tbuckley/cabot-search huggingface dataset:
Abstract 1956: Mirnas hsa-miR-214-3p, -378a-3p e -34a-5p as biomarkers for uterine mesenchymal neoplasms
Authors: Laura G. dos Anjos, Gustavo A. Maciel, Isabela W. Cunha, Edmund C. Baracat, Kátia C. Carvalho
Journal: Cancer Research (2016)

Abstract Background: Uterine mesenchymal tumors have specific mechanisms of development that are largely unknown. One of the molecular mechanisms which may be involved in the appearance and progression of these tumors is the regulation of gene expression by miRNAs. These molecules are small non-coding RNAs that play important roles in several biological pathways. The identification of miRNAs that show particular differences in expression profile can help broaden the diagnostic methods available for these tumors. Objectives: To evaluate the expression profile of microRNAs described as sequences related to tumors development in uterine leiomyosarcomas samples, comparing to leiomyomas and normal myometrium. Methods: We selected 37 samples of uterine leiomyosarcoma (LMS), 16 unconventional leiomyomas (LMA), 10 conventional leiomyomas (LM) and 2 myometrium (used as reference samples). Samples were obtained from the Discipline of Gynecology of the Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo and Department of Pathology of the A C Camargo Cancer Center, both in Sao Paulo, Brazil. The total RNA was obtained and used to perform the synthesis of cDNA.The real time PCR reactions was performed using the Kit miScript SYBR Green PCR (Qiagen) for analysis from the 84 miRNAs sequences already described in the literature as tumor development related sequences. Results: The data analysis from the 84 sequences of microRNA showed wide variation in the regulation of these molecules expression. After computational analysis, we selected only those miRNAs with different expression profile between LM, LMA and LMS. The goal was to obtain a molecular signature that differentiate and identify each tumor using normal tissue as a reference. We found that hsa-mir-214-3p and hsa-miR-378-3p (fold regulation of -2.32 and -2.97; respectively) presented down-regulation in samples from the uterine LMS. In LMA we found a down regulation of hsa-miR-34a-5p (-3.12 fold regulation). Conclusions: We identified three miRNAs (hsa-mir-214-3p, and -378-3p and -34a-5p) differentially expressed in LMA and LMS. Analyzes of target genes of these miRNAs may identify specific proteins for use in the differential diagnosis, prognosis and patients management in these tumors. Citation Format: Laura G. dos Anjos, Gustavo A. Maciel, Isabela W. Cunha, Edmund C. Baracat, Kátia C. Carvalho. Mirnas hsa-miR-214-3p, -378a-3p e -34a-5p as biomarkers for uterine mesenchymal neoplasms. [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 1956.
Abstract 3587: Multiplexed nuclear area and micronucleus screening identifies SKP1 as a human chromosome instability gene
Authors: Laura Thompson, Allison Baergen, Zelda Lichtensztejn, Kirk McManus
Journal: Cancer Research (2016)

Abstract Chromosome instability (CIN) is defined as an increase in the rate at which whole chromosomes or large chromosomal fragments are gained or lost. It is hallmark of cancer that occurs frequently in both solid and liquid tumors. In addition, CIN is associated with highly aggressive tumors, the acquisition of multi-drug resistance, tumor recurrence and poor patient prognosis. Despite this, the majority of human CIN genes have yet to be elucidated, highlighting the need for studies aimed at identifying the defective genes that underlie CIN. In this study we utilized two complementary, image-based approaches capable of detecting CIN-associated phenotypes following RNAi-based silencing of candidate CIN genes. The first assay involves quantifying nuclear areas following silencing, where changes in mean nuclear area relative to controls act as a surrogate marker of CIN. The second approach monitors micronucleus (MN) formation where increases in the number of micronuclei are indicative of DNA damage or the mitotic defects that underlie CIN. These assays were employed in a high-content screen of 164 human candidate CIN genes in two unrelated cell lines, HT1080 and hTERT. In HT1080, the nuclear area and MN enumeration assays identified 88 and 96 putative CIN genes, respectively. In hTERT, the nuclear area and MN assays identified 112 and 19 putative CIN genes, respectively. Promising putative CIN genes such as SKP1 were identified and prioritized for subsequent validation based on the number of assays that identified the gene, and the strength of the CIN phenotype. Preliminary data collected through Western blotting, mitotic chromosome spreads and flow cytometry, provides evidence to support the validation of SKP1 as a bona fide human CIN gene. Identification and characterization of human CIN genes will provide critical insights into CIN and tumorigenesis, as well as identify potential targets that could be exploited in novel, precision medicine approaches for superior cancer treatment. Citation Format: Laura Thompson, Allison Baergen, Zelda Lichtensztejn, Kirk McManus. Multiplexed nuclear area and micronucleus screening identifies SKP1 as a human chromosome instability gene. [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 3587.
An open-label, multicenter, phase III trial of nab-paclitaxel (NP) versus dacarbazine (DTIC) in previously untreated patients (PTs) with metastatic malignant melanoma (MMM).
Authors: E. Hersh, M. Millward, I. Elias, J. Iglesias
Journal: Journal of Clinical Oncology (2010)

TPS314 Background: Nab-paclitaxel (Abraxane; NP) a Cremophor-free, nanoparticle albumin formulation of paclitaxel targets albumin receptors on tumor cells and is preferentially taken up and retained by cells expressing SPARC (secreted protein acidic and rich in cysteine), an albumin-binding protein. In preclinical and clinical models it has a better safety profile and less toxicity than seen with standard Cremophor formulation of paclitaxel. NP is approved for metastatic breast cancer. In a phase II study of NP in MMM a clinical benefit of 49% and a median survival of 9.6 months was noted in chemotherapy-naïve PTs and 38% and 12.1 months in previously treated PTs. Methods: To determine the efficacy of NP compared to standard therapy with DTIC we have initiated this randomized phase III study. Cytotoxic chemotherapy-naïve PTs with stage IV MMM and typical inclusion and exclusion criteria are randomized to NP, 150 mg/m2 weekly X 3/4 weeks or DTIC 1000 mg/m2 Q 3 W. Dosage reductions of NP to 120 and 90 mg/m2 and of DTIC to 800 and 600 mg/m2 and the use of filgrastim for neutropenic fever are allowed. Assessments of efficacy by CT scans are conducted every 8 weeks in both arms. The primary efficacy endpoint is progression-free survival and the main secondary endpoint is overall survival. Other secondary endpoints include safety and tolerability of the regimens, NP pharmacokinetic parameters, effects of therapy on and the relationship of response to the levels of SPARC and gene methylation, mutational and other biomarkers, response rate, stable disease rate at ≥ 16 weeks and duration of response. The study is planned to randomize 257 PTs per arm (514 total). A total of 104 multinational sites are anticipated and currently 34 are open. The protocol opened in May 2009 and accrual is to be completed in 2010. Currently 60 PTs have been entered on the trial and accrual is on schedule. In summary, this is a registration trial for NP monotherapy as first-line treatment for MMM. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience Abraxis BioScience Abraxis BioScience Abraxis BioScience
Common peptide epitopes induce cross-reactivity in hypersensitivity pneumonitis serodiagnosis
Authors: Laurence Millon, Benedicte Rognon, Benoit Valot, Coralie Barrera, Anne Pauline Bellanger, Sandrine Roussel, Jean-Charles Dalphin, Michel Monod, Gabriel Reboux
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 1867: Activation of RHO-DIAPH signaling impairs RAS-driven exosome biogenesis
Authors: Julie Davis-Turner, Andrew M. Howard, Arthur S. Alberts
Journal: Cancer Research (2016)

Abstract Like oncogenic RAS, the RAS homologues RHOA and RHOB are conventionally thought to support the malignant platform by governing cell structure remodeling by effectors that include the Diaphanous (DIAPH) family formins. RHO-activated DIAPHs generate linear actin filaments (F-actin) that physically support membrane protrusions at the leading edge of migrating cells and the trafficking of growth factor receptors, which are processes that may be required for malignant progression. However, our cellular, genetic, and pharmacological studies argue that both RHO and DIAPHs function as tumor suppressors whose loss of function triggers or augments malignant progression. DIAPH1 and DIAPH3 inhibition, for example, reduces cortical F-actin sufficiently to cause non-apoptotic blebbing. Combined with oncogenic RAS, DIAPH inhibition and blebbing accelerate exosome release. These exosomes have the capacity to foment oncogenesis by seasoning cells of the tumor microenvironment in ways that promote inflammation, survival, immune escape, and metastasis. We have identified a mechanism whereby RAS uses its own guanine-nucleotide releasing protein, SOS, to inhibit DIAPHs and facilitate its own escape within exosomes. Consistent with this idea, pharmacological activation of RHO and DIAPH signaling inhibits tumorigenesis and invasion. RHO and DIAPH agonist/activation strategies may prove to be an effective alternative for impairing RAS-driven oncogenesis where conventional inhibitors of RAS-MAPK signaling have failed or have been met by poorly understood resistance mechanisms. Citation Format: Julie Davis-Turner, Andrew M. Howard, Arthur S. Alberts. Activation of RHO-DIAPH signaling impairs RAS-driven exosome biogenesis. [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 1867.
Abstract 2001: Elucidate the functions of TBX3 in AR positive prostate cancer
Authors: sinan zhu.
Journal: Cancer Research (2016)

Abstract TBX3 is a transcriptional repressor belonging to the T-box gene family. It is involved in lineage specification in mammary gland, limb and heart during embryonic development. Mutations in TBX3 can cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair and genital development. TBX3 is amplified/mutated in a variety of cancers, including melanoma, bladder, breast and prostate cancer. Recent findings suggest there is a strict correlation between estrogen receptor and TBX3 expression in mammary gland and TBX3 is mutated in 9% of invasive lobular breast cancer. However, little is known about the functions of TBX3 in hormone-dependent tumors. Here we screened several AR+ and AR- prostate cancer cell line and we found that the expression of TBX3 and AR is positively correlated. Moreover, in benign human prostate tissue, TBX3 localization is overlapped with that of AR. Knocking down TBX3 by siRNA resulted in decreased cell proliferation and cell cycle arrest in AR+ cell line Lncap and Vcap, but there was no effect on AR- cell line PC3 and DU14 upon TBX3 knock-down. TBX3 ChIP-seq in both Lncap and Vcap revealed co-binding of TBX3, ETS transcriptional factors and FOXA1 on AR targeted genes. Gene Set Enrichment Analysis (GSEA) of RNA-seq data from Lncap cells infected with lentivirus expressing siSCR or siTBX3 indicated that TBX3 suppresses AR and ETV1 signaling. In conclusion, our data suggests that TBX3 is essential for AR+ prostate cancer cell growth and may play a role in regulating androgen signaling. Citation Format: sinan zhu. Elucidate the functions of TBX3 in AR positive prostate 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 2001.
Volumetric perfusion CT assessment of concurrent combretastatin-A4-phosphate (CA4P) and radiotherapy (RT) in non-small cell lung cancer
Authors: H. C. Mandeville, V. Goh, Q. S. Ng, J. Milner, M. I. Saunders, P. J. Hoskin
Journal: Journal of Clinical Oncology (2008)

14584 Background: Preclinical studies demonstrated enhanced growth delay with concurrent CA4P and RT (Chaplin, D.J et al. Anticancer Res. 1999; 19: 189–195). In human advanced non-small cell lung carcinoma (NSCLC) this has been explored in a Phase 1B study where a volumetric helical Perfusion CT technique has been developed to assess the acute and late vascular effects throughout the entire tumour. Methods: Eligible patients had histologically confirmed inoperable NSCLC,unsuitable for radical radiotherapy, ECOG PS ≤ 2. All patients received RT, 27 Gray in 6 fractions over 3 weeks. 18 patients (3 cohorts of 6 patients) were treated prospectively. Intravenous CA4P (50mg/m2) was given in an escalation schedule: Cohort 1 single dose CA4P after 2 fractions RT, Cohort 2 weekly CA4P after 2, 4 + 6 fractions RT and Cohort 3 twice weekly CA4P after every fraction RT. Up to 8 volumetric Perfusion CT were performed in 14 patients using a 16-MDCT scanner (Sensation 16, Siemens Medical Solutions, Germany): 2 baseline, post RT (2,4+6 fractions) then 4 hours post CA4P. Whole tumour blood volume (BV) and extraction fraction (EF) were determined on a pixel by pixel basis for each patient using software based on Patlak analysis (FuncCT, Siemens). Changes in vascularity were compared using t testing; statistical significance was at 5%. Results: See Table. Cohorts 1+2 had significant group decrease in BV 4h post CA4P (p=0.029) not seen in Cohort 3. No other significant group effects were observed. Conclusion: Demonstrated changes in tumour vascularity may indicate a schedule dependant synergistic interaction between CA4P and RT in NSCLC. Changes in group mean from baseline (%) 2# RT 4h CA4P 4# RT 4h CA4P 6# RT 4h CA4P BV (mL/100 mL) Cohorts 1+2 12.92 − 5.39 0.60 −7.77 −12.26 −20.38 Cohort 3 45.00 15.71 6.32 11.26 0.39 23.46 EF (mL/100 mL/min) Cohorts 1+2 14.55 5.22 7.80 20.74 14.26 22.69 Cohort 3 16.34 8.51 10.16 16.79 4.94 13.43 No significant financial relationships to disclose.
Abstract 3813: Potent compounds targeting the human MutT homolog 1 (hMTH1) activity and their cytotoxicity evaluation
Authors: Wenjuan Zhou, Liying Ma, Biao Hu, Lingyu Li, Bo Wang, Hong-Min Liu, Wen Zhao
Journal: Cancer Research (2016)

Abstract Recently, it has been reported that MTH1, a sanitizing protein for the oxidized dNTP pool, plays an important role in cancer-associated damage in the dNTP pool and is required for survival in cancer cells. To study the antitumor mechanism of MTH1 and screen effective anti-cancer drugs, the current study was designed to set up an in vitro expressing and activity evaluation system for MTH1, which will be used for MTH1 specific inhibitor screening. Briefly, the acquired recombinant vector pET-28b-MTH1 was transfected into E.Coli BL21(DE3). The MTH1 protein expression was induced by IPTG and purified by Ni2+ affinity chromatography. Through converting dGTP to dGMP and pyrophosphate by MTH1, the latter of which can then be hydrolyzed to inorganic pyrophosphate by inorganic pyrophosphatase, the MTH1 activity is evaluated through measuring the amount of inorganic pyrophosphate after reacting with malachite green and ammonium molybdate at 630nm. Using this method, we have successfully generated a reliable in vitro evaluation system for MTH1 activity. Furthermore, five brand new series of hybrids with total more than one hundred compounds were virtually designed and synthesized. Their potential MTH1 inhibitory effects were screened based on our system. We found that some of them exhibited moderate to excellent inhibitory activity toward MTH1 with nanomole IC50 values, which also showed significant cytotoxicity on several gastric cancer cell lines by MTT assay (with IC50 below 10μM). On the other hand, our studies in human gastric cancer patients also indicated that MTH1 expression levels were significantly enhanced in these patients’ cancer tissues, compared to the para-cancer ones. Our findings suggest that MTH1 may be a potential therapeutic target in gastric cancer. Compounds specifically designed to target MTH1 activity may represent a novel and useful strategy for anti-gastric cancer drug discovery. *Corresponding author: Wen Zhao, Ph.D, Tel.: 01186-15003898187. Email: zhaowen100@139.com Funding Sources. This work was supported by National Natural Science Foundation of China (Project No. 81430085, No. 21372206 and No. 81172937 for H.-M.L.; Project No. 81270270 and No. 81470524 for W.Z.); Ph.D Educational Award from Ministry of Education (No. 20134101130001, for H.-M.L. and No. 20134101110013, for W.Z.); The 2013 Scientific Innovation Talent Award from Department of Education of Henan Province (No. 13HASTIT029, for W.Z.). Citation Format: Wenjuan Zhou, Liying Ma, Biao Hu, Lingyu Li, Bo Wang, Hong-Min Liu, Wen Zhao. Potent compounds targeting the human MutT homolog 1 (hMTH1) activity and their cytotoxicity evaluation. [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 3813.
Response to vinflunine treatment after prior platinum-based chemotherapy in patients with advanced urothelial carcinoma independent of primary tumor location.
Authors: Axel Hegele, Patrick De Geeter, Peter J. Goebell, Ullrich Matz, Wito de Schultz, Birgit Edlich, Margitta Retz
Journal: Journal of Clinical Oncology (2015)

e15536 Background: The outcome of chemotherapy in patients with metastatic urothelial carcinoma (UC) of the upper tract (UT) is generally assumed to be worse compared to bladder as a primary location. However, prospective data on the response to a cytotoxic agent in UTUC are scarce. Here we present data from a non-interventional study of patients with UTUC and lower tract UC (LTUC) treated with vinflunine after failure of platinum-based chemotherapy. Methods: Data were prospectively collected on platinum-pretreated UC patients undergoing vinflunine treatment in 39 German hospitals or outpatient units. Dosing of vinflunine, tumor assessments and concomitant medications were performed according to physician’s usual practice. Results: Out of 77 patients recruited UC was located in the UT in 18 patients (23 %) and the LT in 59 patients (77 %). Performance status in both groups was comparable (Karnofsky index 83.9 % vs. 83.7 %) and patients with UTUC were on average four years older (68.2 y vs. 64.4 y). The main grade 3/4 toxicities in the overall population, UTUC and LTUC patients were leucopenia 16.9/27.8/13.6 %, anemia 6.5/5.6/6.8 %, elevated liver enzymes 6.5/5.6/6.8 % and constipation 5.2/0/6.8 %. Efficacy was comparable in the UTUC and LTUC group regarding the overall response rate (22.2 % vs. 23.7 %), disease control rate (50.0 % vs. 54.2 %) and progression-free survival (2.76 [CI 1.38-8.28] months vs. 2.76 [CI 2.27-3.38] months). Conclusions: This prospective study confirms that vinflunine provides meaningful benefits with a good safety profile to patients pretreated with a platinum-based regimen in both advanced/metastatic UTUC and LTUC in routine practice. These findings support further application of vinflunine in UTUC patients.
Abstract 4692: Targeting the BET bromodomain proteins and anti-apoptotic protein BCL2 in small cell lung cancer
Authors: Lloyd T. Lam, Xiaoyu Lin, Emily Faivre, Ziping Yang, Xiaoli Huang, Ricky Bellin, Xin Lu, Yu Shen, Tamar Uziel
Journal: Cancer Research (2016)

Abstract 10% to 15% of all lung cancers are small cell lung cancer (SCLC), named for the size of the cancer cells when seen under a microscope. SCLC often starts in the bronchi near the center of the chest. It usually grows and spreads quickly to distant parts of the body before it is diagnosed. Unfortunately, no new treatment has been identified in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other oncogenic transcription factors that drive disease pathology. Pharmacologic inhibition of BET binding to acetylated proteins has been shown to inhibit tumor growth in MYC-dependent cancers, such as acute myeloid leukemia, multiple myeloma and neuroblastoma. Here, we demonstrate that ∼40% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor ABBV-075. Whereas most SCLC cell lines undergo cell cycle arrest with ABBV-075 treatment, a few cell lines undergo apoptosis. Sensitivity does not correlate with MYC status (amplification/expression). However, downregulation of anti-apoptotic protein BCLxL and BCL2 by ABBV-075 was observed in sensitive SCLC cells. Synergy was observed when co-treating BET inhibitor and BCL2 inhibitors, venetoclax (ABT-199) or navitoclax (ABT-263), and it positively correlated with BCL2 expression. Thus, high BCL2 protein expression could potentially be a biomarker predictive of these therapeutic combinations. The potential higher synergy with venetoclax may be explained by downregulation of BCLxL with BET inhibition and potent activity of venetoclax against BCL2. Our studies have provided evidence for treating SCLC by BET inhibition and/or combination with BCL2 inhibitors and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Lloyd T. Lam, Xiaoyu Lin, Emily Faivre, Ziping Yang, Xiaoli Huang, Ricky Bellin, Xin Lu, Yu Shen, Tamar Uziel. Targeting the BET bromodomain proteins and anti-apoptotic protein BCL2 in 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 4692.
PoPoolationTE2: Comparative Population Genomics of Transposable Elements Using Pool-Seq
Authors: Robert Kofler, Daniel Gómez-Sánchez, Christian Schlötterer
Journal: Molecular Biology and Evolution (2016)

The evolutionary dynamics of transposable elements (TEs) are still poorly understood. One reason is that TE abundance needs to be studied at the population level, but sequencing individuals on a population scale is still too expensive to characterize TE abundance in multiple populations. Although sequencing pools of individuals dramatically reduces sequencing costs, a comparison of TE abundance between pooled samples has been difficult, if not impossible, due to various biases. Here, we introduce a novel bioinformatic tool, PoPoolationTE2, which is specifically tailored for the comparison of TE abundance among pooled population samples or different tissues. Using computer simulations, we demonstrate that PoPoolationTE2 not only faithfully recovers TE insertion frequencies and positions but, by homogenizing the power to identify TEs across samples, it provides an unbiased comparison of TE abundance between pooled population samples. We anticipate that PoPoolationTE2 will greatly facilitate the analysis of TE insertion patterns in a broad range of applications.