tbuckley/cabot-search huggingface dataset:
Abstract 1278: Popdc proteins: novel targets in inhibiting breast cancer cell migration and proliferation
Authors: Johanna N. Amunjela, Steven J. Tucker
Journal: Cancer Research (2016)

Abstract Tumour growth and metastasis are major challenges in cancer treatment and metastasis is the primary cause of death in more than 90% of cancer patients with solid tumours (Gupta &amp; Massagué 2006). This necessitates identification and validation of clinically relevant anticancer therapeutic targets that result in maximum clinical efficacy with minimal side-effects when manipulated by drugs. Our research project has identified Popeye domain containing (Popdc) proteins as promising potential therapeutic targets in the treatment of breast cancer. Popdc proteins are a class of membrane-tethered proteins encoded by the three members of the Popdc gene family Popdc1, Popdc2 and Popdc3. Their suppression has been correlated with disease progression and poor clinical outcomes in various cancers including breast cancer, gastric cancer, lung cancer, hepatocellular carcinoma and colorectal cancer (Kim et al., 2010, Luo et al., 2012, Williams et al., 2011, Wang et al., 2011). Loss of Popdc protein expression has been correlated with increased cancer cell migration, invasion, metastasis, drug-resistance and poor patient survival (Luo et al., 2012, Williams et al., 2011, Han et al., 2014). In breast cancer, Popdc1 suppression has been reported in breast carcinoma cells while upregulation of Popdc2 has been linked to the mechanism by which arsenic trioxide mediates breast cancer cell death (Williams et al., 2011, Wang et al., 2011). Our use of various assays including single-cell migration assays, cell population migration assays, cell proliferation assays and fluorescent imaging strongly implicate Popdc proteins as drivers of cancer cell migration and proliferation. Expression patterns of Popdc proteins revealed high expression levels in non-malignant (HMepC) breast cells and low expression in breast cancer (MCF7) cells. This suggests that loss of Popdc protein expression correlates with an increasingly malignant phenotype. Furthermore, knocking down Popdc1, Popdc2 and Popdc3 in MCF7 breast cancer cells significantly promoted cell migration both at single cell and at cell population level while Popdc2 knockdown significantly promoted unstimulated MCF7 cell division. Taken together, this strong data set suggests that Popdc proteins play significant roles in the migration and proliferation of different cancer cell lines and that they indeed represent promising potential therapeutic targets in reducing breast cancer cell division and migration. Citation Format: Johanna N. Amunjela, Steven J. Tucker. Popdc proteins: novel targets in inhibiting breast cancer cell migration and proliferation. [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 1278.
Abstract 3418: Differential prognostic effect of smoking and multivitamin use on lung cancer survival by sex
Authors: Mi Yang, Hyun-Kyung Oh, Young Mog Shim, Myung-Hee Shin
Journal: Cancer Research (2016)

Abstract Incidence of lung cancer is decreasing among men and increasing among women in developed countries and also in Korea. However, mortality of lung cancer is still the highest among male cancers. Smoking is one of the group 1 carcinogens for lung cancer development, but its prognostic effect on lung cancer survival is not well established. Beta-carotene supplement increased the risk of lung cancer among smokers but the role of multivitamin supplement on the risk and survival of lung cancer is unclear either. We aimed to evaluate the association between smoking and multivitamin use on lung cancer survival by sex. We interviewed 910 pathologically confirmed lung cancer patients who were diagnosed between 2010 and 2012 in Samsung Medical Center. Questionnaire included current smoking status, age at first smoking, daily smoking amount, alcohol intake, past medical history, and multivitamin use. Pathological type, stage, and treatment information was collected from the electronic medical records. We followed the patients until December 31, 2012. Hazard Ratios (HR) and 95% Confidence Intervals (CI) were estimated using Cox's proportional hazard model (SAS9.4). We found significant difference in age at diagnosis, pathological type and stage between male and female patients; Female patients were younger, smoked less, used more multivitamin, and had more adenocarcinoma and earlier stage cancer than male patients. Smoking increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for those who smoked more than 40 pack-years compared to those who never smoked was 5.64 (95%CI = 1.43, 22.28) in women and 1.17 (95%CI = 0.61, 2.26) in men (p-interaction = 0.01) when adjusted for age, stage, and pathologic type. Multivitamin use also increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for multivitamin users was 4.14(95%CI = 1.77, 9.73) in women and 1.46 (95%CI = 0.71, 3.00) in men (p-interaction = 0.17). The association between multivitamin use and lung cancer mortality was strongest among female non-smokers (HR = 4.10, 95%CI = 1.72, 9.77). In conclusion, smoking and multivitamin use worsen the survival of female lung cancer. Prognostic effect of multivitamin use may be stronger among non-smokers. Citation Format: Mi Yang, Hyun-Kyung Oh, Young Mog Shim, Myung-Hee Shin. Differential prognostic effect of smoking and multivitamin use on lung cancer survival by sex. [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 3418.
Abstract 4678: Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosis
Authors: YAN GAO, Jacson Shen, Rosemary Foster, Francis J. Hornicek, Zhenfeng Duan
Journal: Cancer Research (2016)

Abstract Purpose: Overexpression of cyclin-dependent kinase (CDK) 4 has been shown in a variety of cancers and contributes to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. Here we investigated the therapeutic effect of CDK4 inhibitor, palbociclib, in combination with paclitaxel in ovarian cancer cells. Experimental Design: Cell viability was determined by MTT assay after incubating with different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the potential effects and mechanisms of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 in ovarian cancer cells. Immunohistochemistry was performed to evaluate the clinical relevance of CDK4 expression in an ovarian cancer tissue microarray. Results: The combination of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb positive (Rb+) and Rb negative (Rb-) ovarian cancer cells. Palbociclib suppressed the phosphorylation of pRb (Ser 807-811, Ser 795, and Ser 780) in multidrug resistant SKOV3TR (Rb+) cells. When combined with paclitaxel, palbociclib induced significant apoptosis in both SKOV3TR (Rb+) and OVCAR8TR (Rb-) cells. Palbociclib also inhibited the activity of P-glycoprotein (Pgp). Additionally, transfection of CDK4 siRNA showed effective knockdown of CDK4 expression and sensitized multidrug resistant SKOV3TR and OVCAR8TR cells to paclitaxel. Furthermore, primary ovarian cancer patients with high expression of CDK4 tended to have unfavorable clinical outcomes. Conclusions: Inhibition of CDK4 either by palbociclib or by specific siRNA can increase the in vitro paclitaxel sensitivity in either Rb+ or Rb- multidrug resistant ovarian cancer cells through increased apoptosis. Therefore, CDK4 may be a promising target in the treatment of ovarian cancer. Citation Format: YAN GAO, Jacson Shen, Rosemary Foster, Francis J. Hornicek, Zhenfeng Duan. Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosis. [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 4678.
Safety and efficacy of paclitaxel liposome monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer: A prospective, multicenter, uncontrolled phase II study.
Authors: Zhenyu Ding, Lin Zhou, You Lu
Journal: Journal of Clinical Oncology (2012)

e18086 Background: Recently, a novel form of paclitaxel encapsuled within liposome was developed with increased solubility and a longer half life in vivo. The aim of this study was to evaluate the safety and efficacy of paclitaxel liposome as a single agent chemotherapy for elderly patients with NSCLC. Methods: This study was a prospective, uncontrolled, open-label, multi-center, registered phase II trial (ChiCTR-TNC-00000226).Patients aged over 70 years with metastatic or recurrent non-small cell lung cancer were enrolled. Eligibility criteria included presence of measurable lesions, an ECOG PS of 0-2 as well as adequate organ function. Patients received paclitaxel liposome at an escalating dose of 135mg/m 2 , 150 mg/m 2 and 175 mg/m 2 every 3 weeks, and were monitored for safety and efficacy. Results: From 8 participating centers, 42 patients were enrolled with a median age of 73 years (range 70-81). A total of 89 cycles of chemotherapy was administered. No complete response was observed. 6.7%, 14.2% and 7.7% of patients obtained partial response, and 13.3%, 42.9% and 38.5% had stable disease from the escalating dose groups, respectively. The toxicity was mainly neutropenia, thrombopenia and digestive tract toxicity.There were 4 (26.7%), 3 (21.4%) and 3 cases (25%) of grade 3 or 4 neutropenia in the three dose group. Other non-hematological toxicities over grade 3 were rare. Pre-mature cease of chemotherapy occurred in 1 (7.1%) and 2 (16.6%) patients from the dose group of 150 mg/m 2 and 175 mg/m 2 respectively, all because of persistent toxicity. Median follow-up was 12.4 months (1.0-22.3 months). TTP in three dose group was 1.2 months (95%CI, 1.1-1.3 months), 1.2 months (95%CI, 0.9-1.3 months) and 1.9 months (95%CI, 1.4-2.3 months). Median OS in the dose group of 135 mg/m 2 was 4.9 months (95%CI, 1.0-11.5 month), and not reached in the other groups. Conclusions: Paclitaxel liposome administered at the dose of 150 mg/m 2 every 3 weeks seems to be safe and effective among these three dose levels. Although the toxicity profile was mild, the overall therapeutic effects were disappoiting.
Abstract 3757: A novel class of chemicals that react with damaged DNA and specifically kill B-cell cancers
Authors: Shanqiao Wei, Madusha Watuthanthrige, Sophia Shalhout, Ashok S. Bhagwat
Journal: Cancer Research (2016)

Abstract Majority of B-cell malignancies arise in germinal center, where the processes of somatic hypermuation (SHM) and class switch recombination (CSR) for antibody maturation are initiated by activation-induced demainase (AID). AID belongs to the AID/APOBEC family and deaminates cytosine in DNA creating uracil. We have previously shown that B-cell lymphoma cell lines and patient tumors express AID at high levels and contain high levels of uracils in their genome. These cells also contain uracil-DNA glycosylase that removes uracils generating high levels of abasic (AP) sites. AP sites exist in equilibrium with the open form of deoxyribose sugar that reacts with alkoxyamines forming a stable oxime. This principle was used to block the repair of excess AP sites in B cell cancers using an alkoxyamine, AA3. We found that AA3 effectively kills B-cell lymphoma cell lines which have high levels of endogenous AP sites. In contrast, AA3 is not toxic to normal human B cells and mouse splenocytes, as well as non-hematological cancers. To elucidate the molecular mechanism of selective cell killing by AA3, we compared the number of AP sites in B cell cancers and non-hematological cancers and confirmed that B cell cancer cells contained many more AP sites in their genome. Additionally, we found that AA3 was covalently linked to B cell cancer genome and AA3-DNA adducts caused cell death by blocking DNA replication and elevating DNA strand breaks. To determine which functionality of AA3 is responsible for its cytotoxicity and to discover better candidates for killing B cell cancers, we designed and synthesized a series of AA3 analogues. Using this approach, we have defined the functional groups required for AA3 toxicity. Overall, we have discovered that AA3 is selectively toxic to B cell cancers. This new family of chemicals could be developed further as novel and unique anti-cancer drugs. Citation Format: Shanqiao Wei, Madusha Watuthanthrige, Sophia Shalhout, Ashok S. Bhagwat. A novel class of chemicals that react with damaged DNA and specifically kill B-cell cancers. [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 3757.
Nanobodies to Study G Protein–Coupled Receptor Structure and Function
Authors: Aashish Manglik, Brian K. Kobilka, Jan Steyaert
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen-binding fragments of camelid heavy-chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Active-state stabilizing nanobodies have elucidated several agonist-bound structures of hormone-activated GPCRs and have provided insight into the dynamic character of receptors. Nanobodies have also been used to stabilize transient GPCR transmembrane signaling complexes, yielding the first structural insights into GPCR signal transduction across the cellular membrane. Beyond their in vitro uses, nanobodies have served as conformational biosensors in living systems and have provided novel ways to modulate GPCR function. Here, we highlight several examples of how nanobodies have enabled the study of GPCR function and give insights into potential future uses of these important tools.
Abstract 813: The association of androgen metabolizing enzymes and prostate cancer in a multiethnic study
Authors: Delores J. Grant, Lauren Howard, Emily Wiggins, Amanda De Hoedt, Adriana Vidal, Skyla T. Carney, Jill Squires, Clara E. Magyar, Jiaoti Huang, Stephen J. Freedland
Journal: Cancer Research (2016)

Abstract Introduction: Uridine 5’-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients. Methods: We determined the expression of the three enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each biomarker's percent positive and H-score and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were split at the median and we tested the association between UGT2B17 group and risk of BCR. Results: The median follow-up was 118 months (IQR: 85-144). We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found patients with UGT2B17 total positive above the median had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041) but this association was attenuated in the adjusted model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088). Conclusions: Our findings suggest that UGT2B17 overexpression was associated with a significant increased risk of BCR. These results are consistent with previous reports that show UGT2B17 significantly expressed in prostate cancer metastases. Citation Format: Delores J. Grant, Lauren Howard, Emily Wiggins, Amanda De Hoedt, Adriana Vidal, Skyla T. Carney, Jill Squires, Clara E. Magyar, Jiaoti Huang, Stephen J. Freedland. The association of androgen metabolizing enzymes and prostate cancer in a multiethnic study. [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 813.
Translational Breast Cancer Research Consortium (TBCRC) Patient Advocate Working Group (PAWG): An approach to research advocacy.
Authors: C. Chauhan, M. L. Smith, N. E. Carbine, L. Cargen, D. K. Cline, E. S. Frank, R. Kleban, P. Lee, S. A. Mertz, A. H. Meyn, J. Perlmutter, C. A. Rufenbarger, P. A. Spears, E. A. Swaringen, L. V. Vincent, K. E. Wright, A. C. Wolff
Journal: Journal of Clinical Oncology (2011)

e19539 Background: Cancer research patient advocates act as a connection between the patient population and the research community, bringing the patient perspective to the research table and the research agenda to the patient community. Advocates may impact the direction and expression of the science in its application to patients. The TBCRC is a collaborative group of 16 academic research centers with the goal of conducting innovative, high-impact breast cancer clinical trials. TBCRC trialists test novel strategies and work to understand the underlying cause and biology of breast cancer. Methods: TBCRC centers nominate a patient advocate to the Patient Advocate Working Group (PAWG). PAWG was formed in 2008 and is structured like all other TBCRC working groups with two co-chairs and institutional representatives. PAWG meets monthly by phone and yearly in person. PAWG members participate in TBCRC clinical and research working groups, collaborating with researchers to evaluate patient friendliness and acceptability of proposed trials and accrual issues as well as to educate patients. PAWG initiates and develops its own projects to support and enhance TBCRC's mission. Results: Examples of activities of the PAWG include consulting to PIs on proposed trial designs and a recruitment tool kit for activated studies; tissue banking surveys to provide a foundation for "best practices" for the TBCRC members; reviewing forms to provide consistency and patient focus when reviewing concepts, protocols and informed consent documents; creating a brochure for patients and the public to publicize the work of the TBCRC; composing letters from the advocates to prospective trial participants explaining specific trials and offering support and compassion; and adding questions to a surgical trial to better understand the patient experience. Conclusions: The TBCRC PAWG is a viable, proactive part of the TBCRC that participates in advancing the science through dynamic interaction with and participation in other TBCRC working groups, support of trial initiatives and activation of its own projects. The TBCRC PAWG enhances the achievement of the goals and mission of the TBCRC.
P179 Forced vital capacity, systemic inflammation and cardiometabolic markers in adulthood: a cross-sectional analysis: Abstract P179 Table 1.
Authors: NJ Saad, M Kaakinen, A Da Silva Couto Alves, C Minelli, MR Jarvelin, PGJ Burney
Journal: Thorax (2013)

<h3>Introduction</h3> Forced vital capacity (FVC) is a powerful predictor of mortality, more than airflow obstruction (Burney <i>et al</i>. Thorax 2011;66:49–54). FVC is associated with systemic inflammation as well as with cardiovascular disease and diabetes. Given that systemic inflammation is also associated with cardiovascular disease and diabetes, systemic inflammation could explain the observed association between FVC and cardiometabolic markers. Here, we examined the association between FVC, cardiometabolic markers and systemic inflammation in 3,731 individuals belonging to the Northern Finland Birth Cohort 1966. <h3>Methods</h3> Using linear regression, we examined the association between i) cardiometabolic markers (systolic blood pressure, diastolic blood pressure, LDL cholesterol, triglycerides, fasting glucose, insulin and HOMA-IR) and inflammatory markers (C-reactive protein (CRP) and white blood cell count (WBC)), ii) FVC and inflammatory markers, and iii) FVC and cardiometabolic markers. We then tested whether the association between FVC and cardiometabolic markers could be explained by systemic inflammation, by adjusting the linear regression models of FVC on each cardiometabolic marker for the two inflammatory markers. <h3>Results</h3> Increasing levels of inflammatory markers were associated with a decrease in FVC, -12mL per mg/L of CRP (95% confidence interval (CI): -17 to -7 mL) and -17 mL per 10<sup>9</sup> cells/L of WBC (95% CI: -28 to -7 mL), and with increasing levels of the cardiometabolic markers. FVC also decreased with increasing levels of cardiometabolic markers (Table, column 1) and adjusting these associations for the inflammatory markers did not substantially alter them (Table, column 2). <h3>Conclusion</h3> The association between FVC and cardiometabolic markers is not explained by variation in inflammatory markers, as measured by CRP and WBC. However, due to the cross-sectional nature of the analysis, no inference can be made with regard to the directionality of the associations.
Applying evidence: What’s the next action?
Authors: Paul Glasziou
Journal: Annals of Internal Medicine (2009)

Every fortnight my practice group gathers for an early morning “journal club” where we discuss a paper that we think could change our practice. A large pot of tea, an informal atmosphere, and lively discussions have made the sessions popular. But our interest is not the entertainment of pulling apart papers or curiosity about pathophysiology: our central interest is in clinical practice improvement. As in other journal clubs, we critically appraise the paper, calculate the number needed to treat (NNT), and decide on the clinical bottom line. But most journal clubs end there, assuming that everyone will implement the change. But, as we’ve repeatedly experienced, that assumption is often false.1 So following the traditional evidence-based practice steps, we ask, “So what is the next action?”2

The “next action” can be a variety of things. Sometimes the next action is garnering some additional information through another search, writing to the authors, or writing to a local expert. It doesn’t need to be a whole implementation plan, just the next physical action and who is responsible for it.2 For example, at a recent journal club, we discussed measuring blood pressure in both arms. A useful systematic review3 of blood pressure differences between arms made us …