tbuckley/cabot-search huggingface dataset:
Abstract 046: Longitudinal Associations of Omega-6 and Omega-3 Plasma Phospholipid Polyunsaturated Fatty Acids With Dementia in Older Adults: the Cardiovascular Health Study
Authors: Marcia C de Oliveira Otto, Jason H Wu, Evan L Thacker, Heidi Lai, Rozenn N Lemaitre, Barbara McKnight, Nikhil Padhye, Xiaoling Song, Irena B King, Oscar Lopez, David Siscovick, Dariush Mozaffarian
Journal: Circulation (2019)

Background: Polyunsaturated fatty acids (PUFA) are essential nutrients for normal brain function, constituting nearly 35% of brain lipids. Experimental studies suggest that omega-3 and omega-6 PUFA, present in plant foods and fish, may reduce risk of dementia. Most prior studies assessed self-reported estimates and used one baseline measure of objective PUFA biomarkers, which may lead to poor estimation of long-term risk. Aims: Investigate prospective associations of serial measures of plasma phospholipid omega-3 (ALA [18:3], EPA [20:5], DPA [22:5], DHA [22:6]) and omega-6 (LA [18:2], AA [20:4]) PUFA with risk of total dementia and dementia subtypes (Alzheimer’s Disease [AD] and vascular and mixed dementia [VaD]) in older adults in the Cardiovascular Health Study. Methods: Among 3,307 U.S. adults aged ≥65y and free of stroke, cognitive impairment or dementia at baseline, circulating levels were measured serially at baseline, 6 years and 13 years using standardized methods. Dementia was identified using neuropsychological tests or hospitalization records adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare administrative data. Prospective associations were assessed by multivariate-adjusted Cox models incorporating time-varying fatty acid measures and covariates. Results: During 22,288 person-years of follow-up (1992-2015), 1,164 dementia cases were identified, with 530 AD and 256 VaD cases. After adjustment for demographic, lifestyle and dietary factors, higher circulating levels of AA were associated with lower risk of total dementia and AD (see Table). There were no statistically significant associations between circulating omega-3 PUFA or LA and incident dementia. Conclusion: In older adults, higher circulating AA was inversely associated with risk of total dementia and AD, but not other dementia subtypes. These findings highlight the need to identify mechanisms influencing circulating AA levels that could be effective for the prevention of dementia later in life.
Clinical and molecular analysis of patients treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy.
Authors: Vincenza Conteduca, Clara Oromendia, Panagiotis J. Vlachostergios, Amy Hackett, Charlene Thomas, Aidan Case, Jyothi Manohar, Kenneth Eng, Andrea Sboner, Karla V. Ballman, Olivier Elemento, David M. Nanus, Himisha Beltran, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2019)

272 Background: PSMA targeted therapy has recently emerged as a promising approach for patients with advanced prostate cancer. However, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses. Methods: Baseline, treatment and outcomes data along with tumor whole-exome sequencing (WES) data were retrospectively evaluated in anti-PSMA-treated patients (pts). Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with overall/progression-free/survival (OS/PFS) and PSA response. Results: We analyzed 25 pts treated with PSMA targeted radionuclide therapies refractory to standard therapy. 15 received 177Lu-J591, 8 received 177Lu-PSMA-617, 1 received both, and 1 225Ac-J591. WES data (n=28) showed an incidence of AR, BRCA1, BRCA2, ATM alterations (copy number variations and point somatic mutations) in 71.4% (n=20), 11.1% (n=3), 29.6% (n=8), and 14.3% (n=4), respectively. Variables found with backward selection with AIC criterion for PFS and OS suggest significant clinical and molecular predictors of PFS/OS (Table). Conclusions: Knowledge of prognostic factors such as baseline narcotic use and ALP, and BRCA1/BRCA2 and TP53 alterations may have potential clinical utility in patients being considered for anti-PSMA targeted radionuclide therapies. Validation of these findings in larger prospective trials is warranted.[Table: see text]
P38α/JNK Signaling Restrains Erythropoiesis By Suppressing Ezh2-Mediated Epigenetic Silencing of Bim
Authors: Ping Hu, Angel Nebreda, Helmut Hanenberg, Garrett Kinnebrew, Mircea Ivan, Mervin C. Yoder, Marie-Dominique Filippi, Hal E. Broxmeyer, Reuben Kapur
Journal: Blood (2018)
Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells
Authors: Takahiro Kamiya, See Voon Seow, Desmond Wong, Murray Robinson, Dario Campana
Journal: Journal of Clinical Investigation (2019)

A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA class I molecule (HLA-E) in tumor cells, which suppresses NK cell activity via ligation of the NK inhibitory receptor CD94/NK group 2 member A (NKG2A). Gene expression data from approximately 10,000 tumor samples showed widespread HLAE expression, with levels correlating with those of KLRC1 (NKG2A) and KLRD1 (CD94). To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endoplasmic reticulum–retention domains. After retroviral transduction in human peripheral blood NK cells, these NKG2A protein expression blockers (PEBLs) abrogated NKG2A expression. The resulting NKG2Anull NK cells had higher cytotoxicity against HLA-E–expressing tumor cells. Transduction of anti-NKG2A PEBL produced more potent cytotoxicity than interference with an anti-NKG2A antibody and prevented de novo NKG2A expression without affecting NK cell proliferation. In immunodeficient mice, NKG2Anull NK cells were substantially more powerful than NKG2A+ NK cells against HLA-E–expressing tumors. Thus, NKG2A downregulation evades the HLA-E cancer immune checkpoint and increases the antitumor activity of NK cell infusions. Because this strategy is easily adaptable to current protocols for clinical-grade immune cell processing, its clinical testing is feasible and warranted.
Autism Risk and Serotonin Reuptake Inhibitors
Authors: George M. Anderson
Journal: JAMA Psychiatry (2019)

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 Psychiatry 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 Psychiatry journal
Gestational Diabetes Mellitus
Authors: Steven G. Gabbe
Journal: New England Journal of Medicine (1986)

For decades, physicians caring for women whose pregnancies have been complicated by diabetes mellitus have recognized that fetal hyperglycemia, a consequence of maternal hyperglycemia, contributes to excessive fetal growth. In 1954, the Danish internist Jorgen Pedersen hypothesized that maternal hyperglycemia led to fetal hyperglycemia and finally to fetal hyperinsulinemia.1 In the past, fetal deaths in utero, neonatal respiratory distress syndrome, and birth trauma and asphyxia resulting from fetal macrosomia were responsible for the increased perinatal mortality in pregnancies complicated by diabetes mellitus, and all could be linked to fetal hyperinsulinemia. At present, the perinatal mortality rate in patients with insulin-dependent . . .
Placebo-controlled, double-blinded multi-center phase III trial of XELIRI/FOLFIRI plus simvastatin in metastatic colorectal cancer.
Authors: Sung Hee Lim, Tae Won Kim, Sae-Won Han, Hye Jin Kang, In Gyu Hwang, Ji Yun Lee, Min-Young Lee, Hae Su Kim, Seung Tae Kim, Jeeyun Lee, Joon Oh Park, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Jun soo Ham, Seonggyu Byeon, Hee Kyung Kim, Won Ki Kang
Journal: Journal of Clinical Oncology (2015)

3576 Background: The purpose of this randomized phase III trial was to evaluate the addition of synthetic 3-hydroxy-3methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to XELIRI/FOLFIRI in patients with previously treated metastatic colorectal cancer. Methods: We undertook a double-blind, placebo-controlled phase III trial of 269 patients with previously treated metastatic colorectal cancer, enrolled to 5 centers in South Korea. Patients were randomly assigned (1:1) to receive irinotecan 180 mg/m2 as a 90-min infusion followed by leucovorin 200mg/m2 in a 2-h infusion, and then 5-FU 400mg/m2 bolus injection followed by 2400mg/m2 as a 46-h continuous infusion (FOLFIRI) or irinotecan 250mg/m2 as a 90-min infusion with capecitabine 1000mg/m2 twice daily for 14days (XELIRI) plus simvastatin (134 patients) or XELIRI/FOLFIRI plus placebo (135 patients). The primary end point was progression-free survival (PFS) and secondary end points included response rate, duration of response, overall survival (OS), time to progression (TTP) and toxicity. Results: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median progression-free survival (PFS) was 5.9 months (95% CI, 4.5-7.3) in XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) for XELIRI/FOLFIRI plus placebo group (P = 0.937). There was no significant difference in overall survival (median, 15.9 months (simvastatin) vs. 19.9 months (placebo), P = 0.826). Grade 3 or higher grade nausea and anorexia were noted slightly more in patients with simvastatin arm compared to placebo arm (4.5 vs 0.7%, 3.0 vs 0% respectively). Conclusions: These results show that the addition of 40mg simvastatin to XELIRI/FOLFIRI did not improve PFS in previously treated metastatic colorectal cancer although it does not increase toxicity. Clinical trial information: NCT01238094.
Overall survival in solid tumor patients with abnormal renal function or renal insufficiency.
Authors: Vincent Launay-Vacher, Nicolas Janus, Isabelle Laure Ray-Coquard, Philippe Beuzeboc, Juliette Thariat, Gilbert Deray
Journal: Journal of Clinical Oncology (2015)

1589 Background: Data still remain scanty on the potential impact of renal insufficiency (RI) on the mortality of cancer patients. The results of 3 clinical studies we conducted (IRMA-2, CANDY and MARS) were pooled. In all 3, methodology and investigators were the same regarding RI. Pooled analysis was thus allowed to study the potential association between RI and overall survival (OS), and to stratify the risk, if any, depending on the GFR Methods: The KDIGO definition and classification of CKD was used. GFR was estimated with the MDRD formula. RI was defined as GFR<60 ml/min/1.73 m². Results: Population included 5908 solid tumor patients (2181 breast, 854 colorectal, 556 lung, 366 ovarian, 293 prostate for the main tumors). Median age 59.2, mean BMI 24.4, 64.0% were women. 70.7% of these patients were alive at the end of the follow-up period of one year. Univariate analysis reported that RI was strongly linked to mortality (p < 0.0001), when analysing together all types of patients and tumors. Furthermore, Hazard-Ratio became statistically significant at a GFR of 85 ml/min/1.73m2. For non-metastatic patients (n = 4671), RI was also significantly associated with mortality (p = 0.008), with a significant higher risk of death starting at a GFR of 86. Finally, multivariate Cox model adjusted for sex, age, metastasis and the 5 main types of tumor reported that GFR was significantly associated with OS with an increased risk of mortality at a GFR of 75. This risk gradually increased along with the decrease in GFR. Conclusions: The IRMA studies already reported the high prevalence of RI in cancer patients. But our pooled analysis reported that the reduced OS began at an early stage of CKD, for a GFR< 75. These results underline that assessing, monitoring and managing renal function in cancer patients is crucial in order to prevent or at least minimise renal dysfunction because of its potential impact on survival. Multivariate Cox model regression. GFR cut-off HR [95% CI]; p-value GFR < 90 GFR < 85 GFR < 75 GFR < 60 GFR < 30 HR = 1.03 [0.93-1.14]; p > 0.05 HR = 1.06 [0.96-1.17]; p > 0.05 HR = 1.13 [1.02-1.26]; p = 0.01 HR = 1.15 [1.03-1.27]; p = 0.01 HR = 1.53 [1.23-1.86]; p = 0.0001 GFR = Glomerular Filtration Rate (mL/min/1.73m²); HR=Hazard-Ratio
Comparison of patient characteristics and chromosomal abnormalities by first-line treatment in chronic lymphoid leukemia (CLL) patients in Canada.
Authors: Marc Lapierre
Journal: Journal of Clinical Oncology (2015)

e18029 Background: With recent approval of targeted agents and continued development of novel therapies, the first-line treatment of patients with chronic lymphocytic leukemia (CLL) has undergone a significant evolution in the past year. This retrospective study investigates patient characteristics and genetic abnormalities by first-line treatment choice in CLL patients in Canada. Methods: This study utilized IMS Brogan Enhanced Tumor Studies, an anonymised patient database collected through quarterly physician panel survey, which provides comprehensive insight into total cancer care. Patient characteristics (including age, co-morbidities and ECOG performance status), genetic markers and first-line drug treatments were identified in CLL patients treated in Canada between October 2013 and September 2014. Results: See Table. Analysis of 273 first-line CLL patients identified that younger patients (≤70) with more favorable disease characteristics (co-morbidities=0-1, good renal function, & ECOG=0-1) were predominantly treated with fludarabine-based regimens in the first-line. Older patients (>70) with less favorable disease characteristics (co-morbidities=2+, renal disease & ECOG=2-3) were mostly treated with chlorambucil-based regimens, bendamustine-based regimens and novel treatments in the first-line (see table). Of the 190 first-line CLL patients (70%) that were tested for chromosome abnormalities, 63% tested positive. 53% of patients possessing deletion 13q or trisomy 12 abnormalities were prescribed fludarabine-based regimens. Conversely, 44% of patients with 17p or 11q deletions were prescribed chlorambucil-based regimens. Conclusions: The analysis of first-line CLL patients in this study has identified differences in patient fitness and genetic markers. It therefore demonstrates the importance of these factors in determining treatment choice. First-line Treatment FLUD-based (exc. FCR) (n=75) FCR (n=45) CHLOR-based (n=78) BEND-based (n=21) NOVEL (n=5) Age ≤70: 68% ≤70: 86% >70: 59% >70: 62% >70: 25% Co-morbidities 0-1: 87% 0-1: 82% 2+: 41% 2+: 48% 2+: 40% Renal Disease 4% 9% 12% 29% 20% ECOG Status 0-1: 63% 0-1: 72% 2-3: 36% 2-3: 52% 2-3: 60%
Abstract P003: Evaluating Comprehensive Smoke Free Policy at the Community Level Using Systems Modeling
Authors: Whitney R Garney, Kristen M Garcia
Journal: Circulation (2019)

Introduction: Advocating for comprehensive smoke-free policies is a priority for many community-based organizations. However, it is difficult to appeal to law makers and gain community support without being able to estimate the population-level health outcomes that could result from new policy. Hypothesis: We expect that by using agent based modeling, we can estimate the effects of comprehensive smoke-free policy in a way that is useful for community-level decision making. Methods: Using an agent-based model, we were able to estimate the potential effects of comprehensive smoke-free policies both Arlington and Mesquite, Texas. The model simulates the intervention effects based on established effect sizes from published literature. The simulation was conducted in 2017 and was used to determine the effects of policy change on reducing CVD risk over a 10- and 20-year periods. Results: In Arlington, Texas, the smoke-free policy was estimated to decrease population rates for myocardial infarction from 4.9% to 4.7%, stroke from 3.0% to 2.7%, and diabetes from 20.3% to 20.2% over 10 years. The effect of the comprehensive smoke free policy was more pronounced over a 20-year period, with all effects being statistically significant (p&lt;.001). In Mesquite, Texas, the policy did not have a significant impact on the proportion of population experiencing stroke in 10 years (p=.107). However, in 20 years, the policy was shown to decrease the rate of diabetes from 29.5% to 28.4%, myocardial infarction from 8.5% to 7.9%, and stroke from 3.3% to 3.0%, all of which are statistically significant (p&lt;.001). Conclusions: This data is helpful in understanding the potential community-level impact of policy on cardiovascular health over time. Population-level health interventions are powerful tools, however, the length of time that they take to show an impact limits uptake. By using systems modeling, we can estimate the potential long-term impacts of policies and garner intervention support in a timelier manner. In conclusion, this tool can be used to build support for smoke-free policies or other CVD interventions in a variety of communities.
Evaluation of prognostic effects of MSI, PD-L1 and TIL in resected bladder cancer.
Authors: Deniz Tural, Emre Akar, Halil Firat Baytekin, Volkan Tugcuoglu
Journal: Journal of Clinical Oncology (2019)

465 Background: The aim of the study was evaluating prognostic significance of tumor infiltrating lymphocytes (TIL), microsatellite instability (MSI) and programmed cell death ligand-1 (PD-L1) expression which are used as predictive biomarkers in immunotherapy. Methods: Clinic and pathologic features of bladder cancer patients who were underwent radical cystectomy were retrospectively analyzed from patients’ records in this single-center study. PD-L1, PD-L1 in TIL, PMS2, MSH2, MSH6 and MLH1 immunohistochemistry staining were carried out to archived resected tumor specimens of the eligible patients. MSI was evaluated according to existing of PMS2, MSH2, MSH6 and MLH1. Results: Fifty-six males (91.8%) and 5 females (8.2%) of total 61 patients were eligible for the study. Median age was 61.72 (35-81). PD-L1 expression in tumor cells and PD-L1 expression in TIL were positive in 14,8% (n = 9) and 16.4% (n = 10) of total 74 patients, respectively. MSI was high in 15 patients (24.6%). Intratumoral TIL rate was &lt; 10% in 49 patients (80.3%) while &gt; 10% in 12 patients. (19.7%) In Chi-square test, there was no statistically significant relationship between PD-L1, PD-L1 in TIL, MSI and TIL rate and patients’ characteristics including sex, stage, pathologic grade and lymph node status. Three-years overall survival (OS) rate was calculated as 43%. Univariate analysis did not reveal any significant difference in 3-years OS in PD-L1 expression in tumor, PD-L1 expression in TIL and TIL rate &gt; 10% . (p = 0.822, p = 0.638, p = 0.318; respectively ). There was a positive trend with MSI high patients and OS (p = 0.089). At also; age and stage showed statistically significant difference in multivariate analysis. (p = 0.023, p = 0.011, respectively). Conclusions: This study revealed that there is no prognostic significance of PD-L1 and TIL. However, there are positive trend between OS and MSI, which is proven as predictive biomarker of immunotherapy, in patients who were followed with same treatment and follow-up approach in single center. These results must be corroborated with large and prospective investigations in order to better understanding biology and behavior of bladder cancer.
Sequencing of chemotherapy and androgen-axis inhibitors (AAIs) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ravinder Dhawan, Tony Yang, Raymond Miao, Daniel Hennessy, Guru Sonpavde
Journal: Journal of Clinical Oncology (2015)

e16030 Background: Optimal treatment sequencing for mCRPC is unclear. We retrospectively assessed real-world treatment patterns in pts with mCRPC to provide insight into treatment sequencing. Methods: MarketScan, a US national claims database, was used to identify pts aged ≥ 18 years with: ≥ 1 medical claim for prostate cancer, either prior docetaxel (D) or no prior D, start of cabazitaxel (C) or AAI (abiraterone [A] and/or enzalutamide [E]) therapy between May 2011 and March 2013, continuous health plan enrollment for ≥ 12 months prior to drug initiation, and 9−16 months of follow-up. Sequences were characterized by descriptive statistics. Results: Of 2,299 pts identified, 1,052 (46%) had prior D and 1,247 (54%) were D-naïve at C or AAI initiation. In the post-D group, 766 pts (73%) received AAIs only post-D (589 [56%] received one AAI; 177 [17%] received two AAIs). 149 pts (14%) received an AAI then chemotherapy (99 [9%] received an AAI → C; 98 received one AAI → C; 1 received two AAIs → C). Seventy pts (7%) received C → AAI therapy and 67 (6%) received chemotherapy only (54 [5%] received C; 13 [1%] received C → D or other). For pts who received AAI → chemotherapy or C → AAI post-D, mean time (SD; median) from first-line D to second-line (2L) therapy was 405 days (± 365; 226) and 376 days (± 312; 269), respectively, and time from 2L to third-line treatment was 145 days (± 105; 118) and 153 days (±104; 128), respectively. All 18 pts who received all four drugs received D → C → A → E. In the D-naïve group, all 1,247 pts received AAI therapy: 1,179 (95%) received AAI therapy only (941 [75%] received one AAI; 238 [19%] received two AAIs) and 68 pts (5%) received AAI therapy → chemotherapy (C, D, other). Characteristics of pts receiving different sequences will be presented. Conclusions: Results suggest that in a community setting, in pts receiving subsequent therapies post-D, AAIs are administered more often than C. However, a small minority of D-naïve pts receive chemotherapy after AAI therapy. All pts exposed to all four treatments in this dataset received initial chemotherapy with D and C in sequence followed by both AAIs in sequence. Optimal treatment sequencing warrants further clarification. Funding: Sanofi.