tbuckley/cabot-search huggingface dataset:
Heart Rate or Beta-Blocker Dose? Association With Outcomes in Ambulatory Heart Failure Patients With Systolic Dysfunction
Authors: Mona Fiuzat, Daniel Wojdyla, Ileana Pina, Kirkwood Adams, David Whellan, Christopher M. O’Connor
Journal: JACC Heart Failure (2015)

This study aimed to compare whether reduced heart rate (HR) or higher beta-blocker (BB) dose affected outcomes to a greater extent in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial population.Recent data have shown that HR is an important modifiable factor in reducing mortality in heart failure (HF) patients. It has also been shown that titration of doses of BBs improves outcomes of morbidity and mortality in chronic HF patients with reduced ejection fraction. We aimed to compare whether reduced HR or higher BB dose affected outcomes to a greater extent in the HF-ACTION trial population.HF-ACTION was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. BB dose at baseline was standardized by use of carvedilol equivalents. BB dose and HR were analyzed by discrete groups (higher/lower dose; higher/lower HR). The relationship of BB dose, HR, and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints were determined before and after adjustment for variables found to be significantly associated with outcome in the HF-ACTION cohort.There was a significant inverse relationship between either BB dose (higher was better) or HR (lower was better) and all-cause death or hospitalization in unadjusted analysis; however, only BB dose was significant for improved mortality outcomes. After adjustment for other predictors of outcome, only BB dose remained significant for improving all-cause death or hospitalization. BB dose, but not HR, was associated with improved outcomes of other cardiovascular endpoints in unadjusted analysis but did not remain significant when adjusted for other predictors of outcome in this cohort.There were more associated improvements in outcomes with higher BB dose than with reduced HR in this well-treated HF cohort with systolic dysfunction, which suggests that titration of BB doses may confer a greater benefit than reduction of HR in such patients. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437).
Studies of Mouse Mammary Glands. I. Cytomorphology of the Normal Mammary Gland&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: K. K. Sekhri, D. R. Pitelka, K. B. DeOme
Journal: JNCI Journal of the National Cancer Institute (1967)

As a basis for further work on transplantation of normal, preneoplastic, and neoplastic mammary tissues, the cytology of normal mammary glands of 244 C57BL/Crgl mice, ranging from 19-day fetuses to retired multiparous breeders, was investigated by light and electron microscopy. The fetal and 1-day-old glands were characterized by a rudimentary duct system terminating in end-buds. The end-buds, missing in 1-3-week-old glands, reappeared at the 4-week stage. Under the electron microscope, the end-bud cells revealed hypertrophied Golgi apparatus, numerous mitochondria, moderately developed endoplasmic reticulum, and myriad microvesicles, in marked contrast to the virgin duct cells. Lactating epithelial cells displayed the characteristics of typical secreting cells. Protein granules were consistently associated with the Golgi apparatus and were released by reverse pinocytosis. Lipid droplets were extruded with bits of adherent cytoplasm. There was, however, no evidence of apocrine secretion. Virgin primary, secondary, and tertiary ducts were lined by a 1-3-cell-thick epithelium, which became hyperplastic during lactation. After parturition, only the tertiary duct cells displayed fine structural features like those of alveolar cells and hence were both secretory and excretory. The appearance of colostrum corpuscles within 12 hours of weaning proved a sensitive indicator of the onset of involution. Their ultrastructural characteristics suggested they were sloughed secretory epithelial cells. In involuting alveoli, the appearance of large cytoplasmic vacuoles presumably containing resorbed protein particles, sloughing of the microvilli, disruption of the endoplasmic reticulum, deposition of the fat, and formation of residual bodies were characteristic events in cytolysis. The results provide no evidence for the existence of inflammatory phenomena during post-secretory mammary involution.
Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies
Authors: Raoel Maan, Robert J de Knegt, Bart J Veldt
Journal: Drugs (2015)

Thrombocytopenia (platelet count <150 × 10(9)/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6% among non-cirrhotic patients with chronic liver disease to 70% among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia.
Development of a lung slice methodology to study the mechanisms of lung uptake and lysosomal trapping
Authors: Erica Bäckström, Anders Lundqvist, Petter Svanberg, Elin Boger, Pär Ewing, Margareta Hammarlund-Udenaes, Markus Fridén
Journal: European Respiratory Journal (2014)

Introduction: Inhalation drug projects face the challenge of identifying the lung target site unbound drug concentration to better understand the pharmacokinetic/pharmacodynamic (PK/PD) relationships. This study describes the development and application of a new lung slice methodology to study drug uptake in the rat lung and the mechanisms by which it occurs.

Methods: Slices (500 µm) from agarose-inflated rat lungs were incubated for 6 hours with prototypic basic, neutral, and acidic drugs (propranolol, diazepam, and indomethacin, respectively). Drug concentrations were measured in buffer and tissue using LC-MS/MS. The unbound drug volume of distribution in the lung (Vu,lung) was calculated by dividing the amount, i.e. total concentration of drug in slices by the buffer concentration, taking into account the volume of the airway spaces estimated with 14C-inulin. Co-incubation with monensin, a known modulator of lysosomal pH, was made to assess the impact of lysosomal trapping.

Results: Vu,lung for propranolol, diazepam and indomethacin was 297, 19.3, and 11.2 ml/g, respectively. The uptake of propranolol was concentration-dependently inhibited by monensin and reached 98% inhibition at the highest concentration of monensin. The uptake of diazepam and indomethacin was unaffected by monensin.

Conclusions: The uptake of propranolol was related to remarkably extensive lysosomal trapping in lung tissue which did not occur for diazepam and indomethacin. The presented methodology to study drug distribution in the lung can facilitate and improve the knowledge of PK/PD relationships of lung targeted drugs.
Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.
Authors: B J Dezube, J H Von Roenn, J Holden-Wiltse, T W Cheung, S C Remick, T P Cooley, J Moore, J P Sommadossi, S L Shriver, C W Suckow, P S Gill
Journal: Journal of Clinical Oncology (1998)

PURPOSE Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS Patients with AIDS-related KS were required to have cutaneous disease with &gt; or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had &gt; or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.
A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.
Authors: K K Jain, E S Casper, N L Geller, T B Hakes, R J Kaufman, V Currie, W Schwartz, C Cassidy, G R Petroni, C W Young
Journal: Journal of Clinical Oncology (1985)

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.
Endoplasmic reticulum stress in bronchial tissue in patients with COPD and lung cancer
Authors: Belen Nunez, Sergio Scrimini, Alvar Agustí, Amanda Iglesias, Borja Cosio, Meritxell Lopez, Angel Rios, Juan Antonio Torrecilla, Jaume Sauleda
Journal: European Respiratory Journal (2014)

COPD is a risk factor for lung cancer (LC). The mechanisms for this association are unknown. Both diseases can associate disturbances in endoplasmic reticulum stress (ERS).   Hypothesis:  ERS could be a mechanism for LC in COPD patients.   Aims:  To compare different ERS markers in non-tumour bronchial tissue in smoking patients with/without COPD (with /without LC) and healthy non-smoking controls.   Population and methods:  Forty subjects distributed into 4 groups according to the presence or not of COPD and LC. Clinical history, lung function tests and bronchoscopy with bronchial biopsy were performed in all subjects. The most representative markers for ERS (BIP, IRE, xBPS, PERK, CHOP, EIF, ATF6) were analysed by RT-PCR.The values were normalised according to the GADPH.   Results:  Smoking subjects with normal lung function without LC, n=7 (5 men, 57 ± 15 years, FEV1 95±14% , FEV1/FVC 78 ± 8%);COPD patients without LC, n=13 (10 men, 66 ± 9 years, FEV1 88 ± 11%, FEV1/FVC 62 ± 6%);Smoking subjects with normal lung function with LC, n=5 (4 men, 58 ± 6 years FEV1 95±12 %, FEV1/FVC 76 ± 3%); COPD patients with LC, n=15 (12 men, 64 ± 11 years, FEV1 72±15 %, FEV1/FVC 60 ± 6%). We found more cellular cycles to detect IRE, PERK and CHOP in patients with COPD and LC compared with those smoking subjects with normal lung function (p   Conclusions:  The patients with COPD and LC show a decreased ERS in bronchial tissue.  Funded partially by FIS PI 12/02793, Grups Competitius MAR Govern Balear 2011-2013.
Abstract 58: Identification Of miRNA-34 Networks In Pathological Cardiac Remodeling
Authors: Jenny Y Ooi, Bianca C Bernardo, Esther J Boey, Ruby C Lin, Julie R McMullen
Journal: Circulation Research (2014)

Introduction: MicroRNAs (miRNAs) are altered in heart disease and have emerged as promising therapeutic targets. We recently reported that therapeutic inhibition of the miR-34 family (with an 8 mer antimiR) was effective in attenuation of pathological cardiac remodeling. We hypothesized the efficacy of antimiR-34 may be due to its regulation of other miRNAs, producing direct and indirect target effects. Objectives: To identify miRNAs regulated by miR-34 and understand miRNA networks involved in miR-34 inhibition therapy for pathological cardiac hypertrophy. Methods: MiRNA sequencing (Illumina HiSeq 2000) was performed on hearts of mice subjected to transverse aortic constriction (TAC) for 5 weeks, and subcutaneously administered a locked nucleic acid (LNA)-antimiR-34 for 6 weeks (n=3-4). Results: Expression of miR-34 family members (miR-34a, miR-34b, miR-34c) is increased in the hearts of TAC mice compared to Sham controls (1.7, 2.5, 4-fold, P&lt;0.05) and attenuated with antimiR-34 treatment (85% decrease [0.85 of 1], p&lt;0.05). TAC mice developed pathological cardiac hypertrophy (60% increase [4.8 of 8] in heart weight/tibial length ratio compared to Sham controls, P&lt;0.05) and treatment with antimiR-34 significantly attenuated heart size (P&lt;0.05). To uncover the underlying miRNA interactions, we carried out miRNA-Seq to identify other miRNAs that might be dysregulated in response to antimiR-34-based therapy. We identified several miRNAs (e.g., miR-3083 and miR-20b) that were downregulated in hearts from TAC vs Sham but not significantly downregulated in the TAC antimiR-34 group. Conversely, two miRNAs (miR-8103, miR-1933) were increased in response to TAC vs Sham but not significantly upregulated in TAC antimiR-34 treated mice. Our data suggests that miR-34 can regulate other miRNA and that these miRNAs can work together to regulate pathways leading to pathological cardiac hypertrophy. Conclusion: The identification of other miRNAs regulated by miR-34 may improve our understanding of miRNA networks for optimization of better therapeutic targets for treatment of complex diseases such as heart failure.
Secular Trends in Mortality From Malignant Melanoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. A. H. Lee, Ann P. Carter
Journal: JNCI Journal of the National Cancer Institute (1970)

The reported number of deaths from malignant melanoma has been rising rapidly in both the United States and England and Wales. This rise is found in all age groups and, at ages under 65, is too large to be accounted for by a transfer of deaths from unspecified skin cancer. The trends of age-specific mortality rates are compatible with a generation effect, beginning with those born around the turn of the century. These findings more likely result from an increase in the incidence of malignant melanoma than from a systematic improvement in certification.
Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute.
Authors: A S Lichter, M E Lippman, D N Danforth, T d'Angelo, S M Steinberg, E deMoss, H D MacDonald, C M Reichert, M Merino, S M Swain
Journal: Journal of Clinical Oncology (1992)

PURPOSE Mastectomy versus excisional biopsy (lumpectomy) plus radiation for the treatment of stage I and II breast cancer was compared in a prospective randomized study. PATIENTS AND METHODS From 1979 to 1987, 247 women were randomized and 237 were treated on this study. All patients received a full axillary dissection and all node-positive patients received adjuvant chemotherapy with cyclophosphamide and doxorubicin. Radiation consisted of external-beam therapy to the whole breast with or without supraclavicular nodal irradiation followed by a boost to the tumor bed. RESULTS The minimum time on the study was 18 months and the median time on the study was 68 months. No differences in overall survival or disease-free survival were observed. Actuarial estimates at 5 years showed that 85% of mastectomy-treated patients were alive compared with 89% of the lumpectomy/radiation patients (P2 = .49; 95% two-sided confidence interval [CI] about this difference, 0% to 9% favoring lumpectomy plus radiation). The probability of failure in the irradiated breast was 12% by 5 years and 20% by 8 years according to actuarial estimates. Of 15 local breast failures, 14 were treated with and 12 were controlled by mastectomy; the ultimate local-regional control was similar in both arms of the trial. CONCLUSION These data add further weight to the conclusion that breast conservation using lumpectomy and breast irradiation is equivalent to mastectomy in terms of survival and ultimate local control for stage I and II breast cancer patients.
Pharmacological effect of lysozyme for COPD and bronchial asthma with sputum: A randomized, placebo-controlled, cross-over study
Authors: Hiroyuki Ohbayashi, Yasuhiro Setoguchi, Yoshinosuke Fukuchi, Kai Shibata, Yukinori Sakata, Toshihisa Arai
Journal: European Respiratory Journal (2014)

Background/Aim  Mucolytic agents are often used in patients with COPD and bronchial asthma (BA) in Japan to decrease excessive mucus production, which is followed by improvement in dyspnea and QOL. However, the precise mechanism is unknown.Therefore, the actual mechanism of lysozyme hydrochloride (LYS), an oral anti-inflammatory enzyme preparation, in patients with COPD/BA was investigated.  Method  This study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-fourpatients with COPD and twenty-four patients with BA were enrolled.LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods.  The results ofimpulse oscillometry system (IOS) and spirometry examinations, as well as the changes in the symptoms ofsputum production, were evaluated after the treatment period.  Results  On IOS examination, resistance of the respiratory system at 5 Hz (R5) levels was significantly improved only in patients with COPD (LYS vs placebo: -0.455 cm H 2 O/L/s vs 0.095 cmH 2 O/L/s, p =0.012). Similar trends were also found in R20, X5, and AX. On spirometry, airway function (FEV1)improved in patients with COPD after administration of LYS (LYS vs placebo: 0.062 L vs 0.025 L, p = 0.062). Similar trends were also found in %FEV1 in COPD patients. Subjective symptoms of sputum production also tended to improve only during the LYS treatment period. No adversereactions were observed during the study.  Conclusion  LYS, a mucolytic agent, may improve the function of peripheral airways, which is followed by improvement in the patients9 symptoms and QOL.
Lessons learned and unlearned in periodontal microbiology
Authors: Ricardo Teles, Flavia Teles, Jorge Frias‐Lopez, Bruce Paster, Anne Haffajee
Journal: Periodontology 2000 (2013)

Abstract Periodontal diseases are initiated by bacterial species living in polymicrobial biofilms at or below the gingival margin and progress largely as a result of the inflammation elicited by specific subgingival species. In the past few decades, efforts to understand the periodontal microbiota have led to an exponential increase in information about biofilms associated with periodontal health and disease. In fact, the oral microbiota is one of the best‐characterized microbiomes that colonize the human body. Despite this increased knowledge, one has to ask if our fundamental concepts of the etiology and pathogenesis of periodontal diseases have really changed. In this article we will review how our comprehension of the structure and function of the subgingival microbiota has evolved over the years in search of lessons learned and unlearned in periodontal microbiology. More specifically, this review focuses on: (i) how the data obtained through molecular techniques have impacted our knowledge of the etiology of periodontal infections; (ii) the potential role of viruses in the etiopathogenesis of periodontal diseases; (iii) how concepts of microbial ecology have expanded our understanding of host–microbe interactions that might lead to periodontal diseases; (iv) the role of inflammation in the pathogenesis of periodontal diseases; and (v) the impact of these evolving concepts on therapeutic and preventive strategies to periodontal infections. We will conclude by reviewing how novel systems‐biology approaches promise to unravel new details of the pathogenesis of periodontal diseases and hopefully lead to a better understanding of their mechanisms.
Prospective Randomized Multicenter Clinical Trial on the Use of Interferon -2a Plus Acitretin Versus Interferon -2a Plus PUVA in Patients With Cutaneous T-Cell Lymphoma Stages I and II
Authors: R. Stadler, H.-G. Otte, T. Luger, B.M. Henz, P. Kühl, T. Zwingers, W. Sterry
Journal: Blood (1998)