tbuckley/cabot-search huggingface dataset:
miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells
Authors: Graziella Cimino-Reale, Paolo Gandellini, Francesca Santambrogio, Marta Recagni, Nadia Zaffaroni, Marco Folini
Journal: Journal of Hematology & Oncology (2017)

Understanding the molecular/cellular underpinnings of diffuse malignant peritoneal mesothelioma (DMPM), a fatal malignancy with limited therapeutic options, is of utmost importance for the fruitful management of the disease. In this context, we previously found that telomerase activity (TA), which accounts for the limitless proliferative potential of cancer cells, is prognostic for disease relapse and cancer-related death in DMPM patients. Consequently, the identification of factors involved in telomerase activation/regulation may pave the way towards the development of novel therapeutic interventions for the disease. Here, the capability of miR-380-5p, a microRNA negligibly expressed in telomerase-positive DMPM clinical specimens, to interfere with telomerase-mediated telomere maintenance and, hence, with cancer cell growth was assessed on preclinical models of DMPM. DMPM cells were transfected with a miR-380-5p synthetic precursor, and the effects of miRNA replacement were evaluated in terms of growing capability, induction of apoptosis and interference with TA. Reiterated weekly transfections were also performed in order to analyse the phenotype arising upon prolonged miR-380-5p reconstitution in DMPM cells. The ectopic expression of miR-380-5p elicited a remarkable inhibition of TA and resulted in DMPM cell growth impairment and apoptosis induction. In particular, we demonstrated for the first time that these effects were the result of a molecular circuitry converging on telomerase associated protein 1 (TEP1), where the miRNA was able to target the gene both directly in unconventional targeting modality and indirectly via p53 accumulation consequent to miRNA-mediated downregulation of testis-specific protein, Y-encoded-like 5 gene. Moreover, miR-380-5p did not cause telomere attrition and cell growth arrest in long-term DMPM transfectants, which in turn showed slightly elongated telomeres and molecular features (e.g. c-circle DNA and reduced expression levels of chromatin remodeler ATRX) resembling an alternative lengthening of telomeres (ALT) phenotype. miR-380-5p interferes with TA in DMPM cells by targeting TEP1. Notably, in the long-term setting, miR-380-5p-mediated impairment of TA did not result in telomere attrition. Instead, a phenotype reminiscent of ALT emerged in DMPM cells as possible compensatory pathway that safeguards DMPM cell growth, an event that may be regarded as a potential resistance mechanism to anticancer therapies based on telomerase inhibitors.
FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer
Authors: Shucai Yang, Yi Liu, Ming-Yue Li, Calvin S. H. Ng, Sheng-li Yang, Shanshan Wang, Chang Zou, Yujuan Dong, Jing Du, Xiang Long, Li-Zhong Liu, Innes Y. P. Wan, Tony Mok, Malcolm J. Underwood, George G. Chen
Journal: Molecular Cancer (2017)

The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC).One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results.NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial-mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction.FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.
Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult
Authors: Emma C. Morris, Thomas Fox, Ronjon Chakraverty, Rita Tendeiro, Katie Snell, Christine Rivat, Sarah Grace, Kimberly Gilmour, Sarita Workman, Karen Buckland, Katie Butler, Ronnie Chee, Alan D. Salama, Hazem Ibrahim, Havinder Hara, Cecile Duret, Fulvio Mavilio, Frances Male, Frederick D. Bushman, Anne Galy, Siobhan O. Burns, H. Bobby Gaspar, Adrian J. Thrasher
Journal: Blood (2017)
The role of infiltrating immune cells in dysfunctional adipose tissue
Authors: Tomasz J. Guzik, Dominik S. Skiba, Rhian M. Touyz, David G. Harrison
Journal: Cardiovascular Research (2017)

Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases. It is characterized by chronic low-grade inflammation and is observed in obesity, metabolic disorders such as insulin resistance and diabetes. While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFα, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT. These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes. Immune composition varies, depending on the stage and the type of pathology. Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity. The presence of inflammatory cells in AT affects adjacent tissues and organs. In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability. Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity. Anti-inflammatory and protective adiponectin is reduced. AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases. Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target.
Identification of Genetic Alterations Associated with Mutant IL7Ralpha in T-ALL
Authors: Gisele O. L. Rodrigues, Wenqing Li, Sarah Cramer, Livia W. Campos, Priscila P. Zenatti, Angelo A.B.A Laranjeira, Julie A. Hixon, Emilee Senkevitch, Caroline Andrews, Elda P. Noronha, Maria Pombo-de-Oliveira, Silvia Brandalise, Francisco P. Lobo, Jose Andres Yunes, Scott Durum
Journal: Blood (2016)
A Normalization-Free and Nonparametric Method Sharpens Large-Scale Transcriptome Analysis and Reveals Common Gene Alteration Patterns in Cancers
Authors: Qi-Gang Li, Yong-Han He, Huan Wu, Cui-Ping Yang, Shao-Yan Pu, Song-Qing Fan, Li-Ping Jiang, Qiu-Shuo Shen, Xiao-Xiong Wang, Xiao-Qiong Chen, Qin Yu, Ying Li, Chang Sun, Xiangting Wang, Jumin Zhou, Hai-Peng Li, Yong-Bin Chen, Qing-Peng Kong
Journal: Theranostics (2017)

Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption-both sensitive to heterogeneous values.Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods.Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both in vitro and in vivo, to be crucial in tumorigenesis, e.g., alcohol metabolism (ADH1B), chromosome remodeling (NCAPH) and complement system (Adipsin).Together, we present a sharper tool to navigate large-scale expression data and gain new mechanistic insights into tumorigenesis.
Long-term (8 years) assessment of trastuzumab-related cardiac events in the HERA trial.
Authors: Evandro De Azambuja, Marion Jennifer Procter, Dirk van Veldhuisen, Dominique Agbor-Tarh, Otto Metzger Filho, Jutta Steinseifer, Michael Untch, Ian E. Smith, Luca Gianni, Jose Baselga, Christian Jackisch, David A. Cameron, Richard Bell, Brian Leyland-Jones, Mitchell Dowsett, Richard D. Gelber, Martine J. Piccart-Gebhart, Thomas Suter
Journal: Journal of Clinical Oncology (2013)

525 Background: Trastuzumab-related cardiac dysfunction may occur in patients (pts) treated with adjuvant therapy and it is mostly reversible. We report the long-term outcome of pts with cardiac dysfunction treated with adjuvant trastuzumab (T) in the Herceptin Adjuvant (HERA) trial. Methods: HERA is a three-arm, randomized trial that compared 1 year or 2 years of T with observation (Obs) in women with HER2-positive early breast cancer (EBC). Eligible pts had a left ventricular ejection fraction (LVEF) ≥ 55% at study entry (i.e. after completion of (neo)adjuvant chemotherapy with or without radiotherapy). Cardiac function was closely monitored throughout the trial. This analysis at 8-year median follow-up considers pts randomly assigned to 1 year or 2 years of T therapy or observation. Results: 5102 pts were randomized to HERA. The “as treated” safety population is considered: 2 years T (N=1,673), 1 year T (N=1,682) and Obs (N=1,744). Cardiac events leading to T discontinuation in the 1-year and 2-year arms were observed in 5.2% and 9.4% of pts, respectively. Cardiac death, severe congestive heart failure (CHF) and confirmed significant LVEF drop remained low in all three arms (Table). In the 1 year T arm, 71.4% of pts with severe CHF, and 81.2% of pts with confirmed LVEF drop recovered cardiac function (at least 2 sequential LVEF assessments &gt; 50%). The median time to recovery was 9.7 months and 6.3 months, respectively. In the 2 years T arm, 87.5% of pts with confirmed LVEF drop recovered cardiac function and median time to recovery was 8.3 months. Conclusions: At 8-year median follow-up the incidence of cardiac events during adjuvant T remains low and these events are mostly reversible. These results confirm low cardiac events when T is given as part of the adjuvant therapy for pts with HER2-positive EBC. Clinical trial information: NCT00045032. [Table: see text]
Abstract 264: Beta3 Integrin Promotes Protein Ubiquitination and Prosurvival Signaling in Cardiomyocytes
Authors: Dorea L Pleasant, Kamala P Sundararaj, Sundaravadivel Balasubramanian, Dhandapani Kuppuswamy
Journal: Circulation Research (2013)

Cardiac hypertrophy occurs in response to stress, such as increased hemodynamic load. Upon hypertrophic stimulus, β3-integrin, a cell surface receptor that mediates nonreceptor tyrosine kinases (NTKs) and mammalian target of rapamycin (mTOR) signaling, undergoes activation. Using β3-integrin global knockout mice, our recent work shows that β3-integrin is required for mTORC2/ubiquitin-mediated prosurvival signaling during early pressure overload (PO). Also, attenuation of β3-integrin signaling during PO causes cardiomyocyte (CM) apoptosis and thus compromised ventricular function. Therefore, we hypothesized that β3-integrin is essential to ubiquitin-mediated prosurvival signaling in CM, with the involvement of key downstream players, such as NTKs, mTOR, E3 ligases, and apoptotic proteins. To generate CM-specific β3-integrin KO mice, cardiac troponin-T2 promoter (cTnT)-driven, reverse tetracycline-dependent transactivator (rtTA)-inducible Cre mice were crossed with β3-integrin-floxed mice. The resulting cTnT-rtTA-Cre/β3-integrin-floxed mice, were administered doxycycline (Dox) at 1 mg/ml for a period of 7 days before transverse aortic constriction (TAC) or Sham surgery. After 72 h PO, protein was isolated from left ventricle tissue and subjected to immunoblotting. Offspring from the above mating have been bred, genotyped and appropriate colonies have been established. PO-induced β3-integrin expression was lost in CM, but not in cardiac fibroblasts of transgenic mice. Furthermore, a robust reduction in protein Ub was also seen in these mice following Dox treatment and PO. Loss of downstream mediators of cardioprotective signaling is being explored in these transgenic mice. In conclusion, we have developed a mouse with CM-specific deletion of β3 integrin. Initial analysis also demonstrates a lack of protein Ub in isolated CM taken from these animals. Further PO studies will identify downstream mediators of β3-integrin essential to survival in cardiomyocytes. The information gained will identify targets and develop novel therapeutic methods to enhance and/or sustain cardioprotection and thereby prevent/delay maladaptive changes in hypertrophying myocardium.
Occurrence of familial malignant tumors in the first-degree relatives of patients with differentiated (non-medullar) thyroid carcinoma.
Authors: Rodica Mindruta-Stratan, Nicodim F. Belev, Erich M. Sturgis, Li Xu
Journal: Journal of Clinical Oncology (2013)

1567 Background: Family aggregation of thyroid cancer and aggregation of a number of "associated" malignant tumors in one family indicates a possible significant genetic predisposition and an increased risk for developing cancer in blood relatives of these families. Methods: Distribution of malignant tumors in first degree relatives of 1135 patients surgically treated for thyroid tumors during 3 years period was studied. These families don’t refer to hereditary syndromes. Patients were distributed in 3 groups: I group - 453 patients with thyroid carcinoma, II group - thyroid carcinoma on adenoma background (222) and III group - thyroid gland adenoma (460 probands). Results: In the I-st group from 2868 first degree relatives 870(64, 5±1.6%) was affected by cancer. From these: 49(3.9±2.8%) had thyroid cancer (TC), 39(3.1±2.8%) - gastric cancer (GC), 36(2.8±2.7%) - colorectal cancer (CRC), 26(2.05±2, 8%) - breast cancer (BC) and 20(1.6±2.8%) - endometrial cancer (EC). Thyroid adenoma was seen in 86(6, 6%) cases. Incidence of the TC was 23, GC- 11, CRC-5, and BC- 4, EC 12 times higher, respectively in compare with general population. From 1414 relatives (II group) 445(66, 1±2.2%) first degree relatives were affected by cancer. From these: 27(4.3±3.9%) - TC, 22(3.5±4.0%) - GC, 21(3.3±3.9%) - CRC, 14(2.2±4.1%) – BC and 5(0.8%) - EC. Thyroid adenoma was seen in 45(6.9±3.7%) cases. In III group - from 2945 investigated first degree relatives 924(66.6±1.5%) relatives were affected by cancer. From these: 44(3.4±2.7%) - TC, 37(2, 8±2.7%) - GC, 27(2.1±2.8%) - CRC, 34(2.6±2.7%) – BC and 19(1.5±2.8%) - EC. Thyroid adenoma represented 116(8, 6±2.6%) cases. Differences between groups are not statistically significant (p &lt;0,05). Conclusions: The results obtained by clinical and genetic research of non-medullar thyroid cancer patients and their first degree relatives are an important reason to direct the monitoring of these families for the risk assessment of hereditary predisposition to cancer, genetic testing, dynamic monitoring and performing of preventive interventions.
Comparison of the outcome between cervical adenocarcinoma and squamous cell carcinoma patients with adjuvant radiotherapy after radical surgery: SGSG/TGCU Intergroup Surveillance
Authors: M. Shimada, J. Kigawa, R. Nishimura, M. Hiura, M. Hatae, K. Takehara, A. Sato, H. Kurachi, H. Mizunuma, T. Sugiyama
Journal: Journal of Clinical Oncology (2009)

5585 Background: We conducted the present surveillance to clarify the significance of adjuvant radiotherapy and the cause of poor outcome of adenocarcinoma (AC). Methods: A total of 825 patients with FIGO stage Ib-IIb cervical cancer, who underwent type III radical hysterectomy in 10 institutes of SGSG/ TGCU Intergroup between April 1997 and March 2003, were enrolled in this study. There were 543 patients with squamous cell carcinoma (SCC) (261 in stage Ib1, 67 in Ib2, 83 in IIa, 132 in IIb) and 282 with AC (186 in stage Ib1, 39 in Ib2, 11 in IIa, 46 in IIb). Mean age of patients was 49.0 yrs (range: 19–84 yrs) in SCC and 46.6 yrs (range: 18–84) in AC. Two hundred and fifty-five patient with SCC and 69 with AC received adjuvant radiotherapy including CCRT. Results: The 5-year overall survival rate (OS) for patients with SCC and AC were 87.4% and 83.4%. The OS for stage I patients did not differ between SCC and AC. Stage II patients with AC showed significantly worse prognosis compared with SCC (54.5% vs. 87.4% in IIa, 63.3% vs. 78.8% in IIb). There was a significant difference in OS for patients receiving adjuvant treatment between SCC and AC (83.0% vs. 73.9%). Although the OS for stage I patients did not differ between SCC and AC, the OS for stage II patients with AC was significantly lower (86.9% vs. 50.0% in IIa, 75.5% vs. 61.1% in stage IIb). In patients with stage I, SCC showed significantly higher lymphnode involvement compared with AC (16.5% vs. 9.7% in Ib1, 46.3% vs. 20.1% in Ib2). The incidence of lymphnode involvement did not differ between SCC and AC in patients with stage II (36.4% vs.34.9% in IIa and 39.1% vs.45.5% in IIb). When patients had lymphnode involvement, the outcome of patients with AC showed significantly worse than those with SCC (46.4% vs. 72.3%). The local failure defined as recurrence in stump and pelvis was more frequent in patients with AC compared with SCC (24.6% vs.10.7%). Conclusions: Although the incidence of lymphnode involvement did not differ between AC and SCC, AC patients with lymphnode involvement showed significantly worse outcome. The present study indicates that lower sensitivity to radiotherapy might be an important cause for the poorer prognosis in AC. No significant financial relationships to disclose.
A piece of my mind. It's over, Debbie
Authors:  Name Withheld By Request
Journal: JAMA (1988)

A physician who describes himself or herself only as a gynecology resident in a large, private hospital writes in JAMA's "A piece of my mind" column about having administered a lethal dose of morphine to a terminally ill patient. The resident reports that the 20-year-old patient was dying of ovarian cancer, had not eaten or slept in two days, and was suffering from unrelenting vomiting. The resident, who had not seen the patient before, also writes that her only words at the time were "Let's get it over with."
Postremission Therapy with Repeated Courses of HD-Arac, Idarubicin and Limited Autologous Stem Cell Support Achieves a Very Good Long-Term Outcome in ELN Favourable and Intermediate-Risk AML Except in NPM-Mutated Patients Where Relapse May Occur Even after Five Years
Authors: Erika Borlenghi, Mirko Farina, Angela Passi, Chiara Pagani, Elisa Cerqui, Chiara Cattaneo, Vincenza Orlando, Marta Petullà, Angelo Belotti, Giuseppina Ruggeri, Giuseppe Rossi
Journal: Blood (2016)
Association of Clinical Factors With a Major Pathologic Response Following Preoperative Therapy for Pancreatic Ductal Adenocarcinoma
Authors: Jordan M. Cloyd, Huamin Wang, Michael E. Egger, Ching-Wei D. Tzeng, Laura R. Prakash, Anirban Maitra, Gauri R. Varadhachary, Rachna Shroff, Milind Javle, David Fogelman, Robert A. Wolff, Michael J. Overman, Eugene J. Koay, Prajnan Das, Joseph M. Herman, Michael P. Kim, Jean-Nicolas Vauthey, Thomas A. Aloia, Jason B. Fleming, Jeffrey E. Lee, Matthew H. G. Katz
Journal: JAMA Surgery (2017)

We previously demonstrated that a major pathologic response to preoperative therapy, defined histopathologically by the presence of less than 5% viable cancer cells in the surgical specimen, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma. However, to our knowledge, the patients most likely to experience a significant response to therapy are undefined.To identify clinical factors associated with major pathologic response in a large cohort of patients who underwent preoperative therapy and pancreatectomy for pancreatic ductal adenocarcinoma.Retrospective review of a prospectively maintained database at University of Texas MD Anderson Cancer Center. The study included 583 patients with histopathologically confirmed pancreatic ductal adenocarcinoma who received preoperative therapy prior to pancreatectomy between 1990 and 2015.Preoperative therapy consisted of systemic chemotherapy alone (n = 38; 6.5%), chemoradiation alone (n = 261; 44.8%), or both (n = 284; 48.7%) prior to pancreatoduodenectomy (n = 514; 88.2%), distal pancreatectomy (n = 62; 10.6%), or total pancreatectomy (n = 7; 1.2%).Clinical variables associated with a major pathologic response (pathologic complete response or <5% residual cancer cells) were evaluated using logistic regression.Among all patients, the mean (SD) age was 63.7 (9.2) years, and 53.0% were men. A major pathologic response was seen in 77 patients (13.2%) including 23 (3.9%) who had a complete pathologic response. The median overall survival duration was significantly longer for patients who had a major response than for those who did not (73.4 months vs 32.2 months, P < .001). On multivariate logistic regression, only age younger than 50 years, baseline serum cancer antigen 19-9 level less than 200 U/mL, and gemcitabine as a radiosensitizer were associated with a major response. The number of these positive factors was associated with the likelihood of a major response in a stepwise fashion (0, 7.5%; 1, 12.7%; 2, 16.9%; 3, 35.7%; P = .009).Although a major pathologic response occurs infrequently following preoperative therapy for pancreatic ductal adenocarcinoma, it is associated with a significantly improved prognosis. Of the patient- and treatment-related factors we analyzed, only young age, low baseline cancer antigen 19-9, and gemcitabine as a radiosensitizer were associated with a major pathologic response. Given its association with long-term survival, better predictors of response and more effective preoperative regimens should be aggressively sought.
efficacy of an Ask1 Inhibitor to Reduce Fibrosis and Steatosis in a Murine Model of Nash is Associated with Normalization of Lipids and Hepatic Gene Expression and a Reduction in Serum Biomarkers of Inflammation and Fibrosis : 1359
Authors: Satyajit Karnik, Michael R. Charlton, Li Li, Michelle Nash, Maisoun Sulfab, David Newstrom, Erik G. Huntzicker, Dorothy French, Zachary D. Goodman, Tracy Shafizadeh, Steve Watkins, David Breckenridge, Daniel Tumas
Journal: Hepatology (2015)