tbuckley/cabot-search huggingface dataset:
The Urine Anion Gap: Common Misconceptions
Authors: Jaime Uribarri, Man S. Oh
Journal: Journal of the American Society of Nephrology (2021)

Two papers, one in 1986 and another one in 1988, reported a strong inverse correlation between urinary anion gap (UAG) and urine ammonia excretion (UNH 4 ) in patients with metabolic acidosis and postulated that UAG could be used as an indirect measure of UNH 4 . This postulation has persisted until now and is widely accepted. In this review, we discuss factors regulating UAG and examine published evidence to uncover errors in the postulate and the design of the original studies. The essential fact is that, in the steady state, UAG reflects intake of Na, K, and Cl. Discrepancy between intake and urinary output of these electrolytes ( i.e ., UAG) indicates selective extrarenal loss of these electrolytes or nonsteady state. UNH 4 excretion, which depends, in the absence of renal dysfunction, mainly on the daily acid load, has no consistent relationship to UAG either theoretically or in reality. Any correlation between UAG and UNH 4 , when observed, was a fortuitous correlation and cannot be extrapolated to other situations. Furthermore, the normal value of UAG has greatly increased over the past few decades, mainly due to increases in dietary intake of potassium and widespread use of sodium salts with anions other than chloride as food additives. The higher normal values of UAG must be taken into consideration in interpreting UAG.
Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC).
Authors: Bradley Alexander McGregor, Elio Adib, Wanling Xie, Walter Michael Stadler, Yousef Zakharia, M Dror Michaelson, Ajjai Shivaram Alva, Subrina Farah, Amin Nassar, Lauren C Harshman, David J. Kwiatkowski, Rana R. McKay, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.
22P Toxicity profile of immune and non-immune therapies in phase I/II trials: A comprehensive longitudinal analysis
Authors: L. Missri, P. Martin-Romano, C. Helissey, E. Lanoy, C. Baldini, A. Varga, A. Hollebecque, J-M. Michot, A. Gazzah, R. Bahleda, S. Champiat, A. Italiano, V. Ribrag, E. Angevin, J-P. Armand, E. Deutsch, A. Marabelle, J-C. Soria, C. Massard, S. Postel-Vinay
Journal: Annals of Oncology (2021)
Abstract PO045: Impact of fibroblast mediated stromal protection on evolution of resistance to targeted therapies in NSCLC
Authors: Bina Desai
Journal: Cancer Research (2021)

Abstract BACKGROUND: Clinical introduction of tyrosine kinases inhibitors (TKIs) for ALK+ non-small cell lung cancer (NSCLC) has improved patient survival, but it did not translate into cures as acquired resistance inevitably emerges in patients with advanced and metastatic cancers. Cancer associated fibroblasts (CAFs) have emerged as the major determinant of environmental protection. While the ability of stroma to protect tumor cells from TKI is well documented in-vitro, whether the impact of stromal protection is relevant in 3D context and in-vivo remains unresolved. Thus, we hypothesized that stromal protection impacts the initial response of tumor cells to targeted therapies. METHODS: Cancer cell lines were cultured in presence of CAF conditioned media (CM) and treated with TKIs to monitor cell viability. To interrogate molecular mechanism, loss and gain of function experiments were performed using pharmacological inhibitors and recombinant human protein respectively. To address the relevance of stromal protection in-vivo, we worked with tumor xenograft mouse model. We also used mathematical modelling to understand the tumor dynamics, using inferences from xenograft mouse models to build agent-based models. RESULTS: We observed that patient derived matched normal tissue associated fibroblast (NAFs) and CAFs, both confers various level of protection to tumor cells against TKIs. Addition of rh Hepatocyte growth factor (HGF) protein mimicked the effect of CAF CM and addition of small molecule inhibitors of cMET abolished the CAF-mediated protection to tumor cells against TKIs. Our xenograft experiment showed the significant increase in stroma/tumor ratio during the initial tumor response to targeted therapy and we observed increase in tumor proliferating cells in proximity to stroma. Our math model for stroma and pre-existing resistant population showed delay in development of resistance to TKI. CONCLUSION: Fibroblast-mediated stromal protection is critically dependent on HGF-cMET axis. Dual inhibition of ALK and MET signaling abolished the fibroblast-mediated protection and increased the cell sensitivity to ALK TKIs, suggesting the crucial role of microenvironment-mediated resistance in NSCLC. To study tumor dynamics using mathematical models, we addressed that space could be key to understand the impact of stromal protection in-vivo. Our study shows that understanding the signaling changes carried by fibroblast in response to therapy may lead to potential better combination therapy. Citation Format: Bina Desai. Impact of fibroblast mediated stromal protection on evolution of resistance to targeted therapies in NSCLC [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO045.
Prevalence of mental disorders, suicidal ideation and suicides in the general population before and during the COVID-19 pandemic in Norway: A population-based repeated cross-sectional analysis
Authors: Ann Kristin Skrindo Knudsen, Kim Stene-Larsen, Kristin Gustavson, Matthew Hotopf, Ronald C. Kessler, Steinar Krokstad, Jens Christoffer Skogen, Simon Øverland, Anne Reneflot
Journal: The Lancet Regional Health - Europe (2021)
Does Reduced Renal Function Predispose to Cancer-specific Mortality from Renal Cell Carcinoma?
Authors: Diego Aguilar Palacios, Emily C. Zabor, Carlos Munoz-Lopez, Gustavo Roversi, Furman Mahmood, Emily Abramczyk, Maureen Kelly, Brigid Wilson, Robert Abouassaly, Steven C. Campbell
Journal: European Urology (2021)
Reporting practices for genomic epidemiology of tuberculosis: a systematic review of the literature using STROME-ID guidelines as a benchmark
Authors: Brianna Cheng, Marcel A Behr, Benjamin P Howden, Theodore Cohen, Robyn S Lee
Journal: The Lancet Microbe (2021)

BackgroundPathogen genomics have become increasingly important in infectious disease epidemiology and public health. The Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) guidelines were developed to outline a minimum set of criteria that should be reported in genomic epidemiology studies to facilitate assessment of study quality. We evaluate such reporting practices, using tuberculosis as an example.MethodsFor this systematic review, we initially searched MEDLINE, Embase Classic, and Embase on May 3, 2017, using the search terms "tuberculosis" and "genom* sequencing". We updated this initial search on April 23, 2019, and also included a search of bioRxiv at this time. We included studies in English, French, or Spanish that recruited patients with microbiologically confirmed tuberculosis and used whole genome sequencing for typing of strains. Non-human studies, conference abstracts, and literature reviews were excluded. For each included study, the number and proportion of fulfilled STROME-ID criteria were recorded by two reviewers. A comparison of the mean proportion of fulfilled STROME-ID criteria before and after publication of the STROME-ID guidelines (in 2014) was done using a two-tailed t test. Quasi-Poisson regression and tobit regression were used to examine associations between study characteristics and the number and proportion of fulfilled STROME-ID criteria. This study was registered with PROSPERO, CRD42017064395.Findings976 titles and abstracts were identified by our primary search, with an additional 16 studies identified in bioRxiv. 114 full texts (published between 2009 and 2019) were eligible for inclusion. The mean proportion of STROME-ID criteria fulfilled was 50% (SD 12; range 16–75). The proportion of criteria fulfilled was similar before and after STROME-ID publication (51% [SD 11] vs 46% [14], p=0·26). The number of criteria reported (among those applicable to all studies) was not associated with impact factor, h-index, country of affiliation of senior author, or sample size of isolates. Similarly, the proportion of criteria fulfilled was not associated with these characteristics, with the exception of a sample size of isolates of 277 or more (the highest quartile). In terms of reproducibility, 100 (88%) studies reported which bioinformatic tools were used, but only 33 (33%) reported corresponding version numbers. Sequencing data were available for 86 (75%) studies.InterpretationThe reporting of STROME-ID criteria in genomic epidemiology studies of tuberculosis between 2009 and 2019 was low, with implications for assessment of study quality. The considerable proportion of studies without bioinformatics version numbers or sequencing data available highlights a key concern for reproducibility.FundingNone.
Mobilising evidence, data, and resources to achieve global maternal and child undernutrition targets and the Sustainable Development Goals: an agenda for action
Authors: Rebecca A Heidkamp, Ellen Piwoz, Stuart Gillespie, Emily C Keats, Mary R D'Alimonte, Purnima Menon, Jai K Das, Augustin Flory, Jack W Clift, Marie T Ruel, Stephen Vosti, Jonathan Kweku Akuoku, Zulfiqar A Bhutta
Journal: The Lancet (2021)
Circulating tumor DNA analysis of genomic alterations in metastatic urothelial carcinoma from NCT03113266 study.
Authors: Haige Chen, Ruiyun Zhang, Feng Xie, Pan Du, Yue Zhang, Shidong Jia, Guanglei Zhuang, Yiran Huang
Journal: Journal of Clinical Oncology (2021)

486 Background: Recent studies have suggested the predictive value of liquid biopsies for immune checkpoint inhibitors. NCT03113266 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-PD-1) in metastatic urothelial carcinoma (mUC). Here we report the initial circulating tumor DNA (ctDNA) analysis of genomic alterations from a single-institution biomarker cohort. Methods: Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled and consented to Institutional Review Board-approved protocols permitting biomaterial collection and genetic sequencing. Serial plasma specimens were obtained at baseline and every two cycles. The 600-gene panel (PredicineATLAS) liquid biopsy assay was applied to assess somatic variants and blood tumor mutational burden (bTMB). Results: The ctDNA assays were performed successfully for 100% of baseline samples (n = 27) with average read depth of 24,389 (range 14,000-31,700). A total of 571 non-synonymous mutations were identified, demonstrating prevalent aberrations in TP53 (63%), TERT promoter (30%), KDM2D (26%), PPM1D (26%), and KDM6A (26%). In 5 patients, FGFR3 variants were detected, including 6 missense sites and 4 FGFR3- TACC3 fusion events. Copy number gain ( FGFR1, ERBB2) and loss ( PTEN, BRCA2, CDKN2A) were pinpointed. TMB estimation revealed one case with an exceptionally high bTMB (62.6 mutations/Mb) and genomic features of microsatellite instability (MSI). Concordance with tumor-based genotyping and ctDNA kinetics during toripalimab treatment are being determined. Conclusions: Prospective ctDNA analysis using the PredicineATLAS liquid biopsy assay is feasible and represents a minimally invasive approach to detecting cancer-specific genetic landscape and potentially guiding personalized therapeutic decisions in mUC patients. Clinical trial information: NCT03113266 . Research Sponsor: Shanghai Junshi BioSciences; Huidu Shanghai Medical Sciences Ltd
Quantitative analysis of inulin distribution in the brain focused on nose-to-brain route via olfactory epithelium by reverse esophageal cannulation
Authors: Mitsuyoshi Fukuda, Takanori Kanazawa, Shingo Iioka, Takayuki Oguma, Ryohei Iwasa, Saki Masuoka, Naoto Suzuki, Yasuhiro Kosuge, Toyofumi Suzuki
Journal: Journal of Controlled Release (2021)
Early Noninvasive Cardiac Testing in Emergency Department Patients—Reply
Authors: Aniket A. Kawatkar, Benjamin C. Sun, Adam L. Sharp
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
Genome-wide association study of asthma, total IgE, and lung function in a cohort of Peruvian children
Authors: Ayobami T. Akenroye, Tonya Brunetti, Karina Romero, Michelle Daya, Kanika Kanchan, Gautam Shankar, Sameer Chavan, Meher Preethi Boorgula, Elizabeth A. Ampleford, Héllen Freitas Fonseca, Gregory A. Hawkins, Helena Mariana Pitangueira Teixeira, Monica Campbell, Nicholas Rafaels, Alexandra Winters, Eugene R. Bleecker, Alvaro A. Cruz, Mauricio L. Barreto, Deborah A. Meyers, Victor E. Ortega, Camila A. Figueiredo, Kathleen C. Barnes, William Checkley, Nadia N. Hansel, Rasika A. Mathias
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 15998: Therapeutic Effectiveness Against Heart Failure With Preserved Ejection Fraction by the Activation of the Growth Hormone-releasing Hormone Receptor in a Murine Model
Authors: Raul A Dulce, Rosemeire M Kanashiro-takeuchi, Lauro Takeuchi, Alessandro Salerno, Wayne Balkan, Renzhi Cai, Andrew Schally, Joshua M Hare
Journal: Circulation (2020)

Introduction: Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone-agonists (GHRH-As) reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their therapeutic effect in HFpEF is unknown. Hypothesis: We hypothesized that activation of GHRH receptor signaling prevents pathological remodeling and targets cardio-myocyte (CM) excitation-contraction coupling, ameliorating the compromised myocardial performance associated with HFpEF. Methods: CD1 mice implanted with a mini-osmotic pump (Alzet) to deliver angiotensin-II (Ang-II) for 8 weeks, were randomized at week 4 to receive daily injections of either GHRH-A (MR-356; n=12) or vehicle (n=12). Echocardiographic data and pressure-volume loops were recorded. Biometric measurements and fibrosis were assessed. CMs were isolated and intracellular Ca2 + and sarcomere length acquired. Results: Ang-II-treated mice exhibited functional and morphologic features consistent with HFpEF. CMs exhibited reduced sarcomere length, indicating an inability to relax. The Ca2 + decay rate and sarcomere re-lengthening were delayed. MR-356 treatment reverted the structural remodeling, including fibrosis, improving diastolic function (Figure Top panel). This treatment also abrogated the HFpEF-associated delay in Ca2 + decay and further enhanced sarcomere re-lengthening rate (Figure Bottom panel). Conclusions: Our findings confirm that chronic infusion of Ang-II mediates functional changes in CMs consistent with HFpEF and demonstrate that activation of GHRH receptor signaling pathways targets mechanisms of excitation-contraction coupling, inflammation and fibrosis, thereby preventing HFpEF-associated dysfunctional CM relaxation and myocardial remodeling.
Paternity, relationship, sexual activity and fertility in testicular cancer (TC) survivors (TCS): Results from a single institution observational prospective study.
Authors: Davide Bimbatti, Francesco Pierantoni, Marco Maruzzo, Filippo Maria Deppieri, Aichi Msaki, Maura Gatti, Michele Dionese, Eleonora Lai, Dario Marino, Umberto Basso, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2021)

380 Background: TC represents 1% of male neoplasms but it is the most common in young adults. Interdisciplinary management with chemotherapy, radiotherapy and surgery has led to a 10-year relative survival rate of up to 95%. These treatments (Tx) have short- and long-term side effects. While sexual dysfunction can reduce fertility, psychosocial distress can create relationship problems and finally affect the ability to procreate. Methods: From February 2020, we submitted a series of questionnaires to all the patients (pts) currently followed-up at the Istituto Oncologico Veneto free from TC recurrence for at least 2 years from the last Tx. International Index of Erectile Function (IIEF-15) and Premature Ejaculation Diagnostic Tool (PEDT) were used. We also set up a questionnaire to investigate paternity and family status. Data about disease and treatments were collected from medical records. Results: 84 TCS completed the questionnaires, clinical data are reported in the table below. 29,8% of pts fathered children before diagnosis with a strong correlation with older age at diagnosis (45,4 vs 30,8 years, p&lt;0,001). After Tx, 14 pts had children: 9 of which naturally, 2 out 6 were successful via assisted reproductive technology (ART) (including one patient that received high-dose chemotherapy and stem cell transplantation), 3 via adoption. 89,3% of pts had stable relationships. Of pts who did not have children: 13,1% claimed to be due to lack of a partner, 39,3% claimed to be unready, while 14,3% had tried unsuccessfully to conceive. While 28,6% pts claim to currently have fertility issues, only 8,3% of pts reported to have these issues before diagnosis. 70,2% of pts performed a spermiogram after Tx, 10 pts had spermatogenic impairment. Higher rate of sexual dysfunction after Tx was detected by questionnaires while only 4 pts claimed to have had a pre-existing issue prior to TC diagnosis. PEDT shows that 38,1% had premature ejaculation and that in 22,6% this issue is highly probable. IIEF confirms a high rate of erectile dysfunction (14,3% severe and 10,7% mild or moderate). No correlations were identified between sexual dysfuntion and previous Tx. Conclusions: Most TCS had not planned fatherhood while 16,7% had children after Tx and 14.3% tried unsuccessfully to conceive. ART and adoption is possible but challenging and little used. PEDT and IIEF found high rates of sexual dysfunction but no association with previous Tx were found. [Table: see text]
TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib.
Authors: Brian I. Rini, Sumanta K. Pal, Bernard Escudier, Michael B. Atkins, Thomas E. Hutson, Camillo Porta, Elena Verzoni, Michael N. Needle, David F. McDermott
Journal: Journal of Clinical Oncology (2021)

278 Background: Tivozanib (T) is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for RCC. Axitinib is also a potent and selective VEGF-R inhibitor now commonly part of front-line aRCC treatment. The activity of T after axitinib has not been previously defined. The activity of T after prior therapy types including axitinib is of clinical relevance. Methods: The pivotal TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective of the overall trial was to compare progression free survival (PFS) by blinded independent radiological review. Patients with prior axitinib received as monotherapy in the second or third line setting and other predefined subgroups were reviewed for outcome with T. Results: Patients treated with T after prior axitinib had a PFS of 5.5 months and an ORR of 13% compared to 3.7 months and 8% for patients treated with S. Other subgroups are presented in the table below. Clinical trial information: NCT02627963 . Conclusions: Tivozanib improved PFS vs. sorafenib in patients who have progressed after multiple VEGFR-TKIs, including patients with prior second or third line axitinib treatment. These results suggest differential activity from tivozanib and axitinib despite both being potent and selective VEGF-R inhibitors. [Table: see text]