tbuckley/cabot-search huggingface dataset:
Treatment of mild hypertension: results of a ten-year intervention trial.
Authors: Smith Wm
Journal: Circulation Research (1977)

Three hundred and eighty-nine subjects, ages 21-55, with diastolic blood pressures between 90 and 115 mm Hg were studied prospectively for 7-10 years in a controlled intervention trial to determine whether pressure lowering reduces the incidence of cardiovascular complications and death. The assignment to therapy, either a combination of a diuretic and rauwolfia serpentina, or an identical placebo, was random. Adverse effects required termination in only 23 (5.9%) cases. Diastolic blood pressure (DBP) was reduced an average of 10 mm Hg (systolic equals 16 mm Hg) in the active treatment group with no change in the placebo group. The major end points of death, myocardial infarction, and stroke totaled 17 and were nearly equally divided between treatment and placebo. Other manifestations of coronary disease were also equally distributed. Complications such as electrocardiographic hypervoltage, left ventricular hypertrophy, radiogrpahic cardiomegaly, and retinopathy occurred in the placebo group at a rate of 53.1 per 100 subjects compared to 23.8 per 100 in those on active drugs. Treatment failure occurred in 24 placebo-treated cases and none of the active group. The overall effectiveness of pressure lowering in reducing these complications and treatment failure was 60%. It is concluded that given the lower level of excess risk in mild uncomplicated hypertension, and the failure of active drug therapy to protect against coronary disease, systematic follow-up without drugs while attempting hygienic intervention and control of other risk factors may be a reasonable alternative for this large group.
Determining knowledge transfer gaps in the life cycle of evidence for chemotherapy in non-small cell lung cancer (NSCLC) through cumulative meta-analysis
Authors: M. N. Reaume, M. Nurbhai, J. McGowan, K. O'Rourke, P. L. Moja, W. K. Evans, I. D. Graham, J. M. Grimshaw
Journal: Journal of Clinical Oncology (2007)

6555 Background: The uptake of research findings into practice is often delayed (Antman et al. JAMA 1992). We investigated the relative role of evidence in determining clinical recommendations and practice for NSCLC. Novel chemotherapy agents (NCA) approved for use in Canada between 1992 and 2002 were eligible. Methods: We conducted a systematic review of evidence for vinorelbine (V), paclitaxel (P) and gemcitabine (G) in combination with a platinum agent for the treatment of advanced NSCLC. Primary endpoint of efficacy was median survival. For each included randomized controlled trial (RCT), the publications dates of abstracts and journal articles were considered. At each time point when new data was available, a new meta-analysis using the Follman methodology was performed. Bibliometric analyses were performed to identify key milestones for each drug (e.g. Health Canada Notice of Compliance, provincial drug funding, and clinical recommendations). Results: 3,399 references were obtained for NCA in advanced NSCLC. Eligibility review identified 20 references for V representing 6 RCTs (1994–2002), 16 for P representing 4 RCTs (1997–2000), and 10 for G representing 7 RCTs (1998–2003). All drugs trended towards median survival benefit throughout the time of analysis. However, over time the estimated effect for V became weaker, remained stable for P and became stronger for G. The 1997 ASCO guideline recommended V and P as standard therapy; G was only cited as a promising investigational agent. By 2003, the ASCO guideline recommended G as a standard. Only V received Ontario provincial funding in 1997, while G and P received funding in 2002 and 2003 respectively. Conclusions: This study demonstrates the relatively small pool of RCT evidence for NCAs. These three commonly used NCAs demonstrate different patterns of evolution of evidence. For advanced NSCLC, the time gap between evidence and clinical recommendations is short. Caution should be used for generating recommendations using early results, when the evidence base is not stable, which may either over or underestimate true effectiveness. No significant financial relationships to disclose.
Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy
Authors: Daniel A. Mulrooney, Gregory T. Armstrong, Sujuan Huang, Kirsten K. Ness, Matthew J. Ehrhardt, Vijaya M. Joshi, Juan Carlos Plana, Elsayed Z. Soliman, Daniel M. Green, Deokumar Srivastava, Aimee Santucci, Matthew J. Krasin, Leslie L. Robison, Melissa M. Hudson
Journal: Annals of Internal Medicine (2016)

Background: Studies of cardiac disease among adult survivors of childhood cancer have generally relied on self-reported or registry-based data. Objective: To systematically assess cardiac outcomes among survivors of childhood cancer. Design: Cross-sectional study. Setting: St. Jude Children's Research Hospital. Patients: 1853 adult survivors of childhood cancer, aged 18 years or older, who received cancer-related cardiotoxic therapy at least 10 years earlier. Measurements: Baseline history and physical examination, fasting metabolic and lipid panels, echocardiography, electrocardiography, and 6-minute walk test. Results: One half of the survivors (52.3%) were men with a median age of 8 years (range, 0 to 24 years) at cancer diagnosis and 31 years (range, 18 to 60 years) at evaluation. Cardiomyopathy was present in 7.4% survivors (newly identified at the time of evaluation in 4.7%), coronary artery disease in 3.8% (newly identified in 2.2%), valvular regurgitation or stenosis in 28.0% (newly identified in 24.8%), and conduction or rhythm abnormalities in 4.4% (newly identified in 1.4%). Nearly all survivors were asymptomatic. The prevalence of cardiac conditions increased with age at evaluation, ranging from 3% to 24% among survivors aged 30 to 39 years to 10% to 37% among those aged 40 years or older. In multivariable analysis, survivors exposed to anthracycline doses of 250 mg/m2 or more had greater odds of cardiomyopathy (odds ratio, 2.7 [95% CI, 1.1 to 6.9]) than those who were not exposed. Survivors exposed to heart radiation also had increased odds of cardiomyopathy (odds ratio, 1.9 [CI, 1.1 to 3.7]) compared with those who were not exposed. Radiation exposure greater than 1500 cGy with any anthracycline exposure conferred the greatest odds for valve findings. Limitations: Sixty-one percent of survivors exposed to anthracycline chemotherapy or cardiac-directed radiation participated. A comparison group and longitudinal assessments were not available. Conclusion: Cardiovascular screening identified considerable subclinical disease among adult survivors of childhood cancer. Primary Funding Source: National Cancer Institute, American Lebanese Syrian Associated Charities.
Adjuvant systemic therapy for breast cancer in the elderly: competing causes of mortality. International Breast Cancer Study Group.
Authors: M Castiglione, R D Gelber, A Goldhirsch
Journal: Journal of Clinical Oncology (1990)

Between 1978 and 1981 we conducted a trial in which adjuvant endocrine therapy consisting of tamoxifen (T = 20 mg/d) and low-dose prednisone (p = 7.5 mg/d) for the duration of one year (p + T), was compared with no adjuvant therapy (observation) in 320 women with operable breast cancer aged 66 to 80 years (median age, 70 years). All patients had axillary lymph node metastases after at least a total mastectomy and axillary clearance. At 96 months median follow-up, 9.1% of the patients died without apparent relapse from cancer. An additional 1.9% had a second malignant neoplastic disease (not breast cancer). The 8-year disease-free survival (DFS) percentages (+/- SE) for the p + T and the observation groups were 36% (+/- 4%), and 22% (+/- 3%), (P = .004). The 8-year overall survival percentages were 49% (+/- 4%) and 42% (+/- 4%), respectively (P = .43). We conclude that despite a large proportion of deaths without relapse of breast cancer, a significant advantage for the p + T group in terms of DFS was demonstrated. We hypothesize that an endocrine therapy of longer duration might have an overall survival benefit in a population of elderly patients.
Access to specialized cancer care and clinical trials for cancer patients from non-urban areas is facilitated by a Cancer Network organization
Authors: J. Brunet, B. Martin, S. Del Barco, I. Juez, A. García, G. Viñas, X. Hernández, M. Arnedos, J. M. Borràs, R. Colomer
Journal: Journal of Clinical Oncology (2006)

16006 Background: In non-urban areas, there is a controversy about whether medical cancer treatments should be administered exclusively in referral cancer centers (CC) or in community hospitals (CH) (Br J Cancer 2004; 90: 1688). Limitations such as geographical distance or absence of treatment guidelines may reduce the access to specialized cancer care or clinical trials. A network organization that involves at the same time a CC and the CH from the same geographical area may provide an adequate balance between proximity, equity and quality of cancer services. Methods: We designed a cancer network in 2003 in order to consolidate all Oncology resources in an area covering a population of 700,000. A CC is placed adjacent to a general hospital in a centrally located urban area of 250,000. The remaining area is served by 6 CH. Our cancer network is based on: 1) approximately half of the Medical Oncology Dpt staff members work part-time at a CH, participating in outpatient clinic, chemotherapy treatments administration, and multidisciplinary meetings; and 2) other cancer health professionals are organized in network groups like the pharmacy group and the chemotherapy nursing group. Specialized medical cancer care included concomitant radio-chemotherapy, complex outpatient or inpatient therapies, genetic counseling and therapy for some pre-defined malignancies such as germ cell and ovarian cancers. Results: From January to December 2004, 1862 new patients were visited, 1013 (54%) at the CC (Medical Oncology Dpt.), and 849 (46%) at the CH. One-hundred ninety-three cancer patients were referred from the CH to the CC. In total, 141 of the cancer patients seen at the CC were included in clinical trials. It is remarkable that clinical trial participation was much enhanced by referrals, since 101 (72%) of patients in clinical trials came from non-urban areas. Conclusions: The establishment of a cancer network facilitates access to specialized cancer care and clinical trials for patients living in non-urban areas, therefore contributing to therapeutic equity. No significant financial relationships to disclose.
Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer
Authors: Paige Chandler, Bose S. Kochupurakkal, Samina Alam, Andrea L. Richardson, David I. Soybel, Shannon L. Kelleher
Journal: Molecular Cancer (2016)

Zinc (Zn) hyper-accumulates in breast tumors and malignant cell lines compared to normal mammary epithelium. The mechanisms responsible for Zn accumulation and the consequence of Zn dysregulation are poorly understood. Microarrays were performed to assess differences in the expression of Zn transporters and metallothioneins (MTs) in human breast tumors and breast cancer cell lines. Real-time PCR and immunoblotting were employed to profile Zn transporter expression in representative luminal (T47D), basal (MDA-MB-231), and non-malignant (MCF10A) cell lines. Zn distribution in human tumors was assessed by X-ray fluorescence imaging. Zn distribution and content in cell lines was measured using FluoZin-3 imaging, and quantification and atomic absorption spectroscopy. Functional consequences of ZnT2 over-expression in MDA-MB-231 cells including invasion, proliferation, and cell cycle were measured using Boyden chambers, MTT assays, and flow cytometry, respectively. Gene expression profiling of human breast tumors and breast cancer cell lines identified subtype-specific dysregulation in the Zn transporting network. X-ray fluorescence imaging of breast tumor tissues revealed Zn hyper-accumulation at the margins of Luminal breast tumors while Zn was more evenly distributed within Basal tumors. While both T47D and MDA-MB-231 cells hyper-accumulated Zn relative to MCF10A cells, T47D cells accumulated 2.5-fold more Zn compared to MDA-MB-231 cells. FluoZin-3 imaging indicated that Zn was sequestered into numerous large vesicles in T47D cells, but was retained in the cytoplasm and found in fewer and larger, amorphous sub-cellular compartments in MDA-MB-231 cells. The differences in Zn localization mirrored the relative abundance of the Zn transporter ZnT2; T47D cells over-expressed ZnT2, whereas MDA-MB-231 cells did not express ZnT2 protein due to proteasomal degradation. To determine the functional relevance of the lack of ZnT2 in MDA-MB-231cells, cells were transfected to express ZnT2. ZnT2 over-expression led to Zn vesicularization, shifts in cell cycle, enhanced apoptosis, and reduced proliferation and invasion. This comprehensive analysis of the Zn transporting network in malignant breast tumors and cell lines illustrates that distinct subtype-specific dysregulation of Zn management may underlie phenotypic characteristics of breast cancers such as grade, invasiveness, metastatic potential, and response to therapy.
DSM-III field trials: I. Initial interrater diagnostic reliability
Authors: R L Spitzer, J B Forman, J Nee
Journal: American Journal of Psychiatry (1979)

The interrater agreement for major diagnostic categories in studies using DSM-I and DSM-II was usually only fair or poor. In phase one of the DSM-III field trials the overall kappa coefficient of agreement for axis I diagnoses of 281 adult patients was .78 for joint interviews and .66 for diagnoses made after separate interviews; for axis II--personality disorders and specific developmental disorders--the coefficients of agreement were .61 and .54. The interrater reliability of DSM--III is, in general, higher than that previously achieved and may be due to changes in the classification itself, the separation of axis I from axis II conditions, the systematic description of the various disorders, and the inclusion of diagnostic criteria.
The effect of metformin on cell proliferation in patients with endometrial cancer.
Authors: A. Mitsuhashi, T. Uehara, H. Usui, S. Tate, K. Kato, K. Yamazawa, M. Shozu
Journal: Journal of Clinical Oncology (2011)

e15577 Background: Metformin, a widely used anti-diabetic drug, is thought to suppress oncogenesis and/or improve prognosis in a variety of malignancies. Diabetes-related metabolic disorders, obesity and insulin resistance are risk factors for endometrial cancer, and together form a potential target for metformin therapy. Thus, we assumed that metformin might have some impact on the prevention and treatment of endometrial cancer. We examined the influence of metformin on cell proliferation of human endometrial cancer cells in vitro and in vivo. Methods: The Ishikawa and HEC-IB endometrial cancer-cell lines were treated with metformin and cell-cycle progression was assessed by flow cytometry. Activation of the MAPK, AMPK and mTOR signalling pathways as well as cell-cycle proteins was evaluated by Western blotting. Changes in signalling pathways were also assessed in endometrial tissues obtained from 15 patients with stage I endometrial cancer who received metformin (1,500-2,250mg/day) for 21-28 days. Results: Metformin inhibited the growth of Ishikawa and HEC-IB cells in a dose- and time-dependent fashion. The cell cycle was arrested at G0/G1 phase, with decreased cyclin D1 and phospho-pRB levels and increased p27Kip1 levels. Addition of metformin induced phosphorylation of AMPKa and de-phosphorylation of S6K1 and ERK1/2. siRNA-mediated knockdown of AMPKα failed to completely prevent the anti-proliferative activity of metformin, suggesting that metformin has AMPK independent effect on cell cycle. Metformin activity was also determined in patient-derived endometrial tissues. In western blotting, pre-operative metformin therapy showed same effect on cell line. Metformin effect of reducing the S6K1 phosphorylation and ERK1/2 phosphorylation were also identified in immunohistochemistry. Conclusions: The anti-neoplastic activity of metformin was demonstrated by in vitro and in vivo experiments. This effect is thought mTOR inhibition via AMPK and cell cycle regulation via AMPK independent pathway. This work gives the possibility for clinical application of endometrial cancer treatment using metformin.
Concurrent chemoradiation in locally advanced head and neck cancers: A comparison of weekly paclitaxel with cisplatin-based regimen
Authors: R. Sharma, D. Abrol, S. Kaur, P. Kalsotra, D. Kumar, A. Gupta
Journal: Journal of Clinical Oncology (2008)

17032 Background: Concurrent cisplatin-based chemoradiation is the standard of care for patients with unresectable locally advanced squamous cell carcinoma of head and neck (LA-SCCHN) with 5-year locoregional control rates between 35–70%. Taxane-based chemotherapies might improve locoregional control as has been shown in phase I and II trials. This retrospective analysis compares the outcome and toxicity of weekly paclitaxel with weekly cisplatin-based concurrent chemoradiation in LA-SCCHN. Methods: 107 patients of unresectable stage III, IVA and IVB cancers of oropharynx, hypopharynx and larynx were retrospectively analyzed for outcome and toxicity. A retrospective chart review was used to create a data base of clinical and pathologic characteristics of these patients using Microsoft Excel. 58 patients received concurrent weekly paclitaxel (30 mg/m2) and 49 patients were administered weekly cisplatin (40 mg/m2) during radiation therapy with conventional fractionation and curative intention. Results: The median duration of follow up was 12 months in each group (range 3–53 months). In the paclitaxel arm, 43 (74.13%) patients remained alive and disease-free whereas in the cisplatin arm, 33 (67.34%) patients were alive disease-free. This difference was not statistically significant (p=0.34). In the paclitaxel group, among the patients completing radiation in 47 or less days, 26 (81.25%) were alive and disease free in comparison with 17 (65.38%) in those completing radiation in longer than 47 days (odds ratio = 2.29, p=0.16). In the cisplatin arm, alive disease-free status was seen in 18 (67.34%) patients completing radiation in 47 days or less and 15 (65.21%) in those taking longer than 47 days to complete radiation therapy (odds ratio=1.2, p=0.76). The projected mean locoregional relapse free survival in Paclitaxel arm was 33.42 months, and 32.18 months in the cisplatin arm (p=0.73). The 2-year locoregional relapse free survival was 60% in the Paclitaxel arm and 52% in the Cisplatin arm. Conclusion: At 12 months median follow up, weekly paclitaxel-based concurrent chemoradiation regimen provides no additional efficacy and tolerability benefits over and above those provided by weekly cisplatin. No significant financial relationships to disclose.
Abstract P1-07-18: Loss of Rab1B promotes triple-negative breast cancer metastasis by activating TGF-β/Smad signaling
Authors: HongLin Jiang, Hefen Sun, Wei Jin
Journal: Cancer Research (2015)

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype associated with poor prognosis. The onset of metastasis in organs such as the lung,bone and brain is a major cause of mortality in TNBC patients. Thus, identification of novel targets for the treatment of triple-negative breastcancer is urgent for improved outcomes in patients with this disease. Methods and Results:Here we conducted quantitative proteomic analyses in breast cancer cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC-MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. We identified for the first time that Rab1B, a member of RAS oncogene family, was down-regulated in high metastatic human breast cancer cells. In a panel of breast tumor tissues, Immunohistochemical analysis demonstrated an inverse correlation between metastatic propensity and the expression of Rab1B. Compared with primary tumors, Rab1B expression was notably decreased in lymph node metastases. Low Rab1B expression also correlated with poorer survival in triple-negative breast cancer patients. Through in vitro assays, we confirmed that silencing of Rab1B expression by RNAi in MDA-MB-231 and MDA-MB-468 breast cancer cells, can potentiate the proclivity to metastasize in Transwell assay and enhance lung colonization by tail vain injection in mice. In a reverse-complimentary approach, we determined that elevated Rab1B expression in highly metastatic breast cancer cell lines (MDA-MB-231HM and MDA-MB-231Bo) can suppress the ability of invasion and metastasis in vitro and in vivo. Mechanistically, we establish that the metastatic behavior strongly correlates with increased phosphorylated Smad3 levels and overexpression of TGF-β type I receptor (TβRI). Conversely, restoration of Rab1B can inhibit the activation of this pathway in MDA-MB-231HM and MDA-MB-231Bo cells. Conclusion:By utilizing a series of mammary tumor cell lines, animal models, and clinically sourced tissues, we demonstrate that Rab1B acts as a metastasis suppressor in triple-negative breast cancer through regulating TGF-β/Smad signaling pathway. Citation Format: HongLin Jiang, Hefen Sun, Wei Jin. Loss of Rab1B promotes triple-negative breast cancer metastasis by activating TGF-β/Smad signaling [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-18.
Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1
Authors: Tae-Dong Kim, Fang Jin, Sook Shin, Sangphil Oh, Stan A. Lightfoot, Joseph P. Grande, Aaron J. Johnson, Jan M. van Deursen, Jonathan D. Wren, Ralf Janknecht
Journal: Journal of Clinical Investigation (2016)

Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition.