Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-ß Production.

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

Simply structured polarization-independent high efficiency multilayer dielectric gratings.

A polarization-independent multilayer dielectric diffraction grating with a low aspect ratio and high diffraction efficiency was designed and fabricated. The diffraction grating designed with a grating density of 1200 lines/mm had an aspect ratio of 0.59, mean polarization-independent diffraction efficiency in the Littrow angle of ±2.5∘, and 1030-1080 nm wavelength range of 97.2%. The designed grating was fabricated using ion assisted deposition and reactive ion etching techniques. The mean polarization-independent diffraction efficiency of the fabricated grating was 96.1%, and its standard deviation was 0.68%. The fabricated diffraction grating was irradiated with a 1064 nm cw laser, with a power density of 30kW/cm2, for 1 min to measure the temperature change before and after the laser application. It was verified that the temperature variation of the diffraction grating without heat treatment was 8.8°C, and the temperature variation after heat treatment at 400°C decreased to 2.3°C.

The lymphocyte/monocyte ratio and red blood cell transfusion during radical retropubic prostatectomy.

PURPOSE: Despite improvements of strategy in radical retropubic prostatectomy, blood loss is still a major concern. The lymphocyte/monocyte (LM) ratio is a prognostic indicator for various diseases. We identified the risk factors, including the LM ratio, for red blood cell (RBC) transfusion during radical retropubic prostatectomy. METHODS: This retrospective study assessed patients who underwent radical retropubic prostatectomy between March 2009 and December 2020. To determine the risk factors for RBC transfusion, a multivariate logistic regression analysis was conducted. A receiver operating characteristic (ROC) curve analysis was also performed. Postoperative outcomes, including acute kidney injury (AKI), hospitalization duration, and intensive care unit (ICU) admission, were also evaluated. RESULTS: Among 1302 patients, 158 patients (12.1%) received an intraoperative RBC transfusion. Multivariate logistic regression analysis demonstrated that the risk factors for RBC transfusion were the LM ratio, hemoglobin, 6% hydroxyethyl starch amount, and positive surgical margin. The area under the ROC curve of LM ratio was 0.706 (cut-off = 4.3). The LM ratio at ≤ 4.3 was significantly related to transfusion in multivariate-adjusted analysis (odds ratio = 4.598, P < 0.001). AKI and ICU admission were significantly higher, and the hospitalization duration was significantly longer in patients with RBC transfusion. CONCLUSIONS: The LM ratio was a risk factor for RBC transfusion in radical retropubic prostatectomy. The optimal cut-off value of the LM ratio to predict transfusion was 4.3. RBC transfusion was associated with poor postoperative outcomes. Therefore, our results suggest that the LM ratio provide useful information on RBC transfusion in radical retropubic prostatectomy.

Adjuvant administration of hypertonic saline in lumbar epidural intervention may be associated with successful response in patients with probable neuropathic radicular pain Screened by Douleur Neuropathique 4.

Background: Chronic lumbar radicular pain often accompanies neuropathic pain. The treatment may follow a screening for probable neuropathic pain rather than the definitive diagnosis, which is often difficult in daily practice. However, interventional management may have limited effects on symptoms in patients with neuropathic radicular pain refractory to conservative treatments. The purpose of this study is to evaluate the factors associated with successful responses after lumbar epidural intervention in patients with chronic lumbar neuropathic radicular pain determined by Douleur Neuropathique 4 (DN4). Methods: We retrospectively reviewed 221 chronic lumbar radicular pain patients using a DN4 questionnaire prior to the epidural interventional procedure. The patients were divided into two groups according to the DN4 questionnaire: <4-point DN4 and ≥4 DN4. The numerical rating scale (NRS) for pain intensity, changes in physical functional status, and the use of pain medication were obtained before and 1 month after the procedure. Successful responder was defined based on robust combination of outcome parameters. The factors associated with successful response were analyzed using univariate and multivariate regression. Results: We found 170 (76.9%) patients with DN4 <4 and 51 (23.1%) with a score ≥4. Among the total 221 patients, 129 (58.4%) were successful responders and 92 (41.6%) were non-responders regardless of DN4 score. We observed a significantly lower proportion of successful responders among patients with a DN4 score ≥4 (22, 43.1%) than patients with a score <4 (107, 62.9%) (P=0.012). After adjusting in multivariate regression analysis, the DN4 score was independently associated with response after lumbar epidural intervention (odds ratio [OR]=0.838; 95% confidence interval [CI]=0.718-0.978; P=0.025). In subgroup logistic regression analysis according to the DN4 score, adjuvant administration of hypertonic saline during epidural interventions in patients with a DN4 score ≥4 (OR=3.71; CI=1.142-12.457; P=0.029) was associated with the success of the lumbar epidural procedure at 1 month. Conclusion: The adjuvant use of hypertonic saline in lumbar epidural interventions may be effective at least 1 month after the intervention in patients with probable neuropathic lumbar radicular pain ≥4 using the DN4.

Relationship between fatty infiltration and gene expression in patients with medium rotator cuff tear.

BACKGROUND: Fatty infiltration (FI) is a key prognostic factor that affects outcomes after rotator cuff repair and is radiologically evaluated using the Goutallier classification. The purpose of this study was to assess alterations in gene and protein expression according to the Goutallier classification in the supraspinatus muscle and any relationships among various gene expression profiles. METHODS: Twenty-four samples of the supraspinatus muscle from 12 patients with a high FI grade (grade 3 or 4) and 12 patients with a low FI grade (grade 1 or 2) with medium-sized tears were acquired during arthroscopic surgery. Alterations in the expression of genes and proteins associated with adipogenesis, fibrosis, inflammation, and muscle atrophy were compared between the high- and low-FI groups using reverse-transcription quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. RESULTS: mRNA expression of not only the adipogenic genes (peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α; P < .001 and P = .020) but also the fibrosis-related gene (α-smooth muscle actin; P < .001), inflammation-related genes (interleukin [IL]-1ß and tumor necrosis factor α; P = .041 and P = .039), and muscle atrophy-related genes (atrogin 1 and myostatin; P = .006 and P < .001) was higher in the high-FI group compared with that in the low-FI group. In addition, adipogenic gene expression was significantly correlated with the expression of other categories of genes (all P < .05, except atrogin 1). A correlation of gene and protein expression was observed for IL-1ß (P = .027) and myostatin (P = .029). CONCLUSIONS: The radiologic grading of FI was associated with the expression of various genes, including adipogenic, fibrotic, inflammatory, and atrophy-related genes, and these genes were closely correlated with each other in terms of expression. This information could be helpful in patient counseling.

Sugammadex versus neostigmine on postoperative pulmonary complications after robot-assisted laparoscopic prostatectomy: a propensity score-matched analysis.

PURPOSE: Robot-assisted laparoscopic prostatectomy (RALP) requires particular surgical conditions, such as carbon dioxide pneumoperitoneum and steep Trendelenburg positioning, which may have adverse effects on the respiratory system. The effect of sugammadex on postoperative pulmonary complications (PPCs) is controversial. Therefore, we evaluated the incidence of PPCs according to the type of neuromuscular blockade reversal agents in RALP. METHODS: We retrospectively analyzed RALP patients. We compared the incidence of PPCs between patients receiving neostigmine (neostigmine group) and those receiving sugammadex (sugammadex group) as a neuromuscular blockade reversal agent. Propensity score-matched analysis was performed. Other postoperative outcomes, such as duration of hospital stays, major adverse cardiac events during hospital stays, and death during hospital stays, were also compared between the two groups. RESULTS: The incidence of PPCs was 28.9% (137/474) in RALP. The incidence of PPCs was significantly lower in the sugammadex group than in the neostigmine group (18.6% [44/237] vs. 39.2% [93/237], p < 0.001). The incidence of atelectasis was significantly lower in the sugammadex group than in the neostigmine group (18.6% vs. 39.2%, p < 0.001). The incidence of pneumonia was not significantly different between the sugammadex and neostigmine groups after RALP (0.0% vs. 0.4%, p > 0.999). Besides these, other postoperative outcomes were not significantly different between the two groups. CONCLUSIONS: The incidence of PPCs after RALP was significantly lower in patients receiving sugammadex than in those receiving neostigmine. These results can provide useful information on the appropriate selection of neuromuscular blockade reversal agents in RALP.

Altered gene and protein expressions of vitamin D receptor in skeletal muscle in sarcopenic patients who sustained distal radius fractures.

Despite the presence of vitamin D receptor (VDR) in skeletal muscle cells, the relationship between VDR expressions and muscle mass or function has not been well studied. The purpose of this study was to compare VDR gene and protein expression in the forearm muscle between sarcopenic and non-sarcopenic individuals who have sustained distal radius fractures. Twenty samples of muscle tissue from sarcopenic patients (mean age 63.4 ± 8.1 years) and 20 age- and sex-matched control tissues (62.1 ± 7.9 years) were acquired from the edge of dissected pronator quadratus muscle during surgery for distal radius fractures. The mRNA expression levels of VDR as well as the myokines of interest that may be associated with muscle mass change (myogenin and myostatin) were analyzed with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, Western blot assay and immunohistochemistry for VDR were performed. Sarcopenic patients showed a significantly lower level of gene expression for VDR and myogenin, but a greater level of gene expression for myostatin than the controls according to qRT-PCR analysis. The density of VDR protein expressions was 2.1 times greater, while that of myostatin was 2.6 times lower, in the control group than in the sarcopenic group according to Western blot analysis. On immunohistochemical analysis, the density of the cells expressing VDR was significantly decreased in the sarcopenic patients. Sarcopenic patients who sustained distal radius fractures presented lower vitamin D receptor gene and protein expression in skeletal muscles compared to non-sarcopenic individuals.

Influence of Smoking on the Expression of Genes and Proteins Related to Fat Infiltration, Inflammation, and Fibrosis in the Rotator Cuff Muscles of Patients With Chronic Rotator Cuff Tears: A Pilot Study.

PURPOSE: To evaluate the altered gene and protein expression patterns in the rotator cuff muscles of smokers and non-smokers with rotator cuff tears and to identify the smoking-associated key genetic factor(s) involved in rotator cuff muscle physiology. METHODS: Twenty-four samples of rotator cuff muscle from 12 current heavy smokers (mean age 61.8 ± 5.1 years) and age- and sex-matched 12 non-smokers (mean age 61.8 ± 6.9 years) with medium-sized tears were acquired during arthroscopic surgery. As a statistical method, the propensity score matching technique was used to select control group by 1:1 matching for age and sex. Inclusion criteria were patients who underwent arthroscopic repair for medium-sized full-thickness rotator cuff tears and those that were current smokers with a smoking history >20 packs/year. Patients lacking medium-sized tears, those with recent steroid injection history, isolated subscapularis tear, preoperative stiff shoulder, acute traumatic tear, or previous surgery on the same shoulder, or those that declined to participate were excluded. Alterations in the expression of genes and proteins associated with myogenesis, inflammation, adipogenesis, and muscle fibrosis were compared between smokers and non-smokers with reverse-transcription quantitative polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: Histologic analysis revealed increased inflammation and remarkable fat accumulation and fibrogenesis in the rotator cuff muscle from smokers compared with that from non-smokers. The mRNA expression levels of inflammatory high mobility group box 1 (HMGB1; P = .043), adipogenic CCAAT/enhancer-binding protein alpha (P = .046) and peroxisome proliferator-activated receptor gamma (PPARγ; P = .048), myogenic differentiation 1 (P = .032), fibrogenic alpha-smooth muscle actin (α-SMA; P = .033), and metalloproteinase 9 (P = .036) were significantly greater in samples from smokers than from non-smokers. A correlation was observed between gene and protein expression of HMGB1 (P = .034), PPARγ (P = .021), and α-SMA (P = .021). CONCLUSIONS: Smokers with rotator cuff tears showed high inflammation, large fat infiltration, and fibrosis in rotator cuff muscle that is associated with the increased expression of HMGB1, PPARγ, and α-SMA, respectively. LEVEL OF EVIDENCE: Case control study (Prognostic level III).

Altered Gene and Protein Expressions in Torn Rotator Cuff Tendon Tissues in Diabetic Patients.

PURPOSE: To analyze and compare the gene and protein expression characteristics in torn rotator cuff tendon tissues between diabetic and nondiabetic patients. METHODS: This was a pilot study. Twelve samples of rotator cuff tendon tissue from diabetic patients (mean age, 62.3 ± 9.9 years) and 12 age- and sex-matched nondiabetic tendon tissues (62.3 ± 9.9 years) were acquired from the torn tendon end of medium rotator cuff tears during arthroscopic surgery, after applying the same inclusion and exclusion criteria. Expressions of various genes of interest, including collagens I and III, matrix metalloprotease (MMP)-2, MMP-3, MMP-9, MMP-13, interleukin (IL)-1, IL-6, insulin-like growth factor-1, vascular endothelial growth factor, tenomodulin, tumor necrosis factor-α, and p53, were analyzed with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, immunohistochemistry and western blot assay were performed for the genes that revealed significantly different expressions in real-time qRT-PCR between groups. RESULTS: Gene expression levels of MMP-9, MMP-13, IL-6, and tenomodulin were significantly higher in the diabetic than in the nondiabetic group by real-time qRT-PCR analyses (P = .011, .004, .009, and .010, respectively). The density of cells expressing MMP-9 and IL-6 was significantly increased in the torn tendons of the diabetic patients on immunohistochemical analysis, and the density of MMP-9 and IL-6 protein expressions was significantly higher in the diabetic group on western blot (P = .018 and .044, respectively). CONCLUSIONS: Diabetic torn cuff tendon tissues showed MMP-9 and IL-6 overexpressions compared with controls. CLINICAL RELEVANCE: The overexpressions of MMP-9 and IL-6 may be one of the explanations for the high healing failure rate after rotator cuff repair in the diabetic patients.

Combination laser treatment for immediate post-surgical scars: a retrospective analysis of 33 immature scars.

The application of laser treatments beginning on the day of stitch removal has been demonstrated to improve scar quality. However, there are few guidelines for the treatment of immature scars (ISs), which are defined as "scars whose features are not yet expressed." The purpose of this study was to extract information about early combination laser treatment (CLT) beyond what is currently known by analyzing 33 pairs of pre-treatment and post-treatment photographs of ISs. Two hundred fifty medical records of patients with scars were reviewed, and 33 scars were included in the study. The included scars were treated with vascular lasers (585 or 532 nm) followed by 1550-nm fractional lasers from May 2014 to July 2015 (fewer than 52 days after stitch removal, Fitzpatrick's skin types III-IV, mean age = 16.0 years). Blinded evaluators (one plastic surgeon and two dermatologists) evaluated the pre-treatment and post-treatment photographs. The pre-treatment photographs were scored on a spectrum from "0," when no difference with the surrounding unaffected skin was observed, to "100," when the worst scarring was present. The pre-treatment and post-treatment photographs were compared, and the results were graded on a spectrum from 0, when no difference between the pre-treatment and post-treatment photographs was observed, to 100, when no difference was observed between the post-treatment skin and the surrounding unaffected skin. Statistical analyses were performed with PASW 17.0, SPSS Korea, Seoul, Korea (p < 0.05). The improvement scores (ImS) and weighted scores (Wtd: i.e., weighted according to the pre-treatment scores) were used as dependent variables. The average improvement score was 87.98 (median = 90). Seventeen cases were scored as 100-point improvements. The facial and non-facial scars exhibited differences in the ImS and Wtd scores. The Wtd scores were negatively correlated with the temporal gap (in days) between stitch removal and the beginning of CLT. No significant difference in the Wtd scores was demonstrated between the two vascular laser groups. Patient age and Wtd score were negatively correlated, and a significant difference was observed in the Wtd scores between the age groups (≥15 and <15 years old). CLT for ISs results in excellent outcomes. Better results are achieved with earlier CLT initiation following stitch removal. Better outcomes can be expected for younger patients and for facial scars. We found that 532 and 585-nm lasers are equally effective for CLT of ISs.

Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection.

Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Four days after infection with C. rodentium, there were significantly fewer neutrophils (CD11b+ Ly6C+ Ly6G+) in the colons of IL-1R−/− mice than in wild-type mice. Levels of mRNA and protein of KC/CXCL1 were also significantly reduced in colon homogenates of infected IL-1R−/− mice relative to wild-type mice. Of note, infiltrated CD11b+ Ly6C+ Ly6G+ neutrophils were the main source of IL-22 secretion after C. rodentium infection. Interestingly, intestinal stromal cells isolated from IL-1R−/− mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse intestinal stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete KC/CXCL1, which is essential for infiltration of IL-22-secreting neutrophils upon bacterial infection.

Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses.

Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications.

Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice.

AIMS/HYPOTHESIS: Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity. METHODS: We targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling. RESULTS: Conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD(+) levels. CONCLUSIONS/INTERPRETATION: ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.

Therapeutic efficacy of human embryonic stem cell-derived endothelial cells in humanized mouse models harboring a human immune system.

OBJECTIVE: Allogeneic transplantation of human embryonic stem cell (hESC) derivatives has the potential to elicit the patient's immune response and lead to graft rejection. Although hESCs and their derivatives have been shown to have advantageous immune properties in vitro, such observations could not be determined experimentally in vivo because of ethical and technical constraints. However, the generation of humanized mice (hu-mice) harboring a human immune system has provided a tool to perform in vivo immunologic studies of human cells and tissues. Using this model, we sought to examine the therapeutic potential of hESC-derived endothelial cells, human embryonic fibroblasts, and cord blood-derived endothelial progenitor cells in a human immune system environment. APPROACH AND RESULTS: All cell types transplanted in hu-mice showed significantly reduced cell survival during the first 14 days post-transplantation compared with that observed in immunodeficient mice. During this period, no observable therapeutic effects were detected in the hindlimb ischemic mouse models. After this point, the cells demonstrated improved survival and contributed to a long-term improvement in blood perfusion. All cell types showed reduced therapeutic efficacy in hu-mice compared with NOD scid IL2 receptor gamma chain knockout mice. Interestingly, the eventual improvement in blood flow caused by the hESC-derived endothelial cells in hu-mice was not much lower than that observed in NOD scid IL2 receptor gamma chain knockout mice. CONCLUSIONS: These findings suggest that hESC derivatives may be considered a good source for cell therapy and that hu-mice could be used as a preclinical in vivo animal model for the evaluation of therapeutic efficacy to predict the outcomes of human clinical trials.

ATF3 expression is induced by low glucose in pancreatic α and ß cells and regulates glucagon but not insulin gene transcription.

The pancreas is critical for maintaining glucose homeostasis. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. There are major discrepancies in previous reports on pancreatic ATF3; therefore, its role in the pancreas is unclear. To better elucidate the role of ATF3 in the pancreas, we conducted in vitro studies using pancreatic α and ß cell lines, and also evaluated the use of ATF3 antibodies for immunohistochemistry. We determined ATF3 expression was increased by low glucose and decreased by high glucose in both αTC-1.6 and ßTC3 cells. We also showed that adenovirus-mediated ATF3 overexpression increased glucagon promoter activity and glucagon mRNA levels in αTC-1.6 cells; whereas, it had no effect on insulin promoter activity and insulin mRNA levels in ßTC3 cells. Although immunostaining with the C-19 ATF3 antibody demonstrated predominant expression in α cells rather than ß cells, ATF3 staining was still detected in ATF3 knockout mice as clearly as in control mice. On the other hand, another ATF3 antibody (H-90) detected ATF3 in both α cells and ß cells, and was clearly diminished in ATF3 knockout mice. These results indicate that previous discrepancies in ATF3 expression patterns in the pancreas were caused by the varying specificities of the ATF3 antibodies used, and that ATF3 is actually expressed in both α cells and ß cells.

A therapeutic strategy for metastatic malignant fibrous histiocytoma through mesenchymal stromal cell-mediated TRAIL production.

OBJECTIVE: To overcome the therapeutic limitations of malignant fibrous histiocytoma (MFH), we evaluated human adipose tissue-derived mesenchymal stromal cells (MSCs) that secrete tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on metastatic MFH. BACKGROUND: MFH is a highly malignant and metastatic type of sarcoma but surgical removal is the only effective method for treating MFH. MSCs are easily transduced to express a high level of transgene and can migrate toward cancer. For this reason, MSCs are a promising candidate for metastatic MFH therapies. METHODS: In vitro sustainability of MSC-TRAIL against MFH-ino was analyzed by apoptosis assay. For preclinical study, anti-MFH effects of MSC-TRAILs were validated in murine models for local tumorigenesis and metastasis. Furthermore, a time-interval metastasis model of MFH was applied to confirm antimetastatic ability of MSC-TRAIL for preestablished metastatic MFH. RESULTS: We found that MFH-ino is highly susceptible to recombinant TRAIL and MSC-TRAIL, which selectively induce apoptosis via caspase-8 activation in vitro. Moreover, not only MFH-ino but xenograft explants were also significantly inhibited by MSC-TRAIL in local tumorigenesis. In particular, the metastatic ability of MFH-ino was considerably reduced by MSC-TRAIL in metastasis murine model, particularly for preestablished metastatic MFH. CONCLUSIONS: These results suggest that MSC-TRAIL is sufficiently effective in inhibiting MFH-ino metastasis and the application using MSC-TRAIL could be extended to other sarcomas and recurrent metastatic cancers for cell-mediated cancer therapy.

Economic development, intergenerational mobility, and health in South Korea.

A growing number of studies reported the association between social mobility and health. However, few studies investigated whether the association varies by age group. Drawing on the economic environment that facilitated social mobility in South Korea, we postulate each age group had a different extent of social mobility, which would vary with the extent of economic growth and affect the association between social mobility and health. We used data from KDI National Happiness Survey 2018 and measured perceived mobility using respondents' perceived social position and their parents' social position. We examined whether social mobility was associated with self-rated health and psychological well-being. The upwardly mobile individuals were more likely than the stable ones to report 'happy'. Such a positive association between upward mobility and happiness was consistently found when the sample was restricted to the ages 30-59 and 40-49. For self-rated health, the downwardly mobile individuals were less likely to report good health. However, no significant difference in self-rated health was found after the youngest and oldest age groups were excluded. We found that perceived social mobility was strongly associated with psychological well-being rather than self-rated health. Moreover, we found a stronger association between upward mobility and happiness among the aged 40-49, who had the largest proportion of upwardly mobile individuals and spent their adolescence during rapid economic growth. The findings underscore the importance of the economic and social context in which individuals perceive their social position and shape their well-being.

FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and ß-cell-specific FoxO1 knockout mice.

Diabetes is characterized by an absolute or relative deficiency of pancreatic ß-cells. New strategies to accelerate ß-cell neogenesis or maintain existing ß-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits ß-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against ß-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (ß-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not ß-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased ß-cell mass due to increased islet number rather than islet size, indicating accelerated ß-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not ß-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or ß-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits ß-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress.

Mesenchymal stem cells regulate the proliferation of T cells via the growth-related oncogene/CXC chemokine receptor, CXCR2.

Mesenchymal stem cells (MSCs) have known to induce immunosuppressive properties by preventing T cell proliferation. However, it is remains unclear how MSCs inhibit T cell proliferation. To identify the factor that inhibits T cell proliferation, we conducted a cytokine array analysis of culture medium from a co-culture of MSCs and T cells and found that the chemokines, CXCL1, 2 and 3, were induced in T cells. MSCs also induced the expression of the CXCR2 receptor on T cell surface. Particularly, CXCL3 inhibited proliferation and increased apoptosis in T cells, which were reversed by CXCR2 inhibitor treatment. Moreover, CXCL3 decreased JAK2, STAT3, and AKT phosphorylation and these responses were also abolished by CXCR2 inhibitor treatment. MSCs suppressed the proliferation of T cells into tumor tissue. Collectively, these data demonstrate that MSCs directly regulate T cell proliferation by induction of CXCL3 chemokine and its receptor, CXCR2 on the surface in T cells.