tbuckley/cabot-search huggingface dataset:
Baseline characteristics as predictors of adjuvant chemotherapy (AC) discontinuations and modifications in stage III colorectal cancer (CRC) patients.
Authors: Akie Watanabe, Charlie Yang, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

585 Background: Discontinuations and treatment modifications of AC can impact survival in CRC patients. Unfavorable baseline patient characteristics such as old age, poor ECOG performance status, and comorbidities may contribute to early treatment termination, but their precise associations with treatment interruptions are unclear. Methods: We reviewed a population-based cohort of CRC patients treated with adjuvant monotherapy (Capecitabine) or combination therapy (FOLFOX or CAPOX) within 12 weeks of curative resection in British Columbia, and determined the associations between baseline characteristics and treatment modifications (change in regimen and/or cessation of a single agent) or discontinuations. Results: Among 555 patients, median age was 66 years, 52% were men, and 16% were ECOG ≥2. In this cohort, 42% received monotherapy and 58% received combination therapy. 37% of patients had modifications to monotherapy and 31% discontinued it while 44% had modifications to combination therapy and 26% discontinued it. For monotherapy, univariate analyses showed significant associations between survival and treatment modifications ( P= 0.001) and discontinuations ( P&lt; 0.001). Specifically, old age (≥70; P= 0.044) and pre-treatment anemia ( P= 0.016) were associated with permanent discontinuations. On multivariate analyses, non-mucinous adenocarcinoma histology predicted a higher chance of treatment modifications (OR 3.02, 95% CI 1.03-8.83, P= 0.044) while pre-treatment anemia was correlated with discontinuations (OR 2.27, 95% CI 1.14-4.50, P= 0.020). Univariate analyses of combination therapy showed a relationship between survival and discontinuations ( P= 0.005); however, only worse ECOG status (≥2) was predictive of discontinuations on multivariate analyses (OR 2.39, 95% CI 1.03-5.55, P= 0.042). Conclusions: Except for pre-treatment anemia and ECOG status, few baseline characteristics correlated with treatment modifications or discontinuations, underscoring the need for repeated clinical assessments throughout treatment. Baseline features may only be useful in deciding whether or not a patient should initiate chemotherapy.
Gene Therapy Strategies to Restore ER Proteostasis in Disease
Authors: Vicente Valenzuela, Kasey L. Jackson, Sergio P. Sardi, Claudio Hetz
Journal: Molecular Therapy (2018)

Proteostasis alterations are proposed as a transversal hallmark of several pathological conditions, including metabolic disorders, mechanical injury, cardiac malfunction, neurodegeneration, and cancer. Strategies to improve proteostasis aim to reduce the accumulation of specific disease-related misfolded proteins or bolster the endogenous mechanisms to fold and degrade abnormal proteins. Endoplasmic reticulum (ER) stress is a common pathological signature of a variety of diseases, which engages the unfolded protein response (UPR) as a cellular reaction to mitigate ER stress. Pharmacological modulation of the UPR is challenging considering the physiological importance of the pathway in various organs. However, local targeting of ER stress responses in the affected tissue using gene therapy is emerging as a possible solution to overcome side effects. The delivery of ER chaperones or active UPR components using adeno-associated virus (AAV) has demonstrated outstanding beneficial effects in several disease models (e.g., neurodegenerative conditions, eye disorders, and metabolic diseases). Here, we discuss current efforts to design and optimize gene therapy strategies to improve ER proteostasis in different disease contexts.
Obesity, Body Composition, and Breast Cancer
Authors: Elisa V. Bandera, Esther M. John
Journal: JAMA Oncology (2018)

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 Oncology 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 Oncology journal
Response by Olde Engberink et al to Letter Regarding Article, “Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk”
Authors: Rik H.G. Olde Engberink, Bert-Jan H. van den Born, Hessel Peters-Sengers, Liffert Vogt
Journal: Circulation (2018)
Chemotherapy dose reductions in obese patients undergoing adjuvant chemotherapy for colorectal cancer: secondary analyses of trial data and the Greater Manchester and Cheshire Cancer Network Audit.
Authors: Prakhar Srivastava, Lee Malcolmson, Mark P. Saunders, Andrew Renehan
Journal: Journal of Clinical Oncology (2018)

763 Background: In patients with stage II/III colorectal cancer receiving adjuvant chemotherapy, doses are calculated using body surface area (BSA) but often capped at BSA &gt; 2.0. Dose capping might be a mechanism of reported poorer survival in obese patients. We aimed to investigate the different dosing schedules across BMI categories, using trial and ‘real world’ audit datasets, and determine its impact upon overall survival. Methods: Data was accessed for 1122 patients from the control arm of the MOSAIC trial (accessed via the Data Project Sphere) and 327 patients from the Greater Manchester and Cheshire Cancer Network (GMCCN) audit. Pearson’s χ 2 and correlation coefficient were used to assess the relationship between BMI (expressed as normal, overweight and obese: and as continuous, respectively) and dose reductions. A multiple logistic regression model was constructed to compare the odds of receiving dose reductions in each BMI category. 4-year overall survival was calculated for each BMI category and dose status. Results: In MOSAIC, there were increasing dose reductions by BMI category: normal, 3%; overweight, 5%; and obese, 11%, with similar patterns in the GMCCN OxMdG group. Obese patients in MOSAIC and the GMCCN OxMdG group had 3- and 12-fold higher odds (OR = 3.4 and 12.5, CI = 1.6-7.0 and 2.0-78.1), respectively, of receiving dose reductions. However, these differences did not translate to differences in overall survival by BMI category or dose status. Conclusions: In our investigated datasets, there appears to be a relationship between increasing BMI and dose reductions, though it is modest and does not manifest as a detrimental influence on overall survival. Our findings agreed with other studies performed using stage IV cancer patients, although the relationship between increasing BMI and dose reductions is more prominent in patients with metastatic disease. Investigating other outcome measures such as cancer-specific survival and chemotherapy related toxicity is required for clarity.
Comparison of the real-world adherence and compliance patterns with trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) for the treatment of metastatic colorectal cancer (mCRC).
Authors: Anuj K. Patel, Mei Sheng Duh, Victoria Barghout, Mihran Ara Yenikomshian, Yongling Xiao, Willy Wynant, Majid Tabesh, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2018)

666 Background: FTD/TPI and REG both prolong survival in refractory mCRC and have similar indications with different side effect profiles. This study compares real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database. Methods: Retrospective data from 10/2014 to 7/2016 from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for patients receiving FTD/TPI or REG. The index date was the date of first FTD/TPI or REG prescription. Patients were included if: 1) age ≥18 years old, 2) ≥1 CRC diagnosis, 3) no diagnosis of gastric cancer or gastrointestinal stromal tumor, and 4) continuous clinical activity for ≥3 months before and after index date. The observation period spanned from index date to end of data, end of continuous clinical activity, or switch to another mCRC treatment. Adherence was assessed using medication possession ratio (MPR) ≥0.80 and proportion of days covered (PDC) ≥0.80 at 3 months. Compliance was assessed using time to discontinuation over the observation period using allowable gaps of 45, 60, or 90 days. Patients who never discontinued therapy were censored at the end of the observation period. Outcomes were compared between FTD/TPI and REG using multivariate logistic regression and Cox proportional hazards models, adjusting for demographic and clinical baseline characteristics. Results: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. Mean ± standard deviation (SD) age of FTD/TPI patients was 61.0 ± 11.0 compared to 62.8 ± 10.9 for REG patients (p &lt; 0.001). FTD/TPI patients were 80% more likely to have a MPR ≥0.80 compared to those on REG (Odds Ratio [OR] = 1.80, p &lt; 0.001) and more than twice as likely to have a PDC ≥0.80 (OR = 2.66, p &lt; 0.001) at 3 months. FTD/TPI patients were 37% less likely to discontinue their treatment compared to those on REG when using gaps of 60 days (Hazard Ratio = 0.63, p &lt; 0.001). Similar results were found with 45 and 90 days. Conclusions: In this retrospective study of mCRC patients, patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.
99mTechnetium-based Prostate-specific Membrane Antigen–radioguided Surgery in Recurrent Prostate Cancer
Authors: Tobias Maurer, Stephanie Robu, Margret Schottelius, Kristina Schwamborn, Isabel Rauscher, Nynke S. van den Berg, Fijs W.B. van Leeuwen, Bernhard Haller, Thomas Horn, Matthias M. Heck, Jürgen E. Gschwend, Markus Schwaiger, Hans-Jürgen Wester, Matthias Eiber
Journal: European Urology (2018)
To kill a bee: The aptness and moralistic heuristics of reactive attitudes
Authors: Hugo Viciana, Antonio Gaitán, Fernando Aguiar
Journal: Behavioral and Brain Sciences (2018)

Abstract Although we are sensitive to the advantages of reactive attitudes as a starting point, we are concerned that confusion on the level of analysis can easily plague this type of account. We argue that what is needed here is a serious appraisal of the effects on the promotion of values of moralistic responses toward different types of agency.
Inspired Translation: Synthesizing Qualitative Research and Boot Camp Translation to Achieve Meaningful Community Engagement
Authors: Bethany M. Kwan, Suzanne R. Millward, Meleah Himber, Julie Ressalam, Heidi Wald, Matthew Wynia, Marilyn E. Coors
Journal: The American Journal of Bioethics (2018)

This article refers to:Beyond Consent: Building Trusting Relationships With Diverse Populations in Precision Medicine Research
A negative feedback loop between microRNA-378 and Nrf1 promotes the development of hepatosteatosis in mice treated with a high fat diet
Authors: Tianpeng Zhang, Xiaoling Zhao, Clifford J. Steer, Guiqin Yan, Guisheng Song
Journal: Metabolism (2018)

BackgroundsThe incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing due to the prevalence of obesity. NAFLD is a major risk factor of hepatocellular carcinoma (HCC). Even with successful surgical removal, the presence of NAFLD is associated with an increased recurrence of HCC. Despite the extensive study of NAFLD, its underlying mechanism(s) remains essentially unknown and there are no FDA-approved drugs for its treatment. Alterations in microRNA (miR) expression have been observed in human fatty livers. However, regulatory mechanism(s) of miRNA biogenesis and their role in regulating the development of NAFLD is poorly described.MethodsWe used immunohistochemistry, luciferase assays and immunoblotting to study the regulatory mechanism of miR-378 biogenesis. Wild-type mice kept on a high fat diet (HFD) were injected with miR-378 inhibitors or a mini-circle expression system containing miR-378 to study loss and gain-of functions of miR-378.ResultsmiR-378 was significantly increased in fatty livers of dietary obese mice and human hepatoma HepG2 cells with accumulated lipid. Further studies identified NRF1 (Nuclear receptor factor 1), a key regulator of fatty acid oxidation (FAO), as a direct target of miR-378. Overexpression of miR-378 impaired FAO and promoted lipid accumulation in murine hepatoma Hepa1-6 cells. In contrast, knockdown of miR-378 using its ASO (anti-sense oligo) improved FAO and reduced intracellular lipid content in Hepa1-6 cells. Liver-specific expression of miR-378 impaired FAO, which subsequently promoted the development of hepatosteatosis. Antagonizing miR-378 via injecting miR-378-ASO into HFD-treated mice led to increased expression of Nrf1, improved FAO and decreased hepatosteatosis. Additional knockdown of up-regulated Nrf1 offset the effects of miR-378-ASO, suggesting that Nrf1 mediated the inhibitory effect of miR-378-ASO on hepatosteatosis. Furthermore, Nrf1 was identified as a transcriptional repressor of miR-378. Ablation of Nrf1 using its shRNA in livers led to increased miR-378, which subsequently resulted in reduced FAO and elevated hepatic lipid content.ConclusionsThese findings identified a negative feedback loop between miR-378 and Nrf1 that promotes the pathogenesis of hepatosteatosis, and suggests the use of miR-378 as a potential therapeutic target for NAFLD.
KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
Authors: Marta Román, Iosune Baraibar, Inés López, Ernest Nadal, Christian Rolfo, Silvestre Vicent, Ignacio Gil-Bazo
Journal: Molecular Cancer (2018)

Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
Glyphosate Levels in Older Adults
Authors: Katherine Karberg, Daniel Goldstein, S. Eliza Dunn
Journal: JAMA (2018)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Group B streptococcus exploits vaginal epithelial exfoliation for ascending infection
Authors: Jay Vornhagen, Blair Armistead, Verónica Santana-Ufret, Claire Gendrin, Sean Merillat, Michelle Coleman, Phoenicia Quach, Erica Boldenow, Varchita Alishetti, Christina Leonhard-Melief, Lisa Y. Ngo, Christopher Whidbey, Kelly S. Doran, Chad Curtis, Kristina M. Adams Waldorf, Elizabeth Nance, Lakshmi Rajagopal
Journal: Journal of Clinical Investigation (2018)

Thirteen percent of pregnancies result in preterm birth or stillbirth, accounting for fifteen million preterm births and three and a half million deaths annually. A significant cause of these adverse pregnancy outcomes is in utero infection by vaginal microorganisms. To establish an in utero infection, vaginal microbes enter the uterus by ascending infection; however, the mechanisms by which this occurs are unknown. Using both in vitro and murine models of vaginal colonization and ascending infection, we demonstrate how a vaginal microbe, group B streptococcus (GBS), which is frequently associated with adverse pregnancy outcomes, uses vaginal exfoliation for ascending infection. GBS induces vaginal epithelial exfoliation by activation of integrin and β-catenin signaling. However, exfoliation did not diminish GBS vaginal colonization as reported for other vaginal microbes. Rather, vaginal exfoliation increased bacterial dissemination and ascending GBS infection, and abrogation of exfoliation reduced ascending infection and improved pregnancy outcomes. Thus, for some vaginal bacteria, exfoliation promotes ascending infection rather than preventing colonization. Our study provides insight into mechanisms of ascending infection by vaginal microbes.
Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy
Authors: Tina Cascone, Jodi A. McKenzie, Rina M. Mbofung, Simone Punt, Zhe Wang, Chunyu Xu, Leila J. Williams, Zhiqiang Wang, Christopher A. Bristow, Alessandro Carugo, Michael D. Peoples, Lerong Li, Tatiana Karpinets, Lu Huang, Shruti Malu, Caitlin Creasy, Sara E. Leahey, Jiong Chen, Yuan Chen, Helen Pelicano, Chantale Bernatchez, Y.N. Vashisht Gopal, Timothy P. Heffernan, Jianhua Hu, Jing Wang, Rodabe N. Amaria, Levi A. Garraway, Peng Huang, Peiying Yang, Ignacio I. Wistuba, Scott E. Woodman, Jason Roszik, R. Eric Davis, Michael A. Davies, John V. Heymach, Patrick Hwu, Weiyi Peng
Journal: Cell Metabolism (2018)
Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood
Authors: Edward Mitre, Apryl Susi, Laura E. Kropp, David J. Schwartz, Gregory H. Gorman, Cade M. Nylund
Journal: JAMA Pediatrics (2018)

Allergic diseases are prevalent in childhood. Early exposure to medications that can alter the microbiome, including acid-suppressive medications and antibiotics, may influence the likelihood of allergy.To determine whether there is an association between the use of acid-suppressive medications or antibiotics in the first 6 months of infancy and development of allergic diseases in early childhood.A retrospective cohort study was conducted in 792 130 children who were Department of Defense TRICARE beneficiaries with a birth medical record in the Military Health System database between October 1, 2001, and September 30, 2013, with continued enrollment from within 35 days of birth until at least age 1 year. Children who had an initial birth stay of greater than 7 days or were diagnosed with any of the outcome allergic conditions within the first 6 months of life were excluded from the study. Data analysis was performed from April 15, 2015, to January 4, 2018.Exposures were defined as having any dispensed prescription for a histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotic.The main outcome was allergic disease, defined as the presence of food allergy, anaphylaxis, asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, contact dermatitis, medication allergy, or other allergy.Of 792 130 children (395 215 [49.9%] girls) included for analysis, 60 209 (7.6%) were prescribed an H2RA, 13 687 (1.7%) were prescribed a PPI, and 131 708 (16.6%) were prescribed an antibiotic during the first 6 months of life. Data for each child were available for a median of 4.6 years. Adjusted hazard ratios (aHRs) in children prescribed H2RAs and PPIs, respectively, were 2.18 (95% CI, 2.04-2.33) and 2.59 (95% CI, 2.25-3.00) for food allergy, 1.70 (95% CI, 1.60-1.80) and 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.51 (95% CI, 1.38-1.66) and 1.45 (95% CI, 1.22-1.73) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) and 1.44 (95% CI, 1.36-1.52) for allergic rhinitis, and 1.25 (95% CI, 1.21-1.29) and 1.41 (95% CI, 1.31-1.52) for asthma. The aHRs after antibiotic prescription in the first 6 months of life were 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.This study found associations between the use of acid-suppressive medications and antibiotics during the first 6 months of infancy and subsequent development of allergic disease. Acid-suppressive medications and antibiotics should be used during infancy only in situations of clear clinical benefit.