tbuckley/cabot-search huggingface dataset:
Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin
Authors: Kaixin Zhou, Sook Wah Yee, Eric L Seiser, Nienke van Leeuwen, Roger Tavendale, Amanda J Bennett, Christopher J Groves, Ruth L Coleman, Amber A van der Heijden, Joline W Beulens, Catherine E de Keyser, Linda Zaharenko, Daniel M Rotroff, Mattijs Out, Kathleen A Jablonski, Ling Chen, Martin Javorský, Jozef Židzik, Albert M Levin, L Keoki Williams, Tanja Dujic, Sabina Semiz, Michiaki Kubo, Huan-Chieh Chien, Shiro Maeda, John S Witte, Longyang Wu, Ivan Tkáč, Adriaan Kooy, Ron H N van Schaik, Coen D A Stehouwer, Lisa Logie, Calum Sutherland, Janis Klovins, Valdis Pirags, Albert Hofman, Bruno H Stricker, Alison A Motsinger-Reif, Michael J Wagner, Federico Innocenti, Leen M 't Hart, Rury R Holman, Mark I McCarthy, Monique M Hedderson, Colin N A Palmer, Jose C Florez, Kathleen M Giacomini, Ewan R Pearson
Journal: Nature Genetics (2016)
Intestinal Microbiota: From Inflammatory Bowel Disease to Bone Marrow Transplantation
Authors: Ernst Holler, Peter Oefner, Karin Landfried, Josef Koestler, Elisabeth Huber, Katrin Peter, Julia Ammer, Gerhard Rogler, Marina Kreutz, Rainer Spang, Thomas Hehlgans, Matthias Edinger, Daniel Wolff, Andre Gessner, Reinhard Andreesen
Journal: Blood (2012)
EGFR-GRB2 Protein Colocalization Is a Prognostic Factor Unrelated to Overall EGFR Expression or EGFR Mutation in Lung Adenocarcinoma
Authors: Maria I. Toki, Daniel E. Carvajal-Hausdorf, Mehmet Altan, Joseph McLaughlin, Brian Henick, Kurt A. Schalper, Konstantinos N. Syrigos, David L. Rimm
Journal: Journal of Thoracic Oncology (2016)

IntroductionEGFR is a therapeutic target in NSCLC for EGFR-mutant patients. Proximity ligation assay (PLA) is a method to detect functional signaling associated protein complexes. Growth factor receptor bound protein 2 (GRB2) is an adaptor protein that binds to the phosphorylated residues of active EGFR. Interaction of EGFR and GRB2 correlates with active EGFR signaling and leads to activation of the MAPK/ERK pathway.MethodsA PLA developed to detect EGFR-GRB2 interaction was measured by quantitative immunofluorescence using Automated Quantitative Analysis technology. EGFR pathway activation was assessed in patients with NSCLC with different mutation status along with overall EGFR expression. Additionally, the PLA to detect EGFR-GRB2 interaction was evaluated as a prognostic marker in two cohorts of patients with lung adenocarcinoma.ResultsThe PLA to detect EGFR-GRB2 interaction was unrelated to overall EGFR expression or mutation in a series of patients with NSCLC with known mutation status. EGFR-mutant (p = 0.04) and EGFR/KRAS wild-type tumors (p = 0.0049) had significantly higher EGFR pathway activation compared with KRAS-mutant cases, with no significant difference shown between mutation sites. In two series of patients with lung adenocarcinoma, the PLA to detect EGFR-GRB2 interaction was independently associated with longer survival (hazard ratio = 0.46, 95% confidence interval: 0.2–0.78, p = 0.0085 and hazard ratio = 0.48, 95% confidence interval: 0.2–0.85, p = 0.017). Total EGFR protein expression alone was not correlated with outcome.ConclusionsEGFR colocalization with GRB2 as assessed by PLA is not correlated with EGFR expression levels or mutation status, defining a patient group that may show EGFR pathway activation, as illustrated by its prognostic value. Future studies may determine whether this group is more likely to respond to EGFR-targeted therapies.
Abstract 738: Correlation between tumor infiltrating lymphocytes and CCL5 gene expression in chemotherapy-resistant triple negative breast cancer
Authors: Joseph A. Pinto, Zaida D. Morante, Roberto Salgado, Nadezhda Cardenas, Jhajaira Araujo, Jaime Ponce, Franco Doimi, Justin Balko, Henry Gomez
Journal: Cancer Research (2016)

Abstract Background: The presence of tumor infiltrating lymphocytes (TILs) have been associated with a better outcome in triple negative breast cancer (TNBC). In the other hand, we have found that CCL5, a chemokine involved in the recruitment of immune cells to the tumor microenvironment is an independent prognostic marker for distant-recurrence free survival (DFRS) in TNBC. The aim of this work was to evaluate the relationship between these two immunological prognostic markers in chemotherapy-resistant TNBC. Material and Methods: We evaluated a retrospective cohort (n = 74) of TNBC patients with residual disease after neoadjuvante chemotherapy. Residual tumors were profiled with Nanostring for genes previously related to TNBC aggressiveness. Gene expression values for CCL5 were log2 transformed and median centered. TIL count was performed according to the methods published by Salgado et al (2015). Values of TILs count were log2 transformed (values with 0% were removed from the cohort; n = 1). Spearman's rank correlation analysis and proportional hazards regression was used to investigate the relationship and impact in the outcome between these two markers. Results: The median TIL count was 10% (interquartile range: 21.25). A total of 59.5% of cases had TILs &amp;lt;15%. There was a significant correlation between TILs and CCL5 (ñ = 0.345, P = 0.032). In univariate analysis (as continuous variable), TILs (HR = 0.968 per unit of change; 95%IC: 0.946-0.990; P = 0.006) and CCL5 (HR = 0.95 per unit of change; 95%IC: 0.635-0.996; P = 0.046) were both associated with outcome. After adjusting to CCL5 expression, TIL's count, was the only significant marker with a P-value = 0.007 (HR = 0.702 per unit of change; 95%IC: 0.54-0.909), in contrast to CCL5 (HR = 0.925, CI95%:0.717-1,194; P-value = 0.550). Conclusions: TILs and CCL5 gene expression are significantly correlated in chemotherapy-resistant TNBC. However, although CCL5 expression is strongly associated with the progression of BC, particularly TNBC, TIL assessment remains the stronger and more significant prognostic immunological marker. Citation Format: Joseph A. Pinto, Zaida D. Morante, Roberto Salgado, Nadezhda Cardenas, Jhajaira Araujo, Jaime Ponce, Franco Doimi, Justin Balko, Henry Gomez. Correlation between tumor infiltrating lymphocytes and CCL5 gene expression in chemotherapy-resistant triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 738.
P1332 : The astral studies: evaluation of SOF/GS-5816 single tablet regimen for the treatment of genotype 1–6 HCV infection
Authors: T. Asselah, M. Charlton, J. Feld, G.R. Foster, J. Mcnally, D.M. Brainard, J.G. McHutchison, A. Mangia, M. Sulkowski, S. Zeuzem
Journal: Journal of Hepatology (2015)
A phase 1B, open-label, dose-escalation study of bortezomib in combination with gemcitabine (Gem) and cisplatin (Cis) in the first-line treatment of patients with advanced solid tumors: Preliminary results of a phase IB study
Authors: J. Voortman, E. F. Smit, B. C. Kuenen, H. M. Pinedo, C. van Groeningen, A. J. van den Eertwegh, D. Brouwer, H. van de Velde, G. Giaccone
Journal: Journal of Clinical Oncology (2005)

2103 Background: Bortezomib (VELCADE) is a reversible and specific inhibitor of the 26S proteasome. Gem/Cis is an accepted first-line treatment for several advanced solid tumors. This trial aims to determine MTD and investigate tolerability of a weekly and biweekly schedule of bortezomib in combination with Gem/Cis. Methods: Chemotherapy-naïve patients (KPS ≥ 70%) with advanced solid tumors for whom first-line Gem/Cis was considered an acceptable therapeutic option received Gem 1000 mg/m2 on days 1 and 8 and Cis 70 mg/m2 on day 1 of a 21-day cycle. In the weekly schedule, bortezomib was administered on days 1 and 8 at 1.0, 1.3, or 1.6 mg/m2. In the biweekly schedule, bortezomib was administered on days 1, 4, 8, and 11 at 0.70, 1.0, or 1.3 mg/m2. Results: 13 pts have been treated for at least 1 cycle: 7 on the weekly schedule (3 pts at 1.0 mg/m2 and 4 pts at 1.3 mg/m2) and 6 on the biweekly schedule (3 pts at 0.7 mg/m2 and 3 pts at 1.0 mg/m2). Median age: 53 y (range, 35–71); male/female = 9/4; KPS < 80%/> 80% = 1/12; tumor types = 9 NSCLC, 2 bladder ca, 1 pancreas ca, 1 HCC. One first-cycle DLT (gr 4 neutropenia and thrombocytopenia, asymptomatic) was observed in 1 pt on the weekly schedule (1.3 mg/m2). The most common gr 3/4 toxicities were asymptomatic and reversible thrombocytopenia (gr 3: 5 pts; gr 4: 2 pts) and granulocytopenia (gr 3: 2 pts; gr 4: 2 pts).Treatment was generally well tolerated. No drug-induced sensory neuropathies have been observed. The addition of bortezomib did not appear to lead to additional nausea, vomiting, or diarrhea compared with Gem/Cis alone. One gr 2 ototoxicity was observed in a pt with prior cranial radiotherapy. One gr 4 left ventricular dysfunction was observed post-cycle 4 in a pt with no prior cardiologic history. In the first 10 pts evaluated, there were 4 partial responses (2 bladder, 2 NSCLC: 1 squamous, 1 large cell). Conclusion: Dose escalation is ongoing. The combination has been well tolerated. Bortezomib may increase myelosuppression of Gem/Cis chemotherapy. Updated information will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Janssen-Cilag, Johnson & Johnson Johnson & Johnson Millennium
Abstract 3517: Expression studies of RBBP6 in breast and cervical cancer suggests a role in apoptosis activation
Authors: Mpho Choene, Pontsho Moela, Lesetja Motadi
Journal: Cancer Research (2016)

Abstract Ubiquitin-like DWNN domain and RING finger-like domain presence on Retinoblastoma Binding protein 6 (RBBP6), is linked to its function as cancer promoting gene through p53 degradation via its p53-binding domain. RBBP6 bind and regulate the expression of p53 and pRB in the cell machinery implicates RBBP6 in cell proliferation during cancer development (Moela et al 2014). Studies indicate that overexpression of the mouse spliced variants led to apoptosis and cell cycle arrest whilst deregulation in mice led to embryonic lethality followed by p53 accumulation and a widespread apoptosis (Li et al., 2007). In this study, focuses on determining the expression pattern of RBBP6 in human tissue models of breast and cervical cancer. The study further aims to analyze apoptosis and cell cycle following either knockdown or overexpression of RBBP6 coupled to treatment with potential anticancer compounds, camptothecin and GABA. Quantitative analysis by qPCR in HeLa, SiHa, MCF-7and MDA-MB-231 cell lines shows that RBBP6 expression is fairly high in cancer cells when compared to normal lung fibroblast. Following co-treatment with GABA and cDNA or siRNA, in cDNA treated there was a reduction in both apoptosis as measured by flow cytometer and TP53 expression while in siRNA there was increased expression of TP53 and those of Bax and Bak1 which seemed to account for increased apoptosis. Cell cycle presented increase in G0/G1 and the G2/M following treatment with siRNA and GABA. GABA alone could not induce a significant increase in apoptotic cells whereas when combined with siRNA it was able to induce over 30% apoptosis. These results suggest that RBBP6 might be a cancer promoting gene. Citation Format: Mpho Choene, Pontsho Moela, Lesetja Motadi. Expression studies of RBBP6 in breast and cervical cancer suggests a role in apoptosis activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3517.
Optic Disc Hemorrhages and Laminar Disinsertions in Glaucoma
Authors: Glen P. Sharpe, Vishva M. Danthurebandara, Jayme R. Vianna, Noor Alotaibi, Donna M. Hutchison, Anne C. Belliveau, Lesya M. Shuba, Marcelo T. Nicolela, Balwantray C. Chauhan
Journal: Ophthalmology (2016)
BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses
Authors: Mohammad Althubiti, Miran Rada, Jesvin Samuel, Josep M. Escorsa, Hishyar Najeeb, Koon-Guan Lee, Kong-Peng Lam, George D.D. Jones, Nickolai A. Barlev, Salvador Macip
Journal: Cancer Research (2016)

p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy. Cancer Res; 76(18); 5405-14. ©2016 AACR.
Abstract 4855: Discovery of NVP-HDM201 - First disclosure of a Next-Generation Mdm2 inhibitor with superior characteristics
Authors: Philipp Holzer, Patrick Chène, Stéphane Ferretti, Pascal Furet, Tobias Gabriel, Bjoern Gruenenfelder, Vito Guagnano, Francesco Hofmann, Joerg Kallen, Robert Mah, Keiichi Masuya, Rita Ramos, Stephan Ruetz, Caroline Rynn, Thérèse Stachyra-Valat, Stefan Stutz, Andrea Vaupel, Sébastien Jeay.
Journal: Cancer Research (2016)

Abstract Activation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule inhibitors has been pursued for many years as a promising cancer therapeutic strategy. We disclose the identity of NVP-HDM201, a novel, highly optimized and selective inhibitor of the p53-Mdm2 interaction. NVP-HDM201 binds to human Mdm2 protein with a sub-nanomolar Ki value, activates p53 and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. The activity and selectivity of NVP-HDM201 have been tested and confirmed across a panel of cancer cell lines and the molecule displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability. Application of NVP-HDM201 using various dosing schedules triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancers. We report here how a promising lead series was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, culminating in the discovery of NVP-HDM201. The superior characteristics of the compound allowed the fast progression of the compound into the clinic where NVP-HDM201 is currently in Phase 1 clinical trials both as a single agent and as a combination partner in patients pre-selected for p53 wild-type tumors. Citation Format: Philipp Holzer, Patrick Chène, Stéphane Ferretti, Pascal Furet, Tobias Gabriel, Bjoern Gruenenfelder, Vito Guagnano, Francesco Hofmann, Joerg Kallen, Robert Mah, Keiichi Masuya, Rita Ramos, Stephan Ruetz, Caroline Rynn, Thérèse Stachyra-Valat, Stefan Stutz, Andrea Vaupel, Sébastien Jeay. Discovery of NVP-HDM201 - First disclosure of a Next-Generation Mdm2 inhibitor with superior characteristics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4855.
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised controlled trials of statins (vol 366, pg 1267, 2005)
Authors: C Baigent, A Keech, P M Kearney, L Blackwell, G Buck, C Pollicino, A Kirby, T Sourjina, R Peto, R Collins, J Simes
Journal: The Lancet (2008)
Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First‐Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid Arthritis
Authors: Jeffrey A. Sparks, Shun‐Chiao Chang, Kevin D. Deane, Ryan W. Gan, M. Kristen Demoruelle, Marie L. Feser, LauraKay Moss, Jane H. Buckner, Richard M. Keating, Karen H. Costenbader, Peter K. Gregersen, Michael H. Weisman, Ted R. Mikuls, James R. O'Dell, V. Michael Holers, Jill M. Norris, Elizabeth W. Karlson
Journal: Arthritis & Rheumatology (2016)

To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs in a cohort of first-degree relatives (FDRs) of RA patients.We evaluated RA risk factors and inflammatory joint signs in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic factors included 5 HLA-DRB1 shared epitope alleles and 45 RA-associated single-nucleotide polymorphisms; loci were combined using genetic risk scores weighted by RA risk. Environmental factors (smoking, body mass index, education, and parity) and RA-related autoantibodies were assessed at baseline. Physical examination was performed at baseline and 2-year follow-up, by observers who were blinded with regard to autoantibody status, to assess inflammatory joint signs as tender or swollen joints at sites typical for RA. Logistic regression was performed to evaluate associations of genetic, environmental, and serologic factors with inflammatory joint signs.We analyzed 966 non-Hispanic white FDRs at baseline and 262 at 2-year follow-up after excluding those with inflammatory joint signs at baseline. The mean ± SD age was 47.2 ± 15.5 years, 71% were female, and 55% were shared epitope positive. Smoking >10 pack-years was associated with inflammatory joint signs at baseline (odds ratio [OR] 1.89 [95% confidence interval (95% CI) 1.26-2.82]) and at 2 years (OR 2.66 [95% CI 1.01-7.03]), compared to never smokers. There was a significant interaction between smoking and age with regard to risk of inflammatory joint signs (P = 0.02). FDRs younger than 50 years with >10 pack-years had the highest risk of inflammatory joint signs (OR 4.39 [95% CI 2.22-8.66], compared to never smokers younger than 50 years).In a high-risk cohort of FDRs, smoking and age were associated with both prevalent and incident inflammatory joint signs at sites typical for RA. Further prospective investigations of the factors affecting the transitions between preclinical RA phases are warranted.
Pattern of expression of calpain subunits (large and small) in human breast cancer and the prognostic significance
Authors: A. Chhabra, H. Fernando, R. E. Mansel, W. G. Jiang
Journal: Journal of Clinical Oncology (2007)

21078 Background: Calpains belongs to family of non-lysosomal calcium dependent cysteine proteases which are known to regulate cellular migration, apoptosis and cell cycle progression in normal and tumour cells. Calpain has also been indicated in the metastatic process of certain tumours like RCC and identified as a potential tumor suppressor for gastric cancer. Little is known about the expression pattern of calpain in human breast cancer. The current study investigated the expression pattern of the large (calpainL) and small (calpainS) subunits of calpain which are encoded by different genes, in human breast cancer and attempted to correlate the expression with clinical outcome. Methods: RNA was extracted from frozen sections of breast tissue (n=120, median clinical follow up of the patients - 72 months) for gene amplification. The expression of both subunits of calpain was determined by using RT-PCR and quantitative RT-PCR. Statistical analysis was carried out using Mann- Whitney U test and the Kruskal- Wallis test. Results: We found significantly higher level of both calpain subunits in tumour tissue (n=120) as compared to normal non-neoplastic mammary tissues (calpainL, p=0.022 and calpainS, p=0.039). The expression of calpainL was significantly lower in patients with poor clinical outcome (with metastasis, p=0.024, with local recurrence, p=0.024 and who died of breast cancer, p=0.028), than those who were disease free. In contrast, the levels of calpainS were high in patients with poor prognosis, metastasis and who died of breast cancer but were statistically not significant. The expression of calpainL was marginally lower in node positive tumours than the node negative tumours. CalpainS transcripts were higher in node positive than node negative tumours (p=0.23). Similarly, calpainL showed a low level in high grade tumours whereas calpainS displayed a contrasting high level in these tumours. Conclusions: The large and small subunits of calpain have a distinct pattern of expression in human breast cancer. A decrease expression of calpainL but an increase expression of calpainS may be associated with poor prognostic tumours, thus indicating the intimate nature of the molecular pair in the disease progression of human breast cancer. No significant financial relationships to disclose.
Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma
Authors: Asim Amin, David H. Lawson, April K.S. Salama, Henry B. Koon, Troy Guthrie, Sajeve S. Thomas, Steven J. O’Day, Montaser F. Shaheen, Bin Zhang, Stephen Francis, F. Stephen Hodi
Journal: Journal for ImmunoTherapy of Cancer (2016)

<h3>Background</h3> Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with <i>BRAF</i>-mutated advanced melanoma. <h3>Methods</h3> This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960&nbsp;mg twice daily for 6&nbsp;weeks followed by IPI 10&nbsp;mg/kg every 3&nbsp;weeks for 4 doses (induction), then every 12&nbsp;weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI. <h3>Results</h3> All patients who were initially treated with VEM (<i>n</i> = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6&nbsp;%, 21.7&nbsp;%, and 4.3&nbsp;%, respectively. There were no drug-related deaths. At a median follow-up of 15.3&nbsp;months, median overall survival was 18.5&nbsp;months. Median progression-free survival was 4.5&nbsp;months. <h3>Conclusions</h3> VEM (960&nbsp;mg twice daily for 6&nbsp;weeks) followed by IPI 10&nbsp;mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma. <h3>Trial registration</h3> ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012