Prediction of TNFRSF9 expression and molecular pathological features in thyroid cancer using machine learning to construct Pathomics models.

BACKGROUND: The TNFRSF9 molecule is pivotal in thyroid carcinoma (THCA) development. This study utilizes Pathomics techniques to predict TNFRSF9 expression in THCA tissue and explore its molecular mechanisms. METHODS: Transcriptome data, pathology images, and clinical information from the cancer genome atlas (TCGA) were analyzed. Image segmentation and feature extraction were performed using the OTSU's algorithm and pyradiomics package. The dataset was split for training and validation. Features were selected using maximum relevance minimum redundancy recursive feature elimination (mRMR_RFE) and modeling conducted with the gradient boosting machine (GBM) algorithm. Model evaluation included receiver operating characteristic curve (ROC) analysis. The Pathomics model output a probabilistic pathomics score (PS) for gene expression prediction, with its prognostic value assessed in TNFRSF9 expression groups. Subsequent analysis involved gene set variation analysis (GSVA), immune gene expression, cell abundance, immunotherapy susceptibility, and gene mutation analysis. RESULTS: High TNFRSF9 expression correlated with worsened progression-free interval (PFI) and acted as an independent risk factor [hazard ratio (HR) = 2.178, 95% confidence interval (CI) 1.045-4.538, P = 0.038]. Nine pathohistological features were identified. The GBM Pathomics model demonstrated good prediction efficacy [area under the curve (AUC) 0.819 and 0.769] and clinical benefits. High PS was a PFI risk factor (HR = 2.156, 95% CI 1.047-4.440, P = 0.037). Patients with high PS potentially exhibited enriched pathways, increased TIGIT gene expression, Tregs infiltration (P < 0.0001), and higher rates of gene mutations (BRAF, TTN, TG). CONCLUSIONS: The GBM Pathomics model constructed based on the pathohistological features of H&E-stained sections well predicted the expression level of TNFRSF9 molecules in THCA.

Thermal ablation for multifocal papillary thyroid microcarcinoma: a systematic review and meta-analysis.

BACKGROUND: Clinical studies have indicated the potential safety and efficacy of thermal ablation (TA) in treating multifocal papillary thyroid microcarcinoma (MPTMC). However, a comprehensive systematic evaluation of its effectiveness was still lack. METHODS: PubMed, EMBASE and Cochrane Library databases were systematically searched for studies published until October 23, 2023, that reported on the effectiveness of thermal ablation in the management of MPTMC. Data extraction and methodological quality assessment were independently conducted by two reviewers following the guidelines outlined in the PRISMA. RESULTS: This systematic review and meta-analysis identified 389 tumors in 169 patients from four studies. After treatment with different TA, the combined rate of complete disappearance of MPTMC was 92.8% [95% confidence interval (CI): 68.2-100] and the combined rate of overall complications was 4.4% [95% CI: 1.5-8.5]. During the follow-up period, local tumor recurrence was observed in only 2 patients with a combined rate of 0.2% [95% CI: 0.0-2.6]; lymph node metastasis (LNM) was observed in 3 patients with a combined rate of 1.2% [95% CI: 0-4.1]. Additionally, 6 patients developed new PTMC. It is noteworthy that no patients were observed to develop distant metastases during the follow-up period, and no patients had delayed surgery after underwent ablation. CONCLUSIONS: For patients grappling with MPTMC, TA emerges as an excellent approach for achieving localized tumor control. Nonetheless, achieving favorable outcomes necessitates stringent inclusion criteria and a profound level of expertize.

Diabetes Mellitus and Thyroid Cancers: Risky Correlation, Underlying Mechanisms and Clinical Prevention.

The incidences of thyroid cancer and diabetes are rapidly increasing worldwide. The relationship between thyroid cancer and diabetes is a popular topic in medicine. Increasing evidence has shown that diabetes increases the risk of thyroid cancer to a certain extent. This mechanism may be related to genetic factors, abnormal thyroid-stimulating hormone secretion, oxidative stress injury, hyperinsulinemia, elevated insulin-like growth factor-1 levels, abnormal secretion of adipocytokines, and increased secretion of inflammatory factors and chemokines. This article reviews the latest research progress on the relationship between thyroid cancer and diabetes, including the association between diabetes and the risk of developing thyroid cancer, its underlying mechanisms, and potential anti-thyroid cancer effects of hypoglycemic drugs. It providing novel strategies for the prevention, treatment, and improving the prognosis of thyroid cancer.

Placenta-derived mesenchymal stem cells protect against diabetic kidney disease by upregulating autophagy-mediated SIRT1/FOXO1 pathway.

Diabetic kidney disease (DKD) is a common chronic microvascular complication of diabetes mellitus. Although studies have indicated the therapeutic potential of mesenchymal stem cells (MSCs) for DKD, the underlying molecular mechanisms remain unclear. Herein, we explored the renoprotective effect of placenta-derived MSCs (P-MSCs) and the potential mechanism of SIRT1/FOXO1 pathway-mediated autophagy in DKD. The urine microalbumin/creatinine ratio was determined using ELISA, and renal pathological changes were detected by special staining techniques. Immunofluorescence was used for detecting the renal tissue expression of podocin and nephrin; immunohistochemistry for the renal expression of autophagy-related proteins (LC3, Beclin-1, SIRT1, and FOXO1); and western blotting and PCR for the expression of podocyte autophagy- and pathway-related indicators. We found that P-MSCs ameliorated renal tubular injury and glomerular mesangial matrix deposition and alleviated podocyte damage in DKD rats. PMSCs enhanced autophagy levels and increased SIRT1 and FOXO1 expression in DKD rat renal tissue, whereas the autophagy inhibitor 3-methyladenine significantly attenuated the renoprotective effect of P-MSCs. P-MSCs improved HG-induced Mouse podocyte clone5(MPC5)injury, increased podocyte autophagy, and upregulated SIRT1 and FOXO1 expression. Moreover, downregulation of SIRT1 expression blocked the P-MSC-mediated enhancement of podocyte autophagy and improvement of podocyte injury. Thus, P-MSCs can significantly improve renal damage and reduce podocyte injury in DKD rats by modulating the SIRT1/FOXO1 pathway and enhancing podocyte autophagy.

Urine-derived stem cell therapy for diabetes mellitus and its complications: progress and challenges.

Diabetes mellitus (DM) is a chronic and relentlessly progressive metabolic disease characterized by a relative or absolute deficiency of insulin in the body, leading to increased production of advanced glycosylation end products that further enhance oxidative and nitrosative stresses, often leading to multiple macrovascular (cardiovascular disease) and microvascular (e.g., diabetic nephropathy, diabetic retinopathy, and neuropathy) complications, representing the ninth leading cause of death worldwide. Existing medical treatments do not provide a complete cure for DM; thus, stem cell transplantation therapy has become the focus of research on DM and its complications. Urine-derived stem cells (USCs), which are isolated from fresh urine and have biological properties similar to those of mesenchymal stem cells (MSCs), were demonstrated to exert antiapoptotic, antifibrotic, anti-inflammatory, and proangiogenic effects through direct differentiation or paracrine mechanisms and potentially treat patients with DM. USCs also have the advantages of simple noninvasive sample collection procedures, minimal ethical issues, low cost, and easy cell isolation methods and thus have received more attention in regenerative therapies in recent years. This review outlines the biological properties of USCs and the research progress and current limitations of their role in DM and related complications. In summary, USCs have shown good versatility in treating hyperglycemia-impaired target organs in preclinical models, and many challenges remain in translating USC therapies to the clinic.

Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

AIM: To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). METHODS: Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. RESULTS: The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1ß) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. CONCLUSION: We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

Resveratrol improves diabetes-induced cognitive dysfunction in part through the miR-146a-5p/TXNIP axis.

Resveratrol (RSV) has been shown to have a neuroprotective effect in various central nervous system disorders, although the role of RSV in diabetes-induced cognitive dysfunction is still not fully elucidated. Here, we investigated whether RSV improved diabetes-related cognitive dysfunction in vivo and in vitro. We induced a rat diabetic model with a high-fat and high-sucrose diet followed by intraperitoneal injection of streptozotocin and a diabetic neuron cell model by stimulation with high levels of glucose. We observed that RSV improved impairment in spatial learning and memory in the Morris water maze test (MWM) and novel object recognition test (ORT) in diabetic rats. RSV reversed the reduced miR-146a-5p and upregulated thioredoxin-interacting protein (TXNIP) and inhibited the diabetes-induced increase in interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels in vivo and in vitro. RSV also inhibited diabetes-induced endoplasmic reticulum stress (ESR) by reducing ESR-related protein expression in vivo and in vitro. Moreover, inhibition of miR-146a-5p partially abolished the protective effects of RSV in HG-treated primary neurons. Additionally, we used starBase to predict that miR-146a-5p interacts with TXNIP, which we then verified using a luciferase reporter gene assay. We further observed that miR-146a-5p regulates the mRNA and protein expression of TXNIP in vitro, indicating that the miR-146a-5p/TXNIP axis is involved in the regulation of cognitive dysfunction in a rat diabetic model. Collectively, these results demonstrate that RSV plays a neuroprotective role in diabetes-associated cognitive dysfunction at least in part through regulation of the miR-146a-5p/TXNIP axis.

Risk factors and prediction models of lymph node metastasis in papillary thyroid carcinoma based on clinical and imaging characteristics.

BACKGROUND: Papillary thyroid carcinoma (PTC) commonly presents with lymph node metastasis, which may be associated with worsened prognosis. This study aimed to comprehensively evaluate the risk factors of lymph node metastasis in PTC based on preoperative clinical and imaging data and to construct a nomogram model to predict the risk of lymph node metastasis. METHODS: A total of 989 patients with PTC were enrolled and randomly divided into training and validation cohorts in an 8:2 ratio. Independent risk factors for lymph node metastasis in PTC were analyzed using univariate and stepwise multivariate logistic regression. An importance analysis of independent risk factors affecting lymph node metastasis was performed according to the random forest method. Subsequently, a nomogram to predict lymph node metastasis was constructed, and the predictive effect of the nomogram was evaluated using receiver operating characteristic analysis and calibration curves. RESULTS: Univariate regression analysis revealed that age, sex, body weight, systolic blood pressure, free triiodothyronine, nodule location, nodule number, Thyroid Imaging Reporting and Data System (TI-RADS) grade on color Doppler ultrasound, enlarged lymph node present on imaging, and nodule diameter could affect lymph node metastasis in PTC. Stepwise multivariate regression analysis showed that sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade were independent risk factors for lymph node metastasis in PTC. Combining these five independent risk factors, a nomogram prediction model was constructed. The area under the curve (AUC) of the nomogram in the training and validation cohorts was 0.742 and 0.765, respectively, with a well-fitted calibration curve. CONCLUSION: Our study showed that independent risk factors for lymph node metastasis in PTC were sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade. The nomogram constructed based on these independent risk factors can better predict the risk of lymph node metastasis.

Correlations between circulating methylmalonic acid levels and all-cause and cause-specific mortality among patients with diabetes.

Aims: Evidence regarding serum methylmalonic acid (MMA) levels and mortality in individuals with diabetes is limited. This study aimed to evaluate the correlation between MMA and all-cause and cause-specific deaths in patients with diabetes. Materials and methods: This is a population-based cohort study based on data from both the National Health and Nutrition Examination Survey (NHANES) and National Death Index from 1999 to 2014. We assessed the association of serum MMA concentrations with mortality using Cox proportional hazard models after adjusting for lifestyle, demographic factors, and comorbidities. Results: Among the 3,097 participants, 843 mortalities occurred during a median follow-up of 4.42 years. There were 242 deaths due to cardiovascular disease (CVD) and 131 cancer-associated deaths. After multivariate adjustment, elevated serum MMA levels were markedly correlated with a high risk of all-cause, CVD-, and cancer-related deaths. Each one-unit increase in the natural log-transformed MMA level correlated with increased risk of all-cause mortality (2.652 times), CVD mortality risk (3.153 times), and cancer-related mortality risk (4.514). Hazard ratios (95% confidence intervals [CIs]) after comparing participants with MMA < 120 and ≥250 nmol/L were 2.177 (1.421-3.336) for all-cause mortality, 3.560 (1.809-7.004) for CVD mortality, and 4.244 (1.537-11.721) for cancer mortality. Conclusion: Higher serum MMA levels were significantly associated with higher all-cause, CVD, and cancer mortality. These findings suggest that maintaining lower MMA status may lower mortality risk in individuals with diabetes.

Prognostic value and immunological role of BAIAP2L2 in liver hepatocellular carcinoma: A pan-cancer analysis.

Background: In recent years, the role of BAI1-associated protein 2-like 2 (BAIAP2L2) in the prognosis and immune microenvironment of various cancers has attracted increasing attention. However, its clinical value and immune infiltration in liver hepatocellular carcinoma (LIHC) remain unclear. Objective: To investigate the prognostic value of BAIAP2L2 and its correlation with immune infiltration in LIHC, we conducted corresponding data mining. Methods: In this study, The Cancer Genome Atlas, GTEx, StarBase, UALCAN, TIMER, GEPIA, Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, STRING and BioGPS databases were used to analyze BAIAP2L2 in cancers. Logistic regression and Cox regression were performed to analyze the correlation between clinical features and BAIAP2L2 expression in LIHC. In addition, the diagnostic and prognostic values of BAIAP2L2 in LIHC were determined by receiver operating characteristic (ROC) curves and nomograms. Single-sample gene set enrichment analysis (ssGSEA), BioGPS and TIMER were used to analyze the correlation between BAIAP2L2 and immune infiltration. More importantly, quantitative real-time polymerase chain reaction was used to verify BAIAP2L2 expression in a liver cancer cell line and a normal cell line. Visualization of data was mostly achieved using R language, version 3.6.3. Results: High BAIAP2L2 levels indicated poor overall survival (OS) and disease-free survival (DFS) of patients with LIHC. Abnormally increased expression of BAIAP2L2 in LIHC may be the result of both genetic alterations and lower DNA methylation levels. Furthermore, Cox regression analysis showed that high BAIAP2L2 expression was an independent risk factor for OS and DFS in patients with liver cancer. ROC curves and nomograms also confirmed the diagnostic and prognostic values of BAIAP2L2 in LIHC. Additionally, a PPI network of BAIAP2L2 was established and results implyed that BAIAP2L2 interacts with MTSS1, AMPH, FCHO1, SYT9, PDK2, MTSS1L, PM20D1, CHST4 and PALM3. ssGSEA showed that BAIAP2L2 was associated with T cells and natural killer cells. Simultaneously, the TIMER database showed that the expression of BAIAP2L2 in LIHC was positively correlated with tumor infiltrating cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells. Conclusions: Through pan-cancer analysis, prognostic and immunological value of BAIAP2L2 in LIHC was identified. This is the first report on the potential of BAIAP2L2 as a prognostic biomarker and its correlation with immune infiltration in LIHC.

Peripheral Blood Inflammatory Markers Can Predict Benign and Malignant Thyroid Nodules.

Objective: Inflammation is related to the occurrence and development of various cancers. This study was designed to explore the role of peripheral blood platelet count, neutrophil-lymphocyte ratio (NLR), platelet count-lymphocyte count ratio (PLR), systemic inflammation index (SII), and other inflammatory markers in predicting benign and malignant Thyroid Imaging Reporting and Data System (TI-RADS) grade 3 thyroid nodules. Methods: In this retrospective study, 514 patients with TI-RADS grade 3 thyroid nodules were enrolled. According to the pathological results, the patients were divided into the benign and malignant nodule groups. We compared the clinical characteristics between the two groups and analysed the influencing factors for malignant thyroid nodules by univariate and stepwise multivariate logistic regression analyses and then analysed the cutoff value of each influencing factor according to the receiver operating characteristic curve. Results: The leukocyte count, neutrophil count, platelet count, NLR, PLR, and SII of the malignant nodule group were significantly higher than those of the benign nodule group (P < 0.05), the age and the diameter of nodule of the malignant nodule group were significantly smaller than those of the benign nodule group (P < 0.05). After excluding the influence of confounding factors, SII (odds ratio (OR) = 1.006; 95% confidence interval (CI) = 1.003-1.008; P < 0.001), PLR (odds ratio (OR) = 0.981; 95% confidence interval (CI) = 0.981-0.992; P < 0.05), leukocyte count (odds ratio (OR) = 0.654; 95% confidence interval (CI) = 0.466-0.892; P < 0.05), and age (OR = 0.969; 95% CI = 0.954-0.985; P < 0.001) were independent risk factors for malignant thyroid nodules, and the cutoff value of SII and PLR in predicting benign and malignant thyroid nodules were 545.63 × 109/L and 138.63. Conclusion: This study showed that peripheral blood SII, PLR, leukocyte count and age were independent risk factors for malignant thyroid nodules, and the combination of these can better predict benign and malignant thyroid nodules, which can further guide the diagnosis and treatment of TI-RADS grade 3 thyroid nodules.

TTN mutations predict a poor prognosis in patients with thyroid cancer.

OBJECTIVE: We aimed to investigate the relationship between titin (TTN) gene mutations and thyroid cancer (THCA) and to explore the feasibility of the TTN gene as a potential prognostic indicator of THCA. METHODS: From TCGA-THCA cohort, we performed a series of analyses to evaluate the prognostic value and potential mechanism of TTN in THCA. These patients were divided into the mutant-type (MUT) group and the wild-type (WT) group. Differentially expressed genes (DEGs) in the two groups were screened using the 'DESeq2' R package. Functional enrichment analysis was performed, and the protein-protein interaction (PPI) network, transcription factor (TF)-target interaction networks, and competitive endogenous RNA (ceRNA) regulatory networks were established for the DEGs. The TIMER database was applied for immune cell infiltration. Survival analysis and Cox regression analysis were used to analyze the potential prognostic value of the TTN gene. RESULTS: Differential expression analysis showed that 409 genes were significantly up-regulated and 36 genes were down-regulated. Functional enrichment analysis revealed that TTN gene mutations played a potential role in the development of THCA. Analysis of the immune microenvironment indicated that TTN gene mutations were significantly associated with enrichment of M0 macrophages. Survival analysis showed that the MUT group predicted poorer prognosis than the WT group. Cox regression analysis demonstrated that TTN gene mutations were an independent risk factor for THCA. Nomograms also confirmed the prognostic values of the TTN gene in THCA. Conclusions In summary, our results demonstrated that TTN gene mutations predict poor prognosis in patients with THCA. This is the first study to research TTN gene mutations in THCA and to investigate their prognostic value in THCA.

The value of neutrophil-to-lymphocyte ratio combined with the thyroid imaging reporting and data system in the diagnosis of the nature of thyroid nodules.

OBJECTIVE: The aim of this study was to investigate the diagnostic value of peripheral blood neutrophil-to-lymphocyte ratio (NLR) combined with the thyroid imaging reporting and data system (TIRADS) for benign and malignant thyroid nodules. METHODS: A total of 585 adults were enrolled in the study. The receiver operating characteristic curves were used to determine the optimal cut-off values for NLR and Kwak TIRADS (K-TIRADS) grades, which were 1.87 and 4a, respectively. Thyroid nodules were scored as follows: NLR-K-TIRADS score is 2 (both elevated K-TIRADS grade and NLR), NLR-K-TIRADS score is 1 (one of these was elevated) and NLR-k-TIRADS score is 0 (neither were elevated). RESULTS: The proportions of malignant nodules with NLR-K-TIRADS scores of 2, 1 and 0 were 98.59%, 69.62% and 10.19%, and the difference was statistically significant (p < 0.001). In terms of the sensitivity of diagnosis of malignant nodules, NLR-K-TIRADS 1 tends to increase relative to K-TIRADS grades ≥ 4a; in terms of specificity and positive predictive value for the diagnosis of malignant nodules, NLR-K-TIRADS 2 was significantly higher than K-TIRADS grades ≥ 4a (all p < 0.05). CONCLUSIONS: NLR combined with K-TIRADS grades may be a novel method for screening benign and malignant thyroid nodules.

Safety and Efficacy of Placenta-Derived Mesenchymal Stem Cell Treatment for Diabetic Patients with Critical Limb Ischemia: A Pilot Study.

AIM: Diabetic foot has become the main cause of non-traumatic amputation. Stem cell therapy, especially mesenchymal stem cells (MSCs), holds a great promise as a therapy for diabetic foot with ischemia limb arterial disease. The aim of this pilot study is to evaluate the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment for diabetic patients with critical limb ischemia (CLI). METHODS: Four eligible diabetic patients with CLI were consecutively enrolled in this pilot study. On the base of the standard-of-care treatment, these patients accepted P-MSCs treatment by intramuscular injection for successive 3 times at an interval of 4 weeks, and the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment were evaluated. RESULTS: There were no serious adverse events during the period of P-MSCs injection and the 24-weeks follow-up period. The clinical ischemic features of patients were improved 24 weeks after P-MSCs treatment. The scores of resting pain and limb coldness significantly decreased, and pain-free walking distance significantly increased from baseline to 24 weeks after P-MSCs therapy. The resting ankle brachial index increased, but no statistically significant difference was found. The findings of magnetic resonance angiography showed the increase of collateral vessel formation in one patient, but there were no significant changes observed in the other patients. CONCLUSIONS: The data in this pilot study indicated that multiple intramuscular P-MSCs injections may be a safe and effective alternative therapy for diabetic patients with CLI, and larger, placebo-controlled, perspective studies are needed to prove these results.

Construction and analysis of an aberrant lncRNA-miRNA-mRNA network associated with papillary thyroid cancer.

Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) are the main constituents of competing endogenous RNA (ceRNA) networks. Nonetheless, in the lncRNA-related ceRNA network of papillary thyroid cancer (PTC), the function of cancer-specific lncRNAs, as well as their use for the potential prediction of PTC prognosis, remains unclear. In this study, 384 RNA sequencing (RNA-seq) profiles of PTC patients were attained from The Cancer Genome Atlas (TCGA), an open-source database that offers vast amounts of RNA-seq data, and 75 miRNAs, 495 lncRNAs, and 1099 mRNAs (P < .05 and |logFC| >2) were detected when compared with normal tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using the Cytoscape plug-in BinGo. An aberrant lncRNA-mRNA-miRNA ceRNA network consisting of 31 differentially expressed (DE)-lncRNAs, 13 DE-miRNAs, and 134 DE-mRNAs was built in TCGA. On the basis of overall survival (OS) analysis, 6 lncRNAs (CCAT1, SYNPR, SFTA1P, HOTAIR, HCG22, and CLDN10) were identified as prognostic biomarkers for patients in TCGA (P < .05). Through qRT-PCR, we designated 6 cancer-specific lncRNAs as having great significance for survival by verifying their expression in the 60 PTC patients who were diagnosed. The qRT-PCR and TCGA results were completely consistent. Our research provides data for further understanding the lncRNA-miRNA-mRNA ceRNA network and elucidating the molecular mechanisms of PTC.

Effects of different obesity-related adipokines on the occurrence of obstructive sleep apnea.

Obstructive sleep apnea (OSA), characterized by recurrent episodes of apnea during sleep and daytime sleepiness, seriously affects human health and may lead to systemic organ dysfunction. The pathogenesis of OSA is complex and still uncertain, but multiple surveys have shown that obesity is an important factor, and the incidence of OSA in people with obesity is as high as 30%. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and may contribute to OSA. Here, we review the most important and representative research results regarding the correlation between obesity-related adipokines including leptin, adiponectin, omentin-1, chemerin, and resistin and OSA in the past 5 years, provide an overview of these key adipokines, and analyze possible intrinsic mechanisms and influencing factors. The existing research shows that OSA is associated with an increase in the serum levels of leptin, chemerin, and resistin and a decrease in the levels of adiponectin and omentin-1; the findings presented here can be used to monitor the development of OSA and obesity, prevent future comorbidities, and identify risk factors for cardiovascular and other diseases, while different adipokines can be linked to OSA through different pathways such as insulin resistance, intermittent hypoxia, and inflammation, among others. We hope our review leads to a deeper and more comprehensive understanding of OSA based on the relevant literature, which will also provide directions for future clinical research.

Primary hyperparathyroidism associated with non-Hodgkin lymphoma: a case report and literature review.

Primary hyperparathyroidism is the third most common endocrine disease, while primary hyperparathyroidism associated with non-Hodgkin lymphoma(NHL) is extremely rare. We report a case of primary hyperparathyroidism associated with NHL. The first symptom of this patient was hypercalcemia. Hypercalcemia is the primary first clinical manifestation of primary hyperparathyroidism, while NHL may also be diagnosed by hypercalcemia. Clinically, patients with hypercalcemia as the first symptom should be alert to the coexistence of their two diseases. As primary hyperparathyroidism and NHL occur simultaneously, the relationship between the two diseases requires further study. A review of the literature regarding primary hyperparathyroidism associated with NHL was performed, focusing on clinical presentation, diagnosis, treatment, prognosis, and the connection.

Identification of hub genes and key pathways of dietary advanced glycation end products­induced non­alcoholic fatty liver disease by bioinformatics analysis and animal experiments.

Non­alcoholic fatty liver disease (NAFLD) is a common chronic liver disease. Advanced glycation end products (AGEs) negatively affect the liver and accelerate NAFLD progression; however, the underlying mechanisms remain unclear. The present study aimed to examine the effect and mechanism of dietary AGEs on the mouse liver using bioinformatics and in vivo experimental approaches. Gene expression datasets associated with NAFLD were obtained from the Gene Expression Omnibus and differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery and a protein­protein interaction network for the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes database. MCODE, a Cytoscape plugin, was subsequently used to identify the most significant module. The key genes involved were verified in a dietary AGE­induced non­alcoholic steatohepatitis (NASH) mouse model using reverse transcription­quantitative PCR (RT­qPCR). The 462 DEGs associated with NAFLD in the two datasets, of which 34 overlapping genes were found in two microarray datasets. Functional analysis demonstrated that the 34 DEGs were enriched in the 'PPAR signaling pathway', 'central carbon metabolism in cancer', and 'cell adhesion molecules (CAMs)'. Moreover, four hub genes (cell death­inducing DFFA­like effector a, cell death­inducing DFFA­like effector c, fatty acid­binding protein 4 and perilipin 4) were identified from a protein­protein interaction network and were verified using RT­qPCR in a mouse model of NASH. The results suggested that AGEs and their receptor axis may be involved in NAFLD onset and/or progression. This integrative analysis identified candidate genes and pathways in NAFLD, as well as DEGs and hub genes related to NAFLD progression in silico and in vivo.