tbuckley/cabot-search huggingface dataset:
Abstract 792: Super-transactivation TP53 variant in the germline of a family with Li-Fraumeni variant
Authors: Badr Id Said, Han Kim, James Tran, Ana Novokmet, David Malkin
Journal: Cancer Research (2016)

Abstract Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic p53 variants detected in patients with a suspected diagnosis of LFS. We report for the first time the discovery of two novel functional variants in codons 191(c.572C&amp;gt;G; p.P191R) and 360 (c.1079G&amp;gt;T; p.G360V), located, respectively, in the DNA binding domain and in a linker region near the tetramerization domain of TP53. Our data revealed that while the P191R variant decreased the transactivation levels of several p53 targets, it failed to segregate with the disease state. The G360V variant, on the other hand, behaved in a paradoxical fashion by causing a stark upregulation in the activity of several p53 response elements. This tumor suppressive effect was also observed at the level of colony formation and c-Caspase 3 activation. While unlikely to be disease-causing, we propose that these variants may represent novel p53 polymorphisms and potential phenotypic modifiers in LFS. In the future, the enhanced transactivation effects of G360V-p53 may also prove useful in designing more efficacious p53-based gene therapies. Citation Format: Badr Id Said, Han Kim, James Tran, Ana Novokmet, David Malkin. Super-transactivation TP53 variant in the germline of a family with Li-Fraumeni variant. [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 792.
Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3
Authors: Bethany Baumann, Tomoko Hayashida, Xiaoyan Liang, H. William Schnaper
Journal: Kidney International (2016)

The function of hypoxia-inducible factor-1α (HIF-1α) in chronic kidney disease is disputed. Here we report that interactions of HIF-1α with transforming growth factor-β (TGF-β) signaling may promote its fibrotic effects. Knockout of HIF-1α is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that α2(I) collagen expression is directly regulated by HIF-1α binding to a functional hypoxia-responsive element in its promoter at –335 relative to the transcription start site. Activation of COL1A2 transcription by HIF-1α occurred in the absence of hypoxia and is strongly enhanced by TGF-β signaling. TGF-β, in addition to increasing HIF-1α levels, increased both HIF-1α binding to the COL1A2 promoter and HIF-1α N-terminal transactivation domain activity. These effects of TGF-β on HIF-1α were inhibited in Smad3-null mouse embryonic fibroblasts, suggesting a requirement for Smad3. Phosphorylated Smad3 also associated with the –335 hypoxia-responsive element of the COL1A2 promoter independent of a Smad DNA binding sequence. Smad3 binding to the –335 hypoxia-responsive element required HIF-1α both in vitro and in kidney lysate from the disease model, suggesting formation of an HIF-1α–Smad3 transcriptional complex. Thus, HIF-1α-Smad3 has a novel interaction in glomerulosclerosis.
Use of serotype specific serology (IgA and IgG) in the etiologic diagnosis of childhood pneumococcal pneumonia : firts results from the Pediatric Pneumococcal (3P) trial.
Authors: Anne Malfroot, Isabelle De Schutter, Julie Smet, Pierre Smeesters, Filip Surmont, D Tuerlinckx, M. Raes, Jeremy Tresnie, Anne Vergison, Jacques Verhaegen, Françoise Mascart
Journal: European Respiratory Journal (2010)
Functional Analysis of Kinase-Activating Fusions in Ph-like Acute Lymphoblastic Leukemia
Authors: Kathryn G. Roberts, Yung-Li Yang, Debbie Payne-Turner, Richard C. Harvey, I-Ming Chen, Shalini C. Reshmi, Gastier-Foster Julie, Mignon L. Loh, Cheryl L. Willman, Stephen P. Hunger, Charles G. Mullighan
Journal: Blood (2014)
Abstract 1215: Utilization of podoplanin as a chemotherapeutic target for oral squamous cell carcinoma
Authors: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Maria I. Rameriz, Kingsley Yin, Mary Ann Young, Lisa Deluca-Rapone, Alan J. Shienbaum, Lasse D. Jensen, Gary S. Goldberg
Journal: Cancer Research (2016)

Abstract Oral cancer is diagnosed in over 300 thousand people, and kills over 100 thousand people, around the world each year. Current treatments rely on radiation and surgery procedures that often decrease the quality of life for oral cancer survivors. There is a clear need to improve treatments for these patients. Over 90% of oral cancers are formed by oral squamous cell carcinoma (OSCC). Most OSCC cells express the transmembrane receptor podoplanin (PDPN), which has emerged as a promising target for OSCC treatment. The PDPN receptor promotes tumor cell invasion and metastasis which leads to the vast majority of cancer deaths. Here, we describe efforts to target PDPN intracellularly and extracellularly in order to prevent and treat oral cancer. PDPN contains intracellular serine residues that can be phosphorylated by protein kinases including CDK5 and PKA to decrease cell migration. Additionally, the extracellular portion of PDPN can be targeted with Maackia amurensis seed lectin (MASL) to inhibit tumor cell migration and viability. Previous studies suggest that PDPN induces RhoA GTPase activity to promote cell migration. However, we show here that MASL dynamically binds PDPN to downregulate Cdc42 GTPase activity, but not RhoA or Rac1 GTPase activity. These data suggest that MASL suppresses Cdc42 GTPase activity to disrupt cell polarity and inhibit cell migration. Taken together, these data indicate that PDPN can serve as a functionally relevant target to prevent and combat oral cancer. Citation Format: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Maria I. Rameriz, Kingsley Yin, Mary Ann Young, Lisa Deluca-Rapone, Alan J. Shienbaum, Lasse D. Jensen, Gary S. Goldberg. Utilization of podoplanin as a chemotherapeutic target for oral squamous cell carcinoma. [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 1215.
Effect of Serotonin Transporter 5-HTTLPR Polymorphism on Gastrointestinal Intolerance to Metformin: A GoDARTS Study
Authors: Tanja Dujic, Kaixin Zhou, Roger Tavendale, Colin N.A. Palmer, Ewan R. Pearson
Journal: Diabetes Care (2016)

The mechanism causing gastrointestinal intolerance to metformin treatment is unknown. We have previously shown that reduced-function alleles of organic cation transporter 1 (OCT1) are associated with increased intolerance to metformin. Considering recent findings that serotonin reuptake transporter (SERT) might also be involved in metformin intestinal absorption, and the role of serotonin in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in the SERT gene and metformin gastrointestinal intolerance.
Postoperative Radiotherapy Patterns of Care and Survival Implications for Medulloblastoma in Young Children
Authors: Benjamin H. Kann, Henry S. Park, Nataniel H. Lester-Coll, Debra N. Yeboa, Viviana Benitez, Atif J. Khan, Ranjit S. Bindra, Asher M. Marks, Kenneth B. Roberts
Journal: JAMA Oncology (2016)

Postoperative radiotherapy to the craniospinal axis is standard-of-care for pediatric medulloblastoma but is associated with long-term morbidity, particularly in young children. With the advent of modern adjuvant chemotherapy strategies, postoperative radiotherapy deferral has gained acceptance in children younger than 3 years, although it remains controversial in older children.To analyze recent postoperative radiotherapy national treatment patterns and implications for overall survival in patients with medulloblastoma ages 3 to 8 years.Using the National Cancer Data Base, patients ages 3 to 8 years diagnosed as having histologically confirmed medulloblastoma in 2004 to 2012, without distant metastases, who underwent surgery and adjuvant chemotherapy with or without postoperative radiotherapy at facilities nationwide accredited by the Commission on Cancer were identified. Patients were designated as having "postoperative radiotherapy upfront" if they received radiotherapy within 90 days of surgery or "postoperative radiotherapy deferred" otherwise. Factors associated with postoperative radiotherapy deferral were identified using multivariable logistic regression. Overall survival (OS) was compared using Kaplan-Meier analysis with log-rank tests and multivariable Cox regression. Statistical tests were 2-sided.Postoperative radiotherapy utilization and overall survival.Among 816 patients, 123 (15.1%) had postoperative radiotherapy deferred, and 693 (84.9%) had postoperative radiotherapy upfront; 36.8% of 3-year-olds and 4.1% of 8-year-olds had postoperative radiotherapy deferred (P < .001). On multivariable logistic regression, variables associated with postoperative radiotherapy deferral were age (odds ratio [OR], 0.57 per year; 95% CI, 0.49-0.67 per year) and year of diagnosis (OR, 1.18 per year; 95% CI, 1.08-1.29 per year). On survival analysis, with median follow-up of 4.8 years, OS was improved for those receiving postoperative radiotherapy upfront vs postoperative radiotherapy deferred (5-year OS: 82.0% vs 63.4%; P < .001). On multivariable analysis, variables associated with poorer OS were postoperative radiotherapy deferral (hazards ratio [HR], 1.95; 95% CI, 1.15-3.31); stage M1-3 disease (HR, 1.86; 95% CI, 1.10-3.16), and low facility volume (HR, 1.75; 95% CI, 1.04-2.94).Our national database analysis reveals a higher-than-expected and increasing rate of postoperative radiotherapy deferral in children with medulloblastoma ages 3 to 8 years. The analysis suggests that postoperative radiotherapy deferral is associated with worse survival in this age group, even in the modern era of chemotherapy.
Randomized, placebo-controlled phase II trial (MAJA): Efficacy results of maintenance vinflunine after cisplatin chemotherapy (CT) in patients with advanced urothelial carcinoma (UC)—SOGUG 2011-02.
Authors: Albert Font, Begoña Perez-Valderrama, Juan Antonio Virizuela, Susana Hernando Polo, Miguel Angel Climent, Jose Angel Arranz Arija, Jose Carlos Villa Guzman, Maria del Mar LLorente, Nuria Lainez, Begona Mellado, Aranzazu Gonzalez del Alba, Enrique Gallardo Diaz, Daniel Castellano, Urbano Anido Herranz, Montserrat Domenech, Xavier Garcia del Muro, Javier Puente, Rafael Morales, Jesús García-Donas, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2016)

4529 Background: Vinflunine (VFL) is a microtubule inhibitor approved by EMA as treatment after platinum progression in metastatic UC. We evaluated whether maintenance VFL delays progression after response to CT. Methods: Patients (pts) with measurable disease, locally recurrent/metastatic UC and adequate organ function with radiological response or stabilization after 4-6 cycles (cy) of a cisplatin/gemcitabine chemotherapy (carboplatin allowed after cy 4) were randomized (R) 1:1 to receive VFL 320 or 280mg/m2 (in case of PS1, age ≥ 75 years, prior pelvic radiotherapy (RT) or CrCl < 60ml/min) every 21 days vs best supportive care (BSC), until disease progression. Primary endpoint was progression free survival (PFS). With a median PFS considered unacceptable for the experimental arm of 4 months (m) (p0) and acceptable 6.5m (p1). 78 eligible were required for an α-error of 0.05 (one-tailed test) and a 0.1 β-error. Results: 88 pts from 21 institutions of SOGUG were R between 04/2012-01/2015. Forty five in the VFL arm and 43 in the BSC arm. 1 pt was not treated. 1 of 87 treated pts was not eligible due to an excess of time between the last dose of cisplatin and the start of VFL. At the beginning of treatment: median age 64 years [42-83]; PS1 50%; Hb < 10g/dl 8%; liver metastasis 21%. Pts in the VFL arm received a median of 6 cy per patient [1–43]. 10 pts (22.2%) continue in treatment in VFL arm. Most common G3/4AEs (%pts) in VFL arm were constipation (13.6), neutropenia (15.9), fatigue (15.9), and 1 febrile neutropenia (2.3). After a median of 12.2 m of follow-up [0.5-41.4], 59% of pts have progressed and 43% of pts have died in the VFL arm; 81% and 62% pts respectively in the BSC arm. The median PFS was of 6.5 m (1.3-11.7) in the VFL arm and 4.6 m (3.1-6) the BSC arm; HR 0.56 (IC95%; 0.34-0.93, p = 0.024). After progression, 34% of pts received treatment at VFL arm and 60% of pts at BSC arm. Conclusions: Maintenance VFL in patients with disease control after first line cisplatin-based chemotherapy significantly reduces 44% the risk of progression with an acceptable tolerability profile. Trial is maturing to assess the impact of maintenance VFL in survival. Clinical trial information: NCT01529411.
Abstract 1029: Rab1A and Rab1B promote esophageal squamous cell carcinoma through activating mTORC1 signaling and inhibiting autophagy
Authors: Xian-Zi Yang, Ren Wang, Xiao-Xing Li, Yang Yang, Hui-Yun Wang, X. F. Steven Zheng.
Journal: Cancer Research (2016)

Abstract Background: Rab1A has recently been shown to act as an oncogene and promote colorectal and liver tumorigenesis. In this study, we aim to understand the potential role of Rab1A and its homolog Rab1B in esophageal squamous cell carcinoma (ESCC) and the underlying molecular mechanisms. Methods: The expressions of Rab1A and Rab1B in139 paired human ESCC tissues and adjacent normal tissues were evaluated by immunohistochemistry. A series of in vitro and in vivo assays were performed to elucidate the biological functions of Rab1A and Rab1B, and their role in the regulation of mTOR signaling, autophagy and ESCC tumorigenesis. Results: The level of Rab1A and Rab1B is elevated in ESCC tissues, which is positively correlated with tumor TNM stages and N stages. The overall expression of Rab1A and Rab1B is an independent predictor of patient survival (P&amp;lt;0.01). Down-regulation of Rab1A and Rab1B individually and in combination in ESCC cells inhibits cell proliferation and migration, and enhances autophagy. Mechanistically, Rab1A and Rab1B activate mTORC1 to enhance growth and suppress autophagy. Conclusion: Our results suggest that Rab1A and Rab1B cooperatively regulate ESCC proliferation and autophagy by activating mTORC1 signaling. They may serve as promising prognostic biomarkers and/or potential molecular targets of ESCC treatments. Citation Format: Xian-Zi Yang, Ren Wang, Xiao-Xing Li, Yang Yang, Hui-Yun Wang, X. F. Steven Zheng. Rab1A and Rab1B promote esophageal squamous cell carcinoma through activating mTORC1 signaling and inhibiting autophagy. [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 1029.
Comprehensive genomic characterization of clear-cell renal cell carcinomas with sarcomatoid dedifferentiation.
Authors: Ronan Flippot, Gabriel G. Malouf, Xiaoping Su, Eva Comperat, Roger Mouawad, Morgan Roupret, Jean-Philippe Spano, David Khayat
Journal: Journal of Clinical Oncology (2016)

e16076 Background: Clear-cell renal cell carcinomas with sarcomatoid dedifferentiation (sRCC) represent the most aggressive subtype among kidney tumors. Whether these tumors harbored additional genetic aberrations as compared to clear-cell RCC remain fully unknown. Methods: Whole-exome sequencing was performed on 16 primary sRCCs and matched normal tissues, including 2 cases which displayed both sarcomatoid and rhabdoid features. Median coverage obtained for cancer and normal samples were ~110x and ~50x, respectively. Data was compared with clear-cell RCC dataset of the Cancer Genome Atlas Project (TCGA, n = 424). Correlations between mutational load and clinico-pathological tumor features were also performed. Results: The median number of somatic alterations was 55 per case (range: 14-139). Genes most frequently mutated were VHL (69%), PBRM1 (44%), SETD2 (19%) and BAP1 (12%). None of those genes were statistically enriched in sRCC as compared to clear-cell RCC in TCGA dataset. Of note, the majority of sRCC cases harbored either VHL and/or PBRM1 (84%) mutations. Unexpectedly, mutational load was strongly associated with age (p = 0.015) but not with other classical prognostic tumor features such as Fuhrmann grade and TNM stage. Importantly, we independently validated our observation in clear-cell RCC TCGA dataset of high-grade clear-cell RCC (Spearman R = 0.27, P = 0.02). Conclusions: These data pinpoint that genetic of sRCC might not differ from other clear-cell RCC. In addition, correlation between mutational load and age of onset of sRCC suggests an interplay between genetic aberrations and epigenetic drift in aging kidneys. Thus, understanding of epigenetic alterations in sRCC might provide clues on aggressiveness of sarcomatoid variant of clear-cell RCC.
Abstract 2712: Joint somatic mutation and germline variant identification and scoring from tumor molecular profiling and ct-DNA monitoring of cancer patients by high-throughput sequencing
Authors: Francisco M. De La Vega, Ryan T. Koehler, Yannick Pouliot, Yosr Bouhlal, Austin So, Federico Goodsaid, Sean Irvine, Len Trigg, Lincoln Nadauld
Journal: Cancer Research (2016)

Abstract Cancer tumor profiling by targeted resequencing of actionable cancer genes is rapidly becoming the standard approach for selecting targeted therapies and clinical trials in refractory cancer patients. In this clinical scenario, a tumor sample is obtained from an FFPE block and sequenced by targeted next-generation sequencing (NGS) to uncover actionable somatic mutations in relevant cancer genes. Some of the challenges that arise in analyzing tumor-derived NGS data include distinguishing between somatic and germline variants in the absence of normal tissue data, recognizing pathogenic germline variants, and identifying sequencing errors (which occur at about 0.5% rate). Additional challenges arise when considering other clinical applications of NGS such as sequencing cell-free tumor DNA (cf-DNA) from plasma samples to monitor disease response or disease recurrence. Here we present a principled approach to identify both single-nucleotide and small insertion/deletion somatic mutations and germline variants from NGS data of tumor tissue that leverages the allelic fraction patterns in tumors and prior information from external databases through the use of a Bayesian Network algorithm. Our approach allows us to score each putative mutation or variant with respect to its probability of belonging to each variant class, versus classification as a sequencing error. The method enables the joint calling of related samples form the same patient, such as cases where a cf-DNA sample and primary tumor sample are both profiled improving sensitivity and specificity. We validated our method by analyzing data obtained with the TOMA OS-Seq targeted sequencing RUO assay for 98 cancer genes from a mixture of well-known genomes, patient case triads (where normal, tumor and cf-DNA are available), and a retrospective analysis of tumor patient data that underwent clinical tumor profiling for therapy selection. Citation Format: Francisco M. De La Vega, Ryan T. Koehler, Yannick Pouliot, Yosr Bouhlal, Austin So, Federico Goodsaid, Sean Irvine, Len Trigg, Lincoln Nadauld. Joint somatic mutation and germline variant identification and scoring from tumor molecular profiling and ct-DNA monitoring of cancer patients by high-throughput sequencing. [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 2712.
Abstract 1393: Developing a next-generation noninvasive clinical test for non-small cell lung cancer
Authors: Christopher Kasbek, Yang Song, Danielle Quintanilha, Si Chen, QingXuan Song, Tianjiao Wang, Jun T. Huang
Journal: Cancer Research (2016)

Abstract Significance: Non-Small Cell Lung Cancer (NSCLC) is responsible for the largest number of cancer-related fatalities, accounting for 22.8% of all cancer deaths in the United States in 2015. Targeted therapy precisely treats mutated cancer pathways and has significantly higher response rates compared to chemotherapy. However, tumor heterogeneity is prevalent in NSCLC patients, and the common practice of detecting mutations using tissue biopsy from a fraction of a single tumor can be less than satisfactory. Failure to detect molecular resistance emerging from heterogenic tumor cell population is a major reason that, even though highly effective, targeted therapy has not contributed greatly to prolong patient survival. We aim to develop a cost-effective, highly sensitive and specific liquid biopsy for advanced stage NSCLC patients that is able to capture a comprehensive tumor profile and monitor tumor response to therapy. Innovation: BEST (Blocker-based Enrichment System for Tumor DNA) blocks primer extension of over 90% of wild type DNA and allows preferential amplification of the mutant allele. BEST NSCLC liquid biopsy is highly sensitive (limit of detection of &amp;gt; = 0.005%), comprehensive (detects 56 mutations in the EGFR, KRAS, BRAF, ALK, and ROS1 oncogenes), and rapid (estimated 4-day turnaround time). BEST is comprised of a multiplex of circulating tumor DNA enrichment reaction and a multiplex plasma cDNA enrichment reaction. Our BEST NSCLC liquid biopsy panel enriches &amp;gt;100 fold for the above driver mutations. The ability to detect a myriad of mutations in heterogenic tumor cell populations allows dynamic and personalized treatment during the course of the disease. Summary: Our primary focus is to offer a test to detect actionable mutations and subsequently monitor tumor dynamics and the rise of molecular resistance. Our liquid biopsy will be also ideal for patients in follow-up visits in conjunction with the typical X-ray or CT image scans. Our test is also suitable for vulnerable patients from whom a solid biopsy cannot be obtained due to illness or inaccessibility. Citation Format: Christopher Kasbek, Yang Song, Danielle Quintanilha, Si Chen, QingXuan Song, Tianjiao Wang, Jun T. Huang. Developing a next-generation noninvasive clinical test for non-small cell lung 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 1393.
Le paludisme en Italie : incidence et mortalité entre 1999 et 2000
Authors: R Romi, D Boccolini, G Majori
Journal: Eurosurveillance (2001)

En 1999-2000, 2060 cas de paludisme au total ont ete rapportes par l’ISS. La plupart des patients avaient suivi un traitement inapproprie ou aucun traitement. Quatre-vingt-treize pour cent ont ete infectes dans des pays africains impaludes, 4% en Asie et 3% en Amerique latine. P. falciparum etait implique dans 84% des cas, suivi de P. vivax (8%), de P. ovale (5%) et de P. malariae (2%). Les deces correspondaient a un taux annuel de letalite de 0,3% et de 0,5% en 1999 et 2000 respectivement. Les cas importes correspondaient en general a des voyageurs italiens qui ont sous-estime le risque d’infection dans les pays impaludes en Asie et en Amerique latine, et des residents permanents d’origine africaine, qui ont rendu visite a leur famille dans leur pays natal.