Novel and Advanced Ultrasound Techniques for Thyroid Thermal Ablation.

Thyroid radiofrequency ablation and microwave ablation are widely adopted minimally invasive treatments for diverse thyroid conditions worldwide. Fundamental skills such as the trans-isthmic approach and the moving shot technique are crucial for performing thyroid ablation, and advanced techniques, including hydrodissection and vascular ablation, improve safety and efficacy and reduce complications. Given the learning curve associated with ultrasound-guided therapeutic procedures, operators need training and experience. While training models exist, limited attention has been given to ultrasound maneuvers in ablation needle manipulation. This article introduces two essential maneuvers, the zigzag moving technique and the alienate maneuver, while also reviewing the latest ultrasound techniques in thyroid ablation, contributing valuable insights into this evolving field.

Efficacy and mechanism of Wuzi Yanzong pill on the prevention and treatment of EAE.

Objective: Studies have shown that Wuzi Yanzong Pill (WYP) can be used to treat neurological diseases, but its mechanisms for multiple sclerosis (MS) remain unclear. This study aims to determine the effect of WYP on MS in an animal model of experimental autoimmune encephalomyelitis (EAE), and explore its mechanism. To provide theoretical basis for the clinical treatment of MS with WYP. Methods: C57BL/6 female mice were randomly divided into Blank control, EAE control, low dose WYP, medium dose WYP, and high dose WYP groups. One week before model generation, the mice were gavaged with saline (50 mL/kg/d) in Blank control and EAE control groups. The treatment groups was gavaged with different doses of WYP solution (4, 8, or 16 g/kg/d respectively) Clinical scores were recorded daily. Sample collection was conducted on the 14th and 28th days, respectively The expressions of IL-10, IL-17, IL-12, TNF-α and IFN-γ in spleen were detected by ELISA. The expressions of ROCKII, P-MYPT1, TLR4, NF-κB/p65, MCP-1, CCR2 in spleen, brain and spinal cord were detected by Western Blot. The types of macrophages and the contents of intracellular IL-10 and IL-12 were detected by Flow Cytometry. The contents of TNF-α and TLR4 mRNA in the spleen were detected by RT-PCR. Results: WYP treatment improved the clinical score of EAE mice in a significant dose-dependent manner, with the WYP high-dose group showed the most significant improvement in clinical score. Compared with the EAE control group, WYP high dose group had significantly lower levels of IL-17, IFN-γ, ROCKII, P-MYPT1, TLR4, NF-κB/p65, MCP-1, and CCR2 as well as TNF-α and TLR4 mRNA, but increased the number of M2 macrophages and IL-10. Conclusion: WYP treatment relieves clinical symptoms in EAE mice, which may be related to regulate inflammatory pathway and inhibiting expressions of inflammatory cytokines.

Myasthenia Gravis: Novel Findings and Perspectives on Traditional to Regenerative Therapeutic Interventions.

The prevalence of myasthenia gravis (MG), an autoimmune disorder, is increasing among all subsets of the population leading to an elevated economic and social burden. The pathogenesis of MG is characterized by the synthesis of autoantibodies against the acetylcholine receptor (AChR), low-density lipoprotein receptor-related protein 4 (LRP4), or muscle-specific kinase at the neuromuscular junction, thereby leading to muscular weakness and fatigue. Based on clinical and laboratory examinations, the research is focused on distinguishing MG from other autoimmune, genetic diseases of neuromuscular transmission. Technological advancements in machine learning, a subset of artificial intelligence (AI) have been assistive in accurate diagnosis and management. Besides, addressing the clinical needs of MG patients is critical to improving quality of life (QoL) and satisfaction. Lifestyle changes including physical exercise and traditional Chinese medicine/herbs have also been shown to exert an ameliorative impact on MG progression. To achieve enhanced therapeutic efficacy, cholinesterase inhibitors, immunosuppressive drugs, and steroids in addition to plasma exchange therapy are widely recommended. Under surgical intervention, thymectomy is the only feasible alternative to removing thymoma to overcome thymoma-associated MG. Although these conventional and current therapeutic approaches are effective, the associated adverse events and surgical complexity limit their wide application. Moreover, Restivo et al. also, to increase survival and QoL, further recent developments revealed that antibody, gene, and regenerative therapies (such as stem cells and exosomes) are currently being investigated as a safer and more efficacious alternative. Considering these above-mentioned points, we have comprehensively reviewed the recent advances in pathological etiologies of MG including COVID-19, and its therapeutic management.

The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease.

BACKGROUND: To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m2. METHODS: In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m2 with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups. RESULTS: A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68-1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Involvement of nitrergic neurons in colonic motility in a rat model of ulcerative colitis.

BACKGROUND: The mechanisms underlying gastrointestinal (GI) dysmotility with ulcerative colitis (UC) have not been fully elucidated. The enteric nervous system (ENS) plays an essential role in the GI motility. As a vital neurotransmitter in the ENS, the gas neurotransmitter nitric oxide (NO) may impact the colonic motility. In this study, dextran sulfate sodium (DSS)-induced UC rat model was used for investigating the effects of NO by examining the effects of rate-limiting enzyme nitric oxide synthase (NOS) changes on the colonic motility as well as the role of the ENS in the colonic motility during UC. AIM: To reveal the relationship between the effects of NOS expression changes in NOS-containing nitrergic neurons and the colonic motility in a rat UC model. METHODS: Male rats (n = 8/each group) were randomly divided into a control (CG), a UC group (EG1), a UC + thrombin derived polypeptide 508 trifluoroacetic acid (TP508TFA; an NOS agonist) group (EG2), and a UC + NG-monomethyl-L-arginine monoacetate (L-NMMA; an NOS inhibitor) group (EG3). UC was induced by administering 5.5% DSS in drinking water without any other treatment (EG1), while the EG2 and EG3 were gavaged with TP508 TFA and L-NMMA, respectively. The disease activity index (DAI) and histological assessment were recorded for each group, whereas the changes in the proportion of colonic nitrergic neurons were counted using immunofluorescence histochemical staining, Western blot, and enzyme linked immunosorbent assay, respectively. In addition, the contractile tension changes in the circular and longitudinal muscles of the rat colon were investigated in vitro using an organ bath system. RESULTS: The proportion of NOS-positive neurons within the colonic myenteric plexus (MP), the relative expression of NOS, and the NOS concentration in serum and colonic tissues were significantly elevated in EG1, EG2, and EG3 compared with CG rats. In UC rats, stimulation with agonists and inhibitors led to variable degrees of increase or decrease for each indicator in the EG2 and EG3. When the rats in EGs developed UC, the mean contraction tension of the colonic smooth muscle detected in vitro was higher in the EG1, EG2, and EG3 than in the CG group. Compared with the EG1, the contraction amplitude and mean contraction tension of the circular and longitudinal muscles of the colon in the EG2 and EG3 were enhanced and attenuated, respectively. Thus, during UC, regulation of the expression of NOS within the MP improved the intestinal motility, thereby favoring the recovery of intestinal functions. CONCLUSION: In UC rats, an increased number of nitrergic neurons in the colonic MP leads to the attenuation of colonic motor function. To intervene NOS activity might modulate the function of nitrergic neurons in the colonic MP and prevent colonic motor dysfunction. These results might provide clues for a novel approach to alleviate diarrhea symptoms of UC patients.

Integrated strategy of RNA-sequencing and network pharmacology for exploring the protective mechanism of Shen-Shi-Jiang-Zhuo formula in rat with non-alcoholic fatty liver disease.

CONTEXT: Shen-Shi-Jiang-Zhuo formula (SSJZF) exhibits a definite curative effect in the clinical treatment of non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: To explore the therapeutic effect and mechanism of SSJZF on NAFLD. MATERIALS AND METHODS: Sprague Dawley rats were randomly divided into control, NAFLD, positive drug (12 mg/kg/day), SSJZF high-dose (200 mg/kg/day), SSJZF middle-dose (100 mg/kg/day), and SSJZF low-dose (50 mg/kg/day) groups. After daily intragastric administration of NAFLD rats for 8 weeks, lipid metabolism and hepatic fibrosis were evaluated by biochemical indices and histopathology. Then we uncovered the main active compounds and mechanism of SSJZF against NAFLD by integrating RNA-sequencing and network pharmacology, and PI3K/AKT pathway activity was verified by western blot. RESULTS: High dose SSJZF had the best inhibitory effect on hepatic lipid accumulation and fibrosis in rats with NAFLD, which significantly down-regulated total triglycerides (58%), cholesterol (62%), aspartate aminotransferase (57%), alanine aminotransferase (41%) andγ-glutamyl transpeptidase (36%), as well as the expression of ACC (5.3-fold), FAS (12.1-fold), SREBP1C (2.3-fold), and CD36 (4.4-fold), and significantly reduced collagen deposition (67%). Then we identified 23 compounds of SSJZF that acted on 25 key therapeutic targets of NAFLD by integrating RNA-sequencing and network pharmacology. Finally, we also confirmed that high dose SSJZF increased p-PI3K/PI3K (1.6-fold) and p-AKT/AKT (1.6-fold) in NAFLD rats. DISCUSSION AND CONCLUSION: We found for first time that SSJZF improved NAFLD in rats by activating the PI3K/Akt pathway. These findings provide scientific support for SSJZF in the clinical treatment of NAFLD and contribute to the development of new NAFLD drugs.

Diagnostic genes and immune infiltration analysis of colorectal cancer determined by LASSO and SVM machine learning methods: a bioinformatics analysis.

Background: Genetic factors account for approximately 35% of colorectal cancer risk. The specificity and sensitivity of previous diagnostic biomarkers for colorectal cancer could not meet the need of clinical application. The expanding scale and inherent complexity of biological data have encouraged a growing use of machine learning to build informative and predictive models of the underlying biological processes. The aim of this study is to identify diagnostic genes of colorectal cancer by using machine learning methods. Methods: The GSE41328 and GSE106582 data sets were downloaded from the Gene Expression Omnibus (GEO) database. The gene expression differences between colon cancer and normal tissues were analyzed. The key colorectal cancer genes were screened and validated by Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) regression. Immune cell infiltration and the correlation with the key genes in patients with colon cancer were further analyzed by CIBERSORT. Results: Eleven key genes were identified as biomarkers for colon cancer, namely ASCL2, BEST4, CFD, DPEPCFD, FOXQ1, TRIB3, KLF4, MMP7, MMP11, PYY, and PDK4. The mean area under the receiver operating characteristic (ROC) curve (AUC) of all 11 genes for colon cancer diagnosis were 0.94 with a range of 0.91-0.97. In the validation set, the expression of the 11 key genes was significantly different between colon cancer and normal subjects (P<0.05) and the mean AUCs were 0.82 with a range of 0.70-0.88. Immune cell infiltration analyses demonstrated that the relative quantity of plasma cells, T cells, B cells, NK cells, MO, M1, Dendritic cells resting, Mast cells resting, Mast cells activated, and Neutrophils in the tumor group were significantly different to the normal group. Conclusions: ASCL2, BEST4, CFD, DPEPCFD, FOXQ1, TRIB3, KLF4, MMP7, MMP11, PYY, and PDK4 were identified as the key genes for colon cancer diagnosis. These genes are expected to become novel diagnostic markers and targets of new pharmacotherapies for colorectal cancer.

Successful Applications of Food-Assisted and -Simulated Training Model of Thyroid Radiofrequency Ablation.

Background: Radiofrequency ablation (RFA) for benign thyroid nodules is one kind of scarless treatment for symptomatic or cosmetic benign thyroid nodules. However, how to train RFA-naive physicians to become qualified operators for thyroid RFA is an important issue. Our study aimed to introduce a successful training model of thyroid RFA. Materials and Methods: We used a food-assisted and -simulated training model of thyroid RFA. Chicken hearts were simulated into thyroid nodules, three-layer pork meats were simulated into peri-thyroid structure, and gel bottles were simulated into trachea, respectively. Successful training ablations were defined as chicken hearts that were fully cooked. After repeating training ablations of chicken hearts at least 100 times with the nearly 100% success rates for three young trainees, they served as the first assistant for the real procedures of thyroid RFA and then were qualified to perform thyroid RFA on real patients under the supervision of one experienced interventional radiologist. Results: 23 real patients who received RFA and follow-up at least 6 months after treatment were included in Linkou Chang Gung Memorial Hospital from January 1, 2020 to October 1, 2021. Three young endocrinologists performed thyroid RFA independently. The outcomes were volume reduction rate (VRR), major complications and minor complications. The median VRR at 12 months was 82.00%, two major complications were transient hoarseness, and three minor complications were wound pain. All complications were completely recovered within three days. Conclusions: For young and RFA-native physicians without any basic skills of echo-guided intervention, this food-assisted and -simulated training model of thyroid RFA was useful for medical training and education.

Wuzi Yanzong pill attenuates MPTP-induced Parkinson's Disease via PI3K/Akt signaling pathway.

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

Evaluation of recurrence risk in patients with papillary thyroid cancer through tumor-node-metastasis staging: A single-center observational study in Taiwan.

BACKGROUND: Many patients with papillary thyroid cancer (PTC) demonstrate satisfactory outcomes. However, 8%-28% of patients with PTC show tumor recurrence, which may affect prognosis. Therefore, identifying factors associated with tumor recurrence in patients with PTC may be helpful to refine therapeutic strategies. METHODS: To identify factors associated with PTC recurrence, we retrospectively reviewed demographic features (sex and age), operation method, image character, serum thyroglobulin (Tg), accumulated radioactive iodine (I-131) therapeutic dose, I-131 uptake, and metastases at diagnosis in 829 patients with PTC. Patients were grouped into early (stage I and II; n = 698) and advanced (stage III and IV; n = 131) tumor-node-metastasis (TNM) stages. Recurrence rate, mortality rate, risk factors of recurrence, recurrent free survival and overall survival curve were compared between two groups. RESULTS: Patients in the early stage demonstrated a lower recurrence rate (7.2%) than did those in the advanced stage (28.2%, p < 0.05). The mortality rate of patients with recurrence in the advanced stage was higher than that of those in the early stage (51.4% vs. 12.0%). The major impact factors on tumor recurrence in early TNM stage were distant metastasis and lymph node metastasis, while in advanced TNM stage were distant metastasis, male gender, total thyroidectomy with limited lymph node dissection, and a high serum Tg level. CONCLUSIONS: Strategies to monitor tumor recurrence might be refined according to the TNM stages of PTC patients.

Using Deep Convolutional Neural Networks for Enhanced Ultrasonographic Image Diagnosis of Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) from follicular epithelial cells is the most common form of thyroid cancer. Beyond the common papillary thyroid carcinoma (PTC), there are a number of rare but difficult-to-diagnose pathological classifications, such as follicular thyroid carcinoma (FTC). We employed deep convolutional neural networks (CNNs) to facilitate the clinical diagnosis of differentiated thyroid cancers. An image dataset with thyroid ultrasound images of 421 DTCs and 391 benign patients was collected. Three CNNs (InceptionV3, ResNet101, and VGG19) were retrained and tested after undergoing transfer learning to classify malignant and benign thyroid tumors. The enrolled cases were classified as PTC, FTC, follicular variant of PTC (FVPTC), Hürthle cell carcinoma (HCC), or benign. The accuracy of the CNNs was as follows: InceptionV3 (76.5%), ResNet101 (77.6%), and VGG19 (76.1%). The sensitivity was as follows: InceptionV3 (83.7%), ResNet101 (72.5%), and VGG19 (66.2%). The specificity was as follows: InceptionV3 (83.7%), ResNet101 (81.4%), and VGG19 (76.9%). The area under the curve was as follows: Incep-tionV3 (0.82), ResNet101 (0.83), and VGG19 (0.83). A comparison between performance of physicians and CNNs was assessed and showed significantly better outcomes in the latter. Our results demonstrate that retrained deep CNNs can enhance diagnostic accuracy in most DTCs, including follicular cancers.

The Risk of Bladder Cancer in Type 2 Diabetes Mellitus with Combination Therapy of SGLT-2 Inhibitors and Pioglitazone.

Background: Either sodium-glucose cotransporter-2 (SGLT-2) inhibitors or pioglitazone (Pio) has doubtful issues of bladder cancer, especially for the combination therapy with these two drugs. Our study aimed to investigate the risk of bladder cancer under combination therapy of SGLT-2 inhibitors and Pio. Materials and Methods: We included 97,024 patients with type 2 diabetes mellitus (T2DM) in the Chang Gung Research Database in Taiwan from 1 January 2016 to 31 December 2019. The primary outcome was newly diagnosed bladder cancer after combination therapy with SGLT-2 inhibitors and Pio. Group 1 received both study drugs, group 2 received SGLT-2 inhibitors, group 3 received Pio, and group 4 received non-study drugs (the reference group). The secondary outcome in each group was all-cause mortality. Results: In group 1, no newly diagnosed bladder cancer was detected after a mean 2.8-year follow-up and all-cause mortality decreased significantly (adjusted hazard ratio (AHR), 0.70; 95% confidence interval (CI), 0.54-0.92) in comparison to the reference group (group 4). In group 2 and group 3, no trend of increased bladder cancer was observed (group 2: AHR 0.49, 95% CI 0.05-4.94; group 3: AHR 0.48, 95% CI 0.15-1.58) and it still reduced all-cause mortality (group 2: AHR 0.83, 95% CI 0.70-0.99; group 3: AHR 0.90, 95% CI 0.83-0.99). Conclusions: In T2DM patients without previous or active bladder cancer, the combination therapy of SGLT-2 inhibitors and Pio was not associated with newly diagnosed bladder cancer and had lower all-cause mortality.

Circ_0000190 suppresses gastric cancer progression potentially via inhibiting miR-1252/PAK3 pathway.

BACKGROUND: Gastric cancer is a serious malignant tumor associated with aberrant circular RNAs (circRNAs) expression. In this study, we aim to investigate the role and the underlying mechanism of circ_0000190, a circRNA in gastric cancer. METHODS: Circ_0000190 expression in vivo was examined in gastric cancer and adjacent normal tissues by RT-PCR. Circ_0000190 expression in gastric cancer cell lines was detected by FISH and RT-PCR. The role of the circRNA in gastric cancer cells was assessed by the analysis of cell viability, apoptosis, proliferation, cell cycle and migration. The potential effector of circ_0000190 was predicted by computational screen and validated by luciferase reporter assay. Furthermore, Mice model of human gastric cancer was established to observe the underlying mechanisms of circ_0000190. RESULTS: Circ_0000190 was down-regulated in gastric cancer tissues and cells, with a major location in cytoplasm. Circ_0000190 inhibited gastric cancer cell viability, proliferation and migration, and induced apoptosis and cell cycle arrest by regulating the expression of capase-3, p27 and cyclin D. In addition, the circRNA was validated as a sponge of miR-1252, which directly targeted PAK3. The effects of circ_0000190 on the cellular processes were blocked by miR-1252 mimics, which could be rescued after further overexpression of PAK3. CONCLUSIONS: Circ_0000190 suppresses gastric cancer progression potentially via inhibiting miR-1252/PAK3 pathway, employing circ_0000190 might be a promising therapeutic strategy for the treatment of gastric cancer.

BIX-01294 enhanced chemotherapy effect in gastric cancer by inducing GSDME-mediated pyroptosis.

Adjuvant chemotherapy in combination with surgery is expected to be a curative strategy for gastric cancer. However, drug resistance remains an obstacle in effective chemotherapy. Therefore, understanding the potential mechanisms of chemotherapy induced gastric cancer cell death is of great importance. We demonstrated that BIX-01294 (BIX) at low concentration could induce autophagic flux by converting LC3B-I to LC3B-II and directly activate autophagy associated cell death in gastric cancer cell lines at high concentration. BIX at low concentration could help obtain sensitivity of gastric cancer cells to chemotherapy with significantly reduced cell viability. Interestingly, BIX combined Cis (BIX + Cis) treated SGC-7901 cells display pyroptosis related cell death with large bubbles blown around the membrane, significantly decreased cell viability, elevated lactate dehydrogenase release and increased percentage of propidium iodide and Annexin-V double positive cells. Furthermore, the cleavage of gasdermin E (GSDME) and caspase-3 but not GSDMD was detected by immunoblotting and the knockout of GSDME switched pyroptosis into apoptosis in the BIX + Cis combined treated group. Furthermore, the deficiency of Beclin-1 to inhibit BIX induced autophagic flux completely blocked BIX + Cis combined treated induced cell pyroptosis related cell death. Additionally, BIX + Cis in vivo treatment could inhibit tumor growth, which could be reversed by the deficiency of Beclin-1 and be delayed by the deficiency of GSDME. In conclusion, our data was the first to reveal that BIX enhanced the anticancer chemotherapy effect by induced GSDME-mediated pyroptosis through the activation of autophagic flux in gastric cancer cells.

Temporal trends of incident diabetes mellitus and subsequent outcomes in patients receiving kidney transplantation: a national cohort study in Taiwan.

BACKGROUND: Allograft kidney transplantation has become a treatment of choice for patients with end-stage renal disease (ESRD), and post-transplant diabetes mellitus (PTDM) has been associated with impaired patient and graft survival. Taiwan has the highest incidence and prevalence rates of ESRD with many recipients and candidates of kidney transplantation. However, information about the epidemiologic features of PTDM in Taiwan is incomplete. Therefore, we aimed to investigate the prevalence and incidence of PTDM with subsequent patient and graft outcomes. METHODS: Using the Taiwan National Health Insurance Research Database (NHIRD), 3663 kidney recipients between 1997 and 2011 were enrolled. We calculated the cumulative incidences of diabetes mellitus (DM) after transplantation. Cox proportional hazards model with competing risk analysis was used to calculate the hazard ratio (HR) and 95% confidence intervals (CI) between three targeted groups (DM, PTDM, non-DM). The outcomes of primary interest were the occurrence of graft failure excluding death with functioning graft, all-cause mortality, death with functioning graft and major adverse cardiovascular events (MACE) including myocardial infarction (MI), cerebrovascular accident (CVA) and congestive heart failure (CHF). Subgroup analysis for graft failure excluding death with functioning graft, MACE and all-cause mortality was performed, and interaction between PTDM and recipient age was examined. RESULTS: Of 3663 kidney transplant recipients, 531 (14%) had pre-existing DM and 631 (17%) developed PTDM. Compared with non-DM group, the PTDM and DM groups exhibited higher risk of graft failure excluding death with functioning graft (PTDM: HR 1.65, 95% CI 1.47-1.85; DM: HR 1.33, 95% CI 1.18-1.50), MACE (PTDM: HR 1.51, 95% CI 1.31-1.74; DM: HR 1.64, 95% CI 1.41-1.9), all-cause mortality (PTDM: HR 1.79, 95% CI 1.59-2.01; DM: HR 2.03, 95% CI 1.81-2.18), and death with functioning graft (PTDM: HR 1.94, 95% CI 1.71-2.20; DM: HR 1.94, 95% CI 1.71-2.21). Both PTDM and DM groups had increased cardiovascular disease-related mortality (PTDM: HR 2.14, 95% CI 1.43-3.20, p < 0.001; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.002), cancer-related mortality (PTDM: HR 1.56, 95% CI 1.18-2.07, p = 0.002; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.027), and infection-related mortality (PTDM: HR 1.47, 95% CI 1.14-1.90, p = 0.003; DM: HR 2.25, 95% CI 1.77-2.84, p < 0.001) compared with non-DM group. The subgroup analyses showed that the add-on risks of MACE and mortality from PTDM were mainly observed in patients who were younger and those without associated comorbidities including atrial fibrillation, cirrhosis, CHF, and MI. Age significantly modified the association between PTDM and MACE (pinteraction < 0.01) with higher risk in recipients with PTDM aged younger than 55 years (adjusted HR 1.64, 95% CI 1.40-1.92, p < 0.001). A trend (pinteraction = 0.06) of age-modifying effect on the association between PTDM and all-cause mortality was also noted with higher risk in recipients with PTDM aged younger than 55 years. CONCLUSIONS: In the present population-based study, the incidence of PTDM peaked within the first year after kidney transplantation. PTDM negatively impacted graft and patient outcomes. The magnitude of cardiovascular and survival disadvantages from PTDM were more pronounced in recipients aged less than 55 years. Further trials to improve prediction of PTDM and to prevent PTDM are warranted.

Reactivation of microRNA-506 inhibits gastric carcinoma cell metastasis through ZEB2.

MicroRNAs (miRNAs) are frequently dysregulated in a variety of human cancers, including gastric carcinoma. To improve our understanding of the role of miRNAs in gastric carcinoma and potential identify novel biomarkers or therapeutic agents, we performed microarray analysis to identify differentially expressed miRNAs in gastric carcinoma, compared with paired non-cancerous gastric tissues. We identified significantly differentially expressed miRNAs in gastric carcinoma tissues, including miR-506. We validated the microarray results by quantitative reverse transcription polymerase chain reaction in 26 specimens and confirmed significant downregulation of miR-506 in gastric carcinoma. Bioinformatics analysis predicted ZEB2 (zinc finger E-box-binding homeobox 2) as a potential target of miR-506. MiR-506 levels and ZEB2 levels were inversely correlated in gastric carcinoma, and low miR-506 levels in gastric carcinoma were associated with poor prognosis. Overexpression of miR-506 in gastric carcinoma cells significantly inhibited cell migration and invasion, while depletion of miR-506 in gastric carcinoma cells significantly increased cell migration and invasion. Transplantation of miR-506-overexpressing gastric carcinoma cells developed significantly smaller tumor, compared to the control. Thus, our results suggest that miR-506 may function as a tumor suppressor and targets and inhibits ZEB2 in gastric carcinoma.

Circulating epithelial cells as potential biomarkers for detection of recurrence in patients of papillary thyroid carcinoma with positive serum anti-thyroglobulin antibody.

BACKGROUND: Serum thyroglobulin (Tg) is not a reliable tumor marker for monitoring disease status after treatment in patients with papillary thyroid carcinoma (PTC) with positive anti-thyroglobulin antibody (TgAb). The aim of this study was to evaluate the clinical role of circulating epithelial cells (CECs) in PTC patients with positive serum TgAb and undetectable serum Tg. METHODS: A pilot study was performed to evaluate CECs in 25 PTC patients with positive serum TgAb and undetectable serum Tg. CECs were isolated and enriched from peripheral blood with a negative selection system PowerMag. Immunofluorescence staining with anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-thyroid stimulating hormone receptor (anti-TSHR) antibodies were used to define EpCAM+-CECs and TSHR+-CECs. After CECs testing, 25 patients were classified into two groups: recurrence group (n=7) and remission group (n=18) based on biopsy or imaging studies. The diagnostic accuracy and cutoff points of EpCAM+-CECs and TSHR+-CECs were evaluated using receiver operating characteristic (ROC) curves. The optimal cut-off values of CECs were determined by the Youden index (sensitivity+specificity-1). RESULTS: The median numbers of EpCAM+-CECs (72.5 vs. 10.75) and TSHR+-CECs (54 vs. 5.25) were significantly increased in recurrence group compared to remission group. The area under the curve (AUC) showed good performance of EpCAM+-CECs (0.937) and TSHR+-CECs (0.825) to discriminate between recurrence and remission. The cut-off value for EpCAM+-CECs and TSHR+-CECs were set at 48cells/ml and 10cells/ml, respectively and showed a sensitivity (EpCAM+-CECs: 85.7%; TSHR+-CECs: 85.7%) and a specificity (EpCAM+-CECs: 100%; TSHR+-CECs: 77.8%) in predicting the recurrence. CONCLUSIONS: Our study suggests CECs testing could be a potential biomarker to identify recurrence in PTC patients with positive serum TgAb and undetectable serum Tg.