tbuckley/cabot-search huggingface dataset:
Relations of circadian clocks genes with endocrine, proliferation, differentiation, and P53 mutation status in human locally invasive primary breast cancer.
Authors: I. Iurisci, F. Valet, S. Giacchetti, S. Delaloge, E. Brain, J. Pierga, H. de Thé, B. Sigal-Zafrani, M. E. Marty, F. Levi
Journal: Journal of Clinical Oncology (2010)

10589 Background: Circadian clock involves 15 specific genes which control cell cycle, apoptosis, DNA repair and metabolism (Lévi et al. ARPT,2010). Circadian disruption is associated both with an increased risk of breast cancer and poor survival in patients (pts) with metastatic cancer (Innominato et al Cancer Res 2009). Objective: to provide first evidence of relevance of clock genes expression for pathologic determinants of therapeutic sensitivity of human breast cancer. Methods: Affymetrix Hgu133plus2 microarrays data were derived from 189 primary breast cancers. All pts had non metastatic disease and were enrolled in a multicenter phase II trial of neoadjuvant chemotherapy, in which hormonal receptor status and limited tumor size predicted for pathological complete response rate (Valet et al. SABC 2009). Within the tumor transcriptome, expression data of 15 core clock genes, were related to estrogen receptor (ESR1 mRNA expression), tumor mitotic index (MI), Ellis-Elston differentiation grade and P53 mutation (FASAY technique). Statistical validation involved T-test statistics with corrections for multiple testing. Results: In tumor biopsy at baseline, both Per2 and Cry2 expressions correlated positively with ESR1 (r ≥ 0.43; p < 0.001) and negatively with MI (r ≤ -0.28 ; p < 0.007). Consistently, Per2 and Cry 2 expressions were lowest in poorly differentiated breast cancers compared with moderately to well differentiate tumors. A positive correlation was also found for Dec1 with ESR1 (r = 0.65, p < 0.001). P53 mutation was detected in 88/182 samples (48%) and was associated with a selective down-regulation of clock genes Per2, Dec1, Cry2 and Per1, compared with wt P53 tumors (p = 6.10-5,10-4, 5.10-3 and 10-2 respectively). Conclusions: In locally invasive human breast cancer, 4 of the 6 genes in the negative loop of the molecular circadian clock displayed highly statistically significant correlations with the main pathologic features that predict for patients' outcome. These data support a possible role of clock genes in the aggressiveness and therapeutic sensitivity of human breast cancer. Supported by PHRC AOM/2002/02117, Pfizer, Roche, sanofi-aventis. No significant financial relationships to disclose.
Evidence based medicine and bronchiolitis: don’t ignore uncertainties
Authors: Caroline Mawer
Journal: BMJ (2016)

Isn’t the practice update on bronchiolitis in The BMJ on 2 July (p 29) an example of evidence based medicine that injects certainty, rather than doing justice to all of the uncertainties that exist for clinicians and parents?1 I agree strongly that children with viral infections don’t benefit from, and may even be harmed by, antibiotics—and that very …
Increased total serum IgE levels in moderate-to-severe hidradenitis suppurativa
Authors: J.C. Pascual, F.J. García-Martínez, A. Martorell, I. González, P. Hispan
Journal: British Journal of Dermatology (2016)

Hidradenitis Suppurativa (HS) is a chronic, recurrent inflammatory disease mainly affecting the axillary, inguinal and perineal areas. HS commonly presents as painful inflamed nodules that can progress to abscesses, formation of fistulas, odorous discharge and scarring1. HS is considered a systemic chronic disease associated with multiples co-morbidities2.

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Immunoprofiling of leukemic stem cells CD34+/CD38−/CD123+ delineate FLT3/ITD-positive clones
Authors: Adhra Al-Mawali, David Gillis, Ian Lewis
Journal: Journal of Hematology & Oncology (2016)

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder presenting with accumulation of proliferating undifferentiated blasts. Xenograft transplantation studies have demonstrated a rare population of leukemia-initiating cells called leukemic stem cells (LSCs) capable of propagating leukemia that are enriched in the CD34+/CD38− fraction. LSCs are quiescent, resistant to chemotherapy and likely responsible for relapse and therefore represent an ideal target for effective therapy. LSCs are reported to overexpress the alpha subunit of the IL-3 receptor (CD123) compared to normal CD34+/CD38− hematopoietic stem cells. It has not been demonstrated whether CD123-positive (CD34+/CD38−) subpopulation is enriched for any clonal markers of AML or any LSC properties. The aims of this study were to investigate whether FMS-like tyrosine kinase (FLT3)/internal tandem duplication (ITD) mutations are present at LSC level and whether FLT3/ITD mutation is confined to LSC as defined by CD34+/CD38−/CD123+ and not CD34+/CD38−/CD123−. Thirty-four AML cases were analyzed by five-color flow cytometry and sequential gating strategy to characterize of CD34+/CD38−/CD123+ cells. These cells were sorted, analyzed by PCR, and sequenced for FLT3/ITD. In this study, we confirm significant expression of CD123 in 32/34 cases in the total blast population (median expression = 86 %). CD123 was also expressed in the CD34+/CD38− cells (96 ± 2 % positive) from 28/32 for CD123+ AML. CD123 was not expressed/low in normal bone marrow CD34+/CD38− cells (median expression = 0 %, range (0–.004 %). AML samples were tested for FLT3/ITD (10 positive/25). FLT3/ITD+ AML cases were sorted into two putative LSC populations according to the expression of CD123 and analyzed for FLT3/ITD again in the stem cell fractions CD34+/CD38−/CD123+ and CD34+/CD38−/CD123−. Interestingly, FLT3/ITD was only detected in CD34+/CD38−/CD123+ (7/7) and not in CD34+/CD38−/CD123− subpopulation (6/7). This finding shows that FLT3/ITD are present at LSC level and may be a primary and not secondary event in leukemogenesis, and the oncogenic events of FLT3/ITD happen at a cell stage possessing CD123. It shows that CD123 immunoprofiling provides further delineation of FLT3+ LSC clone. This novel finding provides a rationale for treatment involving CD123-targeting antibodies with intracellular FLT3 inhibitors directed against CD34+/CD38−/CD123+. This may result in more effective anti-LSC eradication.
Abstract 1891: PDGF signaling maintains survival of proneural glioma cells by regulating USP1 to stabilize ID2
Authors: Gilbert J. Rahme, Zhonghua Zhang, Alison L. Young, Chao Cheng, Eric J. Bivona, Steven N. Fiering, Yasuyuki Hitoshi, Mark A. Israel
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of GBM has identified distinct molecular subtypes of GBM with the latest report identifying four molecular subtypes: proneural, neural, classical, and mesenchymal. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in proneural GBM and can drive proneural gliomagenesis. However, little is known about the critical determinants of malignancy mediated by PDGF signaling in proneural glioma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulates ubiquitin specific peptidase 1 (Usp1) to promote survival of murine proneural glioma cells. Further experimentation revealed that PDGF-mediated expression of USP1 post-translationally stabilized Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Deletion of the Id2 gene delayed tumor-induced mortality. Pharmacological inhibition of USP1 decreased ID2 levels, and delayed tumorigenesis in mice. Importantly, decreased USP1 expression is associated with prolonged survival in patients with proneural GBM but not with other subtypes of GBM. Our data describe a signaling cascade downstream of PDGF that is required for the survival of proneural GBM cells and suggest that inhibition of the PDGF-USP1-ID2 axis could serve as a therapeutic strategy for the treatment of proneural GBM with increased PDGF signaling. Citation Format: Gilbert J. Rahme, Zhonghua Zhang, Alison L. Young, Chao Cheng, Eric J. Bivona, Steven N. Fiering, Yasuyuki Hitoshi, Mark A. Israel. PDGF signaling maintains survival of proneural glioma cells by regulating USP1 to stabilize ID2. [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 1891.
Effect of nilotinib on proliferation and function of CD8+ T lymphocytes and the role of T cell receptor signaling
Authors: J. Chen, B. Chen, M. Schmitt
Journal: Journal of Clinical Oncology (2008)

14546 Background: The novel, selective BCR-ABL inhibitor nilotinib has produced hematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. As nilotinib might be used in the framework of allo- transplantation and other T cell based immunotherapies, we wondered whether inhibition of ABL kinase by nilotinib might have a detrimental effect on the immune response. In several studies, T lymphocytes from CML patients have been found to be Ph chromosome negative and/or BCR-ABL negative. On the other hand, several of intracellular signaling molecules triggered by the ABL kinase are also involved in the activation pathways of immune cells. Methods: We used Mixed lymphocyte peptide cultures (MLPCs),enzyme linked immunospot (ELISPOT) assays for interferon-γ and Granzyme-B,flow cytometry for activation markers and signal transduction cascade,5-bromo-2-deoxyuridine (BrdU) measurement of cell proliferation,and 51Cr release cytotoxicity assay to detect the inhibitory effects of nilotinib on CD8+ T lymphocytes. Results: Nilotinib inhibits phytohemagglutinin (PHA)-induced proliferation of CD8+ T lymphocytes in vitro at therapeutically relevant concentrations (0.5–4 μM). The inhibition of CD8+ T lymphocytes specific for leukemia or viral antigens through nilotinib was associated with a reduced expansion of antigen peptide specific CD8+ T lymphocytes and with a decreased release of interferon- γ and granzyme B by these cells as analyzed by flow cytometry and ELISPOT assays. The inhibitory effect caused by nilotinib was two times stronger than by imatinib. These effects were mediated through the inhibition of the phosphorylation of ZAP-70, Lck and ERK 1/2 and the NF-κB signaling transduction pathway. Conclusions: Taken together, we observed a strong suppressive impact of nilotinib on the CD8+ T lymphocyte function which should be considered carefully in the framework of allogeneic stem cell transplantation or other T cell based immunotherapies. No significant financial relationships to disclose.
Surveillance de la prévalence du VIH et des comportements des hommes ayant des relations sexuelles avec d’autres hommes à Barcelone, Espagne
Authors: K Pérez, A Rodes, J Casabona Barbarà
Journal: Eurosurveillance (2002)

Differentes etudes chez les hommes ayant des relations sexuelles avec d’autres hommes (HSH) ont recemment revele une augmentation de l’incidence du VIH, et des infections sexuellement transmissibles, de meme qu’une augmentation des comportements a risque. On peut s’attendre a un plus grand relâchement des mesures de protection suite a l’optimisme du aux traitements anti-retroviraux.
BERIL-1: A phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).
Authors: Denis Soulieres, Sandrine J. Faivre, Ricard Mesia, Eva Remenar, Shau-Hsuan Li, Andrey Karpenko, Arunee Dechaphunkul, Ulrich Keilholz, Laura Anna Kiss, Jin-Ching Lin, Rajnish Vasant Nagarkar, Laszlo Tamas, Sung-Bae Kim, Jozsef Erfán, Sabine Turri, Debarshi Dey, Arunava Chakravartty, Paola Aimone, Cristian Massacesi, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2016)

6008 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in HNSCC, contributing to treatment resistance and disease progression. Buparlisib (BUP) is a pan-PI3K inhibitor that elicits tumor control in preclinical models of HNSCC and shows signs of clinical activity in other squamous cancers. Methods: In this phase II study (NCT01852292), patients (pts) with recurrent/metastatic HNSCC progressing after platinum-based therapy were randomized (1:1) to receive BUP (100 mg/day) + paclitaxel (PAC; 80 mg/m2/week) or placebo (PBO) + PAC, stratified by prior lines of treatment (1 vs 2) and study site (North America vs rest of world), until progressive disease (PD) or discontinuation. The primary endpoint was progression-free survival (PFS; per RECIST v1.1). Overall survival (OS) was the key secondary endpoint; other secondary endpoints included overall response rate (ORR) and safety (per CTCAE v4.03). Results: As of August 31, 2015, 158 pts were randomized to receive BUP + PAC vs PBO + PAC (n = 79 each), with 10 (13%) and 7 (9%) pts ongoing, respectively. Median age was 59 vs 58 years; 29% vs 39% of pts had laryngeal/hypopharyngeal primary tumors; 67% vs 79% were human papillomavirus (HPV)-negative; and 52% vs 38% had received a prior EGFR inhibitor. Primary reasons for treatment discontinuation were PD in 46% vs 60% of pts, and adverse events (AEs) in 9% vs 14%. Median PFS was improved for BUP vs PBO (4.6 vs 3.5 months; hazard ratio [HR] 0.65 [95% CI: 0.45–0.95]). Posterior probability of (HR < 1) was > 97.5%. The PFS improvement was consistent across exploratory subgroups. ORR was 39% vs 14%. Median OS at data cut-off was 10.0 vs 6.5 months (HR 0.71 [95% CI: 0.46–1.1]), based on 84/112 (75%) planned deaths. Grade 3/4 AEs ( ≥ 10% of pts) were hyperglycemia (22% vs 3%), anemia (18% vs 12%), neutropenia (17% vs 5%), and fatigue (8% vs 10%). Conclusions: The BERIL-1 study met its primary endpoint, demonstrating improved PFS for the combination of BUP + PAC vs PAC, notably in pts with poor prognosis HNSCC (73% of pts were HPV-negative). The safety profile of the combination was manageable. Follow-up for final OS analysis is ongoing. Clinical trial information: NCT01852292.
Abstract 3164: Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance
Authors: Willemina R.R. Geurts-Giele, Victorien M.T. van Verschuer, Carolien H.M. van Deurzen, Paul J. van Diest, Rute M. Pedrosa, J. Margriet Collee, Linetta B. Koppert, Caroline Seynaeve, Winand N.M. Dinjens
Journal: Cancer Research (2016)

Abstract PURPOSE Female BRCA1/2 mutation carriers commonly develop breast cancer and ovarian cancer. It is of utmost importance to know the clonal relationship between multiple tumor localizations, (multiple primaries or metastasized disease), since prognosis and treatment differ between these tumors and their metastases. We evaluated the value of targeted Next Generation Sequencing (NGS) in the diagnostic workup of BRCA1/2 mutation carriers with ≥2 tumor localizations and uncertain tumor origins. METHODS Forty-two female BRCA1/2 mutation carriers with ≥2 tumor locations with tumor material available for pathologic revision were selected. Median age at first cancer diagnosis was 48.0 years (range 30-68). Four patients with inconclusive tumor origin after histological and immunohistochemical analyses were ‘cases’; 10 patients with certain tumor origin of ≥3 tumors served as ‘controls’. Tumors of cases and controls were analyzed by targeted NGS using a panel including CDKN2A, PTEN and TP53, hotspot mutation sites for 27 different genes and 143 single nucleotide polymorphisms for detection of loss of heterozygosity (LOH). Based on prevalence of identical or different mutations and/or LOH patterns, tumors were classified as ‘multiple primaries’ or ‘one entity’. RESULTS In 44 tumors, 48 mutations were found; 39 (81%) concerned TP53 mutations. In all 10 controls and all 4 cases, the intrapatient clonal relationships between the tumors could be unequivocally identified by molecular analysis. In all controls, tumor origins based on molecular outcomes matched the conventional histopathological diagnosis. CONCLUSION In 90% of BRCA1/2 mutation carriers with multiple tumors routine pathology work-up is sufficient to determine tumor origins and relatedness. In case of inconclusive conventional pathology results, molecular analyses using NGS can reliably determine clonal relationships between tumors, enabling optimal treatment of individual patients. Citation Format: Willemina R.R. Geurts-Giele, Victorien M.T. van Verschuer, Carolien H.M. van Deurzen, Paul J. van Diest, Rute M. Pedrosa, J. Margriet Collee, Linetta B. Koppert, Caroline Seynaeve, Winand N.M. Dinjens. Molecular determination of the clonal relationship between multiple tumors in BRCA1/2-associated cancer patients has clinical relevance. [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 3164.
Abstract 2829: Preclinical analysis and characterization of abemaciclib using three-dimensional patient-derived colorectal cancer organoid cultures
Authors: Karsten Boehnke, Bruna Calsina, Joaquín Amat, Ana Hermoso, Raquel Torres, Christoph Reinhard, Juan A. Velasco, Philip W. Iversen, Alfonso De Dios, Sean Buchanan, Richard P. Beckmann, Dirk Schumacher, Christian RA Regenbrecht, Marie-Laure Yaspo, Hans Lehrach, María José Lallena
Journal: Cancer Research (2016)

Abstract Proper patient-tailoring strategy and the validation of novel therapeutic targets remain enormous challenges during drug discovery processes. Patient-derived three-dimensional organoid cell culture models possess great potential to associate compound sensitivity and disease complexity in order to provide a key missing link between compound screening and clinical trials. Abemaciclib is a reversible, ATP competitive, selective inhibitor of the kinase activity of both CDK4 and CDK6 and is currently undergoing advanced clinical testing. In this study, we established and characterized three-dimensional organoid cultures from primary colorectal cancer patients and validated their use as drug sensitivity models. We aimed to explore the antitumor activity of abemaciclib in colon cancer organoid cultures by assessing markers for cell viability, proliferation, cell cycle, senescence and apoptosis. Single cell suspension of patient-derived samples were precultured for four days to allow for complete morphogenesis of three-dimensional organoid structures. Subsequently, the cultures were treated for at least two population doubling times and analyzed by luminescent cell viability, immunohistochemistry and flow cytometry assays. Our data suggest that abemaciclib treatment decreased the cell viability of patient-derived colorectal cancer organoid cultures characterized by G1 cell cycle arrest and reduced Ki-67-positive cells. Furthermore, treated cultures showed elevated levels of reactive oxygen species and increased markers for early and late apoptosis. In summary, complex organoid models have the potential to further evaluate the antitumor activity of abemaciclib in various tumor types by enabling mechanistic studies in a patient-specific preclinical setting. Citation Format: Karsten Boehnke, Bruna Calsina, Joaquín Amat, Ana Hermoso, Raquel Torres, Christoph Reinhard, Juan A. Velasco, Philip W. Iversen, Alfonso De Dios, Sean Buchanan, Richard P. Beckmann, Dirk Schumacher, Christian RA Regenbrecht, Marie-Laure Yaspo, Hans Lehrach, María José Lallena. Preclinical analysis and characterization of abemaciclib using three-dimensional patient-derived colorectal cancer organoid cultures. [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 2829.
Androgen deprivation therapy use and the risk of venous thromboembolism.
Authors: Adi Joseph Klil-Drori, Hui Yin, Vicky Tagalakis, Armen G. Aprikian, Laurent Azoulay
Journal: Journal of Clinical Oncology (2015)

e16131 Background: The use of androgen deprivation therapy (ADT) has been associated with an increased risk of venous thromboembolism (VTE) in patients with prostate cancer, but data remain limited. Methods: A population-based cohort of 21,729 men newly-diagnosed with prostate cancer between 1998 and 2014 was identified using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalized VTE associated with current and past ADT use, compared with non-use. A secondary analysis was conducted to assess the risk with current use of specific types of ADT. Results: During a mean follow-up of 4.1 years, there were a total of 609 hospitalized incident VTEs. Compared with non-use, current ADT use was associated with a two-fold increased risk of VTE (incidence rates: 10.1 vs 4.8 per 1000 persons per year; HR: 1.99; 95% CI: 1.62-2.43), while there was no association with past use (HR: 1.09, 95% CI: 0.83-1.45). In the secondary analysis, current use of estrogens was associated with the highest risk (HR: 8.73, 95% CI: 4.06-18.79), followed by gonadotropin-releasing hormone (GnRH) agonists and oral antiandrogens (OAA) combined (HR: 2.96, 95% CI: 2.21-3.97), bilateral orchiectomy (HR: 1.68, 95% CI: 0.69-4.11), GnRH agonists alone (HR: 1.61, 95% CI: 1.28-2.01), and OAA alone (HR: 1.48, 95% CI: 1.01-2.16). Conclusions: Current use of ADT was associated with a two-fold increased risk of VTE. The risk was elevated with all ADT types, including GnRH agonists.