tbuckley/cabot-search huggingface dataset:
<i>SATB2-AS1</i> Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent <i>Snail</i> Transcription and Epithelial–Mesenchymal Transition
Authors: Yi-Qing Wang, Dong-Mei Jiang, Sha-Sha Hu, Li Zhao, Lan Wang, Min-Hui Yang, Mei-Ling Ai, Hui-Juan Jiang, Yue Han, Yan-Qing Ding, Shuang Wang
Journal: Cancer Research (2019)

Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in colorectal carcinoma. SATB2-AS1 suppressed colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of colorectal carcinoma. SIGNIFICANCE: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress colorectal cancer progression.See related commentary by Li, p. 3536.
Regional differences in cardiovascular status and events in prostate cancer patients treated with a gonadotrophin-releasing hormone agonist vs antagonist: Results of a pooled analysis.
Authors: Anders Neijber, E. David Crawford, Thomas E. Keane, Zsolt Bosnyak, Anders Malmberg, Michael Borre
Journal: Journal of Clinical Oncology (2015)

e16096 Background: Androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) may increase the risk of cardiovascular (CV) events. A pooled analysis indicated a significantly lower risk of CV events or death in men with pre-existing CV disease (CVD) treated with degarelix vs GnRH agonists. We now report regional differences in baseline CV status and incidence of CV events in degarelix- and GnRH agonist-treated men. Methods: Individual patient level data on baseline CVD and subsequent CV events were pooled from 3 qualifying ( > 6 months exposure) phase 3 trials. CV events were analysed by geographic region: USA/Canada vs Europe and compared using cumulative incidence functions with all-cause mortality as the competing risk and Cox regression analyses. Results: Of 1737 men treated with degarelix and GnRH agonists, 404 (36.1%) and 215 (34.7%) had baseline CVD, respectively. By region, baseline CVD prevalence was similar between Europe (37.4%) and USA/Canada (33.5%; p = 0.085). However, CVD history was more severe in USA/Canada, (e.g. more myocardial infarction and coronary intervention). The presence of multiple CV risk factors were more frequent at baseline in the USA/Canada vs Europe (e.g. smoking [61.1% vs 39.0%], treated type 2 diabetes [17.9% vs 7.0%] and obesity [34.2% vs 16.7%], respectively) (p < 0.05). In men with baseline CVD, the cumulative incidence of a CV event was higher in USA/Canada (9.4, 95% CI 5.7–14.0) than Europe (3.5; 95% CI 1.9–5.7), p = 0.006 (Gray’s test). The treatment hazard ratio (HR; GnRH agonist as reference) was similar in the two regions (group-by-region interaction p = 0.979) with a homogenous HR of 0.42 (95% CI 0.20–0.87). Conclusions: Despite a similar proportion of patients with pre-existing CVD by region, baseline CV risk factors were more common and prior CVD more severe in USA/Canada vs Europe. Therefore geographical differences in the 1-year CV event risk (greater in USA/Canada) are likely due to patient clinical characteristics. Similar reduction in the risk of CV events compared to agonist was seen in degarelix patients in Europe and USA/Canada in line with the earlier reported overall rate.
Management and outcomes of hospitalized patients with primary neuroendocrine tumor (NET) and non-NET appendiceal cancers in the United States.
Authors: Olatunji Boladale Alese, Sungjin Kim, Zhengjia Chen, Walid Labib Shaib, Taofeek Kunle Owonikoko, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2015)

e17722 Background: Surgery has a central role in the management of appendiceal tumors, we report on the management of appendiceal cancers focusing on surgical utilization based on histology. Methods: Hospitalized patients with appendiceal cancer in the US between 2006 and 2010 were included in the study. The Nationwide Inpatient Sample database was employed for univariate and multivariate testing to identify factors significantly associated with patient outcome. Results: A total of 3,799 patient discharges were identified over the five year period covered by the study. Neuroendocrine tumors (NET) was the diagnosis in 291 (7.66%) and non-NET in 3,508 (92.34%) patients. The mean age was 56.8 years (± SD 14.6), with female predominance (54.73% vs. 45.27%). NET patients were younger than those with non-NET (50.7 vs. 57.4 years; p<0.001). NET patients were more commonly treated with appendectomy compared to non-NET (OR 1.59; 95% CI: 1.23-2.07; p<.001). Hyperthermic intraperitoneal chemotherapy (HIPEC) was used in 8.5% of all the cases, mostly in non-NET histology (91% vs. 8%). Majority of the patients treated with HIPEC had no co-morbid medical illness (60%), and received care at high volume hospitals in urban areas. There was a low incidence of in-hospital mortality (2.5%). Conclusions: The described surgical utilization pattern should prompt more research focusing on the barriers for appropriate surgical debulking and HIPEC utilization in non-NET appendiceal cancers. [caption.Demographics and multivariate analysis of covariates.[/caption] Type of surgery Appendectomy Covariate Level Appendectomy (N=698) Other procedures (N=3101) P-value Odds Ratio (95% CI) OR P-value Age (years) Median (Range) 56.5 (12 - 96) 57 (12 - 97) 0.147 - Gender Male (%) 265 (15.55) 1451 (84.45) <.001 0.65 (0.55-0.77) <.001 Female (%) 433 (20.85) 1643 (79.15) 1 (Ref) Histology NET (%) 91 (30.96) 200 (69.04) <.001 1.59 (1.23-2.07) <.001 Non-NET (%) 607 (17.38) 2901 (82.62) 1 (Ref) Location of hospital Rural (%) 89 (23.53) 285 (76.47) 0.027 - Urban (%) 609 (17.96) 2816 (82.04) In-hospital mortality Yes (%) 6 (6.25) 90 (93.75) <.001 - No (%) 692 (18.68) 3011 (81.32)
Genotype-directed phase II study of irinotecan dosing in metastatic colorectal cancer (mCRC) patients receiving FOLFIRI + bevacizumab: The GENIC study.
Authors: Grant Richard Williams, Federico Innocenti, William Allen Wood, Jai Narendra Patel, Gary Bradley Sherrill, Bert H. O'Neil, Jeremiah C. Boles, Ethan M. Basch, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2015)

TPS3621 Background: Infusional fluorouracil/leucovorin plus irinotecan with bevacizumab (FOLFIRI-bev) is a standard first-line option for mCRC. The active metabolite of irinotecan, SN-38, is inactivated via glucuronidation by UGT1A1. Common germline variants of UGT1A1 are well known to alter the rate of glucuronidation and exposure to SN-38. UGT1A1*28 decreases UGT1A1 expression such that *28/*28 homozygotes have greater SN-38 exposure and increased risk of neutropenia. Despite the well-described association of genotype and SN-38 exposure, irinotecan doses have been established independent of genotype. Dose-limiting toxicity in the ~10% of patients homozygous for *28/*28 may have led to under-dosing of patients with other genotypes. In phase I genotype-directed dose-finding studies of FOLFIRI +/- bev, *1/*1 and *1/*28 patients were able to tolerate significantly higher doses of irinotecan (Sharma GI ASCO 2014, Marcuello BJC 2011, Toffoli JCO 2010) with a promising efficacy signal. We hypothesize that genotype-guided irinotecan dosing—in which *1/*28 and *1/*1 genotypes receive higher doses of irinotecan—will increase the overall benefit of FOLFIRI-bev for patients with mCRC with tolerable toxicity. GENIC is a phase II multicenter, single arm trial designed to estimate the progression-free survival (PFS) of genotype-guided irinotecan dosing in patients receiving first-line FOLFIRI-bev for mCRC (NCT02138617). Methods: Patients with unresectable mCRC eligible for FOLFIRI-bev will be assigned irinotecan dose based on UGT1A1 genotype: *1/*1 = 310mg/m2; *1/*28 = 260mg/m2; or *28/*28 = 180mg/m2. Fluorouracil, leucovorin, and bevacizumab are given at standard doses. The primary objective is to estimate PFS compared with recently reported PFS from FIRE-3 and 80405. 100 patients are planned to ensure 86 are evaluable, giving 80% power to detect a 3.5 month improvement in PFS. Secondary objectives will evaluate toxicity, response rate, and overall survival. Efficacy by genotype will be explored. The Patient Reported Outcomes (PRO) version of the CTCAE will evaluate patient reported tolerance and the concordance between patient and clinician assessment. Clinical trial information: NCT02138617.
Germline alterations in urothelial carcinoma (UC) patients with family history of UC.
Authors: Amin Nassar, Kent William Mouw, Edward D. Esplin, Shan Yang, Tom Callis, Pier Vitale Nuzzo, Nieves M. Chanza, Toni K. Choueiri, David J. Kwiatkowski, Guru Sonpavde
Journal: Journal of Clinical Oncology (2019)

474 Background: UC is associated with germline alterations in a small minority of patients (pts). The prevalence of germline alterations in those with familial UC is unknown. We identified genomic alterations among familial UC pts to provide insights into pathogenesis and improve management. Methods: We analyzed deidentified data for UC pts with germline multigene panel testing (Invitae) who had a family history of UC, defined as a 1 st -3 rd degree relative with UC. Massively parallel sequencing used customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number variations (CNVs) for 1-126 genes. Pathogenic and likely pathogenic (P/LP) variants underwent orthogonal confirmation, per standard policy, including single nucleotide variants (SNVs)/small indels/CNVs. Patient characteristics were compared using the Fisher’s Exact and Wilcoxon-Rank Sum test. Results: 79 UC pts with a family history of UC were identified (67 bladder, 6 upper tract, 6 unknown). Six patients (8%) were excluded as the relation of the family member was unknown. 48/73 (66%) pts had first-degree relatives (fdr) with UC (4 upper tract, 39 bladder, 5 unknown) and 25 (34%) had second-degree (or higher) relatives (sdr) (2 upper tract, 22 bladder, 1 unknown). 56 germline alterations were found in 38 (52%) pts. 14 known pathogenic alterations occurred in 13 (18%) pts: SDHC (1), MITF (2), BRIP1 (1), BRCA2 (1), MSH2 (3), BRCA1 (1), CHEK2 (1), PTCH (1), MUTYH (2), BAP1 (1). 8/48 (17%) pts with fdr had pathogenic variants vs. 5/25 (20%) pts with sdr or more. There was no difference in the prevalence of pathogenic variants based on gender (p=0.37) or age (p=0.77). The limitations are modest sample size and differences in panels of genes. Conclusions: This is the first study to our knowledge to report germline alterations in UC pts with a family history of UC. Pathogenic germline alterations were seen in 18% of pts, which were enriched for DNA damage repair gene alterations, and could have important therapeutic implications. Further study of germline alterations using larger panels in pts with family history of UC may provide novel insights, since most pts did not have pathogenic alterations.
Abstract P374: Healthy Lifestyle Factors Are Associated With a Lower Risk of Cardiovascular and Cancer Mortality in Older Men
Authors: Ali Nujaidi, Jiaying Chen, John M Gaziano, Luc Djoussé
Journal: Circulation (2019)

Background: Cardiovascular disease and cancer are the two leading causes of death in the united states. Although individual healthy lifestyle behaviors have been associated with health benefits in middle-age adults, little is known about these factors and mortality in older adults. Objective: To assess the association between modifiable lifestyle factors and risk of CVD and cancer mortality in older men. Methods: We prospectively studied 8314 men aged 65 years and above from Physicians’ Health Study II. Baseline information on lifestyle factors was self-reported. We assessed healthy lifestyle factors as follows: Not smoking, BMI &lt;25 kg/m2, vigorous exercise for at least 5 days a week, and healthy diet habit (assessed as being in the top 2 quintiles of the alternate healthy eating index-2010). We used COX regression analysis to calculate adjusted hazard ratios with 95% CI for cardiovascular disease (CVD) and cancer mortality. Results: After a mean follow up duration of 9 years, 443 participants died due to cardiovascular disease and 349 died due to cancer. Age adjusted hazard ratios (95% CI) of cancer mortality was 0.73 (0.55-0.96), 0.58 (0.43-0.78), and 0.52 (0.36-0.75) for people with one, two, and 3+ healthy lifestyle factors, respectively, compared to people adhering to zero healthy lifestyle factor. Corresponding values for CVD mortality hazard ratios (95% CI) were 1.01 (0.78-1.32), 0.70 (0.53- 0.93), and 0.73 (0.53-1.01), respectively. Conclusion: Adhering to healthy lifestyle behaviors is associated with lower risk of cardiovascular and cancer mortality in older men.
Using Complementary and Alternative Medicine for the Treatment of Psoriasis
Authors: Lawrence Chukwudi Nwabudike, Alin Laurentiu Tatu
Journal: JAMA Dermatology (2019)

To the Editor We were pleased to read the systematic review by Gamret et al1 because it is a field of interest. We would like to comment on some issues that we believe will be of interest to the readers of JAMA Dermatology.
Sunitinib for metastatic renal cell carcinoma: A systematic review and meta-analysis of real world and clinical trials data.
Authors: Michael Moran, Dana J. Nickens, Katherine Adcock, Arial Desscan, Meg Bennetts, Natalie Charnley, Kate Fife
Journal: Journal of Clinical Oncology (2019)

650 Background: Randomized controlled trials (RCTs) are the basis of approval for medical interventions, but may not fully reflect populations seen in clinical practice. Sunitinib is a widely used 1st-line treatment for patients (pts) with metastatic renal cell carcinoma (mRCC). This is the first large-scale meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and real-world data (RWD). Methods: PubMed, Ovid, MEDLINE and EMBASE were searched from 2000-2017 for RCTs and RWD studies of sunitinib as 1st-line treatment in pts with mRCC. Eligible studies contained a cohort of ≥50 adult pts per study arm. The meta-analysis combined RWD and RCT study arms, adjusting for data type (RCT or RWD). Recorded outcomes were: median progression-free survival (mPFS), median overall survival (mOS) and objective response rate (ORR). A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimate. Results: Of the studies that met eligibility criteria, mPFS, mOS and ORR were reported by 18, 19 and 15 studies, respectively. Combined RWD and RCT analyses are presented in the Table. Reported mPFS (RWD, 7.5–11.0; RCTs, 5.6–15.1 months) and ORR data (RWD, 14.0–34.6%; RCTs, 18.8–46.9%) were consistent with the overall estimates. Reported mOS showed greater variation in RWD (6.8–33.2 months) compared with RCTs (21.8–31.5 months). Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS or ORR. Interpretation of these results is limited by differences in trial design and cohort characteristics. Conclusions: This novel, large-scale meta-analysis validates sunitinib as an effective 1st-line treatment for pts with mRCC in both RCTs and everyday clinical practice. [Table: see text]
Abstract P250: Sex-Related Differences in the Associations of Variability in Body Mass Index and Metabolic Health With Incidence of Obesity and Metabolically Unhealthy Status: The Framingham Offspring Study
Authors: Todd R Sponholtz, Ramachandran S Vasan
Journal: Circulation (2019)

Introduction: Higher variability of body mass index (BMI) is associated with both cardiometabolic and cardiovascular disease in high-risk individuals. It is unclear, however if variability of BMI impacts metabolic health or obesity risk in healthy adults and if any potential associations vary for women vs. men. Methods: We classified Framingham Offspring cohort participants (n=3,961, mean age 50.8 years, 53.8% women) according to their obesity (BMI ≥30 kg/m 2 ) and metabolic health status (&lt;2 non-obesity NCEP ATPIII conditions) and followed them prospectively 1987 to 2014. BMI and metabolic syndrome (MetS)-associated measures in the top quintile of the variance independent of the mean were classified as being variable. ‘Variable metabolic health’ (VMH) was defined as ≥2 ‘variable’ non-obesity MetS components. We estimated sex-specific incident rate ratios (IRRs) and 95% confidence intervals (95% CIs) for the associations of time-varying obesity, metabolic health status, and variability of BMI and metabolic health with the incidence of obesity and metabolically unhealthy state using Cox proportional hazards regression for interval-censored outcomes with age as the time scale. Results: On follow-up, 567 participants (313 women) developed new-onset obesity over 9,434 person-periods, and 759 individuals (437 women) developed a metabolically unhealthy state over 5,754 person-periods). After adjustment for covariates, being metabolically unhealthy was associated with a greater risk of new-onset obesity among women (153%, 95% CI 96-229%) compared with men (33%, 95% CI: 1, 79%; p sex- difference =0.005). Similarly, BMI variability was associated with a higher risk of becoming metabolically unhealthy in women (134%, 95% CI: 76, 212%) compared with men (-11%, 95% CI: -49, 53% (p sex-difference =0.0007). Among participants without obesity, BMI variability was associated with a greater risk of incident obesity in women (275%, 95% CI: 185, 393%) compared with men (33%, 95% CI: -22, 129% p sex- difference =0.005). Obesity was positively associated with greater risk of incident unhealthy metabolic state in women (157%, 95% CI: 93, 342%) compared to men (16%, 95% CI: -17, 62%; p sex-difference =0.006). Metabolic health did not alter the risk of either outcome among metabolically healthy or unhealthy individuals. Conclusions: Our longitudinal observations in a community-based sample suggest sex-related differences in the associations of variability of BMI and metabolic health on obesity and cardiometabolic risk. Additional investigations are warranted to replicate our findings and elucidate the biological basis for these sex-related differences. .
Effect of task-shifting HIV testing from laboratory personnel to nurses on paediatric and adolescent HIV testing rate and yield in rural Nigeria: a prospective before-and-after study
Authors: Oriaku Ofem, Tongdiyen Laura Jasper, Nguavese Torbunde, Murna Yashimankut, Hussaini Sadiq, Rosemary Ejekam, Daniel Ikeda, Emmanuel Aiyenigba, Bruce Agins, Nadia Sam-Agudu
Journal: The Lancet Global Health (2019)

BackgroundNigeria has the second highest burden of HIV in children younger than 15 years (220 000) and adolescents 10 –19 years (230 000) in the world. Unfortunately, fewer than a quarter of these children and adolescents are identified and given access to treatment. Decentralisation of HIV testing services to high-yield service delivery points can facilitate identification of undiagnosed HIV-positive children and adolescents. However, decentralisation of testing services is still uncommon, partly due to existing health-care professional boundaries. We evaluated the effectiveness of task-shifting HIV testing services from specialised laboratory personnel to nurses to improve HIV case identification in paediatric and adolescent clients.MethodsWe established a testing point for patients aged 0–19 years in the inpatient ward at a secondary health-care facility in a rural district with high prevalence of HIV in north-central Nigeria. Paediatric nurses were trained by laboratory personnel to provide HIV testing to children and adolescents admitted to the ward. We reviewed the hospital ward admission records and laboratory HIV testing records for patients aged 0–19 years to establish a pre-intervention baseline.FindingsIn the 3 months before the intervention when HIV testing services were provided only by laboratory personnel, 276 children and adolescents were admitted (mean 92·0 admissions/month), of whom only 22 patients (8%) underwent HIV testing and no positive cases were identified. However, in the 4-month intervention period between April and July, 2018, 179 paediatric or adolescent clients were admitted (44·8 admissions/month), of whom 169 (94%) were tested for HIV by nurses and four HIV-positive children were newly identified (a 2·4% yield). Linkage to care and antiretroviral therapy initiation was achieved for all newly identified children within 24 h of diagnosis.InterpretationTask-shifting of paediatric and adolescent inpatient HIV-testing services to nurses was more effective in HIV case identification than was testing by laboratory personnel. In settings where limited human resources remains a major challenge, implementation and scale-up of task shifting for testing services can significantly improve HIV case identification and, therefore, treatment coverage in children and adolescents.FundingCDC-PEPFAR.
Role of Noncoding RNAs in the Pathogenesis of Abdominal Aortic Aneurysm
Authors: Sandeep Kumar, Reinier A. Boon, Lars Maegdefessel, Stefanie Dimmeler, Hanjoong Jo
Journal: Circulation Research (2019)

Abdominal aortic aneurysm (AAA) is a local dilatation of the abdominal aortic vessel wall and is among the most challenging cardiovascular diseases as without urgent surgical intervention, ruptured AAA has a mortality rate of >80%. Most patients present acutely after aneurysm rupture or dissection from a previously asymptomatic condition and are managed by either surgery or endovascular repair. Patients usually are old and have other concurrent diseases and conditions, such as diabetes mellitus, obesity, and hypercholesterolemia making surgical intervention more difficult. Collectively, these issues have driven the search for alternative methods of diagnosing, monitoring, and treating AAA using therapeutics and less invasive approaches. Noncoding RNAs-short noncoding RNAs (microRNAs) and long-noncoding RNAs-are emerging as new fundamental regulators of gene expression. Researchers and clinicians are aiming at targeting these microRNAs and long noncoding RNAs and exploit their potential as clinical biomarkers and new therapeutic targets for AAAs. While the role of miRNAs in AAA is established, studies on long-noncoding RNAs are only beginning to emerge, suggesting their important yet unexplored role in vascular physiology and disease. Here, we review the role of noncoding RNAs and their target genes focusing on their role in AAA. We also discuss the animal models used for mechanistic understanding of AAA. Furthermore, we discuss the potential role of microRNAs and long noncoding RNAs as clinical biomarkers and therapeutics.