tbuckley/cabot-search huggingface dataset:
Abstract 4970: USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination
Authors: Pieter J.A. Eichhorn, Prasanna Iyengar, Patrick Jaynes, Chandra Verma
Journal: Cancer Research (2015)

Abstract Transforming growth factor-β (TGFβ) is a multifunctional cytokine that acts as a tumour suppressor in normal cells and as an oncogene in advanced tumour cells. In the later scenario, TGFβ signaling enhances pro-invasive and pro-metastatic properties of the cancer cell. Ubiquitin modification of the TGF-β pathway components is emerging as a key mechanism of TGF-β pathway regulation. To limit TGF-β responses, TGF-β signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-β receptor (TβR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TβR. However the precise mechanism by which these DUBs act on TβR function remains poorly defined. Here, we demonstrate that apart from targeting the TBR complex directly USP15 also deubiquitinates SMURF2 resulting in enhanced TβR stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-β pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways. Citation Format: Pieter J.A. Eichhorn, Prasanna Iyengar, Patrick Jaynes, Chandra Verma. USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. [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 4970. doi:10.1158/1538-7445.AM2015-4970
Semen quality in men with disseminated testicular cancer (TC): Relation with CAG repeats in the androgen receptor gene and with single nucleotide polymorphisms (SNPs) in the 5 alpha reductase gene.
Authors: D. de Bruin, E. van Ieperen, E. G. J. M. Arts, H. J. Hoekstra, J. D. Dijck-Brouwer, C. Meijer, N. Zwart, I. P. Kema, I. J. de Jong, J. A. Gietema
Journal: Journal of Clinical Oncology (2011)

e15098 Background: Androgens and a normal functioning androgen receptor (AR) are essential for development of the male gender and spermatogenesis. Polymorphisms of the AR gene or 5 alpha reductase (SRD5A2) gene are involved in androgen sensitivity and fertility. Results in literature are conflicting. TC patients do have impaired semen quality. A better insight is needed in the pathophysiology of androgen-dependant semen quality in men with disseminated TC. We studied the influence of CAG repeat number in the AR gene and SNP rs523349 in the SRD5A2 gene on semen quality in patients with disseminated TC Methods: Between 1995-2009 155 patients with disseminated TC (median age 25 yrs, range 16-44) had cryobanked semen before start of chemotherapy and participated in a pharmacogenetics study on outcome of treatment. Semen quality, hormonal status and DNA for genotyping were available. Semen quality was expressed as total motile sperm count per ejaculate (VCM) (106): volume (mL) x concentration (106/mL) x percentage forward motility. We compared VCM in patients with different CAG repeat numbers and in patients with wild type versus variant of SNP in SRD5A2 gene (rs523349; TaqMan assay). Results: The median CAG repeat length was 21 (range 14-29). The VCM was positively correlated with the number of CAG repeats (Rs=0.189, p=0.02).All patients with CAG repeat length <18 had a VCM <20x106. There was no correlation between the number of CAG repeats and testosterone (Rs=0.040, p=0.658) or oestradiol (Rs=0.058, p=0.529). However, a negative correlation was found between CAG repeats and LH (Rs=-0.245, p<0.01) and FSH (Rs=-0.253, p<0.01). The prevalence of wild type, heterozygote variant and homozygote variant of the mutation SNP rs523349 was 51%, 36% and 13% respectively. No statistically significant difference in VCM between wild type and variants was found (p=0.374). No significant differences in sex hormones between both groups were found. Nor VCM, neither sex hormones were associated with SNP rs523349 variants. Conclusions: These data show that semen quality in patients with disseminated TC is related to alterations of the AR gene.
PWE-020 Symptoms and objective measurement of gastro-oesophageal reflux in adults with cystic fibrosis: interim report
Authors: C H Race, L F Smith, S A Riley, F P Edenborough
Journal: Gut (2010)

<h3>Introduction</h3> The association between gastro-oesophageal reflux (GOR) and various respiratory disorders including cystic fibrosis (CF) is widely acknowledged. Although the exact nature of this relationship is uncertain, it is thought that reflux aspiration is a contributing factor in lung dysfunction in these patients. Patients with GOR typically report symptoms such as heartburn, regurgitation, and occasionally atypical symptoms such as cough. It has been hinted that GOR in CF patients may be “silent” making detection and treatment often difficult. We piloted a cross-sectional survey to gain a better understanding of the perception of GOR and its impact on lung function. <h3>Methods</h3> Consenting patients completed two validated questionnaires regarding GOR symptoms which were scored and ranked (Gastro-oesophageal Reflux Symptom Questionnaire and Reflux Symptom Index). Patients were stratified by score and divided into two pilot groups; SGOR (symptomatic-highest scores) and AGOR (asymptomatic-lowest scores). Both groups underwent 24-h multiple intraluminal impedance/pH metry (MII) and high-resolution manometry (HRM) for positioning of MII probe. MII studies were assessed for the number of GOR events, proximal reflux events (PREs), and total proximal bolus exposure (TPBE). Patients remained on all current medication including PPIs. Clinical data were collected and compared retrospectively including most recent lung function results (FEV<sub>1</sub>). <h3>Result</h3> 53/110 patients completed questionnaires and 10 from each group were invited to undergo investigation—11 were completed successfully (age 18–55 years; four male, seven female; seven SGOR, four AGOR). There was little difference in the mean number of events between the groups (range 16–75, mean—SGOR 38, AGOR 42; (normal on PPI=48, off PPI=73)). There was no correlation between symptom scores (SS) and number of GOR events but there was a moderate negative correlation between the number of GOR events/FEV<sub>1</sub>. There was no significant difference in the mean number of PREs between the groups (range 1–31; mean SGOR=11, AGOR=22). TPBE ranged from 0.2–342 s. No correlation was shown between; number of PREs/SS, number of PREs/FEV<sub>1</sub> and TPBE/FEV<sub>1</sub>. <h3>Conclusion</h3> This small pilot study indicated that CF patients demonstrate impaired awareness of GOR and supports the theory that GOR is associated with poorer lung function. While there was no significant difference in the number of PREs between the groups, levels were higher in the AGOR group. This suggests that CF patients have poor perception of proximal reflux, which could increase the likelihood of aspiration. Based on these findings we aim to continue the survey to gain a more comprehensive assessment of the perception of GOR in adults with CF.
97. Stability and Inactivation of AAV Serotype 1 Vectors
Authors: Doug B. Howard, Lowella V. Fortuno, Brandon K. Harvey
Journal: Molecular Therapy (2015)

Adeno-associated viral (AAV) vectors have become a commonplace tool for gene delivery ranging from cell lines to human gene therapy. One feature that makes AAV desirable for gene delivery is its relative safety owing to no known disease associated with wild-type AAV. For this reason, it is often used with BSL1 practices negating the need for dedicated BSL2 facilities. Another useful property of AAV is its stability, both the duration of transgene expression and retention of infectivity as a viral particle. In the current study, we examine the stability of AAV serotype 1 vectors which are capable of transducing human cells and are routinely produced and used in our facility. First, we examined stability at 4° C for up to 7 weeks and found <10% decrease in transduction efficiency compared to a freshly-thawed aliquot. After 10 freeze-thaw cycles, 25% loss in transduction efficiency was observed. These data indicated that AAV serotype 1 is a highly stable viral particle with regards to retaining infectivity. Using small stainless steel slugs to mimic a biosafety cabinet or metal lab bench surface, we demonstrate that infectious AAV vector expressing Cre-recombinase can be reconstituted and used up to 7 days at room temp, although there was a clear decrease in transgene expression over time. The stability of AAV is a desired feature as a tool; however, it is important that the vector can be inactivated to avoid transgene delivery to end users or cross-contamination of non-disposable instruments. AAV decontamination procedures can vary. We tested multiple disinfectants commonly used in the laboratory for their ability to inactivate an AAV serotype 1 vector. The vector was added directly into solution for 5 or 30 minutes at a 1:10 ratio. It was then diluted, dialyzed, concentrated, and tested for transduction on primary neurons. Of the decontamination procedures tested, only autoclaving, 3.9% peracetic acid, iodine or 10% Clorox bleach completely prevented the subsequent detection of transgene expression. Although the nature of the transgene (e.g. proto oncogene or toxin) can elevate an AAV vector to BSL2, our data show that when working with AAV serotype 1 vectors, it's important that safety procedures for handling and decontaminating AAV are effective to avoid inadvertent transgene expression in human cells or cross contamination of AAV vectors used in non-disposable instruments. Other serotypes have not yet been tested.
Substrate Stress‐Relaxation Regulates Scaffold Remodeling and Bone Formation In Vivo
Authors: Max Darnell, Simon Young, Luo Gu, Nisarg Shah, Evi Lippens, James Weaver, Georg Duda, David Mooney
Journal: Advanced Healthcare Materials (2016)

The rate of stress relaxation of adhesion substrates potently regulates cell fate and function in vitro, and in this study the authors test whether it can regulate bone formation in vivo by implanting alginate gels with differing rates of stress-relaxation carrying human mesenchymal stem cells into rat calvarial defects. After three months, the rats that received fast-relaxing hydrogels (t1/2 ≈ 50 s) show significantly more new bone growth than those that received slow-relaxing, stiffness-matched hydrogels. Strikingly, substantial bone regeneration results from rapidly relaxing hydrogels even in the absence of transplanted cells. Histological analysis reveals that the new bone formed with rapidly relaxing hydrogels is mature and accompanied by extensive matrix remodeling and hydrogel disappearance. This tissue invasion is found to be prominent after just two weeks and the ability of stress relaxation to modulate cell invasion is confirmed with in vitro analysis. These results suggest that substrate stress relaxation can mediate scaffold remodeling and thus tissue formation, giving tissue engineers a new parameter for optimizing bone regeneration.
Efficacy and Safety of Rituximab in the Treatment of Refractory/Relapsed Idiopathic Thrombocytopenic Purpura (ITP): Results of a Meta-Analysis of 299 Patients.
Authors: Jeyanthi Ramanarayanan, Frank Brodzik, Myron S. Czuczman, Francisco J. Hernandez-Ilizaliturri
Journal: Blood (2006)
Clinical relevance of cytokeratin-negative circulating tumor cells.
Authors: C. V. Pecot, F. Z. Bischoff, Y. G. Lin, P. Jaladurgam, W. M. Merritt, T. J. Pircher, S. Mikolajczyk, J. A. Mayer, K. Wong, T. Pham, J. N. Bottsford-Miller, R. L. Stone, J. Celestino, A. M. Nick, C. Eng, A. Sood
Journal: Journal of Clinical Oncology (2011)

e21101 Background: Current enrichment techniques rely upon epithelial markers for capture of circulating tumor cells (CTCs). We developed a new method of isolating CTCs that lack EpCAM and/or cytokeratin (CK) expression; presumably cells that have undergone epithelial-to-mesenchymal transition (EMT). We sought to assess if such CTCs have clinical significance. Methods: After IRB approval, blood from ovarian or colorectal carcinoma patients was collected. A microfluidic-based (CEE) platform and antibody cocktail targeting epithelial and mesenchymal markers was utilized for capture and analysis of CTCs. Cells that were CK+/CD45- and CK-/CD45- were enumerated then examined for aneuploid status by fluorescent in situ hybridization (FISH) to further classify each cell as either normal or aneuploid (≥2 abnormalities by FISH). Results were then correlated with clinical outcome. Results: Total numbers of normal and aneuploid CK+ cells were significantly higher than either CK+ or CK- aneuploid cells for ovarian (p<0.09) and colorectal (CK+ aneuploid, p<0.01; CK- aneuploid, p<0.05) cancers. Overall, numbers of CK+ and CK- aneuploid cells were not significantly different (ovarian p=1.0, colorectal p=0.34). For ovarian cancer patients, presence of CK- aneuploid cells correlated with four-fold shorter progression free survival (PFS) (8 months with v. 33 months without detection; p<0.04). No significant difference in PFS was seen when CK+ aneuploid cells were detected (41 months with v. 25 months without detection; p<0.49). Preliminary results further suggest that detection of CK- aneuploid cells is associated with suboptimal tumor debulking. Conclusions: Enumeration of total CK+ cells was found to be higher than CK- cell populations in both cancer types. However, only CK- aneuploid cells were significantly associated with clinical outcome. These data suggest post-EMT (CK-) CTCs occur with lower frequency than classically defined CK+ CTCs, however they may carry more clinical relevance.
Infections after Allogeneic Hematopoietic Stem Cell Transplantation with a Nonmyeloablative Conditioning Regimen.
Authors: Pascale Frère, Frédéric Baron, Christoffe Bonnet, Kaoutar Hafraoui, Maguy Pereira, Evelyne Willems, Georges Fillet, Yves Beguin
Journal: Blood (2004)
Phase I study of ABT-700, an anti-c-Met antibody, in patients (pts) with advanced gastric or esophageal cancer (GEC).
Authors: Yoon-Koo Kang, Patricia LoRusso, Ravi Salgia, Chia-Jui Yen, Chia-Chi Lin, Ramesh K. Ramanathan, Patrick Kaminker, Irina Sokolova, Anahita Bhathena, Lan Wang, Louie Naumovski, John H. Strickler
Journal: Journal of Clinical Oncology (2015)

167 Background: MET is a receptor tyrosine kinase associated with treatment resistance. MET amplification (MA) results in c-Met overexpression and activation through autodimerization, and may be an important oncogenic driver in patients (pts) with advanced GEC. MA is relatively rare in primary tumors (&lt;5%), but may increase under the selective pressure of systemic therapy. ABT-700 is an anti-c-Met antibody with significant preclinical single-agent activity against MA human xenograft tumors. Efficacy and safety data for ABT-700 in patients with MA advanced GEC are presented. Methods: MA was assessed in tumor biopsy tissue by fluorescence in situ hybridization (FISH; Abbott Molecular Diagnostics) or DNA sequencing. MA, identified by FISH, was defined as a MET/CEP7 ratio&gt;2 in ≥20% of cells. The dose of ABT-700 is 15 mg/kg IV, once every 3 weeks, established during the dose escalation phase of the study. Responses were assessed using RECIST version 1.1. Results: As of May 31, 2014, 6 pts with chemotherapy refractory GEC have been treated with ABT-700. All pts had disease progression on 3 or more prior lines of chemotherapy. 4/6 pts had MA. 1 pt had MA identified retrospectively, and 3 pts had MA identified through a prospective screening effort. Among the 4 pts with MA GEC, 3 pts had a partial response (PR) and 1 pt had progressive disease (PD) as best response (ORR= 75%). Of the 3 pts who responded, the best response in target lesions was –56%,-52%, and –58%, and the PFS was 27, 18, and 24 weeks, respectively. Each of these three responders had a longer PFS with ABT-700 than with their preceding chemotherapy. In each of the 4 cases of MA identified in this study, MA was only detected in metastatic recurrent tumors and not the primary tumor tissue. The 2 pts without MA had PD as best response. ABT-700 was well tolerated, with no treatment related Grade 3-5 adverse events. Conclusions: In 4 pts with MA GEC, ABT-700 was well tolerated and appeared to have substantial single-agent activity. In this small cohort of gastric patients MA appears to be more common in treatment-refractory tumors than in primary untreated tumors, suggesting that screening efforts should focus on this treatment-refractory patient population. Clinical trial information: NCT01472016.
A randomized placebo-controlled trial of testosterone replacement for fatigue in male hypogonadic patients with advanced cancer.
Authors: E. Del Fabbro, J. Garcia, R. Dev, J. L. Palmer, C. Klingner-Winton, L. E. Roberts, J. Allo, G. Cardwell, E. Bruera
Journal: Journal of Clinical Oncology (2011)

TPS238 Background: Advanced cancer patients frequently identify fatigue as the main impairment to quality of life. Fatigue can stem from multiple causes, encompassing physical and psychosocial domains.Prior studies show a high prevalence of hypogonadism in males with cancer, particularly those on opioid therapy. Low testosterone levels correlated with fatigue, depression, poor appetite, insomnia and decreased libido. Currently there are few effective therapies for cancer related fatigue. Symptomatic hypogonadic male patients may benefit from testosterone replacement. Methods: A multicenter randomized double-blind placebo controlled trial. Treatment: Gluteal injections of 150 or 200 mg (weight based) testosterone enanthate or placebo (sesame seed oil) at baseline, day 15, 29, 43 and 57. Objectives: Primary objective is whether the decrease in fatigue from baseline to day 29 in patients who received testosterone replacement is greater than placebo as measured by a standardized questionnaire, the Functional Assessment of Chronic Illness Therapy-Fatigue subscale. Secondary objectives are the effect of testosterone replacement therapy on depression (Hospital Anxiety and Depression Scale), low sexual desire (Sexual Desire Inventory) and anorexia/cachexia (Functional Assessment of Anorexia/Cachexia Treatment scale). Functional outcomes include spontaneous activity (actigraphy), strength (handgrip) and endurance (6 minute walk). Laboratory correlates include C-reactive protein levels and serum cytokines. Eligibility criteria include male patients with advanced cancer (metastatic or locally recurrent), bioavailable testosterone < 70 ng/dL., Edmonton Symptom Assessment System fatigue score > 3 (0 to 10 scale), Prostatic Specific Antigen (PSA) <4.0 ng/mL, hemoglobin ≥9 g/dL. Patients are excluded if they have prostate cancer, severe benign prostatic hypertrophy, breast cancer, untreated obstructive sleep apnea, Class IV heart failure, thyroid disease. Current enrollment is 22 of a planned 126 patients. (NCT00965341)
Abstract 1458: Characterization of novel thyroid PDX models and their response to combination therapies
Authors: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Daniel L. Small, Aidan J. Synnott, Dragana Milosevic, Brian C. Netzel, Stefan K. Grebe, Kevin Wu, Robert C. Smallridge, John A. Copland
Journal: Cancer Research (2015)

Abstract Patient derived xenografts (PDX) mouse models for many types of cancer have demonstrated therapeutic responses similar to those seen in patients. Thus, resected patient tumor tissue directly implanted into immune compromised mice followed by therapy and tumor growth analysis is thought to be the closest preclinical model to predict patient therapeutic responses. To date, few models are available for the different histotypes of thyroid cancer derived from follicular thyrocytes; these include papillary, follicular, Hurthle cell, squamous and anaplastic thyroid carcinoma. We have developed eight PDX models in athymic nude mice representing all of these subtypes. The models have been extensively characterized for mutational status (i.e. BRAF, telomerase, RAS, PTEN, TP53, RB, etc) as well as validation by short tandem repeat (STR) analysis to match that of the originating patient tumor tissue. Squamous and anaplastic thyroid cancers are rare tumor types with no FDA approved therapies. Each model demonstrated their own unique responses to radiation, cytotoxic or molecular targeted therapies such as doxorubicin, sorafenib (tyrosine kinase inhibitor), cisplatin, paclitaxel, sunitinib (tyrosine kinase inhibitor), erlotinib (EGFR inhibitor), trametinib (MEK inhibitor) and vemurafenib (BRAF inhibitor). We expect that these models may provide useful in vivo models for thyroid cancer research as well as models for therapeutic guidance based upon histotype, mutational status and response to therapies. Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Daniel L. Small, Aidan J. Synnott, Dragana Milosevic, Brian C. Netzel, Stefan K. Grebe, Kevin Wu, Robert C. Smallridge, John A. Copland. Characterization of novel thyroid PDX models and their response to combination therapies. [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 1458. doi:10.1158/1538-7445.AM2015-1458