tbuckley/cabot-search huggingface dataset:
Forecasted Size of Measles Outbreaks Associated With Vaccination Exemptions for Schoolchildren
Authors: David R. Sinclair, John J. Grefenstette, Mary G. Krauland, David D. Galloway, Robert J. Frankeny, Clayton Travis, Donald S. Burke, Mark S. Roberts
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Vaccine exemptions, which allow unvaccinated children to attend school, have increased by a factor of 28 since 2003 in Texas. Geographic clustering of unvaccinated children facilitates the spread of measles introductions, but the potential size of outbreaks is unclear. <h3>Objective</h3> To forecast the range of measles outbreak sizes in each metropolitan area of Texas at 2018 and future reduced school vaccination rates. <h3>Design, Setting, and Participants</h3> An agent-based decision analytical model using a synthetic population of Texas, derived from the 2010 US Census, was used to simulate measles transmission in the Texas population. Real schools were represented in the simulations, and the 2018 vaccination rate of each real school was applied to a simulated hypothetical equivalent. Single cases of measles were introduced, daily activities and interactions were modeled for each population member, and the number of infections over the course of 9 months was counted for 1000 simulated runs in each Texas metropolitan area. <h3>Interventions</h3> To determine the outcomes of further decreases in vaccination coverage, additional simulations were performed with vaccination rates reduced by 1% to 10% in schools with populations that are currently undervaccinated. <h3>Main Outcomes and Measures</h3> Expected distributions of outbreak sizes in each metropolitan area of Texas at 2018 and reduced vaccination rates. <h3>Results</h3> At 2018 vaccination rates, the median number of cases in large metropolitan areas was typically small, ranging from 1 to 3 cases, which is consistent with outbreaks in Texas 2006 to 2017. However, the upper limit of the distribution of plausible outbreaks (the 95th percentile, associated with 1 in 20 measles introductions) exceeded 400 cases in both the Austin and Dallas metropolitan areas, similar to the largest US outbreaks since measles was eliminated in 2000. Decreases in vaccination rates in schools with undervaccinated populations in 2018 were associated with exponential increases in the potential size of outbreaks: a 5% decrease in vaccination rate was associated with a 40% to 4000% increase in potential outbreak size, depending on the metropolitan area. A mean (SD) of 64% (11%) of cases occurred in students for whom a vaccine had been refused, but a mean (SD) of 36% (11%) occurred in others (ie, bystanders). <h3>Conclusions and Relevance</h3> This study suggests that vaccination rates in some Texas schools are currently low enough to allow large measles outbreaks. Further decreases are associated with dramatic increases in the probability of large outbreaks. Limiting vaccine exemptions could be associated with a decrease in the risk of large measles outbreaks.
Improved Prostate Cancer Biopsy Grading by Incorporation of Invasive Cribriform and Intraductal Carcinoma in the 2014 Grade Groups
Authors: Geert J.L.H. van Leenders, Charlotte F. Kweldam, Eva Hollemans, Intan P. Kümmerlin, Daan Nieboer, Esther I. Verhoef, Sebastiaan Remmers, Luca Incrocci, Chris H. Bangma, Theodorus H. van der Kwast, Monique J. Roobol
Journal: European Urology (2019)
Macrophage ABHD5 Suppresses NFκB-Dependent Matrix Metalloproteinase Expression and Cancer Metastasis
Authors: Shenglan Shang, Xinran Ji, Lili Zhang, Jun Chen, Chuan Li, Rongchen Shi, Wei Xiang, Xia Kang, Dapeng Zhang, Fan Yang, Rongyang Dai, Peng Chen, Shan Chen, Yongchuan Chen, Yongsheng Li, Hongming Miao
Journal: Cancer Research (2019)

Metabolic reprogramming in tumor-associated macrophages (TAM) is associated with cancer development, however, the role of macrophage triglyceride metabolism in cancer metastasis is unclear. Here, we showed that TAMs exhibited heterogeneous expression of abhydrolase domain containing 5 (ABHD5), an activator of triglyceride hydrolysis, with migratory TAMs expressing lower levels of ABHD5 compared with the nonmigratory TAMs. ABHD5 expression in macrophages inhibited cancer cell migration in vitro in xenograft models and in genetic cancer models. The effects of macrophage ABHD5 on cancer cell migration were dissociated from its metabolic function as neither triglycerides nor ABHD5-regulated metabolites from macrophages affected cancer cell migration. Instead, ABHD5 deficiency in migrating macrophages promoted NFκB p65-dependent production of matrix metalloproteinases (MMP). ABHD5 expression negatively correlated with MMP expression in TAMs and was associated with better survival in patients with colorectal cancer. Taken together, our findings show that macrophage ABHD5 suppresses NFκB-dependent MMP production and cancer metastasis and may serve as a prognostic marker in colorectal cancer. SIGNIFICANCE: These findings highlight the mechanism by which reduced expression of the metabolic enzyme ABHD5 in macrophages promotes cancer metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5513/F1.large.jpg.
Lack of effect of prophylactic hematopoeitic colony stimulating factors in cancer patients and stem cell transplant recipients on short term survival: A meta-analysis of randomized trials
Authors: L. Sung, P. C. Nathan, S. M. Alibhai, G. A. Tomlinson, J. Beyene
Journal: Journal of Clinical Oncology (2007)

6605 Background: Previous randomized trials and meta-analyses have failed to determine with certainty whether prophylactic hematopoietic colony-stimulating factors (CSFs) influence survival in adults and children receiving cancer chemotherapy or undergoing stem cell transplantation (SCT). The primary objective was to determine whether prophylactic CSFs improve short-term overall survival. Secondary objectives were to determine whether prophylactic CSFs affected infection-related mortality, documented infections, microbiologically documented infections or febrile neutropenia. Methods: We performed electronic searches of OVID Medline from 1966 to November 2006; EMBASE from 1980 to November 2006; and the Cochrane Central Register of Controlled Trials until the second quarter, 2006. We included studies if there was randomization between CSFs and placebo/no therapy; CSFs were given concurrently with or following initiation of chemotherapy in the prophylactic setting; and chemotherapy/conditioning regimen or supportive care were not planned to be systematically different between study arms. From 4,019 reviewed titles and abstracts, 145 studies were included. Independent extraction was performed by two observers using a standardized data collection sheet. Results: Prophylactic CSFs did not affect short-term overall survival, with a relative risk (RR) of 1.00 (95% confidence interval [CI] 0.99 to 1.01; P=.9). This result was consistent across different patient populations (including patient age and underlying disease) and study characteristics. The effect of prophylactic CSFs on infection-related mortality was less clear (RR 0.83, 95% CI 0.67 to 1.03; P=.09). Intervention did reduce documented infections (rate ratio 0.85, 95% CI 0.78 to 0.92; P&lt;.00001), microbiologically documented infections (rate ratio 0.85, 95% CI 0.75 to 0.95; P=.004) and febrile neutropenia (rate ratio 0.70, 95% CI 0.62 to 0.79; P&lt;.00001). Conclusions: Prophylactic CSFs do not improve short-term overall survival but are associated with decreased rates of infection. Decision-making around this intervention should be based upon further exploration of costs, preferences and quality of life. No significant financial relationships to disclose.
Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex
Authors: Zachary S. Lorsch, Peter J. Hamilton, Aarthi Ramakrishnan, Eric M. Parise, Marine Salery, William J. Wright, Ashley E. Lepack, Philipp Mews, Orna Issler, Andrew McKenzie, Xianxiao Zhou, Lyonna F. Parise, Stephen T. Pirpinias, Idelisse Ortiz Torres, Hope G. Kronman, Sarah E. Montgomery, Yong-Hwee Eddie Loh, Benoit Labonté, Andrew Conkey, Ann E. Symonds, Rachael L. Neve, Gustavo Turecki, Ian Maze, Yan Dong, Bin Zhang, Li Shen, Rosemary C. Bagot, Eric J. Nestler
Journal: Nature Neuroscience (2019)
Survival benefits of adjuvant chemotherapy in high-grade stage II and III colon cancer.
Authors: Walter Tsang, Argyrios Ziogas, Chaitali Singh Nangia, Jason A. Zell
Journal: Journal of Clinical Oncology (2013)

e14529 Background: High-grade (HG; poorly differentiated and undifferentiated) colon carcinoma has an increased risk of recurrence after surgical resection compared to low-grade tumors. However, the benefits of adjuvant chemotherapy (AC) in this patient population remain unclear. Using a large population-based database, we examined survival outcomes of HG stage II/III colon cancer patients treated with or without AC. Methods: Stage II/III adult colon cancer patients with HG tumors who have undergone resection were identified in the California Cancer Registry from 1989 to 2006, with follow-up through 2009. Estimates of Colorectal Cancer Specific Survival (CRC-SS) were generated using Kaplan-Meier methods. CRC-SS multivariate analyses were performed using Cox proportional-hazard regression models adjusted for age, gender, race/ethnicity, histology, tumor site, chemotherapy, time period of diagnosis (1989-1994, 1995-2000, 2001-2006) and socioeconomic status. Results: Significant CRC-SS improvements were observed in stage III patients treated with AC (n=3,793) versus no AC (n=2,582) in univariate (Table) and multivariate analyses (HR=0.89, 95% CI 0.82-0.96). In contrast, among stage II patients treated with AC (n=1,232) vs. no AC (n=3,470), no differences were observed in univariate analyses (Table); furthermore, an increased risk of CRC-specific mortality was observed in multivariate analyses (HR=1.23, 95% CI 1.06-1.44). Conclusions: In high-grade colon cancer, despite significant survival benefits of adjuvant chemotherapy to stage III patients, adjuvant chemotherapy was independently associated with increased mortality in stage II patients. These findings invoke new questions about the utility of adjuvant chemotherapy among patients with high-grade stage II colon cancer. [Table: see text]
The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D
Authors: Rachel S. Kelly, Bo L. Chawes, Feng Guo, Li Zhang, Kevin Blighe, Augusto A. Litonjua, Benjamin A. Raby, Bruce D. Levy, Daniela Rago, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Xiaobo Zhou, Jessica A. Lasky-Su, Scott T. Weiss
Journal: European Respiratory Journal (2019)

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (β 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing ORMDL3 (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on the 17q21 genotype.
Patient’s characteristics and outcomes in necrotising soft-tissue infections: results from a Scandinavian, multicentre, prospective cohort study
Authors: Martin Bruun Madsen, Steinar Skrede, Anders Perner, Per Arnell, Michael Nekludov, Trond Bruun, Ylva Karlsson, Marco Bo Hansen, Peter Polzik, Morten Hedetoft, Anders Rosén, Edoardo Saccenti, François Bergey, Vitor A. P. Martins dos Santos, Anna Norrby-Teglund, Ole Hyldegaard
Journal: Intensive Care Medicine (2019)
Colorectal cancer in young population: Yangon, Myanmar.
Authors: Khin Khin Nwe
Journal: Journal of Clinical Oncology (2012)

e14055 Background: CRC is the tenth most common cause of cancer in 2006 Myanmar Cancer Statistic. Recently, increased incidence of CRC among young age has been seen in our population. Methods: Demographic data of CRC pts registered in medical oncology unit, YGH from January 2009 to September, 2011 were studied. Age under 40 yrs was considered as a young patient. Stage distribution were analyzed to study about young onset CRC pattern. Results: Among 351 CRC patients registered, 120pts (34.19%) were under 40 yrs old. In young age group, age range from 12 to 40 yrs (median 29.5 yrs). Male to female ration was 1:1.26. Left-sided cancer (splenic flexure to rectum) in 93 patients (77.5%) and right sided (caecum to transverse colon) cancer in 27 pts (22.5%). Six pts (5%) were stage I, 41 people (34.17%) with stage II. Forty-four patients (36.67%) were node positive Stage III and 29 people (24.17%) with distant metastasis, Stage IV. Conclusions: Three percent of colorectal cancers occur in patients younger than 40 years of age in World Cancer Data. However, one third of CRC pts registered within 3 yrs in our unit were under age 40.The commonest stage seen in those pts were stage III at initial diagnosed. According to this data, younger onset of CRC in Myanmar is increasing although it doesn’t reflect the whole population. Further larger study is required to prove it. [Table: see text]
Heparan Sulfate–Editing Extracellular Sulfatases Enhance VEGF Bioavailability for Ischemic Heart Repair
Authors: Mortimer Korf-Klingebiel, Marc R. Reboll, Karsten Grote, Hauke Schleiner, Yong Wang, Xuekun Wu, Stefanie Klede, Yuliya Mikhed, André Nobre, Johann Bauersachs, Michael Klintschar, Carsten Rudat, Andreas Kispert, Hans W. Niessen, Torben Lübke, Thomas Dierks, Kai C. Wollert
Journal: Circulation Research (2019)

Rationale: Mechanistic insight into the inflammatory response after acute myocardial infarction may inform new molecularly targeted treatment strategies to prevent chronic heart failure. Objective: We identified the sulfatase SULF2 in an in silico secretome analysis in bone marrow cells from patients with acute myocardial infarction and detected increased sulfatase activity in myocardial autopsy samples. SULF2 (Sulf2 in mice) and its isoform SULF1 (Sulf1) act as endosulfatases removing 6- O -sulfate groups from heparan sulfate (HS) in the extracellular space, thus eliminating docking sites for HS-binding proteins. We hypothesized that the Sulfs have a role in tissue repair after myocardial infarction. Methods and Results: Both Sulfs were dynamically upregulated after coronary artery ligation in mice, attaining peak expression and activity levels during the first week after injury. Sulf2 was expressed by monocytes and macrophages, Sulf1 by endothelial cells and fibroblasts. Infarct border zone capillarization was impaired, scar size increased, and cardiac dysfunction more pronounced in mice with a genetic deletion of either Sulf1 or Sulf2. Studies in bone marrow-chimeric Sulf-deficient mice and Sulf-deficient cardiac endothelial cells established that inflammatory cell-derived Sulf2 and endothelial cell-autonomous Sulf1 promote angiogenesis. Mechanistically, both Sulfs reduced HS sulfation in the infarcted myocardium, thereby diminishing Vegfa (vascular endothelial growth factor A) interaction with HS. Along this line, both Sulfs rendered infarcted mouse heart explants responsive to the angiogenic effects of HS-binding Vegfa 164 but did not modulate the angiogenic effects of non-HS-binding Vegfa 120 . Treating wild-type mice systemically with the small molecule HS-antagonist surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide, 1 mg/kg/day) for 7 days after myocardial infarction released Vegfa from HS, enhanced infarct border-zone capillarization, and exerted sustained beneficial effects on cardiac function and survival. Conclusions: These findings establish HS-editing Sulfs as critical inducers of postinfarction angiogenesis and identify HS sulfation as a therapeutic target for ischemic tissue repair.
Phase I study of ECO-4601, a novel Ras pathway inhibitor
Authors: P. Kavan, D. Melnychuk, A. Langleben, S. D. Baker, A. Bangash, C. Gauthier, M. Ranger, H. Gourdeau, M. D. Harvey, P. Falardeau, G. Batist
Journal: Journal of Clinical Oncology (2007)

14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m 2 /day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]
Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors
Authors: Minyoung Lee, Jiyu Sun, Minkyung Han, Yongin Cho, Ji-Yeon Lee, Chung Mo Nam, Eun Seok Kang
Journal: Diabetes Care (2019)

OBJECTIVE Dipeptidyl peptidase 4 inhibitors (DPP-4i) are useful incretin-based antidiabetes drugs. However, there is a concern that DPP-4i may adversely impact the exocrine pancreas, owing to their pleiotropic effects. In this study, we investigated whether DPP-4i are associated with pancreatitis and pancreatic cancer using a nationwide population-based cohort study. RESEARCH DESIGN AND METHODS We included patients newly diagnosed with type 2 diabetes who were treated with antidiabetes drugs (n = 33,208) from 2007 to 2013. The data were obtained from the Korean National Health Insurance Service–Health Screening Cohort database (n = 514,866). Risk was estimated using a Cox proportional hazards model with time-dependent covariates. A 6-month lag time was used to account for a possible latency time. The risk across various time segments since the first prescription of DPP-4i was also analyzed. RESULTS Out of 33,208 subjects, 10,218 were new users of DPP-4i and 22,990 were new users of other antidiabetes drugs. DPP-4i significantly increased the risks of pancreatitis (adjusted hazard ratio [aHR] 1.24, 95% CI 1.01–1.52; P = 0.037) and pancreatic cancer (aHR 1.81, 95% CI 1.16–2.82; P = 0.009) with a 6-month drug use lag period. The risk of pancreatitis and pancreatic cancer was generally consistent in the first 12 months and 1 year after the initial prescription without showing an increasing trend according to exposure duration. CONCLUSIONS DPP-4i use is associated with increased risks of pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. However, the absence of increasing trend according to exposure duration suggests the chances of reverse causality, and long-term pancreatic safety of DPP-4i has to be further investigated.
DNA Methylation Profiling of Myeloma Trial Patients Reveals Specific Epigenetic Changes Associated with Outcome
Authors: David C Johnson, Dil B Begum, Sidra Ellis, Amy L Sherborne, Amy Price, Charlotte Smith, Fabio Mirabella, Karen Menezes, Scott Kimber, John R Jones, Charlotte Pawlyn, Matthew W Jenner, Richard S Houlston, Gordon Cook, Nigel H. Russell, Alina Striha, Corinne Collett, Anna Waterhouse, Walter M Gregory, David A Cairns, Mark T Drayson, Roger G Owen, Faith E Davies, Gareth J Morgan, Graham H Jackson, Martin F Kaiser
Journal: Blood (2016)