Elucidation of Spatial Cooperativity in Chemo-Immunotherapy by a Sequential Dual-pH-Responsive Drug Delivery System.

Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL16.9, Dox5.3), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox)5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8+ T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development.

FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress­mediated ferroptosis.

BACKGROUND: Ferroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism. METHODS: We identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real-time PCR (qRT-PCR) and western blot analysis. RESULTS: The expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway. CONCLUSIONS: Collectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.

Inhibiting sEH suppresses NF-κB p65 signaling and reduces CXCL10 expression as a potential therapeutic target in HT.

BACKGROUND: Although Hashimoto's thyroiditis (HT) is one of most common autoimmune thyroid diseases, its treatment remains focused on symptom relief. The soluble epoxide hydrolase (sEH) shows potential functions as drug target in alleviating some autoimmune diseases, however, we seldom know its role in HT. METHODS: The protein expression of sEH and related downstream molecules were evaluated by immunohistochemistry, western blotting, enzyme linked immunosorbent assay or immunofluorescence staining. RNA sequencing of tissue samples was performed to analyze differential genes and dysregulated pathways in HT and controls. The thyroid follicular epithelial cells (TFECs) and rat HT model were used to verify the biological function of sEH and the inhibition role of adamantyl-ureido-dodecanoic acid (AUDA) in HT. RESULTS: The sEH was significantly up-regulated in HT patients compared with healthy individuals. Transcriptome sequencing showed cytokine-related pathways and chemokine expression, especially chemokine CXCL10 and its receptor CXCR3 were aberrant in HT patients. In TFECs and rat HT model, blocking sEH by AUDA inhibitor could effectively inhibit the autoantibody, pro-inflammatory NF-κB signaling, chemokine CXCL10/CXCR3 expression and type-1 helper CD4+ T cells. CONCLUSIONS: Our findings suggest that sEH/NF-κB p65/CXCL10-CXCR3 might be promising therapeutic targets for HT.

Structural and Functional Alterations of Hippocampal Subfields in Patients with Adult-onset Primary Hypothyroidism.

CONTEXT: Hypothyroidism is often associated with cognitive and emotional dysregulation; however, the underlying neuropathological mechanisms remain elusive. OBJECTIVE: The study aimed to characterize abnormal alterations in hippocampal subfield volumes and functional connectivity (FC) in patients with subclinical hypothyroidism (SCH) and overt hypothyroidism (OH). METHODS: This cross-sectional observational study comprised 47 and 40 patients with newly diagnosed adult-onset primary SCH and OH, respectively, and 53 well-matched healthy controls (HCs). The demographics, clinical variables, and neuropsychological scale scores were collected. Next, the hippocampal subfield volumes and seed-based FC were compared between the groups. Finally, correlation analyses were performed. RESULTS: SCH and OH exhibited significant alterations in cognitive and emotional scale scores. Specifically, the volumes of the right granule cell molecular layer of dentate gyrus (GC-ML-DG) head, CA4 and CA3 head were reduced in SCH and OH groups. Moreover, the volumes of the right molecular layer (ML) head, CA1 body, left GC-ML-DG head, and CA4 head were lower in SCH. In addition, the hippocampal subfield volumes decreased more significantly in SCH than OH. The seed-based FC decreased in SCH but increased in OH compared with HCs. Correlation analyses revealed thyroid hormone (TH) was negatively correlated with FC values in hypothyroidism. CONCLUSIONS: Patients with SCH and OH might be at risk of cognitive decline, anxiety, or depression, and exhibited alterations in the volume and FC in specific hippocampal subfields. Furthermore, the reduction in volume was more pronounced in SCH. This study provides novel insights into the neuropathological mechanisms of brain impairment in hypothyroidism.

Impaired Sensitivity to Thyroid Hormones is Associated with the Risk of Diabetic Nephropathy in Euthyroid Patients with Type 1 Diabetes Mellitus.

Purpose: This study aims to investigate the relationship between thyroid and type 1 diabetic nephropathy (T1DN) in euthyroid populations, focusing on thyroid hormone sensitivity. Methods: A cross-sectional study was conducted between January 2016 and December 2021, including 357 euthyroid patients with type 1 diabetes mellitus (T1DM). Parameters representing thyroid hormone sensitivity were assessed, including the thyroid feedback quantile-based index (TFQI), parameter thyroid feedback quantile index (PTFQI), thyroid stimulating hormone index (TSHI), thyrotropin thyroxine resistance index (TT4RI), and free triiodothyronine/free thyroxine (FT3/FT4). Logistic regression and restricted cubic spline regression were performed to detect the association between thyroid hormone sensitivity and the risk of T1DN. Results: The study found a negative correlation between the risk of T1DN and FT3/FT4 in euthyroid T1DM patients (OR 0.71, 95% CI 0.51-0.97, P <0.01). PTFQI (P<0.05), TSHI (P<0.05), and TT4RI (P<0.01) showed an M-shaped nonlinear relationship with the risk of T1DN. Elevated risk of T1DN was associated with PTFQI, TSHI, and TT4RI values outside the range of zero, 2.3-3.88, and 27.56-32.19, respectively. Conclusion: This study confirms the relationship between impaired thyroid hormone sensitivity and the risk of T1DN in euthyroid patients. It emphasizes the importance of evaluating thyroid hormone sensitivity in T1DM patients, even when their thyroid function appears normal, to promptly prevent the occurrence of T1DN.

Study on the Ultimate Load Failure Mechanism and Structural Optimization Design of Insulators.

This study aims to enhance the productivity of high-voltage transmission line insulators and their operational safety by investigating their failure mechanisms under ultimate load conditions. Destructive tests were conducted on a specific type of insulator under ultimate load conditions. A high-speed camera was used to document the insulator's failure process and collect strain data from designated points. A simulation model of the insulator was established to predict the effects of ultimate loads. The simulation results identified a maximum first principal stress of 94.549 MPa in the porcelain shell, with stress distribution characteristics resembling a cantilever beam subjected to bending. This implied that the insulator failure occurred when the stress reached the bending strength of the porcelain shell. To validate the simulation's accuracy, bending and tensile strength tests were conducted on the ceramic materials constituting the insulator. The bending strength of the porcelain shell was 100.52 MPa, showing a 5.6% variation from the simulation results, which indicated the reliability of the simulation model. Finally, optimization designs on the design parameters P1 and P2 of the insulator were conducted. The results indicated that setting P1 to 8° and P2 to 90.062 mm decreased the first principal stress of the porcelain shell by 47.6% and Von Mises stress by 31.6% under ultimate load conditions, significantly enhancing the load-bearing capacity. This research contributed to improving the production yield and safety performance of insulators.

Effect of glycemic control on cognitive function in patients with type 1 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: It is controversial whether the level of glycemic control in patients with type 1 diabetes mellitus (T1DM) correlates with reduced cognitive function. This study explored the influence of glycemic management quality on cognitive function in T1DM patients by examining the association between glycemic control level and impaired cognitive function. METHODS: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal database, Wanfang database, and China Biology Medicine disc database were systematically searched to identify eligible studies published before January 2023. Search, selection, and data extraction were performed by two independent reviewers. RevMan 5.4 software was used for meta-analysis, and standardized mean difference (SMD) between groups was calculated. RESULTS: Six studies involving 351 patients with T1DM were included in this study. Compared with T1DM subjects with good glycemic control, those with poor glycemic control performed worse in full-scale intellectual quotient (P = 0.01, SMD = -0.79, 95%CI = -1.42 to -0.17), but no significant differences were observed in verbal intellectual quotient (P = 0.08, SMD = -1.03, 95%CI = -2.20 to 0.13), memory (P = 0.05, SMD = -0.41, 95%CI = -0.82 to 0.00), and attention (P = 0.23, SMD = -0.26, 95%CI = -0.69 to 0.16). CONCLUSIONS: T1DM patients with suboptimal glycemic control may have a worse cognitive function, mainly focusing on the full-scale intellectual quotient. The current study highlights the significance of maintaining satisfactory glycemic control in T1DM patients to improve their health status and quality of life. Standardized tests should be employed in clinical neuropsychological practice to provide early and complete cognitive assessment of individuals with poor glycemic control. SYSTEMATIC REVIEW REGISTRATION: The study protocol has been registered in the PROSPERO database (CRD42023390456).

[MOR106 alleviates inflammation in mice with atopic dermatitis by blocking the JAK2/STAT3 signaling pathway and inhibiting IL-17C-mediated Tfh cell differentiation].

Objective To explore the significance of interleukin-17C(IL-17C)-mediated follicular helper T cell (Tfh) differentiation in atopic dermatitis (AD) model. Methods BALB/c mice were divided into control group, AD model group, low-dose MOR106 (anti-IL-17C huIgG1)(MDR106-L)treatment group and high-dose MOR106 (MOR106-H) treatment group, 8 mice in each group. Except for the control group, all the other groups were treated with 2, 4- dinitrochlorobenzene (DNCB) to establish AD models. The low-dose and high-dose MOR106 groups were treated with 5 mg/kg or 10 mg/kg MOR106 respectively. The differentiation of Tfh cell subsets in peripheral blood of mice was analyzed by flow cytometry, and the expression of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) signal pathway protein in skin tissue was detected by Western blot analysis. Results Compared with the control group, the dermatitis severity score, mass difference between two ears, spleen mass and spleen index of DNCB group increased significantly, while those of MOR106-L group and MOR106-H group decreased significantly. Compared with the control group, the Tfh subgroup of AD mice showed deregulated differentiation, resulting in a significant increase in the percentage of CD4+CXCR5+IFN-γ+Tfh1 cells, CD4+CXCR5+IL-17A+Tfh17 and CD4+CXCR5+IL-21+Tfh21 cells, and a significant decrease in the percentage of CD4+CXCR5+IL-10+Tfh10 cells and CD4+CXCR5+FOXP3+Tfr cells in peripheral blood. The protein levels of phosphorylated JAK2(p-JAK2) and p-STAT3 were significantly increased. MOR106 effectively reversed these changes of Tfh1, Tfh10, Tfh17, Tfh21 and Tfr cells in peripheral blood of AD mice. Compared with AD group, the levels of p-JAK2 and p-STAT3 protein in low-dose and high-dose MOR106 treatment groups decreased significantly. Conclusion MOR106 can reduce the inflammatory response of AD mice by blocking JAK2/STAT3 signaling pathway and inhibiting the differentiation of Tfh cells mediated by IL-17C.

Hepatic Sinusoid Capillarizate via IGTAV/FAK Pathway Under High Glucose.

The incidence of diabetic patients with non-alcoholic fatty liver disease (NAFLD) is continuously increasing worldwide. However, the specific mechanisms of NAFLD patients with diabetes are still not clear. Recent studies have indicated that integrins play an important role in NAFLD. In this study, we considered the relationship between integrin αv (IGTAV)/FAK pathway and sinusoidal capillarization. We investigated the difference between the expression of IGTAV, laminin (LN), focal adhesion kinase (FAK), and phosphor-FAK protein in human liver sinusoidal endothelial cells (HLSECs) to explore the specific mechanisms of the diseases of NAFLD with diabetes under high glucose. We cultured and identified the HLSECs and constructed the recombinant lentivirus vector with IGTAV shRNA by quantitative real-time PCR (qRT-PCR) to silence the IGTAV gene. Cells were divided into groups of 25 mmol/L glucose and 25 mmol/L mannitol. We measured the protein levels of IGTAV, LN, FAK, and phosphor-FAK by western blot at 2 h, 6 h, and 12 h before and after IGTAV gene silencing. The lentivirus vector was successfully constructed with IGTAV shRNA. The HLSECs under high glucose were observed by scanning electron microscope. SPSS19.0 was used for statistical analysis. High glucose significantly increased the expression of IGTAV, LN, and phosphor-FAK protein in HLSECs; the shRNA IGTAV could effectively inhibit the expression of phosphor-FAK and LN at 2 h and 6 h. Inhibition of the phosphor-FAK could effectively decrease the expression of LN in HLSECs at 2 h and 6 h under high glucose. Inhibition of IGTAV gene of HLSECs under high glucose could improve hepatic sinus capillarization. Inhibition of IGTAV and phosphor-FAK decreased the expression of LN. High glucose led to hepatic sinus capillarization via IGTAV/ FAK pathway.

Naringenin ameliorates atopic dermatitis by inhibiting inflammation and enhancing immunity through the JAK2/STAT3 pathway.

OBJECTIVE: Atopic dermatitis (AD) is an inflammatory skin disease. Naringenin (Nar) possesses an anti-inflammatory property. This paper attempts to discuss the functional mechanism of Nar in AD mice through the Janus kinase 2 (JAK2)/signal transducer and activation of transcription 3 (STAT3) pathway. METHODS: Mouse models of DNFB-induced AD were established and treated with Nar, followed by intraperitoneal injection with the JAK2/STAT3 pathway activator Coumermycin A1. Dermatitis severity was scored and the thickness of right ear was measured. The pathological changes in dorsal skin tissues were observed by HE staining. The number of infiltrated mast cells and eosinophilic granulocytes was counted by TB staining. The serum IgE level and levels of TNF-α, IL-6, IFN-γ, IL-12, and IL-5 in dorsal skin tissues were measured by ELISA. The levels of p-JAK2, JAK2, p-STAT3, and STAT3 were determined by Western blot. RESULTS: Nar decreased dermatitis scores and right ear thickness, alleviated skin lesions, and reduced the number of infiltrated mast cells and eosinophilic granulocytes in AD mice. The serum IgE level and levels of TNF-α, IL-6, IFN-γ, IL-12, and IL-5 in dorsal skin tissues of AD mice were diminished after Nar treatment in a dose-dependent manner. Nar inhibited the activation of the JAK2/STAT3 pathway. The activation of the JAK2/STAT3 pathway partially nullified the therapeutic function of Nar on AD mice. CONCLUSION: Nar protects mice from AD by inhibiting inflammation and promoting immune responses through the inhibition of the JAK2/STAT3 pathway.

Effect of Thyroid-Stimulating Hormone Suppression Therapy on Cardiac Structure and Function in Patients With Differentiated Thyroid Cancer After Thyroidectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppression therapy on cardiac structure and function in patients with differentiated thyroid cancer (DTC) following thyroidectomy. METHODS: Two investigators independently searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published from inception to January 6, 2023, without any restrictions on language. Standard mean differences and 95% confidence intervals were calculated using fixed or random effects models. Thirteen clinical outcomes were analyzed, mainly evaluating cardiac morphology, systolic function, and diastolic function. RESULTS: Thirteen studies were included in the quantitative analysis. Compared to healthy controls, left ventricular mass index, left ventricular posterior wall thickness, interventricular septal thickness, and isovolumic relaxation time values increased; the ratio of E-wave velocity to A-wave velocity and E-wave velocity values decreased. The left ventricular ejection fraction and cardiac output did not change in patients with DTC who underwent long-term TSH suppression therapy. Interventricular septal thickness values were significantly correlated with the duration of TSH suppression therapy. CONCLUSION: Long-term TSH suppression therapy leads to cardiac hypertrophy and impaired cardiac diastolic function in patients with DTC. These changes may be related to the duration of TSH suppression therapy. Large prospective studies with long follow-up periods are needed to validate these findings.

Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

Lipidomics analysis of impaired glucose tolerance and type 2 diabetes mellitus in overweight or obese elderly adults.

Aims: Aging, obesity, and type 2 diabetes mellitus (T2DM) form a metabolic disease continuum that has a continuously increasing prevalence. Lipidomics explains the complex interactions between lipid metabolism and metabolic diseases. We aimed to systematically investigate the plasma lipidome changes induced by newly diagnosed impaired glucose tolerance (IGT) and T2DM in overweight/obese elderly individuals and to identify potential biomarkers to differentiate between the IGT, T2DM, and control groups. Methods: Plasma samples from 148 overweight/obese elderly individuals, including 52 patients with IGT, 47 patients with T2DM, and 49 euglycemic controls, were analyzed using a high-coverage nontargeted absolute quantitative lipidomics approach. Results: We quantified 1840 lipids from thirty-eight classes and seven lipid categories. Among overweight/obese elderly individuals, the lipidomic profiles of IGT and T2DM patients were significantly different from those of controls, while they were similar in the IGT and T2DM groups. The concentrations of diglycerides, triglycerides, phosphatidylcholines, and ceramides were obviously altered in the IGT and T2DM groups. Particularly, IGT and T2DM induced the accumulation of triglycerides with longer carbon atom numbers (C44-50) and saturated or lower double bond numbers (n (C=C) = 0-2). Furthermore, a total of 17 potential lipidic biomarkers were identified to successfully differentiate between the IGT, T2DM, and control groups. Conclusions: In overweight/obese elderly patients, IGT and T2DM induced apparent lipidome-wide changes. This study's results may contribute to explaining the complex dysfunctional lipid metabolism in aging, obesity, and diabetes.

DAP1 regulates osteoblast autophagy via the ATG16L1-LC3 axis in Graves' disease-induced osteoporosis.

OBJECTIVE: This study aimed to uncover a critical protein and its mechanisms in modulating autophagy in Graves' disease (GD)-induced osteoporosis (OP). METHODS: We discovered the target protein, death-associated protein 1 (DAP1), using bone proteomics analysis. Furthermore, genetic overexpression and knockdown (KD) of DAP1 in bone and MC3T3-E1 cells revealed DAP1 effects on autophagy and osteogenic markers, and autophagic vacuoles in cells were detected using transmission electron microscopy and the microtubule-associated protein 1 light chain 3 alpha (MAP1LC3/LC3) dual fluorescence system. An autophagy polymerase chain reaction (PCR) array kit was used to identify the key molecules associated with DAP1-regulated autophagy. RESULTS: DAP1 levels were significantly higher in the bone tissue of GD mice and MC3T3-E1 cells treated with triiodothyronine (T3). DAP1 overexpression reduced LC3 lipidation, autophagic vacuoles, RUNX family transcription factor 2 (RUNX2), and osteocalcin (OCN) expression in MC3T3-E1 cells, whereas DAP1 KD reversed these changes. In vivo experiments revealed that GD mice with DAP1 KD had greater bone mass than control mice. DAP1-overexpressing (OE) cells had lower levels of phosphorylated autophagy-related 16-like 1 (ATG16L1) and LC3 lipidation, whereas DAP1-KD cells had higher levels. CONCLUSIONS: DAP1 was found to be a critical regulator of autophagy homeostasis in GD mouse bone tissue and T3-treated osteoblasts because it negatively regulated autophagy and osteogenesis in osteoblasts via the ATG16L1-LC3 axis.

Long-term outcomes in lean and non-lean NAFLD patients: a systematic review and meta-analysis.

BACKGROUND: Although nonalcoholic fatty liver disease (NAFLD) commonly occurs in overweight or obese individuals, it is increasingly being identified in the lean population. The association between lean and an increased risk of all-cause mortality among patients with NAFLD remains controversial. We aimed to perform a systematic review and meta-analysis of the literature to evaluate this association and compare the long-term outcomes of lean NAFLD patients and non-lean NAFLD patients. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, and Chinese Biomedical Literature Database (CBM) from inception to October 15, 2021, for relevant original research articles without any language restrictions. Our primary outcome was to compare the all-cause mortality in lean NAFLD patients and non-lean NAFLD patients by qualitative synthesis. Relative risks (RRs) and corresponding 95% confidential intervals (CIs) were pooled with a random effect model. Heterogeneity was evaluated using I-squared (I²) statistics while publication bias was determined using Egger's tests. Subgroup and sensitivity analyses were performed. As for secondary outcomes, we estimated total, cardiovascular, and liver-related mortality, as well as the incidence of diabetes, hypertension, cirrhosis, and cancer in lean and non-lean individuals with NAFLD by quantitative synthesis. Person-years of follow-up were used as the denominator to estimate the mortality and incidence. RESULTS: We identified 12 studies (n = 26,329), 7 of which (n = 7924) were used to evaluate the risk of all-cause mortality between lean and non-lean NAFLD patients. Lean patients with NAFLD were found to be at an elevated risk of death compared to non-lean patients (RR = 1.39, 95% CI 1.08-1.82, heterogeneity: I² = 43%). Among the lean NAFLD population, all-cause mortality was 13.3 (95% CI: 6.7-26.1) per 1000 person-years, 3.6 (95% CI: 1.0-11.7) for liver-related mortality, and 7.7 (95% CI: 6.4-9.2) for cardiovascular-related mortality. The incidence of new-onset diabetes was 13.7 (95% CI 8·2-22.7) per 1000 person-years, new-onset hypertension was 56.1 (95% CI: 40.2-77.9), cirrhosis was 2.3 (95% CI: 1.0-5.0), and cancer was 25.7 (95% CI: 20.3-32.4). CONCLUSIONS: Lean patients with NAFLD had a higher risk of all-cause death than non-lean patients. Body mass index (BMI) should not be used as a criterion to determine whether further observation and therapy of patients with NAFLD are warranted.

Alterations in Gray Matter Morphology and Functional Connectivity in Adult Patients with Newly Diagnosed Untreated Hypothyroidism.

Background: Untreated adult hypothyroidism may be associated with cognitive and emotional impairment, but the precise underlying neuropathological mechanism is unknown. We investigated the brain morphological and functional abnormalities associated with cognition and emotion in hypothyroidism. Methods: This is a cross-sectional observational study. Forty-four newly diagnosed adult hypothyroid patients and 54 well-matched healthy controls (HCs) were enrolled. All participants underwent three-dimensional T1-weighted imaging and resting-state functional magnetic resonance imaging (MRI). Morphological and seed-based functional connectivity (FC) analyses were performed to compare the intergroup differences. Neuropsychological tests, including the Montreal Cognitive Assessment (MoCA) Scale, 24-item Hamilton Depression Rating Scale (HAMD-24), and Hamilton Anxiety Rating Scale (HAMA) were administered. Thyroid function test and blood lipid levels were measured. Correlations were computed between neuropsychological and biochemical measures with neuroimaging indices. Sensitive morphological or functional neuroimaging indicators were identified using receiver operating characteristic (ROC) analysis. Results: Compared with HCs, hypothyroid patients demonstrated lower total and subdomain scores on the MoCA and higher HAMD-24 and HAMA scores. Morphological analysis revealed the hypothyroid patients had significantly reduced gray matter (GM) volumes in the right superior frontal gyrus, superior temporal gyrus, left dorsolateral superior frontal gyrus, middle frontal gyrus, and supplementary motor area as well as significantly increased GM volumes in the bilateral cerebellar Crus I and left precentral gyrus. Furthermore, seed-based FC analysis of hypothyroid patients showed increased FC between the right cerebellar Crus I and left precentral gyrus, triangular part of the inferior frontal gyrus, and angular gyrus of the inferior parietal lobe. The language scores of the MoCA were positively correlated with Jacobian values of the left supplementary motor area (r = 0.391, p = 0.046) and precentral gyrus (r = 0.401, p = 0.039). ROC analysis revealed FC value between cerebellar Crus I and angular gyrus could differentiate groups with relatively high accuracy (sensitivity: 75%, specificity: 77.8%, area under the curve: 0.794 [CI 0.701-0.888], p < 0.001). Conclusions: Untreated adult-onset hypothyroidism may be associated with impaired cognition and anxiety or depression. GM morphological alterations and FC of the cerebellum with subregions of the frontal and parietal lobes may represent key neuropathological mechanisms underlying the cognitive deterioration and mood dysregulation observed in hypothyroid adults. Clinical Trial Registration Number: chiCTR2000028966.

Effect of thyroid dysfunction on N-terminal pro-B-type natriuretic peptide levels: A systematic review and meta-analysis.

Purpose: Thyroid hormones (THs) significantly affect the cardiovascular system. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful biomarker for diagnosing, evaluating, and predicting outcomes in heart failure (HF). This comprehensive review and meta-analysis aimed to investigate the effects of thyroid dysfunction (hypothyroidism and hyperthyroidism) on NT-proBNP levels. Methods: Two investigators independently searched PubMed, Embase, Cochrane Library, and Web of Science databases for studies published from inception to July 31, 2022, without any restrictions on language. Results: 21 studies were included. In participants without HF, NT-proBNP levels may be elevated in those with overt hyperthyroidism (standardized mean difference [SMD] 2.38, 95% confidence interval [CI]:1.0-3.76). Notably, among patients with preexisting HF, significantly higher NT-proBNP levels were found in patients with overt hyperthyroidism, overt hypothyroidism, or subclinical hypothyroidism than in euthyroid subjects (SMD [95%CI] = 0.31[0.01, 0.62], 0.32[0.08, 0.56], and 0.33[0.21, 0.46], respectively). Seven trials compared NT-proBNP levels in patients with thyroid dysfunction before and after therapy, and significant drops in NT-proBNP levels were observed in patients with hyperthyroidism (SMD [95%CI] = -1.53[-2.50, -0.55]) upon achieving a euthyroid state. In contrast, increased NT-proBNP levels were observed in hypothyroid patients after treatment (SMD [95%CI] = 1.07[0.28, 1.85]). Conclusion: Thyroid dysfunction can significantly affect NT-proBNP levels, which may change upon achieving a euthyroid state. Notably, the effect of thyroid dysfunction on cardiac function may depend on the underlying cardiac status. Thus, timely recognition and effective treatment of cardiac symptoms in patients with thyroid dysfunction are mandatory because the prognosis of HF may be improved with appropriate treatment of thyroid dysfunction. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022353700.

Segmental Abnormalities of White Matter Microstructure in Primary Hypothyroidism Identified by Automated Fiber Quantification.

INTRODUCTION: Hypothyroidism leads to impaired white matter (WM) integrity, associated with cognitive/neuropsychiatric dysfunction. However, the specific segmental abnormalities of the fibers remain unexplored. Therefore, this study aimed to investigate whether the damage of the WM is limited to a specific segment or the entire bundle via diffusion metrics using automated fiber quantification. METHODS: A cross-sectional study was conducted on 31 hypothyroid patients and 28 healthy controls. Thyroid-related hormone levels, cognitive/neuropsychiatric function, and diffusion tensor image data were collected and analyzed. Correlation and random forest analyses were also performed. RESULTS: The mean fractional anisotropy (FA) values were reduced at the fiber tract level. The mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were increased in several fiber tracts, i.e., cingulum cingulate (CC), anterior forceps of corpus callosum (CCF_A). Significant correlations were found between cognitive function and diffusion indicators such as the FA value of the left corticospinal tract and arcuate fasciculus (AF), the MD value of left CC, the RD value of left AF, the AD value of left CC, and CCF_A. The widespread microstructure disruption was spread on multiple specific segments of different tracts at the point-wise level. The random forest revealed that the accuracy of recognizing hypothyroid patients was 82.5%, with the anterior component of CCF_A having the most significant contribution. CONCLUSION: WM microstructural integrity impairments were found in multi-segments of the multiple fiber bundles in hypothyroidism, which might be a potential mechanism of the underlying neurocognitive decline and cerebral impairment. The CCF_A might serve as a neuro biomarker for early warning of cerebral impairment in hypothyroidism.

Oncolytic Newcastle disease virus expressing the co-stimulator OX40L as immunopotentiator for colorectal cancer therapy.

NDV as an attractive candidate for oncolytic immunotherapy selectively lyses tumor cells but shows limited anti-tumor immunity. Immune co-stimulator OX40 ligand (OX40L) boosts anti-tumor immunity response by delivering a potent costimulatory signal to CD4+ and CD8+ T cells. To improve the anti-tumor immunity of NDV, the recombinant NDV expressing the murine OX40L (rNDV-mOX40L) was engineered. The viral growth kinetics was examined in CT26 cell lines. The ability of rNDV-mOX40L to express mOX40L was detected in the infected tumor cells and tumor tissues. The anti-tumor activity of rNDV-mOX40L was studied in the CT26 animal model. Tumor-specific CD4+, CD8+ and OX40+ T cells were examined by immunohistochemistry staining. The virus growth curve showed that the insertion of the mOX40L gene did not affect the growth kinetics of NDV. rNDV-mOX40L expresses mOX40L and effectively inhibits the growth of CT26 colorectal cancer in vivo. The tumor inhibition rate of the rNDV-mOX40L-treated group was increased by 15.8% compared to that of  NDV-treated group in the CT26 model. Furthermore, immunohistochemistry staining of tumor tissues removed from the CT26 model revealed that intense infiltration of tumor-specific CD4+, CD8+ T cells, especially OX40+ T cells were found in the rNDV-mOX40L-treated group. FACS showed that rNDV-mOX40L significantly enhanced the number of CD4+ and CD8+ T cells in spleen. Moreover, compared to the NDV-treated group, the level of mouse IFN-γ protein in the tumor site increased significantly in the rNDV-mOX40L-treated group. Taken together, rNDV-mOX40L exhibited superior anti-tumor immunity by stimulating tumor-specific T cells and may be a promising agent for cancer immunotherapy.