tbuckley/cabot-search huggingface dataset:
Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients
Authors: David Sullivan, Anders G. Olsson, Rob Scott, Jae B. Kim, Allen Xue, Val Gebski, Scott M. Wasserman, Evan A. Stein
Journal: JAMA (2012)

An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels.To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects.A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites.Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks.The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe.Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.
Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes
Authors: Majken K. Jensen, Traci M. Bartz, Luc Djoussé, Jorge R. Kizer, Susan J. Zieman, Eric B. Rimm, David S. Siscovick, Bruce M. Psaty, Joachim H. Ix, Kenneth J. Mukamal
Journal: Diabetes Care (2013)

OBJECTIVE Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (&amp;gt;5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993. RESULTS Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P &amp;lt; 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer
Authors: Harold J. Burstein, Ann Alexis Prestrud, Jerome Seidenfeld, Holly Anderson, Thomas A. Buchholz, Nancy E. Davidson, Karen E. Gelmon, Sharon H. Giordano, Clifford A. Hudis, Jennifer Malin, Eleftherios P. Mamounas, Diana Rowden, Alexander J. Solky, MaryFran R. Sowers, Vered Stearns, Eric P. Winer, Mark R. Somerfield, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2010)

To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer.A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations.An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences.The Update Committee recommends that postmenopausal women with hormone receptor-positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy.
The Effect of Smoking on the Transcriptional Regulation of Lung Inflammation in Patients with Chronic Obstructive Pulmonary Disease
Authors: Patryk Szulakowski, Ann J. L. Crowther, Luis A. Jiménez, Kenneth Donaldson, Ruth Mayer, Thomas B. Leonard, William MacNee, Ellen M. Drost
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke.In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated.Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12). The levels of inhibitor kappaB-alpha (IkappaB-alpha), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-kappaB (NF-kappaB), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured.IkappaB-alpha levels were significantly decreased in healthy smokers and current and ex-smoking patients with COPD when compared with nonsmokers (p < 0.001), with an associated increase in NF-kappaB DNA binding in current smokers (p < 0.05). An increase in acetylated histone 4 (ac-H4; p < 0.01) was found in current smokers. Conversely, ex-smokers with COPD showed an increase in ac-H3 (p < 0.05). Decreased levels of cytoplasmic, but not nuclear, HDAC2 protein levels were detected. From the cytokine profiles, no significant differences were detected; however, interleukin-12p40 expression correlated with ac-H4 in current smokers with COPD (p < 0.01).These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.
Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration
Authors: Youlan L. Gu, Marthe A. Kampinga, Wouter G. Wieringa, Marieke L. Fokkema, Maarten W. Nijsten, Hans L. Hillege, Ad F.M. van den Heuvel, Eng-Shiong Tan, Gabija Pundziute, Rik van der Werf, Siyrous Hoseyni Guyomi, Iwan C.C. van der Horst, Felix Zijlstra, Bart J.G.L. de Smet
Journal: Circulation (2010)

administration of the glycoprotein IIb/IIIa inhibitor abciximab is an effective adjunctive treatment strategy during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Although small-scale studies have suggested beneficial effects of intracoronary over intravenous administration of abciximab, this has not been investigated in a medium-scale randomized clinical trial.a total of 534 ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration within 12 hours of symptom onset were randomized to either an intracoronary or an intravenous bolus of abciximab (0.25 mg/kg). Patients were pretreated with aspirin, heparin, and clopidogrel. The primary end point was the incidence of restored myocardial reperfusion, defined as complete ST-segment resolution. Secondary end points included myocardial reperfusion as assessed by myocardial blush grade, enzymatic infarct size, and major adverse cardiac events at 30 days. The incidence of complete ST-segment resolution was similar in the intracoronary and intravenous groups (64% versus 62%; P=0.562). However, the incidence of myocardial blush grade 2/3 was higher in the intracoronary group than in the intravenous group (76% versus 67%; P=0.022). Furthermore, enzymatic infarct size was smaller in the intracoronary than in the intravenous group (P=0.008). The incidence of major adverse cardiac events was similar in both groups (5.5% versus 6.1%; P=0.786).in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration, intracoronary administration of abciximab compared with intravenous administration does not improve myocardial reperfusion as assessed by ST-segment resolution. However, intracoronary administration is associated with improved myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size.
Effects of Chemotherapy in AIDS-Associated Non-Hodgkin's Lymphoma on Kaposi's Sarcoma Herpesvirus DNA in Blood
Authors: Lan Lin, Jeannette Y. Lee, Lawrence D. Kaplan, Bruce J. Dezube, Ariela Noy, Susan E. Krown, Alexandra M. Levine, Yanxing Yu, Gary S. Hayward, Richard F. Ambinder
Journal: Journal of Clinical Oncology (2009)

To determine the relative frequency with which Kaposi's sarcoma-associated herpesvirus/HHV-8 (KSHV) DNA is detected in peripheral-blood mononuclear cells (PBMCs) and in plasma of patients with AIDS-KS and AIDS-associated non-Hodgkin's lymphoma (NHL; AIDS-NHL); to determine whether the presence of viral DNA in plasma reflects lysis of tumor cells or reflects the presence of viremia (ie, virion-encapsidated DNA); and to determine the effect of lymphoma therapy on KSHV DNA.Samples were obtained from patients enrolled in AIDS Malignancy Consortium clinical trials and from healthy donors. Real time PCR was used to quantify KSHV DNA in peripheral blood mononuclear cells (PBMC) and plasma. DNase digestion and fragment size determination studies were used to characterize the DNA detected.In patients with AIDS-KS, KSHV DNA was detected in PBMC (54%) and in plasma (62%). In patients with AIDS-NHL, KSHV DNA was detected in PBMC (19%) and in plasma (22%). Median copy numbers also differed. KSHV DNA in plasma appeared to be encapsidated. In six patients with AIDS-NHL who were treated with chemotherapy (with or without rituximab), KSHV copy number declined in PBMC and in plasma.KSHV DNA is sometimes detected in PBMC or in plasma of patients with AIDS-NHL without KS. Among patients with KSHV DNA detected in PBMC or in plasma, copy number does not distinguish between patients with AIDS-NHL and AIDS-KS. KSHV DNA in plasma likely reflects viremia and not simply lysis of tumor or other KSHV-infected cells. KSHV DNA copy number in PBMC and in plasma declined with lymphoma-directed cytotoxic chemotherapy in each of the six patients studied.
Quality of Life After Breast Cancer Diagnosis and Survival
Authors: Meira Epplein, Ying Zheng, Wei Zheng, Zhi Chen, Kai Gu, David Penson, Wei Lu, Xiao-Ou Shu
Journal: Journal of Clinical Oncology (2010)

To examine the association of quality of life (QOL) after diagnosis of breast cancer with mortality and recurrence.From 2002 to 2004, a total of 2,230 breast cancer survivors completed the General Quality of Life Inventory-74 6 months after diagnosis as part of the Shanghai Breast Cancer Survivor Study. Also collected at baseline was information on demographic and clinical characteristics. At 36 months postdiagnosis, 1,845 of these women were re-evaluated for QOL. Outcomes were ascertained by in-person interview and record linkage to the vital statistics registry. The association of QOL with total mortality and cancer recurrence was assessed by using Cox regression analysis.During a median follow-up of 4.8 years after the 6-month postdiagnosis QOL assessment, 284 deaths were identified. Recurrence was documented in 267 patients after 108 patients with stage IV breast cancer or recurrence before study enrollment were excluded. Women with the highest tertile of social well-being QOL score, compared with those with the lowest score, had a 38% decreased risk of mortality (95% CI, 0.46 to 0.85; P for trend = .002) and a 48% decreased risk of breast cancer recurrence (95% CI, 0.38 to 0.71; P for trend < .001). QOL assessed at 36 months postdiagnosis was not significantly associated with subsequent risk of mortality or recurrence.Social well-being in the first year after cancer diagnosis is a significant prognostic factor for breast cancer recurrence or mortality, suggesting a possible avenue of intervention by maintaining or enhancing social support for women soon after their breast cancer diagnosis to improve disease outcomes.
Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density&lt;SUBTITLE&gt;The Women's Health Initiative Randomized Trial&lt;/SUBTITLE&gt;
Authors: Jane A. Cauley
Journal: JAMA (2003)

In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures.To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures.Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years.Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk.Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction =.54).This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.
Impact of imaging measurements on response assessment in glioblastoma clinical trials
Authors: D. A. Reardon, K. V. Ballman, J. C. Buckner, S. M. Chang, B. M. Ellingson
Journal: Neuro-Oncology (2014)

We provide historical and scientific guidance on imaging response assessment for incorporation into clinical trials to stimulate effective and expedited drug development for recurrent glioblastoma by addressing 3 fundamental questions: (i) What is the current validation status of imaging response assessment, and when are we confident assessing response using today's technology? (ii) What imaging technology and/or response assessment paradigms can be validated and implemented soon, and how will these technologies provide benefit? (iii) Which imaging technologies need extensive testing, and how can they be prospectively validated? Assessment of T1 +/− contrast, T2/FLAIR, diffusion, and perfusion-imaging sequences are routine and provide important insight into underlying tumor activity. Nonetheless, utility of these data within and across patients, as well as across institutions, are limited by challenges in quantifying measurements accurately and lack of consistent and standardized image acquisition parameters. Currently, there exists a critical need to generate guidelines optimizing and standardizing MRI sequences for neuro-oncology patients. Additionally, more accurate differentiation of confounding factors (pseudoprogression or pseudoresponse) may be valuable. Although promising, diffusion MRI, perfusion MRI, MR spectroscopy, and amino acid PET require extensive standardization and validation. Finally, additional techniques to enhance response assessment, such as digital T1 subtraction maps, warrant further investigation.
Long-term administration of massive doses of Sn-protoporphyrin in anemic mutant mice (sphha/sphha).
Authors: S Sassa, G S Drummond, S E Bernstein, A Kappas
Journal: The Journal of Experimental Medicine (1985)

The effects of long-term administration of very large doses of Sn-protoporphyrin on hematological indices, histological changes, plasma bilirubin levels, tissue heme oxygenase activity, and activities of heme biosynthetic enzymes, were examined in genetically anemic mutant mice with hemolytic anemia (sphha/sphha). Long-term weekly treatment with Sn-protoporphyrin (100 mumol/kg body weight for 32 wk) did not alter hematological indices, histological findings, or enzyme activities related to heme biosynthesis, even though it resulted in sustained decreases in microsomal heme oxygenase activity in the liver, kidney, and spleen, and a prolonged decrease in plasma bilirubin concentration. Inhibition of heme oxygenase did not alter the level of cytochrome P-450 in the liver and the kidney. The results indicate that long-term treatment with massive doses of Sn-protoporphyrin suppresses bilirubin formation but does not produce significant histopathological changes or appreciably interfere with heme synthesis, in this strain of genetically anemic mice. These findings provide further support for the idea that suppression of heme degradation to bile pigment by the inhibition of heme oxygenase may prove useful to the prevention of severe hyperbilirubinemia in humans.
Single-Cycle Induction Chemotherapy Selects Patients With Advanced Laryngeal Cancer for Combined Chemoradiation: A New Treatment Paradigm
Authors: Susan Urba, Gregory Wolf, Avraham Eisbruch, Francis Worden, Julia Lee, Carol Bradford, Theodoros Teknos, Douglas Chepeha, Mark Prince, Norman Hogikyan, Jeremy Taylor
Journal: Journal of Clinical Oncology (2005)

Purpose Primary chemoradiotherapy in patients with advanced laryngeal cancer can achieve high rates of organ preservation without sacrificing survival compared with radiation alone or conventional laryngectomy. Appropriate selection of patients for organ preservation approaches could enhance overall treatment outcome and quality of life. We conducted a phase II organ preservation trial for patients with stage III and IV larynx cancer to determine whether late salvage surgery rates could be decreased and survival improved by selecting patients for organ preservation based on response to a single cycle of induction chemotherapy. Patients and Methods The chemotherapy was cisplatin 100 mg/m 2 on day 1 and fluorouracil 1,000 mg/m 2 /d for 5 days. Patients who achieved less than 50% response had immediate laryngectomy. Patients who achieved more than 50% response went on to concurrent chemoradiotherapy. Histologic complete responders after chemoradiotherapy received two more cycles of chemotherapy. Patients with residual disease after chemoradiotherapy had planned salvage surgery. Results Of 97 eligible patients, 73 (75%) achieved more than 50% response and received chemoradiotherapy. A total of 29 patients (30%) had salvage surgery; 19 patients (20%) had early salvage surgery after the single cycle of induction chemotherapy, three patients (3%) had late salvage surgery after chemoradiotherapy, six patients (6%) eventually had salvage surgery for recurrence, and one patient had laryngectomy for chondroradionecrosis. The median follow-up time was 41.9 months. The overall survival rate at 3 years is 85%. The cause-specific survival rate was 87%. Larynx preservation was achieved in 69 patients (70%). Conclusion These results confirm excellent larynx preservation and improved overall survival rates compared with historical results.
A CASE OF SCLERODACTYLIA WITH SUBCUTANEOUS CALCAREOUS CONCRETIONS
Authors: R. E. SCHOLEFIELD, F. PARKES WEBER
Journal: British Journal of Dermatology (1911)

Journal Article A CASE OF SCLERODACTYLIA WITH SUBCUTANEOUS CALCAREOUS CONCRETIONS Get access R. E. SCHOLEFIELD, M.A., M.B., R. E. SCHOLEFIELD, M.A., M.B. Search for other works by this author on: Oxford Academic Google Scholar F. PARKES WEBER, M.A., M.D., F.R.C.P. F. PARKES WEBER, M.A., M.D., F.R.C.P. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 23, Issue 9, 1 September 1911, Pages 276–281, https://doi.org/10.1111/j.1365-2133.1911.tb16682.x Published: 01 September 1911