tbuckley/cabot-search huggingface dataset:
microRNAs and the expression of the progesterone receptor in breast cancer.
Authors: Ayelet Shai, Avital Gilam, Mariana Steiner, Noam Shomron
Journal: Journal of Clinical Oncology (2014)

e11529 Background: The progesterone receptor (PgR) is a prognostic factor in ER positive breast cancers treated by hormonal therapy and loss of PgR expression might be involved in resistance to hormonal treatment. The regulation of PgR has not been extensively studied. MicroRNAs regulate gene expression either at the mRNA or the protein translation level. Our hypothesis is that microRNA's are involved in the regulation of expression of PgR. Methods: RNA was extracted from ER positive, PgR positive and negative breast tumors and from adjacent benign tissue. The expression of PgR and microRNAs was assessed by RT-PCR. Later, a luciferase reporter assay was performed using the 3' UTR of the PgR gene (WT construct) and a site directed mutated construct in the microRNA binding sites. MicroRNAs were co-transfected with these constructs into MCF-7 cells and the levels luciferase activity was analyzed. Results: The PgR gene contains potential conserved binding sites for MicroRNAs 23a, 181a, 135a and 26b. Of these, miR- 23a and miR-181a showed inverse expression relative to the PgR mRNA and protein expression in normal and tumor tissue, as expected. The PgR mRNA was downregulated in tumors compared to adjacent benign tissues in 75% of samples. Mir-26b was upregulated in all tumor samples compared to adjacent tissue, and an inverse correlation was seen between the expression of mir-26b and the PgR mRNA. The Luciferase reported assay demonstrated reuced luciferase activity when mir-23a, mir-181a and mir-26b were co-transfected with a WT construct into MCF-7 cells, compared to the activity when co-transfected with a mutated construct. This suggests direct binding of these microRNA's to the PgR gene 3'UTR. Conclusions: We suggest that microRNAs regulate the level of the progesterone receptor in breast cancer. Our results might contribute to the understanding of the mechanisms leading to PgR loss and resistance to hormonal therapy. miR-181a miR-23a Tumor group RQ st-err ttest RQ st-err ttest PR PCR low, IHC- (n=3) 1 0.126 - 1 0.497 - PR PCR high, IHC- (n=4) 0.756 0.555 0.578 0.722 0.655 0.646 PR PCR high, IHC+ (n=4) 0.352 0.582 0.026 0.286 0.729 0.287
Phase II, open-label study of dabrafenib plus trametinib in patients with BRAF mutation-positive melanoma brain metastases: A GSK-sponsored trial.
Authors: Michael A. Davies, Karla D. Martins, Tracey Sessa, Suzanne Swann
Journal: Journal of Clinical Oncology (2014)

TPS9106 Background: Data from BREAK-MB (phase II, metastatic melanoma, BRAF V600 mutation positive, with brain metastases, dabrafenib monotherapy) demonstrated a 39.2% overall intracranial response rate and a 81.1% intracranial disease control in cohort A (no prior local therapy), and a 30.8% overall intracranial response rate and a 89.2% intracranial disease control in cohort B (previous local therapy). Median survival was 33.1 and 31.4 weeks for cohorts A and B, respectively. [Long G, et al. Lancet Oncol. 2012;13:1087-95]. Data from BRF113220 (phase I/II, metastatic melanoma, BRAF V600 mutation-positive, brain metastasis patients excluded, dabrafenib + trametinib) reported a median progression-free survival (PFS) of 9.4 months with dabrafenib 150mg BID and trametinib 2mg QD combination therapy (150/2), and 5.8 months with dabrafenib monotherapy (HR 0.39, p<0.0001). [Flaherty K, et al. N Engl J Med. 2012;367(18):1694-703] The median overall survival for the 150/2 therapy was 23.8 months compared with 20.2 months for dabrafenib monotherapy (HR 0.73, not significant). [Daud A, et al. Presented at the Society for Melanoma Research Congress, 2013]. This trial is expected to build the body of evidence regarding the safety and efficacy of dabrafenib plus trametinib combination therapy in patients with BRAF V600 mutation positive, unresectable melanoma brain metastases (MBM). Methods: This study will evaluate the safety and efficacy of 4 cohorts. A) V600E, asymptomatic MBM, no prior local therapy; B) V600E, asymptomatic MBM, prior local therapy; C) V600D/K/R, asymptomatic MBM, with or without prior local therapy; D) V600D/E/K/R, symptomatic MBM, with or without prior local therapy. Patients will receive dabrafenib 150 mg BID + trametinib 2 mg QD therapy. 120 patients will be enrolled beginning in January 2014. The primary objective of the study is intracranial response in cohort A patients. Secondary endpoints include; intracranial response in patients in cohorts B, C and D; intracranial disease control; extracranial response; overall response; duration of intracranial, extracranial and overall response; PFS; overall survival; and safety. Clinical trial information: NCT02039947.
CD4+ T cells in PBMC to predict the outcome of anti-PD-1 therapy.
Authors: Hiroshi Kagamu, Ou Yamaguchi, Ayako Shiono, Atsuto Mouri, Sachiko Miyauchi, Harue Utsugi, Fuyumi Nishihara, Takahiro Uchida, Yoshitake Murayama, Kunihiko Kobayashi
Journal: Journal of Clinical Oncology (2017)

11525 Background: Antibody blockade of programmed death 1 (PD-1), has led to durable responses and significant prolongation of overall survival in metastatic cancers including non-small cell lung cancer (NSCLC). However, in clinical trials, response rates were as low as 20 %, and approximately 50 % of the patients did not achieve benefits to prolong progression free survival. These results bring us a hypothesis that there are subgroups with distinct pre-existing anti-tumor immunity resulting in different responses to anti-PD-1 therapy. We reported that effector T cells, which are capable of mediating antitumor reactivity, are primed in LNs draining growing tumors and that these T cells exclusively belong to the T cells that down-regulated CD62L (CD62L low ) subpopulation. In the absence of purified tumor antigenic proteins or peptides on many tumors, the expression of the homing molecule CD62L on T cells may serve as a surrogate marker for identifying tumor-specific immune cells. Methods: We analyzed the peripheral blood mononuclear cells (PBMC) of 50 consecutive NSCLC patients who were planned to be treated with anti-PD-1 Ab, Nivolumab after obtaining written informed consent. The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. Results: The NSCLC patients who achieved partial response (PR) or stable disease (SD) had significantly (p = 4.1x10 -7 ) more CD62L low CD4 + T cells in PBMC than progressive disease (PD) patients. The percentages of CD62L low in CD4 + T cells provided sensitivity 92.9 %, and specificity 96.7 % to predict the patients who had PD. Moreover, SD patients had significantly (p = 0.0067) less regulatory T cell subpopulation than PR patients, thus, it was possible to predict PR from SD. Conclusions: These results show that the major differences in pre-existing immunity among PR, SD, and PD patients to anti-PD-1 Ab existed in CD4 + T cell balance between primed effector and regulatory T cells. Further characterization of CD62L low CD4 + T cells including mRNA microarray, checkpoint molecules, and chemokine receptors is going on.
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling
Authors: Samir Softic, Manoj K. Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T. O’Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B. Newgard, David E. Cohen, C. Ronald Kahn
Journal: Journal of Clinical Investigation (2017)

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
A phase 2 trial of ODM-201 maintenance therapy in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a AR targeting agent and non-progressive on a second line taxane (SAKK 08/16)
Authors: S. Gillessen, S. Hayoz, A. Fuhrer, C. Biaggi Rudolf, A. Pedrazzini, G. Procopio, R. Cathomas
Journal: Annals of Oncology (2017)
GW28-e0629 Interleukin 37 attenuates osteo-fibrotic responses mediated by the advanced glycation end-products modified low density lipoprotein in human aortic valve intersitial cells
Authors: Xi Yang, Qingchun Zeng, Jiaying Li, Tianyu Xu, Dingji Zhu, Dongqi An, Haobin Zhou, Zuheng Liu, Wanqiang Cai, Qiong Zhan, Wenyan Lai, Dingli Xu
Journal: Journal of the American College of Cardiology (2017)
A single-arm, phase ii study assessing the efficacy of pembrolizumab (pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC)
Authors: H.L. McArthur, C.A. Barker, A. Gucalp, L. Lebron Zapata, Y.H. Wen, A. Phung, M. Wilgucki, M. Henrich, B.B. Arnold, Z. Zhang, A. Ho
Journal: Annals of Oncology (2017)
Impact of duration of response (DOR) on overall survival (OS) in patients with metastatic melanoma treated with dacarbazine (DTIC), vemurafenib (V), or cobimetinib plus vemurafenib (C+V): a pooled analysis
Authors: K. Lewis, J. Larkin, A. Ribas, K.T. Flaherty, G.A. McArthur, P.A. Ascierto, B. Dréno, E. McKenna, Q. Zhu, Y. Mun, A. Hauschild
Journal: Annals of Oncology (2017)
Emergência de uma nova estirpe de MRSA adquirida na comunidade, na Alemanha
Authors: W Witte, C Cuny, B Strommenger, C Braulke, D Heuck
Journal: Eurosurveillance (2004)

A analise de Staphylococcus aureus resistente a meticilina (MRSA-c) produtores de leucocidina de Panton-Valentine adquiridos na comunidade, na Alemanha, mostra um padrao unico de macrorestriccao SmaI, diferente das estirpes epidemicas nosocomiais. Este padrao molecular e semelhante ao encontrado em estirpes de MRSA-c isoladas noutros paises da Uniao Europeia. Todos os isolamentos mostraram uma resistencia ao acido fusidico, o qual e codificado pelo gene far-1. Segundo os dados sobre a disseminacao geografica e a ocorrencia temporal, esta estirpe parece ter emergido na Alemanha no segundo semestre de 2002, o que sugere uma disseminacao ainda mais alargada. A emergencia de MRSA resistente ao acido fusidico e o primeiro indicio da emergencia de um clone de MRSA positivo para PVL.
Abstract #1391: MiR-221&222 enhance migration and invasiveness of NSCLC and hepatocarcinoma cells by targeting PTEN tumor suppressor
Authors: Michela Garofalo, Gianpiero Di Leva, Giulia Romano, Apolinaire Ngankeu, Sung-Suk Suh, Hannes Alder, Stefan Costinean, Mario Acunzo, Gerard Nuovo, Yuri Pekarsky, Gerolama Condorelli, Carlo Croce
Journal: Cancer Research (2009)

Lung and liver cancer are among the most deadly type of cancer. Despite improvements in treatment over the past few decades, survival in patients remains poor. MicroRNAs (miRNA) represent a novel class of small RNAs that function as negative regulators of gene expression, deeply involved in the pathogenesis and progression of several types of cancers. In our previous work we found that miR-221 and miR-222, are markedly upregulated in TRAIL-resistant and downregulated in TRAIL-sensitive non small cell lung cancer (NSCLC) cells. Our data indicated that miR-221 and -222 modulate TRAIL sensitivity in NSCLC mainly by interfering with p27 kip1  expression and TRAIL-induced caspase machinery. Here, we show that miR-221 and miR-222, are overexpressed in aggressive NSCLC and Hepatocarcinoma cells (Calu-1 and Snu-387 cells) as compared with less invasive (H460 and Sk-Hep1 cells) and/or normal lung and liver cell lines. In all 20 different cell lines tested we found an inverse relationship between the expression of miR-221 and miR-222 and the tumor suppressor PTEN. By bioinformatic analysis, we identified one binding site for miR-221&222 in the 39 untranslated region of the tumor suppressors PTEN mRNA, and we demonstrated, by luciferase assay and by western blot, that PTEN is a direct targets of miR-221/222. Besides modulating AKT pathway, and thus cell survival, PTEN down-regulation enhances invasiveness and cellular migration as assessed by migration and invasion assays,through the activation,evidenced by western blot, of the ERKs pathway. Moreover, by MTT, Annexin-FITC assay and caspase 3/7 activity, we found that miR-221&222 overexpression induce cell survival and TRAIL resistance both in NSCLC and Hepatocarcinoma cells through the down-regulation of PTEN protein and activation of Akt pathway. In vitro and in vivo functional studies such as the use of anti-miRs oligonucleotides, immunohistochemistry and  in situ  hybridization on 20 primary lung and liver tumor specimens, suggest that miR-221/222 can be regarded as oncogenes in those types of cancer, because they directly target and down-regulate the tumor suppressor PTEN. Furthermore, their overexpression might be an important factor contributing to TRAIL resistance and to invasiveness of NSCLC and Hepatocarcinoma cells.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1391.
Actividades de vigilância epidemiológica de doenças infecciosas, no Norte de Portugal, durante o EURO 2004
Authors: G Gonçalves, L Castro, A M Correia, Laurinda Queirós
Journal: Eurosurveillance (2005)

Decorreu em Portugal, entre 12 de Junho e 4 de Julho de 2004, o torneio de futebol EURO 2004. A Autoridade Regional de Saude do Norte cobre uma populacao de 3,2 milhoes de pessoas. Esta foi a regiao de Portugal onde decorreram mais jogos (doze). Descrevemos aqui as actividades de vigilância de doencas transmissiveis, nesta regiao de saude, durante o EURO 2004. Foram detectados 10 surtos de toxi-infeccoes alimentares, sete casos de doenca meningococica e um caso de doenca dos legionarios. Nenhum visitante foi afectado e nao parece que os casos verificados entre residentes tenham sido influenciados pela presenca de milhares de visitantes. Um padrao semelhante a este foi tambem observado noutros eventos de massas, nos quais tinham sido levadas a cabo actividades especiais de vigilância epidemiologica. Isto nao diminui a importância da vigilância de saude publica durante acontecimentos em que se juntam grandes multidoes. Para alem disso, a avaliacao destas actividades especiais de vigilância deveria constituir uma oportunidade para recolocar na agenda questoes relativas aos recursos, prioridades, organizacao e treino na area da vigilância de doencas transmissiveis.
Organ‐on‐a‐Chip Systems for Women's Health Applications
Authors: Janna Nawroth, Julia Rogal, Martin Weiss, Sara Y. Brucker, Peter Loskill
Journal: Advanced Healthcare Materials (2017)

Abstract Biomedical research, for a long time, has paid little attention to the influence of sex in many areas of study, ranging from molecular and cellular biology to animal models and clinical studies on human subjects. Many studies solely rely on male cells/tissues/animals/humans, although there are profound differences in male and female physiology, which can significantly impact disease mechanisms, toxicity of compounds, and efficacy of pharmaceuticals. In vitro systems have been traditionally very limited in their capacity to recapitulate female‐specific physiology and anatomy such as dynamic sex‐hormone levels and the complex interdependencies of female reproductive tract organs. However, the advent of microphysiological organ‐on‐a‐chip systems, which attempt to recreate the 3D structure and function of human organs, now gives researchers the opportunity to integrate cells and tissues from a variety of individuals. Moreover, adding a dynamic flow environment allows mimicking endocrine signaling during the menstrual cycle and pregnancy, as well as providing a controlled microfluidic environment for pharmacokinetic modeling. This review gives an introduction into preclinical and clinical research on women's health and discusses where organ‐on‐a‐chip systems are already utilized or have the potential to deliver new insights and enable entirely new types of studies.
Timing of onset of symptoms in people with idiopathic pulmonary fibrosis
Authors: Thomas Hewson, Tricia M McKeever, Jack E Gibson, Vidya Navaratnam, Richard B Hubbard, John P Hutchinson
Journal: Thorax (2017)

Little is known about when symptoms of idiopathic pulmonary fibrosis first develop. We identified incident cases of idiopathic pulmonary fibrosis-clinical syndrome (IPF-CS) from a UK primary care database and assessed the frequency of consultations for common symptoms in the 5 years prior to diagnosis. 1671 cases were identified with 5 years of data prior to diagnosis. Breathlessness was the most common symptom, followed by cough. Cases were significantly more likely than controls to experience these symptoms (p&lt;0.001), even 4–5 years before diagnosis (OR for breathlessness for this period 2.79, 95% CI 2.13 to 3.65). This suggests that some patients with IPF may be symptomatic for more than 5 years before diagnosis.
Association of polymorphic drug metabolizing enzymes (DME) with outcomes in breast cancer patients treated on the ECOG 2190/Intergroup 0121 (E2190/Int0121) study
Authors: P. P. Gor, R. J. Gray, M. Horn, T. R. Rebbeck, P. A. Gimotty, R. Aplenc, M. Pins, M. S. Tallman, A. DeMichele
Journal: Journal of Clinical Oncology (2007)

596 Background: Disparate outcomes of breast cancer patients after adjuvant chemotherapy may be influenced by variation in drug metabolism due to genetic polymorphisms in DME. Cyclophosphamide and thiotepa require activation by cytochrome P450 (CYP) and detoxification by glutathione-S-transferase, two highly polymorphic enzymes. We hypothesized that variants in CYP3A4(*1B), GSTM1 and GSTT1 would impact survival outcomes after adjuvant chemotherapy, with effects potentially modulated by chemotherapy dose. Methods: We performed a retrospective cohort study of patients enrolled on E2190/Int0121, a randomized trial of cyclophosphamide (C), doxorubicin (A), and fluorouracil (F) versus CAF + high dose chemotherapy (HDC) using cyclophosphamide and thiotepa followed by stem cell rescue; disease-free survival (DFS) and overall survival (OS) were equivalent in the clinical trial. PCR-based methods were used to genotype hematologic stem cells. Hazard ratios for genotypes were obtained using Cox regression. Results: Stem cell samples and clinical data from August 1, 1991 through August 1, 2005 were available for 347/540 of patients enrolled; 151 patients on CAF and 196 on CAF + HDC arms, respectively. Median follow-up was 9.8 years. See table . CYP3A4*1B allele carriers had significantly poorer DFS (HR 1.84) in the combined cohort and CAF arm (HR 1.87), but not in the HDC arm; OS was not significant by CYP3A4 genotype. GSTM1 null homozygotes in the combined cohort and HDC arm had significantly better DFS (HR 0.70 and 0.66, respectively) and OS (HR 0.67 and 0.57, respectively), but not in the CAF arm. GSTT1 null homozygotes had significantly worse DFS (HR 2.3) and OS (2.02) in the CAF arm, but not in the HDC arm or combined cohort. Conclusions: In the overall E2190/Int0121 cohort, polymorphisms in activating (CYP3A4*1B) and inactivating (GSTM1) DME significantly impact DFS and OS. The detrimental effect of GSTT1 in the CAF arm appears to be ameliorated by HDC. [Table: see text] No significant financial relationships to disclose.
GW28-e1161 Simultaneous transcatheter intervention for compound congenital heart disease: 10-year experience of a single center
Authors: Qiguang Wang, Xianyang Zhu, Duanzhen Zhang, Chuanju Hou, Chunsheng Cui, Po Zhang, Huoyuan Chen, Xiumin Han, Xiaotang Sheng, Lili Meng, Wang Shuang
Journal: Journal of the American College of Cardiology (2017)
Genetic landscape in HBOC families from Brazil: A mutational analysis
Authors: E. Dos Santos, B. Rossi, E.M.M. Santos, E. Rouleau, S.M. Caputo, C. Urbeteli de Sa, M.F. Sa Ribeiro, N.F. Vaz, B. Garicochea
Journal: Annals of Oncology (2017)
Proton pump inhibitor use associated with changes in gut microbiota composition
Authors: Kelly R Reveles, Caitlin N Ryan, Luisa Chan, Reese A Cosimi, Wanda L Haynes
Journal: Gut (2017)

We read with great interest the recent publications in Gut by Imhann et al and Jackson et al , which assessed the impact of proton pump inhibitor (PPI) use on gut microbiota diversity and composition in humans.1 2 PPIs are one of the most commonly used drug classes worldwide. Once initiated, they are often used chronically without clear therapeutic intent.3 PPIs alter GI pH4 and delay gastric emptying rate,5 which could directly affect gut microbiota and survival of enteric pathogens. Using three independent cohorts (211 PPI users and 1604 non-users), Imhann et al 1 reported a significant decrease in alpha diversity and changes in 20% of bacterial taxa in PPI users compared with non-users. Among 1827 healthy twins, Jackson et al 2 also found a significant decrease in alpha diversity and alteration of bacterial composition in PPI users. Notably, both studies found a higher abundance of oral commensals, including Streptococcaceae …
Preliminary results from subsets of patients (pts) with advanced gastric cancer (GC) and esophageal carcinoma (EC) in a dose-escalation/expansion study of BGB-A317, an anti-PD-1 monoclonal antibody (mAb)
Authors: J. Desai, M. Millward, Y. Chao, H. Gan, M. Voskoboynik, B. Markman, A. Townsend, V. Atkinson, A. Zhu, J. Song, Q. Qi, A. Kang, S. Deva
Journal: Annals of Oncology (2017)