tbuckley/cabot-search huggingface dataset:
Abstract 11691: Atorvastatin Reverses Impaired Voltage-gated K <sup>+</sup> Channels-mediated Coronary Vasodilation By Upregulating PPARγ In Diabetes <i>(Best of Basic Science Abstract)</i>
Authors: Wen Su, Wei-Ping Li, Miao Chen, Hui Chen, Hong-Wei Li
Journal: Circulation (2015)

Aims: Voltage-gated K + (K v ) channels in vascular smooth muscle cells (VSMCs) play an important role in the regulation of coronary microcirculation. Atorvastatin (ATV) has shown some beneficial effects on vascular function, but the effect of ATV on K v channels-mediated coronary vasodilation remains unknown. The present study was designed to investigate the role of ATV in improving K v channels-mediated coronary dilator function in diabetes and the underlying mechanisms. Methods: Isolated VSMCs were incubated in normal or high glucose medium plus a different dose of ATV for 24 h at 37 o C. Patch-clamp recording and molecular biological techniques were used to assess the function and expression of K v channels. Control or type 2 diabetic rats were treated with ATV (50 mg/kg daily) by oral gavage for 10 weeks. Vasodilation of isolated rat coronary arteries was measured using a pressurized myograph. GW9662, the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, was used to determine whether the mechanism of ATV-improved K v channel function can be explained by upregulation of PPARγ pathway. Results: Patch-clamp analysis revealed that high glucose reduced K v current density by 58.7 ± 4.6%, which was accompanied by a downregulation of K v 1.2 and K v 1.5 expression. Treatment with ATV reversed the inhibitory effect of high glucose on K v current density in a dose-dependent manner (1 μmol/L, 15.0 ± 2.6%; 10 μmol/L, 49.1 ± 3.8%; 100 μmol/L, 69.9 ± 4.8%; P &lt; 0.05). In addition, ATV restored high glucose-induced downregulation of K v channel protein expression, and the difference was significant in both 10 μmol/L and 100 μmol/L groups. For in vivo study, K v channels-mediated coronary vasodilation was decreased in diabetic rats, compared with controls (9.1 ± 1.3 vs. 36.7 ± 1.4%, P &lt; 0.05), whereas this decrease was partly corrected by ATV (25.0 ± 2.8 vs. 9.1 ± 1.3%, P &lt; 0.05). Treatment with ATV prominently increased protein expression of PPARγ both in vitro and in vivo . The effect of ATV in regulating K v channels and K v channels-mediated vasodilation was markedly blunted by GW9662. Conclusions: In conclusion, treatment with ATV activates PPARγ pathway and preserves K v channel activity in VSMCs, thus providing improvement of coronary dilator function in diabetic rats.
MicroRNA Gene Regulation in Extremely Young and Parallel Adaptive Radiations of Crater Lake Cichlid Fish
Authors: Paolo Franchini, Peiwen Xiong, Carmelo Fruciano, Ralf F Schneider, Joost M Woltering, Christopher Darrin Hulsey, Axel Meyer
Journal: Molecular Biology and Evolution (2019)

Abstract Cichlid fishes provide textbook examples of explosive phenotypic diversification and sympatric speciation, thereby making them ideal systems for studying the molecular mechanisms underlying rapid lineage divergence. Despite the fact that gene regulation provides a critical link between diversification in gene function and speciation, many genomic regulatory mechanisms such as microRNAs (miRNAs) have received little attention in these rapidly diversifying groups. Therefore, we investigated the posttranscriptional regulatory role of miRNAs in the repeated sympatric divergence of Midas cichlids (Amphilophus spp.) from Nicaraguan crater lakes. Using miRNA and mRNA sequencing of embryos from five Midas species, we first identified miRNA binding sites in mRNAs and highlighted the presences of a surprising number of novel miRNAs in these adaptively radiating species. Then, through analyses of expression levels, we identified putative miRNA/gene target pairs with negatively correlated expression level that were consistent with the role of miRNA in downregulating mRNA. Furthermore, we determined that several miRNA/gene pairs show convergent expression patterns associated with the repeated benthic/limnetic sympatric species divergence implicating these miRNAs as potential molecular mechanisms underlying replicated sympatric divergence. Finally, as these candidate miRNA/gene pairs may play a central role in phenotypic diversification in these cichlids, we characterized the expression domains of selected miRNAs and their target genes via in situ hybridization, providing further evidence that miRNA regulation likely plays a role in the Midas cichlid adaptive radiation. These results provide support for the hypothesis that extremely quickly evolving miRNA regulation can contribute to rapid evolutionary divergence even in the presence of gene flow.
Factors impacting time to diagnosis in pediatric, adolescent and young adult (AYA) patients with solid tumors.
Authors: Elysia Marie Alvarez, Lena Winestone, Jeffrey McPheeters, Diane Puccetti, Jennifer Jill Wilkes, Henry J. Henk, Smita Bhatia, Jill P. Ginsberg, Theresa Keegan, Brad H. Pollock
Journal: Journal of Clinical Oncology (2019)

e21515 Background: While cancer is the leading cause of non-accidental death in children and AYAs, factors associated with delays in diagnosis in young patients with cancer are poorly understood; we sought to fill this knowledge gap. Methods: Using the OptumLabs Data Warehouse’s claims data for commercially insured enrollees in a large US health plan—we identified pediatric [0-14 years (y)] and AYA (15–39 y) patients diagnosed with soft tissue sarcomas (STS), bone tumors (BT) and germ cell tumors (GCT) during 2001–17 and continuously enrolled 6 months prior to diagnosis. Time to diagnosis was calculated as days between first medical encounter associated with a possible cancer symptom and diagnosis date. Median times from first symptom to diagnosis were compared using Wilcoxon Rank Sum test. Multivariable logistic regression identified sociodemographic and clinical factors associated with longer time ( &gt; 3 months) from symptom to diagnosis. Results: Of the 11,395 patients, 86% presented to medical care with symptoms prior to diagnosis [STS: 2,228 (89%); BT: 1,565 (87%); GCT: 5,904 (84%)]. The most common symptoms were pain and swelling. STS had the longest median days to diagnosis (92), followed by BT (91) and GCT (49). There was a significant difference (p &lt; 0.001) in median days to diagnosis by age for BT (0–14y: 69; 15–21y: 77; 22–39y: 105) and GCT (0–14y: 96; 15–21y: 34; 22–39y: 49), but not for STS. Patients in households with ≥ a college degree (OR 1.96, 95% CI 1.06–3.64, vs &lt; high school) and seeing a specialist (excluding oncologists) (OR 2.54, CI 2.03–3.19, vs primary care) at first symptom presentation was associated with a longer delay, while older age (22–39y: OR 0.77, CI 0.63–0.94, vs 0-14y) and male sex (OR 0.58, CI 0.51–0.66) were associated with a shorter delay in diagnosis. Conclusions: This study demonstrates that, in a commercially insured population, time to diagnosis varies by cancer type and is impacted by clinical and sociodemographic factors. Shorter time to diagnosis may represent delays in presenting to medical care or more acute presentations of symptoms, therefore patient-reported symptoms and barriers to care data should be collected to better define strategies to reduce delays in diagnosis.
Efficacy and tolerability of FOLFOX6 as first-line treatment for advanced gastric and esophagogastric junction cancers (AGC): A single-center experience.
Authors: Rozana Abdul Rahman, MinYuen Teo, Felicity McDonnell, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2012)

e14705 Background: There are a number of options for first line treatment for AGC. We sought to review the efficacy and tolerability of FOLFOX (F) in AGC, and compare outcomes with anthracycline-based (A) ctx-treated patients (pts). Methods: Pts with AGC treated with F and A (EOX and ECF) were identified from institutional database. Pt. demographics, disease characteristics and treatment details were extracted from medical charts and pharmacy database. Progression-free survival (PFS) and overall survival (OS) were calculated from commencement of ctx to radiographic evidence of progression and death, respectively, estimated with the Kaplan-Meier method. Comparisons were made via log-rank method. Other descriptive statistics calculated via t-test or chi-square methods as appropriate. Results: Between July 05 and December 11, 27 pts were treated with F. Twenty-one (77.8%) were male and median age was 68yrs (range: 42 – 77). ECOG performance status was 0 -1 in 24 pts (88.9%) and 2 in 3 (11.1%). Median Charlson score prior to metastatic disease was 2 (range: 0 – 3). Three had relapsed disease and another three had locally-advanced disease. Sites of metastatic disease were liver (12), peritoneum (12), non-regional nodes (2) and lungs (2). Median number of cycles of F was 5 (range: 1 - 12), 51.8% of pts completed ≥10 cycles, while the rest discontinued treatment due to disease progression (33%) and toxicities (14.8%). 21 pts (77.8%) required dose reduction and 17 (63%) experienced treatment delay. Fourteen (51.8%), 6 and 2 pts had 2 nd , 3 rd and 4 th line of ctx, respectively. Median PFS was 7.2 mos and median OS is 9.7 mos. Sixteen pts were treated with A. Pts were significantly younger (p=0.002) but other characteristics were similar. Median PFS with A was 6.6 mos and median OS was 9.2 mos. The hazard ratio (F vs A) for PFS was 1.11 (95% CI 0.56 to 2.18, p = 0.77) and for OS was 0.73 (95% CI 0.36 to 1.51, p = 0.40). Conclusions: Despite an older pts cohort with co-morbidities, high percentage of treatment delays and dose reductions, our data suggest that significant percentage of pts were able to complete ≥10 cycles of F and subsequent therapies. Outcomes are comparable to our A cohort and published data.
The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity
Authors: Yuichiro Itoh, Lisa C. Golden, Noriko Itoh, Macy Akiyo Matsukawa, Emily Ren, Vincent Tse, Arthur P. Arnold, Rhonda R. Voskuhl
Journal: Journal of Clinical Investigation (2019)

Multiple sclerosis (MS) is a putative T cell–mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4+ T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model showed higher expression in XX compared with XY. Deletion of Kdm6a in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell–mediated autoimmune disease experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.
Neoadjuvant chemotherapy without a fixed number of cycles in advanced ovarian cancer not candidates for optimal primary surgery.
Authors: Cesar Mendiola, Ray Manneh, Tomas Pascual, Guillermo De Velasco, Estela Vega, Luis Manso, Ismael Ghanem, Eva M. Ciruelos, J, Seoane, Hernan Cortes-Funes
Journal: Journal of Clinical Oncology (2012)

e15552 Background: Neoadjuvant chemotherapy (N-CT) is a valid alternative for patients with advanced ovarian cancer (AOC) getting similar survival rates to primary debulking surgery (PDS) followed by chemotherapy (CT), with less postoperatory complications (Vergote et al N Engl J Med 2010;363:943-53). Our objective was to evaluate the results of N-CT with a flexible number of cycles according to the clinical and biological evolution of the patients. Methods: 22 patients with stage IIIC-IV AOC, diagnosed by laparoscope or cytology (no primary laparotomy) were registered between January 2007 and September 2011 and treated with N-CT including paclitaxel 175 mg/m2 and carboplatin AUC 6-5 every 3 weeks. The number of cycles of N-CT was dictated by the clinical response, CT scan and CA125 that could allow an interval debulking surgery (IDS) with intent of optimal cytoreduction (R0). After IDS consolidation chemotherapy treatment was given to complete a total of at least 8 cycles. Results: Median age 63.7 years (40 – 80). Histologic types: serous 28%, adenocarcinoma not specified 66%, endometrioid 4.5%. FIGO stage IIIC 57%, IV 43%, Median CA125 at diagnosis: 1744 U (157 – 14483). Mean N-CT cycles 7.8 (4-23). 90.1 % of patients responded before IDS, 2 patients progressed before surgery. Mean CA125 after N-CT was 20.5 U (9-108). 54% of patients achieved complete resection of all macroscopic disease during IDS (R0). 5/22 (22.7%) obtained a pathological complete response (pCR) (no microscopic tumour in all specimens removed). Complications in the postoperatory occurred in 2 patients consisting in suture dehiscence. The range of total number of CT cycles were as follows: &lt;6: 4.54%; 7-8: 31.8%; 9-10: 31.8%, &gt;10: 31.8%. With a mean follow-up of 22.4 months (4 - 57.6), 50% patients live without recurrence. Median PFS has not been reached. Conclusions: N-CT according to clinical and biologic response and not to a fixed number of cycles is an useful tool for patients with stage IIIC-IV AOC not candidates for optimal /R0 PDS, getting a high proportion of patients with optimal /R0 IDS. The complications of IDS are also very limited. pCR as surrogate marker for long-term survival in other tumours, has to be evaluated in AOC.
Prognostic factors for adult single cord blood transplantation among European and Japanese populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study
Authors: Junya Kanda, Hiromi Hayashi, Annalisa Ruggeri, Fumihiko Kimura, Fernanda Volt, Satoshi Takahashi, Myriam Labopin, Shinichi Kako, Karina Tozatto-Maio, Shingo Yano, Guillermo Sanz, Naoyuki Uchida, Maria Teresa Van Lint, Seiko Kato, Mohamad Mohty, Edouard Forcade, Heiwa Kanamori, Jorge Sierra, Yuju Ohno, Riccardo Saccardi, Takahiro Fukuda, Tatsuo Ichinohe, Minoko Takanashi, Vanderson Rocha, Shinichiro Okamoto, Arnon Nagler, Yoshiko Atsuta, Eliane Gluckman
Journal: Leukemia (2019)
Spontaneous tumor apoptosis, caspase 3 and the survival outcome in medulloblastoma patients treated by postoperative radiotherapy and chemotherapy
Authors: F. Santek, L. Markulin-Grgic, R. Kusec
Journal: Journal of Clinical Oncology (2007)

14136 Background: The role of apoptosis in neurooncology is still an unexplored area. Only a small number of studies which have combined clinically relevant data and treatment modalities, with the apoptotic activity have been published. Methods: The influence of spontaneous tumor apoptosis and its potential regulators caspase 3, BAX, p53 and bcl-2 was analyzed in 30 medulloblastoma patients with a long follow-up period, after the treatment at the Clinic of Oncology and Radiotherapy by postoperative radiotherapy with or without postirradiational chemotherapy. The mean apoptotic and mitotic index ratio (AI/MI) was measured in all tumor samples obtained by the initial neurosurgical procedure. Results: Significantly different survival groups of adequately treated patients were found only if the apoptotic indexes measured by the morphometrical analyzes (AIM) had been correlated with the TUNEL-essay results (AIT) in the same tumor sample, (log rank test=2.0287, p=0.04). The mean apoptotic index measured in the described combined way had slightly higher values AIM+T=38.2±20.3 (median=32.0), than when measured only by morphometrical analysis AM=23.9±24.9 (median=15.0). In the multivariate analysis according, the most relevant variables were the disease free interval (p&lt;0.001) and the number of CT cycles (0.005&lt;p&lt;0.01). Further parameters of significance were the modality of postoperative radiotherapy, and the general condition of patients measured according to the WHO grading system at the end of treatment (p&lt;0.001) as well as on the late controls, ater completion of the treatment (p&lt;0.001) Conclusions: Our expirience in evaluating the metodology of apoptotic index measurement has confirmed the advantage of combined method of detection of the apoptotic index AIM+T over the use of each of the described methods alone. The apoptotic index has shown a significant influence on survival of the medulloblastoma patients only when divided with the mitotic index MI. Using clinical data of our medulloblastoma patients, the index of apoptosis alone as a prognostic factor has not appeared to be of significant relevance. No significant financial relationships to disclose.
Frequent mutations of genes predisposing to Rho GTPase signal activation and autophagy inhibition in metastatic soft tissue sarcoma unveiled by paired somatic and germline genomic analyses.
Authors: Katsuhito Takahashi, Ayako Motoki, Jun Yashima, Noriyuki Masaki, Hiroko Sano, Hiromasa Yamamoto, Junichi Sou, Yuko Takahashi, Shinichi Toyooka, Yu Oyama, Hiroaki Nomori, Hiroyuki Narahara, Junko Yotsumoto, Yasuo Ono, Makoto Tonsho, Satoshi Teraoka
Journal: Journal of Clinical Oncology (2019)

11071 Background: Soft tissue sarcoma (STS) is well-known rare cancer with few therapeutic options. Although recent genomic analyses of sarcoma revealed few somatic mutations, massive copy number variations (CNV) and chromoplexy which correlate with worse clinical outcomes, their molecular and genomic mechanisms remain to be understood. Methods: We recruited 116 patients (102 female and 14 male, mean age 50, 80 LMS, 14 LPS, 3 AS and others) and performed whole exome sequencing with the methods as reported in ASCO2018. In addition to somatic mutations, we evaluated germline and CNV contributions in tumor to find LOH mutations by Strelka and Virmid analysis softwares. Results: Of the total of 135-4717 (mean 1129) mutations in tumors, 3-111 (mean 32) mutations were found in 595 COSMIC genes including both somatic and LOH mutations. Less than 33% LOH in the total of somatic and LOH mutations significantly correlated with improved 5-year survival rate as compared with patients with more LOH (81% vs 52%, P=0.01). Among the 224 genes reported in somatic mutations of sarcoma, damaging mutations in ARHGAPs, Rho GTPase signal inactivating genes, were most frequently detected in 59% of total (n=116) and 63% of leiomyosarcoma (n=80) patients as in somatic and/or LOH mutations. Patients with ARHGAP mutations were significantly reduced 5-year survival rates as compared with patients without mutation (51% vs 76%, P=0.007). Among the 163 genes involved in autophagy, a key silencing process for active RhoGTPase, one or more damaging mutations as in somatic and/or LOH mutations were found in 87% in total and 96% in leimyosarcoma patients. Conclusions: Our results, for the first time, suggest an important role of mutations in genes involved in Rho GTPase and autophagy signaling, both well known regulator of chromosomal stability, invasion and metastasis of tumor cells, and thus implicate a potential therapeutic target in STS.
Predicting Major Adverse Events in Patients With Acute Myocardial Infarction
Authors: Thomas Nestelberger, Jasper Boeddinghaus, Desiree Wussler, Raphael Twerenbold, Patrick Badertscher, Karin Wildi, Òscar Miró, Beatriz López, F. Javier Martin-Sanchez, Piotr Muzyk, Luca Koechlin, Benjamin Baumgartner, Mario Meier, Valentina Troester, Maria Rubini Giménez, Christian Puelacher, Jeanne du Fay de Lavallaz, Joan Walter, Nikola Kozhuharov, Tobias Zimmermann, Danielle M. Gualandro, Eleni Michou, Eliska Potlukova, Nicolas Geigy, Dagmar I. Keller, Tobias Reichlin, Christian Mueller, Benjamin Hafner, Dayana Flores, Kathrin Meissner, Caroline Kulangara, Michael Freese, Stefan Osswald, Claudia Stelzig, Roland Bingisser, Carolina Isabel Fuenzalida Inostroza, Esther Rodríguez Adrada, Ewa Nowalany-Kozielska, Damian Kawecki, Jiri Parenica, Eva Ganovská, Jens Lohrmann, Melissa Amrein, Jana Steude, Andreas Buser, Karin Grimm, Beate Hartmann, Beata Morawiec, Katharina Rentsch, Arnold von Eckardstein, Ewalina Biskup, Isabel Campodarve, Joachim Gea
Journal: Journal of the American College of Cardiology (2019)
Re: van Dijk et al: Half-dose photodynamic therapy versus high-density subthreshold micropulse laser treatment in patients with chronic central serous chorioretinopathy: The PLACE trial Reply
Authors: E.H.C. van Dijk, S. Fauser, M.B. Breukink, R. Blanco-Garavito, J.E.E. Keunen, J.M.M. Groenewoud, P.J.H. Peters, G. Dijkman, E.H. Souied, R.E. Maclaren, G. Querques, S.M. Downes, C.B. Hoyng, C.J.F. Boon
Journal: Ophthalmology (2019)
Molecular subsets of male breast carcinoma in southern Brazil
Authors: M. S. Graudenz, L. M. Silva, N. V. Toscani, A. M. Freitas, M. Caleffi
Journal: Journal of Clinical Oncology (2007)

21167 Background: Molecular profiling can identify subsets of breast cancers with different tumor behavior. There is few data regarding breast cancer in males, since it's an uncommon disease, accounting for less then 1% of all malignancies in man. Treatment and prognosis are often extrapolated from female breast cancer, but differences and/or similarities between these two diseases are not well established. The aim of this study is to report the molecular profile defined by immunohistochemistry (IHC) of male breast carcinoma (MBC) in southern Brazil. Methods: We reviewed 25 cases of MBC diagnosed between January 1993 and December 2006. Retrieved data included disease stage, tumor grade, size, and lymphnode status. IHC was performed with the following primary antibodies: ER (Novocastra), Cytokeratin 5/6, Cytokeratin 8/18 (DAKO, Carpinteria, CA), HER1 (DAKO) and HER2 (CB11 clone, DAKO). Results were scored by IHC according to established criteria in the literature. The study was approved by the institutional Ethics Committee. Results: Patient's median age at diagnosis was 66 years-old (44–84 yrs). All cases were invasive ductal carcinoma of no special type except for one lobular carcinoma. Median tumor size was 2.5cm (0.6–5.2cm). IHC was performed in 17 cases. The overall frequency of ER positivity was 82% (14/17); CK5/6 11.8% (2/17); CK8/18 94.1% (16/17); HER1 23.56% (4/17) and HER2 17.6% (3/17). Using the whole panel of antibodies we determined that 11 cases (64.7%) were of the ER+/luminal phenotype, 3 (17.6%) of the HER2 overexpressing, 2 (11.7%) of the normal breast like and 1 (5.9%) tumor of the basal phenotype (HER1+ and CK5/6-). Conclusions: Male breast carcinoma presents similar expression profiling frequencies to that of female breast carcinomas. To our knowledge, this is the largest series of male breast cancer ever studied in Brazil. Despite intrinsic gender differences, breast carcinoma may share common tumor biology characteristics in males and females. No significant financial relationships to disclose.