tbuckley/cabot-search huggingface dataset:
PUROMYCIN INHIBITION OF PROTEIN SYNTHESIS
Authors: MARJORIE A. DARKEN
Journal: Pharmacological Reviews (1964)

Puromycin blocks protein synthesis in vitro and in vivo and is a useful agent in demonstrating the role of protein synthesis in acute physiological response. Its action appears to occur at the stage of formation of the polypeptide chain at the ribosomal site. The transfer of the amino acids from sRNA into ribosomal protein is inhibited in the presence of puromnycin, and a subsequent release of incomplete, soluble protein from the ribosome then takes place without ribosomnal breakdown. Maximum inhibition of protein synthesis is obtained with puromycin analogs that contain an aromatic amino acid attached to the 3' amino group. Although the specificity of this antibiotic for the amino acid portion of the muolecule is an established fact, the reasons for this specificity remain obscure, and current concepts include a direct reaction with the enzyme system and a metabolic analogue response. Because of this inhibition of protein synthesis, puromycin is a useful agent for metabolic studies involving either enzymatic or hormonal systems.
Outcomes following breast conservation versus mastectomy in BRCA1/2 carriers with early-stage breast cancer
Authors: L. J. Pierce, K. A. Griffith, S. Buys, D. Gaffney, B. Haffty, M. Moran, M. Ben-David, J. Garber, S. D. Merajver, A. Meirovitz, S. Domchek
Journal: Journal of Clinical Oncology (2008)

536 Background: Although randomized trials of breast conservation (BCT) and mastectomy (M) have been conducted in early- stage breast cancer and proven the equivalence of these therapies in sporadic disease, similar trials have not been nor are likely to be performed in women with early-stage breast cancer associated with a BRCA1/2 mutation. We presently report outcomes in women prospectively followed with BRCA1/2-associated breast cancer treated locally with M vs. breast-conserving surgery and radiotherapy (RT). Methods: Investigators from 8 institutions in the US and Israel identified in their databases women with nonmetastatic breast cancer and deleterious BRCA1/2 mutations who consented to longitudinal follow-up. 160 patients were identified who underwent BCT and RT; 213 underwent M (60 with RT; 148 without; 5 unknown) as local therapy. Tumor and treatment characteristics were compared by cohort, and rates of local failure/new cancers and distant failure, contralateral breast cancers (CBC), and survival are reported at 15 years. Results: With mean follow-up of 9.9 and 10.1 years for BCT and M cohorts respectively, 15-year actuarial rates of local recurrence/new cancers were 21.5% following BCT vs. 7.1% for M (p=0.0043; HR 3.1). Rates of distant failure were comparable by cohort, with 15-year estimates of 11.2% and 12.7%, respectively (p=0.29). 15-year rates of CBC were 47.9% for BCT, 43% for M without RT, and 33% for M with RT (p=0.77). RT was not associated with an increased risk of CBC on univariate analysis. Breast-cancer specific and overall survivals were not significantly different by cohort (p=0.85 and p=0.55), respectively. Conclusions: With long-term follow-up, BRCA1/2 carriers with breast cancer are at significantly greater risk for local failure/new cancers following BCT vs. M but this did not translate into differences in breast-cancer specific and overall survival. Moreover, 15-year rates of CBC were comparable with and without RT, suggesting no detectable increase in CBC from scatter RT. These results should be discussed with BRCA1/2 carriers with breast cancer as they consider their local treatment options. No significant financial relationships to disclose.
Inhibition of tumorigenesis by intratumoral delivery of the circadian gene mPer2
Authors: Hui Hua, Jiao Wang, Li Xu, Yangfu Jiang
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

B30 

Biological clocks are intrinsic time-keeping systems that regulate behavior and physiological functions in most living organisms. Previous works suggested a possible link between the endogenous circadian clock and cell cycle regulation. The mammalian Period-2 gene (mPer2), an indispensable component of the circadian clock, not only modulates circadian oscillations, but also regulates organic function. In this study, we examined whether overexpression of mPer2 in tumor cells influences cell growth and induces apoptosis. Overexpression of mPer2 in the mouse Lewis lung carcinoma cell line (LLC) and mammary carcinoma cell line (EMT6) results in reduced cellular proliferation and rapid apoptosis, but not in NIH 3T3 cells. Overexpressed mPER2 also altered the expression of apoptosis-related genes. The mRNA and protein levels of c-Myc , Bcl-XL and Bcl-2 were downregulated, whereas the expression of p53 and bax was upregulated in mPER2-overexpressing LLC cells compared with control cells transferred with empty plasmid. In addition, we found that polyethylenimine-mediated intratumoral Per2 gene delivery had significant antitumor effects in C57BL/6 mice transplanted with Lewis lung carcinoma. Our study illustrated that the Per2 gene delivery inhibited PCNA expression and induced apoptosis. Our results suggest that the circadian gene mPeriod2 may play an important role in tumor suppression by inducing apoptotic cell death, which is attributable to enhanced pro-apoptotis signaling and attenuated anti-apoptosis processes. These findings support the emerging role of the circadian clock in critical aspects of tumorigenesis, and underscore the potential use of Per2 gene delivery as a novel therapeutic intervention for the treatment of malignant tumors.
Therapeutic care in metastatic renal cell carcinoma during the follow-up phase of the RECORD-1 phase III trial
Authors: D. Wiederkehr, R. Casciano, L. Stern, J. Zheng, J. Baladi
Journal: Journal of Clinical Oncology (2009)

e17531 Background: Following drug discontinuation for progression or adverse event in a clinical trial for relapsed or stage IV kidney cancer, supportive care including surgery, palliative radiotherapy, or bisphosphonates continue to be recommended by National Comprehensive Cancer Network (NCCN). However, published data on active therapeutic agents given to patients following study drug discontinuation in recent clinical trials is limited. Methods: World Health Organization Anatomical Therapeutic Chemical codes or therapeutic names, captured from the follow-up phase in a phase III clinical trial (RECORD-1) of patients with metastatic renal cell carcinoma (mRCC) patients, were used to describe antineoplastic therapies following discontinuation of study drug. Prior to trial, patients had progressed on at least one VEGFr-TKI therapy. Results: Of the 130 patients with follow-up after discontinuation of study drug, 78.5% received at least one of the following: corticosteroids, radiotherapy, protein kinase inhibitors, mTOR inhibitor, pyrimidine analogues, monoclonal antibodies, interferons, and investigational drugs. Among patients who received an active agent, nearly three-quarters (73.5%) utilized targeted therapy (protein kinase inhibitors, mTOR inhibitor, monoclonal antibodies). Conclusions: In a clinical trial setting with mRCC patients who have received several classes of systemic therapy, care delivered following study drug discontinuation often includes an active antineoplastic agent, despite the limited supportive evidence in this setting. While the placebo control with supportive care in a double-blind phase is acceptable to evaluate the efficacy and safety of a therapy for regulatory approval purposes, decision makers must also consider how these data may inform comparisons with the usual alternatives available to and used by physicians and patients in the non-trial setting. [Table: see text]
Predictive value of FCGR3A genotype on response to rituximab induction and maintenance therapy (MT) in follicular non-Hodgkin's lymphoma (NHL).
Authors: K. A. Pierz, S. Gu, M. E. Lewis, S. Hsu, C. Falandry, G. A. Salles, M. F. Fey, G. Martinelli, F. Hitz, M. E. Ghielmini
Journal: Journal of Clinical Oncology (2010)

8065 Background: The F158V variant of the Fc gamma 3A receptor (FCGR3A) correlates with clinical response to rituximab. In SAKK 35/98 (NCT00003280), patients (pts) received rituximab induction therapy followed by observation or MT. Pts with a 158V/V genotype showed improved event-free survival. Further analyses of FCGR3A genotype and response to rituximab induction therapy and MT in this trial were conducted. Methods: 306 pts with indolent NHL [follicular (FL) or mantle cell] were treated with rituximab induction (375 mg/m2 qw x4). Pts with stable disease, or partial or complete response at 12 weeks (N=212) were randomized to observation or MT. MT consisted of single injections of rituximab (375 mg/m2) every 2 months for 4 additional doses. FCGR3A genotype in FL pts from whom complete data were available (N=151) was analyzed for response at 12 and 52 weeks. Association of genotype with clinical endpoints was determined using the exact Cochran Armitage trend test. Results: Pts with 1 or 2 copies of the V allele (F/V, N=74 or V/V, N=26) demonstrated a 57% overall response rate (ORR) at 12 weeks compared to 39% in F/F pts (N=51; p=0.0412). The genotype effect on response was long-lasting; in the observation arm, V/V pts had a marginally higher ORR (58%) than V/F pts (54%), but much higher than F/F carriers (33%; p=0.20), and showed a greater clinical benefit (CR+PR+SD; 75% vs 54% vs 33%; p=0.028) when assessed at 52 weeks. In the maintenance arm, 89% of V/V pts achieved an ORR vs 68% of V/F pts, and 35% of F/F pts (p=0.0066). A similar pattern was identified for clinical benefit (89% vs 71% vs 41%; p=0.0114). Comparison between arms suggests that V/V pts benefit most from MT over observation (ORR 89% vs 58%), while F/F pts received the least benefit (ORR 35% vs 33%). Conclusions: These exploratory analyses expand upon previous findings that FCGR3A genotype correlates with response to induction treatment with rituximab in FL. Pts with 158V/V and 158F/V genotypes responded better to rituximab induction and MT than did pts with the 158 F/F genotype, suggesting that F/F pts may not benefit from rituximab MT. Studies are planned to validate the utility of FCGR3A genotyping in additional pts with FL. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PGxHealth, LLC Bayer, Bioalliance, Celgene, Roche Clinical Data - CLDA Bayer, Celgene, Roche Genentech, Roche, Schering-Plough
严重的社区获得性肺炎 尽早将抗生素由静脉换成口服用药，安全且减少住院时间
Authors: Graham, Mills, Richard, Laing, 王巍伟（译）, 童朝辉（校）
Journal: BMJ (2007)

过去20年来对于社区获得性肺炎（CAP）的研究焦点集中在寻找衡量肺炎严重性的指标及如何选用抗生素这两个方面。一些指标可以帮助临床医生在工作当中识别严重的CAP。对于患有严重CAP的患者，国际上的指南推荐早期应用广谱抗生素，其抗菌谱要覆盖非典型病原菌。
Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial.
Authors: T E Witzig, L Letendre, J Gerstner, G Schroeder, J A Mailliard, G Colon-Otero, R F Marschke, H E Windschitl
Journal: Journal of Clinical Oncology (1995)

Malignant cells from non-Hodgkin's lymphomas (NHL) have been shown to express the somatostatin receptor on their cell surface and most NHL are visible on somatostatin radioscintigraphy scans. This provided the rationale to conduct a phase II trial of a somatostatin analog in patients with B- and T-cell lymphoproliferative disorders.Sixty-one patients with measurable or assessable lymphoproliferative disorders (31 stage III or IV low-grade NHL; 21 chronic lymphocytic leukemia [CLL]; and nine cutaneous T-cell NHL [CTCL]) were enrolled. Patients were treated with somatostatin 150 micrograms subcutaneously (SQ) every 8 hours for 1 month. Patients with stable or responding disease received 2 additional months of therapy; those who responded after 3 months were treated for an additional > or = 3 months.Sixty patients were assessable for toxicity and 56 for response. There were no complete remissions. In the low-grade NHL group, 36% (10 of 28 patients; 95% confidence interval [CI], 19% to 56%) had a partial remission. Forty-four percent (four of nine; 95% CI, 14% to 79%) of patients with CTCL had a partial response. No patients with CLL had a partial remission. Among 45 patients with stable disease or a partial remission, the mean time to progression (TTP) was 10.9 months (median, 6.2; range, 1.6 to 48.5). The drug was well tolerated, with the most common side effects being diarrhea and hyperglycemia.Somatostatin at a dose of 150 micrograms every 8 hours is well tolerated and has activity in low-grade NHL.
Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)–Organized Dyads
Authors: Ying Fu, Seiji A. Shaw, Robert Naami, Caresse L. Vuong, Wassim A. Basheer, Xiuqing Guo, TingTing Hong
Journal: Circulation (2016)

The key pathophysiology of human acquired heart failure is impaired calcium transient, which is initiated at dyads consisting of ryanodine receptors (RyRs) at sarcoplasmic reticulum apposing CaV1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through β-adrenergic receptor (β-AR)-mediated phosphorylation of dyadic proteins. Phosphorylated RyRs (P-RyR) have increased calcium sensitivity and open probability, amplifying calcium transient at a cost of receptor instability. Given that bridging integrator 1 (BIN1) organizes t-tubule microfolds and facilitates CaV1.2 delivery, we explored whether β-AR-regulated RyRs are also affected by BIN1.Isolated adult mouse hearts or cardiomyocytes were perfused for 5 minutes with the β-AR agonist isoproterenol (1 µmol/L) or the blockers CGP+ICI (baseline). Using biochemistry and superresolution fluorescent imaging, we identified that BIN1 clusters P-RyR and CaV1.2. Acute β-AR activation increases coimmunoprecipitation between P-RyR and cardiac spliced BIN1+13+17 (with exons 13 and 17). Isoproterenol redistributes BIN1 to t-tubules, recruiting P-RyRs and improving the calcium transient. In cardiac-specific Bin1 heterozygote mice, isoproterenol fails to concentrate BIN1 to t-tubules, impairing P-RyR recruitment. The resultant accumulation of uncoupled P-RyRs increases the incidence of spontaneous calcium release. In human hearts with end-stage ischemic cardiomyopathy, we find that BIN1 is also 50% reduced, with diminished P-RyR association with BIN1.On β-AR activation, reorganization of BIN1-induced microdomains recruits P-RyR into dyads, increasing the calcium transient while preserving electric stability. When BIN1 is reduced as in human acquired heart failure, acute stress impairs microdomain formation, limiting contractility and promoting arrhythmias.
Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury
Authors: Xiaojia Huang, Zhiyu Dai, Lei Cai, Kai Sun, Jaehyung Cho, Kurt H. Albertine, Asrar B. Malik, Dean E. Schraufnagel, You-Yang Zhao
Journal: Circulation (2016)

Background— The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury. Methods and Results— Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg −/− mice after lipopolysaccharide challenge. Pik3cg −/− mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg −/− mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease. Conclusions— We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.
Abstract P337: Identifying Abnormal Cholesterol in Underserved Urban Communities through Health Fairs
Authors: David C Landy
Journal: Circulation (2012)

Introduction: Cholesterol screening at health fairs in underserved urban communities is becoming common, though little evidence guides these efforts. We sought to describe the proportion of patients identified with elevated low-density lipoprotein cholesterol (LDL) and reduced high-density lipoprotein cholesterol (HDL) at such fairs and the changes in LDL and HDL over time for returning patients. We hypothesized that patients would reduce their LDL in association with weight loss. Methods: DOCS is a medical student run service organization providing free screening services, health education, and when indicated referrals to low cost clinics. We reviewed the records of new patients receiving cholesterol screening at an annual DOCS fair in an underserved urban community in South Florida (Little Haiti, Hialeah, and Pompano Beach) in 2007 and any future visits. Results: In 2007, 223 new patients received cholesterol screening, of whom 111 (50%) were 45 to 64 yrs old, 136 (61%) Hispanic, 50 (22%) Haitian, and 142 (80%) uninsured. Of the 221 new patients, 102 (46%) had an LDL above 129 mg/dL (59 from 130-159, 30 from 160−189, and 13 &gt;189) and 82 (37%) had an HDL below 40 mg/dL for males or 50 for females. An LDL above 129 mg/dL was common across all ages, sexes, and BMIs ( Figure ) and not associated with age (Spearman’s rho=.08, P=.22), BMI (rho=.08, P=.27), or sex (P=.38). Among patients with an LDL above 129 mg/dL, 14 (14%) returned for a screening in 2008 or 2009 and 9 (64%) reduced their LDL by at least 20 mg/dL (6 by &gt;30) though only 2 (14%) increased HDL by at least 5 mg/dL. LDL and BMI reductions were not associated (rho = .10, P=.77). Conclusions: Cholesterol screening at fairs in underserved urban communities identified patients with elevated LDL and reduced HDL across all ages, sexes, and BMIs. While few patients returned to a subsequent fair, most who did lowered their LDL substantially without a change in BMI or HDL. This may suggest that referrals to low cost clinics and pharmacotherapy play an important role in the potential of fairs to reduce LDL. Funding(This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico&amp;Tennessee)
Multiplicity of Cell Response to the BAI Strain A (Myeloblastosis) Avian Tumor Virus. V. Elaboration of Virus by Pancreas of Chickens Inoculated With the Agent&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Ursula Heine, Guy de Thé, Dorothy Beard, J. W. Beard
Journal: JNCI Journal of the National Cancer Institute (1963)

An electron microscopic examination was made to determine the presence or absence of virus particle buds in the pancreas of normal chickens and chickens diseased with various strains of avian tumor viruses. No virus particles were detected in the gland of 11 normal birds, in that of 10 hosts with erythroblastosis induced with strain R, and in 6 chicks with erythroblastosis after inoculation with ES4 strain. Pancreas of 5 of 14 birds with myeloblastosis induced with BAI strain A contained particles. Budding occurred in 4 of these hosts and in the pancreas of 4 of 12 chickens that received transplants of BAI-strain-A-induced nephroblastoma whether it grew or not. The results indicate the possibility of response of the pancreas to the BAI strain A in the specific process of virus-particle budding as contrasted with no response to other strains under the experimental conditions. The significance of the findings is discussed in relation to multiplicity of host response to the BAI strain A and to the potential activity of the pancreas in the maintenance of tumor viruses in the chicken population.—J Nat Cancer Inst 30: 817–835, 1963.
Identification of serum markers of glioblastoma multiforme patients using image-guided genomic and proteomic analysis
Authors: S. Guccione, Y. Yang, Y. Chia, D. Rubin, Y. Wang, G. Harsh, S. Atlas, M. Bednarski
Journal: Journal of Clinical Oncology (2006)

20008 Background: Biomarkers in serum has been demonstrated to play a critical role in caner diagnostics. Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis and low survival rate, which often has significant heterogeneity in morphology and increased vascular permeability and vessel density. In this study we identified molecules related to angiogenesis and vasculature development for GBM using a combination of contrast enhanced MR imaging, genomic and proteomic analysis, and enzyme immunoassay (ELISA). Methods: GBM patient without any prior procedures were scanned on a GE 1.5T MRI scanner using standard T1- and T2-weighted pulse sequences and gadopentetate dimeglumine as contrast agent. Samples from regions with contrast agent accumulation (contrast-enhancing, CE) and no uptake (non-enhancing, NE) were collected for microarray, Mass spectroscopic analysis and immunochemical staining. Patient serum samples were collected for protein expression quantification using ELISA assay. Results: Tissue samples from the CE and NE regions of 13 patients reveal significantly distinct gene expression patterns. Mass spectroscopy using MALDI system will also be examined. Growth factors such as laminin receptor, IGFBP-2, IGFBP-3, IGFBP-5, aFGF were all up-regulated in the CE regions, and immunohistochemical staining confirmed their protein expression. The presence of proteins with MW &lt; 30 kD in the serum were examined using ELISA. IGFBP-2 showed to have a higher mean value (86.1 ± 29.1 ng/ml) in GBM serum as compared to healthy individuals (55.7 ± 9.9 ng/ml). Other potential markers such as IGFBP-3 and aFGF do not exhibit significant difference. Conclusions: CE-MRI using the clinical MRI agent Gd(DTPA) can reveal imaging features associated with increased vascular permeability and vessel density, and areas of fluid accumulation and necrosis. We have observed that differences in spatial resolution in the tumor correlate to changes in gene expression profiles, resulting in potential molecules that have high gene and protein expression levels in tumor area with high vascular activity and in serum. These targets can be used for diagnostic and clinical monitoring of the patient before and after therapeutic intervention. No significant financial relationships to disclose.