatment candidates that failed in trials, despite recent advancements in understanding of genetic, pathophysiologic and clinical characteristics of the disease. This review reflects some of the most current concepts and controversies in developing disease-modifying and new symptomatic treatments. It elaborates on recent changes in the AD research strategy for broadening drug targets, and potentials of emerging non-pharmacological treatment interventions. Established and novel biomarkers are discussed, including emerging cerebrospinal fluid and plasma biomarkers reflecting tau pathology, neuroinflammation and neurodegeneration. These fluid biomarkers together with neuroimaging findings can provide innovative objective assessments of subtle changes in brain reflecting disease progression. A particular emphasis is given to neurophysiological biomarkers which are well-suited for evaluating the brain overall neural network integrity and function. Combination of multiple biomarkers, including target engagement and outcome biomarkers will empower translational studies and facilitate successful development of effective therapies.
HEMODYNAMIC ALTERATIONS DUE TO SALMONELLA TYPHOSA ENDOTOXIN WITH SPECIAL REFERENCE TO THE CORONARY VASCULAR BED*
Authors: Edward D. Frohlich, Jerry B. Scott, Elmo S. Dooley
Journal: Journal of Clinical Investigation (1962)

Abstract : Under the conditions of these experiments (constant coronary blood flow in a beating, non-perfusing heart) the administration of 0.6 mg/kg of S. typhosa endotoxin directly into the coronary arteries resulted in a progressive decrease in coronary vascular resistance and total peripheral resistance. The observed decreases in coronary vascular and total peripheral resistances appeared to be due to active vasodilation.
Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis
Authors: Xinhua Chen, Zhiyuan Chen, Andrew S Azman, Xiaowei Deng, Ruijia Sun, Zeyao Zhao, Nan Zheng, Xinghui Chen, Wanying Lu, Tingyu Zhuang, Juan Yang, Cecile Viboud, Marco Ajelli, Daniel T Leung, Hongjie Yu
Journal: The Lancet Global Health (2021)

BackgroundA rapidly increasing number of serological surveys for antibodies to SARS-CoV-2 have been reported worldwide. We aimed to synthesise, combine, and assess this large corpus of data.MethodsIn this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and five preprint servers for articles published in English between Dec 1, 2019, and Dec 22, 2020. Studies evaluating SARS-CoV-2 seroprevalence in humans after the first identified case in the area were included. Studies that only reported serological responses among patients with COVID-19, those using known infection status samples, or any animal experiments were all excluded. All data used for analysis were extracted from included papers. Study quality was assessed using a standardised scale. We estimated age-specific, sex-specific, and race-specific seroprevalence by WHO regions and subpopulations with different levels of exposures, and the ratio of serology-identified infections to virologically confirmed cases. This study is registered with PROSPERO, CRD42020198253.Findings16 506 studies were identified in the initial search, 2523 were assessed for eligibility after removal of duplicates and inappropriate titles and abstracts, and 404 serological studies (representing tests in 5 168 360 individuals) were included in the meta-analysis. In the 82 studies of higher quality, close contacts (18·0%, 95% CI 15·7–20·3) and high-risk health-care workers (17·1%, 9·9–24·4) had higher seroprevalence than did low-risk health-care workers (4·2%, 1·5–6·9) and the general population (8·0%, 6·8–9·2). The heterogeneity between included studies was high, with an overall I2 of 99·9% (p<0·0001). Seroprevalence varied greatly across WHO regions, with the lowest seroprevalence of general populations in the Western Pacific region (1·7%, 95% CI 0·0–5·0). The pooled infection-to-case ratio was similar between the region of the Americas (6·9, 95% CI 2·7–17·3) and the European region (8·4, 6·5–10·7), but higher in India (56·5, 28·5–112·0), the only country in the South-East Asia region with data.InterpretationAntibody-mediated herd immunity is far from being reached in most settings. Estimates of the ratio of serologically detected infections per virologically confirmed cases across WHO regions can help provide insights into the true proportion of the population infected from routine confirmation data.FundingNational Science Fund for Distinguished Young Scholars, Key Emergency Project of Shanghai Science and Technology Committee, Program of Shanghai Academic/Technology Research Leader, National Science and Technology Major project of China, the US National Institutes of Health.TranslationFor the Chinese translation of the abstract see Supplementary Materials section.
A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma
Authors: Paul D Brown, Caroline Chung, Diane D Liu, Sarah McAvoy, David Grosshans, Karine Al Feghali, Anita Mahajan, Jing Li, Susan L McGovern, Mary-Fran McAleer, Amol J Ghia, Erik P Sulman, Marta Penas-Prado, John F de Groot, Amy B Heimberger, Jihong Wang, Terri S Armstrong, Mark R Gilbert, Nandita Guha-Thakurta, Jeffrey S Wefel
Journal: Neuro-Oncology (2021)

Abstract Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.
Sputum proteomic analysis for distinguishing between pulmonary tuberculosis and non-tuberculosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS): preliminary results
Authors: Thi Loi Dao, Van Thuan Hoang, Tran Duc Anh Ly, Jean Christophe Lagier, Sophie Alexandra Baron, Didier Raoult, Philippe Parola, Johan Courjon, Pierre Marty, Hervé Chaudet, Philippe Gautret
Journal: Clinical Microbiology and Infection (2021)
Stents and glycoprotein IIb/IIIa inhibitors do not improve 30-day outcome in bypass graft percutaneous interventions: a retrospective registry-based analysis
Authors: Marco Roffi, Albert Chan, Derek Chew, Mark Robbins, Debabrata Mukherjee, Deepak Bhatt, Abdulhay Albirini, Leslie Cho, R Agah, Eric Topol, Stephen Ellis
Journal: Journal of the American College of Cardiology (2001)