tbuckley/cabot-search huggingface dataset:
Inhibition of Stat3 sensitizes resistant human ovarian cancer cells to paclitaxel
Authors: Zhenfeng Duan, Rosemary Foster, Jennifer Mahoney, Michael Seiden
Journal: Cancer Research (2005)

3292  Recent evidence demonstrates that IL-6 may contribute to anti-apoptotic effects and multi-drug resistance in many tumor cell types. IL-6 signal transduction is mediated through the Stat3 pathway. Previous studies have determined that IL-6 levels are elevated in ascites and blood of ovarian cancer patients. Additionally, the IL-6 receptor is expressed on paclitaxel resistant ovarian cancer cell lines. Our laboratory evaluated the IL-6-Stat3 signaling pathway in both paclitaxel sensitive and resistant ovarian cancer and further evaluated the effects of disrupting either Stat3 expression or activation on the drug resitant phenotype. Examination of relative Stat3 expression levels in paclitaxel sensitive and resistant human cancer cell lines demonstrated that Stat3 and activated phosphorylated Stat3 are overexpressed in a subset of paclitaxel resistant cells as compared to their expression in paclitaxel sensitive cells. Analysis of Stat3-dependent gene expression using a luciferase reporter construct confirmed that the elevated Stat3 and phosphoStat3 detected in resistant lines led to increased luciferase expression in all three drug resistant cell lines studied. Transfection of paclitaxel resistant cells with Stat3 siRNAs resulted in a highly significant decrease in paclitaxel resistance with Western blot analysis confirming a decrease in Stat3 expression levels in transfected cells. Similar results in the same cell lines were obtained with the JAK kinase inhibitor AG490. These results demonstrate that Stat3 pathway inhibitors are able to reverse the drug resistant phenotype in tumor cells. Our current data provide important information about the specific role of Stat3 in mediating paclitaxel resistance and suggest that either paracrine or autocrine activation of the IL-6/Stat-3 pathway may support the drug resistant phenotype in human ovarian cancer.
Roles of cyberbullying, sleep, and physical activity in mediating the effects of social media use on mental health and wellbeing among young people in England: a secondary analysis of longitudinal data
Authors: Russell M Viner, Aswathikutty Gireesh, Neza Stiglic, Lee D Hudson, Anne-Lise Goddings, Joseph L Ward, Dasha E Nicholls
Journal: The Lancet Child & Adolescent Health (2019)
Evaluating the safety of anti-CTLA-4 therapy in the elderly with unresectable melanoma.
Authors: Sunandana Chandra, Kathleen M. Madden, Rajni Kannan, Anna C. Pavlick
Journal: Journal of Clinical Oncology (2013)

9063 Background: Anti-CTLA-4 monoclonal antibodies demonstrated an improvement in overall survival in patients with metastatic melanoma and ipilimumab (ipi) was FDA approved in 2011. We performed a retrospective analysis of 74 elderly (age ≥ 65) patients (pts) who were treated with anti-CTLA-4 therapy (tx) and evaluated their treatment related adverse events (AEs) as well as clinical response. Methods: 65 pts were treated with ipi 3 mg/kg x 4, among whom 8 pts were re-treated with ipi 3 mg/kg x 4; 3 pts were treated with ipi 10 mg/kg x 4 with 2 pts who went on to receive maintenance tx; 2 pts were treated with tremelimumab (treme) 15 mg/kg q 3 months; 4 pts are currently undergoing tx with ipi 3 mg/kg x 4. There were 17 treatment naïve pts, and 57 pts were previously treated with 1-4 prior therapies. Thirty-nine pts received all 4 doses of ipi. There were 46 males and 28 females. Ages ranged from 65 to 90, median age 74. Melanoma subtypes included: 55 cutaneous, 8 mucosal, 7 ocular, 3 acral, and 1 unknown primary. Ten pts had M1a, 18 M1b, and 45 M1c disease. One pt had unresectable stage IIIC disease. Results: The most common tx related AEs included rash (33 AEs ≤ grade 3), diarrhea/colitis (21 AEs ≤ grade 3, with 1 grade 4 AE), fatigue (17 AEs ≤ grade 2), and pain at tumor site (17 AEs ≤ grade 2). There were 3 hepatotoxicity-related AEs, including 1 grade 5 AE; and 3 endocrinopathy-related AEs, including 1 grade 4 hypopituitarism. Toxicities were managed with corticosteroids, anti-histamines, anti-motility agents, analgesics, thyroid and cortisol supplementation. Of the 69 pts evaluable for response, 16 pts (23%) had complete response (CR) or partial response (PR), and 9 pts (13%) had stable disease (SD) as measured radiographically using mWHO criteria at least 12 weeks post completion of treatment. When analyzed within melanoma subtypes, 17 cutaneous pts (31%) had tumor response (CR, PR, SD), 6 mucosal (75%), and 2 ocular (29%). Conclusions: Anti-CTLA-4 tx, including ipi and treme, was safe and well tolerated by the elderly population. Reported adverse events and response rates were consistent with published data in younger cohorts.
Prostate Serum Antigen levels and dietary heterocyclic amines in African Americans: A prospective clinic-based study
Authors: Kenneth T. Bogen, Elizabeth A. Holly, June Chan, Garrett A. Keating, Leslie J. Paine, Earnest L. Simms, David O. Nelson, James S. Felton
Journal: Cancer Research (2006)

2015  In The Netherlands, part of the population experienced food restriction and severe famine before and during World War II. Generally, energy restriction is believed to reduce cancer risk, which has mainly been shown in animal experiments. The purpose of this study was to investigate the effects of energy restriction early in life and risk of ovarian cancer later in life. We examined the hypothesis in the Netherlands Cohort Study on diet and cancer (NLCS), among 62573 women aged 55-69 years. Baseline information on diet and other risk factors was collected with a questionnaire in 1986. Information was collected on paternal employment status in 1932-1940, residence during the war years (1940-1944) and the Hunger Winter (1944-1945) as indicators of exposure. After 11.3 years of follow-up, 280 incident cases of sporadic ovarian cancer were available for analysis. In multivariate case-cohort analyses, most rate ratios in energy-restricted categories were below 1, but confidence intervals did not exclude 1 (table). Only living in a city in the west during the Hunger Winter did not show rate ratios below 1. Energy restriction due to unemployment of the father and residence in a city during World War II was less extreme than during the Hunger Winter in Western cities, but the duration was longer and cohort members were younger at exposure. Energy restriction has been associated with an increased age of menarche and decreased height, which have been associated with a reduction in ovarian cancer risk; therefore cohort members may have been too old during the Hunger Winter to experience effects related to the risk of ovarian cancer. The age of our cohort members during the Hunger Winter ranged from 14 to 29 years. There are indications for an inverse association of energy restriction at a younger age and risk of ovarian cancer.
Gun violence: US doctors’ groups call for action
Authors: Janice Hopkins Tanne
Journal: BMJ (2019)

After the mass shootings last week in El Paso, Texas, and Dayton, Ohio, seven leading US medical and public health organisations have called for comprehensive steps against gun violence, which they called a critical public health issue.1

“As with other public-health crises, firearm-related injury and death are preventable,” the organizations said.

The American College of Physicians, the Academy of Family Physicians, the American Academy of Pediatrics, the American College of Surgeons, the American Medical Association, the American Psychiatric Association, and the American Public Health Association—together representing some 731 000 physicians—issued an eight step policy paper.

The paper …
DNA repair polymorphisms and overall survival in early stage non-small cell lung cancer
Authors: Rebecca Heist, Wei Zhou, Geoffrey Liu, Kofi Asomaning, Li Su, Donna Neuberg, John Wain, Thomas Lynch, David Christiani
Journal: Cancer Research (2007)

142  Introduction: Polymorphisms in genes in the nucleotide excision repair (NER) and base excision repair (BER) pathways have been described that may lead to differential DNA repair capacity. In the absence of chemotherapy, decreased DNA repair may lead to increased accumulation of genetic mutations in tumor cells, increased biologic aggressiveness, and worse survival.  Methods: We evaluated the relationship between DNA repair polymorphisms and overall survival (OS) among patients with early stage NSCLC treated with surgical resection at Massachusetts General Hospital from 1992 to 2001. Analysis was restricted to patients who did not receive any neoadjuvant or adjuvant treatment. We specifically investigated the polymorphisms XRCC1 Arg399Gln, hOGG1 Ser326Cys, APE1 Asp148Glu, ERCC2 Asp312Asn, ERCC2 Lys751Gln, and ERCC1 8092C/A, from the BER and NER pathways. Analyses of genotype associations with survival outcomes were performed using Cox proportional hazards models and Kaplan-Meier methods and the log-rank test.  Results: There were 430 patients. Median age was 69 years (range 31-89). 49% were women. 238 (55%) were Stage IA, 134 (31%) were Stage IB, 10 (2%) were Stage IIA, and 48 (11%) were Stage IIB. The histologies were: 48% adenocarcinoma, 29% squamous cell, 12% bronchioalveolar, 5% large cell, and 6% NSCLC not otherwise specified. There were 28 (6%) never smokers, 232 (54%) former smokers, and 170 (40%) current smokers. All patients had surgical resection as their treatment, with 62% having lobectomy, 27% wedge or segmentectomy, and 11% other resections. There have been 214 deaths. On analysis of individual polymorphisms, the variant Cys allele of the hOGG1 polymorphism was associated with better overall survival (p = 0.02 by log rank test; 5 yr OS for Ser/Ser 53%(95% CI 46-60), for Ser/Cys + Cys/Cys 65% (95% CI 57-72). Using the group with total 0-2 variant alleles as a reference group (n=110), we analyzed groups with 3-4 (n=151) and > 5 variant alleles (n=169). Adjusting for age, sex, pack-years of smoking and stage, we found that that higher number of variant alleles was associated with better survival (adjusted HR for > 5 variant alleles 0.67 (0.47-0.95), for 3-4 variant alleles 0.72 (0.51 - 1.03), Ptrend = 0.03).  Conclusions: Increasing numbers of variant alleles among the DNA repair polymorphisms in the NER and BER pathways may be associated with improved overall survival in early stage NSCLC treated with surgery alone.  Supported by NIH grants CA074386, CA092824, CA090578, Flight Attendants Medical Research Institute Young Clinical Scientist Award, American Cancer Society Postdoctoral Fellowship, Doris Duke Charitable Foundation
Using Google Trends to investigate global COPD awareness
Authors: Chan-Na Zhao, Qian Wu, Hai-Feng Pan
Journal: European Respiratory Journal (2019)

We read the recent article published in the European Respiratory Journal by Boehm et al. [1] with great interest: their study is the first to explore global chronic obstructive pulmonary disease (COPD) awareness using Google searches. Currently, with the development of the internet and search engines, Google Trends has emerged as a robust tool to investigate the interest of the general population in medical conditions [2–4]. In the study by Boehm et al. [1], it was found that the awareness of COPD in the real world is rising, while it is highly under-represented in the public interest compared with other common conditions. In addition, public interest in seeking COPD information through Google searches presented a seasonal pattern, with peaks in the first and the fourth quarter of the year. These findings may help to improve programmes to guide interventions for COPD and contribute to the development of preventative healthcare for this disease. Google Trends provides new evidence for public interest and seasonal patterns in COPD <http://bit.ly/2xsGbIE>
Nomogram predicting long-term survival probability of thoracic esophageal squamous cell carcinoma after radical esophagectomy.
Authors: Weimin Mao, Xinming Zhou, Qixun Chen, Youhua Jiang, Xun Yang, Jie Wu, Kaiyi Tao, Weihui Zheng, Zhen Yan, Liang Liu, Shaoyuan Wu, Dan Su
Journal: Journal of Clinical Oncology (2013)

4094 Background: Nomograms have been widely and successfully used for numerous cancers to obtain reliable prognostic information for each individual patient.To date, however, no studies have conducted survival estimates using nomograms for esophageal squamous-cell carcinoma (ESCC) in Chinese population.The purpose of this study is to develop a nomogram to predict the long-term survival probabilities in patients diagnosed with ESCC after radical esophagectomy. Methods: This study involves a dataset containing 1923 patients who underwent radical esophagectomy for ESCC at Zhejiang Cancer Hospital in Hangzhou, China. Among them, 1,578 patients with no missing data were used to build a prognostic nomogram based on Cox proportional hazard regression model. A multivariate survival analysis using Cox regression model was applied to identify significant variables with P-values &lt;0.05. On the basis of the predictive model with the identified variables, a nomogram was constructed for predicting five-year and ten-year overall survival probabilities. The prediction model was internally validated using bootstrap resampling, assessing its optimism-corrected discrimination and calibration. Results: The median of overall survival times of 1578 ESCC patients was 35.6 months, and the 5-year and 10-year survival rate was 32% and 20%, respectively. The multivariate Cox model identified alcohol, tumor length, surgical approach, number of surgical removed lymph node, ratio of metastatic lymph nodes, region of lymph nodes dissection, depth of invasion, differentiation of tumor, postoperative complications as covariates significantly associated with survival. Across the 100 bootstrap replicates, the median optimism-corrected summary C-index for predicting survival was 0.713 (SE=0.011). Conclusions: A nomogram predicting 5- and 10-year overall survival after radical esophagectomy for ESCC in Chinese population was constructed and validated based on nine significant variables. The nomogram can be applied in daily clinical practice for individualized survival prediction of ESCC patients after potentially curative esophagectomy.
Abstract 10260: Thrombin is a Novel Target of the Treatment of Dilated Cardiomyopathy
Authors: Keiichi Ito, Kenichi Hongo, Taro Date, Yusuke Kashiwagi, Takuya Yoshino, Tomohisa Nagoshi, Susumu Minamisawa, Michihiro Yoshimura
Journal: Circulation (2015)

Introduction: A state of hypercoagulability has been observed in patients with dilated cardiomyopathy (DCM) compared to healthy subjects. In addition to being found in blood, thrombin is also expressed in the heart. Hypothesis: We hypothesize that thrombin in the heart tissue may contribute to the pathology of DCM and thrombin inhibition may be beneficial for the development of DCM. Methods: We evaluated the expression of thrombin by immunohistochemical analysis in the left ventricle of 5 patients with DCM undergoing Batista operation and that of 4 patients without heart disease serving as controls. The immunohistochemical staining was scored subjectively on a semi-quantitative scale of 0-4. We investigated the effects of the direct thrombin inhibitor, dabigatran, in the development of DCM in a mouse model carrying a deletion mutant of cardiac troponin T (DCM mouse) which causes human DCM, by using echocardiography and Kaplan-Meier method. We also estimated the apoptotic index using the terminal dUTP nick-end labeling (TUNEL) assay using the heart tissue from DCM mouse. Results: Immunohistochemical analysis showed strong thrombin expression in DCM patients compared to patients without heart disease [3.60 in DCM (n=5), 1.25 in control (n=4), p&lt;0.001]. Dabigatran significantly improved impaired left ventricular function of DCM mouse by echocardiographic examination; fractional shortening was 15.6±5.7 % in DCM mouse and was 42.7±7.3 % in DCM with dabigatran (p=0.03, n=4). Dabigatran also significantly improved the poor outcome of DCM mouse (p=0.02, n=7) (Figure1). Although there were no significant differences, dabigatran tended to reduce the apoptotic index; the percentage of TUNEL-positive nuclei was 0.20±0.04 % in DCM mouse and was 0.08±0.05 % in DCM with dabigatran (p=0.11, n=4). Conclusion: Upregulation of tissue thrombin may be involved in the pathogenesis of DCM. The direct thrombin inhibitor, dabigatran, may be a possible treatment option against DCM.
Dose-escalated image-guided radiation and weekly cisplatin for inoperable squamous cell carcinoma of thoracic esophagus.
Authors: Srinivas Chilukuri, Yeshwanth S. Pawar, Sai Shanmugam Subramanian, K. Kiran Kumar, Nalini Yadala, Pramod K. Tike, M. Kathirvel, Arun Gandhi, Thirumalai Swamy, Nikhil Ghadyalpatil
Journal: Journal of Clinical Oncology (2013)

e15120 Background: This study evaluates feasibility, toxicity and early outcomes of image guided volumetric modulated arc therapy (IG-RA) and weekly cisplatin for locally advanced inoperable squamous cell carcinoma (LAI-SCC) of thoracic esophagus. Methods: 41 patients diagnosed with LAI-SCC were included. Patients with performance status (ECOG) more than 1, involvement of cervical esophagus or gastroesophageal junction, distant metastasis were excluded from study. Radiotherapy was planned in two phases to a dose of 5940cGy. Phase I CTV was generated by expanding the GTV-primary craniocaudally(CC) by 4cm and laterally to include electively, the corresponding level mediastinal nodes. In the Phase II, GTV was expanded by 2cm CC and 1cm radially. ITV was generated by expanding the CTV by 0.5cm which was then expanded by 0.5cm to yield PTV. Chemotherapy consisted of 4-6 cycles of weekly cisplatin 40mg/m2. Results: The median age of patients was 53 yrs (43-72). The median length of involvement was 6cm with 80% of lesions in upper and middle third. 37/41(90%) patients completed planned chemotherapy with atleast 4 cycles of cisplatin and 40/41 patients completed full dose of radiotherapy. 10% of patients required tube feeding and 5% required hospital admission for supportive care. Endoscopy at 8 weeks post treatment was performed in 38/41 patients of whom 53% had CR, 42% had PR and 5% had stable disease locally. With a median follow up of 19 (6-32) months, 41% of total patients (17/41) are alive at last follow-up of which 32% (13/41) are disease free with no dysphagia, the 1 and 2 year overall survival are 70% and 40% respectively and median survival of 14 months. 16% alive patients have post radiotherapy stricture. The analysis of CBCT and KV image data sets showed a significant intra-fraction and inter-fraction motion of the target. The ITV and PTV margins of 0.5cm each were found to be adequate with current imaging protocol. Conclusions: IG-RA to a dose of 60Gy with concurrent weekly cisplatin is a feasible treatment option for LAI-SCC of thoracic esophagus with low acute and late toxicity and with promising early clinical outcomes. The ITV and PTV margins of 0.5cm were found to be adequate only with image guidance.
Outcomes that matter to patients: The Geriatric Oncology Surgical Assessment and Functional rEcovery after Surgery (GOSAFE) study—Analysis of 471 patients.
Authors: Isacco Montroni, Giampaolo Ugolini, Antonino Spinelli, Giorgio Ercolani, Michael T. Jacklitsh, Siri Rostoft, Ponnandai Sadasivan Somasundar, Barbara Van Leeuwen, Nicola de Liguori Carino, Nicole M. Saur, Giovanni Ferrari, Federico Ghignone, Giacomo Sermonesi, Francesca Rita Di Candido, Flavia Foca, Chiara Zingaretti, Bernadette Vertogen, Riccardo Audisio
Journal: Journal of Clinical Oncology (2019)

11511 Background: Older cancer patients value functional outcomes as much as survival but surgical studies lack functional recovery (FR) data. The international, multicenter GOSAFE study (ClinicalTrials.gov NCT03299270) aims to evaluate patients’ quality of life (QoL)and FR after cancer surgery and to assess predictors of FR. Methods: GOSAFE prospectively collects functional and clinical data before and after major elective cancer surgery on senior adults (≥70 years). Surgical outcomes are recorded (30 days, 90 days, and 180 dayspost-operatively) with QoL(EQ-5D-3L) and FR (Activities of Daily Living (ADL) + Timed Up and Go (TUG) + MiniCog), 28centers are prospectively enrolling patients; accrual ends February 2019. Results: 643 patients underwent major cancer surgery with curative(94%) or palliative (6%) intent (February 2017-September 2018). Median age was 78(range 70-94); 51.6% males, ASA III-IV 52%. Patients dependent (ADL &lt; 5) were 8%. Frailty was detected by G8 &gt; 14 in 32% and fTRST≥2 in 36% of patients. 639 (99%) lived at home, 32% lived alone, and 88% were able to go out. Major comorbidities (CCI &gt; 6) were detected in 36% and 22% had cognitive impairment according to MiniCog (5% self-reported). 26% had &gt; 3 kg weight loss, 30% were hospitalized in the last 90 days, 45% had ≥3 medications (6% none). For 471 patients, a 90-day comprehensive evaluation was available. Postoperative morbidity was 42% (30 day) and 63.3% (90 day), but Clavien-Dindo III-IV complications were only 11.2% and 17.6%. 90-day mortality was 7.4% (5% 30-day). QoL improved 90 days after surgery (mean EQ-5D index from 0.76 to 0.80). Patients with EQ-5D VAS score &gt; 60 raised from 73.9% at baseline to 82.8% at 90 days. 29% had complete FR (ADL score &gt; 4, MiniCog &gt; 2, TUG &lt; 20). Decreased functional capacity was seen in 23.4% of patients alive at 90-days. Conclusions: GOSAFE is the largest prospective study on older cancer patients undergoing major surgery. Interim analysis reports decreased functional capacity in a quarter of patients. The study will allow clinicians to associate clinical outcomes with individual factors of the preoperative assessment and create a user-friendly tool to predict outcomes that matter to patients.
Social media can harm when use displaces sleep or exercise or involves bullying, finds study
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The frequency of social media use is unlikely to cause direct harm to young girls, but if use of it displaces sleep and exercise or involves cyberbullying then it can have a negative effect, a study concludes.1

Researchers from Imperial College London and the Great Ormond Street Institute of Child Health at University College London looked at the associations between adolescents’ frequency of social media use and later mental health and wellbeing, and how these effects might be mediated.

They found that much of the harm attributed to social media was “unlikely to be directly related to social media use” but was instead related to what content was consumed or whether its use resulted in less sleep or physical activity.

Therefore interventions to reduce social media use to improve mental health may be misplaced, the researchers said, and instead actions to prevent cyberbullying and ensure that young people had …