Week 2 Adalimumab Levels Predict Short-term Clinical Remission in Patients With Inflammatory Bowel Disease.

BACKGROUND AND GOALS: The role of early proactive therapeutic drug level monitoring for anti-tumor necrosis factor therapies is unclear. We aimed to determine whether a week 2 serum trough level in patients with inflammatory bowel disease (IBD) using adalimumab may predict clinical outcomes. MATERIALS AND METHODS: This was a retrospective study of consecutive IBD patients with a week 2 serum adalimumab level available. Receiver operating characteristic curve analysis was conducted to determine an optimal week 2 threshold level for adalimumab. Patients above the threshold were compared for the primary outcome of week 12 clinical remission (CR) and the secondary outcome of short-term endoscopic healing. Multivariate logistic regression analysis was performed to evaluate the relationship between week 2 adalimumab level and CR. RESULTS: Forty-six patients had a week 2 adalimumab level performed. Receiver operating characteristic curve analysis suggested an optimal adalimumab level of 11.9 mcg/mL based on the area under the curve. Patients with week 2 adalimumab levels >11.9 mcg/mL had higher odds of week 12 CR than those with levels below or equal to this threshold (odds ratio=3.34, 95% confidence interval: 1.01-12.11, P =0.04). Other covariates were not found to have a significant association with the primary outcome. The rate of short-term endoscopic healing was numerically higher in patients with adalimumab week 2 levels above 11.9 mcg/mL; however, was not statistically significant (71.4% vs. 28.5%, P =0.11). CONCLUSIONS: Serum adalimumab levels at week 2 appears to be a predictor of short-term CR. Further research should explore whether patients with a week 2 adalimumab level equal to or below 11.9 mcg/mL benefit from early dose optimization.

Low Socioeconomic Status but Resilient: Panacea or Double Trouble? John Henryism in the International IMIAS Study of Older Adults.

John Henry (JH) theory provides a framework for understanding the physiological toll exerted on low socioeconomic status (SES) individuals as they overcome psychosocial stressors imposed by their environments. This theory suggests that resilience, a seemingly positive social adaptation, may in fact be physically deleterious. JH theory has been well-described in low-SES rural male African Americans, however it is currently unclear whether validity of this theory extends to women, other races and outside the rural US. We assessed whether, in individuals with low income, there is an association between self-mastery/resilience and either blood pressure or depressive symptoms that is different from the association seen in individuals with higher income. Data were obtained from 1353 older men and women participants of the International Mobility in Aging Study (IMIAS). Across 3 countries and 4 sites, higher self-mastery/resilience was associated with lower depressive symptoms in both low and high income groups. In low income individuals from Saint-Hyacinthe, Québec, higher self-mastery/resilience was associated with both higher mean systolic blood pressure (n = 240, ß = 0.135, p ≤ 0.05) and higher mean diastolic blood pressure (n = 240, ß = 0.241, p ≤ 0.0001). In the high income group of Saint-Hyacinthe, no such associations were observed. The findings in the Saint-Hyacinthe cohort (but not the other settings), are consistent with the John Henry hypothesis, and demonstrates this effect extends beyond a rural African American population. This finding indicates that in certain populations, the positive psychological effects of resilience come with a cost to physical health.

The Circular RNA Interacts with STAT3, Increasing Its Nuclear Translocation and Wound Repair by Modulating Dnmt3a and miR-17 Function.

Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.

Inhibition of Dexamethasone-induced Fatty Liver Development by Reducing miR-17-5p Levels.

Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisome proliferator-activated receptor-α (PPAR-α) dysregulation. Through examining the effect of PPAR-α on fatty liver development, we found that PPAR-α is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-α. Ectopic expression of miR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-α as a target of miR-17-5p. On the other hand, PPAR-α bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-5p and PPAR-α played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-α expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-α expression while decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients.

Anti-microRNA-378a enhances wound healing process by upregulating integrin beta-3 and vimentin.

Delayed or impaired wound healing is a major public health issue worldwide, especially in patients with diabetes mellitus and vascular atherosclerosis. MicroRNAs have been identified as key regulators of wound healing. Here, we show that miR-Pirate378a transgenic mice (and thus have inhibited miR-378a-5p function) display enhanced wound healing. Expression of vimentin and ß3 integrin, two important modulators of wound healing, is markedly elevated in the transgenic mice. MiR-Pirate378a-transfected cells display greater mobility during migration assays, which was hypothesized to be due to the upregulation of vimentin and ß3 integrin. Both molecules were confirmed to be targets of miR-378a, and thus their expression could be rescued by miR-Pirate378a. Overexpression of vimentin also contributed to fibroblast differentiation, and upregulation of ß3 integrin was responsible for increased angiogenesis. Mice treatment with miR-Pirate378a-conjugated nanoparticles displayed enhanced wound healing. Thus, we have demonstrated that knockdown of miR-378a increased the expression of its target proteins, vimentin, and ß3 integrin, which accelerated fibroblast migration and differentiation in vitro and enhanced wound healing in vivo.

Fecal microbiota transplantation: in perspective.

There has been increasing interest in understanding the role of the human gut microbiome to elucidate the therapeutic potential of its manipulation. Fecal microbiota transplantation (FMT) is the administration of a solution of fecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient's gut microbial composition and confer a health benefit. FMT has been used to successfully treat recurrent Clostridium difficile infection. There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders.

MicroRNA-17 inhibits tumor growth by stimulating T-cell mediated host immune response.

BACKGROUND: Melanoma is one of the fastest-rising types of cancer in North American. Accumulating evidence suggests that anti-tumor immune tolerance plays a critical role in tumor development. METHODS: B16 melanoma cells were injected into wild type and miR-17 overexpressing transgenic mice. Tumor growth was monitored and tumor bearing mice were sacrificed by the end of the forth week. Peripheral blood and spleen cells were subject to flow cytometry analysis and tumor samples were subject to immunohistochemistry staining. Meanwhile, Jurkat cells transfected with mock-control or miR-17 overexpressing plasmid were co-cultured with B16 cells. The influence of miR-17 on cell cycle, proliferation and survival was evaluated. RESULTS: The melanoma tumors formed in mice overexpressing miR-17 were less than that in wild type mice. In addition, the miR-17 tumors were less invasive and less angiogenic. The percentage of CD8+ T cells was suppressed in miR-17 transgenic mice before melanoma cell injection. Its level was significantly increased upon tumor grafting. More tumor infiltrating CD8+ cytotoxic T lymphocyte could be found in transgenic mice with tumor formation. Luciferase assay and protein analysis indicated that STAT3 was the target of miR-17. Decreased levels of STAT3 were associated with miR-17 over-expression. Down-regulation of STAT3 in Jurkat cells promoted cell proliferation and mitosis. CONCLUSIONS: MiR-17 inhibits melanoma growth by stimulating CD8+ T cells mediated host immune response, which is due to its regulation of STAT3.

Temperature and pressure based NMR studies of detergent micelle phase equilibria.

Bulk thermodynamic and volumetric parameters (ΔGmic°, ΔHmic°, ΔSmic°, ΔCp,mic°, ΔVmic°, and Δκmic°) associated with the monomer­micelle equilibrium, were directly determined for a variety of common detergents [sodium n-dodecyl sulfate (SDS), n-dodecyl phosphocholine (DPC), n-dodecyl-ß-d-maltoside (DDM), and 7-cyclohexyl-1-heptyl phosphocholine (CyF)] via 1H NMR spectroscopy. For each temperature and pressure point, the critical micelle concentration (cmc) was obtained from a single 1H NMR spectrum at a single intermediate concentration by referencing the observed chemical shift to those of pure monomer and pure micellar phases. This permitted rapid measurements of the cmc over a range of temperatures and pressures. In all cases, micelle formation was strongly entropically favored, while enthalpy changes were all positive, with the exception of SDS, which exhibited a modestly negative enthalpy of micellization. Heat capacity changes were also characteristically negative, while partial molar volume changes were uniformly positive, as expected for an aggregation process dictated by hydrophobic effects. Isothermal compressibility changes were found to be consistent with previous measurements using other techniques. Thermodynamic measurements were also related to spectroscopic studies of topology and micelle structure. For example, paramagnetic effects resulting from the addition of dioxygen provided microscopic topological details concerning the hydrophobicity gradient along the detergent chains within their respective micelles as detected by 1H NMR. In a second example, combined 13C and 1H NMR chemical shift changes arising from application of high pressure, or upon micellization, of CyF provided site-specific details regarding micelle topology. In this fashion, bulk thermodynamics could be related to microscopic topological details within the detergent micelle.