Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.

Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human ß cells, cadaveric donor islets, and iPSC-derived islets were treated in vitro with IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced ß cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of ß cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin. In vivo administration of BMS-986202 in two mouse models of T1D ( RIP-LCMV-GP mice and NOD mice) reduced systemic and tissue-localized inflammation, prevented ß cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for ß cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.

miR-146a-5p mediates inflammation-induced ß cell mitochondrial dysfunction and apoptosis.

We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with ß cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in ß cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL-1ß, IFNγ, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA sequencing data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers was observed in islets derived from NOD mice. Collectively, these data suggest that miR-146a-5p may promote ß cell dysfunction and death during inflammatory stress by suppressing mitochondrial function.

Outcomes of Endovascular Treatment for Infective Aortic Aneurysms　- A Multicenter Retrospective Study.

BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.Methods and Results: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.

Histone Deacetylase Inhibitors Prevent Cytokine-Induced ß Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry.

Histone deacetylase inhibitors (HDIs) modulate ß cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been determined. In this study, we investigated the impact of the HDI sodium butyrate (NaB) on ß cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 ß cells. Consistently, NaB partially rescued glucose-stimulated Ca2+ oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+ in the ß cell is governed by changes in endoplasmic reticulum (ER) Ca2+ levels, next we explored the relationship between NaB and store-operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+ levels through STIM1-mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+ levels and restored SOCE in IL-1ß-treated INS-1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine-treated INS-1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent ß cell death in response to IL-1ß treatment. Mechanistically, NaB counteracted cytokine-mediated reductions in phosphorylation levels of key signaling molecules, including AKT, ERK1/2, glycogen synthase kinase-3α (GSK-3α), and GSK-3ß. Taken together, these data support a model whereby HDI treatment promotes ß cell function and Ca2+ homeostasis under proinflammatory conditions through STIM1-mediated control of SOCE and AKT-mediated inhibition of GSK-3.

Case Report: High-dose steroid and IVIG successful treatment in a case of COVID-19-associated autoimmune encephalitis: a literature review.

Autoimmune encephalitis is a rare but critical complication of COVID-19. The management of COVID-19-associated autoimmune encephalitis includes the use of steroids, intravenous immunoglobulin (IVIG), plasmapheresis, and monoclonal antibody therapy. This study presented a patient with critical COVID-19 autoimmune encephalitis who rapidly recovered after the initiation of corticosteroids and IVIG therapy. This study reviewed the current literature on the pathophysiological mechanisms, diagnosis, and management of COVID-19-associated autoimmune encephalitis.

SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells.

AIMS/HYPOTHESIS: Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in type 1 and type 2 diabetes. Previous studies have suggested that Ca2+ signalling within beta cells regulates insulin processing and secretion; however, the mechanisms that link impaired Ca2+ signalling with defective insulin maturation remain incompletely understood. METHODS: We generated mice with beta cell-specific sarcoendoplasmic reticulum Ca2+ ATPase-2 (SERCA2) deletion (ßS2KO mice) and used an INS-1 cell line model of SERCA2 deficiency. Whole-body metabolic phenotyping, Ca2+ imaging, RNA-seq and protein processing assays were used to determine how loss of SERCA2 impacts beta cell function. To test key findings in human model systems, cadaveric islets were treated with diabetogenic stressors and prohormone convertase expression patterns were characterised. RESULTS: ßS2KO mice exhibited age-dependent glucose intolerance and increased plasma and pancreatic levels of proinsulin, while endoplasmic reticulum (ER) Ca2+ levels and glucose-stimulated Ca2+ synchronicity were reduced in ßS2KO islets. Islets isolated from ßS2KO mice and SERCA2-deficient INS-1 cells showed decreased expression of the active forms of the proinsulin processing enzymes PC1/3 and PC2. Additionally, immunofluorescence staining revealed mis-location and abnormal accumulation of proinsulin and proPC2 in the intermediate region between the ER and the Golgi (i.e. the ERGIC) and in the cis-Golgi in beta cells of ßS2KO mice. Treatment of islets from human donors without diabetes with high glucose and palmitate concentrations led to reduced expression of the active forms of the proinsulin processing enzymes, thus phenocopying the findings observed in ßS2KO islets and SERCA2-deficient INS-1 cells. Similar findings were observed in wild-type mouse islets treated with brefeldin A, a compound that perturbs ER-to-Golgi trafficking. CONCLUSIONS/INTERPRETATION: Taken together, these data highlight an important link between ER Ca2+ homeostasis and proinsulin processing in beta cells. Our findings suggest a model whereby chronic ER Ca2+ depletion due to SERCA2 deficiency impairs the spatial regulation of prohormone trafficking, processing and maturation within the secretory pathway. DATA AVAILABILITY: RNA-seq data have been deposited in the Gene Expression Omnibus (GEO; accession no.: GSE207498).

Advances in understanding of the pathogenesis and therapeutic implications of drug reaction with eosinophilia and systemic symptoms: an updated review.

Drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome (DRESS/DIHS) is one type of severe cutaneous adverse reaction (SCAR). It is featured by fever, widespread skin lesions, protracted clinical course, internal organ involvement, and possibly long-term autoimmune sequelae. The presence of high-risk human leukocyte antigen (HLA) alleles, hypersensitivity reaction after culprit drug ingestion, and human herpesvirus reactivation may all contribute to its complex clinical manifestations. Some recent studies focusing on the roles of involved cytokines/chemokines and T cells co-signaling pathways in DRESS/DIHS were conducted. In addition, some predictors of disease severity and prognosis were also reported. In this review, we provided an update on the current understanding of the pathogenesis, potential biomarkers, and the relevant therapeutic rationales of DRESS/DIHS.

Stromal Interaction Molecule 1 Maintains ß-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling.

Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with ß-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with ß-cell-specific STIM1 deletion (STIM1Δß mice) were generated and challenged with high-fat diet. Interestingly, ß-cell dysfunction was observed in female, but not male, mice. Female STIM1Δß mice displayed reductions in ß-cell mass, a concomitant increase in α-cell mass, and reduced expression of markers of ß-cell maturity, including MafA and UCN3. Consistent with these findings, STIM1 expression was inversely correlated with HbA1c levels in islets from female, but not male, human organ donors. Mechanistic assays demonstrated that the sexually dimorphic phenotype observed in STIM1Δß mice was due, in part, to loss of signaling through the noncanonical 17-ß estradiol receptor (GPER1), as GPER1 knockdown and inhibition led to a similar loss of expression of ß-cell maturity genes in INS-1 cells. Together, these data suggest that STIM1 orchestrates pancreatic ß-cell function and identity through GPER1-mediated estradiol signaling. ARTICLE HIGHLIGHTS: Store-operated Ca2+ entry replenishes endoplasmic reticulum (ER) Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). ß-Cell-specific deletion of STIM1 results in a sexually dimorphic phenotype, with ß-cell dysfunction and loss of identity in female but not male mice. Expression of the noncanonical 17-ß estradiol receptor (GPER1) is decreased in islets of female STIM1Δß mice, and modulation of GPER1 levels leads to alterations in expression of ß-cell maturity genes in INS-1 cells.

An updated review of the immunological mechanisms of keloid scars.

Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.

Coexisting Nodular Sclerosis Hodgkin Lymphoma and Kimura's Disease: A Case Report and Literature Review.

Kimura's disease (KD) is a rare lymphoproliferative fibroinflammatory disorder that commonly affects the subcutaneous tissue and lymph nodes of the head and neck. The condition is a reactive process involving T helper type 2 cytokines. Concurrent malignancies have not been described. Differential diagnosis with lymphoma can be challenging without tissue biopsy. Here, we present the first reported case of coexisting KD and eosinophilic nodular sclerosis Hodgkin lymphoma of the right cervical lymphatics in a 72-year-old Taiwanese man.

Comparison of Clinical Manifestations and Pathology between Kimura Disease and IgG4-Related Disease: A Report of Two Cases and Literature Review.

Kimura disease (KD) is a rare, chronic proliferative condition presenting as a subcutaneous mass predominantly located in the head and neck region; it is characterized by eosinophilia and elevated serum IgE levels. IgG4-related disease (IgG4RD) is a fibroinflammatory condition characterized by swelling in single or multiple organs and the infiltration of IgG4 plasma cells. Herein, we presented two cases. Case 1 is a 38-year-old man with a painless mass in his right postauricular region, and Case 2 is a 36-year-old man with painless lymphadenopathy in his bilateral postauricular region. After surgical excision, they showed good recovery with no relapse. Although Cases 1 and 2 shared several overlapping pathological manifestations, there were a few differences that allowed the differentiation of KD and IgG4RD.

Plasmapheresis for a Patient with Catatonia and Systemic Lupus Erythematosus: A Case Report and Literature Review.

Neuropsychiatric systemic lupus erythematous (NPSLE) encompasses various psychiatric and neurological manifestations that develop in patients with systemic lupus erythematous (SLE), secondary to the involvement of the central nervous system (CNS). Although neuropsychiatric manifestations are commonly described in NPSLE, catatonia has been less frequently reported in patients with SLE. The roles of benzodiazepines (BZDs), immunosuppression, therapeutic plasma exchange (TPE), and electroconvulsive therapy (ECT) have all been reported in the management of catatonia. Furthermore, another research reported that catatonic symptoms associated with NPSLE were considerably improved by TPE. We, herein, report a case of catatonia in a patient with newly diagnosed NPSLE who exhibited a favorable prognosis through the early initiation of systemic immunosuppressants and TPE. Furthermore, we have reviewed the literature on the role of medication and plasmapheresis (PP), or TPE, in the treatment of catatonia that is associated with SLE.

Kimura's disease: A clinicopathological study of 23 cases.

Introduction: Kimura's disease (KD) is an uncommon lymphoproliferative fibroinflammatory disorder. Patients present with head and neck subcutaneous nodules with or without lymphadenopathy. Peripheral blood eosinophilia and elevated serum immunoglobulin E (IgE) levels are typical. This study was designed to delineate the clinicopathological features, pattern of care, and disease course of 23 Taiwanese patients with KD. Methods: We retrospectively analyzed the clinical data of 23 consecutive cases (16 male and 7 female; age at diagnosis: 12-77 years) of KD diagnosed at our institution from 2015 to 2020. Results: The median time from presentation to diagnosis was 1 month. Twenty-one patients presented with unilateral or bilateral head and neck masses. The remaining two presented with right flank and right arm lesions, respectively. Peripheral blood eosinophilia was observed in nine, and elevated IgE levels were observed in four. All were diagnosed using either excisional or core-needle biopsy. Seven patients underwent fine needle aspiration without a diagnostic yield. Salivary gland and lymph node involvement was observed in three and seven patients, respectively. Most lesions showed tissue eosinophilia (100%) and florid follicular hyperplasia (78.26%). Three cases had histological KD-IgG4-RD overlap and three had comorbid IgG4-RD were recognized. Thirteen patients underwent surgical resection, one received adjuvant therapy, and two received prednisolone monotherapy. Conclusion: KD should be considered in patients with subcutaneous masses, eosinophilia, and elevated IgE levels. Biopsy remains the gold standard of diagnosis. Increased recruitment of IgG4+ plasma cells is a common feature. Consideration of IgG4-RD in all KD patients may be prudent.

The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets.

Alternative splicing (AS) within the ß cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1ß + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. ExonImpact identified 129 events predicted to impact protein structure. AS occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB. Single molecule RNA FISH confirmed increased HLA-DMB splicing in pancreatic sections from human donors with established T1D and autoantibody positivity. Serine and Arginine Rich Splicing Factor 2 was implicated in 37.2% of potentially pathogenic events, including Exon5 exclusion in HLA-DMB. Together, these data suggest that dynamic control of AS plays a role in the ß cell response to inflammatory signals during T1D evolution.

The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets.

Alternative splicing (AS) within the ß cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1ß + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. ExonImpact identified 129 events predicted to impact protein structure. AS occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB. Single molecule RNA FISH confirmed increased HLA-DMB splicing in pancreatic sections from human donors with established T1D and autoantibody positivity. Serine and Arginine Rich Splicing Factor 2 was implicated in 37.2% of potentially pathogenic events, including Exon5 exclusion in HLA-DMB. Together, these data suggest that dynamic control of AS plays a role in the ß cell response to inflammatory signals during T1D evolution.

Lysosomal Acid Lipase Deficiency Controls T- and B-Regulatory Cell Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants.

Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune rejection and allows growth of human lung cancer cells in lal-/- mice. In the lal-/- lymph nodes, the percentages of both T- and B-regulatory cells (Tregs and Bregs, respectively) are increased, with elevated expression of programmed death-ligand 1 and IL-10, and decreased expression of interferon-γ. Levels of enzymes in the glucose and glutamine metabolic pathways are elevated in Tregs and Bregs of the lal-/- lymph nodes. Pharmacologic inhibitor of pyruvate dehydrogenase, which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal-/- lymph nodes. Blocking the mammalian target of rapamycin or reactivating peroxisome proliferator-activated receptor γ, an LAL downstream effector, reduces lal-/- Treg and Breg elevation and PD-L1 expression in lal-/- Tregs and Bregs, and improves human cancer cell rejection. Treatment with PD-L1 antibody also reduces Treg and Breg elevation in the lal-/- lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain antitumor immunity.

Cigarette smoke exposure impairs ß-cell function through activation of oxidative stress and ceramide accumulation.

OBJECTIVES: Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic ß-cell function using rodent and in vitro models. METHODS: Beginning at 8 weeks of age, C57BL/6 J mice were concurrently fed a high-fat diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured INS-1 ß-cells and primary islets were exposed ex vivo to CS extract (CSE), and ß-cell function and viability were tested. Since CS increases ceramide accumulation in the lung and these bioactive sphingolipids have been implicated in pancreatic ß-cell dysfunction in diabetes, islet and ß-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry. RESULTS: Compared to HFD-fed, ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and had accelerated worsening of their glucose tolerance. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of ß-cell dysfunction, significantly lower ß-cell mass (p = 0.017), reduced ß-cell proliferation (p = 0.006), and increased islet ceramide content compared to non-smoking control mice. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide levels, which was correlated with reduced insulin gene expression and glucose-stimulated insulin secretion, and increased ß-cell oxidative and endoplasmic reticulum (ER) stress. Treatment with the antioxidant N-acetylcysteine markedly attenuated the effects of CSE on ceramide levels, restored ß-cell function and survival, and increased cyclin D2 expression, while also reducing activation of ß-cell ER and oxidative stress. CONCLUSIONS: Our results indicate that CS exposure leads to impaired insulin production, processing, secretion and reduced ß-cell viability and proliferation. These effects were linked to increased ß-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of the mechanisms by which CS exposure impairs ß-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

Transthyretin Stimulates Tumor Growth through Regulation of Tumor, Immune, and Endothelial Cells.

Early detection of lung cancer offers an important opportunity to decrease mortality while it is still treatable and curable. Thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells, and alveolar myeloid cells of the CCSP-rtTA/(tetO)7-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. Further analyses showed that TTR treatment enhanced the reactive oxygen species production in myeloid cells and enabled them to become functional myeloid-derived suppressive cells. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, these 13 Stat3 downstream inducible secretory protein biomarkers potentially can be used for lung cancer diagnosis, classification, and as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood.

Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic ß-Cell.

Store-operated Ca2+ entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca2+ stores through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in ß-cell ER Ca2+ have been observed in diabetes. However, a role for impaired SOCE in this phenotype has not been tested. We measured the expression of SOCE molecular components in human and rodent models of diabetes and found a specific reduction in STIM1 mRNA and protein levels in human islets from donors with type 2 diabetes (T2D), islets from hyperglycemic streptozotocin-treated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca2+ oscillations and insulin secretion, and these effects were phenocopied by ß-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca2+ storage and increased ER stress, whereas STIM1 gain of function rescued ß-cell survival under proinflammatory conditions and improved insulin secretion in human islets from donors with T2D. Taken together, these data suggest that the loss of STIM1 and impaired SOCE contribute to ER Ca2+ dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca2+ transients may have the potential to improve ß-cell health and function.

Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.