Analysis of expression profiling data suggests explanation for difficulties in finding biomarkers for nasal polyps.

BACKGROUND: Identification of clinically useful biomarkers for Nasal Polyposis in chronic rhinosinusitis (CRSwNP) has proven dif-ficult. We analyzed gene expression profiling data to find explanations for this. METHODS: We analyzed mRNA expression profiling data, GSE36830, of six uncinate tissues from healthy controls and six NP from CRSwNP patients. We performed Ingenuity Pathway Analysis (IPA) of differentially expressed genes to identify pathways and predicted upstream regulators. RESULTS: We identified 1,608 differentially expressed genes and 177 significant pathways, of which Th1 and Th2 activation pathway and leukocyte extravasation signaling were most significant. We identified 75 upstream regulators whose activity was predicted to be upregulated. These included regulators of known pathogenic and therapeutic relevance, like IL-4. However, only seven of the 75 regulators were actually differentially expressed in NP, namely CSF1, TYROBP, CCL2, CCL11, SELP, ADORA3, ICAM1. Interes-tingly, these did not include IL-4, and four of the seven were receptors. This suggested a potential explanation for the discrepancy between the predicted and observed expression levels of the regulators, namely that the receptors, and not their ligands, were upregulated. Indeed, we found that 10 receptors of key predicted upstream regulators were upregulated, including IL4R. CONCLUSION: Our findings indicate that the difficulties in finding specific biomarkers for CRSwNP depend on the complex underly-ing mechanisms, which include multiple pathways and regulators, each of which may be subdivided into multiple components such as ligands, soluble and membrane-bound receptors. This suggests that combinations of biomarkers may be needed for CRSwNP diagnostics.

Erythrocyte sedimentation rate measured using microhemagglutination is not elevated in monoclonal gammopathy compared with other diseases.

BACKGROUND: The erythrocyte sedimentation rate (ESR) as measured using the Westergren method is extremely elevated in patients with monoclonal gammopathy (MG) owing to the abundance of positively charged paraproteins. However, it has not been determined if the ESR is likewise high in patients with MG when measured using alternate ESR methods. METHODS: The ESR was measured using both the modified Westergren and microhemagglutination method (TEST1) in 36 patients with MG and in 159 individuals with other diseases. RESULTS: Erythrocyte sedimentation rates measured by the Westergren vs microhemagglutination methods showed substantial, but not remarkably high correlation. ESR measured using the Westergren method was higher in MG than in non-MG patients; however, ESR measured using microhemagglutination was not different in the 2 groups, resulting in a larger ΔESR (microhemagglutination ESR-Westergren ESR) in MG patients. When considered as continuous variables, none of the tested interfering plasma proteins (C-reactive protein, globulin, or fibrinogen) showed substantial correlations with Westergren or microhemagglutination ESRs. MG and low hematocrit were the only factors independently associated with ΔESR on multivariate analysis. CONCLUSION: We demonstrated, for the first time, that the ESR as measured by microhemagglutination is not elevated in patients with MG compared with those without. The ESR does not correlate with a particular plasma protein, showing that its measurement is multifactorial. The presence of MG is an independent factor for ΔESR.

Comparison of robotic and coblation tongue base resection for obstructive sleep apnoea.

OBJECTIVES: To compare the efficacy and safety of transoral robotic surgery (TORS) with endoscope-guided coblation tongue base resection. DESIGN: Retrospective case-control study. SETTING: University-based tertiary care medical center. PARTICIPANTS: Patients with obstructive sleep apnoea (OSA) who underwent endoscope-guided tongue base coblation resection or transoral robotic surgery (TORS) in combination with lateral pharyngoplasty at a single institution in South Korea between April 2013 and December 2016 were investigated. Forty-five patients who had moderate-to-severe OSA with tongue base collapse and a minimum follow-up period of 6 months with postoperative polysomnography (PSG) were enrolled in this study. MAIN OUTCOME MEASURES: All patients underwent pre- and postoperative (at least 4 months after surgery) overnight PSG. Available information on results of the PSG, Epworth sleepiness scale and complications of the TORS and coblation groups were compared. RESULTS: Postoperative PSG studies showed improved sleep quality for most patients. The mean postoperative apnoea-hypopnea index (AHI) was reduced significantly from 45.0 to 17.0 events/h (P < .0001) in the TORS group and from 45.6 to 16.2 events/h (P < .0001) in the coblation group. The mean rates of improvement (AHI reduction > 50%) were 75.0% in TORS patients and 62.1% in coblation patients and the difference was not significant. Less frequent postoperative morbidity, including bleeding, taste dysfunction and foreign body sensation, was recorded in TORS patients. CONCLUSIONS: Both the coblation and TORS groups showed similar surgical outcomes, TORS achieved PSG results non-inferior to and complication rates comparable to coblation.

Effect of oregano oil and tannic acid combinations on the quality and sensory characteristics of cooked chicken meat.

The antioxidant effects of oregano essential oil and tannic acid combinations on ground chicken breast and thigh meats were studied. Six treatments, including: 1) control (none added), 2) 100 ppm oregano essential oil + 5 ppm tannic acid, 3) 100 ppm oregano essential oil + 10 ppm tannic acid, 4) 200 ppm oregano essential oil + 5 ppm tannic acid, 5) 200 ppm oregano essential oil + 10 ppm tannic acid, and 6) 5 ppm butylated hydroxyanisole (BHA) for breast or 14 ppm for thigh meat, were prepared. Cooked meat samples were individually vacuum-packaged in oxygen-impermeable vacuum bags and then cooked in-bag to an internal temperature of 75°C. After cooling to room temperature, the cooked meat was re-packaged in new oxygen-permeable bags and stored at 4°C for 7 days. Cooked ground chicken meats were analyzed for lipid and protein oxidation and volatiles at 0, 3, and 7 d of storage. The significant differences among the treatments were very clear in cooked meat samples: Thigh meat patties showed higher 2-thiobarbituric acid reactive substances (TBARS), total carbonyl, and volatiles content compared to the breast meat during storage. A combination of 200 ppm oregano oil with 10 ppm tannic acid showed the most significant effects (P < 0.05) on TBARS, total carbonyl, and off-odor volatile formation for both breast and thigh meats. Oregano oil (200 ppm) and 10 ppm tannic acid combination also showed positive effects on the sensory scores of chicken thigh meat. In conclusion, the combination of 200 ppm oregano oil and 10 ppm tannic acid could be a good replacement for the synthetic antioxidants in ground cooked chicken meat.

The effect of PPARγ agonist on SGLT2 and glucagon expressions in alpha cells under hyperglycemia.

BACKGROUND: Although sodium glucose cotransporter 2 (SGLT2) inhibitors have many beneficial effects for type 2 diabetes, including decreased cardiovascular death, recent reports that they increased glucagon through SGLT2 inhibition raised some concern. Troglitazone, Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, was reported to increase SGLT2 in renal proximal tubule cells, but its role on pancreatic alpha cells have not been reported. We investigated the effect of troglitazone on SGLT2 expression in alpha cells and subsequent glucagon regulation in hyperglycemia. METHODS: An Alpha TC1-6 cell line was cultured in control (5 mM) or hyperglycemia (HG, 15 mM) for 72 h. We applied troglitazone with or without PPARγ antagonist (GW9662 10 µM). To investigate the involvement of PI3K/Akt pathway, we applied troglitazone with or without Wortmanin. We measured sodium glucose transporter 2 (SGLT2) and glucagon (GCG) mRNA and protein expression. PPAR gamma, PI3K and Akt protein were also measured. RESULTS: Exposure of alpha TC cells to HG for 72 h increased glucagon mRNA and protein expression. HG decreased SGLT2 mRNA and protein expression. Troglitazone significantly reversed HG-induced reduction of SGLT2 expression and increase of glucagon secretion. PPARγ antagonist (GW9662 10 µM) decreased the expression of SGLT2 and increased glucagon as HG did. Hyperglycemia increased PI3K and pAkt expression in alpha cells. Wortmanin (PI3K inhibitor, 1 µM) reversed HG-induced SGLT2 decrease and glucagon increase. Troglitazone treatment decreased PI3K and pAkt expression in HG. CONCLUSION: In conclusion, PPARγ agonist, troglitazone improved glucose transport SGLT2 dysfunction and subsequent glucagon dysregulation in alpha cell under hyperglycemia. Those effects were through the involvement of PI3K/pAkt signaling pathway. This study may add one more reason for the ideal combination of PPARγ agonist and SGLT2 inhibitor in clinical practice.

Generation of RUNX3 knockout pigs using CRISPR/Cas9-mediated gene targeting.

Pigs are an attractive animal model to study the progression of cancer because of their anatomical and physiological similarities to human. However, the use of pig models for cancer research has been limited by availability of genetically engineered pigs which can recapitulate human cancer progression. Utilizing genome editing technologies such as CRISPR/Cas9 system allows us to generate genetically engineered pigs at a higher efficiency. In this study, specific CRISPR/Cas9 systems were used to target RUNX3, a known tumour suppressor gene, to generate a pig model that can induce gastric cancer in human. First, RUNX3 knockout cell lines carrying genetic modification (monoallelic or biallelic) of RUNX3 were generated by introducing engineered CRISPR/Cas9 system specific to RUNX3 into foetal fibroblast cells. Then, the genetically modified foetal fibroblast cells were used as donor cells for somatic cell nuclear transfer, followed by embryo transfer. We successfully obtained four live RUNX3 knockout piglets from two surrogates. The piglets showed the lack of RUNX3 protein in their internal organ system. Our results demonstrate that the CRISPR/Cas9 system is effective in inducing mutations on a specific locus of genome and the RUNX3 knockout pigs can be useful resources for human cancer research and to develop novel cancer therapies.

Prevalence and risk factors of chronic rhinosinusitis in South Korea according to diagnostic criteria.

BACKGROUND: We aimed to compare the prevalence and risk factors of chronic rhinosinusitis (CRS) using two different diagnostic criteria with the same statistical data from the Korean National Health and Nutrition Examination Survey in 2009. METHODS: Symptom-based CRS was defined as CRS diagnosed by questionnaires related to nasal symptoms. Endoscopy-based CRS was defined based on endoscopic findings and nasal symptoms of symptom-based CRS. RESULTS: The overall prevalence of CRS based on the different diagnostic criteria was as follows: symptom-based CRS was 10.78% (797 of 7,394) and endoscopy-based CRS was 1.20% (88 of 7,343). Comparing symptom-based CRS to endoscopy-based CRS showed slight agreement (kappa = 0.183 (0.150-0.216, 95% confidence interval)). Allergic rhinitis was identified as a common risk factor for CRS based on the two diagnostic criteria. CONCLUSIONS: The prevalence and risk factors of CRS were quite different from each other according to the different criteria, even in the same population. Therefore, it would be important to consider what specific diagnostic criteria have been adopted in the studies comparing the prevalence of CRS.

Prevalence and risk factors of tooth discolouration after orthognathic surgery: a retrospective study of 1455 patients.

This study was conducted to evaluate the prevalence of tooth discolouration and to examine the factors that may pose a higher risk for tooth discolouration after orthognathic surgery. This was a retrospective study of 1455 orthognathic surgeries. The following data were collected for analysis: presence of discoloured teeth, sex, age at operation, the extent of the surgical displacement of the maxilla, and whether patients had undergone genioplasty, zygomaplasty, or descending palatine artery (DPA) ligation. Out of 1339 patients who underwent double-jaw surgery, 49 received root canal treatment due to tooth discolouration. No tooth discolouration was found in the 116 patients undergoing single-jaw surgery. DPA ligation, genioplasty, and mandibular sub-apical osteotomy were associated with a significant risk of tooth discolouration. Patients should be informed preoperatively of the possibility of tooth discolouration. Additionally, the DPA should be preserved during Le Fort I osteotomy to reduce the risk of tooth discolouration.

Lymph node size is not a reliable criterion for predicting nodal metastasis in rectal neuroendocrine tumours.

AIM: The study was designed to assess the correlation between lymph node (LN) size and LN metastasis in patients with rectal neuroendocrine tumours (NETs). METHOD: Forty patients who underwent curative resection with lymphadenectomy for a rectal NET between January 2007 and December 2012 were included. The short and long diameters of entire nodes were microscopically measured using a slide gauge. RESULTS: In all, 1052 LNs were collected from the 40 patients, with 49 (4.7%) showing evidence of metastasis. Metastasis-positive LNs had significantly greater long and short diameters (P < 0.001) than metastasis-negative LNs. Of the 49 metastatic LNs, 29 (59.2%) were ≤ 5 mm in largest diameter. In five patients, the largest metastatic LN was only 2-3 mm in diameter. In clinically node-negative (cN0) patients, 18 (51.4%) patients had metastatic LNs (pN1). CONCLUSION: The size of LNs containing metastasis varied widely, with some being very small. LN size alone is therefore not a sufficient predictor of tumour metastasis in rectal NETs. Radical surgery with lymphadenectomy should be considered for patients with rectal NETs with high risk factors for LN metastasis, even those without LN enlargement.

Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering.

The present work investigated the osteogenic potential of injectable, dual thermally and chemically gelable composite hydrogels for mesenchymal stem cell (MSC) delivery in vitro and in vivo. Composite hydrogels comprising copolymer macromers of N-isopropylacrylamide were fabricated through the incorporation of gelatin microparticles (GMPs) as enzymatically digestible porogens and sites for cellular attachment. High and low polymer content hydrogels with and without GMP loading were shown to successfully encapsulate viable MSCs and maintain their survival over 28 days in vitro. GMP incorporation was also shown to modulate alkaline phosphatase production, but enhanced hydrogel mineralization along with higher polymer content even in the absence of cells. Moreover, the regenerative capacity of 2 mm thick hydrogels with GMPs only, MSCs only, or GMPs and MSCs was evaluated in vivo in an 8 mm rat critical size cranial defect for 4 and 12 weeks. GMP incorporation led to enhanced bony bridging and mineralization within the defect at each timepoint, and direct bone-implant contact as determined by microcomputed tomography and histological scoring, respectively. Encapsulation of both GMPs and MSCs enabled hydrogel degradation leading to significant tissue infiltration and osteoid formation. The results suggest that these injectable, dual-gelling cell-laden composite hydrogels can facilitate bone ingrowth and integration, warranting further investigation for bone tissue engineering.

Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection.

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-γ-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

Lymphangioma Arising From the Ovary.

Primary lymphangioma arising from the ovary is a rare tumor, with only 24 cases reported to date. As it is often accompanied by ascites or recurrence, similar to a malignant tumor, an aggressive treatment approach is used for disease control. In this report, we describe a 75-year-old woman with a left ovarian lymphangioma that increased in size during the menopause period. Microscopic examination of the tumor showed thin-walled multilocular cystic spaces and immunoreactivity for D2-40, a specific marker for lymphatic endothelium, lining the cystic spaces. The patient has been doing well for 5 years postoperatively. Ovarian cystic lymphangioma should be included in the differential diagnosis of an ovarian cyst and long-term follow-up is recommended to exclude malignant behavior. We also summarize a total of 25 cases, including the case presented here.

CXC chemokine ligand 12a enhances chondrocyte proliferation and maturation during endochondral bone formation.

OBJECTIVE: We investigated the roles of CXC chemokine ligand 12a (CXCL12a), also known as stromal cell-derived factor-1α (SDF-1α), in endochondral bone growth, which can give us important clues to understand the role of CXCL12a in osteoarthritis (OA). METHODS: Primary chondrocytes and tibial explants from embryonic 15.5 day-old mice were cultured with recombinant mouse CXCL12a. To assess the role of CXCL12a in chondrogenic differentiation, we conducted mesenchymal cell micromass culture. RESULTS: In tibia organ cultures, CXCL12a increased total bone length in a dose-dependent manner through proportional effects on cartilage and bone. In accordance with increased length, CXCL12a increased the protein level of proliferation markers, such as cyclin D1 and proliferating cell nuclear antigen (PCNA), in primary chondrocytes as well as in tibia organ culture. In addition, CXCL12a increased the expression of Runx2, Col10 and MMP13 in primary chondrocytes and tibia organ culture system, implying a role of CXCL12a in chondrocyte maturation. Micromass cultures of limb-bud mesenchymal progenitor cells (MPCs) revealed that CXCL12a has a limited effect on early chondrogenesis, but significantly promoted maturation of chondrocytes. CXCL12a induced the phosphorylation of p38 and Erk1/2 MAP kinases and IκB. The increased expression of cyclin D1 by CXCL12a was significantly attenuated by inhibitors of MEK1 and NF-κB. On the other hand, p38 and Erk1/2 MAP kinase and NF-κB signaling were associated with CXCL12a-induced expression of Runx2 and MMP13, the marker of chondrocyte maturation. CONCLUSION: CXCL12a promoted the proliferation and maturation of chondrocytes, which strongly suggest that CXCL12a may have a negative effect on articular cartilage and contribute to OA progression.

Temporal changes in foveal contour after macular hole surgery.

BACKGROUND: To investigate the changes in inner foveal contour after surgery for macular hole (MH) and its clinical implications. METHODS: This retrospective observational case series included 66 eyes from 66 patients who underwent surgery for MH. Notching of tissue was defined as an abrupt alteration in the inner contour of the parafoveal tissue based on postoperative optical coherence tomography (OCT) image. The distance between the parafoveal edges of the outer plexiform layer (OPL) was defined as the inter-OPL distance. The inter-OPL distance was divided into nasal, temporal, superior, and inferior lengths. The difference in the lengths of each direction between the early and late postoperative period was compared between directions with and without notching. RESULTS: The early and late postoperative examination was performed at 4.6±2.9 weeks and 6.2±0.6 months, respectively. Notching of tissue was noted in 54 eyes (81.8%). In 53 eyes with a measurable inter-OPL distance, the notching of tissue was noted in 45 eyes (84.9%) regardless of preoperative MH size. The mean amount of foveal tissue elongation that occurred during the designated period was 104.6±68.8 and 78.4±72.9 µm in the directions with and without the notching of tissue (P<0.001), respectively. CONCLUSIONS: The changes in the inner foveal contour, including notching of tissue and elongation of foveal tissue, were noted in the majority of eyes after MH surgery. Notching of tissue on OCT image could be a clinical marker for the development of foveal tissue elongation after MH surgery.

Acute postoperative pain relief with immediate-release tapentadol: randomized, double-blind, placebo-controlled study conducted in South Korea.

OBJECTIVE: To broaden the ethnic groups in which tapentadol IR is evaluated for treating acute postoperative pain to include Asians. METHODS: In this phase 3, multicenter, double-blind, randomized study, 352 Korean adults with moderate-to-severe pain following hallux valgus surgery received tapentadol IR 50 or 75 mg or placebo orally every 4-6 hours for 72 hours. Patients requesting other (rescue) analgesics during this period were discontinued for lack of efficacy. The primary endpoint, sum of pain intensity difference (SPID) over 48 hours, was evaluated based on the difference between tapentadol IR and placebo in least squares (LS) mean change from baseline using analysis of covariance (ANCOVA). Secondary endpoints included the time to first rescue medication use and the distribution of responder rates. RESULTS: A treatment effect, favoring tapentadol IR, was observed for SPID48 (p < 0.001 for both doses vs. placebo, ANCOVA). The between-group difference (vs. placebo) in LS means of SPID48 was 76.4 (95% CI: 51.0, 101.7) for tapentadol IR 50 mg and 90.6 (95% CI: 65.1, 116.1) for tapentadol IR 75 mg. Time to first rescue medication use was delayed for tapentadol IR (p < 0.001 for both doses vs. placebo; log-rank test). The distribution of responders at 12, 24, 48, and 72 hours favored tapentadol IR (p ≤ 0.001 for both doses vs. placebo; Cochran-Mantel-Haenszel test). Dizziness, nausea, and vomiting were each reported in ≥ 10% tapentadol-treated patients and at an incidence ≥ 2-fold higher vs. placebo. The study findings may be limited by study drug dosing every 4 to 6 hours and frequent monitoring during treatment, neither of which mimic pain treatment in clinical practice. However, any potential bias based on this systematic monitoring of patients would be mitigated by the randomized, double-blind nature of the study, with all treatment groups similarly affected by such biases, if any. CONCLUSIONS: Tapentadol IR reduced acute pain intensity, significantly more than placebo, after orthopedic surgery in Korean patients. CLINICAL TRIAL REGISTRATION: NCT01516008.

Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model.

OBJECTIVE: To investigate the ability of cell-laden bilayered hydrogels encapsulating chondrogenically and osteogenically (OS) pre-differentiated mesenchymal stem cells (MSCs) to effect osteochondral defect repair in a rabbit model. By varying the period of chondrogenic pre-differentiation from 7 (CG7) to 14 days (CG14), the effect of chondrogenic differentiation stage on osteochondral tissue repair was also investigated. METHODS: Rabbit MSCs were subjected to either chondrogenic or osteogenic pre-differentiation, encapsulated within respective chondral/subchondral layers of a bilayered hydrogel construct, and then implanted into femoral condyle osteochondral defects. Rabbits were randomized into one of four groups (MSC/MSC, MSC/OS, CG7/OS, and CG14/OS; chondral/subchondral) and received two similar constructs bilaterally. Defects were evaluated after 12 weeks. RESULTS: All groups exhibited similar overall neo-tissue filling. The delivery of OS cells when compared to undifferentiated MSCs in the subchondral construct layer resulted in improvements in neo-cartilage thickness and regularity. However, the addition of CG cells in the chondral layer, with OS cells in the subchondral layer, did not augment tissue repair as influenced by the latter when compared to the control. Instead, CG7/OS implants resulted in more irregular neo-tissue surfaces when compared to MSC/OS implants. Notably, the delivery of CG7 cells, when compared to CG14 cells, with OS cells stimulated morphologically superior cartilage repair. However, neither osteogenic nor chondrogenic pre-differentiation affected detectable changes in subchondral tissue repair. CONCLUSIONS: Cartilage regeneration in osteochondral defects can be enhanced by MSCs that are chondrogenically and osteogenically pre-differentiated prior to implantation. Longer chondrogenic pre-differentiation periods, however, lead to diminished cartilage repair.

Phospholipase D1 decreases type I collagen levels in hepatic stellate cells via induction of autophagy.

Hepatic stellate cells (HSCs) are major players in liver fibrogenesis. Accumulating evidence shows that suppression of autophagy plays an important role in the development and progression of liver disease. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA) and choline, was recently shown to modulate autophagy. However, little is known about the effects of PLD1 on the production of type I collagen that characterizes liver fibrosis. Here, we examined whether PLD1 regulates type I collagen levels in HSCs through induction of autophagy. Adenovirus-mediated overexpression of PLD-1 (Ad-PLD1) reduced type I collagen levels in the activated human HSC lines, hTERT and LX2. Overexpression of PLD1 in HSCs led to induction of autophagy as demonstrated by increased LC3-II conversion and formation of LC3 puncta, and decreased p62 abundance. Moreover, inhibiting the induction of autophagy by treating cells with bafilomycin or a small interfering (si)RNA for ATG7 rescued Ad-PLD1-induced suppression of type I collagen accumulation in HSCs. The effects of PLD on type I collagen levels were not related to TGF-ß/Smad signaling. Furthermore, treatment of cells with PA induced autophagy and inhibited type I collagen accumulation. The present study indicates that PLD1 plays a role in regulating type I collagen accumulation through induction of autophagy.

Triiodothyronine induces proliferation of pancreatic ß-cells through the MAPK/ERK pathway.

BACKGROUND: 3,5,3'-Triiodothyronine (T3) has a stimulatory effect on cellular growth via thyroid hormone receptors (TRs) in several cell lines. TR expression in the pancreas suggests that pancreatic beta cell proliferation might be induced by T3. The purpose of this study was to demonstrate that T3 induces pancreatic beta cell proliferation through the mitogen activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway. METHODS: INS-1 cells were plated as a monolayer at densities of 4×104, cultured in RPMI 1,640 with 10% fetal bovine serum with 2-mercaptoethanol, respectively, in 6-well multiplates. After 48 h, they were exposed to 10-7 M T3 or to vehicle alone. Viable cells were harvested after 24, 48, and 72 h of continuous exposure. Cell proliferation and TRα1 and TRß1 expression were analyzed by flow-assisted cell sorting analysis, Ki-67 staining, and Western blotting. The p38 MAPK, ERK, and Akt pathways were analyzed by Western blotting. Beta cell function was evaluated by assaying insulin secretion. RESULTS: T3 enhanced INS-1 cell proliferation at a dose of 10-7 M in a time-dependent manner via the MAPK/ERK pathway and promoted insulin secretion. CONCLUSIONS: Our results demonstrate that MAPK/ERK pathway plays an important role in the T3 induced pancreatic beta cell proliferation.

An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia.

Human immunodeficiency virus-1 (HIV-1) infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T-cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T-cell activation, inflammation, and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1-infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared with uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1-infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.