Miracle-dz/UniFAR-FTUs huggingface dataset:
The Achilles Heel of ErbB-2/HER2: Regulation by the Hsp90 Chaperone Machine and Potential for Pharmacological Intervention

Signal transduction mediated by ErbB/HER receptor tyrosine kinases is crucial for the development and maintenance of epithelial tissues, and aberrant signaling is frequently associated with malignancies of epithelial origin. This review focuses on the roles played by the Hsp90 chaperone machinery in the regulation of signaling through the ErbB/HER network, and discusses potential therapeutic strategies that disrupt chaperone functions. Hsp90 and its associated co-chaperones regulate ErbB signal transduction through multiple mechanisms. The chaperone system controls the stability of the nascent forms of both ErbB-1 (EGF-receptor) and ErbB-2/HER2, while regulation of the mature form is restricted to ErbB-2. Regulation by the Hsp90 complex extends to downstream effectors of ErbB signaling, namely Raf-1, Pdk-1 and Akt/PKB. Disrupting the function of Hsp90 results in the degradation of both the receptors and their effectors, thereby inhibiting tumor cell growth. The importance of an Hsp90-recognition motif located within the kinase domain of ErbB-2 is discussed, as well as a direct role for Hsp90 in regulating tyrosine kinase activity. In light of recent observations, we emphasize the ability of specific tyrosine kinase inhibitors to selectively target ErbB-2 to the chaperone-mediated degradation pathway. ErbB-specific drugs are already used to treat cancers, and clinical trials are underway for additional compounds that intercept ErbB signaling, including drugs that target Hsp90. Hence, the dependence of ErbB-2 upon Hsp90 reveals an Achilles heel, which opens a window of opportunity for combating cancers driven by the ErbB/HER signaling network.
Activation of neutrophils within pulmonary microvessels of rabbits exposed to cigarette smoke.

Previous studies have shown that polymorphonuclear leukocytes (PMN) are delayed in the pulmonary capillaries by the presence of cigarette smoke. To determine if the PMN delayed by smoking are activated, we estimated the in vivo expression of CD11/CD18 and L-selectin on the surface of PMN in lungs and peripheral blood of rabbits because these molecules are known to be upregulated and downregulated, respectively, on the surface of activated PMN. New Zealand white rabbits (3.5 +/- 0.1 kg) were exposed to either air (n = 5) or cigarette smoke (n = 5), and we used an established protocol to measure pulmonary vascular blood flow, volume, and red blood cell (RBC) transit time in the left lung. The right lungs were then fixed in 0.025% glutaraldehyde and stored in liquid nitrogen. Ultrathin sections were immuno-labeled with either the anti-CD18 monoclonal antibody 60.3 or the anti-L-selectin antibody Dreg-200, followed by a secondary antibody conjugated to 10 nm colloidal gold. The target antigens were quantified by counting the number of gold particles per micron (G/microns) of PMN surface membrane. The data show that smoke exposure had no effect on pulmonary blood flow, volume, or RBC transit time. However, it increased the expression of CD11/CD18 on intravascular PMN in the upper region of the lung (control, 7.4 +/- 1.3 G/microns; smoke-exposed, 13.2 +/- 3.3 G/microns; P < 0.05) and decreased the expression of L-selectin on intravascular PMN in both the lower (control, 5.5 +/- 2.0 G/microns; smoke-exposed, 2.6 +/- 1.5 G/microns; P = 0.05) and the upper (control, 6.8 +/- 1.4 G/microns; smoke-exposed, 2.6 +/- 1.2 G/microns; P < 0.05) regions. (ABSTRACT TRUNCATED AT 250 WORDS)
Catecholamine‐synthesizing neuronal projections to the nucleus tractus solitarii of the rat

The objective of the present study was to determine the location of the neurons that give rise to catecholamine‐containing terminals in the nucleus tractus solitarii. This was done by injecting rhodamine‐filled latex microspheres into the nucleus tractus solitarii of rats to retrogradely label neuronal cell bodies and by processing sections from the brains of these animals to determine if the labelled neurons were immunoreactive for the catecholamine‐synthesizing enzymes, dopamine‐beta‐hydroxylase (DBH) and phenyl‐ethanolamine‐N‐methyl transferase (PNMT).
Coagulation Factor V: An Old Star Shines Again

Blood coagulation factor V plays an important role in the regulation of thrombin formation. Activation of factor V by traces of activated coagulation factors (thrombin, factor Xa or meizothrombin) yields factor Va, the non-enzymatic cofactor of the prothrombinase complex. Since factor Va accelerates prothrombin activation under physiological conditions more than 10(4)-fold it is not surprising that down-regulation of factor Va cofactor activity by the protein C pathway is a very effective way for maintaining the hemostatic balance. In this paper we have reviewed the present status of structural knowledge of factor V and Va, the molecular changes in factor V that occur during factor V activation, the function of factor Va in prothrombin activation and the molecular mechanism of inactivation of factor Va by APC. Although considerable insight in the structure-function relationship of factor V and Va has been achieved, the study of mutated factor V molecules obtained by recombinant DNA technology will undoubtedly resolve remaining questions. The latter is illustrated by the fact that the discovery of factor VaLeiden has significantly contributed to our present knowledge on the regulation of the cofactor activity of factor Va via the protein C pathway. It appears that modulation of the activity of APC by protein S and factor Xa will strongly affect the in vivo activity of this pathway. Factor V not only plays an important role in the regulation of the activity of the prothrombinase complex but also acts as cofactor in APC-mediated inactivation of factor VIIIa. This gives rise to a rather intricate mechanism of regulation of thrombin formation by APC that thus far has been mainly studied in model systems containing purified proteins. Thus, extensive studies in plasma will be required in order to get more insight in the in vivo regulation of thrombin formation via the protein C pathway.
The relationship of structural ischemic brain damage to neurobehavioural deficit: the effect of postischemic MK-801.

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in neurobehavioural performance, using a learning-set water task. Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporalis muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done. The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen. Quantitative neuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CA1 pyramidal cells, as opposed to 72.4% in untreated controls. Extra-hippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neocortex and thalamus. Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated histopathology due to compounding interanimal variation in performance abilities. (ABSTRACT TRUNCATED AT 400 WORDS)
Loss aversion and hypoxia: less loss aversion in oxygen-depleted environment

Abstract Hypoxia, the deprivation of adequate oxygen supply, constitutes a direct threat to survival by disrupting cardiovascular or respiratory homeostasis and eliciting a respiratory distress. Although hypoxia has been shown to increase brain vulnerability and impair basic cognitive functions, only one study has examined its effect on decision-making. The present study examined the effect of mild hypoxia on individual’s loss aversion, that is, the tendency to be more affected by losses than equal sized gains. A sample of 26 participants were asked to either accept or reject a series of mixed gambles once in an oxygen-depleted environment (14.1% oxygen concentration) and once in a normoxic environment (20.9% oxygen concentration). Each gamble involved a 50–50 chance of winning or losing specified amounts of money. Mild hypoxia decreased loss aversion: on average in the normoxic condition participants accepted gambles if the gain was at least 2.4 times as large as the loss, whereas in the oxygen-depleted condition participants accepted gambles if the gain was at least 1.7 times as large as the loss. Mild hypoxia may push individuals to be less cautious in daily decisions that involve a trade-off between a gain and a loss.
An Approach to Algorithm Design by Patterns

This paper proposes two behavioral patterns called DIVIDE-&-CONQUER and BACKTRACKING to facilitate the development of algorithms based upon algorithm design techniques. The common informal seudocode that specifies the solving strategy for a general algorithm design technique is enhanced to provide a helpful guide to develop particular algorithms by following the divide and conquer and the backtracking design techniques.
Interdisciplinary design methodology for systems of mechatronic systems focus on highly dynamic environmental applications

This paper discusses a series of research challenges in the design of systems of mechatronic systems. A focus is given to environmental mechatronic applications within the chain “Renewable energy production — Smart grids — Electric vehicles”. For the considered mechatronic systems, the main design targets are formulated, the relations to state and parameter estimation, disturbance observation and rejection as well as control algorithms are highlighted. Finally, the study introduces an interdisciplinary design approach based on the intersectoral transfer of knowledge and collaborative experimental activities.
Comparison of vitamin D levels in obese and non obese patients with polycystic ovarian syndrome in a South Indian population

Polycystic ovary syndrome (PCOS) is the most common metabolic abnormality occurring in young women of reproductive age. Low vitamin D levels were found to be associated with the development of obesity and insulin resistance in young women with PCOS. The study was conducted as a prospective observational study involving 121 women with PCOS. The diagnosis of PCOS cases were based on the revised Rotterdam consensus criteria. Vitamin D levels were compared in the obese and non obese PCOS groups and also with the controls. In the PCOS group, sixty subjects were obese with BMI of ≥25 kg/m 2 and forty seven subjects were found to be non obese. In the control group, sixteen subjects were obese and sixty five subjects were non obese. The mean vitamin D level in the PCOS group was 15.45±7.88 ng/ml and in the control group was 12.83±5.76ng/ml. The mean vitamin D levels in the obese and non obese group with PCOS were 16.11±8.9ng/ml and 14.61±6.1ng/ml respectively. Majority of the patients and controls had vitamin D deficiency and there was no difference in the vitamin D levels in PCOS group and controls as well as obese and non obese groups.
Pain and other side effects after MR arthrography: prospective evaluation in 1085 patients.

PURPOSE To prospectively evaluate pain and other side effects after magnetic resonance (MR) arthrography. MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. MR arthrography was performed in 1085 patients. In 1011 patients, 2 mmol/L gadopentetate dimeglumine was injected. In patients whose wrists were examined, 5 mmol/L gadoterate dimeglumine was injected. Pain was measured directly after injection, 4 hours after injection, 1 day [18-30 hours] after injection, and 1 week [6-8 days] after injection and compared with pain at baseline (before contrast material was injected). A visual analogue scale or verbal rating scale (score range, 0-10) was used to measure pain. When increased pain persisted at the end of the observation period, additional assessment was performed to exclude infection. Evaluated factors with a potential effect on pain were time after injection, joint type, contrast agent volume, patient age and sex, and radiologist experience. Repeated measures analysis of variance was used. RESULTS Mean pain increase was most pronounced 4 hours after injection (P < .0001). This increase was most pronounced in the hip, followed by the elbow, knee, wrist, ankle, and shoulder. (Differences between joints were not significant [P = .26].) Pain scores returned to baseline levels 1 week after injection. Patients younger than 30 years had more pronounced pain than did patients in other age groups at all time points (P = .044). Joint type, contrast agent volume (P = .44), patient sex (P = .29), and radiologist experience (P = .10) did not significantly affect pain scores. No patient had infection or any other severe side effect. Besides joint pain, minor side effects included pressure, headache, muscle ache, swollen hand, fatigue, vertigo, increased blood glucose level, and pruritus. CONCLUSION MR arthrography temporarily increases joint-related pain. Such pain depends on patient age but not on joint type, contrast material volume, patient sex, or radiologist experience.
Improvement of High‐Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial

Abnormal function of high‐density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL‐associated proteins over 2 years of follow‐up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial.
Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.

BACKGROUND Evidence of an inverse relationship between central serotonergic (serotonin [5-hydroxytryptamine]) system function and impulsive aggressive behavior has been accumulating for more than 2 decades. If so, pharmacological enhancement of serotonin activity should be expected to reduce impulsive aggressive behavior in subjects in whom this behavior is prominent. METHODS A double-blind, placebo-controlled trial of the selective serotonin-uptake inhibitor fluoxetine hydrochloride was conducted in 40 nonmajor-depressed, nonbipolar or schizophrenic, DSM-III-R personality-disordered individuals with current histories of impulsive aggressive behavior and irritability. Measures included the Overt Aggression Scale-Modified for Outpatients, Clinical Global Impression Rating of Improvement, and several secondary measures of aggression, depression, and anxiety. RESULTS Fluoxetine, but not placebo, treatment resulted in a sustained reduction in scores on the Irritability and Aggression subscales of the Overt Aggression Scale-Modified for Outpatients that was first apparent during months 2 and 3 of treatment, respectively. Fluoxetine was superior to placebo in the proportion of "responders" on the Clinical Global Impression Rating of Improvement: first at the end of month 1, and then finally demonstrating a sustained drug-placebo difference from the end of month 2 through the end of month 3 of treatment. These results were not influenced by secondary measures of depression, anxiety, or alcohol use. CONCLUSION Fluoxetine treatment has an antiaggressive effect on impulsive aggressive individuals with DSM-III-R personality disorder.
Pulmonary lymphangioleiomyomatosis (LAM): Progress and current challenges

Lymphangioleiomyomatosis (LAM), a rare lung disease, is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)‐like LAM cells, which lead to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. LAM is a disease predominantly affecting women and is exacerbated by pregnancy; only a lung transplant can save the life of a patient. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 protein complex functions as a negative regulator of the mTOR/S6K1 signaling pathway. These two pivotal observations paved the way for the first rapamycin clinical trial for LAM. The recent discoveries that TSC1/TSC2 complex functions as an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy heightened the interest regarding this rare disease because the elucidation of disease‐relevant mechanisms of LAM will promote a better understanding of other metabolic diseases such as diabetes, cancer, and cardiovascular diseases. In this review, we will summarize the progress made in our understanding of TSC1/TSC2 cellular signaling and the molecular mechanisms of LAM; we will also highlight some of the lesser explored directions and challenges in LAM research. J. Cell. Biochem. 103: 369–382, 2008. © 2007 Wiley‐Liss, Inc.
Comparing the Effects of Isoflurane-Sufentanil Anesthesia and Propofol-Sufentanil Anesthesia on Serum Cortisol Levels in Open Heart Surgery with Cardiopulmonary Bypass

Background Major surgeries such as open-heart surgery with cardiopulmonary bypass are associated with a complexity of stress response leading to post-operative complications. Studies have confirmed that anesthesia can mitigate the surgically induced stress response. Objectives The aim of this study was to compare the effects of propofol and isoflurane, both supplemented with Sufentanil, on the stress response in coronary artery bypass graft surgery with cardiopulmonary bypass, using cortisol as a biochemical marker. Methods This double-blind randomized clinical trial was conducted on 72 patients who underwent coronary artery bypass grafting (CABG) with cardiopulmonary bypass meeting the inclusion criteria. The subjects were randomly divided into two groups of isoflurane (n = 36) and propofol (n = 36) both supplemented with sufentanil. Serum cortisol levels were measured and compared between the groups; 30 minutes before the surgery (T0), at the end of the cardiopulmonary bypass (T1), and 24 hours after the surgery (T2). Results Compared to the baseline (T0), at the end of cardiopulmonary bypass (T1), both groups demonstrated a decrease in plasma cortisol levels with no statistical significant difference (P = 0.4). At T2 measuring time point, the level of plasma cortisol significantly increased in both groups (P = 0.02), however this increase was less in the Isoflurane group. Conclusions In CABG with cardiopulmonary bypass, using plasma cortisol level as a measure, Isoflurane-Sufentanil significantly reduces the stress response to the surgery, when compared to propofol-Sufentanil.
Accuracy of Infrared Ear Thermometry in Children

Background. Accurate determination of temperature is important, especially in the diagnosis and treatment of febrile illnesses in the pediatric population. False negative measurement can lead to miss febrile and false positive measurement can cause excessive medical care. Temperatures can be measured at various sites, but we have not found the ideal thermometer yet. As a relatively new and popular alternative over traditional methods, infrared ear thermometry has many advantages, but its accuracy remains a major concern. Design. Systematic review and meta-analysis. Data Sources. Medline, Ovid, Elsevier, Google Scholar, Cochrane Library. Study Selection. Cross-sectional, prospective design. Data Extraction. Two investigators independently assessed selected studies and extracted data. Disagreements were resolved by discussion with other reviewers. Results. Mean tympanic temperature was always lower than rectal temperature. The overall pooled (random effects) mean difference between tympanic and rectal temperature was 0.22°C (95% limits of agreement −0.44°C to 1.30°C), which is similar to the within rectal device groups (mercury, 0.21°C, −0.44°C to 1.27°C; electronic, 0.24°C, −0.46°C to 1.34°C). In febrile children group, the pooled mean temperature difference between tympanic and rectal temperature was 0.15°C (95% limits of agreement −0.32°C to 1.10°C). Conclusion. The mean difference was large and the 95% limits of agreement was wide. The accuracy of infrared ear thermometry in children is poor, and it cannot replace rectal thermometry in clinical practice of children.
Interior immigration enforcement policy and the subjective well-being of US residents: evidence from secure communities

ABSTRACT There were increased efforts to enhance interior enforcement of immigration laws in the United States in recent years. Considering that more interior immigration enforcement measures are going to be proposed in the near future, there is a need to evaluate whether such policy can achieve its objective and imparts some benefits to the population it is supposed to help. In this article, I examine the impact of one of the largest interior immigration enforcement effort – Secure Communities – on the subjective well-being of US residents. The analyses show that there is no evidence that Secure Communities statistically significantly increased the proportion of white or black non-Hispanics reporting that they were satisfied with their life. Evaluated at the mean, at 10% significance level, the results suggest that I can rule out an effect size larger than 0.5% and 1% for white and black non-Hispanics, respectively. Since only a small share of white or black non-Hispanics are foreign-born, this finding suggests that the benefit of Secure Communities to US-born individuals that are coming through an increase in their life satisfaction is not economically large.