tbuckley/cabot-search huggingface dataset:
Association of BRAF V600E mutation with survival in patients with metastatic mismatch repair-deficient colorectal cancer.
Authors: Elaine Tan, Junmin Whiting, Hao Xie, Iman Imanirad, Estrella M. Carballido, Seth Felder, Jessica M. Frakes, Qianxing Mo, Christine Marie Walko, Jennifer Permuth, Richard D. Kim, Daniel A. Anaya, Jason B. Fleming, Ibrahim Halil Halil Sahin
Journal: Journal of Clinical Oncology (2022)

174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p&lt;0.001). Pts older than 50 had a lower median OS vs. those who were ≤50 at 21.4 months vs. 38.7 months (HR 1.66, 95% CI: 1.33-2.07, p&lt;0.001). When comparing MSH2/MSH6 mutations to MLH1/PMS2, a trend towards improved OS was seen with median survival of 35.2 months vs. 22.7 months, respectively (HR 0.79, 95% CI: 0.61-1.02, p=0.067). On multivariate analysis, BRAF mutation and older age continued to be associated with differences in survival, while KRAS mutation and specific MMR gene loss did not. Conclusions: BRAF V600E mutation and age greater than 50 are associated with decreased survival for pts with MMR-D mCRC. KRAS mutations and specific MMR alterations are not associated with differences in survival.
Acute urethral syndrome in women.
Journal: BMJ (1981)

3with pacemakers has been designed to permit continuous monitoring of the reliability of the devices and to facilitate national surveys.A special organisation called Stimarec has been formed in France and operates in many European countries, including the United Kingdom, for monitoring early malfunction of pacemakers.A new journal, Pace,7 appeared in January 1978 claiming that its existence represented a watershed in the discipline and arguing that no journal of general interest could do justice to a highly technical subject which had grown so rapidly.Certainly data on the worldwide experience of and initiatives in pacing need to be readily available to practitioners so that they can keep in touch with developments in a discipline in which change is unusually rapid.
Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,915 patients on 15 randomized trials
Authors: D. J. Sargent, S. Wieand, J. Benedetti, R. Labianca, D. G. Haller, L. E. Shepherd, J. F. Seitz, G. Francini, A. De Gramont, R. M. Goldberg
Journal: Journal of Clinical Oncology (2004)

3502 Background: The traditional endpoint for colon adjuvant clinical trials (CT) is OS, with 5 years (yrs) used to demonstrate adequacy of follow-up (f-u). A shorter-term endpoint providing both clinically and statistically convincing evidence to allow a comparison of treatments could significantly speed both the CT process and the translation of advances into clinical practice. Methods: Individual patient data were pooled from 15 large randomized phase III colon adjuvant CT. Trials included 33 arms: 9 no chemotherapy control arms, 24 5-FU based chemotherapy arms, with a pooled sample size of 12,915 patients (pts). The primary hypothesis was that DFS, with 3 yrs f-u, is an appropriate primary endpoint to replace OS with 5 yrs f-u in phase III colon adjuvant CT. Median f-u was 8 yrs; 5 yr f-u was available on 93% of patients (pts). Results: The recurrence rate for yrs 1–5 was 11%, 13%, 7%, 4%, and 3%. Median time from recurrence to death was 14 months. 95% of pts alive and disease-free at 3 yr were alive at 5 yrs; 86% of pts with recurrence by 3 yrs died before 5 yrs. Overall per-pt concordance between 2, 3, and 4 yr DFS and 5 yr OS was 88%, 92%, and 92% respectively. Across all 33 study arms, correlation between 3 yr DFS and 5 yr OS was 0.94. Correlation of the difference in 3 yr DFS and 5 yr OS comparing control vs experimental arms within each trial was 0.88. Within trial log-rank testing using DFS with 3 yrs of f-u versus OS with 5 yrs f-u resulted in the same conclusion in 15 of 18 cases (83%); all three discordant results were only marginally significant for DFS (0.03 < p < 0.05). Differences in 5 yr OS retained 92% of the difference in 3 yr DFS (95% CI 67%–117%). Conclusions: In pts treated on phase III adjuvant colon CT, 3 yr DFS and 5 yr OS are highly correlated, both within pts and across trials. Within-trial comparisons of 3 yr DFS predict 5 yr OS comparisons with high concordance. These results suggest that DFS after 3 years f-u is an appropriate endpoint for adjuvant colon CTs of 5-FU-based regimens, although marginally significant 3 yr DFS improvements may not translate into significant 5 yr OS benefits. No significant financial relationships to disclose.
Hydrogen—Ionized and Otherwise
Authors: J. R. E.
Journal: Annals of Internal Medicine (1962)

Editorials1 October 1962Hydrogen—Ionized and OtherwiseJ. R. E.J. R. E.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-57-4-687 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptWhen God made the world he began, presumably, with hydrogen. Hydrogen is the first element in the periodic table and consists of two primary particles: a positively charged nucleus, the proton, and an orbiting negatively charged satellite, the electron. When these two components of the hydrogen atom are separated, the positively charged proton, or hydrogen ion, becomes a sort of chemical "agitator" that arouses a high degree of reactivity and instability among its ionic and molecular neighbors. In the beginning there was chaos and hydrogen, in the end there is—among other results of creation—acid-base balance and the oft-confused physician who...References1. For references to the literature on acid-base terminology, see p. 660. Google Scholar2. HUCKABEE W: Henderson vs. Hasslebalch. Clin. Res. 9: 116, 1961. Google Scholar3. CAMPBELL EJ: RIpH. Lancet 1: 681, 1962. CrossrefMedlineGoogle Scholar4. CAMPBELL EJ: Letter to the editor. Lancet 2: 154, 1962. (The other letters to which this is a reply are listed here.) Ibid. Lancet 2: 299, 1962. Google Scholar5. HOYLE F: Frontiers of Astronomy, Harper & Brothers, New York, 1955. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byIl centenario del pH (1909-2009) - Parte seconda. Ma era proprio necessario sostituire l’equazione di Henderson con quella di Henderson-Hasselbalch?Il centenario del pH (1909-2009). Ma in medicina, è proprio indispensabile utilizzare i logaritmi negativi per misurare gli idrogenioni? Parte ILogland: A Gibbsian view of acid-base balance 1 October 1962Volume 57, Issue 4Page: 687-688 ePublished: 1 December 2008 Issue Published: 1 October 1962 PDF downloadLoading ...
Immunity and Inflammation in Atherosclerosis
Authors: Dennis Wolf, Klaus Ley
Journal: Circulation Research (2019)

There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease. Lessons from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice, and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb atherosclerosis. Here, we summarize and discuss the pathogenesis of atherosclerosis with a focus on adaptive immunity. We discuss some limitations of animal models and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment.
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers
Authors: Alvaro Teijeira, Itziar Migueliz, Saray Garasa, Vaios Karanikas, Carlos Luri, Asunta Cirella, Irene Olivera, Marta Cañamero, Maite Alvarez, Maria C. Ochoa, Ana Rouzaut, Maria E. Rodriguez-Ruiz, Miguel F. Sanmamed, Christian Klein, Pablo Umaña, Mariano Ponz, Marina Bacac, Ignacio Melero
Journal: Theranostics (2022)

Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.
The Beat
Authors: Erin E. Dooley
Journal: Environmental Health Perspectives (2008)

Strong Signal for Cell Phone EffectsWith 3 billion cell phone users worldwide and more than 260 million in the United States alone-among them 46% of U.S. children aged 8-12, according to Nielsen Mobile figures released 10 September 2008human exposure to low-energy radiation in the 800-to 2,000-megahertz range is at an all-time high.The most recent attempt to systematically review the epidemiologic evidence for increased risk of brain tumors related to cell phone use indicates that repercussions from this global experiment are coming to light.In a meta-analysis published in the May 2008 issue of the International Journal of Oncology, Swedish researchers found significant associations between longterm cell phone use and brain tumor risk."We found that cell phone use is linked to gliomas [malignant brain tumors] and acoustic neuromas [benign tumors of the brain's auditory nerve] and are showing up after only ten years," says lead author Lennart Hardell, an oncologist and cancer epidemiologist at University Hospital in Örebro, Sweden.Specifically, for studies that included at least 10 years of exposure, there was a doubling in the risk of gliomas for ipsilateral (same-side) but not contralateral (opposite-side) exposures to the head (as reflected by which hand the subject typically used to hold his/her cell phone).A 2.4-fold increase in risk was seen for acoustic neuromas due to ipsilateral exposures, whereas no increased risk occurred for meningiomas (tumors that occur in the membranes covering the brain and spinal cord)."Clearly we need more studies of longterm cell phone usage to better assess the cancer risks," says coauthor Michael Carlberg.Cell phones have been in mainstream usage for only a decade or so, and yet radiation-induced brain tumors normally take about 10-15 years to develop, according to the American Cancer Society.Hardell's research team was itself the source of several studies included in the meta-analysis.In the October 2006 issue of the World Journal of Surgical Oncology, the investigators reported a 70% increased risk of grade III-IV astrocytomas (highly aggressive brain tumors) for analog cell phone users.This same study found a nearly 4-fold increase in risk for acoustic neuromas after 15 years of exposure to analog cell phones.
Changes in pressure half-time with acute alterations of preload and afterload in chronic aortic regurgitation Yong Jin Kim, Michael Jones, Takahiro Shiota, Fabrice Bauer, Jian Xin Qin, Marta Sitges, Hiroyuki Tsujino, Lisa A. Cardon, Arthur D. Zetts, James D. Thomas. The Cleveland Cleveland Foundation, Cleveland, OH, National Heart, Lung and Blood Institute of Health, Bethesda, MD
Journal: Journal of the American College of Cardiology (2001)
Comparison of Self-harm or Overdose Among Adolescents and Young Adults Before vs During the COVID-19 Pandemic in Ontario
Authors: Joel G. Ray, Peter C. Austin, Kayvan Aflaki, Astrid Guttmann, Alison L. Park
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Self-harm and deaths among adolescents and young adults are notably related to drug poisonings and suicide. With the emergence of the COVID-19 pandemic, there are projections about a greater likelihood of such events arising among adolescents and young adults. <h3>Objective</h3> To evaluate the risk of self-harm, overdose, and all-cause mortality among adolescents and young adults during the COVID-19 pandemic. <h3>Design, Setting, and Participants</h3> This population-based cohort study took place in Ontario, Canada, where a universal health care system captures all emergency department (ED) visits, hospitalizations, and deaths. The participants included all adolescents and young adults born in Ontario between 1990 and 2006, who were aged 14 to 24 years between March 1, 2018, and June 30, 2021. <h3>Exposures</h3> The COVID-19 pandemic era (April 1, 2020 to June 30, 2021), relative to the 2 years preceding the pandemic (March 1, 2018 to February 28, 2020). <h3>Main Outcomes and Measures</h3> ED encounters or hospitalizations for self-harm or overdose. A secondary outcome was self-harm, overdose, or all-cause mortality. Cause-specific hazard models to estimate hazard ratios (HR) and 95% CIs were used for the primary outcome. Follow-up started at March 1, 2018, or the individual's 14th birthday, whichever was later, and age was used as the time scale. <h3>Results</h3> In this study, 1 690 733 adolescents and young adults (823 904 [51.3%] female participants) were included with a median (IQR) age of 17.7 (14.1-21.4) years at start of follow-up. After 4 110 903 person-years of follow-up, 6224 adolescents and young adults experienced the primary outcome of self-harm or overdose during the pandemic (39.7 per 10 000 person-years) vs 12 970 (51.0 per 10 000 person-years) prepandemic, with an HR of 0.78 (95% CI, 0.75-0.80). The risk of self-harm, overdose, or death was also lower during than before the pandemic (HR, 0.78; 95% CI, 0.76-0.81), but not all-cause mortality (HR, 0.95; 95% CI, 0.86-1.05). <h3>Conclusions and Relevance</h3> Among adolescents and young adults, the initial 15-month period of the COVID-19 pandemic was associated with a relative decline in hospital care for self-harm or overdose.
Fibroblast pathology in inflammatory diseases
Authors: Kevin Wei, Hung N. Nguyen, Michael B. Brenner
Journal: Journal of Clinical Investigation (2021)

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.
Abstract 348: Interleukin 13 is Required for Neonatal Heart Regeneration
Authors: Caitlin C O’Meara, Dana Murphy, Angela Lemke, Michael J Flister
Journal: Circulation Research (2017)

Shortly after birth neonatal mice can fully regenerate their hearts, but this potential is lost in the first week of life. Cell cycle entry of existing cardiomyocytes is thought to be an essential mechanism enabling neonatal mouse heart regeneration. In previous studies we found that the cytokine interleukin 13 (IL13) was a an upstream regulator of differentially expressed gene networks during neonatal heart regeneration and stimulated cell cycle activity of cultured rat cardiomyocytes, suggesting that this factor might be important in neonatal heart regeneration in vivo . In the present study, we subjected wildtype and IL13 knockout mice to ventricular apical resection at one day of age and assessed heart regeneration 21 days post resection (dpr). Compared to wildtype controls, IL13 knockout mice failed to regenerate their hearts as determined by extensive scar formation at the ventricular apex. To gain insight into the mechanism of impaired regeneration, we quantified cardiomyocyte proliferation and expression of macrophage markers at 7 dpr. We found no difference in gene expression of macrophage markers in IL13 knockout mice compared to wildtype. Interestingly, IL13 knockout mice demonstrate a significant increase cardiomyocyte cell cycle activity as determined by phosphorylated Histone H3 (pH3) staining. This seemingly contradictory result appears to be due to an underlying developmental defect in IL13 knockout hearts. Cardiomyocytes in IL13 knockout mice appeared large and disorganized. Cardiomyocytes from IL13 knockout unoperated mice showed decreased pH3 staining and had increased expression marker of hypertrophic growth such as Nppb and Nppa. Histologically, hearts from IL13 knockout mice appeared to have a dilated cardiomyopathy phenotype. Collectively our data suggests that during heart development IL13 influences proliferative versus hypertrophic growth. We surmise that following neonatal apical resection in IL13 knockout mice the significant increase in cardiomyocyte proliferation is a compensatory attempt to repair the injury, but the underlying cardiomyocyte phenotype inhibits complete regeneration. These data are the first to report a role for IL13 in normal heart development and neonatal heart regeneration.
Comparative effects of ventricular resynchronization therapy in patients with LV systolic dysfunction of idiopathic or ischemic origin Christophe Leclercq, Sr., Christine Alonso, Sr., Dominique Pavin, Sr., Gilles Rouault, Sr., Philippe Mabo, Sr., Claude Daubert, Sr., Departement de Cardiologie CHU, Rennes, France
Journal: Journal of the American College of Cardiology (2001)
Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes
Authors: Helen C. Looker, Laura Pyle, Tim Vigers, Cameron Severn, Pierre J. Saulnier, Behzad Najafian, Michael Mauer, Robert G. Nelson, Petter Bjornstad
Journal: Diabetes Care (2022)

OBJECTIVE Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury. RESEARCH DESIGN AND METHODS Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age &amp;lt;25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models. RESULTS At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P &amp;lt; 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th–75th percentile 17–470] vs. 27 [13–73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable. CONCLUSIONS Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.