tbuckley/cabot-search huggingface dataset:
COPD and cardiovascular diseases: now is the time for action!
Authors: Fernando Sergio Leitao Filho, Don D Sin
Journal: Thorax (2018)

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, responsible for 31% of all deaths and accounting for 18 million deaths annually.1 Chronic obstructive pulmonary disease (COPD), which is characterised by airflow limitation that is usually progressive and associated with persistent small airway inflammation, is an important (though frequently under-recognised) risk factor for CVDs.2 For example, the population attributable risk of COPD for mortality related to ischaemic heart disease is approximately 30%, independent of the effects of cigarette smoking.3 Indeed, some studies have shown that the risk imposed by COPD for CVDs may be as large as (if not larger than) those related to well-established CVD risk factors such as hypertension and hypercholesterolaemia.3 A more recent study showed that COPD is associated with increased risk of sudden cardiac deaths, with the risk increasing by more than threefold among patients with COPD who have a history of frequent exacerbations.4

In this issue of Thorax , Morgan and colleagues extend our current understanding of the relationship between COPD and CVDs by demonstrating that COPD is a significant risk factor for 12 different CVD conditions including angina, myocardial infarction (MI), heart failure, sudden cardiac arrest, atrial fibrillation, abdominal aortic aneurysm, peripheral arterial disease, pulmonary arterial hypertension, ischaemic stroke, haemorrhagic stroke and transient ischaemic attacks.5 Most importantly, they showed that the highest risks were observed among relatively young individuals with COPD (aged 35–54 years) with HRs related to …
Consequences of Asexuality in Natural Populations: Insights from Stick Insects
Authors: Jens Bast, Darren J Parker, Zoé Dumas, Kirsten M Jalvingh, Patrick Tran Van, Kamil S Jaron, Emeric Figuet, Alexander Brandt, Nicolas Galtier, Tanja Schwander
Journal: Molecular Biology and Evolution (2018)

Recombination is a fundamental process with significant impacts on genome evolution. Predicted consequences of the loss of recombination include a reduced effectiveness of selection, changes in the amount of neutral polymorphisms segregating in populations, and an arrest of GC-biased gene conversion. Although these consequences are empirically well documented for nonrecombining genome portions, it remains largely unknown if they extend to the whole genome scale in asexual organisms. We identify the consequences of asexuality using de novo transcriptomes of five independently derived, obligately asexual lineages of stick insects, and their sexual sister-species. We find strong evidence for higher rates of deleterious mutation accumulation, lower levels of segregating polymorphisms and arrested GC-biased gene conversion in asexuals as compared with sexuals. Taken together, our study conclusively shows that predicted consequences of genome evolution under asexuality can indeed be found in natural populations.
Neonatal Genistein Exposure and Glucocorticoid Signaling in the Adult Mouse Uterus
Authors: Shannon D. Whirledge, Edwina P. Kisanga, Robert H. Oakley, John A. Cidlowski
Journal: Environmental Health Perspectives (2018)

Background: Female reproductive tract development is sensitive to the endocrine-disrupting potential of environmental estrogens. Early-life exposure to the dietary phytoestrogen genistein impairs fertility and persistently alters the transcriptome in the oviduct and uterus of rodents. Glucocorticoid signaling, which has recently been shown to be essential for normal fertility in the female mouse uterus, is antagonized by genistein. Objective: Our goal was to determine whether early-life exposure to genistein disrupts glucocorticoid signaling in the mouse uterus, which may contribute to infertility. Methods: Female C57Bl/6 mice were exposed to either 50mg/kg per day genistein, 10μg/kg per day estradiol, or vehicle (corn oil) on postnatal days 1–5 (PND1–5), and then treated with the synthetic glucocorticoid dexamethasone (Dex: 1mg/kg) or vehicle (saline) on PND5, at weaning on PND21, or as adults on PND56 following adrenalectomy and ovariectomy to evaluate glucocorticoid responsiveness. Uteri were isolated following treatment for gene expression or chromatin immunoprecipitation. Results: Neonatal exposure to genistein altered the uterine transcriptome of adult mice and caused substantial changes to the transcriptional response to glucocorticoids. Although expression of the glucocorticoid receptor was not affected, genistein exposure disrupted glucocorticoid receptor recruitment to specific regulatory sites in target genes. Many genes involved in chromatin remodeling were dysregulated in genistein-exposed mice, suggesting that epigenetic reprograming may contribute to the altered glucocorticoid response of the uterus following early-life exposure to genistein. These changes affected the biological activity of glucocorticoids within the uterus, as glucocorticoids antagonized the proliferative effects of estradiol in the uterus of control mice but not genistein-exposed mice. Conclusions: Our findings suggest that disruption of glucocorticoid signaling due to early-life exposure to environmental estrogens may in part render the uterus unable to support implantation. https://doi.org/10.1289/EHP1575
Compliance with NCCN screening and chemoprevention recommendations among carriers of deleterious mutations in the adenomatous polyposis coli gene.
Authors: Syed Mohammad Ali Kazmi, Caitlin Mauer, Sara Pirzadeh-Miller, Elise Watson, Muhammad Shaalan Beg, Theodora S. Ross
Journal: Journal of Clinical Oncology (2018)

571 Background: Deleterious mutations in adenomatous polyposis coli gene (APC) lead to familial adenomatous polyposis [FAP] and attenuated FAP (aFAP) syndromes associated with hereditary colorectal cancer (CRC) and extra-colonic neoplasms. Reports suggest only two-third of such patients (pts) comply with recommended screening guidelines. The objective of this study was to assess compliance of FAP/aFAP pts with NCCN recommended guidelines of screening endoscopies and chemoprevention in our population. Methods: Retrospective review of clinical charts of pts with APC mutations, identified through multi-gene panel or single-gene testing, and seen in our NCI designated Comprehensive Cancer Center between 01/2013 and 09/2017. Results: Out of 53 pts with deleterious APC gene mutations, 31 pts (58.5%) had mutations associated with an FAP (27 pts; mean-age 31 years) or aFAP (4 pts, mean-age 33 years) phenotype and were included in analyses. Ten of these 31 pts (32.3%) were diagnosed with FAP after diagnosis of CRC; the rest had family history of FAP/aFAP. Documentation of total-colectomy was found in 17 pts (54.8%), 4 pts (12.9%) did not undergo colectomy and this information was unknown in 10 pts (32.3%). Colonoscopy/EGD after diagnosis of FAP/aFAP was documented in 22 pts (71.1%) while subsequent annual EGD/colonoscopy was documented only in 14 pts (45.1%); records were missing in 13 pts (41.9%). Extra-colonic secondary neoplasms such as duodenal polyps were documented in 8 pts, gastric polyps in 7 pts, desmoid tumor in 2 pts and malignant cancer of ampulla of Vater in 1 pt. Other malignant neoplasms, unrelated with FAP/aFAP, were reported in 3 pts (9.6%, 1 breast, 1 kidney and 1 endometrial cancer). Chemoprevention with sulindac was used in 3 pts (9.7%), 3 pts (9.7%) declined such treatment, 17 pts (54.8%) records were without evidence of this being discussed. Conclusions: The rate of compliance in FAP/aFAP pts with NCCN recommended screening and chemoprevention guidelines in our cohort was low but similar to prior literature. A multidisciplinary approach and interventions to improve compliance among pts are necessary to improve annual screening and chemoprevention rates.
Mapping human pluripotent stem cell differentiation pathways using high throughput single-cell RNA-sequencing
Authors: Xiaoping Han, Haide Chen, Daosheng Huang, Huidong Chen, Lijiang Fei, Chen Cheng, He Huang, Guo-Cheng Yuan, Guoji Guo
Journal: Genome biology (2018)

Human pluripotent stem cells (hPSCs) provide powerful models for studying cellular differentiations and unlimited sources of cells for regenerative medicine. However, a comprehensive single-cell level differentiation roadmap for hPSCs has not been achieved. We use high throughput single-cell RNA-sequencing (scRNA-seq), based on optimized microfluidic circuits, to profile early differentiation lineages in the human embryoid body system. We present a cellular-state landscape for hPSC early differentiation that covers multiple cellular lineages, including neural, muscle, endothelial, stromal, liver, and epithelial cells. Through pseudotime analysis, we construct the developmental trajectories of these progenitor cells and reveal the gene expression dynamics in the process of cell differentiation. We further reprogram primed H9 cells into naïve-like H9 cells to study the cellular-state transition process. We find that genes related to hemogenic endothelium development are enriched in naïve-like H9. Functionally, naïve-like H9 show higher potency for differentiation into hematopoietic lineages than primed cells. Our single-cell analysis reveals the cellular-state landscape of hPSC early differentiation, offering new insights that can be harnessed for optimization of differentiation protocols.
Lenalidomide Induces Ubiquitination and Degradation of CSNK1A1 in MDS with Del(5q)
Authors: Emma C. Fink, Jan Krönke, Slater N. Hurst, Namrata D. Udeshi, Tanya Svinkina, Rebekka K. Schneider, Marie E. McConkey, Marcus Järås, Lars Bullinger, Steven A. Carr, Benjamin L. Ebert
Journal: Blood (2014)
Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent
Authors: Josep M. Piulats, August Vidal, Francisco J. García-Rodríguez, Clara Muñoz, Marga Nadal, Catia Moutinho, María Martínez-Iniesta, Josefina Mora, Agnés Figueras, Elisabet Guinó, Laura Padullés, Àlvaro Aytés, David G. Molleví, Sara Puertas, Carmen Martínez-Fernández, Wilmar Castillo, Merce Juliachs, Victor Moreno, Purificación Muñoz, Milica Stefanovic, Miguel A. Pujana, Enric Condom, Manel Esteller, Josep R. Germà, Gabriel Capella, Lourdes Farré, Albert Morales, Francesc Viñals, Xavier García-del-Muro, Julián Cerón, Alberto Villanueva
Journal: Clinical Cancer Research (2018)

Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. ©2018 AACR.
Comparative effectiveness of nonsurgical therapies for localized hepatocellular carcinoma: Analysis of the National Cancer Database.
Authors: Devalkumar Rajyaguru, Andrew Borgert, Peter James Polewski, Angela Smith
Journal: Journal of Clinical Oncology (2018)

425 Background: Data guiding selection of optimal nonsurgical therapies for management of localized hepatocellular carcinoma (HCC) are lacking. Because there are limited prospective comparative data for these treatment modalities, we aimed to compare the effectiveness of chemotherapy (systemic or arterial directed) versus radiofrequency ablation (RFA) versus radioembolization (RE) in nonsurgically managed patients with stage I and II HCC using the National Cancer Database. Methods: We identified patients who received chemotherapy, RFA or RE for nonsurgically managed Stage I (T1N0M0) and II (T2N0M0) HCC between 2008 and 2013. Patients excluded included those who received upfront lobectomy or resection or extended lobectomy or hepatectomy or transplant, and if they had Ishak fibrosis score of 5-6 or total bilirubin &gt; 3 mg/dl or international normalized ratio (INR) of &gt; 3. Overall survival (OS) was compared between treatment groups using propensity score matched (1:1:1) and weighted analyses. We also verified balance of all available confounders, and assessed sensitivity to unobserved confounding. Results: Overall 2622 (73.2%), 837 (23.3%) and 125 (3.5%) patients with nonsurgically managed stage I and II HCC received chemotherapy, RFA and RE, respectively. RE treated patients tend to be older, live in the areas with a higher median income and higher percentage of high school- educated residents, and have stage II disease. The propensity matched cohort included 303 patients with baseline characteristics well balance between all arms. After propensity matching, 5-year OS was 17.4% (95% CI, 6.6% to 32.3%) in the chemotherapy group, 27.2% (95% CI, 14.2% to 42%) in the RFA group and 36.6% (95% CI, 23.1% to 50.1%) in RE group (p = 0.48). Conclusions: To our knowledge, this is the first study comparing various different nonsurgical therapies for localized HCC. All chemotherapy, RFA and RE are effective treatment options for nonsurgically managed patients with stage I and II HCC. Although these data are retrospective, RE appears to be a reasonable first-line treatment of nonsurgically managed stage I and II HCC in carefully selected patients.
Randomized study of intravesical chemotherapy using pirarubicin in patients with non-muscle-invasive bladder cancer in Japan: Comparing one immediate postoperative intravesical chemotherapy with short-term adjuvant intravesical chemotherapy after TURBT: Subanalysis in patients with intermediate risk.
Authors: Yoshio Naya, Kazuya Mikami, Natsuki Takaha, Koji Okihara, Tsuneharu Miki, Osamu Ukimura
Journal: Journal of Clinical Oncology (2017)

4536 Background: The objective is to evaluate the efficacy defining of 2-year tumor recurrence free rate of intravesical chemotherapy using pirarubicin (THP) for patients with intermediate risk. Methods: Between October 2010 and January 2015, 206 patients were enrolled in this study and finally 113 were randomized to one immediate postoperative intravesical instillation of THP 30mg (Group A), or additional intravesical instillation of THP 30mg weekly for 8 weeks after single postoperative instillation (Group B). The recurrent risk was stratified using EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2009 update. Of 113, 100 with intermediate risk were analyzed in this study. The patients were examined by cystoscopy and urine cytology every 3 months after trans urethral resection to determine bladder tumor recurrence. The primary endpoint was 2 year-recurrence-free survival rates. A statistical analysis was performed by SAS (SAS Institute Inc., Cary, USA). Results: The 2-year recurrence free survival rates were 66.2% in Group A and 86.1% in Group B, respectively (log rank test, p = 0.0043). In patients with recurrence score between 5 and 9, the 2-year recurrence free survival was 92.3% in Group B and 22.2% in Group A (log rank test, p = 0.0013). Cox regression analysis revealed that only additional instillation of THP was significant independent factor for recurrence free rate in patients with intermediate risk. There was no patient with progression during this period. Frequent adverse effects were frequent urination and micturition pain without severe adverse effect (Grade 3 or more). Limitation of this study is a failure to enroll sufficient number for statistical analysis. Conclusions: Additional instillation of THP 30mg weekly for 8 weeks reduced the risk of tumor recurrence without severe toxicity in NMIBC patients with intermediate recurrent risk.
Safety and tolerability of 5-FU, irinotecan (IRI), and nab-paclitaxel (FOLFIRABRAX) with genotype-guided dosing of IRI in previously untreated patients with advanced gastrointestinal (GI) malignancies.
Authors: Smita Suhas Joshi, Theodore G. Karrison, Daniel V.T. Catenacci, Jaclyn D Peterson, Mark Zalupski, Brooke Elizabeth Phillips, Ahad Ali Sadiq, Amikar Sehdev, James Lloyd Wade, Vincent J. Picozzi, Andrea Louise Amico, Mark Kozloff, Blase N. Polite, Hedy L. Kindler, Manish Sharma
Journal: Journal of Clinical Oncology (2018)

423 Background: 5-FU, IRI, and nab-paclitaxel (NP) are active in advanced GI cancers; the combination (FOLFIRABRAX) has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in patients with this allele may be warranted. Primary objective: to determine the dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary objectives included determining objective response rates (ORR) in GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 patients (pts) received initial IRI doses of 180, 135, and 90mg/m 2 , respectively. 5-FU 2400mg/m 2 over 46 hours (no bolus), leucovorin 400mg/m 2 , and NP 125mg/m 2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay &gt; 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype would allow for an α level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs being tolerable. Results: 39 pts are evaluable for toxicity: 23 pancreatic cancer (PC), 6 gastroesophageal cancer (GE), 9 biliary tract cancer (BTC), 1 neuroendocrine. DLTs were observed in 4/20 (20%) *1/*1 pts, 1/15 (7%) *1/*28 pts, and 0/4 *28/*28 pts. DLTs were Gr 3 diarrhea (2 pts), Gr 3 nausea (2), and Gr 3 FN (1). ORR is 6/29 (21%), with responses in PC (3/17 evaluable pts, 18%) and GE (3/5 pts, 60%), but no responses in BTC (0/7 pts). Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. There is activity in PC and GE but not in BTC. Accrual is ongoing to the 3 genotype cohorts to a goal of 51 pts. Study conducted by the University of Chicago Personalized Cancer Care Consortium Clinical trial information: NCT02333188.
Results from a phase III trial (GRID) evaluating regorafenib (REG) in metastatic gastrointestinal stromal tumour (GIST): Subgroup analysis of outcomes based on pretreatment characteristics.
Authors: Heikki Joensuu, Paolo Giovanni Casali, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Gordon Leahy, Margaret von Mehren, Giuseppe Badalamenti, Martin E. Blackstein, Axel Le Cesne, Patrick Schoffski, Robert G. Maki, Jian-Ming Xu, Toshirou Nishida, Christian Kappeler, Iris Kuss, George D. Demetri
Journal: Journal of Clinical Oncology (2013)

10551 Background: REG, an oral receptor kinase inhibitor with activity against KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced GIST following failure of at least imatinib (IM) and sunitinib (SU). To understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based on sex, age, and mitotic index of primary GIST tissue, as well as duration and number of lines of previous therapies. Methods: Adult pts with metastatic GIST (n=199) progressing after at least IM and SU were randomized 2:1 to receive oral REG 160 mg or PL once daily for the first 3 weeks of each 4-week cycle. Subgroup analysis of centrally assessed PFS was performed, based on sex, age (&lt;65, ≥65 years), mitotic index of primary GIST (&lt;5, ≥5 to &lt;10, ≥10 mits/50 hpf), duration of IM and SU treatment (&lt;6, ≥6 to &lt;18, ≥18 months), and number of prior anticancer treatment lines (2 or ≥3). Mitotic index data on primaries were available for 119 patients. Results: REG demonstrated improvement in PFS vs PL in all subgroups, as summarized in the Table. Conclusions: REG had substantial efficacy in all patient subgroups included in this analysis. Clinical trial information: NCT01271712. [Table: see text]