To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy.

There is considerable evidence that hypertension may increase the levels of cytokines via endothelial stimulation and may stimulate inflammatory reactions. The purpose of this study was to evaluate the effect of oral coenzyme Q10 supplementation on pro-inflammatory factors and adiponectin in mildly hypertensive patients.

Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD.

Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to patients treated with exemestane. Additionally, we assessed the added value of metformin as this drug may lower IGF1R stimulation.

Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed.

The beneficial effects of omega-3 polyunsaturated fatty acids on lipid levels are well documented. However, the related molecular mechanisms are widely unknown. Omega-3 polyunsaturated fatty acids are natural ligand for peroxisome proliferator-activated receptor γ (PPARγ).

This study was conducted to evaluate microRNAs (miRNAs) as biomarkers for use in predicting the efficacy of maintenance therapy with pemetrexed in patients with stage IIIb or IV lung adenocarcinoma and who had already received first-line treatment with pemetrexed plus platinum. Patients who were negative for epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations were assigned to a pemetrexed group and an observation group. Patients in the pemetrexed group (n = 76) received maintenance treatment with pemetrexed (500 mg/m(2), once every 21 days) plus best supportive care. Patients in the observation group (n = 72) agreed to receive only best supportive care until disease progression. Blood samples were collected from all patients in both groups before treatment and were used to detect expression levels of various miRNAs in serum by the Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method. The expression levels of miR-25, miR-145, and miR-210 were significantly different in the 2 groups of patients. Furthermore, the median progression-free survival (PFS) times for patients in the pemetrexed and observation groups were 4.5 and 2.9 months, respectively. The PFS times among patients in the pemetrexed group varied significantly and were related to patient expression levels of miR-25, miR-145, and miR-210, whereas patients in the observation group showed no differences in PFS time. Our data suggest miR-25, miR-145, and miR-210 as predictors for the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who were negative for EGFR mutations or ALK translocations.

T-2 and HT-2 toxins belong to mycotoxins which are found in human foods and animal chow. We investigated the toxicity and oxidative stress induced by T-2/HT-2 in broilers and chicken hepatocytes. Maize cultures of Fusarium poae was fed to broilers for 42 d, and the physiological index, biochemical index and expression of mRNAs related to oxidative stress were analyzed. Chicken hepatocytes were treated with different levels of T-2/HT-2, and the following parameters were detected: cell viability, GSH and MDA concentration, LDH leakage, activities of ALT/AST, ROS, GSH-PX, SOD and CAT, and expression of mRNA related to oxidative stress. In vivo, high levels of mycotoxins (4 mg/kg T-2 and 0.667 mg/kg HT-2) in feed caused significant reductions in body weight, weight gain, and serum total protein, and significant increases in feed conversion ratio, ALP, ALT/AST activities, and expression of mRNA related to oxidative stress. In vitro, cells treated with T-2/HT-2 showed reductions of GSH concentration and significant increases in LDH leakage, ALT/AST ROS, GSH-PX, SOD and CAT activities, MDA concentration, and expression of mRNA related to oxidative stress. Consequently, F. poae culture material and T-2/HT-2 induced toxicity and oxidative stress in vivo and in vitro, respectively.

The duration of immunosuppressive effects following oral cyclosporine in dogs is unknown. This study used flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to evaluate the effects of high-dose oral cyclosporine across a 12-h dosing interval. Expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) was compared before and after 8 days of cyclosporine at 10 mg/kg every 12 h in six healthy dogs. Samples were collected at 0, 2, 4, and 8 h postdosing for analysis of unactivated and activated T-cell and whole blood cytokine expression using flow cytometry and qRT-PCR, respectively, and at 0, 2, 4, 6, 8, and 10 h postdosing for measurement of cyclosporine concentrations. Flow cytometry and qRT-PCR both demonstrated significant marked reductions in IL-2 and IFN-γ levels at 0, 2, 4, and 8 h after dosing compared to pretreatment levels (P < 0.05) for activated samples, with less consistent effects observed for unactivated samples. Both flow cytometry and qRT-PCR are viable techniques for measuring cyclosporine pharmacodynamics in dogs, yielding comparable results with activated samples. Two hours postdrug administration is the preferred time for concurrent assessment of peak drug concentration and cytokine expression, and T-cell activation is needed for optimal results.

ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development.

Cimaglermin (neuregulin 1β3, glial growth factor 2) is a neuregulin growth factor family member in clinical development for chronic heart failure. Previously, in a permanent middle cerebral artery occlusion (pMCAO) rat stroke model, systemic cimaglermin treatment initiated up to 7 days after ischemia onset promoted recovery without reduced lesion volume. Presented here to extend the evidence are two studies that use a rat stroke model to evaluate the effects of cimaglermin dose level and dose frequency initiated 24 hr after pMCAO. Forelimb- and hindlimb-placing scores (proprioceptive behavioral tests), body-swing symmetry, and infarct volume were compared between treatment groups (n = 12/group). Possible mechanisms underlying cimaglermin-mediated neurologic recovery were examined through axonal growth and synapse formation histological markers. Cimaglermin was evaluated over a wider dose range (0.02, 0.1, or 1.0 mg/kg) than doses previously shown to be effective but used the same dosing regimen (2 weeks of daily intravenous administration, then 1 week without treatment). The dose-frequency study used the dose-ranging study's most effective dose (1.0 mg/kg) to compare daily, once per week, and twice per week dosing for 3 weeks (then 1 week without treatment). Dose- and frequency-dependent functional improvements were observed with cimaglermin without reduced lesion volume. Cimaglermin treatment significantly increased growth-associated protein 43 expression in both hemispheres (particularly somatosensory and motor cortices) and also increased synaptophysin expression. These data indicate that cimaglermin enhances recovery after stroke. Immunohistochemical changes were consistent with axonal sprouting and synapse formation but not acute neuroprotection. Cimaglermin represents a potential clinical development candidate for ischemic stroke treatment.

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Minimizing the decrease in intracellular pH during high-intensity exercise training promotes greater improvements in mitochondrial respiration. This raises the intriguing hypothesis that pH may affect the exercise-induced transcription of genes that regulate mitochondrial biogenesis. Eight males performed 10x2-min cycle intervals at 80% VO2speak intensity on two occasions separated by ~2 weeks. Participants ingested either ammonium chloride (ACID) or calcium carbonate (PLA) the day before and on the day of the exercise trial in a randomized, counterbalanced order, using a crossover design. Biopsies were taken from the vastus lateralis muscle before and after exercise. The mRNA level of peroxisome proliferator-activated receptor co-activator 1α (PGC-1α), citrate synthase, cytochome c and FOXO1 was elevated at rest following ACID (P<0.05). During the PLA condition, the mRNA content of mitochondrial- and glucose-regulating proteins was elevated immediately following exercise (P<0.05). In the early phase (0-2 h) of post-exercise recovery during ACID, PGC-1α, citrate synthase, cytochome C, FOXO1, GLUT4, and HKII mRNA levels were not different from resting levels (P>0.05); the difference in PGC-1α mRNA content 2 h post-exercise between ACID and PLA was not significant (P = 0.08). Thus, metabolic acidosis abolished the early post-exercise increase of PGC-1α mRNA and the mRNA of downstream mitochondrial and glucose-regulating proteins. These findings indicate that metabolic acidosis may affect mitochondrial biogenesis, with divergent responses in resting and post-exercise skeletal muscle.

The objective of this study was to investigate the effects of immunological challenge on the skeletal muscle fiber type conversion of piglets. Sixteen Large White weaned barrows (28 ± 3 d, 8.22 ± 0.89 kg BW) were allotted by weight and litter to 2 groups: the control group and the lipopolysaccharide (LPS) group. Saline (control) or LPS was injected intravenously via a jugular catheter on d 1, 3, 5, 7, 9, 11, 13, and 15 at an initial dosage of 80 μg/kg BW, which was increased by 30% at each subsequent injection. Blood samples were collected via the jugular catheter 3 h after the LPS challenge on d -1, 1, 5, 9, and 13. Muscle tissue samples were collected from the LM after exsanguination on d 15. The LPS challenge increased the plasma IL-6, tumor necrosis factor-α (TNF-α), cortisol, IL-1β, and haptoglobin concentrations on d 1 and 5 ( < 0.01) and increased the plasma IL-6 ( < 0.05), TNF-α ( < 0.05), and haptoglobin ( < 0.01) levels on d 9. Compared with that of the control group, the ADG of the LPS group decreased by 40.00% ( < 0.01), 29.52% ( < 0.05), and 19.30% ( < 0.05), and the ADFI decreased by 25.09% ( < 0.01), 23.15% ( < 0.05), and 19.47% ( < 0.05) during d 1 to 4, d 5 to 8, and d 9 to 15, respectively. In the LM of LPS-challenged piglets, myosin heavy chain 1 (MyHC1) mRNA and protein expression tended to be reduced ( = 0.08, 0.09), whereas mRNA, mRNA, and MyHC2 protein expression increased ( < 0.05). The LPS challenge reduced succinic dehydrogenase (SDH) activity ( < 0.05) and increased lactate dehydrogenase (LDH) activity ( < 0.05) in the LM of piglets. Compared with those in the control group, transcriptional peroxisome proliferator-activated receptor coactivator-α () mRNA ( < 0.05), calcineurin (CaN) mRNA, and protein expression were reduced ( < 0.05), and PGC-α protein expression tended to be reduced ( = 0.08) in the LM of LPS-challenged piglets. These results show that immunological challenge induced by LPS resulted in a shift from type I to type II fibers in the LM of piglets, which may be mediated by the downregulation of the CaN/PGC-α signaling pathway.

International Normalized Ratio (INR) is currently used to monitor vitamin K antagonist therapy, and the bleeding incidence becomes exponential for INR>4.5. Inversely, more than 50% of patients with a supratherapeutic INR are asymptomatic. Therefore it could be of interest to identify patients with a higher bleeding risk. Microparticles derived from different cell types express procoagulant phospholipids (PPL) which can be evaluated by a chronometric coagulation assay where a shortening of the clotting times is associated with increased levels of PPL. In a series of 174 consecutive patients referred to our Emergency Department with an INR>5, median level of PPL was significantly (p=0.004) lower (38.2s) in the 119 asymptomatic patients than in patients with nonmajor (43.6s, n=35) or major bleeding (46.6s, n=19), indicating higher levels of procoagulant phospholipids in asymptomatic patients. By receiver operating characteristic curve analysis, a cut-off of 43.5s discriminated patients with higher haemorrhagic risk (area under the curve=0.648). In contrast, thrombomodulin levels, quantified either by immunological or functional assays were not significantly different between both groups. In conclusion, evaluation of PPL could be of interest to define the haemorrhagic risk of VKA- treated patients.

In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an investigational drug for acute myocardial infarction (MI) at clinical trial, obtained from healthy male subjects with molecular activity profiles in the Connectivity Map. We identified dyphilline, an FDA-approved drug for bronchial asthma, as a top ranked connection with LC28-0126. Subsequently, we demonstrated that LC28-0126 effectively ameliorates the pathophysiology of neutrophilic bronchial asthma in OVALPS-OVA mice accompanied with a reduction of inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), inhibition of the release of proinflammatory cytokines, relief of airway hyperactivity, and improvement of histopathological changes in the lung. Taken together, we suggest that LC28-0126 could be a potential therapeutic for bronchial asthma. In addition, this study demonstrated the potential general utility of computational drug repositioning using clinical profiles of the investigational drug.

In the present study we introduced a two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry-based proteomic workflow to identify proteins that show altered expression as a result of the addition of 2% of water extract of inulin-type fructans to the diet of growing piglets. This analysis allowed us to detect an average of 240 spots per gel with a mass range from 10 to 250 kDa and a pH ranging from 3 to 10. Twenty protein spots were found to show statistically significant differences in their expression. Of these, 7 protein spots were up-regulated, whereas 13 showed down-regulation in response to the experimental diet. In total, 13 spots were identified, representing 8 distinct gene products. The experimental diet caused a significant change in proteins directly or indirectly involved in hemostasis and the innate immune response. Increased levels of fibrinogen along with decreased plasminogen expression may indicate that a fructan-rich diet favours the deposits of fibrin and promotes blood clotting. We also found increased expression of vitronectin and the alpha subunit of the complement component C8 which may protect the host organism against excessive cytolitic activity of the activated complement. The piglets from the experimental group had slightly increased values of IgG and IgA, whereas the IgM level tended to be decreased. The fructan-rich diet did not have any influence on plasma total cholesterol, HDL and LDL cholesterol and triglyceride levels.

This open-label, randomized, parallel-group comparative study compared the efficacy of rosuvastatin (5mg/day) and atorvastatin (10mg/day) for reduction of small dense low-density lipoprotein cholesterol (sd LDL-C) levels in Japanese patients with type 2 diabetes mellitus (T2DM).

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 dose-escalation study.

Follicular dendritic cell-secreted protein (FDC-SP) has been found to be expressed in periodontal ligament (PDL), a layer of soft connective tissue between tooth root and alveolar bone, and involved in immunoreaction. This study was performed to explore the potential role of FDC-SP in periodontal disease.