Miracle-dz/UniFAR-FTUs huggingface dataset:
Specific Inhibition of Nuclear Factor-κB–Dependent Inflammatory Responses by Cell Type-Specific Mechanisms upon A2A Adenosine Receptor Gene Transfer

Adenosine is a potent inhibitor of inflammatory processes, and the A2A adenosine receptor (A2AAR) plays a key nonredundant role as a suppresser of inflammatory responses in vivo. In this study, we demonstrate that increasing A2AAR gene expression suppressed multiple inflammatory responses in both human umbilical vein endothelial cells (HUVECs) and rat C6 glioma cells in vitro. In particular, the induction of the adhesion molecule E-selectin by either tumor necrosis factor α (TNFα) or Escherichia coli lipopolysaccharide (LPS) was reduced by more than 70% in HUVECs, whereas inducible nitric-oxide synthase (iNOS) induction was abolished in C6 cells after exposure to interferon-γ in combination with LPS and TNFα, suggesting that the receptor inhibited a common step in the induction of each of these pro-inflammatory genes. Consistent with this hypothesis, A2AAR expression inhibited the activation of NF-κB, a key transcription factor whose proper function was essential for optimal iNOS and E-selectin induction. However, although NF-κB binding to target DNA was severely compromised in both cell types, the mechanisms by which this occurred were distinct. In C6 cells, A2AAR expression blocked IκBα degradation by inhibiting stimulus-induced phosphorylation, whereas in HUVECs, A2AAR expression inhibited NF-κB translocation to the nucleus independently of any effect on IκBα degradation. Together, these observations suggest that A2AAR-mediated inhibition NF-κB activation is a critical aspect of its anti-inflammatory signaling properties and that the molecular basis of this inhibition varies in a cell type-specific manner.
System dynamics modelling and forecasting health tourism demand: the case of Russian resorts

This article presents the results of the system dynamics modelling of the regional market of health tourism in the Krasnodar region of Russia. The research was based on various indicators characterizing the supply and demand for this type of tourism for years 2006–2012. The medium-term forecast made by constructed model shows a possible decrease in number of health tourists and income of sanatorium organizations. Price competition of inexpensive foreign resorts was a key factor influencing the market of tourist services; therefore ruble devaluation to US dollar may improve the prognostic indicators.
A monoclonal antibody against tumour necrosis factor-alpha improves survival in experimental multiple organ dysfunction syndrome.

A single intraperitoneal administration of zymosan induces multiple organ dysfunction syndrome (MODS) in C57BL/6 mice. The authors investigated the effect of a monoclonal antibody V1q against murine tumour necrosis factor alpha (TNF-alpha) on the development of zymosan-induced MODS and on plasma concentrations and the production capacity of interleukin 6 (IL-6) by peritoneal cells. C57BL/6 mice received doses of V1q starting either simultaneously with administration of zymosan every four days, or from 4 or 8 days after administration of zymosan onwards. The animals were monitored for survival, condition, and body weight and temperature. Twelve days after zymosan all surviving animals were killed to obtain plasma, organs and peritoneal cells. Plasma concentrations of IL-6 and lipopolysaccharide-stimulated production of IL-6 by peritoneal cells were measured; organs were weighed as an indicator for organ damage and lung damage was assessed macroscopically. Survival improved when the animals were treated with V1q starting at either time point, and a subpopulation developed from the group receiving V1q from day 0 onwards that displayed improved body weight and temperature when compared to the animals receiving zymosan only. Also, the wet organ weights improved in this subgroup, indicating a beneficial effect of the monoclonal antibody. However, V1q administered could neither decrease the circulating IL-6 concentrations toward control values, nor did V1q treatment normalize IL-6 production capacity (stimulated or unstimulated). The development of zymosan-induced MODS can be attenuated by the monoclonal antibody V1q.
Completely video-assisted thoracoscopic lobectomy versus open lobectomy for non-small cell lung cancer greater than 5 cm: a retrospective study.

BACKGROUND Completely video-assisted thoracoscopic lobectomy is a reasonable treatment for early-stage non-small-cell lung cancer (NSCLC). At present, the indication for this procedure is stage Ia and Ib peripheral lung cancer (≤ 5 cm); however, for larger tumors, it remains controversial whether this surgical technique is comparable to open lobectomy. This study aimed to evaluate the safety, completeness, and efficacy of thoracoscopic lobectomy, and to compare this technique with open lobectomy for the treatment of non-small-cell lung cancer when the tumor's diameter was greater than 5 cm. METHODS From May 2001 to April 2011, 802 patients underwent a lobectomy for treatment of non-small-cell lung cancer at our center. In 133 patients, the tumor was > 5 cm. There were 98 men and 35 women, median age 63 years (range: 29 - 81 years). We divided the patients into two groups, group V (completely video-assisted thoracoscopic surgery), and group T (open lobectomy), and evaluated the two groups for age, gender, tumor size, pathological type, location, duration of surgery, blood loss, lymph node dissection, pathological stage, time of drainage, hospitalization, complications, overall survival and recurrence. RESULTS There were 46 cases in group V and 87 cases in group T. Age, gender, tumor size, location, pathological type and stage were similar between the two groups. Group V had shorter operative duration ((186.5 ± 62.8) minutes vs. (256.7 ± 67.5) minutes, P < 0.001) and reduced bleeding ((218.5 ± 174.6) ml vs. (556.9 ± 187.2) ml, P < 0.001). There were no significant differences between the two groups in complications, lymph node dissection, time of drainage and hospitalization. The recurrence between the two groups was equivalent (2.4% vs. 3.8%, P = 0.670). The overall survival at 1, 2 and 3 years was 95.1%, 81.6% and 69.6% for group V and 88.3%, 78.8% and 64.0% for group T. Kaplan-Meier survival curves showed that there was no significant differences between the two groups (P = 0.129). CONCLUSIONS Completely video-assisted thoracoscopic lobectomy was similar to open lobectomy in safety, completeness, and efficacy, but had a shorter operative duration, and reduced bleeding. This is a minimally invasive procedure that is feasible for a subset of non-small-cell lung cancer patients with tumor size > 5 cm.
In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants

Abstract Aims: We determined the association between short-term neonatal morbidities, such as bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH), and Ureaplasma spp. in amniotic fluid, placental and amniotic mem-brane of preterm infants. Methods: This study enrolled 257 patients who were born by cesarean section at <34 weeks’ gestation. Patients were divided into two groups according to detection of Ureaplasma spp. by culture-based and/or polymerase chain reaction (PCR) techniques. Results: Significant differences were observed between both groups for all IVH (P=0.032) and IVH grades III or IV (P=0.013), as wells as for BPD [odds ratio (OR) 5.46, 95% confidence interval (CI) 2.02–14.77], oxygen requirement at 28 days postnatal age (OR 1.93, 95% CI 1.00–3.70), and for death between 28 days and 36 postmenstrual weeks or BPD (OR 4.20, 95% CI 1.77–9.96). Ureaplasma spp. was a significant predictor (P<0.001) of BPD after correcting for birth weight (P=0.003) and positive pressure ventilation (P=0.001). Conclusions: In our study population Ureaplasma spp. was associated with BPD and IVH in preterm infants even after adjustment for multiple risk factors.
Preplanned initial safety analysis of ACTS-CC 02 trial: A large randomized phase III trial of SOX versus UFT/LV as adjuvant chemotherapy for high-risk stage III colon cancer.

572 Background: The ACTS-CC 02 trial is designed to verify the superiority of postoperative adjuvant chemotherapy of S-1/Oxaliplatin (SOX) for patients with anyT, N2 colon cancer compared with UFT/Leucovorin (UFT/LV), which is one of standard adjuvant chemotherapies in Japan. To date, there have been no reported phase III trials evaluating SOX as postoperative adjuvant chemotherapy. This report presents initial safety data obtained from 50 patients who received SOX in the trial. METHODS Patients who underwent curative resection for anyT, N2 colon cancer were randomly assigned to receive either SOX (100 mg/m2 of oxaliplatin on day1, and 80 to 120 mg/day according to body surface area (BSA) of S-1 on days 1-14, every 21 days, 8 courses) or UFT/LV (300 to 600 mg/day according to BSA of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 courses). Data were collected from initial consecutive 50 patients assigned to the SOX group and analyzed when they were considered evaluable for safety as planned in the protocol. This ongoing trial is designed to accrue 1200 patients. As of September 15, 2011, 319 patients have been accrued. RESULTS Of 50 patients assigned to receive SOX, 48 were evaluable for safety. The median number of treatment courses was 5 (range: 1-8). The relative dose intensity of S-1 was 83.8% and that of oxaliplatin was 86.6%. Grade 3 adverse events were neutropenia (14.6%), thrombocytopenia (2.1%), ALT elevation (2.1%), diarrhea (8.3%), fatigue (2.1%), and peripheral sensory neuropathy (2.1%). Grade 4 adverse effects were not observed. CONCLUSIONS In this initial safety analysis, the incidence and severity of adverse events with SOX were acceptable in patients with high risk stage III colon cancer after curative resection. Enrollment of patients is ongoing.
Looking through the eyes of fungi: molecular genetics of photoreception

Filamentous fungi respond to a variety of environmental signals. One of them is light, providing critical information about orientation, or impending stress. Cells of filamentous fungi appear to sense blue light through a unique transcription factor that has a flavin chromophore and activates its targets in a light‐dependent manner, the white collar (WC) complex. Fungal photophysiology, though, predicted a greater complexity of responses to the whole visible spectrum. The rapidly growing fungal genome database provides candidates to explain how fungi see not only blue, but also near‐UV, green and red light. At the same time, there are surprises in the genomes, including photoreceptors for which there are no obvious photoresponses. Linking these genes and their functions will help understand how a list of only a few biological chromophores accounts for such a diversity of responses. At the same time, deeper mechanistic understanding of how the WC complex functions will lead to fundamental insights at the point where the environment impinges, in this case in the form of photons, on the transcriptional machinery of the cell.
Smoking and the Microbiome in the Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, destructive, inflammatory, polyarticular joint disease, characterized by infiltration of inflammatory cells, followed by the destruction of cartilage and bone [1]. Inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and interleukin-1 (IL-1) as well as chemokines such as pulmonary and activation-regulated chemokine /CCL18 and monocyte chemoattractant protein-4 /CCL13 play important roles in the pathogenesis of RA. These cytokines have emerged as important pro-inflammatory mediators and dominant molecular targets for the therapeutic strategies [2]. The nuclear factor κB (NF-κB) family of transcriptional activators regulates the expression of a variety of cytokines involved in the pathology of RA, including TNFα, IL-6 and IL-1 [3]. Thus, NF-κB is also an important target of RA treatment [4].
Gender bias in the diagnosis of COPD.

BACKGROUND COPD is thought to be more prevalent among men than women, a finding usually attributed to higher smoking rates and more frequent occupational exposures of significance for men. However, smoking prevalence has increased among women and there is evidence that women may be more susceptible to the adverse pulmonary function effects of smoking than men. There may also be underdiagnosis and misdiagnosis of COPD in both sexes because objective measures of lung function are underused. OBJECTIVES We undertook the present study to determine if there is gender bias in the diagnosis of COPD, such that women are less likely than men to receive a diagnosis of COPD. We also attempted to determine if underuse of lung function measurements was a factor in any bias detected. METHODS We surveyed a random sample of 192 primary-care physicians (96 American and 96 Canadian; 154 men and 38 women) using a hypothetical case presentation and a structured interview. The case of cough and dyspnea in a smoker was presented in six versions differing only in the age and sex of the patient. After presentation of the history and physical findings, physicians were asked to state the most probable diagnosis and to choose the diagnostic studies needed. Physicians were then presented with spirometric findings of moderate or severe obstruction without significant bronchodilator response, and the questions repeated. Finally, the negative outcome of an oral steroid trial was described. RESULTS Initially, COPD was given as the most probable diagnosis significantly more often for men than women (58% vs 42%; p < 0.05). The likelihood of a COPD diagnosis increased significantly and initial differences between sexes decreased as objective information was provided. After spirometry, COPD diagnosis rates for men and women were 74% vs 66% (p = not significant); after the steroid trial 85% vs 79% (p = not significant). Only 22% of physicians would have requested spirometry after the initial presentation. CONCLUSIONS In North America, primary-care physicians underdiagnosed COPD, particularly in women. Spirometry reduces the risk of underdiagnosis and gender bias but is underused.
Viral gene expression and pathogenesis in three emerging diseases: HIV and AIDS; HTLV-I and HAM/TSP; and HHV-8 and Kaposi's sarcoma.

Recent studies of the pathogenesis of three emerging diseases will be used to illustrate unifying concepts regarding mechanisms of viral persistence and disease expression. Two of these diseases, acquired immunodeficiency syndrome (AIDS) and the slowly progressive disease referred to as HTLV-I-associated myelopathy (HAM) or tropical spastic paraparesis (TSP), are caused by retroviruses, and the third disease, Kaposi's sarcoma (KS), has been linked recently to a new herpesvirus. Results of investigations of these diseases in our laboratory using quantitative methods to detect viral gene expression at the cellular level in tissue sections will be used to illustrate strategies that allow viruses to persist unrecognized for years, decades, or even millennia, and emerge without warning as important human pathogens [1–3]. Fig. 1, which depicts the life cycle of human immunodeficiency virus (HIV), provides a framework for this discussion. It illustrates the two phases of retroviral replication: the productive or activated phase and the chronic or latent phase. The genome of the infecting virus is processed by reverse transcription which transfers the genetic information to double-stranded linear DNA that becomes known as the provirus after its integration into the host chromosome. The expression of proviral genes is a critical control point somewhat analogous to a spigot. If the spigot is open, the infection is in a productive and activated state, and the virus goes on to produce RNA. Tens of thousands of copies of the viral proteins and thousands of viral particles are made. When that spigot is turned down, only a trickle of genetic information is expressed — a defining characteristic of chronic persistent infection, as I will show — and little or no virus may be produced. I am going to discuss the outcomes of studies that put these two phases under the microscope, using single-cell technologies …
Co‐vaccination with adeno‐associated virus vectors encoding human papillomavirus 16 L1 proteins and adenovirus encoding murine GM‐CSF can elicit strong and prolonged neutralizing antibody

Non‐infectious human papillomavirus‐like particles (VLPs), encoded by the major capsid gene L1, have been shown to be effective as vaccines to prevent cervical cancer. We have developed the genetic immunization of the L1 gene to induce a neutralizing antibody. We constructed and generated a recombinant adeno‐associated virus encoding human papillomavirus (HPV) 16 L1 protein that could form virus‐like particles in transduced cells. Previous reports have demonstrated that the formation of VLP is necessary to induce high titers of neutralizing antibodies to protect an animal from viral challenge. Therefore, we carried out a single intramuscular (i.m.) injection with recombinant adeno‐associated virus encoding HPV‐16 L1 protein (rAAV‐16L1) in BALB/c mice, which ultimately produced stronger and more prolonged neutralizing L1 antibodies, when compared to the DNA vaccine. Immunohistochemistry showed that the accumulation of antigen presenting cells, such as macrophages and dendritic cells, in rAAV‐16L1 and L1 DNA‐injected muscle fibers may be due to the L1 protein expression, but not to AAV infection. When compared to the L1 VLP vaccine, however, the titers of neutralizing L1 antibodies induced by VLP were higher than those induced by rAAV‐16L1. Co‐vaccinating with rAAV‐16L1 and adenovirus encoding murine GM‐CSF (rAAV‐16L1/rAd‐mGM‐CSF) induced comparable higher levels of neutralizing L1 antibodies with those of VLP. This implies that a single i.m. co‐injection with rAAV‐16L1/rAd‐mGM‐CSF can achieve the same vaccine effect as a VLP vaccine requiring 3 booster injections.
Work of breathing and sleep pattern behavior in COPD. How much oxygen or high-flow nasal cannula?

to the editor: We read the article by Biselli et al. ([1][1]) carefully and congratulate the authors on their original research about the use of high-flow nasal cannula (HFNC) in patients with chronic obstructive pulmonary disease (COPD) during sleep. HFNC oxygen is an emerging technique in
Prevalence of osteoporosis in women: variation with skeletal site of measurement of bone mineral density.

OBJECTIVE To determine retrospectively the prevalence of osteoporosis in a referral population of female patients and to compare the sensitivity for diagnosing osteoporosis by dual-energy x-ray absorptiometry (DXA) measurements of bone mineral density (BMD) at multiple skeletal sites. METHODS We studied the data from 625 consecutive women (mean age, 57.3 +/- 13.9 years), who had been referred to our center for lumbar spine (anteroposterior [AP] and lateral region) and hip (femoral neck [FN], Ward's triangle [WT], trochanter, intertrochanteric region, and total hip) BMD measurements with use of DXA (Hologic QDR-2000) between June 1994 and July 1998. RESULTS Osteoporosis (based on the World Health Organization definition--T-score of -2.5 or lower for BMD) was diagnosed by DXA at the following sites: AP spine in 21.7%, lateral spine in 43.2%, FN in 33.6%, WT in 49.1%, trochanter in 26.1%, intertrochanteric region in 25.9%, and total hip in 28.4% of study patients. Significant site differences were found in the prevalence of osteoporosis between the lateral and AP spine (P < 0.001), as well as between WT and the FN, trochanter, intertrochanteric region, and total hip (P < 0.001). In a subgroup of 71 women, forearm (ultradistal radius and radius 1/3 region) BMD results indicated low sensitivity for diagnosing osteoporosis, similar to that seen at the AP spine, trochanter, and intertrochanteric region. Not surprisingly, the prevalence of osteoporosis increased with advancing age (15.5% in patients younger than 50 years, in comparison with 59.6% in those older than 69 years of age). The frequency of misclassification of patients (osteoporosis at one site and normal BMD at another) with use of the seven measurement sites was 16.6% (104 of the 625 patients). CONCLUSIONS For diagnosis of osteoporosis, DXA BMD measurements are significantly more sensitive at the lateral spine than at the AP spine, as well as at WT than at the FN, trochanter, intertrochanteric region, and total hip sites.
Modulation of cardiac CaV1.2 channels by dihydropyridine and phosphatase inhibitor requires Ser-1142 in the domain III pore loop

Dihydropyridine-sensitive, voltage-activated calcium channels respond to membrane depolarization with two distinct modes of activity: short bursts of very short openings (mode 1) or repetitive openings of much longer duration (mode 2). Here we show that both the dihydropyridine, BayK8644 (BayK), and the inhibitor of Ser/Thr protein phosphatases, okadaic acid, have identical effects on the gating of the recombinant cardiac calcium channel, CaV1.2 (α1C). Each produced identical mode 2 gating in cell-attached patches, and each prevented rundown of channel activity when the membrane patch was excised into ATP-free solutions. These effects required Ser or Thr at position 1142 in the domain III pore loop between transmembrane segments S5 and S6, where dihydropyridines bind to the channel. Mutation of Ser-1142 to Ala or Cys produced channels with very low activity that could not be modulated by either BayK or okadaic acid. A molecular model of CaV1.2 indicates that Ser-1142 is unlikely to be phosphorylated, and thus we conclude that BayK binding stabilizes mode 2 gating allosterically by either protecting a phospho Ser/Thr on the α1C subunit or mimicking phosphorylation at that site.
Mitigating Interest Rate Risk in Variable Annuities: An Analysis of Hedging Effectiveness under Model Risk

ABSTRACT Variable annuities are investment vehicles offered by insurance companies that combine a life insurance policy with long-term financial guarantees. These guarantees expose the insurer to market risks, such as volatility and interest rate risks, which can be managed only with a hedging strategy. The objective of this article is to study the effectiveness of dynamic delta-rho hedging strategies for mitigating interest rate risk in variable annuities with either a guaranteed minimum death benefit or guaranteed minimum withdrawal benefit rider. Our analysis centers on three important practical issues: (1) the robustness of delta-rho hedging strategies to model uncertainty, (2) the impact of guarantee features (maturity versus withdrawal benefits) on the performance of the hedging strategy, and (3) the importance of hedging interest rate risk in either a low and stable or rising interest rate environment. Overall, we find that the impact of interest rate risk is equally felt for the two types of products considered, and that interest rate hedges do lead to a significant risk reduction for the insurer, even when the ongoing low interest rate environment is factored in.