tbuckley/cabot-search huggingface dataset:
Association of NOTCH1 mutations in pediatric T-cell acute lymphoblastic leukemia with treatment relapse and expression of genes relevant to chemotherapy response
Authors: Amanda Gedman, Yubin Ge, Katherine LaFiura, Meenakshi Devidas, Stephen Linda, Jeffrey Taub, Larry Matherly
Journal: Cancer Research (2007)

1796  Recent reports have identified high frequency gain-of-function mutations in the heterodimeric NOTCH1 receptor in T-cell acute lymphoblastic leukemia (T-ALL). Although this suggests an important role for NOTCH1 signaling in the molecular pathogenesis of this disease, the prognostic significance of these findings remains controversial. In this report, we explore the association between NOTCH1 mutations in T-ALL, treatment failure, and expression of individual genes relevant to T-ALL chemotherapy and encoding metabolizing enzymes, transporters, drug targets, or apoptosis proteins. Lymphoblast RNAs from a case-control population of 40 T-ALL patients [21 relapsed within 4 y (cases), 19 did not relapse (controls)] were analyzed by RT-PCR and DNA sequencing to identify mutations in NOTCH1 heterodimerization (HD) and PEST domains, reported to be mutation “hot spots”. Transcript levels were measured by real-time RT-PCR for (a) ABCG2, (b) ABCC1, (c) ABCC2, (d) ABCC3, (e) ABCC4, (f) ABCC5, (g) asparagine synthetase, (h) BCL2, (i) BCL-XL, (j) dihydrofolate reductase (DHFR), (k) folylpolyglutamate synthetase, (l) glucocorticoid receptor, (m) human reduced folate carrier, (n) hypoxanthine phosphoribosyl transferase (HPRT), (o) MDR1, (p) topoisomerase 2 α (TOP2A), and (q) topoisomerase 2 β (TOP2B). NOTCH1 mutations were detected in 14 patients (6 HD, 3 PEST, and 5 HD plus PEST together) including point mutations, deletions and insertions. Wild type NOTCH1 sequence was detected in 26 patients. There was no difference in the frequency of relapse between groups of patients (8/14) who harbored NOTCH1 mutations and those who did not (13/26). However, for the 23 children treated with a single (POG8704) protocol, NOTCH1 mutations were associated with a reduced incidence of relapse (3/13 cases and 6/10 controls harbored NOTCH1 mutations). Mutated NOTCH1 was associated with 2-7-fold decreased transcript levels for ABCG2, ABCC1, ABCC4, DHFR, BCL-XL, HPRT, TOP2A, and TOP2B. Our results imply that the presence of NOTCH1 mutations confers a good prognosis in pediatric T-ALL, however, this appears to be protocol dependent. NOTCH1 mutations result in decreased expression of genes that impact chemotherapy sensitivity, thereby influencing the effectiveness of therapy, depending on the drug combinations employed.
3D organotypic models of ductal carcinoma in situ (DCIS): Models for assessing stromal effects on progression to invasion and increased proteolysis
Authors: Christopher Jedeszko, Mansoureh Sameni, Galia Blum, Matthew Bogyo, Bonnie Sloane
Journal: Cancer Research (2008)

396  Most breast cancers progress from morphologically distinct pre-invasive lesions (DCIS) to invasive carcinomas. Often, sites of transition from DCIS to invasive carcinoma are characterized by a breakdown of the basement membrane and an increased number of stromal cells and cytokines. We have sought to mimic in vitro the in vivo tumor microenvironment through organotypic co-cultures in which comedo type DCIS cells derived from MCF-10A human breast epithelial cells (MCF10.DCIS.com) are grown in a three dimensional (3D) co-culture of reconstituted basement membrane (rBM) with either normal human breast fibroblasts, or human breast myoepithelial cells. We also analyzed the effects of co-culture with HGF over-secreting fibroblasts in order to mimic the elavated levels of HGF often found within the activated breast tumor microenvironment. Along with these contact co-cultures, conditioned media from tumor-stimulated stromal cultures was used to evaluate effects on DCIS morphology, growth, progression to invasion and proteases thought to be involved in ECM turnover. Live images of co-cultures revealed that both fibroblast lines migrated actively, whereas DCIS cells formed stationary disorganized spheroids that eventually connected with neighboring structures. In co-culture with HGF-secreting fibroblasts, DCIS cells formed dynamic structures that developed invasive foci and degraded the rBM. By adding myoepithelial cells, we can reciprocate in vivo morphology in which the myoepithelial cells form a single layer surrounding luminal epithelial cells. Myoepithelial co-culture with DCIS cells reversed or delayed DCIS progression by inhibiting disorganized growth and the onset of invasive foci. A novel confocal microscope based proteolysis assay was used to show that conditioned media of fibroblasts and myoepithelial cells increased and decreased, respectively, the degradation of both type I and type IV collagen by DCIS cells. Employing cysteine cathepsin selective activity-based probes we are able to co-localize cysteine cathepsin activity with intracellular cleavage products of type IV and type I collagen. We have created several in vitro 3D organotypic models which mimic the changing microenvironments (myoepithelial contact, normal fibroblasts and activated fibroblasts) of DCIS in vivo. We are in the process of analyzing the proteases and protease inhibitors in the 3D organotypic DCIS co-cultures.
Carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab in first-line metastatic squamous NSCLC: Results from the KEYNOTE-407 east Asia subgroup
Authors: T. Kato, S. Lee, Y. Cheng, G.-W. Lee, K. Lee, A. Luft, J. Trigo, R. Hui, B. Balint, A. Robinson, I. Okamoto, G.J. Gerstner, L. Paz-Ares, X. Li, Y. Shentu, B. Piperdi, A. Tafreshi
Journal: Annals of Oncology (2018)
MicroRNA-621 Acts as a Tumor Radiosensitizer by Directly Targeting SETDB1 in Hepatocellular Carcinoma
Authors: Yingjie Shao, Xing Song, Wenjie Jiang, Yuan Chen, Zhonghua Ning, Wendong Gu, Jingting Jiang
Journal: Molecular Therapy (2018)

Radiotherapy is one of the most important treatment methods of tumors. However, the application of radiotherapy in hepatocellular carcinoma (HCC) is limited due to the low tolerance of normal liver cells for radiation and inherent radiation resistance in HCC. With the in-depth study of microRNAs (miRNAs) in tumor therapy, the regulation of tumor radiosensitivity by miRNAs has been a research hotspot in recent years. In the present study, the expression of miR-621 was lower in HCC tissues and cells, and such low expression of miR-621 was associated with poor prognosis in HCC patients. In addition, in vivo and in vitro assays confirmed that the high expression of miR-621 could significantly enhance the radiosensitivity of HCC. Moreover, the expressions of miR-621 and SETDB1 in HCC tissues were negatively correlated. Dual-luciferase reporter assays indicated that miR-621 could directly target the 3′ UTR of SETDB1. In addition, miR-621 enhanced the radiosensitivity of HCC cells via directly inhibiting SETDB1. Besides, the miR-621 and/or SETDB1 axis improved the radiosensitivity of HCC cells via activating the p53-signaling pathway. Taken together, miR-621 and/or SETDB1 might be used as a novel therapeutic target for the treatment of HCC. Radiotherapy is one of the most important treatment methods of tumors. However, the application of radiotherapy in hepatocellular carcinoma (HCC) is limited due to the low tolerance of normal liver cells for radiation and inherent radiation resistance in HCC. With the in-depth study of microRNAs (miRNAs) in tumor therapy, the regulation of tumor radiosensitivity by miRNAs has been a research hotspot in recent years. In the present study, the expression of miR-621 was lower in HCC tissues and cells, and such low expression of miR-621 was associated with poor prognosis in HCC patients. In addition, in vivo and in vitro assays confirmed that the high expression of miR-621 could significantly enhance the radiosensitivity of HCC. Moreover, the expressions of miR-621 and SETDB1 in HCC tissues were negatively correlated. Dual-luciferase reporter assays indicated that miR-621 could directly target the 3′ UTR of SETDB1. In addition, miR-621 enhanced the radiosensitivity of HCC cells via directly inhibiting SETDB1. Besides, the miR-621 and/or SETDB1 axis improved the radiosensitivity of HCC cells via activating the p53-signaling pathway. Taken together, miR-621 and/or SETDB1 might be used as a novel therapeutic target for the treatment of HCC.
A clinical pharmacodynamic (Pd) and pharmacokinetic (Pk) phase I study of I.V. R101933, an inhibitor of MDR1 P-glycoprotein (PgP) given alone and in combination with Taxol in patients with solid tumors
Authors: Ahmad Awada, Pierre Bourgeois, Nathalie Cornez, Harry Bleiberg, Scott Mccabe, Thierry Gil, F.F. Lehmann, Dominique de Valeriola, A. Di Leo, Martine Piccart-Gebhart
Journal: Clinical Cancer Research (1999)
Plant lipids: Key players of plasma membrane organization and function
Authors: Adiilah Mamode Cassim, Paul Gouguet, Julien Gronnier, Nelson Laurent, Véronique Germain, Magali Grison, Yohann Boutté, Patricia Gerbeau-Pissot, Françoise Simon-Plas, Sébastien Mongrand
Journal: Progress in Lipid Research (2018)
Suicide Rates by Major Occupational Group — 17 States, 2012 and 2015
Authors: Cora Peterson, Deborah M. Stone, Suzanne M. Marsh, Pamela K. Schumacher, Hope M. Tiesman, Wendy LiKamWa McIntosh, Colby N. Lokey, Aimée-Rika T. Trudeau, Brad Bartholow, Feijun Luo
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

During 2000-2016, the suicide rate among the U.S. working age population (persons aged 16-64 years) increased 34%, from 12.9 per 100,000 population to 17.3 (https:// www.cdc.gov/injury/wisqars).To better understand suicide among different occupational groups and inform suicide prevention efforts, CDC analyzed suicide deaths by Standard Occupational Classification (SOC) major groups for decedents aged 16-64 years from the 17 states participating in both the 2012 and 2015 National Violent Death Reporting System (NVDRS) (https://www.cdc.gov/violenceprevention/nvdrs).The occupational group with the highest male suicide rate in 2012 and 2015 was Construction and Extraction (43.6 and 53.2 per 100,000 civilian noninstitutionalized working persons, respectively), whereas the group with the highest female suicide rate was Arts, Design, Entertainment, Sports, and Media (11.7 [2012] and 15.6 [2015]).The largest suicide rate increase among males from 2012 to 2015 (47%) occurred in the Arts, Design, Entertainment, Sports, and Media occupational group (26.9 to 39.7) and among females, in the Food Preparation and Serving Related group, from 6.1 to 9.4 (54%).CDC's technical package of strategies to prevent suicide is a resource for communities, including workplace settings (1).NVDRS combines data on all violent deaths (defined as those resulting from the intentional use of physical force or power, threatened or actual, against oneself, another person, or a group or community), including suicide, based on death certificates, coroner/medical examiner reports, and law enforcement reports.Data on usual lifetime occupation among 22,053 suicide decedents aged 16-64 years from the 17 states* that participated in NVDRS in 2012 and 2015 were analyzed.
Abstract 15462: Gender-related Outcomes of Thoracic Endovascular Aortic Repair for Descending Thoracic Aortic Aneurysms
Authors: Wilmo C Orejola, David J O'Connor, Yeu Liu, Themba Nyirenda, Michael J Wilderman, Elie M Elmann, Massimo M Napolitano, Gregory T Simonian
Journal: Circulation (2015)

Objectives: To review and re-evaluate the poor outcome of thoracic endovascular repair in women at our institution. Methods and Materials: We reviewed our data on thoracic endovascular aortic repair from 2006 to 2014 for descending thoracic aortic aneuryms only. Pre-operative comorbidities, size of aneurysm, endograft usage, postoperative complications and mortalities were compared. A 24-month follow-up data was plotted in Kaplan-Meier survival curve. Results: There were 26 women and 21men, mean ages 81.7 ± 6.8 years and 72.8 ± 11.9 years (p &lt; .004), respectively. Average aortic size was 6.2 cm and 4 (5.7%) ruptured aneurysms in women and 5.5 cm with only one noted rupture in men. Congestive heart failure as comorbidity showed a higher risk of death associated with TEVAR by logistic regression analysis. Less than 30 days mortality was 2 (7.7%) and &gt; 30 days 6 (23%) in the women group. There were no early or late deaths in the men group (p &lt; 0.0056). Deaths were only in women. Kaplan-Meier curve showing comparative 24-month survival between gender. The 24-month overall survival was 100% for males and 23.3% for females. Lack of mortality events among males resulted in no hazard ratio and 95% confidence interval for HR for gender. Conclusion: Congestive heart failure as comorbidity poses a greater risk of death postoperatively in TEVAR. Women undergoing TEVAR have greater mortality risk than men, because of larger size of the aneurysm and incidence of rupture during intervention.
Phase II KEYNOTE-164 study of pembrolizumab (pembro) monotherapy for patients (pts) with previously treated, mismatch repair–Deficient (dMMR) advanced colorectal cancer (CRC): Primary and Japan subgroup analyses
Authors: H. Hara, T. Yoshino, H. Taniguchi, K. Akagi, K. Shitara, T. Masuishi, Y. Kuboki, T. Shimamoto, K. Ueki, S.R. Han, K. Noguchi, L.A. Diaz
Journal: Annals of Oncology (2018)
Unhealthy Alcohol Use in Primary Care—The Elephant in the Examination Room
Authors: E. Jennifer Edelman, Jeanette M. Tetrault
Journal: JAMA Internal Medicine (2018)

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Vitamin D does not reduce cancer or cardiovascular events in healthy adults, trial finds
Authors: Susan Mayor
Journal: BMJ (2018)

High dose vitamin D supplementation does not reduce invasive cancer or cardiovascular events in healthy people over 50, a large randomised trial has found.1 Further results showed no benefits from omega 3 fatty acids in primary prevention.2

Supplemental vitamin D is currently used to prevent and treat bone related disorders, but interest has been growing in its use for preventing cancer and cardiovascular disease. This is mainly based on studies showing lower death rates from cancer and cardiovascular disease in regions with greater sun exposure, which is assumed to increase …
Letter to the Editor: Patient‐Reported Outcomes for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis: Rationale for Expanded Use
Authors: Patrizia Carrieri, Martin Duracinsky, Fabienne Marcellin, Jeffrey V. Lazarus
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To the Editor: It is estimated that one in four adults around the world has nonalcoholic fatty liver disease (NAFLD), a condition that can lead to nonalcoholic steatohepatitis (NASH), serious liver damage, and, ultimately, death. The arrival of new treatment options and prevention strategies for NAFLD/NASH will result in an increasing number of clinical trials targeting this disease. Younossi outlined1 the increasing importance of including patient‐reported outcomes (PROs) in future clinical trials for NAFLD/NASH treatment. We fully agree and wish to underline additional points that deserve consideration when dealing with PROs and NAFLD/NASH. In an era where available treatments for NAFLD/NASH are still highly comparable in terms of effectiveness, PROs could make the difference. PROs include specific indicators that may be more sensitive to detect between‐treatment differences than generic health‐related quality of life, such as perceived toxicity (self‐reported symptoms), which has been correlated with treatment discontinuation in liver disease.2 Additional reasons encourage the use of PROs in the context of NAFLD/NASH. To date, the most effective “treatment” that can stop or reverse the evolution of NASH is still prevention,3 that is, a wide spectrum of interventions targeting weight loss based on lifestyle changes and reduced caloric intake. Such interventions are likely to be incorporated in future NASH clinical trials as a combined approach. An extended spectrum of PROs, including stigma and discrimination experienced in different settings or toward behaviors associated with the disease or body image, willingness/readiness to initiate lifestyle changes, sleep quality, and patient/health staff relationships can be a useful set of outcomes and are possible determinants of both adherence to, and effectiveness of, the evaluated intervention. Moreover, trial selection criteria for NAFLD/NASH tend to exclude patients with the worst PROs health profiles at baseline (e.g., people with psychiatric or addictive disorders), compromising the external validity of the results. Measuring PROs in pragmatic trials, longitudinal observational setting, or in postmarketing surveillance would allow a more “representative” group of people affected by NAFLD and its more‐serious form NASH to express their experience with the treatment and disease and increase validity of the results. Finally, we need to also address NAFLD and NASH epidemics in low‐resource settings and/or socially vulnerable areas, where interventions to prevent or cure NASH are likely to arrive last, and for which PROs need to be adapted to the context in question.
Relationship Between Left Ventricular Ejection Fraction and Mortality in Asymptomatic and Minimally Symptomatic Patients With Severe Aortic Stenosis
Authors: Yohann Bohbot, Christophe de Meester de Ravenstein, Gagandeep Chadha, Dan Rusinaru, Khadija Belkhir, Camille Trouillet, Agnes Pasquet, Sylvestre Marechaux, Jean-Louis Vanoverschelde, Christophe Tribouilloy
Journal: JACC. Cardiovascular imaging (2018)
Activation of ULK1 Kinase Mediates Clearance of Free Alpha-Globin in Human Beta-Thalassemic Erythroblasts
Authors: Christophe Lechauve, Julia Keith, Eugene Khandros, Stephanie Fowler, Kalin Mayberry, Abdullah Freiwan, Christopher Thom, Jingjing Zhang, Heather Tillman, Mondira Kundu, Irene Motta, Maria Domenica Cappellini, Mitchell J. Weiss
Journal: Blood (2018)
CD95-ligand contributes to abdominal aortic aneurysm progression by modulating inflammation
Authors: Zhibo Liu, Matthew Fitzgerald, Trevor Meisinger, Rishi Batra, Melissa Suh, Harrison Greene, Alexander J Penrice, Lijun Sun, B Timothy Baxter, Wanfen Xiong
Journal: Cardiovascular Research (2018)

Abdominal aortic aneurysm (AAA) is one of the number of diseases associated with a prominent inflammatory cell infiltration, matrix protein degradation, and smooth muscle cell apoptosis. CD95 is an inflammatory mediator and an apoptosis inducer. Previous studies have shown elevated expression of CD95 or CD95L in the aortic tissue of AAA patients. However, how the CD95L/CD95 contributes to aneurysm degeneration and whether blocking its signalling would be beneficial to disease progression remains largely unknown. In the present study, we sought to determine the role of CD95L and its downstream target, caspase 8, in AAA progression.By using the CaCl2 murine model of AAA, abdominal aortic aneurysms were induced in C57BL/6 mice. We found that both mRNA and protein levels of CD95L were increased in aneurysm tissue compared with NaCl-treated normal aortic tissue. To determine whether CD95L contributes directly to aneurysm formation, we used CD95L null (CD95L-/-) mice to examine their response to CaCl2 aneurysm induction. Six weeks after periaortic application of CaCl2, aortic diameters of CD95L-/- mice were significantly smaller compared to CaCl2-treated wild-type controls. Connective tissue staining of aortic sections from CaCl2-treated CD95L-/- mice showed minimal damage of medial elastic lamellae which was indistinguishable from the NaCl-treated sham control. Furthermore, CD95L deficiency attenuates macrophage and T cell infiltration into the aortic tissue. To study the role of CD95L in the myelogeous cells in AAA formation, we created chimaeric mice by infusing CD95L-/- bone marrow into sub-leathally irradiated wild-type mice (WT/CD95L-/-BM). As controls, wild-type bone marrow were infused into sub-leathally irradiated CD95L-/- mice (CD95L-/-/WTBM). WT/CD95L-/-BM mice were resistant to aneurysm formation compared to their controls. Inflammatory cell infiltration was blocked by the deletion of CD95L on myeloid cells. Western blot analysis showed the levels of caspase 8 in the aortas of CaCl2-treated wild-type mice were increased compared to NaCl-treated controls. CD95L deletion inhibited caspase 8 expression. Furthermore, a caspase 8-specific inhibitor was able to partially block aneurysm development in CaCl2-treated aneurysm models.These studies demonstrated that inflammatory cell infiltration during AAA formation is dependent on CD95L from myelogeous cells. Aneurysm inhibition by deletion of CD95L is mediated in part by down-regulation of caspase 8.
Tumor mutation index as a biomarker for responsive stratification on multi-targeted TKI anlotinib: An ALTER-0303 companion diagnostic study
Authors: J. Lu, W. Zhang, B. Yan, H. Li, L. Zhang, Y. Dong, J. Qian, S. Wang, B. Zhang, J. Wu, X. Zhao, Y. Zhao, B. Han
Journal: Annals of Oncology (2018)