tbuckley/cabot-search huggingface dataset:
Effect of COVID-19 precautions on the gut microbiota and nosocomial infections
Authors: Armin Rashidi, Maryam Ebadi, Tauseef Ur Rehman, Heba Elhusseini, Harika Nalluri, Thomas Kaiser, Shernan G Holtan, Alexander Khoruts, Daniel J. Weisdorf, Christopher Staley
Journal: Gut Microbes (2021)

COVID-19 precautions decrease social connectedness. It has been proposed that these measures alter the gut microbiota, with potential clinical consequences. We tested this hypothesis in patients with acute myeloid leukemia (AML) receiving inpatient chemotherapy, a population with extensive exposure to the nosocomial setting and at high risk for infections. Hospitalized patients with AML contributed stool samples to a biorepository protocol that was initiated before COVID-19 and continued without change through the pandemic. Patient-, disease-, and treatment-related characteristics remained the same in the two eras and the only change in clinical care was the implementation of COVID-19 precautions in March 2020. The incidence of all-cause nosocomial infections during the pandemic was lower than in the pre-COVID-19 era. Multivariable analysis revealed an imprint of COVID-19 precautions in the gut microbiota as a viable mechanistic explanation. In conclusion, COVID-19 precautions alter the gut microbiota, thereby mediating pathogen susceptibility and nosocomial infections.
Challenges towards serologic diagnostics of emerging arboviruses
Authors: Carlo Fischer, Wendy K Jo, Verena Haage, Andrés Moreira-Soto, Edmilson F de Oliveira Filho, Jan Felix Drexler
Journal: Clinical Microbiology and Infection (2021)

Appropriate laboratory diagnostics for emerging arboviruses are key for patient management, surveillance and intervention, including molecular tests and serological tests detecting viral antigen or virus-specific antibodies.We provide an overview of the challenges towards serological testing for the most important emerging arboviruses, including Zika, dengue and chikungunya viruses.We retrieved a data set on performance of commercially available antibody- and antigen-detecting tests from 89 peer-reviewed articles conducting a systematic literature research in PubMed.We identified commonly used antibody- and antigen-detecting tests and analysed their overall performance. We discuss how timing of serological testing and the use of paired samples from acute and convalescent phases of infection are crucial to optimize diagnostic sensitivity and specificity. We then exemplify how serological diagnostics are challenged by the patient's infection history through the 'original antigenic sin' and cross-reactive antibodies in the context of global co-circulation of antigenically related viruses. We highlight how individual infection histories with different arboviruses and with other pathogens such as herpes viruses and Plasmodia can produce inaccurate test results. We show that rapid tests for antibody and antigen detection in point-of-care settings have a significantly lower sensitivity compared with laboratory-based tests such as ELISA. We show that the performance of antibody- and antigen-detecting tests varies greatly between tropical regions of endemic transmission and non-endemic regions. Finally, we highlight that test sensitivity and specificity have to be equilibrated carefully and frequently either of them must be prioritized over the other, depending on disease prevalence and intended use of tests.For reliable serological diagnostics, it is essential to be aware of inherent test limitations. Although multiplexed testing and testing of convalescence samples can improve diagnostic performance, global spread of (re-)emerging viruses requires careful implementation and evaluation of serological testing and unambiguous results may not always be achievable.
Transcription shapes DNA replication initiation to preserve genome integrity
Authors: Yang Liu, Chen Ai, Tingting Gan, Jinchun Wu, Yongpeng Jiang, Xuhao Liu, Rusen Lu, Ning Gao, Qing Li, Xiong Ji, Jiazhi Hu
Journal: Genome biology (2021)

Abstract Background Early DNA replication occurs within actively transcribed chromatin compartments in mammalian cells, raising the immediate question of how early DNA replication coordinates with transcription to avoid collisions and DNA damage. Results We develop a high-throughput nucleoside analog incorporation sequencing assay and identify thousands of early replication initiation zones in both mouse and human cells. The identified early replication initiation zones fall in open chromatin compartments and are mutually exclusive with transcription elongation. Of note, early replication initiation zones are mainly located in non-transcribed regions adjacent to transcribed regions. Mechanistically, we find that RNA polymerase II actively redistributes the chromatin-bound mini-chromosome maintenance complex (MCM), but not the origin recognition complex (ORC), to actively restrict early DNA replication initiation outside of transcribed regions. In support of this finding, we detect apparent MCM accumulation and DNA replication initiation in transcribed regions due to anchoring of nuclease-dead Cas9 at transcribed genes, which stalls RNA polymerase II. Finally, we find that the orchestration of early DNA replication initiation by transcription efficiently prevents gross DNA damage. Conclusion RNA polymerase II redistributes MCM complexes, but not the ORC, to prevent early DNA replication from initiating within transcribed regions. This RNA polymerase II-driven MCM redistribution spatially separates transcription and early DNA replication events and avoids the transcription-replication initiation collision, thereby providing a critical regulatory mechanism to preserve genome stability.
Real-world utilization of advanced therapies and racial disparity among patients with metastatic castration-sensitive prostate cancer (mCSPC): A Medicare database analysis.
Authors: Stephen J. Freedland, Neeraj Agarwal, Krishnan Ramaswamy, Rickard Sandin, Dave Russell, Agnes Hong, Hongbo Yang, Wei Gao, Kaitlin Hagan, Daniel J. George
Journal: Journal of Clinical Oncology (2021)

5073 Background: Several randomized controlled trials have shown that adding docetaxel or novel hormonal therapy (NHT) to androgen deprivation therapy (ADT) improves survival in mCSPC patients. This study aimed to evaluate the real-world utilization of advanced therapies over time and to provide data on utilization patterns among racial minorities that are often under-represented in clinical trials. Methods: This was a retrospective analysis of a Medicare database (Jan 2009-Dec 2018). Adult men with ≥1 claim for prostate cancer (PC) who initiated ADT (index date) within 90 days prior to or any time after a metastasis diagnosis were included. The first-line (1L) treatment was grouped by PC drugs prescribed within 30 days prior to and 120 days after the index date, in 4 categories: ADT alone, ADT + first-generation anti-androgen (AA; ≥90 days to avoid capturing AA for flare control), ADT + docetaxel, and ADT + NHT (abiraterone, apalutamide, and enzalutamide). The 1L treatment distributions were described over time and stratified by race. Results: A total of 35,195 patients with mCSPC were included in the study, with a mean (SD) age of 76.5 (7.9) years. 11.8% were Black, 5.3% Hispanic, and 78.5% White. 76.4% received ADT alone as 1L treatment, 14.3% ADT + AA, 4.8% ADT + docetaxel, and 4.5% ADT + NHT. While the proportion of patients treated with ADT alone and ADT + AA slowly decreased over time, the utilization of ADT + docetaxel increased since 2015 and the utilization of ADT + NHT increased since 2017 (Table). After the emergence of NHTs for treatment of mCSPC in 2017, treatment intensification with ADT + NHT was numerically lower for Black than White patients. Data from before 2017 also suggest a similar lower use of ADT + AA in Black patients (Table). Survival analysis across treatment cohorts and race are ongoing. Conclusions: In this large and nationally representative sample of mCSPC patients, less than one-third of patients received treatment intensification by 2018, possibly due to patient/disease characteristics, provider awareness or therapeutic inertia, or cost. Importantly, the data showed less frequent treatment intensification in Black vs White patients. Further study is required to elucidate underlying reasons for this disparity.[Table: see text]
Mycobiota dysbiosis and gastric tumorigenesis
Authors: Nicolas Papon, Tobias M. Hohl, Bing Zhai
Journal: Theranostics (2021)

The gastrointestinal tract contains a vast and diverse microbial reservoir composed of bacteria, fungi, and viruses that contribute positively to human health. There is growing evidence that perturbation of the normal microbiota can promote a variety of human disease states that include tumorigenesis. Whether the fungal component of the gut microbiota (i.e., the mycobiota) can influence tumor development has not been investigated in detail. In the recent issue of the Theranostics, Zhong et al (2021) shed light on an association between mycobiota dysbiosis and gastric cancer. These findings implicate the mycobiota in gastric carcinogenesis and set the stage for future mechanistic studies to explore whether fungal dysbiosis is a cause or consequence of gastric carcinogenesis, with important implications for preventative strategies.
Therapeutic Implications of Germline Testing in Patients With Advanced Cancers
Authors: Zsofia K. Stadler, Anna Maio, Debyani Chakravarty, Yelena Kemel, Margaret Sheehan, Erin Salo-Mullen, Kaitlyn Tkachuk, Christopher J. Fong, Bastien Nguyen, Amanda Erakky, Karen Cadoo, Ying Liu, Maria I. Carlo, Alicia Latham, Hongxin Zhang, Ritika Kundra, Shaleigh Smith, Jesse Galle, Carol Aghajanian, Nadeem Abu-Rustum, Anna Varghese, Eileen M. O'Reilly, Michael Morris, Wassim Abida, Michael Walsh, Alexander Drilon, Gowtham Jayakumaran, Ahmet Zehir, Marc Ladanyi, Ozge Ceyhan-Birsoy, David B. Solit, Nikolaus Schultz, Michael F. Berger, Diana Mandelker, Luis A. Diaz, Kenneth Offit, Mark E. Robson
Journal: Journal of Clinical Oncology (2021)

PURPOSE Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer. METHODS Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype–directed therapy were determined. RESULTS Among 11,947 patients across &gt; 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; &lt; 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype–directed therapy. Germline genotype–directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2, 75% of mismatch repair, 43% of PALB2, 35% of RAD51C/D, 24% of BRIP1, and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting. CONCLUSION In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype–directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.
Pathologic U Waves Secondary to Severe Hypophosphatemia During Refeeding Syndrome
Authors: George A. Weatherall, David L. Jardine
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Single-Cell Drug Profiling Reveals Maturation Stage-Dependent Drug Responses in AML
Authors: Heikki Kuusanmäki, Maija Leppä, Mika Kontro, Olli Dufva, Debashish Deb, Bhagwan Yadav, Satu Mustjoki, Kimmo Porkka, Caroline A Heckman
Journal: Blood (2017)
Laryngeal Mask Airway in Medical Emergencies
Authors: Geoffrey Lighthall, T. Kyle Harrison, Larry F. Chu
Journal: New England Journal of Medicine (2013)

This video demonstrates the placement of a laryngeal mask airway, an alternative airway device that is both efficacious and easy to place. The laryngeal mask airway is routinely used for patients receiving general anesthesia and, increasingly, in patient resuscitation.
Characterization of resistance to cytosine arabinoside (Ara-C) in leukemia cells with five different cell lineages
Authors: Eiju Negoro, Yoshimasa Urasaki, Takahiro Yamauchi, Takanori Ueda
Journal: Cancer Research (2008)

690  Objective:  Cytosine arabinoside (Ara-C) is one of the most commonly used agents for leukemia chemotherapy, but the chemotherapeutic resistance remains as limitations in the successful treatment of acute myeloid leukemia. Factors that reduce the intracellular concentration of triphosphorylated cytarabine (Ara-CTP) may induce resistance to Ara-C. However, Ara-C resistance-related changes in hematological cell lines have not been well investigated using a genome-wide approach. In this study, we attempt to elucidate the common factor responsible for Ara-C resistance, in different cell lineages. This knowledge may be used as the clinical surrogate marker of Ara-C resistance.  Material and Methods:  The resistant cell lines were isolated from these wild-type cells with different lineages (THP-1, K562, HL60, CEM, U937) by application of Ara-C at low drug concentrations attainable in clinical treatment. In this study we have established five hematological cell lines (THP-1/AC, K562/AC, HL60/AC, CEM/AC, U937/AC) that were 5~60-fold more resistant to Ara-C than their wild type cell lines (CEM/AC: 5-fold, U937/AC 6-fold, HL60/AC: 6-fold, K562/AC: 15-fold, THP1/AC: 60-fold resistance). Ara-C influx was determined by the measurement of [3H]araC influx. DCK and 5NT was measured using a radiochemical assay, and using western blotting for measure protein expression of DCK. We used cDNA microarray to examine the change in the comprehensive expression levels of genes in these cell lines in relation to resistance to Ara-C.  Results:  THP-1/AC, K562/AC, HL60/AC showed decreased enzyme activity and protein-expression of DCK, HL60/AC also showed decreased ara-C influx, U937/AC, elevation of 5NT enzyme assay and CEM/AC showed decreased protein-expression of topoisomerase II alpha. By the genome-wide quantitative analysis of mRNA expression within these Ara-C reisistant cell lines, we could not determine common gene expression in the all cell lines to be responsible to Ara-C resistance. Only at THP-1/AC which showed the highest resistance to Ara-C in this study, DCK was down-regulated with more than 2 fold change of statistical significance among the factors related to Ara-CTP. Each cell line demonstrated the cross-resistance (HL60: F-araA, dFdC, K562: F-araA, CEM: dFdC, VP16, MIT, THP1: dFdC), despite employment of the common method to induce resistance to Ara-C.  Conclusion:  We have established five Ara-C resistant cell lines, from different cell lineages and investigated the Ara-C resistance-related changes. These results may suggest the mechanism of resistance of hematological cell lines to Ara-C was varied among each cell line and common gene expression in the Ara-C resistance cell lines could not be detected by genome-wide approach.
Cardiotoxic safety communications after FDA approval of novel cancer therapies.
Authors: Janice Bonsu, Onaopepo Kola-Kehinde, Lisa Kim, Patrick Ruz, Maryam B. Lustberg, Jonathan Edward Brammer, Daniel Addison
Journal: Journal of Clinical Oncology (2021)

e18629 Background: Proliferation of novel anticancer therapies has dramatically improved survival. However, in practice, cardiovascular disease (CVD) events have become an increasing concern. Post-market safety communications by the US Food and Drug Administration (FDA) are a primary source of new safety information for patients and providers. Yet, the prevalence and factors associated with the issuance of CVD warnings among cancer therapies are unknown. Methods: Leveraging the Drugs@FDA database and publicly available FDA drug reviews, we identified all anticancer drugs given new-drug applications from 1998-2018. Characteristics related to approval, including drug class, therapeutic area, priority review status, accelerated approval status, orphan product status, regulatory review times, near-regulatory deadline approval status, and post-market safety events were evaluated. Post-market safety communications were defined as the composite of safety-related drug withdrawals and the issuance of black box label warnings or precautions. CVD was defined as heart failure, hypertension (HTN), coronary disease, myocardial infarction, stroke, thromboembolic disease, arrhythmia/electrocardiographic change, or sudden cardiac death. Multivariable logistic regression was used to assess for characteristics associated with the need for CVD safety communications. Results: Overall, there were 125 novel anticancer therapies, including 24 biologics, 10 immunotherapies, and 48 targeted drugs. There were 177 safety communications (41 black box warnings, 7 withdrawals, 4 dose adjustments, and 84 general warnings). Cardiac safety warnings were issued for 63 (51.2%) of therapies, including 23 (36.5% of all) black box warnings. CVD was the most common reason for a black box warning; Table. Among all CVD warnings, arrhythmias (21.6%) followed by heart failure (13.9%), thromboembolic disease (13.9%), uncontrolled HTN (11.8%), sudden CVD death (9.0%), ischemic disease (6.9%), stroke (4.9%), and other CVD events (12.5%) were found. In a multivariable model, only therapeutic class and prior in-class cardiotoxicity were associated with the issuance of CVD safety communications. Conclusions: Among novel cancer therapies, cardiac safety communications are prevalent.[Table: see text]
Assessment of compliance with national guidelines in genetic testing and tumor profiling in patients diagnosed with pancreatic adenocarcinoma: A retrospective review.
Authors: Karthik Shankar, Srividya Srinivasamaharaj, Yazan Samhouri, Saleha Rizwan, Deep Shah, Jiaxiang Liu, Alexander M Helfand, Naga Sai Krishna Patibandla, Katherine Miller, Pragnan Kancharla, Ahmed Khattab, Richard White, Veli Bakalov, Dulabh K. Monga
Journal: Journal of Clinical Oncology (2021)

e16260 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of poor prognosis, portending a 5-year survival rate of 9% when considering all stages. Although the mainstay of treatment of PDAC remains cytotoxic chemotherapy in both the early and advanced stages, recent advances in tumor profiling and germline testing have allowed for the incorporation of poly-ADP-ribose polymerase (PARP) inhibitors, immune checkpoint inhibitors and targeted therapy to be utilized in the maintenance and subsequent-line settings for metastatic PDAC, respectively. We sought to identify our institutional compliance rate in germline testing and tumor profiling in all patients diagnosed with PDAC. Methods: A retrospective review was conducted of all patients diagnosed with PDAC from 2017-2019 at Allegheny General Hospital. Data analysis was completed using IBM SPSS v23. Summary statistics were presented using percentages for categorical variables and medians with interquartile ranges for continuous variables. Results: Out of 171 patients reviewed, 121 received and completed treatment in our institution, and were included in the analysis. Median age was 69 years. 55 patients (45%) were male and 66 (55%) were female. Germline testing was done in 28 patients (23%) and tumor molecular profiling was done in 25 patients (21%). Testing for microsatellite instability was performed in 28 patients (23%). Testing for programmed death-ligand (PD-L1) expression was done in 16 patients (13%). On univariate analysis, family history of malignancy was a predictor for germline testing (OR 5.3; 95% CI 1.4-2.01; p=0.01). No predictors were identified in association with tumor molecular profiling likely due to low sample size. Conclusions: Our analysis reveals an institutional compliance rate of 20-23% in adherence to national guidelines with respect to germline testing and tumor profiling in the management of PDAC. A family history of malignancy demonstrated predictive association with germline testing. Factors which may limit pathological evaluation of microsatellite stability status, assessment of PD-L1 expression and molecular profiling include lack of institutional protocol for reflex histological testing, financial or insurance constraints, and lack of adequate tissue. As part of our Quality improvement project, we identified that incorporation of reflex histological testing based on tumor-type, standardization of tissue biopsy to optimize yield, and utilization of support staff, such as Oncology Navigators, to facilitate scheduling for germline testing may increase compliance rates.