tbuckley/cabot-search huggingface dataset:
Abstract 9763: Discovery of a New Role of Human Resistin in Hepatocyte Low-Density Lipoprotein (LDL) Receptor Suppression Mediated by PCSK9
Authors: Michelle Melone, Shirya Rashid
Journal: Circulation (2011)

Background: Serum levels of the adipose tissue-derived signalling protein, resistin, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular disease (ASCVD). However, the function of resistin in humans has been enigmatic. An elevation in serum low-density lipoprotein (LDL) levels is both necessary and sufficient for ASCVD development in humans. However, few physiological factors have been identified that directly affect LDL levels through its main receptor, the LDL receptor (LDLR). In this study, we wished to determine if human resistin plays a role in regulating the uptake of atherogenic LDL in human hepatocytes. Methods: Human hepatocytes (HepG2 and primary) were treated for 24 hours with: (1.) purified human resistin at various concentrations, with and without PCSK9 siRNA, and with and without lovastatin; and (2.) obese human serum with elevated resistin levels or serum from which resistin was removed via antibody-immunoprecipitation. The effect of the treatments on cellular LDL receptor (LDLR) and PCSK9 mRNA and protein levels were determined via real-time PCR and Western blotting, respectively. Results: Resistin, at physiological levels observed in human obesity (50 ng/mL), downregulated hepatocyte LDLR expression substantially by 40%. A key mechanism by which human resistin inhibited hepatocyte LDLR was via increased expression of the recently identified protease, PCSK9, which enhances intracellular LDLR lysosomal degradation. To support this notion, we showed that the addition of resistin reversed the marked over 100% elevation in LDLR expression induced with PCSK9 siRNA treatment. The quantitatively important role of human resistin in LDLR expression was demonstrated by antibody-immunoprecipitation removal of resistin in obese human serum, which increased serum stimulation of LDLR markedly by 80%. Furthermore, resistin diminished statin-mediated upregulation of LDLR by 70%, implicating resistin in the relative ineffectiveness of statins in selective target populations. Conclusions: These results reveal for the first time that resistin is potentially a highly attractive therapeutic target in ameliorating elevated serum LDL, and, thereby, ASCVD, in obese humans.
Changes in the populations of blood T-lymphocytes containing chemokine receptors in non-smoking patients with COPD
Authors: Aliaksei Kadushkin, Anatoliy Tahanovich, Tatiana Shman
Journal: European Respiratory Journal (2013)

Background. Chemokine receptors are considered to play an important role in regulating the migration of immune cells, including T-cells, from the peripheral blood into inflamed tissue, such as the lung. However their role has not been studied in non-smoking patients with chronic obstructive pulmonary disease (COPD).

Aim. The aim of the study was to determine the percentage of CD3+CXCR3+ and CD3+CCR5+ lymphocytes in blood of COPD patients.

Methods. For analysis of lymphocytes subtypes the flow cytometry method was used. The study population consisted of 21 non-smokers with COPD, 20 smokers with COPD, 20 healthy non-smokers and 21 healthy smokers.

Results. There were no significant differences in the proportion of T-cells (CD3+) between the groups. We observed an increase in blood T-cells expressing receptors CXCR3 and CCR5 in non-smokers with COPD compared with healthy non-smokers (CXCR3+ T-cells: median value was 46.2% vs 36.6%, respectively, p<0.05; CCR5+ T-lymphocytes: 5.2% vs 2.7%, respectively, p<0.001). The percentage of T-cells containing receptors CXCR3 and CCR5 was significantly higher in blood of smokers with COPD when compared to healthy smokers (CXCR3+ T-lymphocytes: median value was 40.5% vs 37.3%, respectively, p=0.001; CCR5+ T-cells: 4.6% vs 3.1%, respectively, p<0.05). No differences were seen in the proportion of CD3+CXCR3+ and CD3+CCR5+ lymphocytes between COPD smokers and COPD non-smokers.

Conclusion. Our findings suggest a similar mechanism of T-cells migration from blood into the airways in non-smoking and smoking COPD patients.
The cancer stem cell niche in medulloblastoma.
Authors: Christopher R. Calabrese, Helen Poppleton, Andrew Davidoff, Richard J. Gilbertson
Journal: Cancer Research (2006)

5640   Recent data from our group and those of others indicate that glial and neuroectodermal brain tumors are maintained by rare fractions of cancer stem cells (CSC) that express the neural stem cell markers CD133 and Nestin (Singh SK  et. al.,  Nature, 2004; Taylor MD  et. al. , Cancer Cell 2005). In the normal brain, neural stem cells lie within a vascular niche in which endothelial cells release soluble factors that stimulate stem cell self-renewal and inhibit differentiation. Here, we show that endothelial cells similarly maintain the self-renewal capacity and undifferentiated phenotype of medulloblastoma (MB) stem cells and that these cells are closely associated with tumor capillaries  in vivo . We further show that ERBB2 signaling, an indicator of poor prognosis in MB patients, promotes VEGF production, vascular endothelial cell proliferation and angiogenesis in tumors and that these processes can be effectively inhibited  in vitro  and  in vivo . These data show that endothelial cells provide a critical component of the cancer stem cell niche in MB and identify this niche as an important new target for novel therapeutic approaches.
Treatment of depression in the medically ill elderly with methylphenidate
Authors: Wayne Katon, Murray Raskind
Journal: American Journal of Psychiatry (1980)

Three depressed geriatric patients had a marked therapeutic response to the psychostimulant drug methylphenidate. These patients either had been unable to tolerate tricyclic antidepressants or had a medical illness that contraindicated tricyclic therapy. The lack of adverse effects in our elderly patients and methylphenidate's effectiveness as an antidepressant were consistent with the findings of other investigators. These results suggest that psychostimulants deserve further evaluation as antidepressant agents in the geriatric population.
A prospective analysis of the incidence of postoperative lymphedema 1 to 2 years after surgery and axillary dissection in early breast cancer (BC) patients treated with concomitant irradiation and anthracyclines followed by paclitaxel.
Authors: C. Fontaine, H. Van Parijs, L. Decoster, N. Adriaenssens, D. C. Schallier, M. Vanhoey, G. Verfaillie, M. Boels, J. Lamote, J. De Greve
Journal: Journal of Clinical Oncology (2010)

e11059 Background: Lymphedema (LE), a debilitating complication after axillary dissection and irradiation, is caused by the accumulation of interstitial fluid of the affected arm due to a blockage or a malfunction in the lymphatic system. The incidence of postoperative LE varies from 6% to 62.5% due to various measurement criteria and different patient and treatment risk factors. We have examined prospectively the incidence of postoperative LE in early BC patients (pts) treated with concomitant radiotherapy and adjuvant anthracyclines followed by paclitaxel. Methods: Early BC pts were treated with surgery and axillary dissection followed by concurrent postoperative irradiation and chemotherapy consisting of 4*FEC (500/75/600 mg/m2) followed by 12*weekly paclitaxel (80 mg/m2). We measured prospectively the largest circumference of the ipsilateral arm via tape measure every three weeks during the adjuvant chemotherapy and every three months during the first year after surgery, then every 6 months during the second. Finding a difference of > 1.5 cm in limb girth between the two arms was considered to be a clinical diagnosis of LE. Results: Fifty two patients were prospectively enrolled. At 1 to 2 years post-diagnosis an LE incidence of 40% was found, 80% of which developed early during the adjuvant therapy with paclitaxel, suggesting a possible causal relationship with the use of taxanes. Conclusions: This is the first prospective analysis of the incidence of LE in early BC pts treated with concomitant postoperative irradiation and anthracyclines followed by taxanes. The early onset during adjuvant taxane treatment suggests that capillary leakage, together with the previous concomitant chemo-irradiation, is a potential mechanism that contributes to the occurrence of LE. In a second prospective study we will further investigate whether and how the onset of LE during paclitaxel can be monitored, prevented or blunted. No significant financial relationships to disclose.
Survival from Cardiac Arrest in the Accident and Emergency Department
Authors: A R Cope, D N Quinton, A F Dove, J P Sloan, S H Dave
Journal: Journal of the Royal Society of Medicine (1987)

One hundred consecutive patients who were treated in an Accident and Emergency Department for 'cardiac arrest' were studied prospectively. Of these 30% had arrested within the community, 21% in transit and 49% in hospital. The immediate outcome was that 40 left the A&E Department alive; of these, 13 left hospital alive. The 'survivors' included 3 cases of documented asystole. Patients who were over the age of 65, who arrested out of hospital and at night, were found to have a poor prognosis. The time between arrest and arrival of the ambulance was found to affect outcome. Patients with ventricular fibrillation had the best prognosis and those with electromechanical dissociation the worst.
Prognostic factors of survival among adult patients admitted in the ICU due to severe H1N1 pneumonia
Authors: Afroditi Boutou, Georgia Pitsiou, Paschalina Kontou, Kalliopi Chatzika, Fotini Abatzidou, Ioannis Stanopoulos, Ioannis Kioumis
Journal: European Respiratory Journal (2011)

Background:  Data on the mortality of H 1 N 1  pneumonia among patients admitted in the Intensive Care Unit (ICU) vary.   Aim:  To describe the characteristics of the adult patients who were admitted in three ICUs of a major Greek hospital due to H 1 N 1  virus pneumonia and to identify predictors of survival.   Methods:  25 patients with H 1 N 1  pneumonia (72% male; 28% female; 49.7±15 years old) who were admitted in the ICU between October 2009 and February 2011, were retsrospectively studied. Severity of disease scores, comorbidities, disease complications, time of diagnosis and treatment effect were recorded. Mann-Whitney test and x 2  test were used for statistical comparisons.   Results:  At ICU admission, APACHE II score and CURB-65 score were 15.8±4.9 and 2.4±0.9 correspondingly, while 40% of patients presented with ≥2 major complications (ARDS, acute renal failure, myocardial ischemia or shock). Obesity, immunocompromise, coronary heart disease and diabetes mellitus were present in 36%, 32%, 24% and 24% of patients correspondingly, while 44% of them were smokers. The detection of pharyngeal smear antigen took place in 5.5±3.7 days, oseltamivir initiation in 6.2±3.9 days and ICU admission in 7.3±6.8 days, since the establishment of the disease. H 1 N 1  infection was fatal for 72% of patients.The improvement of the radiologic pattern after oseltamivir initiation (p   Conclusions:  The mortality of patients admitted in ICU due to H 1 N 1  virus pneumonia was high. Although oseltamivir administration was beneficial in some cases, there was a delay in the diagnosis of the disease and the initiation of treatment.
Abstract 86: Live-cell profiling of inhibitors targeting the N/C interaction within the androgen receptor
Authors: Larisa Yurlova, Andrea Buchfellner, Jacqueline Gregor, Tina Romer, Ian Hickson
Journal: Cancer Research (2015)

Abstract Androgen receptor (AR) is an important target for drug therapies combating prostate cancer. However, various acquired mutations within the AR sequence often render resistance to these treatments. Since intramolecular interactions between the N- and C-terminus of AR are implicated in AR activation, it is essential to understand how AR inhibitors alter the N/C interaction within the AR, both for the wt receptor and for its mutant forms. In this study we applied our recently developed Fluorescent-Two Hybrid (F2H) assay for live-cell analysis of AR N/C interactions. F2H enables real-time visualization and quantitative analysis of interactions between GFP- and RFP- tagged proteins in live mammalian cells. The F2H principle employs a tethering strategy: a GFP-tagged protein is enriched at the protein interaction platform of engineered F2H-BHK cells and serves as bait, whereas an RFP-tagged protein serves as a prey. Here, AR-LBD (wt or mut) was fused to GFP, AR-TAD was fused to RFP, both constructs were co-transfected into the F2H cells, treated with modulatory compounds and the LBD/TAD interactions were evaluated by fluorescence microscopy. With F2H we analyzed the effects of DHT +/- flutamide, abiraterone, bicalutamide and enzalutamide in live cells. As expected, we observed striking differences in the effects of these treatments on the interactions between the AR-TAD and wt or mut AR-LBD (wt vs W741L, F876L, T877A, F876L-T877A). Further, we compared the effects of the selected compounds on AR-TAD and AR-LBD (wt vs mut) interactions in dose-response F2H assays. We also compared kinetics of these inhibitors with real-time imaging in F2H cells. We further validated our F2H findings with cell-lysate-ELISA on GFP-multiTrap plates. The acquired results correlate well with the published proliferation/reporter-assay data and clarify the role of the intramolecular AR N/C interactions in downstream effects. Taken together, our results demonstrate that the fully reversible cellular F2H assay enables side-by-side profiling of new inhibitors and activators of protein-protein interactions with respect to their intracellular activity, cell penetration and kinetics. Citation Format: Larisa Yurlova, Andrea Buchfellner, Jacqueline Gregor, Tina Romer, Ian Hickson. Live-cell profiling of inhibitors targeting the N/C interaction within the androgen receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 86. doi:10.1158/1538-7445.AM2015-86
Invasive pulmonary aspergillosis: What is the role of surgery in the voriconazole era?
Authors: Mathilde Neuville, Anne Bergeron, Patricia Ribaud, Emmanuel Raffoux, Bernard Maitre, Dominique Gossot
Journal: European Respiratory Journal (2012)

Invasive pulmonary aspergillosis (IPA) is one of the most severe infections in immunocompromised patients. In the 909s, surgery was considered a potentially curative treatment. Since voriconazole has become the first line treatment, the role of surgery has not been evaluated.  Thirty immunocompromised patients who underwent surgery for a suspected IPA between 1990 and 2010 were retrospectively reviewed and separated into two groups: the group A (n=20) who received amphotericin B or itraconazole before the surgery, and the group B (n=10) treated by voriconazole.  The diagnosis of IPA before surgery was certain or probable for 60% of the patients. The main indications for surgery were: the resection of a persistent pulmonary lesion prior to subsequent immunosuppressive treatments (50%), incomplete control of the infection (43%), and risk of haemoptysis (10%). The median duration of antifungal treatment before surgery was 1.3 months in the group A, and 2.5 months in the group B (p=0.2). Persisting aspergillosis was confirmed for 85% among the patients from the group A, and only 20% of the group B (p  Surgery is a therapeutic option for IPA with low mortality in a well trained surgical team. In the voriconazole era, the proportion of resected pulmonary lesions containing   Aspergillus   appears to be decreasing, whereas other fungal infections are detected. The role of surgery has to be defined in patients previously treated with voriconazole, particularly for remaining pulmonary lesions.
Five‐Year Followup of Knee Joint Cartilage Thickness Changes After Acute Rupture of the Anterior Cruciate Ligament
Authors: F. Eckstein, W. Wirth, L. S. Lohmander, M. I. Hudelmaier, R. B. Frobell
Journal: Arthritis & Rheumatology (2014)

Objective Anterior cruciate ligament (ACL) rupture involves an increased risk of osteoarthritis. The purpose of this study was to explore changes in cartilage thickness over 5 years after ACL rupture. Methods A total of 121 young active adults (ages 18–35 years; 26% women) from the Knee ACL, Nonsurgical versus Surgical Treatment (KANON) study, who had acute traumatic rupture of the ACL were studied. Sagittal magnetic resonance images were acquired within 4 weeks of ACL rupture (baseline) and at the 2‐year and 5‐year followup assessments. Medial and lateral femorotibial cartilage was segmented (with blinding to acquisition order), and the mean cartilage thickness was computed across 16 femorotibial subregions. Total femorotibial cartilage thickness change was the primary analytic focus. Maximal subregional mean cartilage thickness loss (ordered value 1 [OV1]) and gain (ordered value 16 [OV16]), independent of its specific location in individual knees, were the secondary analytic focus. Results Overall femorotibial cartilage thickness increased by 31 μm/year over 5 years (95% confidence interval 18, 44). The increase was similar in men and women and was significantly greater in those younger, as compared with those older, than the median age (25.3 years). The rate of total cartilage thickness change did not differ significantly between the first 2 years and the later 3 years. However, the maximal annualized subregional cartilage loss (OV1) and gain (OV16) were both significantly greater ( P &lt; 0.001 and P &lt; 0.05, respectively) during the earlier interval than during the later interval (−115 versus −54 μm [OV1] and 116 versus 69 μm [OV16]). Conclusion Cartilage thickening was observed over 5 years following ACL injury, particularly in the medial femorotibial compartment and in younger subjects. Major perturbations in cartilage homeostasis were seen over the first 2 years after ACL rupture, with simultaneous subregional thinning and thickening occurring within the same cartilage plate or compartment.
Fat Digestion in the Newborn
Authors: Margit Hamosh, John W. Scanlon, Dvora Ganot, Melodie Likel, Kathleen B. Scanlon, Paul Hamosh
Journal: Journal of Clinical Investigation (1981)

We have measured lipolytic activity in gastric aspirates obtained at birth in a group of 142 infants. The infants ranged in gestational age from 26 to 41 wk. Lipolytic activity, measured by the hydrolysis of long chain triglyceride ([tri-3H]oleate), and expressed as nanomoles FFA per milliliter gastric aspirate per minute was 333±66 in 55 small premature infants (gestational age 26-34 wk and body wt 750-2,000 g) and 558±45 in a group of 87 larger infants (gestational age 35-41 wk and body wt 2,020-4,000 g). No activity was detected in seven infants with an unusually low pH in the gastric aspirate, 2.88±0.44 (compared with a mean pH level of 5.59±0.22 in the other 135 infants).
Liver sinusoidal endothelial cells in hepatic fibrosis
Authors: Laurie D. DeLeve
Journal: Hepatology (2014)

Capillarization, lack of liver sinusoidal endothelial cell (LSEC) fenestration, and formation of an organized basement membrane not only precedes fibrosis, but is also permissive for hepatic stellate cell activation and fibrosis. Thus, dysregulation of the LSEC phenotype is a critical step in the fibrotic process. Both a vascular endothelial growth factor (VEGF)‐stimulated, nitric oxide (NO)‐independent pathway and a VEGF‐stimulated NO‐dependent pathway are necessary to maintain the differentiated LSEC phenotype. The NO‐dependent pathway is impaired in capillarization and activation of this pathway downstream from NO restores LSEC differentiation in vivo . Restoration of LSEC differentiation in vivo promotes HSC quiescence, enhances regression of fibrosis, and prevents progression of cirrhosis. (H epatology 2015;61:1740–1746)
Analysis of the impact on respiratory tract by accidental leak of hydrofluoric acid
Authors: Hun Gyu Hwang, Myung Shin Kim, Gune Il Lim, Seong Yong Yoon
Journal: European Respiratory Journal (2014)

PURPOSE : The purpose of this study is to identify the acute and chronic influence of hydrofluoric acid spill on respiratory tract in community, which occurred on Sep 27, 2012. METHODS: In first period of study, a total of 1,364 patients were included between Oct 2012 and Jan 2013. In second period of study, between Feb 2013 and Jun 2013, 141 patients underwent detailed examination and received questionnaires. Degree of exposure were evaluated on the basis of environmental factors retrospectively. Pulmonary function test and radiologic examination were included. RESULTS: Of 141 patients, 69(48.9%) patients were high-exposed, 41(29.1%) moderate, 24(17.0%) low, and 7(5.0%) none, according to the degree of exposure to hydrofluoric acid. Symptoms such as dyspnea, cough, and phlegm were found in 83 patients(58.9%). The level of exposure was significantly associated with dyspnea and phlegm which patients complained of (p
Dose Escalation in Non–Small-Cell Lung Cancer Using Three-Dimensional Conformal Radiation Therapy: Update of a Phase I Trial
Authors: James A. Hayman, Mary K. Martel, Randall K. Ten Haken, Daniel P. Normolle, Robert F. Todd, J. Fred Littles, Molly A. Sullivan, Peter W. Possert, Andrew T. Turrisi, Allen S. Lichter
Journal: Journal of Clinical Oncology (2001)

PURPOSE: High-dose radiation may improve outcomes in non–small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes ≥ 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.