tbuckley/cabot-search huggingface dataset:
Impact of CD8 stromal lymphocytes in BC patients with the addition of autologous dendritic CELL vaccination to neoadjuvant chemotherapy.
Authors: Pablo Sala Elarre, Luis Daniel Mejias, Belen Perez Solans, Lucia Ceniceros, Inaki Eguren SantamarÃa, Jaime Espinós, Patricia Martin Romano, Jairo Legaspi, Susana Inoges Sancho, Ascension Lopez Diaz de Cerio, Jose M. Aramendia, Ignacio Gil-Bazo, Miguel A. Idoate, Marta Santisteban
Journal: Journal of Clinical Oncology (2016)

1081 Background: Levels of tumor infiltrating lymphocytes (TILs) at diagnosis have shown to improve survival in TNBC and HER2 overexpressing breast cancer (BC) patients. Indeed, high levels of TILs after neoadjuvant chemotherapy (NAC) in the residual tumor have been related to a better outcome in BC patients. Thus, we have quantified stromal CD8 TILs pre- and postNAC in our cohort of patients treated with NAC plus dendritic cell vaccines (cohort V) (NCT01431196) and in an historic cohort of patients treated with the same NAC without the vaccine (cohort C) in order to check if the addition of immunotherapy helps to increase TILs in the residual BC. Our previous data have showed an improved pCR and the stimulation of lymphocyte populations in the blood in cohort V. Methods: Classification of molecular subtypes was performed based on IHC. We evaluated percentage of TILs by two different pathologists using stained CD8 core biopsy sections taken at diagnosis and after NAC therapy in a prospectively defined retrospective analysis. Results: TNBC patients achieved a pCR of 17% vs 67% in the C and V groups. Thirty patients who did not reach pCR to NAC in the C cohort and 24 in the V cohort were included. Age, molecular subtypes, Ki67 and TNM stage were well balanced between cohorts. According to stromal TIL quantification, no statistical differences were found at diagnosis (median 5% (1, 40) for both C and V; p = 0.76) and after treatment (5% (1, 50) and 2% (1, 50); p = 0.22) nor in the C and V cohorts. Levels of stromal TILs in paired samples (pre- and postNAC) were not significant in the C (p = 0.69) and the V cohorts (p = 0.09). However, stratifying to molecular subtypes, TNBC patients showed increased TILs after vaccine (37.5% vs. 42.5%; p = 0.01). A correlation analysis stated a strong association between stromal postNAC CD8 TILs and IHC subtypes (R = 0.71). A moderate association between postNAC stromal CD8 TILs and Ki67% (R = 0.45) was shown. Conclusions: pCR were higher in TNBC patients treated with NAC who received the vaccines. The addition of dendritic cell vaccines to NAC increases significantly stromal CD8 TILs in TNBC patients who did not reach pCR and this fact could improve patient’s outcome.
Potent anticancer activity of the deacetylase inhibitor panobinostat (LBH589) in colon cancer cell lines and patient-derived primary colon cancer xenografts
Authors: Youzhen Wang, Joseph Growney, Jane Cheng, Colleen Kowal, Guizhi Yang, Rebecca Mosher, Ronald Meyer, Yan Yan-Neale, Minying Pu, Wenlin Shao, Yun Feng, Paul Kwon, Peter Atadja, Stephen Fawell, Yung-mae Yao
Journal: Cancer Research (2008)

2442   Deacetylase inhibitors (DACi) are a promising group of novel anticancer agents that inhibit the activity of histone deacetylases, which remove acetyl groups from both histone and non-histone cellular proteins. Panobinostat (LBH589) is a potent DACi, which induces cell-cycle arrest, differentiation, and apoptosis of cancer cells, and has shown clinical efficacy in patients with hematologic and solid cancers. We have shown previously that panobinostat treatment induces potent histone and tubulin acetylation in colon cancer cell lines, and decreases levels of thymidylate synthase in colon cancer cells. To further explore the anti-tumor effects of panobinostat in colon cancer, we conducted preclinical studies on the activity of panobinostat as a single agent in colon cancer cell lines and colon cancer xenograft mouse models, including subcutaneous models with patient-derived primary colon tumor xenografts. Panobinostat exhibits potent antiproliferative effects against 35 colon cancer cell lines, with IC 50  values in the low nanomolar concentration range. Intravenous administration of panobinostat led to tumor growth inhibition and tumor regression in the HCT116 tumor xenograft model, and resulted in robust and durable acetylation of histones H3 and H4, indicating potent inhibition of histone deacetylase activities  in vivo . Combination of panobinostat (i.v. 30 mg/kg 3× per week for 3 weeks) and 5-fluorouracil (5-FU) (i.v. 75 mg/kg 1× per week for 3 weeks) in the Colo205 tumor xenograft model led to a significant level of tumor regression and markedly increased the median time to endpoint compared with either agent alone. As primary tumor models may better reflect patient tumors, we established two patient-derived primary colon xenografts in mice (HCXF1027 and HCXF0933), which maintained the original tumor morphology through passages  in vivo . A staggered regimen of panobinostat administration (i.v. 15 mg/kg 5×, 2×, 3× per week over 3 weeks) resulted in significant growth inhibition of HCXF1027 tumors. In studies with HCXF0933 tumors, panobinostat treatment as a single agent was found to inhibit tumor growth to a similar extent to the standard-of-care (SOC) agent irinotecan (CPT-11) (i.v. 40 mg/kg 2× per week for 3 weeks).These preclinical studies demonstrate that the DACi panobinostat has potent anticancer activity in colon cancer, resulting in significant inhibition of tumor growth and even tumor regression. Moreover, panobinostat in combination with SOC chemotherapeutic agents such as 5-FU displayed markedly enhanced anti-tumor effects. These data support the clinical evaluation of panobinostat in colon cancer, both as a single agent and in combination.
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a<i>FLT3</i>Mutation
Authors: Richard M. Stone, Sumithra J. Mandrekar, Ben L. Sanford, Kristina Laumann, Susan Geyer, Clara D. Bloomfield, Christian Thiede, Thomas W. Prior, Konstanze Döhner, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Jürgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Döhner
Journal: New England Journal of Medicine (2017)

Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
Insulin Receptor Isoforms in Physiology and Disease: An Updated View
Authors: Antonino Belfiore, Roberta Malaguarnera, Veronica Vella, Michael C Lawrence, Laura Sciacca, Francesco Frasca, Andrea Morrione, Riccardo Vigneri
Journal: Endocrine Reviews (2017)

The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.
Hormone receptor (AR/ER/PR) expression as a prognostic marker and novel candidate for drug development across multiple tumor types.
Authors: Shiraj Sen, Jason Roszik, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2017)

2537 Background: Hormone receptor (HR) [androgen receptor (AR), estrogen receptor (ER), progesterone receptor (PR)] expression is ubiquitous across tumor types and central to breast and prostate cancer treatment. While implicated in tumorigenesis, its role as a prognostic biomarker and therapeutic target in other tumor types has yet to be elucidated. Methods: We performed bioinformatic analyses of HR expression [reported as median transcripts per million (TPM)] using RNAseq from the Cancer Genome Atlas and completed Kaplan-Meier analyses to identify associations between HR expression and median overall survival (OS). Results: 9,743 samples from 9,674 patients across 33 tumor types were analyzed. AR was highly expressed in GBM (2 TPM), low grade glioma (2 TPM), breast (15 TPM), prostate (14 TPM), ovarian (6 TPM), renal clear cell carcinoma (4 TPM) and HCC (2 TPM) . Tumors with the highest quartile of expression had improved OS in renal clear cell [53 months (mo) vs not reached (NR), p = 4x10 -11 ] and adrenocortical carcinoma (45 mo vs NR, p = .03) and worse OS in low grade glioma (119 vs 64 mo, p = 6x10 -4 ). PR was highly expressed in uterine (12 TPM), breast (5 TPM), and renal chromophobe (2 TPM) carcinoma. PR expression was associated with improved OS in sarcoma (49 mo vs NR, p = .03), endometrial (NR, p = .02) and renal clear cell carcinoma (58 mo vs NR, p = .003) and worse OS in low grade glioma (53 vs 97 mo, p = .01), gastric adenocarcinoma (7 vs 17 mo, p = .04), and possibly pancreatic adenocarcinoma (21 vs 44 mo, p = .07). ER was highly expressed in breast (116 TPM), endometrial (87 TPM), ovarian (32 TPM), cervical (4 TPM), thyroid (4 TPM), prostate (3 TPM), and lung adenocarcinoma (2 TPM). ER expression was associated with improved OS in mesothelioma (15 vs 28 mo, p = .03) and endometrial cancer (NR, p = .001) and worse OS in squamous lung cancer (80 vs 48 mo, p = .02). Conclusions: HR expression may represent a novel prognostic marker in multiple tumor types and a candidate for drug development in low grade glioma, gastric adenocarcinomas, squamous cell lung cancer, and pancreatic adenocarcinomas. Protein-based IHC testing and early phase clinical trials targeting HR signaling in these tumor types is warranted.
Run-in bias in randomised trials: the case of COPD medications
Authors: Samy Suissa
Journal: European Respiratory Journal (2017)

Most randomised trials of newer and established medications in chronic obstructive pulmonary disease (COPD) enrol patients who have already been treated, often with drugs of the same class or even with the very same drugs that are to be studied. Some trials such as UPLIFT evaluated the effect of a drug as an add-on, with patients continuing their existing treatments [1]. Other trials, such as OPTIMAL and the Salford Lung Study, discontinued the regular maintenance treatment and replaced it with a randomly allocated active treatment [2, 3]. Finally, trials such as TORCH and SUMMIT had patients discontinue their regular maintenance treatment and directly receive the randomly allocated treatment, which included placebo [4, 5]. This last approach, however, has been shown to complicate the interpretation of results, particularly under the placebo group after the discontinuation of maintenance therapy [6, 7]. Randomised trials of COPD medications involving a "run-in" period could be biased: interpret results with caution <http://ow.ly/wDR830bPuca>
Abstract 190: Protein Phosphatase 2Ce Is a Novel Phospholamban Phosphatase that Exacerbates Cell Death and Suppresses Cardiac Contractility
Authors: Toru Akaike, Gang Lu, Yibin Wang, Hongmei Ruan
Journal: Circulation Research (2012)

Regulation of sarcoplasmic reticulum (SR) calcium-ATPase (SERCA) activity is critical for calcium homeostasis in cardiomyocytes, and has a major impact on contractility and cellular viability of cardiomyocytes. The key regulators for SERCA activity include protein kinases, cAMP dependent protein kinase A and calcium/calmodulin dependent protein kinase II, and protein phosphatase 1. In this report, we have discovered that protein phosphatase 2Ce (PP2Ce) is a novel serine/threonine protein phosphatase specifically targeted to SR membrane in cardiomyocytes. PP2Ce was detected to interact with phosphlamban in heart. Recombinant PP2Ce protein showed a potent and specific activity towards the calcium/calmodulin dependent protein kinase II dependent phospholamban phosphorylation at threonin 17 site with no significant activity to cAMP dependent protein kinase A dependent phospholamban phosphorylation at serine 16 site. Expression of PP2Ce blunted β-adrenergic stimulated increase of phospholamban phosphorylation without affecting phosphorylation of ryanodine recepter or troponin I. PP2Ce expression reduced β-adrenergic stimulated intracellular calcium transient in isolated adult rabbit ventricular myocytes, and promoted hydrogen peroxide induced cell death in cultured neonatal rat ventricular myocytes. Transgenic mice with cardiac specific expression of PP2Ce showed no significant basal phenotype. However, in isolated perfusion heart preparation, β-adrenergic stimulated contractility was significant reduced in PP2Ce transgenic hearts comparing to wild type controls. Furthermore, we observed significantly larger infarct sizes and more impaired functional recovery following global ischemia/reperfusion injury in the transgenic hearts comparing to wild type controls. Therefore, PP2Ce is a novel component of SR calcium regulatory network that has a potentially important role in cell death regulation and cardiac contractility.
Le profil épidémiologique des hémorragies digestives ulcéreuses: est-il différent au Maroc?
Authors: D Benajah, M El Abkari, I Mellouki, A Ibrahimi
Journal: Endoscopy (2006)

Préciser le profil épidémiologique des patients présentant des hémorragies digestives ulcéreuses au CHU Hassan II de Fés-Maroc, et évaluer les facteurs pronostiques relatifs à cette population de malades.
Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets
Authors: Difeng Fang, Jinfang Zhu
Journal: The Journal of Experimental Medicine (2017)

CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type–specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets.
Augmentation of adoptive T-cell therapy for Merkel cell carcinoma with avelumab.
Authors: Kelly Garneski Paulson, Maurizio Perdicchio, Rima Kulikauskas, Felecia Wagener, Candice Church, Kieu-Thu Bui, Natalie Vandeven, Hannah Thomas, Megan McAfee, Natalie Miller, Kevin M. Chin, Zhen Su, Philip D Greenberg, Upendra Parvathaneni, Shailender Bhatia, Paul Nghiem, Aude Chapuis
Journal: Journal of Clinical Oncology (2017)

3044 Background: 80% of Merkel cell carcinomas (MCCs) are caused by Merkel cell polyomavirus (MCPyV) oncoproteins. Although absent in most cases, abundant MCPyV-specific CD8+ TIL are associated with good MCC outcomes, implying tumor susceptibility to immune attack. Indeed, anti-PD-1 axis blockade has a response rate of 32-56%. However, half of patients do not respond, suggesting a lack of adequate MCPyV-specific T cells and/or tumor evasion from MCC-related reduced HLA expression. We hypothesized the combination of adoptive transfer of MCPyV-specific T cells with HLA upregulation and PD1 axis blockade would be more effective than either approach alone. Methods: 8 adult patients with MCPyV-associated metastatic MCC without pre-existing immune deficiencies were enrolled. The safety and efficacy of ex vivo expanded MCPyV-specific T-cells plus HLA-upregulation (radiation or interferon) with (triple therapy) and without (double therapy) avelumab (mAb against PD-L1, dose 10 mg/kg IV q2weeks) were compared in 2 related phase I/II studies. Results: All 4 patients who received triple therapy (100%) are alive (median follow-up 10 months), and experienced objective responses (RECIST 1.1) with 3 of 4 sustained complete responses (CRs) at last follow-up (longest 13 mo). This compared favorably to outcomes among the 4 patients who received double therapy (3 with progression and 1 CR (25%) for 14 months before progression) and published data for avelumab monotherapy – response rate 32% and CR rate 9% in patients who had failed chemotherapy (Kaufman et al, Lancet Oncol, 2016). Grade 3-4 T cell-related adverse events were similar and anticipated in both groups, including transient lymphopenia (n = 7) and modest cytokine release syndrome lasting &lt; 24 hours, manageable on the general ward (n = 4). No grade 3-4 toxicities were attributed to avelumab. Among patients receiving triple therapy, transferred T cells persisted, and peak frequencies correlated with rate of tumor regression. Conclusions: The combination of MCPyV-specific T cells, avelumab and HLA upregulation is safe and correlative studies suggest avelumab enhances the T cell responses to MCC. This strategy has potential for MCC treatment, and can be readily applied to other solid tumors. Clinical trial information: NCT01758458 and NCT02584829.
Genetic counseling to outpatient cancer population.
Authors: Juliano Ce Coelho, Henrique de Araujo Vianna Trasel, Bruno Lopes Koech, Cristina Oliveita Netto, Sergio J Azevedo, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2017)

e13009 Background: Recent advances in genetics and molecular biology have made possible to define the hereditary risk of certain diseases. About 10% of cancer are due to a hereditary syndrome and increasing access to genetic testing allows us to identify people or families at risk. Methods: A multidisciplinary team composed of clinical oncologists and geneticists retrospectively evaluated all cancer patients referred to the outpatient clinics of the Hospital de Clínicas de Porto Alegre Cancer Center between October 1 st , 2014 and July 31 st , 2015. Epidemiological data, pathological examination and family history of cancer recorded in the electronic database at the first visit to the oncologist were analyzed. Results: A total of 708 patients were analyzed. 44 (6.21%) patients were identified and referred for genetic evaluation by the clinical oncologist. Another 85 (12.0%) patients were identified by the multidisciplinary team, completing a total of 129 (18.22%), patients that should be evaluated to the presence of a hereditary syndrome. 164 (23.16%) patients could not be evaluated by the multidisciplinary team because insufficient data were recorded especially those related to family history of cancer. The main diagnosis that indicated genetic evaluation were colorectal cancer (47 cases - 36.43%), breast cancer (36 cases - 27.90%) and ovarian cancer (8 cases - 6.20%). Conclusions: A multidisciplinary evaluation of the oncologic patient is mandatory. Few patients are referred to a genetic counseling and 1 out of 4 patient could not be evaluated because there was missing data in the medical records. A precise genetic evaluation can identify patient / families at risk to develop cancer, allowing the development of cancer prevention strategies in this high-risk population.
Les technologies WEB au service d'un atlas collaboratif en endoscopie digestive
Authors: C Le Guillou, J Logan, B Solaiman, M Robaszkiewicz, JM Cauvin
Journal: Endoscopy (2006)

Les progrès en imagerie numérique simplifient la production d'images et de séquences vidéo, mais la construction d'atlas et leur intégration dans des scénarios d'apprentissage soulèvent de nouveaux problèmes tels que l'indexation, la communication, l'interactivité, la collaboration. Notre projet à pour objectif le développement d'outils collaboratifs d'enseignement en endoscopie digestive, basés sur la technologie WEB.
Triage Scoring System Based on Early Post-Transplant Complications for Patients with Myelodysplastic Syndrome Requiring ICU after Allo-HCT: An SFGM-TC Study
Authors: Alexis Caulier, Elodie Drumez, Marie Robin, Didier Blaise, Yves Beguin, Mauricette Michallet, Patrice Chevallier, Jacques-Olivier Bay, Stéphane Vigouroux, Yohan Desbrosses, Jérôme Cornillon, Stephanie Nguyen, Regis Peffault De Latour, Charles Dauriac, Bruno Lioure, Pierre Simon Rohrlich, Martin Carré, Jean-Henri Bourhis, Anne Huynh, Felipe Suarez, Federico Garnier, Alain Duhamel, Ibrahim Yakoub-Agha
Journal: Blood (2016)
Activation of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Receptor Subunits in a Multipotential Hematopoietic Progenitor Cell Line Leads to Differential Effects on Development
Authors: Caroline A. Evans, Andrew Pierce, Sandra A. Winter, Elaine Spooncer, Clare M. Heyworth, Anthony D. Whetton
Journal: Blood (1999)