tbuckley/cabot-search huggingface dataset:
Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy
Authors: Shlomit Strulov Shachar, Allison M. Deal, Marc Weinberg, Kirsten A. Nyrop, Grant R. Williams, Tomohiro F. Nishijima, Julia M. Benbow, Hyman B. Muss
Journal: Clinical Cancer Research (2016)

Severe skeletal muscle (SM) loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first-line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes.Using computerized tomography (CT) images taken for the evaluation of disease burden, skeletal muscle area (SMA), and density (SMD) were measured at the third lumbar vertebrae. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) ≤ 41. Skeletal muscle gauge (SMG) was created by multiplying SMI × SMD. Fisher exact tests, t tests, the Kaplan-Meier method, and Cox regression modeling were used.MBC patients (N = 40), median age 55 (range, 34-80), 58% sarcopenic, median SMG 1296 AU (SD, 522). Grade 3-4 toxicity was found in 57% of sarcopenic versus 18% of non-sarcopenic patients (P = 0.02). Toxicity-related hospitalizations were also higher in sarcopenic patients (39% vs. 0%, P = 0.005) as were any adverse events-defined as any grade 3-4 toxicities, hospitalizations, dose reductions, or dose delay-(74% vs. 35%, P = 0.02). Low SMG was associated with grade 3-4 toxicity (P = 0.04), hospitalization (P = 0.01), and time to treatment failure (for progression or toxicity; P = 0.03). Low SMG had a borderline significant association with any adverse event (P = 0.06) and overall survival (P = 0.07).SM measures are associated with toxicity outcomes and survival in MBC patients receiving first-line taxane-based chemotherapy. Further studies are needed to explore how routinely obtained CT scans can be used to individualize dosing and improve treatment planning. Clin Cancer Res; 23(3); 658-65. ©2016 AACR.
Abstract 944: The effects of GnRH-(1-5) on endometrial cancer cell lines
Authors: Darwin O. Larco, Madelaine J. Cho-Clark, Maya Sorini, Cameron Lee, T. John Wu.
Journal: Cancer Research (2016)

Abstract The Gonadotropin-Releasing Hormone (GnRH) is a central regulator of reproductive function and behavior. In the periphery, GnRH is secreted by gynecologic tissues to exert local effects. Furthermore, GnRH is processed in the extracellular environment by the metalloendopeptidase EP24.15 to generate the bioactive metabolite, GnRH-(1-5). We have previously demonstrated that GnRH-(1-5) transactivates the epidermal growth factor receptor (EGFR) pathway to promote cell migration by binding the orphan receptor GPR101 in the Ishikawa and ECC-1 endometrial cancer cell lines. In this study, we sought to determine whether the effects of GnRH-(1-5) were dependent on the stage of the endometrial cancer. Cell lines ACI-181, ACI-52, and ACI-80 derived from endometrial cancers representative of stages 1, 2, and 3 respectively were tested in their response to GnRH-(1-5) treatment. Furthermore, the expression of GPR101 was confirmed by western blot analysis. Treatment with 100nM GnRH-(1-5) did not have significant changes in phospho-EGFR (pEGFR) levels in all ACI cell lines. However, subsequent measurement of ERK phosphorylation demonstrated that ACI-181 cells treated with GnRH-(1-5) had significantly (p &amp;lt; 0.05) increased levels in the pERK2 subunit but not pERK1, which parallels our initial findings in the Ishikawa cell line. No changes in pERK1/2 levels were determined in the other cell lines. To measure the effect of GnRH-(1-5) on cell migration, we implemented a wound closure assay. Interestingly, ACI-181 and ACI-52 cells had increased migration in response to GnRH-(1-5) treatment. To determine whether another pro-migratory pathway is regulated by GnRH-(1-5) in these cells, we measured TGF-β bioactivity using a cell-based assay from conditioned media of cells treated with GnRH-(1-5). We found that ACI-181 and ACI-52 cells had significantly (p&amp;lt;0.05) increased TGF-β bioactivity in response to GnRH-(1-5), indicating that these cells produced higher levels of bioactive TGF-β. It is likely that TGF-β and/or other growth factors may promote pro-survival and/or pro-migratory signaling cascades via an autocrine mechanism. These results further suggest that GnRH-(1-5) may exert differential effects on endometrial cancer cells that are not dependent on cancer progression. Funding Sources: This research was supported by grants from the John P. Murtha Cancer Center at Walter Reed National Military Medical Center through the Uniformed Services University and the National Science Foundation (IOS-1052288). Citation Format: Darwin O. Larco, Madelaine J. Cho-Clark, Maya Sorini, Cameron Lee, T. John Wu. The effects of GnRH-(1-5) on endometrial cancer cell lines. [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 944.
Dematin and Adducin Provide a Critical Link between the Spectrin Cytoskeleton and the Erythrocyte Membrane Via Glucose Transporter-1.
Authors: Anwar A. Khan, Toshihiko Hanada, Massimiliano Gaetani, Donghai Li, Brent C. Reed, David W. Speicher, Athar H. Chishti
Journal: Blood (2007)
Abstract 4848: Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma
Authors: Wang Qinghui, Arnst E. Kinsie, Duane D. Miller, Wei Li
Journal: Cancer Research (2016)

Abstract We previously discovered a novel 2-aryl-4-benzoyl-imidazole (ABI) scaffold exerts its potent anti-proliferative effects through interacting with the colchicine binding site in tubulin. Extensive structure-activity relationship (SAR) studies of this novel scaffold showed that the best analog in this series, ABI-231, has an average IC50 = 5.2 nM against panels of melanoma and prostate cancer cell lines, is orally bioavailable, and strongly suppress melanoma tumors in vivo. Analyses of the potential binding pose of ABI-231 at the colchicine binding pocket suggested small substitutions to the indole moiety in ABI-231 could further increase its interactions to tubulin. Based this hypothesis, we have established an efficient synthetic method for the synthesis of ABI-231 analogs by either rotating the indole ring or introducing substituents on the indole of ABI-231. Using this method, we synthesized and tested 27 analogs of ABI-231. Several of the compounds show excellent potency against a panel of melanoma cancer cell lines with a diverse genomic background (mutations in BRAF, TP53, CDKN2A and PTEN) that are frequently encountered in clinical metastatic melanoma tumors. Additionally, they are not substrates for the P-glycoprotein (Pgp) efflux pump and therefore strongly inhibited the multidrug resistant cell lines. The potency of the compounds was further verified by their potent growth inhibition of cancer cell colonies. Results from cell cycle analysis, apoptosis evaluation and tubulin polymerization inhibition are consistent with their expected mechanisms of action. Potential off-target analyses performed by Eurofins Cerep-Panlabs SafetyScreen 44 indicated that they are clean and does not inihibt any of the tested off-targets at 100 fold of its IC50 value in melanoma cells, suggesting the good safety profile for this compound and the probably these scaffold in general. We are currently performing in vivo efficacy studies for the most potent analogs. These compounds hold great promise as a new generation of orally available tubulin inhibitors. Citation Format: Wang Qinghui, Arnst E. Kinsie, Duane D. Miller, Wei Li. Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma. [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 4848.
Abstract 1793: Novel radiation mitigators and anticancer drugs
Authors: Robert H. Schiestl, Michael Davoren, Yelena Rivina
Journal: Cancer Research (2015)

Abstract The possibility of a radiation disaster from a nuclear detonation or accident has existed for over 50 years and spawned much of the basic research in radiobiology in the 1950-60s. The recent Fukushima accident was yet another reminder that there remains a dire need to develop novel therapies against radiation-induced toxicities. Here we report on the development of two novel radiation countermeasure therapies: Yel001 and Yel002. These small, biologically active, drug-like molecules were uncovered in the DEL high throughput assay reducing radiation-induced cyto- and geno-toxicity in yeast. Radiation-modulating activity was further confirmed in yeast plate-based DEL Assay: addition of either Yel001 or Yel002 to irradiated cultures reduced cell death and genomic instability. Further, Yel compounds increases survival to 75% in vivo following an LD100/30 dose of ionizing radiation (IR) with the first therapeutic injection administered 24 hours post exposure followed by injections at 48,72,96, and 120 hours. Additionally, treatment with Yel001 and Yel002 compounds reduces radiation-induced leukemia from 90% to to 50% and 40% respectively. Of note, treatment with either Yel001 or Yel002 reduced spontaneous leukemia rate from 10% to 0%. Furthermore, Yel002 significantly prolonged the life of Atm deficient mice. Treatment with Yel002 following IR accelerates the recovery of the hematopoietic cells and protects stem cells after sub-lethal exposures. In addition, treatment with Yel002 reduces I131, EMS, MMS, UV, cigarette smoke extract as well as nitrogen mustard induced toxicity as well as genotoxicity showing a broad application spectrum. Proteomics shows that Yel002 induces DNA repair mediated by Atm signaling, homologous recombination, nonhomologous end joining, base excision repair, DNA damage binding proteins and chromosome segregation functions. Toxicity has not been observed in neither in vitro or in vivo administrations, even in a two generation teratogenicity assay. Overall, Yel compounds have much potential as stockpile therapies for radiation-induced lethality and cancer as well as spontaneous cancer: they are highly effective when administered up to 24hours post exposure, they reduce radiation-induced sequelae such as leukemia, and appear to have an acceptable toxicity profile. Citation Format: Robert H. Schiestl, Michael Davoren, Yelena Rivina. Novel radiation mitigators and anticancer drugs. [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 1793. doi:10.1158/1538-7445.AM2015-1793
Three are charged in $1bn US Medicare fraud case
Authors: Michael McCarthy
Journal: BMJ (2016)

Three Florida residents have been charged with conspiracy, money laundering, obstruction of justice, and fraud, in connection with a $1bn (£0.76bn; €0.91bn) scheme involving numerous unnamed Miami based healthcare providers.1

Officials from the US Department of Justice, which brought the charges, have called the case the largest single criminal healthcare fraud case ever brought against individuals.

The indictment accuses Philip Esformes, 47, the owner and …
SAT0010 Systemic Lupus Erythematosus in Spanish Males (RELESSER): Table 1.
Authors: A. Riveros-Frutos, I. Casas, I. Rúa-Figueroa, J. Pego-Reigosa, M.J. García, A. Olivé
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To describe the demographic, clinical and immunological manifestations in male patients with Systemic Lupus Erythematosus (SLE). <h3>Methods</h3> Patients diagnosed of SLE that were in the RELESSER data base (National Registry of Patients with Systemic Lupus Erythematosus of the Spanish Society of Rheumatology) were included. This is a multicenter retrospective cross-sectional study. We analyzed 3658 patients with SLE. All met the ACR criteria. Socio- demographic variables, comorbidities, classification, clinical and immunological manifestations were evaluated. Pearson9s chi-square test, t-Student, ANOVA and multivariate logistic regression analysis were performed <h3>Results</h3> A total of 3658 patients were included: 353 men (9.7%) and 3298 women (90.2%), with an average onset of symptoms of 37±17 and 32±14 years of age respectively. In 7 (0.1%) the gender was unknown. The male/female ratio was 9/1.The age of onset of symptoms and age at diagnosis was higher in men than in women (P&lt;0.0001). Diagnosis in males was sooner than in females (P=0.04).The most common age range at diagnosis in both genders was 21-49 years (P&lt;0.0001). Women had a more frequently a history of autoimmune thyroid disease (P&lt;0.001). Males have more cardiovascular comorbidities (P&lt;0.001).Comparing comorbidities in men with SLE by age range, it was found that SLE patients over 50 years of age had more comorbidity with significant differences.A total of 68% (236) of males with SLE required hospitalization in comparison of 53% (1713) of female (P&lt;0.001). During follow-up 208 patients died, 30 (9.3%) were male and 178 (5.9%) women (P=0.02).On multivariate analysis, the only statistically significant variable was age. It was seen that patients over 50 year-old had a higher mortality than those under 50 year-old, regardless of gender, delay in diagnosis, risk factors and clinical features OR: 5.32 (CI: 3.61 to 7.84)P&lt;0.001 <h3>Conclusions</h3> Patients with SLE older than 50 years old are at increased risk of mortality. In male patients with SLE: the age at diagnosis and the onset of symptoms is higher than in women. The diagnostic delay is lower in men than in women. Men have more cardiovascular comorbidities, especially those over 50 years-old and also more serositis, renal and cardiovascular involvement than women. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3832
Abstract LB-375: Childhood body size at age 13 years and associations with ovarian cancer in adult life
Authors: Julie Aarestrup, Michael Gamborg, Nicolas Wentzensen, Lian G. Ulrich, Thorkild IA Sørensen, Jennifer L. Baker
Journal: Cancer Research (2016)

Abstract Background: Among women, body mass index (BMI; kg/m2) and attained height are positively associated with ovarian cancer. Few studies have, however, investigated associations with childhood body size. As such, it remains largely unknown if it is body size development in early life or adult life that contributes to these associations. Therefore, we examined if childhood BMI and height at age 13 years were associated with ovarian cancer in adult life. Methods: Individuals were girls in the Copenhagen School Health Records Register who were born between 1930 and1989 and had available measures of height and weight at age 13 years. BMI and height z-scores were calculated from an internal age-specific reference. Via a personal identification number, individuals were followed up for ovarian cancer diagnosis by linkage to the Danish Cancer Registry. Cox proportional hazard regressions were performed and stratified by birth cohort. Results: Among the included 137,416 girls, 1048 cases of ovarian cancer occurred during 5.2 million person-years of follow-up with a median age of diagnosis of 57 years (range: 19-83 years). BMI tended to be non-linearly associated with ovarian cancer such that only the heaviest girls had positive associations with ovarian cancer. Compared with a 13-year-old girl of average-size (BMI z-score = 0, corresponding to a weight of 45 kg and a height of 157 cm), an equally tall girl who was at least 9 kg heavier (corresponding to a BMI z-score &amp;gt;1.28) had a hazard ratio (HR) for ovarian cancer of 1.33 (95% confidence interval [CI]: 1.08-1.63). In analyses adjusted for childhood height, the association was only marginally attenuated (HR = 1.30, 95% CI: 1.06-1.60). Childhood height was positively and statistically significantly associated with ovarian cancer. At age 13 years, per height z-score (corresponding to approximately 7 cm), the HR for ovarian cancer was 1.07 (95% CI: 1.01-1.14). Conclusion: Body size in early life was associated with ovarian malignancies later in life suggesting that childhood height and BMI might impact if women are later diagnosed with ovarian cancer. As ovarian cancers vary widely in their etiologies, associations with childhood body size may differ depending on the tumor type, which will be investigated. Citation Format: Julie Aarestrup, Michael Gamborg, Nicolas Wentzensen, Lian G. Ulrich, Thorkild IA Sørensen, Jennifer L. Baker. Childhood body size at age 13 years and associations with ovarian cancer in adult life. [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 LB-375.
Abstract 4484: Differentially methylation between ER negative and ER positive breast cancer identifies master regulators to expose potential epigenetic drivers of aggressive disease
Authors: Maria J. Worsham, Kang Mei Chen, Indrani Datta, Josena K. Stephen, Dhananjay Chitale, George Divine
Journal: Cancer Research (2016)

Abstract The majority of published studies investigating driver genes have focused primarily on genomic mutations which have led to novel study designs (basket trials) where patients with a rare mutation, regardless of tumor histology, are matched to a drug expected to work through the mutated pathway. This dominant focus on genomic mutations has yet to configure in epigenetics. There has been relatively little advancement in changing the management of women with ER negative BC, mainly due to a dearth of actionable therapeutic targets. Our drill-down approach to identified an ER negative-specific 16 gene methylation signature (AHNAK, ALPL, ANXA2R, CCND1, CIRBP, CPQ, DST, EGFR, ESR1, GPRC5B, HERC5, IL22RA2, MITF, OBSL1, POU3F3, RB1CC1) starting from a discovery approach (Illumina Infinium HumanMethylation450 BeadChip, 40 ER negative vs. 40 ER positive BC) followed by expression verification, significant rankings in biological pathways (Ingenuity Pathway Analysis), and confirmation by targeted sequencing using Illumina MiSeq. Causal Networks are small hierarchical networks of regulators that control the expression/methylation of dataset targets. They can enhance understanding of the effect of master regulators on disease or function. The objective of this study was to identify regulatory networks utilizing IPA's Causal Network Analysis (CNA) in order to illuminate possible causes and mechanisms underlying the biological activities of the 16 candidate gene signature differentiating ER negative from ER positive BC. To reflect expected gene expression direction implied by methylation changes for the 16 candidate genes, the inverse of the methylation ratio from ER negative vs. ER positive tissue was used for CNA. CNA software identified 4 hierarchical networks and their corresponding master regulatory molecules, diethylstilbestrol, MSH2, 15-ketoprotaglandin E2, and transcription regulator SP1. Diethylstilbestrol and SP1 had direct regulatory influence (depth level 1) to the candidate molecules ALPL, CCND1, EGFR, ESR1 and CCND1, CIRBP, EGFR, ESR1, respectively. CNA raised the profile of ALPL, CCND1, CIRBP, EGFR, ESR1 (5/16 candidate genes) for further consideration as potential epigenetic drivers of ER negative BC. Support: Komen Foundation: KG110218 Citation Format: Maria J. Worsham, Kang Mei Chen, Indrani Datta, Josena K. Stephen, Dhananjay Chitale, George Divine. Differentially methylation between ER negative and ER positive breast cancer identifies master regulators to expose potential epigenetic drivers of aggressive disease. [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 4484.
Abstract LB-001: Functional role of Pak1/Erk signaling in Rac1-related diseases
Authors: Daniela Araiza-Olivera, Jonathan Chernoff
Journal: Cancer Research (2016)

Abstract The RAS/MAPK signaling pathway regulates key cellular processes, including proliferation, differentiation, and survival. Somatic mutations of the RAS pathway are found in 30% of human cancers, including pancreatic, colon, thyroid, lung and melanoma. Furthermore, germ-line mutations in this pathway, collectively termed Rasopathy syndromes, cause abnormal development. Affected patients often present with cognitive defects, heart problems, facial aberrancies, skin abnormalities and in some cases a predisposition to cancer. As p21-activated kinases (Paks) have been shown to be required for the activation of ERK by Ras, we evaluated Pak1 and its activator Rac1 as potential therapeutic targets in both Rasopathies and in melanoma. Using a zebrafish model, we first asked if the phenotypic consequences of Ras pathway overactivation during development could be blocked by Pak small molecule inhibitors. Introducing gain-of-function genes such as BRAF V600E, KRAS 4AG12V, and Rac1 P29S into one-cell zebrafish embryos produced a Rasopathy phenotype, characterized by abnormal head and heart development. These phenotypes were suppressed by a Pak-specific small molecule inhibitor. pERK and pPAK levels were increased in embryos expressing BRAF V600E, KRAS 4AG12V, or Rac1 P29S, and were restored to baseline upon addition of Pak1 or Rac1 small molecule inhibitors. We then studied the effect of these small molecule inhibitors in human malignant melanoma cell lines bearing activating mutations in BRAF, PREX (an activator of Rac1), and/or RAC1. Treatment with PAK or RAC inhibitors decreased the migration and proliferation of cells with mutant PREX or RAC1 mutations, but not those with BRAF mutations; the reverse was true when these cells were treated with a BRAF inhibitor. These data suggest that Pak1 might serve as a useful therapeutic target in PREX- or RAC1-driven cancers such as malignant melanoma. Citation Format: Daniela Araiza-Olivera, Jonathan Chernoff. Functional role of Pak1/Erk signaling in Rac1-related diseases. [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 LB-001.