tbuckley/cabot-search huggingface dataset:
Depletion of Endothelial Prolyl Hydroxylase Domain Protein 2 and 3 Promotes Cardiomyocyte Proliferation and Prevents Ventricular Failure Induced by Myocardial Infarction
Authors: Qiying Fan, Hua Mao, Aude Angelini, Cristian Coarfa, Matthew J. Robertson, William R. Lagor, Xander H.T. Wehrens, James F. Martin, Xinchun Pi, Liang Xie
Journal: Circulation (2019)
Serine-Glycine-One-Carbon Metabolism: The Hidden Achilles Heel of <i>MYCN</i>-Amplified Neuroblastoma?
Authors: Aida Rodriguez Garcia, Marie Arsenian-Henriksson
Journal: Cancer Research (2019)

Abstract In this issue of Cancer Research, Xia and colleagues show that MYC-induced metabolic reprograming results in dependency on the serine-glycine-one-carbon (SGOC) metabolic pathway in neuroblastoma. This occurs through MYCN and ATF4 activation of the SGOC biosynthetic pathway in MYCN-amplified cells. Furthermore, inhibition of de novo serine synthesis generates metabolic stress in MYCN-amplified neuroblastoma cells, causing cell-cycle arrest and autophagy. Together, these data suggest that the SGOC pathway is an attractive therapy target in neuroblastoma. See related article by Xia et al., p. 3837
Patients with rheumatoid arthritis facing sick leave or work disability meet varying regulations: a study among rheumatologists and patients from 44 European countries
Authors: Polina Putrik, Sofia Ramiro, Francis Guillemin, Márta Péntek, Francisca Sivera, Tuulikki Sokka, Maarten de Wit, Anthony D Woolf, Angela Zink, Daina Andersone, Florian Berghea, Irena Butrimiene, Sandra Brouwer, Karen Cassar, Paraskevi Charalambous, Roberto Caporali, Elena Deseatnicova, Nemanja S Damjanov, Axel Finckh, Oliver FitzGerald, Gerður Gröndal, Nino Gobejishjvili, Piotr Gluszko, Marco Hirsch, Igor Jovanovic, Jiří Vencovský, Xavier Janssens, Andras P Keszei, Maria Kovarova, Mart Kull, Luís Cunha Miranda, Miroslav Mayer, Snezana Misevska - Percinkova, Nevsun Inanc, Oleg Nadashkevich, Ingemar F Petersson, Kari Puolakka, Bernadette Rojkovich, Helga Radner, Fruzsina Szabados, Gleb Slobodin, Ivan Shirinsky, Nikolay Soroka, Prodromos Sidiropoulos, Russka Shumnalieva, Sekib Sokolovic, Surayo Shukurova, Argjend Tafaj, Matija Tomšič, Till Uhlig, Suzanne M M Verstappen, Annelies Boonen
Journal: Annals of the Rheumatic Diseases (2019)

Objectives To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system’s performance, across European countries. Methods We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. Results Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (β=−0.5 (95% CI −0.9 to −0.2) and β=−0.5 (95% CI −1.0 to −0.1), respectively). The Scandinavian and Bismarckian system scored best on patients’ and rheumatologists’ perceptions of regulations and system performance. Conclusions There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country’s wealth.
Aprepitant (AP) versus dexamethasone (D) for preventing delayed emesis induced by anthracyclines plus cyclophosphamide (A+C) chemotherapy (CT) in breast cancer patients (pts): A double-blind, multicenter, randomized study.
Authors: Fausto Roila, Enzo Ballatori, Alessandra Fabi, Sonia Fatigoni, Silvana Chiara, Maria Teresa Ionta, Michele Aieta, Mario Clerico, Maria Angela Palladino, Monica Indelli, Ornella Garrone, Sara Bustreo, Benedetta Ruggeri
Journal: Journal of Clinical Oncology (2013)

9614 Background: A combination of AP + a 5-HT3 receptor antagonist + D and AP alone is recommended, respectively, for the prophylaxis of acute and delayed emesis induced by A+C CT in breast cancer pts. In the registrative study the role of AP in delayed emesis was not defined because prophylaxis of acute emesis was different between the two arms, and the superiority of AP on delayed emesis could be the consequence of a dependent effect on the different results achieved in acute phase. Aim of this study was to compare the efficacy of AP versus D in preventing delayed emesis in pts receiving the same prophylaxis of acute emesis. Methods: A randomized double-blind study comparing AP versus D was completed in naive breast cancer pts treated with A+C. Before CT, all pts were treated with intravenous palonosetron 0.25 mg and D 8 mg, and oral AP 125 mg. On days 2 and 3 pts randomly received D 4 mg bid or AP 80 mg qd. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2 - 5 after CT. Results: From September 2009 to July 2012, 580 pts were enrolled; 551 were fully evaluated, 273 in arm D and 278 in arm AP. Day 1 complete response rates were similar: 239/273 (87.6%) in D arm and 236/278 (84.9%) in AP arm. From day 2-5, complete response was the same with both antiemetic prophylaxes (79.5%), and all secondary endpoints (complete protection, total control, no vomiting, no nausea, score of FLIE) assumed similar values. During the delayed phase, incidence of insomnia (2.9% vs. 0.4%) and heartburn (8.1% vs. 3.6%) was significantly superior in D arm. Conclusions: In breast cancer pts submitted to A+C CT and receiving the same antiemetic prophylaxis for acute emesis, D and AP present similar efficacy and toxicity. Clinical trial information: NCT 00869973.
Suppression of thymidine phosphorylase expression by promoter methylation
Authors: C. Blanquicett, V. Guarcello, F. Naguib, M. el Kouni
Journal: Journal of Clinical Oncology (2007)

21100 Background: Thymidine phosphorylase (TP), an important enzyme in the pyrimidine salvage pathway, is also responsible for the activation of capecitabine (CAPE), a 5-FU prodrug. TP expression has been associated with response to CAPE. The regulatory mechanisms of TP expression in human tumor cells remain unclear. Since promoter methylation of CpG sites is a known mechanism of reversible silencing of gene expression, we investigated whether TP promoter methylation is involved in the regulation of TP expression. Methods: TP mRNA levels were determined in 5 cancer cells (SKBR-3, 786-O, HT-29, MDA-231, DLD-1) by Real- Time Quantitative PCR (RT-Q-PCR).The degree of methylation in these cells was identified by examining methylated CpG sites with restriction PCR and bisulfite sequencing. To analyze the TP promoter region, two fragments were PCR amplified from genomic DNA. Minimal promoter activity was determined by Luciferase reporter assays, and DNA-protein interactions were evaluated by Electrophoretic Mobility Shift Assays (EMSA). Results: SKBR-3 cells showed high TP expression, while DLD-1 cells did not express TP, as confirmed by examination of TP mRNA, protein, and enzyme activity. 786-O, HT29, and MDA-231 cells demonstrated intermediate TP expression. Methylation in the promoter, intron 1 and exon1 regions of the TP gene in SKBR-3 was lacking, while in DLD-1 cells, extensive promoter methylation was observed. Treatment of DLD-1 and SKBR-3 cells with the methylation-inhibitor, 5-aza-2-dC, resulted in a concentration-dependent increase in TP mRNA as well as protein levels in DLD-1 but not SKBR-3 cells. Trichostatin-A (TSA), a histone deacetylase inhibitor, improved the 5-aza-2dC induced TP reactivation. Gel shift assays demonstrated that methylation of the TP promoter significantly inhibited transcription factor binding. Supershift Analyses suggest that the Sp1 transcription factor has a role in the regulation of TP expression and to a lesser degree, so does Sp3. Conclusions: These results establish methylation of site-specific CpG in the TP promoter to be a putative mechanism of down-regulated TP expression in cancer cells. Insight into the TP regulatory mechanisms may have implications in CAPE therapy optimization and in modulating prognosis of cancer patients treated with CAPE. No significant financial relationships to disclose.
NAFLD-Associated Comorbidities in Advanced Stage HCC Do Not Alter the Safety and Efficacy of Yttrium-90 Radioembolization
Authors: Clemens Schotten, Lars P. Bechmann, Paul Manka, Jens Theysohn, Alexander Dechêne, Amr El Fouly, Francesco Barbato, Ursula Neumann, Sonia Radünz, Svenja Sydor, Dominik Heider, Marino Venerito, Ali Canbay, Guido Gerken, Ken Herrmann, Heiner Wedemeyer, Jan Best
Journal: Liver Cancer (2019)

Patients with advanced hepatocellular carcinoma (HCC) arising in nonalcoholic fatty liver disease (NAFLD) may not be suitable for systemic therapy due to metabolic syndrome-related diseases. Recent trials did not show a survival benefit of radioembolization (RE) compared to sorafenib in advanced stage HCC but RE may represent an adequate alternative in patients with contraindications to systemic therapy due to its favorable safety profile.To investigate the impact of NAFLD-related comorbidities on safety and efficacy of RE for HCC treatment in a retrospective monocentric cohort study.Safety and efficacy of RE were evaluated in patients with NAFLD-associated HCC. Hepatitis B virus (HBV)-related HCC patients served as controls, exhibiting matching Barcelona Liver Cancer Clinic (BCLC) stages while showing significantly fewer metabolic comorbidities.Overall, 87 HCC patients with NAFLD (mean age 71.3 ± 6.9 years) and 62 HCC patients with HBV (mean age 58.8 ± 10.9 years) not amenable to surgical or conventional locoregional treatments were included. Patients with HBV-related HCC had a comparable liver function to HCC patients with NAFLD. RE treatment-related toxicity did not differ between the two groups (increase in bilirubin Common Terminology Criteria for Adverse Events grade in 29 [38.7%] NAFLD and 20 [39.2%] HBV patients, p = 0.91). Overall survival was similar in HCC patients with NAFLD and HBV (11.1 [interquartile range, IQR, 18.27] vs. 9.3 months [IQR 14.73], p = 0.38), also in the subgroup analyses of BCLC B and C stages.RE showed similar survival outcomes at a comparable toxicity profile in HCC patients with NAFLD and HBV. NAFLD-associated metabolic comorbidities did not exhibit limitations for RE while offering comparable therapeutic efficacy as compared to HBV patients.
Comparison of predictors of survival in colon and rectal cancer patients.
Authors: Ying Margie Tang, Nneoma Olivia Okoronkwo, Neal Patel, Victor Tsu-Shih Chang, Trent P Wang, Tanganyika Barnes, Basil Kasimis, Monica McPherson, Barbara Crump, Fengming Zhong
Journal: Journal of Clinical Oncology (2013)

e14681 Background: We studied comorbidity and other predictors of survival for patients (pts) with colorectal cancer (CRC) and compared pts with colon (C) vs rectal (R) cancer (ca). Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, Hemoglobin (HGB), and Albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts with C vs R ca. Results: There were 279 men. 191 pts (68.5%) had C ca and 88 pts (31.5%) had R Ca. The two groups were similar for stage, grade, age, HGB, CEA, ALB, and ECOG PS. For R ca pts, Median (M) CCI is 3.7 (0.4-13.9), M CIRS15 2.5 (0-5), M CIRS16 5 (0-13), M CIRS 17 2.0 (0-8), M CIRS18 0 (0-1), M CIRS19 0 (0-1), and M KFI 1 (0-3). For C ca pts, M CCI is 4.3 (0.9-19.6), M CIRS15 3.0 (0-6), M CIRS16 6.0 (0-13), M CIRS17 2.0 (0-9), M CIRS18 0 (0-1), M CIRS19 0 (0-2), and M KFI 2 (0-3). In univariate analysis, stage, ECOG PS, HGB, and ALB were significant survival predictors in R ca pts. Age, stage, grade, ECOG PS, HGB, CCI, CIRS16, CIRS17, CIRS19 and KFI were significant for C ca pts. Other significant multivariate predictors are summarized in the table. R ca pts are more likely to die (P=0.003, HR=0.51). Conclusions: In this larger population of pts with CRC, we confirmed our previous findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 are important independent survival predictors for veterans with CRC. Age, grade, stage, ECOG PS, CCI, CIRS 16 and CIRS 19 are independent predictors for colon ca pts. Only Stage and ECOG PS are independent predictors for rectal ca pts. Rectal ca pts are at increased risk of dying. More research is needed to confirm this. Supported by New Jersey Commission for Cancer Research. [Table: see text]
Publisher Correction: Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues
Authors: Marina Cella, Ramya Gamini, Cristiane Sécca, Patrick L. Collins, Shanrong Zhao, Vincent Peng, Michelle L. Robinette, Jorge Schettini, Konstantin Zaitsev, William Gordon, Jennifer K. Bando, Kentaro Yomogida, Victor Cortez, Catrina Fronick, Robert Fulton, Lih-Ling Lin, Susan Gilfillan, Richard A. Flavell, Liang Shan, Maxim N. Artyomov, Michael Bowman, Eugene M. Oltz, Scott A. Jelinsky, Marco Colonna
Journal: Nature Immunology (2019)
Acupuncture as Adjunctive Therapy for Chronic Stable Angina
Authors: Ling Zhao, Dehua Li, Hui Zheng, Xiaorong Chang, Jin Cui, Ruihui Wang, Jing Shi, Hailong Fan, Ying Li, Xin Sun, Fuwen Zhang, Xi Wu, Fanrong Liang
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> The effects of acupuncture as adjunctive treatment to antianginal therapies for patients with chronic stable angina are uncertain. <h3>Objective</h3> To investigate the efficacy and safety of acupuncture as adjunctive therapy to antianginal therapies in reducing frequency of angina attacks in patients with chronic stable angina. <h3>Design, Setting, and Participants</h3> In this 20-week randomized clinical trial conducted in outpatient and inpatient settings at 5 clinical centers in China from October 10, 2012, to September 19, 2015, 404 participants were randomly assigned to receive acupuncture on the acupoints on the disease-affected meridian (DAM), receive acupuncture on the acupoints on the nonaffected meridian (NAM), receive sham acupuncture (SA), and receive no acupuncture (wait list [WL] group). Participants were 35 to 80 years of age with chronic stable angina based on the criteria of the American College of Cardiology and the American Heart Association, with angina occurring at least twice weekly. Statistical analysis was conducted from December 1, 2015, to July 30, 2016. <h3>Interventions</h3> All participants in the 4 groups received antianginal therapies as recommended by the guidelines. Participants in the DAM, NAM, and SA groups received acupuncture treatment 3 times weekly for 4 weeks for a total of 12 sessions. Participants in the WL group did not receive acupuncture during the 16-week study period. <h3>Main Outcomes and Measures</h3> Participants used diaries to record angina attacks. The primary outcome was the change in frequency of angina attacks every 4 weeks from baseline to week 16. <h3>Results</h3> A total of 398 participants (253 women and 145 men; mean [SD] age, 62.6 [9.7] years) were included in the intention-to-treat analyses. Baseline characteristics were comparable across the 4 groups. Mean changes in frequency of angina attacks differed significantly among the 4 groups at 16 weeks: a greater reduction of angina attacks was observed in the DAM group vs the NAM group (difference, 4.07; 95% CI, 2.43-5.71;<i>P</i> &lt; .001), in the DAM group vs the SA group (difference, 5.18; 95% CI, 3.54-6.81;<i>P</i> &lt; .001), and in the DAM group vs the WL group (difference, 5.63 attacks; 95% CI, 3.99-7.27;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Compared with acupuncture on the NAM, SA, or no acupuncture (WL), acupuncture on the DAM as adjunctive treatment to antianginal therapy showed superior benefits in alleviating angina. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT01686230
Risk Factors Associated with Development of Extramedullary Disease in Multiple Myeloma
Authors: Martin Stork, Sabina Sevcikova, Marta Krejci, Zdenek Adam, Viera Sandecka, Vladimir Maisnar, Jakub Radocha, Ivan Spicka, Jan Straub, Jiri Minarik, Tomas Pika, Alexandra Jungova, Evzen Gregora, Petr Pavlicek, David Vrabel, Jiri Jarkovsky, Lucie Brozova, Tomas Jelinek, Roman Hajek, Ludek Pour
Journal: Blood (2018)
Compositional analyses reveal correlations between taxon-level gut bacterial abundance and peripheral T cell marker expression in African infants
Authors: Bryan P. Brown, Heather B. Jaspan
Journal: Gut Microbes (2019)

Although exclusive breastfeeding has been linked to lower rates of postnatal HIV transmission compared to nonexclusive breastfeeding, mechanisms underlying this are unclear. Across a longitudinally sampled cohort of South African infants, we showed that exclusively breastfed (EBF) infants had altered gut bacterial communities when compared to nonexclusively breastfed (NEBF) infants, as well as reduced peripheral CD4 + T cell activation and lowered chemokine and chemokine receptor expression in the oral mucosa. We further demonstrated that the relative abundance of key taxa was correlated with peripheral CD4 + T cell activation. Here, we supplement those findings by using compositional data analyses to identify shifts in the abundance of several Bifidobacteria strains relative to select strains of Escherichia, Bacteroides, and others that are associated with the transition to NEBF. We illustrate that the abundance ratio of these taxa is tightly correlated with feeding modality and is a strong predictor of peripheral T cell activation. More broadly, we discuss our study in the context of novel developments and explore future directions for the field.
Perceptions of Surgery Residents About Parental Leave During Training
Authors: Maria S. Altieri, Arghavan Salles, Lisa A. Bevilacqua, L. Michael Brunt, John D. Mellinger, Jessica C. Gooch, Aurora D. Pryor
Journal: JAMA Surgery (2019)

<h3>Importance</h3> To our knowledge, there has been little research conducted on the attitudes of residents toward their pregnant peers and parental leave. <h3>Objective</h3> To examine the perceptions of current surgery residents regarding parental leave. <h3>Design, Setting, and Participants</h3> A 36-item survey was distributed to current US general surgery residents and residents in surgical subspecialties through the Association of Program Directors in Surgery listserv and social media platforms. Questions were associated with general information/demographics, parental leave, having children, and respondents' knowledge regarding the current parental leave policy as set by the American Board of Surgery. The study was conducted from August to September 2018 and the data were analyzed in October 2018. <h3>Main Outcomes and Measures</h3> Main outcomes included the attitudes of residents toward pregnancy and parental leave, parental leave policy, and the association of parental leave with residency programs. <h3>Results</h3> A total of 2188 completed responses were obtained; of these, 1049 (50.2%) were women, 1572 (75.8%) were white, 164 (7.9%) were Hispanic/Latinx, 75 (3.6%) were African American, 2 (0.1%) were American Indian or Alaskan Native, 263 (12.7%) were Asian, and 5 (0.2%) were Native Hawaiian or Pacific Islander. From the number of residents who had/were expecting children (581 [28.6%]), 474 (81.6%) had or were going to have a child during the clinical years of residency. Many residents (247 [42.5%]) took fewer than 2 weeks of parental leave. Many residents did not feel supported in taking parental leave (177 [30.4%] did not feel supported by other residents and 190 [32.71%] did not feel supported by the faculty). Only 83 respondents (3.8%%) correctly identified the current American Board of Surgery parental leave policy. Residents who took parental leave identified a lack of a universal leave policy, strain on the residency program, a loss of education/training time, a lack of flexibility of programs, and a perceived or actual lack of support from faculty/peers as the top 5 biggest obstacles to taking leave during the clinical years of residency. <h3>Conclusions and Relevance</h3> Most of the modifiable factors that inhibit residents from having children during residency are associated with policies (eg, a lack of universal leave policy and lack of flexibility) and personnel (eg, a strain on the residency program and lack of support from peers/faculty). These data suggest that policies at the level of the Accreditation Council for Graduate Medical Education or Resident Review Committee (RRC), as well as education and the normalization of pregnancy during training, may be effective interventions.
Association of cyclin D2 downregulation with adverse prognostic factors and survival: Analysis of D-type cyclins, cyclin E1, p27, and ki-67 mRNA in breast carcinomas.
Authors: Helena Brizova, Marcela Mrhalova, Roman Kodet
Journal: Journal of Clinical Oncology (2013)

e22208 Background: In a normal mammary gland D-type and E1 cyclins play a significant role in the cell cycle control. Not surprisingly, they are considered to have an oncogenic potential and belong among the most commonly overexpressed genes in breast cancer. Besides, cyclin D2 overexpression is associated with an inhibition of cyclin D1 phosphorylation and with an increase of the p27 inhibitor. Such a complex cell cycle regulation is realized at the quantitative level and results in the proliferation activity control. Therefore, we analyzed the molecules involved in the cell cycle regulation together with the proliferation marker Ki-67 at the quantitative level. Methods: We examined cyclin D1, D2, D3, E1, and p27 and Ki-67 mRNA level by qRT-PCR in 95 fresh frozen invasive ductal breast carcinomas and in 15 non-neoplastic breast tissues. In patients with the carcinoma we correlated the mRNA levels with the ERBB-2 positivity, estrogen and progesterone receptor status, proliferation rate, cyclin D1 protein expression, CCDN1 gene amplification, grade, lymph node status, tumor size and age at diagnosis. We looked for a correlation with overall survival and time to event in 70 patients with available long term follow-up data. Results: The only significant association found in this analysis related to cyclin D2. In comparison with non-neoplastic controls we observed cyclin D2 mRNA down-regulation in breast carcinomas and it was inversely correlated with a higher tumor grade and its greater size, which are considered as parameters related to a less favorable prognosis. Moreover, cyclin D2 mRNA down-regulation together with cyclin D1 and D3 up-regulation revealed a significant association with decreased overall survival and time to event in multivariate analysis. Conclusions: The data indicate that down-regulated cyclin D2 mRNA correlates with a greater malignant potential of breast carcinoma. Thus, establishing cyclin D2 mRNA level may be used as a prognostically relevant investigation and along with other prognostically related data it has a potential in helping to identify patients with an adverse prognosis. Support CZ.2.16/3.1.00/24022 and 00064203.