tbuckley/cabot-search huggingface dataset:
Cell cycle effects of CDK 4/6 inhibitor PD 0332991 in diffuse large B-cell lymphoma cell lines in vitro.
Authors: H. A. Eradat, M. A. Eckardt, E. Dorfman, H. Hamidi, C. Ginther, R. S. Finn, G. Los, J. G. Christensen, S. De Vos, D. J. Slamon
Journal: Journal of Clinical Oncology (2011)

8061 Background: Deregulation of cell cycle proteins is a characteristic feature of lymphomas. The retinoblastoma (Rb) pathway in particular can be disrupted in diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL). PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases 4 and 6 (CDK4/6). To identify potential predictors of response, we evaluated in vitro sensitivity to PD 0332991 in a large panel of human DLBCL cell lines. Methods: Twenty-two molecularly characterized DLBCL cell lines were treated with PD 0332991 over two fold dilutions to determine IC50 values. Western blot, cell cycle analysis, and annexin V staining were conducted to evaluate molecular effects of PD 0332991 in the panel. Microarray gene expression data were analyzed against IC50 to identify genes associated with PD 0332991 response/resistance. Results: Differential sensitivity across the panel was seen. A subset of cell lines was very sensitive, with IC50 values less than 150nM. When compared to cell lines that were resistant, sensitive lines had a decrease in Rb phsophorylation after treatment with PD 0332991. Cell cycle analysis demonstrated that PD 0332991 potently induces G0/G1 arrest in sensitive cell lines and this is not accompanied by induction of apoptosis. Combination studies with PD 0332991 and gemcitabine markedly enhanced growth inhibition, demonstrating synergistic activity. Microarray analysis identified fifty-three genes that were differentially expressed between cell lines representing the extremes of sensitivity (IC50 < 110 nM and IC50 > 5 uM). Conclusions: PD 0332991 represents a promising and specific inhibitor for therapeutic targeting of CDK 4/6 in DLBCL, and possibly other B-cell NHL.
Leading Causes of Cancer Mortality — Caribbean Region, 2003–2013
Authors: Hilda Razzaghi, Sarah Quesnel-Crooks, Recinda Sherman, Rachael Joseph, Betsy Kohler, Glennis Andall-Brereton, Marsha A. Ivey, Brenda K. Edwards, Les Mery, Vilma Gawryszewski, Mona Saraiya
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Cancer is one of the leading causes of deaths worldwide (1); in 2012, an estimated 65% of all cancer deaths occurred in the less developed regions of the world (2). In the Caribbean region, cancer is the second leading cause of mortality, with an estimated 87,430 cancer-related deaths reported in 2012 (3). The Pan American Health Organization defines the Caribbean region as a group of 27 countries that vary in size, geography, resources, and surveillance systems.* CDC calculated site- and sex-specific proportions of cancer deaths and age-standardized mortality rates (ASMR) for 21 English- and Dutch-speaking Caribbean countries, the United States, and two U.S. territories (Puerto Rico and the U.S. Virgin Islands [USVI]), using the most recent 5 years of mortality data available from each jurisdiction during 2003-2013. The selection of years varied by availability of the data from the countries and territories in 2015. ASMR for all cancers combined ranged from 46.1 to 139.3 per 100,000. Among males, prostate cancers were the leading cause of cancer deaths, followed by lung cancers; the percentage of cancer deaths attributable to prostate cancer ranged from 18.4% in Suriname to 47.4% in Dominica, and the percentage of cancer deaths attributable to lung cancer ranged from 5.6% in Barbados to 24.4% in Bermuda. Among females, breast cancer was the most common cause of cancer deaths, ranging from 14.0% of cancer deaths in Belize to 29.7% in the Cayman Islands, followed by cervical cancer. Several of the leading causes of cancer deaths in the Caribbean can be reduced through primary and secondary preventions, including prevention of exposure to risk factors, screening, early detection, and timely and effective treatment.
Body Composition and Mortality in a Large Cohort With Preserved Ejection Fraction-Untangling the "Obesity Paradox"
Authors: Alban De Schutter, Carl J. Lavie, Sergey Kachur, Dharmendrakumar Patel, Richard V. Milani
Journal: Circulation (2013)

Abstract  Objective  To evaluate the effects of body composition as a function of lean mass index (LMI) and body fat (BF) on the correlation between increasing body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and decreasing mortality, which is known as the obesity paradox.  Patients and Methods  We retrospectively assessed 47,866 patients with preserved left ventricular ejection fraction (≥50%). We calculated BF by using the Jackson-Pollock equation and LMI using (1 − BF) × BMI. The population was divided according to the sex-adjusted BMI classification, sex-adjusted LMI classification, and sex-adjusted BF tertiles. The population was analyzed by using multivariate analysis for total mortality over a mean follow-up duration of 3.1 years by using the National Death Index, adjusting for left ventricular ejection fraction, left ventricular mass index, age, sex, and relative wall thickness.  Results  In the entire population, higher BMI was narrowly associated (hazard ratio [HR], 0.99;  P  P  P  P= .23 with LMI). In the lean patients, low BMI was clearly associated with higher mortality (HR, 0.92;  P  P  P= .83 with LMI). The underweight patients stratified by BF seemed to have an increased mortality (HR, 1.91; 95% CI, 1.56-2.34) that was independent of LMI. However, in obese patients, both BMI (HR, 1.03;  P  P =.003) were associated with higher mortality, even after adjusting for LMI, which remained protective (HR, 0.57;  P   Conclusion  Body composition could explain the inverse J shape of the mortality curve noted with increasing BMI. Body fat seems to be protective in this cohort only if no adjustment was made for LMI, although being underweight stratified by BF seems to be an independent risk factor. Lean mass index seems to remain protective in obese patients even when BMI is not.
Tumor Protein D52 (TPD52): A Novel B Cell/Plasma Cell Molecule Identified through a Proteomic Approach and Characterized by Unique Expression Pattern and Ca2+-Dependent Association with Annexin VI.
Authors: Enrico Tiacci, Pier-Luigi Orvietani, Barbara Bigerna, Alessandra Pucciarini, Roberta Pacini, Garry Corthals, Valentina Pettirossi, Maria Paola Martelli, Arcangelo Liso, Niccolo Bolli, Alessia Tabarrini, Federica Frenguelli, Roberta Benedetti, Stefano Pileri, Jennyfer A. Byrne, Brunangelo Falini
Journal: Blood (2004)
Aurora Kinase Is a Therapeutic Target in Ibrutinib-Resistant Waldenstrom Macroglobulinemia: In-Silico Target Identification and in-Vitro Validation
Authors: Aneel Paulus, Kasyapa S. Chitta, Sharoon Akhtar, Hassan Yousaf, Davitte Cogen, Shireen Vali, Ansu Kumar, Neeraj Kumar Singh, Taher Abbasi, James M. Foran, Candido E. Rivera, Taimur Sher, Vivek Roy, Sikander Ailawadhi, Asher Alban Chanan-Khan
Journal: Blood (2015)
The Landscape of Clinical Trials Evaluating the Theranostic Role of PET Imaging in Oncology: Insights from an Analysis of ClinicalTrials.gov Database
Authors: Yu-Pei Chen, Jia-Wei Lv, Xu Liu, Yuan Zhang, Ying Guo, Ai-Hua Lin, Ying Sun, Yan-Ping Mao, Jun Ma
Journal: Theranostics (2016)

In the war on cancer marked by personalized medicine, positron emission tomography (PET)-based theranostic strategy is playing an increasingly important role. Well-designed clinical trials are of great significance for validating the PET applications and ensuring evidence-based cancer care. This study aimed to provide a comprehensive landscape of the characteristics of PET clinical trials using the substantial resource of ClinicalTrials.gov database. We identified 25,599 oncology trials registered with ClinicalTrials.gov in the last ten-year period (October 2005-September 2015). They were systematically reviewed to validate classification into 519 PET trials and 25,080 other oncology trials used for comparison. We found that PET trials were predominantly phase 1-2 studies (86.2%) and were more likely to be single-arm (78.9% vs. 57.9%,
The Effect of Subsequent Therapies in the Patients with Chronic Lymphocytic Leukemia Previously Treated with Cladribine and Prednisone or Chlorambucil and Prednisone in Randomized Studies.
Authors: Tadeusz Robak, Jerzy Z. Blonski, Marek Kasznicki, Joanna Gora-Tybor, Anna Dmoszynska, Maria Wojtaszko, Aleksander Skotnicki, Wieslaw Nowak, Andrzej Hellmann, Krzysztof Lewandowski, Barbara Zdziarska, Lech Konopka, Bernadeta Ceglarek, Jadwiga Dwilewicz-Trojaczek, Piotr Boguradzki, Kazimierz Kuliczkowski, Kazimierz Sulek, Krzysztof Warzocha
Journal: Blood (2004)
Progress toward active or passive HIV-1 vaccination
Authors: Amelia Escolano, Pia Dosenovic, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2016)

AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful. Here, we review the key breakthroughs and remaining obstacles to the development of active and passive HIV-1 vaccines.
Multicenter Phase II Study of KW-0761, a Defucosylated Anti-CCR4 Antibody, In Relapsed Patients with Adult T-Cell Leukemia-Lymphoma (ATL)
Authors: Takashi Ishida, Tatsuro Joh, Naokuni Uike, Kazuhito Yamamoto, Atae Utsunomiya, Shinichiro Yoshida, Yoshio Saburi, Toshihiro Miyamoto, Shigeki Takemoto, Hitoshi Suzushima, Kunihiro Tsukasaki, Kisato Nosaka, Hiroshi Fujiwara, Kenji Ishitsuka, Hiroshi Inagaki, Michinori Ogura, Shiro Akinaga, Masao Tomonaga, Kensei Tobinai, Ryuzo Ueda
Journal: Blood (2010)
Human Alloreactive CD4+ T Cells as Potent Effector Cells and Sole Mediators of Anti-Tumor Responses in a NOD/SCID Mouse Model for Human Acute Leukemia.
Authors: Sanja Stevanovic, Marieke Griffioen, Marianke LJ Van Schie, Roelof Willemze, J.H. Frederik Falkenburg, Bart Nijmeijer
Journal: Blood (2008)
Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic
Authors: Christopher B. Weldon, Arin L. Madenci, Sosipatros A. Boikos, Katherine A. Janeway, Suzanne George, Margaret von Mehren, Alberto S. Pappo, Joshua D. Schiffman, Jennifer Wright, Jonathan C. Trent, Karel Pacak, Constantine A. Stratakis, Lee J. Helman, Michael P. La Quaglia
Journal: Journal of Clinical Oncology (2017)

Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (± SE) was 72.6 ± 5.4% at 1 year, 57.6 ± 6.2% at 2 years, 23.7 ± 6.0% at 5 years, and 16.3 ± 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P = .04) and &gt; 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS ( P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS ( P &lt; .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding.
444. One-Time Gene Therapy to Prevent Peanut-Induced Anaphylaxis
Authors: Odelya E. Pagovich, Bo Wang, Christina C. Price, Clarisse Jose, Stephen M. Kaminsky, Maria J. Chiuchiolo, Ronald G. Crystal
Journal: Molecular Therapy (2015)

Peanut allergy is a major public health problem that accounts for the majority of fatal food-induced anaphylactic reactions. There are no curative or preventative therapies. Therapy with omalizumab, a human anti-IgE monoclonal antibody, is transiently effective, but it must be administered parenterally, has a short half-life and is costly, thus it is challenging to use as a preventative for peanut allergy. To circumvent this challenge, we hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of omalizumab would provide persistent high circulating levels of anti-IgE sufficient to protect against repeated peanut exposure in the peanut allergic host. To assess this hypothesis, we created a humanized murine model of peanut allergy by reconstituting NOD-scid IL2rgnull mice with 3 x107 blood mononuclear cells (PBMC) derived from peanut allergic individuals or non-allergic controls and treating the mice with a non-human primate serotype rh.10 AAV expressing omalizumab (AAVrh.10anti-IgE) or control vector. Administration of a single dose (1×1011 gc) of AAVrh.10anti-IgE resulted in persistent high levels of anti-IgE in both wild type and humanized mouse models, with anti-IgE levels > 400 mg/ml at 6 wk and remained at similar levels to the last time point evaluated at 24 wk in wild type mice and levels above 220 mg/ml were achieved in NSG mice at wk 8. No anti-IgE was detected in serum from mice that received a non-relevant control vector or PBS alone. The humanized NOD-scid IL2rgnull mice were sensitized intraperitoneally with crude peanut extract (CPE) weekly for 4 wk and then challenged with CPE via oral gavage. Total serum human IgG, IgE and peanut-specific IgE were measured weekly. After challenge, allergic phenotype was assessed using an anaphylaxis score, histamine levels, rectal temperature and behavior. All NSG mice were successfully reconstituted with mononuclear cells as measured by persistent levels of human IgG. Mice treated with AAVrh.10anti-IgE had elevated total and peanut-specific IgE from day 28 onwards with total IgE lower in the AAVrh.10anti-IgE treated mice. Strikingly, after peanut challenge, AAVrh.10anti-IgE treated mice displayed a less severe allergic phenotype compared to those that received the control vector as defined by decreased histamine release, a lower anaphylaxis score, no drop in rectal temperature and suppressed ambulation. These results demonstrate that a single treatment with AAVrh.10anti-IgE provides long term protection from peanut allergen challenge in the peanut sensitized population, representing a paradigm shift in current therapeutic approaches.
Abstract 1859: Discerning the molecular basis of DNA-PK pro-tumorigenic functions and translational capacity as a therapeutic target in prostate cancer
Authors: Emanuela Dylgjeri, Jonathan Goodwin, Karen Knudsen
Journal: Cancer Research (2015)

Abstract Prostatic adenocarcinoma (PCa) is dependent on androgen receptor (AR) signaling at all stages of disease, as AR activation induces both cell proliferation and survival. Though organ-confined disease can be treated, the response is transient and reactivation of AR results in incurable state of disease (castration resistant prostate cancer, CRPC). Thus, there is a significant need to discern the mechanisms by which aberrant AR activity arises, and to develop new means to clinically target advanced disease. Recently, AR activation was found to promote tumor cell survival and proliferation through a feed-forward loop involving the repair factor DNA-dependent protein kinase (DNA-PK). Emerging new data correlates elevated DNA-PK expression with poor prognosis and identifies DNA-PK as a driver of metastatic signaling. Although the role of DNA-PK activity in DNA repair is well characterized, the underpinning mechanisms and consequences of DNA-PK in transcriptional regulation are understudied. Data to be discussed will build on our new preliminary DNA-PK interactome data to identify sequence-specific transcription factors found in complex with DNA-PK. In order to molecularly dissect DNA-PK transcriptional events, the DNA-PK cistrome and transcriptome will be defined using clinically relevant models, resulting in a detailed understanding of DNA-PK mediated transcriptional regulation. The correlation of high expression of DNA-PK with poor prognosis in advanced PCa, as well as the known roles of DNA-PK in cancer-relevant pathways make DNA-PK a viable therapeutic target for PCa. Despite the current clinical assessment of DNA-PK inhibitors in multiple tumor types, there are no existing trials targeting PCa. Additional studies that assess the efficacy of current DNA-PK inhibitors in PCa will be presented and used to determine the best clinical space for their use. Citation Format: Emanuela Dylgjeri, Jonathan Goodwin, Karen Knudsen. Discerning the molecular basis of DNA-PK pro-tumorigenic functions and translational capacity as a therapeutic target in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1859. doi:10.1158/1538-7445.AM2015-1859
Phase II study of Ccr-based dose-control of S-1 in 1st line SOX + bevacizumab regimen for advanced colorectal cancer
Authors: Dai Manaka, Ryuta Nishitai, Sayuri Konishi, Shinya Hamasu, Kenji Yoshino, Satoshi Kantou, Shunpei Kanai, Eisei Mitsuoka, Ryo Kudo
Journal: Annals of Oncology (2015)
Can Activation Induced Cytidine Deaminase Lead to Genetic Instability in Bcr-Abl Negative Myeloproliferative Neoplasms?
Authors: Hasan Dermenci, Aynur Daglar, Basak Peker Akadam, Veysel Sabri Hancer, Yusuf Gelmez, Melih Aktan, Meliha Nalcaci, Akif S. Yavuz
Journal: Blood (2012)
Abstract 105: A rational approach for the discovery of inhibitors of NSD2 for the treatment of cancer
Authors: Claudia Fromond, Xavier Espanel, Anne Soudé, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua
Journal: Cancer Research (2015)

Abstract Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. In addition, the NSD2 overactivity is also observed in prostate and lung cancers. Thus, NSD2 is a potential target for cancers, for which no selective drug is available to date. Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay is based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox activity were excluded. This strategy allowed us to identify about 200 compounds. To focus on the most interesting ones, an orthogonal counterscreen based on 3H SAM incorporation is being completed. In parallel to the biochemical screening, we are developing secondary cellular assays based on the H3K36me2 methylation and proliferation to further confirm hit activity. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening effort performed by other groups. Our library has already produced new chemical starting points for other KMTs, and we believe that our hits could be promising starting points to generate potent and selective NSD2 inhibitors. Citation Format: Claudia Fromond, Xavier Espanel, Anne Soudé, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua. A rational approach for the discovery of inhibitors of NSD2 for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2015-105