tbuckley/cabot-search huggingface dataset:
Tuberculosis care among refugees arriving in Europe: a ERS/WHO Europe Region survey of current practices
Authors: Masoud Dara, Ivan Solovic, Giovanni Sotgiu, Lia D'Ambrosio, Rosella Centis, Richard Tran, Delia Goletti, Raquel Duarte, Stefano Aliberti, Fernando Maria de Benedictis, Graham Bothamley, Tom Schaberg, Ibrahim Abubakar, Vitor Teixeira, Brian Ward, Christina Gratziou, Giovanni Battista Migliori
Journal: European Respiratory Journal (2016)

No evidence exists on tuberculosis (TB) and latent TB infection (LTBI) management policies among refugees in European countries.A questionnaire investigating screening and management practices among refugees was sent to 38 national TB programme representatives of low and intermediate TB incidence European countries/territories of the WHO European Region.Out of 36 responding countries, 31 (86.1%) reported screening for active TB, 19 for LTBI, and eight (22.2%) reporting outcomes of LTBI treatment. Screening for TB is based on algorithms including different combinations of symptom-based questionnaires, bacteriology and chest radiography and LTBI screening on different combinations of tuberculin skin test and interferon-γ release assays. In 22 (61.1%) countries, TB and LTBI screening are performed in refugee centres. In 22 (61.1%) countries, TB services are organised in collaboration with the private sector. 27 (75%) countries answered that screening for TB is performed as per national and international guidelines, while 19 (52.7%) gave the same answer with regards to LTBI screening. Infection control measures are inadequate in several of the countries surveyed.There is need for improved coordination of TB screening in Europe to implement the End TB Strategy and achieve TB elimination.
Abstract 4882: Identification of potential immune targets in controlling endometrioid endometrial carcinoma metastatic progression
Authors: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen
Journal: Cancer Research (2016)

Abstract Endometrial adenocarcinoma is a common cause of gynecological cancer death in Europe and North America. The most dominant subtype, Endometrioid Endometrial Cancer (EEC) accounts for &amp;gt;80% of this cancer and is estrogen-dependent. At diagnosis, 75% of women have the disease confined to the uterus, which is considered Stage One. Five-year survival for Stage One patients is 80%, however, about 15-20% develop metastasis. Total RNA extracted from tissues obtained after surgical resection from three women at stage one EEC was subjected to RNA-sequencing. The publicly available dataset (SRP045645) was downloaded directly from the Sequence Read Archive and the FASTQ files were processed with Biomedical Genomics Workbench for secondary analysis including mapping, quantification and differential expression analysis. Through streamlined integration the data was uploaded to Ingenuity Pathway Analysis (IPA) for biological interpretation. We show how in silico solutions developed by QIAGEN Bioinformatics enable us to analyze the biological parameters involved in EEC metastatic progression from an early stage in the three patients diagnosed at Stage One. By comparing these patients’ RNA-seq results, we determined that key Canonical Pathways and other biological processes differentiated the three patients from one other. In particular, the predicted transcriptional program allowed us to visualize key upstream drivers. Three of these transcriptional drivers are immune related molecules (two cytokines: CXCL14 and GDF15 and one growth factor FGF3). They have been predicted to be potential master regulators of a Causal Network that drives increase of EEC, metastasis, epithelial-to-mesenchymal-transition (EMT), and cellular invasion in one of the three patients. Based on these results we propose these three immune molecules as possible therapeutic targets to counteract the metastatic processes in EEC. Citation Format: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen. Identification of potential immune targets in controlling endometrioid endometrial carcinoma metastatic progression. [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 4882.
Abstract 41: DCA bind to EGFR/EGFRvIII/PDK1 and affect the proliferation and growth in TMZ resistant glioblastoma model
Authors: Kiran Kumar Velpula, Kamlesh Sahu, Jack Tuszynski, Maheedhara R. Guda, Swapna Asuthkar, Sarah E. Martin, Justin D. Lathia, Andrew J. Tsung
Journal: Cancer Research (2016)

Abstract Glioblastomas are characterized by amplification of epidermal growth factor receptor (EGFR). Approximately half of the GBM tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). This phenotype represents a tumor specific target correlating with a high growth potential. Despite advances in treatment, whether surgery, chemotherapeutics or molecular targeted therapies, very few have shown promise. Temozolomide (TMZ), as standard of care alkylation therapy, demonstrates improved survival when administered with concomitant radiotherapy. Unfortunately, acquired TMZ chemo-resistance is observed in more than 90% of recurrent GBMs. To understand the mechanisms in the context of TMZ resistance, we generated an in vitro TMZ resistant model by continuous exposure of U373 cells constitutively expressing EGFRvIII (U373vIII) to 150uM TMZ for 6 months (U373vIIIR). Dicholoroacetate (DCA) is a known metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1). Its application to cancer has recently been revived in the realm of metabolic oncology, where reversal of the Warburg effect has resulted in decreased tumor growth. Treatment of U373, U373vIII, and U373vIIIR GBM cell lines with DCA was found to induce cytotoxicity and reduced cell survival across all cell lines. Further, micro array studies conducted on U373vIII or U373vIIIR and their subsequent treatment with DCA revealed that PDK1 is the sole target in TMZ resistant tumors expressing EGFRvIII. Additionally, we demonstrated that 1mM DCA induced mitochondrial membrane potential change as evidenced in JC-1 staining and electron microscopic studies confirming mitochondrial apoptosis. Consistent with our previous findings that EGFR interacts with PDK1, our computational analysis revealed that DCA aligns itself to the binding sites of both EGFR and EGFRvIII with strong binding affinity apart from its binding to PDK1. Clinically, expression of EGFRvIII correlated with PDK1 when compared to EGFR in GBM surgical specimens. Collectively, our studies demonstrate that principles of metabolic oncology and DCA are active in GBM treatment despite resistance providing new insight into the development of alternative treatment in TMZ failure. Citation Format: Kiran Kumar Velpula, Kamlesh Sahu, Jack Tuszynski, Maheedhara R. Guda, Swapna Asuthkar, Sarah E. Martin, Justin D. Lathia, Andrew J. Tsung. DCA bind to EGFR/EGFRvIII/PDK1 and affect the proliferation and growth in TMZ resistant glioblastoma 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 41.
Abstract 663: Factors affecting genome editing using CRISPR/Cas9 in mouse model
Authors: Qi Zheng, Ling-Jie Kong, Huanyu Jin, Jinling Li, Ruby Yanru Chen-Tsai
Journal: Cancer Research (2016)

Abstract CRISPR/Cas9 joined genome editing family and became a powerful tool for cancer researches. While CRISPR is effective for generating knock-out, knock-in or point mutation animal models, the protocols and success rates to generate CRISPR mouse model vary significantly among different laboratories. We examined a series of parameters for generating various types of mouse models using CRISPR/Cas9. The efficiency and toxicity of gRNA, Cas9 mRNA and donor concentration, insert size and injection methods were thoroughly analyzed. We also evaluated strategies generating conditional knock-out models using CRISPR. The optimized protocols for successful mouse model generation for knock-in, knock-out, point mutation and conditional knock-out using CRISPR will be proposed. Citation Format: Qi Zheng, Ling-Jie Kong, Huanyu Jin, Jinling Li, Ruby Yanru Chen-Tsai. Factors affecting genome editing using CRISPR/Cas9 in mouse 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 663.
Abstract 3604: Validated structural variant detection with prioritisation of known cancer related changes
Authors: Miika Ahdesmäki, Brad Chapman, Sally Luke, Hedley Carr, Daniel Stetson, Oliver Hofmann, Justin Johnson
Journal: Cancer Research (2016)

Abstract Reliable detection of structural variation (SV) is playing an increasingly important role in cancer diagnostics and treatments. We introduce a best practice integrative workflow for detecting large structural variations (SVs) such as deletions, duplications, inversions, fusions and translocations from standard DNA re-sequencing techniques, annotating and prioritising for clinically actionable events. While established RNA-Seq fusion workflows exist to detect and filter fusion events in tumors detecting large structural changes from exome- and WGS data remains challenging. Current DNA-based SV callers predict a large percentage of false positive events, and the resulting event lists are not prioritised for validation. To streamline follow-up studies we automate running multiple structural variant callers (Manta, WHAM, Lumpy, MetaSV), identifying potentially disruptive large scale events. We evaluate the integrated workflow sensitivity and specificity against the ICGC-TCGA DREAM Mutation Calling Challenge data set, optimise filtering criteria based on quality and supporting information, and annotate the filtered calls using known cancer related alterations from CIViC and publicly available gene lists from AstraZeneca. This enables us to prioritise known and potentially interesting events over intergenic events or non-whole exon deletions. We show validation results from test data and clinically actionable inversions, duplications and fusion events from cancer cell lines. Our approach is based on a two tier approach of first focusing on known events that yield fusion transcripts such as the TACC3-FGFR3 tandem duplication and ALK-EML4 inversion, and secondarily on events in oncogenes and tumor suppressors of interest. While whole genome sequencing is the preferred approach to detecting these events, we also show how by design or by the nature of the breakpoint being close enough to exons, hybrid capture data can also be surprisingly useful for SV inference. Citation Format: Miika Ahdesmäki, Brad Chapman, Sally Luke, Hedley Carr, Daniel Stetson, Oliver Hofmann, Justin Johnson. Validated structural variant detection with prioritisation of known cancer related changes. [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 3604.
Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer
Authors: Rafael Duran, Sahar Mirpour, Vasily Pekurovsky, Shanmugasundaram Ganapathy-Kanniappan, Cory F. Brayton, Toby C. Cornish, Boris Gorodetski, Juvenal Reyes, Julius Chapiro, Rüdiger E. Schernthaner, Constantine Frangakis, MingDe Lin, Jessica D. Sun, Charles P. Hart, Jean-François Geschwind
Journal: Clinical Cancer Research (2016)

To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model.VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 μm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH).cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT.HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR.
Phase II trial of daclizumab in human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL).
Authors: J. L. Berkowitz, J. E. Janik, D. M. Stewart, S. Fioravanti, E. S. Jaffe, T. A. Fleisher, N. Urquhart, G. H. Wharfe, T. A. Waldmann, J. C. Morris
Journal: Journal of Clinical Oncology (2010)

8043 Background: ATL is an aggressive malignant lymphoproliferative disorder with a poor prognosis and no standard therapy. ATL can be classified into four subtypes: acute, lymphomatous, chronic and smoldering. Daclizumab is a humanized monoclonal antibody that prevents binding of interleukin-2 by recognizing the α-chain of the interleukin-2 receptor (CD25), which is over-expressed on ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed daclizumab treatment improved survival. A phase I trial demonstrated that up to 8 mg/kg daclizumab was well tolerated with clinical evidence of antitumor activity in ATL. Based on this data, a phase II trial was initiated. Methods: A single institution open-label Phase II trial was conducted, with a primary endpoint of response rate. Eligibility: All ATL subtypes with ≥10% of tumor cells expressing CD25. Patients received intravenous daclizumab 8 mg/kg on days 1 and 15, and then every 3 weeks to complete 6 doses. Responding patients continued to receive daclizumab 8 mg/kg every 3 weeks. After 9 patients were treated, the study was amended to include only patients with chronic or smoldering ATL. Results: Nineteen patients, median age 46 years (range, 14-79 years), eight men, eleven women, with a median of 1 (range, 0-3) prior systemic therapies, were treated. No responses were observed in eight patients with acute or lymphomatous ATL. Four partial responses (RR 36%) were observed in eleven patients with chronic and smoldering ATL that were treated. The median response duration was 114 weeks (range, 12.4-202+ weeks). Six patients experienced CTC version 2.0 grade III/IV non-hematological toxicities, most of which were unrelated to therapy. One episode each of congestive heart failure and the development of severe psoriasis were attributed as possibly related to daclizumab. Conclusions: Daclizumab is well tolerated with antitumor activity in chronic and smoldering ATL. Daclizumab appears to have little activity in the more aggressive acute and lymphoma subtypes of ATL. This research was supported by the Intramural Research Program of the NIH, NCI. No significant financial relationships to disclose.
Using presurgical sunitinib to select patients with newly diagnosed metastatic clear cell renal cell carcinoma for cytoreductive nephrectomy: A phase II study.
Authors: Eric Jonasch, Christopher G. Wood, Paul G. Corn, Padmanee Sharma, Lance C. Pagliaro, Ana Aparicio, Kim-Anh Do, Xuemei Wang, Valerie D. Marcott, Surena F. Matin, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2013)

371^ Background: Timing of cytoreductive nephrectomy (CN) is still a matter of debate in mRCC. This study was designed to test the hypothesis that lead-in treatment with sunitinib (Su) selects patients (pts) most likely to benefit from nephrectomy, and can aid in assessing determinants of response and resistance. Methods: Pts with biopsy proven, newly diagnosed clear cell mRCC with measurable disease, performance status of 0/1, and resectable primary tumor were eligible. Pts received one cycle of sunitinib 50mg PO QD on a 28 day on/14 day off cycle, were restaged, and if stable/responding underwent nephrectomy between day 7 and 21 of second cycle of Su. If disease remained stable on postop scans, pts continued Su. Mutations in a 200 gene cancer gene panel as well as copy number variation were used to correlate molecular changes with clinical outcome. Results: 50 pts were enrolled: 36 (72%) were male and 38 (76%) Caucasian, Median age 61 years (range: 43–84). 44 had intermediate MSKCC score and 6 were poor risk. 45 pts (90%) were evaluable. No drug-related perioperative complications were noted. A total of 9 (18%) pts did not have nephrectomy: 6 because of progression, 2 because of drug related toxicity, and one who required emergency surgery during the first cycle for bowel obstruction. Median primary tumor shrinkage after 1 cycle was 4 percent (range -18 to +11%). 4 (8%) pts were found to have nonclear cell pathology at nephrectomy (2 sarcomatoid, 1 papillary, 1 unclassified). Among the 45 evaluable pts, the median PFS was 8.7 months (95% CI: 5.8 – 37.3 months). 24 (53%) pts came off for progressive disease, and five (11%) pts came off for toxicity. With a median follow-up time of 27.3 months, median OS was 32.2 months (95% CI: 17.2 – Not estimable). To date, 20 (40%) pts have died. Copy number and genomic data analysis are underway, and will be presented and correlated with clinical outcome. Conclusions: Pretreatment with Su safely triaged mRCC pts into nephrectomy versus nonnephrectomy groups, with acceptable efficacy and OS. Ongoing studies will define molecular characteristics defining subgroups most likely to benefit from Su. Clinical trial information: NCT00715442.
Abstract 2815: Antitumor activity of CDK4/6 inhibition in combination with radiation therapy on glioblastoma stem cells
Authors: Christopher Nguyen, Yuji Piao, Juan Emmanuel Martinez-Ledesma, Jianwen Dong, Soon Yeung Park, Roel Verhaak, Erik Sulman, John F. De Groot
Journal: Cancer Research (2016)

Abstract Almost 80% of glioblastoma tumors have alterations in the CNKN2A-CDK-Rb pathway. Cyclin dependent kinases 4 and 6 (CDK4/6) act as cell cycle regulators and have been recognized as therapeutic targets for glioblastoma (GBM). In the current study, we determined the antitumor activity of CDK4/6 inhibition (palbociclib and abemaciclib) alone and in combination with radiation on a panel of glioblastoma stem cells (GSCs). The GSCs were molecularly characterized using multiple ‘omimcs’ techniques and Western blots identified specific phospho- and total protein levels. Approximately 50% of cell lines have homozygous deletion of CDKN2A although CDK4 and CDK6 protein expression was significantly elevated in most of the GSCs. RB protein was constitutively phosphorylated in only a subset (45%): GSC11, GSC262, GSC231, GSC304 and GSC7-2. In our panel of GSCs, there were total of three cell lines with CDKN2A loss, RB phosphorylation and CDK4/6 overexpression (GSC262, GSC11 and GSC231). Our data showed that GSC262, GSC11, GSC231 (CDKN2A deletion, RB intact), GSC7-2 and GSC300 (CDKN2A WT, RB intact) were sensitive to CDK4/6 treatment (IC50 ≤ 1μM). CDK4/6 inhibitor treated GSCs showed G1 cell cycle arrest and decreased phospho-RB levels in GSC262 and GSC7-2 cells. We next determined whether CDK4/6 inhibition combined with radiation has additive or synergistic antitumor effect. A clonogenic assay demonstrated that neurosphere formation was significantly decreased by CDK4/6 inhibition in combination with radiation compared to either treatment in GSC262 (resistant to radiation treatment) or GSC7-2 (sensitive to radiation treatment) cell lines. The radiation resistant GSC (GSC262) treated with radiation and CDK4/6 inhibitor became sensitive to radiation therapy whereas radiation sensitive GSC (GSC7-2) had a significant decrease in colony formation compared to radiation alone. CDK4/6 combined with radiation increased γ-H2AX protein expression levels and decreased cyclin D1 protein expression in a time dependent manner compared to single drug treatment. These data indicate synergistic antitumor effects of CDK4/6 inhibition combined with radiation therapy in GSCs in vitro. Further investigation is ongoing to evaluate this combination therapy. Citation Format: Christopher Nguyen, Yuji Piao, Juan Emmanuel Martinez-Ledesma, Jianwen Dong, Soon Yeung Park, Roel Verhaak, Erik Sulman, John F. De Groot. Antitumor activity of CDK4/6 inhibition in combination with radiation therapy on glioblastoma stem cells. [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 2815.
Abstract 2874: Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development
Authors: Xiaowen Zhang, Sreejith J. Nair, Huai-Chin Chiang, Yao Wang, Md Jamiul Jahid, Jianhua Ruan, Victor X. Jin, Yanfen Hu, Rong Li
Journal: Cancer Research (2016)

Abstract Breast cancer susceptibility gene BRCA1 is well known for its function in double strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. Cofactor of BRCA1 (COBRA1) is a BRCA1-binding protein and an important regulator of transcription elongation. Here we used mouse genetics to interrogate functional interaction between BRCA1 and COBRA1 during mammary gland development. Tissue-specific deletion of Cobra1 reduced mammary epithelial compartments and blocked ductal morphogenesis, alveologenesis, and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout were largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restored developmental transcription at puberty, altered luminal epithelial homeostasis, yet remained deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription program during mammary gland development. Citation Format: Xiaowen Zhang, Sreejith J. Nair, Huai-Chin Chiang, Yao Wang, Md Jamiul Jahid, Jianhua Ruan, Victor X. Jin, Yanfen Hu, Rong Li. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. [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 2874.