tbuckley/cabot-search huggingface dataset:
Abstract 2061: DK049, a novel acid-sensitive prodrug of gemcitabine: design, <i>in vitro</i> properties and <i>in vivo</i> efficacy
Authors: David Koester, Javier Garcia, Olga Fuchs, Felix Kratz
Journal: Cancer Research (2016)

Abstract Gemcitabine (Gemzar®) is an anticancer nucleoside that is widely used to treat solid tumors. Unfortunately, at its recommended dose of ∼1000 mg/m2 approximately 90% are deactivated by cytidine deaminase to the inactive uridine metabolite and excreted in the urine. A further disadvantage resulting in chemo-resistance is the low expression level of the human equilibrative nucleoside transporter 1 (hENT1) on the cell surface of cancer cells thus preventing substantial uptake of gemcitabine. In order to circumvent these disadvantages, we designed an innovative gemcitabine prodrug DK049 that a.) is capped at the amino group of the cytosine moiety with acetyl benzoic acid preventing deamination, and b.) incorporates a proprietary maleimide-bearing LADR™ linker forming a stable, but acid-sensitive hydrazone bond. At its 5′-OH position a phosphate group was introduced rendering water-solubility. Following intravenous administration, DK049 binds rapidly and selectively to circulating albumin and utilizes the advantages of albumin-mediated tumor uptake as well as cellular uptake by endocytosis (1). After cleavage of the acid-sensitive benzoyl hydrazone bond, we could show that the acetyl benzoic acid is decapped by carboxylesterase 2. In a head-to-head comparison with gemcitabine (4 × 240 mg/kg on a weekly basis) in four subcutaneous human patient-derived tumor xenografts (NSCLC: LXFE397, LXFE937, ovarian cancer: OVXF899, and pancreatic cancer: Panc11159; 8-10 nude mice per group), DK049 (4 × 24 mg/kg gemcitabine equivalents or 8 × 18 mg/kg gemcitabine equivalents over 4 weeks) demonstrated distinctly superior antitumor efficacy versus gemcitabine (p &amp;lt; 0.05). In the LXFE937 and OVXF899 model, DK049 induced long-term significant regressions for several weeks after end of therapy without any loss in body weight or bone marrow toxicity. In summary, these results show a superior long-term antitumor efficacy of DK049 compared to gemcitabine at a significantly reduced dose. (1) Felix Kratz, Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 8;132:171-83, 2008. Citation Format: David Koester, Javier Garcia, Olga Fuchs, Felix Kratz. DK049, a novel acid-sensitive prodrug of gemcitabine: design, in vitro properties and in vivo efficacy. [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 2061.
Abstract 5290: ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data
Authors: Patrick Jongeneel, Selena Lin, Jamin Steffen, Surbhi Jain, Ying-Hsiu Su, Wei Song
Journal: Cancer Research (2016)

Abstract The purpose of this study was to develop a computational method of extracting viral integration events from NGS data in an intuitive way that could accommodate access from users of all disciplines. Viral integration into the host genome is a characteristic of many pathogenic viruses, including the hepatitis B virus (HBV) and human papillomavirus (HPV). Gradual insertion of viral components near proto-oncogenes of the host genome over time can induce uncontrolled cellular proliferation, eventually leading to carcinogenesis. While increased availability of high-throughput next generation sequencing (NGS) has provided tools for researchers to discover these underlying host changes due to viral integrations, there is an emerging need for analytical support of this data. Here we present ChimericSeq, a user-friendly program that can quickly identify viral integration events from NGS data. To fully evaluate this program, we compared the functionality of ChimericSeq to other current viral integration programs. A number of synthetic data sets of HBV sequence fragments integrated into 100bp fragments of random human genomic DNA were created to mimic the nature of chimeric reads of NGS data. ChimericSeq was able to correctly identify reads containing at least 25bp of viral sequence at 100% accuracy. This was a major improvement over the current programs, VirusClip and ViralFusionSeq, which could not detect reads with only 25bp of viral sequence, and even had difficulty correctly identifying viral integration sites containing additional viral sequence. Furthermore, ChimericSeq could detect viral events nearly 10X and 100X faster than these current programs, respectively. Upon testing of NGS data from actual HBV-positive human tissue, we found that ChimericSeq was not only much faster, but was also able to detect more unique viral integration events than current viral integration tools. In conclusion, ChimericSeq expands NGS analytical support to a broader spectrum of the scientific community, being the first program of its kind to offer support in an intuitive graphical user interface (GUI) for commonly used operating platforms, such as Windows and Mac. Citation Format: Patrick Jongeneel, Selena Lin, Jamin Steffen, Surbhi Jain, Ying-Hsiu Su, Wei Song. ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data. [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 5290.
Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma
Authors: Mrinal M. Gounder, Alona Zer, William D. Tap, Samer Salah, Mark A. Dickson, Abha A. Gupta, Mary Louise Keohan, Herbert H. Loong, Sandra P. D’Angelo, Stephanie Baker, Mercedes Condy, Kjirsten Nyquist-Schultz, Lanier Tanner, Joseph P. Erinjeri, Francis H. Jasmine, Sharon Friedlander, Robert Carlson, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Joel Ellis, Michael Kauffman, Sharon Shacham, Gary K. Schwartz, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2016)

Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m 2 , 50 mg/m 2 , or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. Results The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Conclusion Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.
Analysis of mTOR Mutations in Chinese Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway Inhibitors.
Authors: Yan Kong, Lu Si, Yi qian Li, Xiao wen Wu, Xiao Wei Xu, Jie Dai, Huan Tang, Meng Ma, Zhihong Chi, Xi Nan Sheng, Chuanliang Cui, Jun Guo
Journal: Journal of Clinical Oncology (2015)

9049 Background: mTOR is a validated target in cancer treatment. mTOR mutations are estimated to be 2.46% of all cancers and 5.76% of cutaneous melanoma. However, mTOR mutations in other types of melanoma have not been reported. Methods: This study involved tumor samples from 412 Chinese melanoma patients, including 210 acral melanomas, 105 mucosal melanomas, 30 melanomas on skin with chronic sun-induced damage and 58 melanomas on skin without chronic sun-induced damage. Tissue samples were analyzed for mutations in all exons of mTOR gene in genomic DNA by Sanger sequencing. Mutation status was confirmed using Agilent’s sureselect target enrichment system. HEK293T cells stably expressing mutant mTOR were constructed by TALEN (Transcription Activator-like Effector Nucleases). Function of mTOR mutants in these cells and in vitro sensitivity of mTOR gain-of-function mutations to PI3K-AKT-mTOR pathway inhibitors were analyzed. Results: The overall incidence of somatic mutations within the mTOR gene was 10.4% (43/412). Increased mTOR mutations were relatively more frequent in acral (11.0%) and mucosal (14.4%) melanomas than in CSD (6.7%) and Non-CSD (3.4%) melanomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. Point mutations resulting in single amino acid substitutions (totaling 40 mutations detected in 43 patients) were the most common type of mTOR mutation. The median survival time for melanoma patients with mTOR mutation was significantly shorter than that for patients without mTOR mutation (P = 0.028). Transient expression of several mTOR mutants in HEK293 cells strongly activated the mTOR/p70S6K pathway. In HEK293 cells with stable expression of H1968Yor P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than Temsirolimus or BYL719 in inhibiting the mTOR/p70S6K pathway. Conclusions: These data demonstrate that mTOR mutations are more frequent in Chinese melanoma patients than in Caucasian melanoma patients. mTOR mutations is a worse prognostic factor in Chinese melanoma patients. Clinical trials with PI3K-AKT-mTOR pathway inhibitors may be beneficial for melanoma patients with mTOR mutations.
Access to Prescription Opioids—<i>Primum Non Nocere</i>
Authors: Patrick D. Tyler, Marc R. Larochelle, John N. Mafi
Journal: JAMA Internal Medicine (2016)

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Abstract 4914: Auristatin-based antibody drug conjugates activate multiple ER stress response pathways resulting in immunogenic cell death and amplified T-cell responses
Authors: Anthony Cao, Ryan Heiser, Che-Leung Law, Shyra J. Gardai
Journal: Cancer Research (2016)

Abstract Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) directed against CD30. This ADC consists of monoclonal antibodies conjugated to the auristatin monomethyl auristatin E (MMAE) a microtubule-disrupting agent. ADC antitumor activity is thought to be primarily the result of intracellular payload release leading to mitotic arrest and apoptotic cell death. We have recently demonstrated that brentuximab vedotin induces surface expression of calreticulin and HSP70 as well as activation of the transcription factor ATF6 which are classical hallmarks of immunogenic cell death (ICD) associated with unfolded protein/ER stress response. In this study, we provide evidence that additional ER stress response pathways are activated. Treatment of CD30+ Hodgkin lymphoma (HL) cells or xenografts with brentuximab vedotin resulted in the phosphorylation of the ER-associated, unfolded-protein response transmembrane protein inositol-requiring transmembrane kinase/endonuclease 1 (IRE1). Activation of IRE1 was confirmed by the increase in phosphorylation of the downstream effector Jun N-terminal kinase (JNK). Kinetics of tubulin disruption, ER stress induction, evidence of ICD, mitotic arrest, and apoptosis was assessed. Onset of ICD occurred concurrently with induction of ER stress response pathways including induction of pIRE1 and pJNK. Interestingly, induction of ER stress response and ICD preceded mitotic arrest and caspase activation. These results indicate that brentuximab vedotin-mediated disruption of the microtubule network contributes to ER stress, which maybe an apoptotic mechanism mediated by auristatin-ADCs in addition to mitotic arrest at G2/M phase of the cell cycle. Induction of ICD may also be a class effect of the auristatin-based ADCs, as the small molecule payload MMAE, was able to activate IRE1 and JNK and induced surface expression of calrecutilin on target cells. Previously, brentuximab vedotin-killed HL cells were shown to induce innate immune cell activation in vitro and in vivo. Addition of ADC-killed tumor-like cells to autologous PBMCs results in the expansion of INFã-secreting cytotoxic T-cells. Via induction of ER stress, tumor cells killed by auristatin-based ADCs may initiate an antitumor immune response and provides a rationale for exploring therapeutic strategies that combine ADCs with other immune stimulatory regimens. Citation Format: Anthony Cao, Ryan Heiser, Che-Leung Law, Shyra J. Gardai. Auristatin-based antibody drug conjugates activate multiple ER stress response pathways resulting in immunogenic cell death and amplified 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 4914.
Efficacy and Safety of Dose Attenuated CHOP Chemotherapy for Peripheral T-Cell Lymphoma in Elderly Patients
Authors: Eun-Ji Choi, Dok Hyun Yoon, Chan-Sik Park, Jooryung Huh, Sang-wook Lee, Eun Jin Chae, Jin-Sook Ryu, Cheolwon Suh
Journal: Blood (2015)
Abstract 3578: Novel insights into the cellular function and gene regulation of a master mutator, APOBEC3B
Authors: Sudheer Kumar Gara, Yi Liu-Chittenden, Shweta Kotian, Dhaval Patel, Electron Kebebew
Journal: Cancer Research (2016)

Abstract Unequivocally, cumulative mutations are required for the development of cancer and many sources of mutagenic activity contribute to tumorigenesis. Recent evidence has implicated that a member of cytidine deaminase family, APOBEC3B (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B or A3B) is enriched in the genomes of many human cancers such as cervical, bladder, lung, head and neck and breast cancers (Burns et al., Nature, 2013). APOBEC3B deaminate cytosines in the host genome to generate C-T mutations. Here we report for the first time that APOBEC3B is overexpressed with adrenocortical carcinoma (ACC), a very aggressive and lethal malignancy. We found that APOBEC3B is significantly overexpressed in primary and metastatic ACC as compared to normal adrenal and cortical adenomas by qPCR, immunofluorescence. We observed that γH2AX, a marker of DNA double-strand breaks co-localizes with the expression of APOBEC3B in patients with primary and metastatic ACC. Also ACC tumor samples with high APOBEC3B expression had high chromosomal gain/loss particularly in chromosome 4 and 8 compared to tumor samples with low APOBEC3B expression. To identify the cellular function of APOBEC3B, we performed transient knock-down studies in three ACC cell lines and found that it reduces cellular proliferation and induces cell cycle arrest. Furthermore, we observed that knockdown of APOBEC3B inhibits MAPK signaling by downregulating phospho ERK1/2 levels. Interestingly, we found that tumors with high APOBEC3B expression levels had twice as many TP53 inactivating mutations as compared to tumors with low levels of APOBEC3B. In order to understand the regulation of APOBEC3B expression, we analyzed the methylation status, copy number variation and potential targeting miRNAs of APOBEC3B from genome wide array platform but found no associations in human ACC samples. Therefore, we did a functional, knockdown screen of 90 cancer-associated transcription factors and found that GATA3 showed positive regulation of APOBEC3B. Our data provide novel insights into the function and regulation of APOBEC3B expression beyond its known mutagenic ability. Citation Format: Sudheer Kumar Gara, Yi Liu-Chittenden, Shweta Kotian, Dhaval Patel, Electron Kebebew. Novel insights into the cellular function and gene regulation of a master mutator, APOBEC3B. [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 3578.
Abstract 4490: Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors
Authors: Ching-Hung Lin, Tzu-Pin Lu, Ruby Yun-Ju Huang, Yen-Shen Lu, Ko-Yun Lo, Kuan-Ting Kuo, Eric Y. Chuang, Pei-Fang Wu, I-Chun Chen, Jean Paul Thiery, Chiun-Sheng Huang, Ann-Lii Cheng
Journal: Cancer Research (2016)

Abstract A rapid surge of female breast cancer has been observed in young East Asians. As a first step toward understanding this phenomenon, we compared the genetic alterations between breast cancer form Taiwan (East) and Western countries (West). Under the same array platforms, the differences in gene copy number alterations (n = 120 in East and 1,948 in West) and gene expressions (n = 327 in East and 423 in West) were analyzed as further stratified by age and estrogen receptor (ER)/ HER2 status. Gene-gene interaction networks were explored by analyzing the overlapping gene with ingenuity pathway analysis. The ingenuity pathway analysis revealed the common differences between East and West in NFkB, PI3K, Akt, MAPK, ERK, IFNα, and Jnk networks. Among the patients &amp;lt;50 years with ER+/ HER2- tumors, we identified a uniquely higher frequency of the APOA1/C3/A4/A5 (the lipid metabolizing genes) gene cluster loss (29% vs. 12%, P = .005) and low expressions of these four genes (East/ West ratios ranged from .07 to .39) in East than that in West. We conclude that NFkB, PI3K, Akt, MAPK, ERK, IFNα, and Jnk networks are common differences between East and West, while APOA1/C3/A4/A5 loss and low expressions are unique genetic alterations for young Asian patients with ER+/ HER2- tumors. Citation Format: Ching-Hung Lin, Tzu-Pin Lu, Ruby Yun-Ju Huang, Yen-Shen Lu, Ko-Yun Lo, Kuan-Ting Kuo, Eric Y. Chuang, Pei-Fang Wu, I-Chun Chen, Jean Paul Thiery, Chiun-Sheng Huang, Ann-Lii Cheng. Comparisons of genetic alterations of breast cancer between East and West: Special emphases on young patients with ER+/HER2- tumors. [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 4490.
La maladie des légionnaires associée aux voyages en Europe en 2000 et 2001
Authors: C A Joseph
Journal: Eurosurveillance (2003)

Les annees 2000 et 2001 ont vu les plus grands nombres de cas declares depuis 1987 au Reseau de surveillance europeen de la maladie des legionnaires associee aux voyages (EWGLINET) : 360 et 481 cas respectivement. Cette hausse resulte de l'amelioration des activites de surveillance, en particulier aux Pays-Bas, en France et en Italie, basees principalement sur la detection d'antigenes urinaires (78% des cas en 2001). Le delai moyen de declaration au reseau est tombe sous la barre des 30 jours au prix d'une perte d'informations sur l'issue de la maladie. En 2000, 28 foyers ont ete detectes contre 72 en 2001, cette augmentation resultant de modifications dans la definition d'un foyer epidemique. En 2000 et 2001, 55 et 140 enquetes environnementales respectivement ont ete rapportees.
Integrative epigenomic analysis reveals unique epigenetic signatures involved in unipotency of mouse female germline stem cells
Authors: Xiao-Li Zhang, Jun Wu, Jian Wang, Tingting Shen, Hua Li, Jun Lu, Yunzhao Gu, Yani Kang, Chee-Hong Wong, Chew Yee Ngan, Zhifeng Shao, Ji Wu, Xiaodong Zhao
Journal: Genome biology (2016)

Germline stem cells play an essential role in establishing the fertility of an organism. Although extensively characterized, the regulatory mechanisms that govern the fundamental properties of mammalian female germline stem cells remain poorly understood. We generate genome-wide profiles of the histone modifications H3K4me1, H3K27ac, H3K4me3, and H3K27me3, DNA methylation, and RNA polymerase II occupancy and perform transcriptome analysis in mouse female germline stem cells. Comparison of enhancer regions between embryonic stem cells and female germline stem cells identifies the lineage-specific enhancers involved in germline stem cell features. Additionally, our results indicate that DNA methylation primarily contributes to female germline stem cell unipotency by suppressing the somatic program and is potentially involved in maintenance of sexual identity when compared with male germline stem cells. Moreover, we demonstrate down-regulation of Prmt5 triggers differentiation and thus uncover a role for Prmt5 in maintaining the undifferentiated status of female germline stem cells. The genome-wide epigenetic signatures and the transcription regulators identified here provide an invaluable resource for understanding the fundamental features of mouse female germline stem cells.