tbuckley/cabot-search huggingface dataset:
Molecular detection of occult nodal metastases in esophageal adenocarcinoma
Authors: I. Altomare, A. Pennathur, L. Xi, W. E. Gooding, V. R. Litle, J. D. Luketich, T. E. Godfrey
Journal: Journal of Clinical Oncology (2007)

4540 Introduction: Esophageal adenocarcinoma (EAC) is an aggressive malignancy whose incidence is on the rise. Approximately 40% of patients with N0 disease will recur after theoretically curative surgery, suggesting that in early stage disease, metastatic spread is often undetected by routine pathology. Molecular techniques may more accurately detect micrometastatic spread of EAC, but the correlation between molecular analysis of nodes and prognosis is unknown. Our lab has previously identified and validated 4 markers whose gene expression levels are able to distinguish benign nodes from nodes with metastatic EAC: CK19, CK20, CEA and TACSTD1. We used quantitative real-time RT-PCR to evaluate the expression of these 4 markers in lymph nodes from 68 N0 and 62 N1 EAC patients to see if molecular staging is predictive of a worse clinical outcome. Methods: RNA was isolated from 1456 lymph nodes obtained from 130 patients who underwent resection of EAC. QRT-PCR was used to analyze gene expression for each of the 4 markers. Relative expression of each marker was compared with expression in 53 benign esophageal lymph nodes previously analyzed. Results: Analysis of 778 lymph nodes from 68 pN0 patients identified 71 nodes (9%) from 30 patients (44%) which showed positive expression of at least one marker, indicating occult metastases (and molecular upstaging). Analysis of 678 lymph nodes from 62 pN1 patients revealed 141 nodes (21%) from 40 patients (65%) which had positive expression of at least one marker in nodes that were pathologically negative. In the pathologically positive nodes from N1 patients, there was an encouraging 88% concordance between pathological and molecular analysis. After a median follow-up of 2 years, 13 N0 patients had recurrence of their cancer. Gene expression levels of 3 of the 4 markers (CK20, CEA and TACSTD1) correlated with significantly worse disease-free and overall survival among these N0 patients, with p values &lt;0.05. Conclusion: We have shown that QRT-PCR of 3 independent genetic markers is predictive of significantly worse disease-free and overall survival among node-negative EAC patients by identifying lymph nodes with occult metastatic disease. Further analysis will reveal if the N1 patients with molecularly positive lymph nodes had significantly worse outcomes as well. No significant financial relationships to disclose.
Covid-19: Portugal closes all medical schools after 31 cases confirmed in the country
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Portugal has temporarily closed all its medical schools in an attempt to slow the transmission of covid-19, after 39 cases were confirmed (as of 10 March).

The decision was announced by the National Council of Medical Schools as a way of reducing contact between students and teachers who treat patients. Around 12 500 students are affected.

The move follows the Italian government’s decision to close all schools and universities across the country. Compared with Portugal, however, Italy has significantly more cases with over 9000 confirmed and more than 400 deaths. The Italian government has placed the entire country …
Joint international consensus statement for ending stigma of obesity
Authors: Francesco Rubino, Rebecca M. Puhl, David E. Cummings, Robert H. Eckel, Donna H. Ryan, Jeffrey I. Mechanick, Joe Nadglowski, Ximena Ramos Salas, Phillip R. Schauer, Douglas Twenefour, Caroline M. Apovian, Louis J. Aronne, Rachel L. Batterham, Hans-Rudolph Berthoud, Camilo Boza, Luca Busetto, Dror Dicker, Mary De Groot, Daniel Eisenberg, Stuart W. Flint, Terry T. Huang, Lee M. Kaplan, John P. Kirwan, Judith Korner, Ted K. Kyle, Blandine Laferrère, Carel W. le Roux, LaShawn McIver, Geltrude Mingrone, Patricia Nece, Tirissa J. Reid, Ann M. Rogers, Michael Rosenbaum, Randy J. Seeley, Antonio J. Torres, John B. Dixon
Journal: Nature Medicine (2020)

Abstract People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.
Long-term survival of patients with AML in remission after reduced intensity allogeneic hematopoietic stem cell transplantation (RISCT)
Authors: U. R. Popat, M. de Lima, P. Anderlini, B. Andersson, D. Couriel, C. Hosing, P. Kebriaei, M. Qazilbash, A. Alousi, R. Champlin, S. Giralt
Journal: Journal of Clinical Oncology (2007)

7002 Background: RISCT was developed to harness graft versus leukemia effect to treat older patients (pts) and pts with comorbidities. Limited data are available on long term outcome of pts with high risk AML treated in complete remission (CR), a group most likely to benefit from this approach. Methods: Thirty six consecutive pts with AML in CR, treated between 1999 and 2006 with Fludarabine 120–125 mg/m 2 and Melphalan 100–140 mg/m 2 are included. Pts were not eligible for myeloablative transplantation because of age or comorbidity. Tacrolimus and Methotrexate were used as GVHD prophylaxis. Additionally pts receiving stem cells from an unrelated donor received rabbit antithymocyte globulin. Results: There were 24 males and 12 females with a median age of 57 (range 21–71). Eighteen(50%) pts had secondary AML. Thirty(83%) pts were in first CR and 6(17%) in second CR. Cytogenetic risk groups were as follows: 2 good risk (in CR2), 22 intermediate risk(61%), and 10(28%) poor risk. Source of stem cells was peripheral blood in 18 pts (50%) and bone marrow in 18 pts (50%). Donors were siblings in 21(58%) pts and unrelated in 15 (42%)pts. Hematopoietic cell transplant specific comorbidity score of 3 or higher was present in 26 pts (72%). All pts engrafted achieving full donor chimerism by day 30 with median time to neutrophil engraftment of 12.5 days (8–19 days). Cumulative incidence of grade 2–4 acute graft versus host disease (GVHD), grade 3–4 GVHD and chronic GVHD was 25% (95% CI; 14%–44%), 11% (95% CI; 4%–28%), and 63% (95% CI; 47%–84%) respectively. Cumulative incidence of nonrelapse mortality was 19% (95% CI; 8%–41%). With a median follow up of 852 days, 3 year overall and disease free survival is 75% (SE 9%) and 63% (SE 10%) respectively. Comorbidity scores didnot impact outcome. Conclusions: Reduced intensity allogeneic transplantation with Fludarabine and Melphalan conditioning produces durable long term remission in pts with high risk AML in complete remission. These results in older pts and/or pts with comorbidities are comparable to published results in younger pts receiving myeloablative transplantation. Comorbidity scores by themselves should not be used to exclude patients from receiving transplant. No significant financial relationships to disclose.
13-cis-retinoic acid (CRA) and interferon-alpha (IFN) combination with or without radiation has a greater in vitro biological effect in reducing bcl-2 expression and inducing apoptosis in prostate cancer cells (LNCaP) than in normal human colorectal (Co-18) and normal human lung fibrolast (IMR-91) cells: Rationale for a clinical trial
Authors: P. Kumar, C. Hill
Journal: Journal of Clinical Oncology (2007)

21157 Background: Over expression of bcl-2 is a major cause of radioresistance and recurrence in prostate cancer patients treated with RT. In order to determine whether CRA/IFN could down-regulate bcl-2 expression, induce apoptosis and reduce radioresistance, we conducted several experiments in LNCaP (which naturally express bcl-2), Co-18 (to mimic radiation effects on rectum) and IMR-91 (to confirm findings in Co-18 cells) cell lines to determine any differential selectivity by CRA/IFN with or without radiation. Methods: LNCaP, Co-18 and IMR-91 cells were treated with CRA (200 nmolar) and IFN (1000 U/ml) for 48 hours to determine bcl-2 expression and apoptosis at various time points (0, 6, 12, 24 &amp; 48 hours) post-drug removal. For determining bcl-2 expression, cells were suspended in trypsin, centrifuged, washed with PBS, pelleted, and sonicated with RIPA buffer and re-centrifuged followed by Western blot analysis. For determining apoptosis, cells were washed and fixed in paraformaldehyde, and stained with Roche Chemical fluorescent apoptosis kit. The number of fluorescing cells vs. total number of cells were then counted in 3 wells using 3 microscope fields per well to determine percent of apoptosis. LNCaP, Co-18 and IMR-91 cells were also treated with radiation (400 cGy) after 48 hours of CRA/IFN exposure to measure bcl-2 expression and apoptosis. Results: In LNCaP cells, CRA/IFN significantly reduced bcl-2 expression with a maximum increase in apoptosis (70%) at 48 hours. In Co-18 and IMR-91 cells, CRA/IFN marginally decreased bcl-2 expression with no induction of apoptosis. Following CRA/IFN exposure and radiation, apoptosis was measured to be at least 90%, 22% and 0% at 48 hours in LNCaP, Co-18 and IMR-91 cells, respectively. Conclusions: CRA/IFN with or without radiation selectively reduces bcl-2 expression and induces apoptosis in LNCaP cells as compared to Co-18 and IMR-91 cells. Our findings provide a therapeutic rationale for clinically evaluating CRA/IFN with RT in patients with high risk prostate cancer. No significant financial relationships to disclose.
Abstract P457: Age Dependence of Genetic Risk Scores in Relation to Coronary Artery Disease
Authors: Chang Liu, Yunfeng Huang, Qin Hui, Arshed A QUYYUMI, Yan Sun
Journal: Circulation (2020)

Background: Coronary artery disease (CAD) is an age-related multi-factorial disease with a high public health burden. Genetic loci for CAD have been discovered and collectively predict CAD risk independent of traditional risk factors. It remains unclear whether age modifies the genetic predisposition to CAD. Methods: A total of 173,315 Caucasian subjects from the UK Biobank were included in this study, including 26,472 CAD patients with age of onset ranging from 32 to 78 years old, and 146,843 control subjects &gt; 60 years old without CAD. CAD diagnosis was extracted from in-patient Hospital Episode Statistics (HES) and National Death Registry based on ICD-10 and OPCS-4 codes. CAD genetic risk score (GRS) was calculated based on the 161 known CAD loci. Sub-GRSs for body mass index (BMI, 16 loci), blood pressure (BP, 26 loci) and lipids (17 loci) were constructed to examine the genetic risk for CAD from certain intermediate trait. The CAD GRSs among onset age groups were compared to the controls using linear regression models, controlling for sex, BMI, creatinine, c-reactive protein, high density lipoprotein, low density lipoprotein, triglyceride, diabetes, heart failure history, hypertension and smoking status. The sub-GRSs were compared using the same models, excluding sub-GRS specific intermediate traits. Interactions of age groups and GRSs were tested using logistic regression models for CAD status, controlling for the same variables described above. Association analyses of each GRS were performed within each category of CAD age at onset comparing to controls. Results: Compared to the controls, the mean CAD GRS in CAD patients with age of onset ≤ 50 years was 0.58 standard deviations (SD) higher (95% CI 0.53-0.63), followed by CAD age of onset between 50 and 60 years (0.50 SD higher, 95% CI 0.48-0.52), between 60 and 70 years (0.35 SD higher, 95% CI 0.33-0.37), and &gt; 70 years (0.25 SD higher, 95% CI 0.21-0.29). The sub-GRSs showed the similar trend. Age of onset stratified analysis revealed a significant CAD GRS-age interaction (p&lt;0.001) on CAD risk where genetic effect is stronger among those early onset CAD patients - the odds ratios (OR) per CAD GRS SD among subjects with CAD onset age ≤ 50, 50 to 60, 60 to 70, &gt; 70 years were 1.80 (95% CI 1.71-1.89), 1.66 (95% CI 1.62-1.70), 1.44 (1.41-1.47), 1.29 (95%CI 1.24-1.35), respectively. Among the three sub-GRSs, significant GRS-age interactions were observed for BP sub-GRS and lipids sub-GRS but not BMI sub-GRS. Conclusion: The observed gene-age interaction indicates that the genetic susceptibility for CAD decreases for older subjects. The contribution of the CAD GRS to CAD risk is almost 64% lower in those developing CAD at age &gt; 70 years compared to those ≤ 50 years. Future considerations and applications of CAD genetic risk in precision medicine needs to include age of onset to accurately evaluate the genetic contribution.
Diagnostic accuracy of pigmented labial macules by in vivo reflectance confocal microscopy and correlation among techniques
Authors: Ignacio Gómez-Martín, Helena Collgros, Peter M. Ferguson, Alicia Barreiro, Pascale Guitera, Evelyn Andrades-López, Susana Puig, Ramon M. Pujol, Carlos Barranco, Llúcia Alòs, Sonia Segura
Journal: Journal of the American Academy of Dermatology (2020)
Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report
Authors: Matthew W. Semler, Gordon R. Bernard, Shawn D. Aaron, Derek C. Angus, Michelle H. Biros, Roy G. Brower, Carolyn S. Calfee, Elizabeth A. Colantuoni, Niall D. Ferguson, Michelle N. Gong, Ramona O. Hopkins, Catherine L. Hough, Theodore J. Iwashyna, Bruce D. Levy, Thomas R. Martin, Michael A. Matthay, Joseph P. Mizgerd, Marc Moss, Dale M. Needham, Wesley H. Self, Christopher W. Seymour, Renee D. Stapleton, B. Taylor Thompson, Richard G. Wunderink, Neil R. Aggarwal, Lora A. Reineck
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising preclinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data," causal inference using observational data, novel clinical trial designs, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including
Disruptive innovation in rheumatology: new networks of global public–private partnerships are needed to take advantage of scientific progress
Authors: Tom WJ Huizinga, V Michael Holers, Jennifer Anolik, Michael B Brenner, Christopher Dominic Buckley, Vivian Bykerk, Sean E Connolly, Kevin D Deane, Jianping Guo, Martin Hodge, Steve Hoffmann, Frank Nestle, Costantino Pitzalis, Soumya Raychaudhuri, Kazuhiko Yamamoto, Zhanguo Li, Lars Klareskog
Journal: Annals of the Rheumatic Diseases (2020)

Patterns of innovation can be sustained (continuous) or rapid, sometimes even ‘disruptive’. A major difference is that in order to support disruptive innovation the support networks and its infrastructure often need to be changed dynamically to accommodate a rapidly evolving landscape to establish the disruptive approach. For example, introducing electric cars disrupts the support network for gasoline cars (network of gas and service stations), and at the same time requires an entirely new system of charging stations. Such disruptions occur in science, and a wonderful example was the creation of monoclonal antibody technologies. The discovery of the principle for production of monoclonal antibodies by Cesar Milstein and Georg Kohler fueled a rapid adoption of new antibody-based technologies in all areas of medicine. This transformation was strongly supported by the open workshops that catalogued antibodies from many laboratories into distinct ‘clusters of differentiation’, thereby providing a new ‘support network’ for the global use of well validated and standardised monoclonal antibodies. This new support network helped the pharmaceutical industry transition from a major focus on small chemical molecules (screened for effects in vitro) to a new targeted approach, first with recombinant proteins, later with monoclonal antibodies with the introduction of anti-tumour necrosis factor (TNF) antibodies as an example.

During the last two decades, in both the USA and Europe, the need to develop public–private partnership support networks has been recognised as a means to accelerate innovation and enable translation of the rapidly expanding cellular and molecular understanding of disease pathogenesis into the development of new therapeutic agents. In Europe, the Innovative Medicine Initiative (IMI) was formed to enhance public–private partnerships, and in the USA the Accelerating Medicines Partnership (AMP).1 Identifying, validating and testing new targets based on enhanced understanding are at the core of both AMP and IMI. To facilitate continuous …
Abstract P492: Circulating Sphingolipids and Risk of Mortality: The Cardiovascular Health Study
Authors: Amanda M Fretts, Paul Jensen, Andrew Hoofnagle, Barbara McKnight, Colleen Sitlani, David S Siscovick, Irena King, Bruce M Psaty, Nona Sotoodehnia, Rozenn Lemaitre
Journal: Circulation (2020)

Introduction: Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences sphingolipid activity, and that associations of ceramides (Cer) and sphingomyelins (SM) with cardiovascular outcomes may differ by lipid species. The purpose of this study was to assess associations of Cer and SM species with mortality among 4,612 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992-2015. Hypothesis: Higher levels of circulating Cer and SM with palmitic acid (Cer-16) are associated with a higher risk of mortality (i.e., deaths from cardiovascular disease (CVD) and non-cardiovascular causes) while higher levels of Cer and SM with very-long chain saturated fatty acids arachidic acid (Cer-20 and SM-20), behenic acid (Cer-22 and SM-22), and lignoceric acid (Cer-24 and SM-24) are associated with a lower risk. Methods: The associations of each sphingolipid with mortality were assessed using Cox proportional hazards models. Models adjusted for age, sex, self-reported race, geographic area, education, smoking, alcohol use, BMI, activities of daily living, HDL and LDL cholesterol, triglycerides, systolic blood pressure, physical activity, use of hypertension or lipid-lowering drugs, self-reported health status, prevalent diabetes, CVD, heart failure (HF), and other sphingolipids species. Results: During a median follow-up of 10.2 years (range 0-23 years), 4,099 deaths occurred. At each time, higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality (Figure). Models that did not adjust for diabetes, CVD, and HF produced similar results. Conclusions: These findings suggest that the associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid, and support the need for future studies to explore mechanisms underlying these relations.
Abstract P325: Cardiometabolic Factors Associated With Alcohol Use; The New Orleans Alcohol Use In Hiv Study
Authors: Tekeda F Ferguson, Liz Simon, Katherine Theall, David Welsh, Patricia E Molina
Journal: Circulation (2020)

As people living with HIV (PLWH) live longer, morbidity and mortality related to chronic illness specifically, cardiovascular disease (CVD) has increased. HIV disease has been associated with hypertension (HTN) and dyslipidemia, which are risk factors for developing CVD. The objective of this study was to determine whether heavy alcohol use among PLWH is associated with increased risk of HTN, dyslipidemia, and metabolic syndrome (MS). To investigate this hypothesis we analyzed data from the New Orleans Alcohol Use in HIV (NOAH) Study. Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT), the Timeline Follow Back (TLFB) Calendar, a Lifetime Drinking History, and the biomarker, Phosphatidylethanol (PEth). HTN stage 1, was defined as a mean systolic 130-139 or diastolic blood pressure 80-89 mmHg; HTN stage 2 as a systolic ≥140 or diastolic ≥ 90 mmHg. MS was defined as having 3 of 5 conditions: HTN, low high-density lipoproteins (≤40 (men)/50 (women)), high triglycerides (≥ 150mg/dl), high glucose (≥100 mg/dl), waist circumference &gt;88(women)/102(men). The NOAH study cohort (n=365) is majority African American (83.6%), mean age 48.2 ±10.4, 68.8% male and 31.2% female. Descriptive statistics and multivariable linear and logistic regression analyses were performed stratifying by sex and adjusting for age, race, smoking, and viral load. Approximately, 41.3% had an AUDIT ≥8 and 14.0% were hazardous drinkers (greater than 40 (women)/60 (men) grams of alcohol per day). MS was prevalent in 36.1%, stage 2 HTN 66.0%, 9.3% with hyperglycemia (&gt;125mg/dl), 23.0% had elevated creatinine, and 27.4% were obese. Creatinine was positively associated with LDH and PEth (p-value &lt;0.04). TLFB grams of alcohol had a positive linear association with glucose among men (beta=0.0033; p=0.0035). LDH was associated with two-fold increase odds of MS (OR=2.69; 95% C.I.: 1.18 - 9.58) with sex as an effect modifier. AUDIT score ≥8 was not a significant predictor of hypertension, dyslipidemia, or MS in adjusted models. Our preliminary results indicate that lifetime drinking history was more associated with increased cardiometabolic risk than recent drinking. As PLWH are living longer, hazardous and chronic alcohol use is a lifestyle choice that has clinical relevance and has to be addressed in the chronic care model of treatment in PLWH. (Supported by: NIH P60AA009803)