tbuckley/cabot-search huggingface dataset:
ATIM-33. INTERIM RESULTS OF A PHASE II MULTI-CENTER STUDY OF ONCOLYTIC ADENOVIRUS DNX-2401 WITH PEMBROLIZUMAB FOR RECURRENT GLIOBLASTOMA; CAPTIVE STUDY (KEYNOTE-192)
Authors: Robert Aiken, Clark Chen, Timothy Cloughesy, Howard Colman, Mariza Daras, Morris Groves, Simon Khagi, Priya Kumthekar, Frederick Lang, Farshad Nassiri, Shirley Ong, Rohan Ramakrishna, Adam Sonabend, Michael Vogelbaum, Gelareh Zadeh, Laura Agensky, Carin Bidwell, Barry Watkins, Frank Tufaro, Joanna Peterkin
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND DNX-2401 (tasadenoturev) is a replication-competent, tumor-selective, oncolytic adenovirus. Phase I studies in adults with recurrent glioblastoma (rGBM) have demonstrated safety and encouraging clinical activity. A Phase II open-label, dose-escalating multi-center study in rGBM was initiated to evaluate DNX-2401 with pembrolizumab. Planned enrollment of 48 subjects is complete. METHODS Subjects ≥ 18 years, with a single tumor, KPS ≥ 70% and adequate organ function were enrolled sequentially into 3 cohorts of DNX-2401 (5e8vp, 5e9vp, 5e10vp). A single intratumoral injection of DNX-2401 was administered followed 7 days later by pembrolizumab (200 mg IV). Thereafter, pembrolizumab was infused Q3wks up to 24 months until progression or toxicity. 5e10vp was determined as the optimal dose and this cohort was expanded. Safety monitoring, assessments of response and survival follow-up are ongoing. RESULTS Nine subjects were treated in the escalation phase; 42 subjects received 5e10vp. No dose-limiting toxicity or unexpected safety issues were identified by an independent review committee, and there were no treatment-related deaths. Adverse events were primarily consistent with underlying disease, effects of the neuro-procedure, expected effects of pembrolizumab, and concomitant use of steroids/anticonvulsants per the standard of care. The majority of events were mild to moderate, and unrelated to DNX-2401. Headache and manageable vasogenic edema were the most common events related to DNX-2401 with pembrolizumab. For the 48 subjects who received pembrolizumab (median 6 cycles), median OS from DNX-2401 administration was 12 months (95% CI, 10.6–14.7), OS6 was 91%, and 47% experienced clinical benefit (stable disease or better). Four subjects (5e10) had a partial response (two with &amp;gt; 94% regression of tumor), and three (5e8; 5e10[2]) are alive &amp;gt; 20 months. Updated safety and efficacy results will be presented. CONCLUSIONS The data continue to demonstrate that DNX-2401 administered with pembrolizumab has an acceptable safety profile. Long-term survival and clinical benefit remain compelling.
Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing
Authors: Olya Mastikhina, Byeong-Ui Moon, Kenneth Williams, Rupal Hatkar, Dakota Gustafson, Omar Mourad, Xuetao Sun, Margaret Koo, Alan Y.L. Lam, Yu Sun, Jason E. Fish, Edmond W.K. Young, Sara S. Nunes
Journal: Biomaterials (2019)
Before the Storm: A Potential Role for Dry Weather in Children’s Risk of Diarrhea
Authors: Lindsey Konkel
Journal: Environmental Health Perspectives (2019)

Diarrheal diseases are the second leading cause of death of young children worldwide, according to the World Health Organization. 1 Recurrent and prolonged episodes of diarrhea in childhood are also associated with malnutrition, stunted growth, and impaired cognitive development. 2A recent study reported in Environmental Health Perspectives investigates climate-related variables and risk of diarrhea among children in rural Tamil Nadu, India. 3iarrheal diseases-which can be spread through contaminated food or drinking water or from person to person through poor hygiene.These diseases are seasonal in many locations. 4Previous studies have found that both high temperatures and heavy rainfall may be linked to greater diarrhea risk in low-income countries. 4Most previous studies on the relationship between temperature, rainfall, and diarrhea risk in low-income countries have focused on groups that drink water from surface sources such as springs, rivers, and lakes."Surface water may be more prone to bacterial contamination than groundwater," says lead study author Andrew Mertens, a PhD candidate in epidemiology at the University of California, Berkeley.Yet in rural South India, where Mertens worked on sanitation and nutrition, hundreds of millions of people rely on groundwater, which is extracted through tube wells and drawn
Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma
Authors: Liang-qing Dong, Li-hua Peng, Li-jie Ma, Dong-bing Liu, Shu Zhang, Shu-zhen Luo, Jun-hua Rao, Hong-wen Zhu, Shuai-xi Yang, Shui-jun Xi, Min Chen, Fan-fan Xie, Fu-qiang Li, Wen-hui Li, Chen Ye, Li-ya Lin, Yu-jue Wang, Xiao-ying Wang, Da-ming Gao, Hu Zhou, Huan-ming Yang, Jian Wang, Shi-da Zhu, Xiang-dong Wang, Ya Cao, Jian Zhou, Jia Fan, Kui Wu, Qiang Gao
Journal: Journal of Hepatology (2019)
Abstract 16252: Predictors of All Cause Mortality and Their Gender Differences in a Hispanic Population From Barranquilla-Colombia Using Machine Learning With Random Survival Forests
Authors: Carlos A Cure-Cure, Pablo Cure, Yuan Gu, Xin Tian, Tejas Patel, Colin O Wu, Helena Sviglin, George Sopko, Gyorgy Csako, Sean Cody, Gauri Dandi, Laboni Hoque, Ye Yan, Nashwan Farooque, Nuha Gani, Morgan Wiese, Anna Kettermann, Michael J Domanski, Eileen Navarro Almario, Frank Pucino, Yves Rosenberg, Ahmed Hasan
Journal: Circulation (2018)

Introduction: The PROUD (Prevalence of Metabolic diseases and their Influence on Macrovascular Disease and Fractures in Barranquilla) study was initiated to assess the prevalence and identify uniqu...
Abstract 15567: Global Longitudinal Strain at Rest and During Exercise Accurately Predicts Extensive Diffuse Myocardial Fibrosis at Histology and T1 Mapping in Aortic Stenosis
Authors: Tomas Ondrus, Radka Kockova, Corina D Mirica, Martin Kotrc, Alena Praveckova, Yujing Mo, Guy Van Camp, Martin Penicka
Journal: Circulation (2016)

Introduction: LV biopsy is a reference standard for the assessment of diffuse myocardial fibrosis (DMF). Magnetic resonance imaging (MRI)-derived native T1 relaxation time provides a noninvasive as...
Abstract 10795: Alirocumab and Cardiovascular Outcomes in Older Patients After an Acute Coronary Syndrome: An ODYSSEY OUTCOMES Trial Analysis
Authors: Peter R Sinnaeve, Gregory G Schwartz, Daniel Wojdyla, Marco Alings, Vera A Bittner, Deepak L Bhatt, Chern-En Chiang, Rafael Diaz, Maria Dorobantu, Shaun G Goodman, J Wouter Jukema, Yong-Un Kim, Robert Pordy, Michael Szarek, Harvey D White, Andreas M Zeiher, Philippe G Steg
Journal: Circulation (2019)

Background: Statins reduce ischemic cardiovascular risk irrespective of age, but the evidence is less strong for older patients. The ODYSSEY OUTCOMES trial compared alirocumab (ALI) with placebo, a...
Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2
Authors: Ritika Dutta, Tian Yi Zhang, Thomas Köhnke, Daniel Thomas, Miles Linde, Eric Gars, Melissa Stafford, Satinder Kaur, Yusuke Nakauchi, Raymond Yin, Armon Azizi, Anupama Narla, Ravindra Majeti
Journal: Journal of Clinical Investigation (2020)

Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and RBC transfusion-independence in patients with acute myeloid leukemia (AML) treated with the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRISPR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed CD71+ progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.
Longitudinal somatic mutational biomonitoring of genotoxic breast cancer chemotherapy reveals considerable interindividual variability in bone marrow response with potential clinical significance
Authors: Stephen G. Grant, Nicole T. Myers, Joseph L. Kelley, Victor G. Vogel, Adam M. Brufsky, William L. Bigbee, Jean J. Latimer
Journal: Cancer Research (2006)

1957  Cancer is the paradigm for late-onset diseases known to occur through a combination of genetic susceptibility and environmental exposure. Molecular toxicologists have developed a broad spectrum of methods to detect carcinogenic agents, including assays of biological function in vivo. Traditional firstline cancer chemotherapy is based on genotoxicity; that is, agents that kill cancer cells by damaging their DNA. Mutagenesis and genotoxicity are the most clearly established mechanisms of carcinogenesis, so, in many cases, genotoxicity assays are “validated” by analyzing patients undergoing chemotherapy. Such analyses often reveal a great range of response, which we suggest may be of clinical import. Since these drugs are delivered directly to the bloodstream there should be little difference in uptake or distribution between treated individuals. Variability in response might therefore be due to differences in elimination of the genotoxic agents or differences in repairing DNA damage. Chemotherapy dose is limited by its effects on normal cell-types, particularly the hematopoietic progenitor cells of the bone marrow. We have developed a fast, simple and inexpensive method of detecting and quantifying bone marrow somatic mutation. The GPA assay evaluates allele loss phenotypes in circulating erythrocytes that arise through somatic mutation in the bone marrow. We have applied this assay to 24 breast cancer patients undergoing five types of genotoxic chemotherapy. We find great (20-200 fold) variation in induced mutation between these patients, fully half of whom showed low to no response to their firstline chemotherapy. This variability in response might be due to differences in metabolism of the genotoxic agents or differences in repairing DNA damage. We are investigating whether our quantitative measure of bone marrow response is associated with clinical parameters of acute toxicity, treatment efficacy and secondary carcinogenesis. Preliminary data suggest that, in its present form, the GPA assay responds too slowly to identify the effects of individual chemotherapeutic cycles, and therefore to identify cycles associated with such acute toxicity. We, and others, have previously shown that persistent levels of induced mutation reflects effects on the bone marrow stem cells, and that such effects are associated with secondary carcinogenesis. We now present preliminary evidence that induced bone marrow mutation is predictive of clinical efficacy, offering the possibility of individually adjusting dose and drug during treatment for optimal effect.
Pharmacokinetic and pharmacodynamic analysis of fluorouracil in nasopharyngeal cancer patients.
Authors: Liping Zhao, Wanli Liu, Chong Zhao, Xiang Guo, Yan Huang, Fei Xu, Zhihuang Hu, Zhiqiang Wang, Hongyun Zhao, Li Zhang
Journal: Journal of Clinical Oncology (2012)

e13021 Background: Pharmacokinetic (PK) variability of 5-FU has been demonstrated for +30 years and a significant link between 5-FU exposure and therapeutic response has been identified. A maximum tolerated exposure (MTE) using area under curve (AUC) has been characterized for various regimens and therapeutic drug management (TDM) has been used to achieve effective dosing in several tumor types. The regimen most used to treat nasopharyngeal cancer (NPC) is cisplatin and 5-FU. The objective of this study was to characterize the PK variability of 5-FU in this population and examine the relationship between AUC and toxicity. The 5-FU MTE in this Chinese population will be compared with the MTE identified for HNC European patients. Methods: Fifty-three treatment naïve Chinese NPC patients were administered cisplatin (80mg/m 2 , day 1) and 5-FU (4g/m 2 , 120 h continuous infusion) and had blood samples collected at steady state after the first 18h of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC calculated from the steady state concentrations. We examined the relationship between 5-FU AUC and 5-FU-related toxicities (mucositis and myelosuppression). Results: The patient AUC values varied widely, ranging from 20 to 103 mg · h/L. 34% of the patients were within the target range of 25-35 mg· h/L , 15% were below and 51% were above the range. Toxicity was recorded for 53 patients. Severe mucositis in 17 and myelosuppression in 1 of 27 patients occurred with 5-FU exposure above the target range, versus no severe toxicity in any of the 27 patients within or below the target range (p=0.000). ROC analysis for 5-FU AUC and severe mucositis identified a cut-point of 37 mg· h/L (p&lt;0.001). Conclusions: Results of this study demonstrate wide PK-variability of 5-FU exposure and a significant relationship between severe toxicity and AUC in Chinese NPC patients. The study confirms that the MTE in this population is similar to a European HNC population treated with cisplatin/5-FU. TDM using the target range of 25-35 mg· h/L may have benefit in lowering toxicity in NPC patients.
Long term exposure to ambient fine particulate matter and incidence of stroke: prospective cohort study from the China-PAR project
Authors: Keyong Huang, Fengchao Liang, Xueli Yang, Fangchao Liu, Jianxin Li, Qingyang Xiao, Jichun Chen, Xiaoqing Liu, Jie Cao, Chong Shen, Ling Yu, Fanghong Lu, Xianping Wu, Liancheng Zhao, Xigui Wu, Ying Li, Dongsheng Hu, Jianfeng Huang, Yang Liu, Xiangfeng Lu, Dongfeng Gu
Journal: BMJ (2019)

Abstract Objective To study the effect of long term exposure to ambient fine particulate matter of diameter ≤2.5 μm (PM 2.5 ) on the incidence of total, ischemic, and hemorrhagic stroke among Chinese adults. Design Population based prospective cohort study. Setting Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project carried out in 15 provinces across China. Participants 117 575 Chinese men and women without stroke at baseline in the China-PAR project. Main outcome measures Incidence of total, ischemic, and hemorrhagic stroke. Results The long term average PM 2.5 level from 2000 to 2015 at participants’ residential addresses was 64.9 μg/m 3 , ranging from 31.2 μg/m 3 to 97.0 μg/m 3 . During 900 214 person years of follow-up, 3540 cases of incident stroke were identified, of which 63.0% (n=2230) were ischemic and 27.5% (n=973) were hemorrhagic. Compared with the first quarter of exposure to PM 2.5 (&lt;54.5 μg/m 3 ), participants in the highest quarter (&gt;78.2 μg/m 3 ) had an increased risk of incident stroke (hazard ratio 1.53, 95% confidence interval 1.34 to 1.74), ischemic stroke (1.82, 1.55 to 2.14), and hemorrhagic stroke (1.50, 1.16 to 1.93). For each increase of 10 μg/m 3 in PM 2.5 concentration, the increased risks of incident stroke, ischemic stroke, and hemorrhagic stroke were 13% (1.13, 1.09 to 1.17), 20% (1.20, 1.15 to 1.25), and 12% (1.12, 1.05 to 1.20), respectively. Almost linear exposure-response relations between long term exposure to PM 2.5 and incident stroke, overall and by its subtypes, were observed. Conclusions This study provides evidence from China that long term exposure to ambient PM 2.5 at relatively high concentrations is positively associated with incident stroke and its major subtypes. These findings are meaningful for both environmental and health policy development related to air pollution and stroke prevention, not only in China, but also in other low and middle income countries.
Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms
Authors: Ji Hoon Jung, Jisung Hwang, Ju-Ha Kim, Deok Yong Sim, Eunji Im, Ji Eon Park, Woon Yi Park, Bum-Sang Shim, Bonglee Kim, Sung-Hoon Kim
Journal: Seminars in Cancer Biology (2019)

Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.
The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3
Authors: Kyle D. Gibbs, Erica J. Washington, Sarah L. Jaslow, Jeffrey S. Bourgeois, Matthew W. Foster, Robyn Guo, Richard G. Brennan, Dennis C. Ko
Journal: Cell Host & Microbe (2019)
Laser‐facilitated epicutaneous immunotherapy with depigmented house dust mite extract alleviates allergic responses in a mouse model of allergic lung inflammation
Authors: Evgeniia Korotchenko, Raquel Moya, Sandra Scheiblhofer, Isabella A Joubert, Jutta Horejs‐Hoeck, Michael Hauser, David Calzada, Víctor Iraola, Jerónimo Carnés, Richard Weiss
Journal: Allergy (2019)

Skin-based immunotherapy of type 1 allergies has recently been re-investigated as an alternative for subcutaneous injections. In the current study, we employed a mouse model of house dust mite (HDM)-induced lung inflammation to explore the potential of laser-facilitated epicutaneous allergen-specific treatment.Mice were sensitized against native Dermatophagoides pteronyssinus extract and repeatedly treated by application of depigmented D pteronyssinus extract via laser-generated skin micropores or by subcutaneous injection with or without alum. Following aerosol challenges, lung function was determined by whole-body plethysmography and bronchoalveolar lavage fluid was analyzed for cellular composition and cytokine levels. HDM-specific IgG subclass antibodies were determined by ELISA. Serum as well as cell-bound IgE was measured by ELISA, rat basophil leukemia cell assay, and ex vivo using a basophil activation test, respectively. Cultured lymphocytes were analyzed for cytokine secretion profiles and cellular polarization by flow cytometry.Immunization of mice by subcutaneous injection or epicutaneous laser microporation induced comparable IgG antibody levels, but the latter preferentially induced regulatory T cells and in general downregulated T cell cytokine production. This effect was found to be a result of the laser treatment itself, independent from extract application. Epicutaneous treatment of sensitized animals led to induction of blocking IgG, and improvement of lung function, superior compared to the effects of subcutaneous therapy. During the whole therapy schedule, no local or systemic side effects occurred.Allergen-specific immunotherapy with depigmented HDM extract via laser-generated skin micropores offers a safe and effective treatment option for HDM-induced allergy and lung inflammation.
Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood
Authors: Nudrat Noor, Andres Cardenas, Sheryl L. Rifas-Shiman, Hui Pan, Jonathan M. Dreyfuss, Emily Oken, Marie-France Hivert, Tamarra James-Todd, Mary-Elizabeth Patti, Elvira Isganaitis
Journal: JAMA Network Open (2019)

While prenatal nutrition and maternal obesity are recognized as important contributors to epigenetic changes and childhood obesity, the role of paternal obesity in the epigenome of offspring has not been well studied.To test whether periconception paternal body mass index (BMI) is associated with DNA methylation patterns in newborns, to examine associations between maternal and paternal BMI and the epigenome of offspring, and to examine persistence of epigenetic marks at ages 3 and 7 years.Project Viva is a prebirth cohort study of mothers and children including 2128 live births that enrolled mothers from April 1999 to July 2002 and followed offspring to adolescence. This study analyzed the subset of participants with available data on paternal BMI and DNA methylation in offspring blood in the newborn period, at age 3 years, and at age 7 years. Data were analyzed from July 2017 to October 2019.The primary exposure was paternal periconception BMI; associations were adjusted for maternal prepregnancy BMI and stratified according to maternal BMI above or below 25.The primary outcome was genome-wide DNA methylation patterns in offspring blood collected at birth, age 3 years, and age 7 years.A total of 429 father-mother-infant triads were included. The mean (SD) periconception paternal BMI was 26.4 (4.0) and mean maternal prepregnancy BMI was 24.5 (5.2); 268 fathers had BMI greater than or equal to 25 (mean [SD], 28.5 [3.3]) and 161 had BMI less than 25 (mean [SD], 22.8 [1.8]). Paternal BMI greater than or equal to 25 was associated with increased offspring birth weight compared with paternal BMI less than 25 (mean [SD] z score, 0.38 [0.91] vs 0.11 [0.96]; P = .004). Cord blood DNA methylation at 9 CpG sites was associated with paternal BMI independent of maternal BMI (q < .05). Methylation at cg04763273, between TFAP2C and BMP7, decreased by 5% in cord blood with every 1-unit increase in paternal BMI (P = 3.13 × 10-8); hypomethylation at this site persisted at ages 3 years and 7 years. Paternal BMI was associated with methylation at cg01029450 in the promoter region of the ARFGAP3 gene; methylation at this site was also associated with lower infant birth weight (β = -0.0003; SD = 0.0001; P = .03) and with higher BMI z score at age 3 years.In this study, paternal BMI was associated with DNA methylation, birth weight, and childhood BMI z score in offspring.