tbuckley/cabot-search huggingface dataset:
Intended Target of the Centers for Disease Control and Prevention Opioid Guidelines—Reply
Authors: Michael J. Fisch, Victor T. Chang
Journal: JAMA Oncology (2016)

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Abstract 3379: Tumor-induced remote extracellular matrix network orientation steers angiogenesis
Authors: Erik H. Danen
Journal: Cancer Research (2016)

Abstract Tumor angiogenesis promotes tumor growth and metastasis. Here, we use automated sequential microprinting of tumor and endothelial cells in extracellular matrix (ECM) scaffolds to study its mechanical aspects. Quantitative reflection microscopy shows that tumor spheroids induce radial orientation of the surrounding collagen fiber network up to a distance of five times their radius. Across a panel of ∼20 different human tumor cell lines, remote collagen orientation is correlated with local tumor cell migration behavior. Tumor induced collagen orientation requires contractility but is remarkably resistant to depletion of collagen-binding integrins. Microvascular endothelial cells undergo directional migration towards tumor spheroids once they are within the tumor-oriented collagen fiber network. Laser ablation experiments indicate that an intact physical connection of the oriented network with the tumor spheroid is required for mechanical sensing by the endothelial cells. Together our findings show that remote physical manipulation of the ECM network by the tumor steers angiogenesis. Citation Format: Erik H. Danen. Tumor-induced remote extracellular matrix network orientation steers angiogenesis. [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 3379.
Abstract 5078: Tumor treating fields (TTFields) reduce migration and invasion properties of human glioma cancer cells <i>in vitro</i>
Authors: Rosa S. Schneiderman, Anna Shteingauz, Moshe Giladi, Tali Voloshin, Yaara Porat, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2016)

Abstract The ability of glioblastoma cells to invade adjacent brain tissue remains one of the major obstacles in obtaining therapeutic success. The development of novel treatment modalities that hinder glioma cancer cell motility could therefore facilitate disease control. TTFields are an effective treatment modality delivered via continuous, noninvasive application of low intensity, intermediate frequency, alternating electric fields. This therapy is approved for the treatment of patients with glioblastoma. Previous investigations have shown that TTFields disrupt microtubules and septin filaments, both of which govern key roles in mitosis. The goal of this study was to evaluate the possible effect of TTFields on human glioma cell migration and invasion properties. Four human glioma cell lines: U-87 MG, A-172, LN-229, and LN-18 (ATCC, USA) were treated with TTFields (1.75 V/cm RMS, 200 kHz) for 24 hours using the inovitro system. Cell migration was measured using in vitro wound healing assays. These were analyzed with Image Pro Premier (Media Cybernetics, USA) to determine migration rates. Invasion assays were performed using modified Matrigel coated Boyden chamber. Cells were stained, photographed and counted using image J (NIH, USA). Application of TTFields in-vitro led to a significant reduction in both migratory and invasive phenotype in all tested cell lines. Specifically, cell migration velocity, as assessed by the wound healing assay, was significantly reduced in U-87 MG (60%, P&amp;lt;0.001), and in A-172 (33%, P&amp;lt;0.001) compared with untreated control cells. The number of invading cells, as assessed by the modified Boyden chamber assay, was reduced in U-87 MG (54%, P&amp;lt;0.01), A-172 (51%, P&amp;lt;0.001), LN-229 (52%, P&amp;lt;0.001) and in LN-18 (30%, P&amp;lt;0.001) compared with untreated control cells. Our results suggest that human glioma cell motility is impaired by exposure to TTFields. Further studies are needed to elucidate the mechanism by which TTFields disrupts cellular motility in glioma cancer cells. Citation Format: Rosa S. Schneiderman, Anna Shteingauz, Moshe Giladi, Tali Voloshin, Yaara Porat, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor treating fields (TTFields) reduce migration and invasion properties of human glioma cancer cells in vitro. [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 5078.
Martinique Crinkled Retinal Pigment Epitheliopathy
Authors: Albert Jean-Charles, Harold Merle, Isabelle Audo, Catherine Desoudin, Béatrice Bocquet, Corinne Baudoin, Moro Sidibe, Martine Mauget-Faÿsse, Benjamin Wolff, Agnès Fichard, Guy Lenaers, José-Alain Sahel, Alain Gaudric, Salomon Yves Cohen, Christian P. Hamel, Isabelle Meunier
Journal: Ophthalmology (2016)
Abstract 4867: The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses
Authors: Erin L. Filbert, Pia Björck, Xiaodong Yang, Ovidiu C. Trifan
Journal: Cancer Research (2016)

Abstract Modulation of co-stimulatory and co-inhibitory molecules on immune cells has become a promising approach for cancer immunotherapy. CD40 engagement on antigen presenting cells (APCs) by its ligand CD154 leads to maturation and expression of co-stimulatory molecules such as CD80, CD86, OX-40L, and 4-1BBL that are requisite for optimal antigen-specific T-cell activation, an essential component of the anti-tumor immune response. To evaluate the therapeutic potential of targeting the CD40-CD154 pathway, Apexigen has developed APX005M - a humanized IgG1 CD40 agonistic antibody that binds with high affinity to human CD40. APX005M mimics CD154, has potent CD40 agonistic activity and promotes activation of APCs. Monocyte-derived dendritic cells treated with APX005M display a mature phenotype characterized by upregulation of CD80, CD86 and HLA-DR and increased secretion of IL-12. In mixed lymphocyte reaction and viral antigen recall assays, APX005M significantly enhances proliferation of and IFN-ã secretion from both naïve and memory T cells. Since CD40-CD154 signaling is involved in the priming phase of T cell activation and acts upstream of many critical costimulatory pathways, CD40 agonistic antibodies may represent an essential component of combination immunotherapy. In support of this, we show that APX005M synergizes with checkpoint inhibitors to promote antigen-specific T-cell responses. Importantly, in an ex vivo tumor assay APX005M induces T-cell proliferation and cytokine secretion. These data demonstrate that APX005M binds to APCs and induces their activation and maturation to ultimately drive a potent tumor-specific T-cell response. T cell activation in cancer patients receiving APX005M will be assessed in current and future clinical studies. Citation Format: Erin L. Filbert, Pia Björck, Xiaodong Yang, Ovidiu C. Trifan. The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses. [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 4867.
Abstract 837: Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model
Authors: Vernon E. Steele, Ronald A. Lubet, Clinton J. Grubbs
Journal: Cancer Research (2016)

Abstract Perhaps the greatest question in biological science is: Can results be reproduced? This problem is of particular concern for a group whose primary mission is to screen for potentially effective agents and rank results by activity. The reproducibility of testing specific agents for chemopreventive activity, testing the same agent in various protocols, and testing multiple agents of a given mechanistic class in the MNU-induced model of ER+ breast cancer in Sprague-Dawley rats is presented. The model employs female virgin Sprague-Dawley rats on a standard 4% Teklad diet which develop ER+ mammary cancers (adenocarcinomas) following MNU injection at 50 days of age (DOA). Preventive agents were given by gavage or diet starting at 55 DOA, and animals monitored for tumor development until approximately 170 DOA. Seven agents which we had previously studied and which were strongly positive [tamoxifen, vorozole (an aromatase inhibitor), Targretin, gefitinib] or strongly negative (naproxen, Lipitor, metformin) were examined in the assays presented. These study results confirmed our previous data. We next tested these same agents in animals given a Western diet (high fat, low calcium) and again obtained the same results. We had thought that the altered physiology and potentially altered pharmacokinetics of rats on a Western diet might alter the observed chemopreventive efficacy. These studies show that the direct repetition of clearly positive and negative agents can be achieved and, in fact, repeated with a significant variation in diet. Importantly, in terms of reproducibility, we find that multiple agents of the same mechanistic class give similar results. Thus, various SERMs (tamoxifen, toremifene, Arzoxifene), RXR agonists (targretin, UAB-30, 4Me-UAB-30), EGFR inhibitors (gefitinib, Erlotinib, lapatinib) are all highly positive (70-95% reduction of cancer multiplicity). In contrast, the negative classes COX inhibitors (naproxen, sulindac, aspirin) or statins (atorvastatin or simvastatin) have been consistently negative (&amp;lt;20% reduction). Therefore, reproducibility of efficacy results appears to be quite solid in our chemoprevention agent development program for rat mammary cancer testing, and we can, with significant certainty, trust our results. Citation Format: Vernon E. Steele, Ronald A. Lubet, Clinton J. Grubbs. Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model. [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 837.
Case 48-1962
Authors: Thomas C. Chalmers, Wallace A. Jones
Journal: New England Journal of Medicine (1962)

Presentation of CaseA fifty-one-year-old man entered the hospital because of weakness and jaundice.Six months previously anorexia developed, and an upper gastrointestinal series performed at another hospital was interpreted as normal. Two months later the patient began an alcoholic binge that continued until the time of entry. During that time he consumed from 3 to 6 quarts of whisky per week, with an estimated daily food intake of 300 calories. He experienced daily episodes of tremor and vomiting, usually in the morning, that were relieved by the ingestion of alcohol; there was no hematemesis. Increasing abdominal girth, persistent anorexia . . .
Abstract 3799: The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal cell carcinoma
Authors: Robert H. Weiss, Omran Abu Aboud, Erkan Baloglu, William Senapedis, Sharon Shacham
Journal: Cancer Research (2016)

Abstract Renal cell carcinoma (RCC) is an increasingly prevalent cancer type that is frequently asymptomatic on presentation and is associated with poor responses and resistance even to the current targeted therapies. Thus, novel therapeutic approaches to treat this disease are urgently needed. P21-activated kinase 4 (PAK4) is a mediator of filopodia formation and stabilizes β-catenin transcriptional activity, both of which are integral to nephrogenesis and cancer. We hypothesized that inhibitors of the PAK4 signaling pathway would result in salutary effects on RCC. To test this, we evaluated the in vitro response of several human RCC cells and normal kidney proximal epithelial cells (NHKs) to the specific PAK4 Allosteric Modulators (PAMs; KPT-8752 and KPT-9274). 786-O (VHL-mutant RCC) and caki-1 (VHL-wt RCC) cells showed decreases in cell viability (MTT), induction of apoptosis and arrest in G2/M phase when incubated with these inhibitors. These responses were diminished in NHK cells which served as a “normal” control cell line. Target and specific pathway proteins (phospho-PAK4, Phospho-β-catenin, c-Myc and cyclin D1) were reduced after RCC, but not NHK, were incubated with KPT-8752 and KPT-9274. To confirm specificity of the inhibitor to PAK4, all these responses were reproduced in RCC cells using specific PAK4 siRNA. Since ∼85% of RCC cases are associated with mutation in vhl we used 786-0 xenograft mouse model to evaluate the clinical candidate KPT-9274. KPT-9274 was orally administered at 100 and 200 mg/kg BIDX5 for 4 weeks, resulting in clear attenuation of tumor growth at both doses. There was no obvious change in the health or weight of any of the animals when compared to vehicle group suggesting manageable tolerability. We are currently evaluating combination therapy and plan to test this inhibitor on a metastatic RCC model. In summary, PAK4 inhibitors show considerable promise as novel treatments of RCC as a single agent and warrants further investigation. Citation Format: Robert H. Weiss, Omran Abu Aboud, Erkan Baloglu, William Senapedis, Sharon Shacham. The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal 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 3799.
P1049 : Lysosomal Acid Lipase activity in patients with non-alcoholic fatty liver disease
Authors: D. Pastori, F. Baratta, L. Polimeni, F. Piemonte, G. Tozzi, S. Di Santo, D. Salzano, A. Pani, F. Violi, M. Del Ben, F. Angelico
Journal: Journal of Hepatology (2015)
Polymorphisms in the CYP450 Genes Influences Regimen Related Toxicity and Outcome in Patients with Beta Thalassaemia Major Undergoing HSCT.
Authors: Poonkuzhali Balasubramanian, Salamun Desire, Vikram Mathews, Kavitha M Lakshmi, Shaji R Velayudhan, Biju George, Auro Viswabandya, Mammen Chandy, Alok Srivastava
Journal: Blood (2009)
Abstract 5190: Correspondence between clinical patient outcome and <i>in vivo</i> carboplatine response of high grade ovarian cancer PDX
Authors: Stan P. du Manoir, Helene Delpech, Beatrice Orsetti, Jeremy Tessier, Pierre-Emmanuel Colombo, Charles G. Theillet
Journal: Cancer Research (2016)

Abstract Survival rate for high grade ovarian cancer (HGOC) remains low and has not significantly evolved for several years. This poor outcome is due to several mechanisms of resistance (initial or acquired) in different context (Homologous recombination deficience, CCNE1 amplification). We developed a collection of High-grade ovarian cancer Patient Derived Xenografts (PDX) with extensive characterization (CGH, transcriptome and exome sequencing, Colombo et al, Oncotarget. 2015 Sep 29;6(29):28327-40). Our objective is to create a panel of HGOC PDX which encompasses main types of platinium sensitivity/resistance in HGOC. We selected 10 PDX models (9 serous histiotypes and one carcinosarcomas) among our collection of 39 HGOC PDXs from two patient extreme platinium response categories (resistant with a progression-free inferior to 6 months and sensible with a progression-free higher than 18 months, some of the sensitives with BRCA1 mutations). These PDXs included PDXs were grafted sub-cutaneously on nude mice and submitted to carboplatin treatment (50mg/kg twice a week, for 4 weeks) and impact on tumor growth was evaluated as well as histological characterization. For the carcinosarcomas, no selection of the epithelial or sarcomatous component upon treatment was observed. Outgrowth of the tumors after end of treatment is currently under assessment. Remarkably, tumor PDXs response was in accordance with clinical status with complete and partial response for the sensitive PDXs; slowed growth under treatment or stabilization for resistant PDXs. Outgrowth of the tumor after the end of treatment is currently under assessment. For each PDXs model, the large majority of the 7-9 treated tumor reacted in identical fashion if classified according to RECIST criteria with occasionally divergent responses reflecting tumor heterogeneity. Genetic and histological characterization of these outliers is ongoing. This collection is a valuable resource to model carboplatine resistance in a well-defined context and will be the cornerstone of our future studies to conduct preclinical drugs tests, in particular for combination selected in vitro and to evaluate clonal evolution under treatment. Citation Format: Stan P. du Manoir, Helene Delpech, Beatrice Orsetti, Jeremy Tessier, Pierre-Emmanuel Colombo, Charles G. Theillet. Correspondence between clinical patient outcome and in vivo carboplatine response of high grade ovarian cancer PDX. [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 5190.
Abstract 1557: Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic TAMs
Authors: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha R. Rosner
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. While physiological inhibitors of metastasis (metastasis suppressors) play key roles in regulating tumor growth, invasion and metastasis, their role in regulating the tumor microenvironment and immune system is unknown. We hypothesized that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) regulates stromal cells, which then affect tumor invasiveness. Using species-specific RNAseq we determined that expression of RKIP in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. While TAMs isolated from TNBC xenografts drive in vitro invasion, RKIP+ derived TAMs did not drive invasion and had decreased secretion of pro-metastatic factors including SLPI, OPN, MMP-12, Galectin-3, VEGF-A, VEGF-D, TNFR2, and PGRN. We determined that RKIP regulates TAM recruitment by blocking HMGA2, which activates CCL5 expression. CCL5 rescued pro-metastatic TAM infiltration as well as tumor intravasation. We additionally showed that factors decreased in RKIP-derived TAMs were restored in CCL5-derived TAMs. CCL5 derived TAMs were also able to promote metastasis when co-injected with MDA-MB-231 tumors. These tumor cells demonstrated permanent increases in both growth and invasive potential after co-injection with highly pro-metastatic CCL5 derived TAMs. To determine the clinical utility of these TAM genes we combined their expression with RKIP signaling in the tumor to create a signature that strikingly separates TNBC patients based on outcome. Our results demonstrate for the first time that metastasis suppressors can regulate the microenvironment, regulating invasion through TAMs. Our results also suggest aggressive triple negative breast cancers could be controlled by attacking CCL5 derived TAMs crucial for promoting metastasis. Funded by: GM087630, CA184494, and CA192780 Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha R. Rosner. Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic TAMs. [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 1557.
Delay in diagnosis of testicular cancer
Authors: J. Fleer, D. T. H. Sleijfer, J. E. H. M. Hoekstra-Weebers, H. J. Hoekstra
Journal: Journal of Clinical Oncology (2004)

4602 Background: Delay in presentation of a testis tumor may result in an advanced stage of disease at diagnosis, which may affect disease free and overall survival. The aim of this study was to determine variables related to delay in diagnosis of testicular cancer (TC). Methods: A questionnaire was developed to assess patient delay (time from first symptom till first consultation with general practitioner (GP)) and doctor delay (time from first consultation with GP till final diagnosis). In addition, patient and disease characteristics possibly related to patient and/or doctor delay, were collected: age, marital status, educational level, extensiveness of the disease (stage I vs disseminated disease), number of symptoms, change in testicle as a symptom, pain as a symptom, patients' knowledge of TC, appraisal of symptoms as threatening, embarrassment, and whether the doctor referred the patient immediately for further examination. Results: 48 men (median age 25, range 16–44 years) who were consecutively referred to the Groningen University Hospital completed the questionnaire. Median patient delay was 30 (range 1–365) days. Only educational level correlated with patient delay (r=-.30, p=.03). Median doctor delay was 14 (0–240) days. After first consultation, only 20 patients (42%) were immediately referred for further examination. The remaining 28 patients were not immediately referred, which led to a significantly longer doctor delay (median = 23 days, t=-4.47, p90 days. Age was significantly related to total delay (r=-.33, p=.03). Six patients (12.5%) did not have a change in testicle as presenting symptom, but this was not related to delay. Extensiveness of disease was not related to delay. Conclusions: Surprisingly, having disseminated disease and having a change in a testicle as presenting symptom were not related to delay, but younger and lower educated men appeared to be more likely to report delay in diagnosis. Over half of the men were not immediately referred for further examination, resulting in a significantly longer GP delay. This finding stresses the responsibility of GPs in the diagnostic process of TC. No significant financial relationships to disclose.
Chemotherapy for Advanced Non–Small-Cell Lung Cancer in Elderly Patients
Authors: Fábio Nasser Santos, Marcelo Rocha Souza Cruz, Rachel Riera
Journal: JAMA Oncology (2016)

Do patients above 70 years of age with newly diagnosed advanced non-small-cell lung cancer benefit from platinum-based combination or should they receive non-platinum agents either as single-agent or in combination?For fit elderly patients platinum-based combination is associated with better overall survival, progression-free survival, and objective response rate, however this improvement should be counter balanced against the higher risk of major adverse events (AE).