Exploring the role of TNF-α, TGF-ß, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis.

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-ß levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-ß was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-ß levels in BD, and higher TGF-ß levels in SCH patients. Using moderated mediation analysis, TGF-ß was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.

Association of serum biomarkers level transforming growth factor-ß and tumor necrosis factor-α with diabetic neuropathy.

BACKGROUND: Many studies have examined the role of inflammation in the development of diabetic neuropathy (DPN). OBJECTIVE: Evaluate the relation of the serum level of Transforming Growth Factor-ß and Tumor Necrosis Factor-α and development of diabetic peripheral neuropathy DPN. METHODS: In a case-control study, randomly selected 140 diabetic patients were included, the randomly selected patients were divided equally and matched into a case group who have diabetic peripheral neuropathy and diabetic neuropathy-free patients as a control group. For both groups whole blood sample was examined to compare for (TGF-ß), and (TNF-α) levels determination by ELISA technique. RESULTS: The age of the study samples ranged from 25 to 80 years with a male ratio of 1.45:1 although the sex differences between both groups were not significant. The mean levels of (TNF-α) and (TGF-ß) was significantly higher among cases group than that of controls group (254.86 ± 75.9 vs158.01 ± 50.600) for TNF-α and for TGF- ß (312.85 ± 62.27 vs. 217.82 ± 52.95) respectively. Both TNF-α and TGF-ß have high sensitivity and specificity in detection of DPN. The sensitivity of TNF-α was 95.7% and specificity of 61.4% area under the ROC curve (AUC) of 0.870 ± 0.029, while the sensitivity of TGF-ß was 91.4%, and specificity of 67.1 with good area under the ROC curve (AUC) of 0.891 ± 0.026 (P=0.000). CONCLUSIONS: TNF-α and TGF -ß are significantly elevated levels in patients with DPN, these cytokines could be used as indicators for the development of DPN.

[Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-ß and IL-10 in Hemophilia A Patients with Fâ § Inhibitor].

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

FOXN2, identified as a novel biomarker in serum, modulates the transforming growth factor-beta signaling pathway through its interaction with partitioning defective 6 homolog alpha, contributing to the pathogenesis of gastric cancer.

BACKGROUND AND OBJECTIVE: Dysregulated expression of Forkhead Box N2 (FOXN2) has been detected in various cancer types. However, the underlying mechanisms by which FOXN2 contributes to the onset and progression of gastric cancer (GC) remain largely unexplored. This study aimed to elucidate the potential role of FOXN2 within GC, its downstream molecular mechanisms, and its feasibility as a novel serum biomarker for GC. METHODS: Tissue samples from GC patients and corresponding non-cancerous tissues were collected. Peripheral blood samples were obtained from GC patients and healthy controls. The expression of FOXN2 was determined using quantitative real-time PCR, western blotting, and immunohistochemistry. The expression of FOXN2 in GC cells was modulated by transfection with small interfering RNA (siRNA) or the pcDNA 3.1 expression vector. Cell proliferation was assessed using the Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assays. The migratory and invasive capacities of cells were evaluated by Transwell assays, apoptosis rates were measured by flow cytometry, and the expression of proliferative, apoptotic, and epithelial-mesenchymal transition (EMT) markers were assessed by western blot analysis. RESULTS: FOXN2 was found to be overexpressed in the serum, tissues, and cells of GC, correlating with distant metastasis and TNM staging. FOXN2 demonstrated diagnostic value in differentiating GC patients from healthy individuals, with higher levels of FOXN2 being indicative of poorer survival rates. Silencing FOXN2 in vitro inhibited the proliferation, invasion, migration, and EMT of GC cells, while promoting apoptosis. FOXN2 was shown to regulate the transforming growth factor-beta (TGFß) receptor signaling pathway in GC cells via its interaction with Partitioning Defective 6 Homolog Alpha (PARD6A). CONCLUSION: In summary, our data suggest that FOXN2 acts as an oncogenic factor in GC, modulating the TGFß pathway by binding to PARD6A, thereby influencing gastric carcinogenesis. This study underscores the functional significance of FOXN2 as a potential serum biomarker and therapeutic target in GC.

Elucidating the role of T-Reg related cytokines: serum transforming growth factor beta and interleukin-35 in alopecia areata.

Previous studies demonstrated that Th1 cytokines like IL-2, IL-12 and IFN-γ have initiatory role in alopecia areata (AA) and positive correlation with disease severity. They informed that serum levels of Th17 cytokines, IL-17, IL-22, IL-23 increased in active AA patients and corelated, particularly IL-17, with disease severity. In recent reports it was showed the balance between Th17 and Treg cells is crucial for maintaining tolerance to self-antigens, and an imbalance towards Th17 may contribute to the development of autoimmune diseases like AA. But research on serum Treg markers in AA is limited. It was aimed to investigate whether the Treg cells have a role in the pathogenesis of AA analyzing the serum levels of Treg cytokines IL-35 and TGF-ß in the patients with AA. 42 AA patients and 38 healthy controls were enrolled. Patient demographics, clinical data, disease severity assessed by Severity of Alopecia Tool (SALT) scores were recorded. Serum samples were collected and analyzed for TGF-ß and IL-35 levels using ELISA kits. The cytokine levels in both groups were statistically compared. Their relation with parameters of demographic and severity of disease was evaluated. The patient and control groups had no statistically significant difference, there was 71.4% males and 28.6% females in patient group, while the control group had 63.2% males and 36.8% females, Severity analysis classified 18 patients with mild AA, 19 with moderate AA, and 5 with alopecia totalis/areata universalis. While TGF-ß levels exhibited no significant difference between groups, IL-35 levels were significantly elevated in AA patients (p = 0.002). Logistic regression identified IL-35 as a significant parameter influencing disease status (OR = 1.055). Correlation analysis revealed a weak positive correlation between patient age and IL-35 levels (r = 0.436; p = 0.004). Notably, IL-35 levels displayed a significant decrease in individuals with antinuclear antibody (ANA) positivity. No correlations were identified between cytokine levels and disease severity, prognosis, or disease activity. Elevated IL-35 levels suggest that IL-35 and specific Treg cell subsets can play a role in AA pathogenesis. The nuanced roles of TGF-ß and IL-35 highlight the need for comprehensive studies to interpret their implications in the complex immunopathogenesis of AA. These findings open avenues for further research, positioning IL-35 as a prospective target for investigating and potentially intervening in AA pathogenesis.

Investigating the role of TGF-ß and BDNF in cancer-related depression: a primary cross-sectional study.

BACKGROUND: Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-ß (TGF-ß), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-ß and BDNF in cancer-related depression. METHODS: This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-ß and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The study revealed elevated plasma TGF-ß levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-ß and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-ß and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-ß and BDNF between cancer and non-cancer groups (P = 0.041). CONCLUSIONS: These findings underscore the active involvement of TGF-ß and BDNF crosstalk in the context of cancer-related depression.

Identification and validation of the surface proteins FIBG, PDGF-ß, and TGF-ß on serum extracellular vesicles for non-invasive detection of colorectal cancer: experimental study.

OBJECTIVES: The absence of non-invasive biomarkers for the early diagnosis of colorectal cancer (CRC) has contributed to poor prognosis. Extracellular vesicles (EVs) have emerged as promising candidates for cancer monitoring using liquid biopsy. However, the complexity of EVs isolation procedures and the absence of clear targets for detecting serum-derived EVs have hindered the clinical application of EVs in early CRC diagnosis. METHODS: In the discovery phase, we conducted a comprehensive 4D-DIA proteomic analysis of serum-derived EVs samples from 37 individuals, performing an initial screening of EVs surface proteins. In the technical validation phase, we developed an extraction-free CRC-EVArray microarray to assess the expression of these potential EVs surface proteins in a multi-centre study comprising 404 individuals. In the application phase, the authors evaluated the diagnostic efficacy of the CRC-EVArray model based on machine-learning algorithms. RESULTS: Through 4D-DIA proteomic analysis, the authors identified seven potential EVs surface proteins showing significantly differential expression in CRC patients compared to healthy controls. Utilizing our developed high-throughput CRC-EVArray microarray, we further confirmed the differential expression of three EVs surface proteins, FIBG, PDGF-ß and TGF-ß, in a large sample population. Moreover, we established an optimal CRC-EVArray model using the NNET algorithm, demonstrating superior diagnostic efficacy with an area under the curve (AUC) of 0.882 in the train set and 0.937 in the test set. Additionally, we predicted the functions and potential origins of these EVs-derived proteins through a series of multi-omics approaches. CONCLUSIONS: Our systematic exploration of surface protein expression profiles on serum-derived EVs has identified FIBG, PDGF-ß, and TGF-ß as novel diagnostic biomarkers for CRC. The development of CRC-EVArray diagnostic model based on these findings provided an effective tool for the large-scale CRC screening, thus facilitating its translation into clinical practice.

Safety of Three-Dimensional Conformal Radiotherapy on the Sheep with Pulmonary Cystic Echinococcosis: A Preliminary Study.

PURPOSE: Radiotherapy showed the potential to effectively kill the cysts of pulmonary cystic echinococcosis (CE). However, little is known about its safety. This study was designed to investigate the safety of three-dimensional conformal radiotherapy (3D-CRT) on the normal lung tissue adjacent to the cyst and blood of sheep naturally infected with pulmonary CE. METHODS: Twenty pulmonary CE sheep were randomly divided into control group (n = 5) and radiation groups with a dose of 30 Gray (Gy) (n = 5), 45 Gy (n = 5), and 60 Gy (n = 5), respectively. Animals in control group received no radiation. Heat shock protein 70 (Hsp70), tumor growth factor-ß (TGF-ß), matrix metalloproteinase-2 (MMP-2) and MMP-9 in the lung tissues adjacent to the cysts, which were considered to be closely related to the pathogenesis of CE, were evaluated after 3D-CRT. A routine blood test was conducted. RESULTS: The results showed that there were multiple cysts of various sizes with protoscoleces in the lung tissues of sheep, and necrotic cysts were found after 3D-CRT. 3D-CRT significantly increased the mRNA level of Hsp70, enhanced the protein level of TGF-ß and slightly increased the expression of MMP-2 and MMP-9 in lung tissues adjacent to the cysts. 3D-CRT did not significantly alter the amount of WBC, HB and PLT in sheep blood. CONCLUSIONS: The results suggested that 3D-CRT may suppress the inflammation and induce less damage of the normal lung tissues and blood. We preliminarily showed that 3D-CRT under a safe dose may be used to treat pulmonary CE.

Concomitant Expression of IL-6 and TGF-ß Cytokines and their Receptors in Peripheral Blood of Patients with Multiple Sclerosis: The Effects of INFß Drugs.

BACKGROUND: Concomitant signals from IL-6 and TGF-ß have a central role in the Th17 cells development and differentiation, and these cells are the main promoters of demyelinating inflammation in the central nervous system (CNS) resulting in multiple sclerosis (MS). OBJECTIVES: To evaluate the simultaneous IL-6 and TGF-ß gene and their receptor protein expression in patients with Relapsing-Remitting (RR)-MS. MATERIALS AND METHODS: IL-6 and TGF-ß mRNA and their receptor expression on the surface of CD4+T cells were evaluated using real-time PCR (RT-PCR) and flow cytometry, respectively. RESULTS: The IL-6 mRNA expression in patients with RRMS was significantly higher than in the controls (p= 0.019). When patients who did not receive any other treatment were compared with the controls, the significant difference was substantial (p=0.006). The TGF-ß mRNA expression in patients was lower than in the controls (p = 0.03). However, in patients receiving IFNß, it increased compared with the other patients (p= 0.036). There was no difference in cytokine receptor expression between patients and the control group. CONCLUSION: Our data conclude an increase and decrease in mRNA expression levels of IL-6 and TGF-ß in patients with RRMS, respectively. Moreover, there were no significant differences in receptor expression of either cytokines. Based on our data the balance of TGF and IL-6 appears to have a positive impact on the disease control.

Human platelets release TGFBIp in acute myocardial infarction.

Transforming growth factor-ß-induced protein (TGFBIp) is released from activated platelets and promotes pro-thrombotic complications like pulmonary embolism. The role of TGFBIp in acute coronary syndrome, especially with a focus on platelets, has not been investigated so far. Using ELISA and immunoblotting, we demonstrate platelet TGFBIp release in patients with myocardial infarction (MI). We investigated TGFBIp-induced platelet adhesion and rolling by flow chamber and chemotactic effects of TGFBIp in transwell experiments. Immunochemistry staining of arterial vessels detected TGFBIp and the platelet-specific protein GPVI in the vessel wall.We demonstrate for the first time that platelet TGFBIp release is significantly increased in MI and correlates with the severity of acute coronary syndromes (STEMI, NSTEMI). After activation with TRAP, platelets release TGFBIp and TGFBIp itself activates platelets. Under flow, TGFBIp-mediated platelet rolling and adherence similarly to collagen. TGFBIp significantly increased platelet transmigration and we demonstrate TGFBIp deposits in the wall of human arteries. In this study, we add novel aspects to the role of TGFBIp in acute coronary syndrome by demonstrating that TGFBIp is partially released from platelets during MI and has activating, pro-adhesive and pro-migratory effects on platelets that could contribute to the disease development of coronary vascular inflammation and MI.

Investigation of serum levels of orexin-A, transforming growth factor ß, and leptin in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disease affecting various inflammatory and nutritional parameters. Therefore, this study aimed to investigate the relationship between the Body Mass Index (BMI) of MS patients and the serum levels of leptin, orexin-A, and Transforming Growth Factor ß (TGF-ß). METHODS: This cross-sectional study included 25 patients suffering from MS and 40 healthy individuals as the case and control groups, respectively. The serum levels of leptin, orexin-A, and TGF-ß were assessed in the participants using the Enzyme-Linked Immunosorbent Assay methods. Moreover, data were analyzed using the descriptive statistical indices, t-test, chi-square test, and linear regression test. RESULTS: According to our results, the participants' mean age was 38.04 ± 7.53 and 40.23 ± 5.88 in the case and control groups, respectively. Also, the groups were not significantly different in gender, age, alcohol consumption, and smoking (p > 0.05). It was found that the mean serum levels of orexin-A and TGF-ß were significantly lower in the MS patients compared to the control group, while the mean serum leptin levels were significantly higher (42.8 vs. 18.9 ng/ml, p < 0.001). Moreover, there was no significant relationship between the BMI of the MS patients and their serum levels of orexin-A, TGF-ß, and leptin (p > 0.05). CONCLUSIONS: In conclusion, we found significantly lower levels of orexin-A and TGF-ß and a significantly higher level of leptin in the MS patients compared to the control group. In addition, there was no significant relationship between the BMI and the serum levels of orexin-A, TGF-ß, and leptin in MS patients.

Increased levels of cortisol are associated with the severity of experimental visceral leishmaniasis in a Leishmania (L.) infantum-hamster model.

BACKGROUND: Several infectious diseases are associated with hypothalamic-pituitary-adrenal (HPA) axis disorders by elevating circulating glucocorticoids (GCs), which are known to have an immunosuppressive potential. We conducted this study in golden hamsters, a suitable model for human visceral leishmaniasis (VL), to investigate the relationship of Leishmania (L.) infantum infection on cortisol production and VL severity. METHODS: L. infantum-infected (n = 42) and uninfected hamsters (n = 30) were followed-up at 30, 120, and 180 days post-infection (dpi). Plasma cortisol was analyzed by radioimmunoassay and cytokines, inducible nitric oxide synthase (iNOS), and arginase by RT-qPCR. RESULTS: All hamsters showed splenomegaly at 180 dpi. Increased parasite burden was associated with higher arginase expression and lower iNOS induction. Cortisol levels were elevated in infected animals in all-time points evaluated. Except for monocytes, all other leucocytes showed a strong negative correlation with cortisol, while transaminases were positively correlated. Immunological markers as interleukin (IL)-6, IL-1ß, IL-10, and transforming growth-factor-ß (TGF-ß) were positively correlated to cortisol production, while interferon-γ (IFN-γ) presented a negative correlation. A network analysis showed cortisol as an important knot linking clinical status and immunological parameters. CONCLUSIONS: These results suggest that L. infantum increases the systemic levels of cortisol, which showed to be associated with hematological, biochemical, and immunological parameters associated to VL severity.

The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a disease with chronic nonspecific low-grade inflammation. The imbalance of immune cells exists in PCOS. Several studies have found that heat shock protein 70 (HSP70) may be involved in the immunological pathogenesis of PCOS, but the relationship between HSP70 and Regulatory T cell (Treg)/T helper cell 17(Th17) ratio remains unclear. This study aims to explore the correlation between HSP70 and Treg/Th17 ratio and to provide evidence for the role of HSP70 in the immunological etiology of PCOS. RESULTS: There was no significant difference in age and body mass index (BMI) between the two groups. The concentrations of basal estradiol (E2), basal follicle-stimulating hormone (FSH) did not show a significant difference between the two groups. The concentrations of basal luteinizing hormone (LH) (P < 0.01), testosterone (T) (P < 0.01), glucose (P < 0.001) and insulin (P < 0.001) in PCOS patients were significantly higher than those in the control group. The protein levels of HSP70 were significantly higher in serum in the PCOS group (P < 0.001). The percentage of Treg cells was significantly lower (P < 0.01), while the percentage of the Th17 cells of the PCOS group was significantly higher than that of the control group (P < 0.05). The ratio of Treg/Th17 in the PCOS group was significantly lower (P < 0.001). The concentrations of Interleukin (IL)-6, IL-17, and IL-23 were significantly higher, while the levels of IL-10 and Transforming growth factor-ß (TGF-ß) were significantly lower in the PCOS group (P < 0.001). Spearman rank correlation analysis showed a strong negative correlation of serum HSP70 levels with Treg/Th17 ratio, IL-10, and TGF-ß levels. In contrast, HSP70 levels were significantly positively correlated with IL-6, IL-17, IL-23, LH, insulin, and glucose levels. CONCLUSION: The abnormal level of HSP70 is correlated with Treg/Th17 imbalance and corresponding cytokines, which indicates that HSP70 may play an important role in PCOS immunologic pathogenesis.

Untimely TGFß responses in COVID-19 limit antiviral functions of NK cells.

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

Lower expression of Hsa_circRNA_102682 in diabetic hyperhomocysteinemia negatively related to creatinemia is associated with TGF-ß and CTGF.

BACKGROUND: Diabetic nephropathy is a kidney disease caused by long-term hyperglycemia. Hsa_circRNA_102682 is related to the pathogenesis of preeclampsia. Preeclampsia is related to hypertension and proteinuria, and diabetic nephropathy is mainly manifested by hypertension and proteinuria. The main pathological change in diabetic nephropathy is glomerular fibrosis. METHODS: This study used serum samples of patients treated at Li Huili Eastern Hospital, Ningbo, China, from July 10, 2018 to February 15, 2019. We included 73 patients with diabetes and divided them into a normal-homocysteine group and a high-homocysteine group. We selected used quantitative reverse transcriptase-polymerase chain reaction to measure Hsa_circRNA_102682 concentration in the serum. Serum transforming growth factor-beta and connective tissue growth factor levels were tested using ELISA. The Pearson correlation test was used to assess the correlations between Hsa_circRNA_102682, transforming growth factor-beta, connective tissue growth factor, homocysteine, and creatinine. RESULT: Hsa_circRNA_102682 was significantly lower in diabetic patients with high levels of homocysteine than in those with normal levels of homocysteine, whereas transforming growth factor-beta and connective tissue growth factor levels were higher in diabetic patients with hyperhomocysteinemia. Hsa_circRNA_102682 was negatively correlated with the levels of transforming growth factor-beta, connective tissue growth factor, homocysteine, and creatinine. Transforming growth factor-beta and connective tissue growth factor were both positively correlated with homocysteine and creatinine. CONCLUSION: Low Hsa_circRNA_102682 was associated with high levels of transforming growth factor-beta and connective tissue growth factor as well as homocysteine and creatinine. These results suggest that Hsa_circRNA_102682 might be related to the pathogenesis of hyperhomocysteinemia in diabetic nephropathy.

Risk Prediction Model Based on Biomarkers of Remodeling in Patients with Acute Anterior ST-Segment Elevation Myocardial Infarction.

BACKGROUND The aim of the present study was to develop a risk prediction model in patients with acute anterior ST-segment elevation myocardial infarction (STEMI). MATERIAL AND METHODS Clinical data from 333 patients with acute anterior STEMI were retrospectively analyzed. Clinical echocardiographic and angiographic data from patients with left ventricular remodeling (LVR) and those without LVR were compared. Factors that influenced risk were identified using multivariate logistic regression analysis. The area under the curve (AUC) of the receiver operating characteristic curve was used to assess the diagnostic performance of the model. RESULTS After 6-month follow-up, 135 of the patients experienced LVR (LVR group), whereas 198 did not (non-LVR group). Results of multivariate analysis showed that the number of stenosed coronary vessels, left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), transforming growth factor-beta (TGF-ß) at admission, and cardiac troponin I 3 days after admission (3-d cTnI) were all factors predictive of LVR in patients with acute anterior STEMI (all P<0.05). The established prediction model was Y=-20.639+0.711×number of stenosed coronary vessels + 0.137×LVEDV-0.129×LVEF+0.026×TGF-ß at admission + 0.162×3-d cTnI. The estimated AUC of this model was 0.978 (95% confidence interval [CI] 0.955-0.991), significantly superior to the single-factor numbers for stenosed coronary vessel of 0.650 (95% CI 0.597-0.702), LVEDV of 0.876 (95% CI 0.836-0.910), LVEF of 0.684 (95% CI 0.631-0.734), TGF-ß at admission of 0.696 (95% CI 0.644-0.745), cTnI at admission of 0.913 (95% CI 0.877-0.941), and 3-d cTnI of 0.945 (95% CI 0.914-0.967). CONCLUSIONS The established model had excellent diagnostic accuracy for predicting LVR in patients with acute anterior STEMI.

A Component-Resolved Therapeutic Vaccine for Cockroach Allergy Made of Per a 9 and Transforming Growth Factor-ß Homologue, an Immunosuppressive Protein of Brugia malayi.

Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (Periplaneta americana) major allergen (Per a 9) and immunosuppressive protein of Brugia malayi nematode named transforming growth factor-beta homologue (TGH) in treatment of CR allergy were investigated along with two other vaccines (L-Per a 9 alone and L-TGH alone). All three vaccines could reduce pathogenic type 2 response and lung immunopathology in the vaccines-treated CR-allergic mice, but by different mechanisms. L-Per a 9 caused a deviation of the pathogenic type 2 to type 1 response (IFN-γ-upregulation), whereas the L-(TGH + Per a 9) and L-TGH generated regulatory immune responses including up-expression of immunosuppressive cytokine genes and increment of serum adenosine and lung indoleamine-2,3-dioxygenase-1 which are signatures of regulatory T cells (Tregs) and tolerogenic dendritic cells, respectively. The L-(TGH + Per a 9) should be further evaluated towards clinical application, as this vaccine has a propensity to induce broadly effective therapeutic effects for inhalant allergies.

Bifunctional TGF-ß trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors.

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-ß (TGF-ß) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-ß neutralizing activity in vitro and sequesters plasma TGF-ß in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+ T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.

Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-ß, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs.