Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

PURPOSE: Despite of very rare, breast cancer patients with double heterozygosity (DH) variants in BRCA1 and BRCA2 genes have been identified in other ethnic groups and seem to be associated with distinctive phenotypes. However, little is known about the frequency and clinical characteristics of Chinese breast cancer patients with BRCA1/2 DH variants. METHODS: Four hundred and eleven unrelated patients with BRCA1 or BRCA2 pathogenic variants (PVs) were identified in a large series of unselected breast cancer patients. Another two siblings with metachronous bilateral breast cancer were referred for genetic counseling, after which BRCA1/2 DH variants were detected. RESULTS: Four unrelated breast cancer patients with BRCA1/2 DH were identified in the cohort of 411 patients with BRCA1 or BRCA2 PVs, the frequency of BRCA1/2 DH was 0.97%. In total, six BRCA1/2 DH patients from five families were found in this study. In two families, the hereditary pattern of DH was speculated to have originated from both sides of the family. BRCA1/2 DH patients were more likely to have a family history of breast cancer than patients with a BRCA1 (100% vs. 29.2%, P = 0.004) or BRCA2 (100% vs. 29.6%, P = 0.004) single PV. BRCA1/2 DH patients were more likely to be triple-negative breast tumors than patients with single BRCA2 PVs (66.7% vs. 14.1%, P = 0.020), which was comparable to the findings in patients with single BRCA1 PVs (66.7% vs. 56.9%, P = 1.00). CONCLUSION: Chinese patients with BRCA1/2 DH exhibit a high percentage of family history of breast cancer. The tumor pathological features of BRCA1/2 DH carriers are similar to those of BRCA1 PV carriers.

Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome.

Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

Fluid shear force and hydrostatic pressure jointly promote osteogenic differentiation of BMSCs by activating YAP1 and NFAT2.

Natural bone tissue features a complex mechanical environment, with cells responding to diverse mechanical stimuli, including fluid shear stress (FSS) and hydrostatic pressure (HP). However, current in vitro experiments commonly employ a singular mechanical stimulus to simulate the mechanical environment in vivo. The understanding of the combined effects and mechanisms of multiple mechanical stimuli remains limited. Hence, this study constructed a mechanical stimulation device capable of simultaneously applying FSS and HP to cells. This study investigated the impact of FSS and HP on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and examined the distinctions and interactions between the two mechanisms. The results demonstrated that both FSS and HP individually enhanced the osteogenic differentiation of BMSCs, with a more pronounced effect observed through their combined application. BMSCs responded to external FSS and HP stimulation through the integrin-cytoskeleton and Piezo1 ion channel respectively. This led to the activation of downstream biochemical signals, resulting in the dephosphorylation and nuclear translocation of the intracellular transcription factors Yes Associated Protein 1 (YAP1) and nuclear factor of activated T cells 2 (NFAT2). Activated YAP1 could bind to NFAT2 to enhance transcriptional activity, thereby promoting osteogenic differentiation of BMSCs more effectively. This study highlights the significance of composite mechanical stimulation in BMSCs' osteogenic differentiation, offering guidance for establishing a complex mechanical environment for in vitro functional bone tissue construction.

Suspension culture promoted the expansion of NK-92 cells ex vivo by enhancing the expression of IL-2 receptor.

Vigorous ex vivo expansion of NK-92 cells is a pivotal step for clinical adoptive immunotherapy. Interleukin-2 (IL-2) is identified as a key cytokine for NK-92 cells, and it can stimulate cell proliferation after binding to the IL-2 receptor (IL-2R). In this work, the differences in IL-2 consumption and IL-2R expression were investigated between the two culture modes. The results showed that suspension culture favored ex vivo expansion of NK-92 cells compared with static culture. The specific consumption rate of IL-2 in suspension culture was significantly higher than that in static culture. It was further found that the mRNA levels of the two IL-2R subunits remained unchanged in suspension culture, but the proportion of NK-92 cells expressing IL-2Rß was increased, and the fluorescence intensity of IL-2Rß was remarkably enhanced. Meanwhile, the proportion of cells expressing IL-2R receptor complex also increased significantly. Correspondingly, the phosphorylation of STAT5, a pivotal protein in the downstream signaling pathway of IL-2, was up-regulated. Notably, the expression level and colocalization coefficient of related endosomes during IL-2/IL-2R complex endocytosis were markedly elevated, suggesting the enhancement of IL-2 endocytosis. Taken together, these results implied that more IL-2 was needed to support cell growth in suspension culture. Therefore, the culture process was optimized from the perspective of cytokine utilization to further improve the NK-92 cell's expansion ability and function. This study provides valuable insight into the efficient ex vivo expansion of NK-92 cells.

Root caries in older adults: A co-citation network analysis (1980-2023).

BACKGROUND: Root caries affect the oral health and quality of life of older adults. This study examines the breadth of global research on this topic, aiming to clarify its expansive scope and to shed light on pertinent trends for new researchers in the field. OBJECTIVE: To identify key advances in root caries research as highlighted in high-quality articles from the Social Science Citation Index (SSCI) as well as to explore emerging trends and perspectives. MATERIALS AND METHODS: Using the Web of Science (WoS) database, we conducted a comprehensive review of articles related to root caries in older adults. Our focus was on finding high-quality SSCI articles, identifying major contributors, journals and research trends and exploring areas such as dentistry, oral surgery and medicine for potential future research. RESULTS: Our analysis included 192 articles, each of which was subjected to bibliometric and VOS viewer evaluations. The results revealed a concentration of studies in dentistry, oral surgery and medicine, with gaps identified in areas like anthropology, biochemistry, molecular biology and chemistry. A notable deficiency was found in root caries management. CONCLUSION: We discuss research gaps and propose future directions based on our findings, emphasising interdisciplinary research approaches.

Ceramide enhanced the hepatic glucagon response through regulation of CREB activity.

BACKGROUND & AIMS: Hyperglycemia is associated with lipid disorders in patients with diabetes. Ceramides are metabolites involved in sphingolipid metabolism that accumulate during lipid disorders and exert deleterious effects on glucose and lipid metabolism. However, the effects of ceramide on glucagon-mediated hepatic gluconeogenesis remain largely unknown. This study was designed to investigate the impact of ceramides on gluconeogenesis in the context of the hepatic glucagon response, with the aim of finding new pharmacological interventions for hyperglycemia in diabetes. METHODS: Liquid chromatography-mass spectrometry was used to quantify ceramide content in the serum of patients with diabetes. Primary hepatocytes were isolated from male C57BL/6J mice to study the effects of ceramide on hepatic glucose production. Immunofluorescence staining was performed to view cAMP-responsive element-binding protein (CREB)- regulated transcription co-activator 2 (CRTC2) nuclear translocation in hepatocytes. Serine palmitoyl-transferase, long chain base subunit 2 (Sptlc2) knockdown mice were generated using an adeno-associated virus containing shRNA, and hepatic glucose production was assessed glucagon tolerance and pyruvate tolerance tests in mice fed a normal chow diet and high-fat diet. RESULTS: Increased ceramide levels were observed in the serum of patients newly diagnosed with type 2 diabetes. De novo ceramide synthesis was activated in mice with metabolic disorders. Ceramide enhanced hepatic glucose production in primary hepatocytes. In contrast, genetic silencing of Sptlc2 prevented this process. Mechanistically, ceramides de-phosphorylate CRTC2 (Ser 171) and facilitate its translocation into the nucleus for CREB activation, thereby augmenting the hepatic glucagon response. Hepatic Sptlc2 silencing blocked ceramide generation in the liver and thus restrained the hepatic glucagon response in mice fed a normal chow diet and high-fat diet. CONCLUSIONS: These data indicate that ceramide serves as an intracellular messenger that augments hepatic glucose production by regulating CRTC2/CREB activity in the context of the hepatic glucagon response, suggesting that CRTC2 phosphorylation might be a potential node for pharmacological interventions to restrain the hyperglycemic response during fasting in diabetes.

S100a16 Deficiency Prevents Alcohol-induced Fatty Liver Injury via Inducing MANF Expression in Mice.

Alcoholic liver disease (ALD) encompasses conditions ranging from simple steatosis to cirrhosis and even liver cancer. It has gained significant global attention in recent years. Despite this, effective pharmacological treatments for ALD remain elusive, and the core mechanisms underlying the disease are not yet fully comprehended. S100A16, a newly identified calcium-binding protein, is linked to lipid metabolism. Our research has discovered elevated levels of the S100A16 protein in both serum and liver tissue of ALD patients. A similar surge in hepatic S100A16 expression was noted in a Gao-binge alcohol feeding mouse model. S100a16 knockdown alleviated ethanol-induced liver injury, steatosis and inflammation. Conversely, S100a16 transgenic mice showed aggravating phenomenon. Mechanistically, we identify mesencephalic astrocyte-derived neurotrophic factor (MANF) as a regulated entity downstream of S100a16 deletion. MANF inhibited ER-stress signal transduction induced by alcohol stimulation. Meanwhile, MANF silencing suppressed the inhibition effect of S100a16 knockout on ethanol-induced lipid droplets accumulation in primary hepatocytes. Our data suggested that S100a16 deletion protects mice against alcoholic liver lipid accumulation and inflammation dependent on upregulating MANF and inhibiting ER stress. This offers a potential therapeutic avenue for ALD treatment.

The Rapid Changes in Bodyweight and Glycemic Control Are Determined by Pre-status After Bariatric Surgery in Both Genders in Young Chinese Individuals.

PURPOSES: The primary aim of this clinical study is to identify the factors associated with rapid glycemic, bodyweight, and lipid profile remission in young obese patients following bariatric surgery. MATERIALS AND METHODS: In a total of 131 Chinese in-patients at Shanghai Pudong Hospital, China, we retrospectively analyzed in-patient data of metabolic parameters, including BMI, waist circumference, blood pressure (BP), and blood laboratory tests, such as plasma lipids and lipoprotein, hemoglobulin A1c (HbA1c), and oral glucose tolerance tests (OGTT) before bariatric surgery. We followed up these indices at the first month, third months, half-year, and one year later. RESULTS: The results showed that bodyweight, BP, fasting plasma glucose (FPG), HbA1c, and triglyceride (TG) levels decreased significantly in one to three months following surgery in both male and female patients (p<0.05). We demonstrated that age (male: ß=-0.181; female: ß=-0.292) and the pre-operation HbA1c levels (male: ß=0.935; female: ß=0.919) were independent predictors of HbA1c reduction in both young obese male and female patients in three months after surgery. For body weight loss, age (ß=-0.229) and pre-operation bodyweight (ß=0.735) are the predictors in females, but only pre-operation body weight (ß=0.798) is the independent predictor in obese young male patients. CONCLUSION:  This study discovered that changes in bodyweight were determined by age, pre-operation status of bodyweight, and HbA1C in obese young Chinese.

Nucleus-Targeting Nanoplatform Based on Dendritic Peptide for Precise Photothermal Therapy.

Photothermal therapy directly acting on the nucleus is a potential anti-tumor treatment with higher killing efficiency. However, in practical applications, it is often difficult to achieve precise nuclear photothermal therapy because agents are difficult to accurately anchor to the nucleus. Therefore, it is urgent to develop a nanoheater that can accurately locate the nucleus. Here, we designed an amphiphilic arginine-rich dendritic peptide (RDP) with the sequence CRRK(RRCG(Fmoc))2, and prepared a nucleus-targeting nanoplatform RDP/I by encapsulating the photothermal agent IR780 in RDP for precise photothermal therapy of the tumor nucleus. The hydrophobic group Fmoc of the dendritic peptide provides strong hydrophobic force to firmly encapsulate IR780, which improves the solubility and stability of IR780. Moreover, the arginine-rich structure facilitates cellular uptake of RDP/I and endows it with the ability to quickly anchor to the nucleus. The nucleus-targeting nanoplatform RDP/I showed efficient nuclear enrichment ability and a significant tumor inhibition effect.

FDC-SP as a diagnostic and prognostic biomarker and modulates immune infiltrates in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC), one of the top 10 causes of cancer death, is responsible for more than 90% of all cases of primary renal cancer worldwide. Follicular dendritic cell-secreted protein (FDC-SP) specifically binds to activated B cells and regulates the generation of antibodies. It is also thought to promote cancer cell invasion and migration, which could help with tumor metastases. This study aimed to assess the efficacy of FDC-SP in the diagnosis and prognosis of RCC and to investigate the relationship between immune infiltration in RCC and these outcomes. RESULTS: RCC tissues had significantly higher levels of FDC-SP protein and mRNA than normal tissues. The high level of FDC-SP expression was linked to the T stage, histological grade, pathological stage, N stage, M stage, and OS event. Functional enrichment analysis identified the major pathways that were enriched as immune response regulation, complement, and coagulation. Immunological checkpoints and immune cell infiltration were observed to substantially correlate with the levels of FDC-SP expression. FDC-SP expression levels showed the ability to precisely distinguish high-grade or high-stage renal cancer (area under the curve (AUC) = 0.830, 0.722), and RCC patients with higher FDC-SP expression levels had worse prognoses. The AUC values for one-, two-, and five-year survival rates were all greater than 0.600. Moreover, the FDC-SP expression is an independent predictive biomarker of OS in RCC patients. CONCLUSION: FDC-SP may be a prospective therapeutic target in RCC as well as a possible diagnostic and prognostic biomarker associated with immune infiltration.

Development of stable HEK293T cell pools expressing CSFV E2 protein: A potential antigen expression platform.

Large quantities of antigens are required since protective antigens, such as classical swine fever virus (CSFV) E2 protein, are widely used in diagnostic reagents and subunit vaccines. Compared to clonal cell lines and transient gene expression, stable cell pools provide a potential alternative platform to rapidly produce large amounts of antigens. In this work, firstly, Human embryonic kidney 293 T (HEK293T) cell pools expressing E2 protein were developed by transduction of lentiviral vectors. On the one hand, the SP7 was selected from 7 well-performing signal peptides to remarkably increase the production of E2 protein. On the other hand, it was found that high MOI could improve the expression of E2 protein by increasing gene copy numbers. Moreover, the HEK293T cell pools were evaluated for stability by passages and batch cultures, demonstrating that the cell pools were stable for at least 90 days. And then, the performance of the cell pools in batch, fed-batch, and semi-perfusion was studied. Among them, the titer of E2 protein was up to 2 g/L in semi-perfusion, which is currently the highest to the authors' knowledge. Finally, the aggregations and immunogenicity of the E2 protein were analyzed by SDS-PAGE and immunization of mice, respectively. There was no significant difference in aggregations and antibody titers of E2 protein in three culture methods. These results suggest that stable HEK293T cell pools are a promising and robust platform for rapid and efficient production of recombinant proteins.

The Evolution of Pancreatic Islet Function in a Diabetic Patient after Pancreatic Neuroendocrine Neoplasm Surgery: A Case Report.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are rare primary tumors of the pancreas. Although these tumors are heterogeneous and can be classified as functional or non-functional according to pancreatic endocrine biomarkers, the more prevalent type is non-functional pNENs with endocrine differentiation but with non-specific symptoms and often late diagnoses. The treatment option for patients often involves surgical management, but the reported outcomes, especially on insulin secretion change and the trend of diabetes in these patients, varied to date. Hence, the purpose of this clinical report is to study the functional change of pancreatic ß- cell corresponding to the mass of tumorectomy of pNEN in a diabetic patient. CASE PRESENTATION: We reported that a 39-year-old man with diabetes was found complicated with neuroendocrine neoplasm. He was admitted to the General Surgery of our hospital for further examination and therapy. The patient received a pancreatectomy + splenectomy + lymphadenectomy on the pancreatic body and tail. We analyzed the pancreatic mass change and performed Oral Glucose Tolerance Test (OGTT) before and after the surgery to evaluate the function of the pancreas. CONCLUSION: This case may provide us a reference to predict the extent of islet function loss before the pancreatectomy, and apply personalized hypoglycemic therapy after surgery in these patients.

CircRNA High Mobility Group At-hook 2 regulates cell proliferation, metastasis and glycolytic metabolism of nonsmall cell lung cancer by targeting miR-331-3p to upregulate High Mobility Group At-hook 2.

Increasing circular RNAs (circRNAs) have been identified as pivotal players in nonsmall cell lung cancer (NSCLC). The study will explore the function and mechanism of circRNA High Mobility Group AT-hook 2 (circHMGA2) in NSCLC. The circHMGA2, microRNA-331-3p (miR-331-3p) and HMGA2 expression analyses were performed via quantitative real-time PCR. Cell proliferation was assessed via Cell Counting Kit-8 and colony formation assays. Transwell migration/invasion assays were used for measuring cell metastasis. Glucose consumption and lactate production were determined for glycolytic evaluation. Western blot was used to detect the protein expression of HMGA2 and glycolytic markers. Target analysis was performed by dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Xenograft tumor assay in mice was conducted for the investigation of circHMGA2 in vivo . CircHMGA2 was overexpressed in NSCLC, and high circHMGA2 level might be related to NSCLC metastasis and poor prognosis. In-vitro assays suggested that NSCLC cell growth, metastasis and glycolysis were retarded by downregulation of circHMGA2. Upregulation of HMGA2 was shown to return the anticancer response of circHMGA2 knockdown in NSCLC cells. Through interacting with miR-331-3p, circHMGA2 could regulate the expression of HMGA2. In addition, circHMGA2/miR-331-3p and miR-331-3p/HMGA2 axes were affirmed in NSCLC regulation. In-vivo analysis indicated that circHMGA2 inhibition also reduced tumorigenesis and glycolysis of NSCLC via the miR-331-3p/HMGA2 axis. This study disclosed the oncogenic role of circHMGA2 and the regulatory circHMGA2/miR-331-3p/HMGA2 axis in NSCLC.

The Relationship between Serum Iron and Thyroid Function in the Patients with Type 2 Diabetes.

PURPOSE: Our primary objective in this study is to determine the relationship between serum iron (Fe3+) and thyroid functions in type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: Glucose metabolic parameters, trace elements, such as Fe3+, and thyroid functions for 1657 type 2 diabetic patients treated at the Shanghai Pudong Hospital's Department of Endocrinology from 2018 to 2021 were assessed. RESULTS: Variations in free thyroid hormones (FTH) and total thyroid hormones (TTH) were insignificant; however, thyroid-stimulating hormone (TSH) levels were markedly elevated in patients with positive thyroid peroxidase antibody (TPOAb) and/or positive antithyroglobulin antibody (TgAb) (p<0.05). Additionally, gender disparities affected FTH levels (p<0.05) but not TTH and TSH levels. The female gender was significantly negatively correlated with serum Fe levels (r=-0.381, p<0.05). Serum Fe3+ deficiency also had an effect on FT3 in both genders, FT4 and TT4 in males (p<0.05), but not TSH (p>0.05). The multilinear regression model showed that TT3 (ß=0.702), eGFR (ß=0.109), Fe3+ (ß=0.003), female gender (ß=-0.061), and age (ß=-0.061) were the major determinants for FT3 change. Moreover, renal function, which was represented as the estimated glomerular filtration rate (eGFR), had no effects on Fe3+ and TSH levels but on the levels of FTH and TTH (p<0.05). FT3/FT4 exhibited correlations with Fe3+ (r=0.252) and eGFR (r=0.285). Finally, changes in Fe3+ levels had no significant impact on fasting plasma glucose (FPG), fasting C-peptide, HbA1c, and glycated albumin levels (p>0.05). CONCLUSION: In addition to age, gender, and renal functions, serum Fe3+ levels in T2DM patients have a significant relationship with thyroid functions.

Effectiveness of different root-end filling materials in modern surgical endodontic treatment: A systematic review and network meta-analysis.

Background/purpose: There is controversial evidence on the best choice for root-end filling materials in follow-up periods and treatment protocols. The purpose of this study was to evaluate the effectiveness of different root-end filling materials in modern surgical endodontic treatment. Materials and methods: A total of 16 studies with a minimum follow-up of 12-months were qualified to be reviewed, involving randomized control trials and observational studies in PubMed, Cochrane library and Scopus until September 1, 2021. The outcome of modern surgical endodontic treatment was assessed based on clinical and radiographic success. Direct comparisons were combined to estimate indirect comparisons, and the estimated effect size was analyzed using the odds ratio (OR). The comparative effectiveness of all materials for target outcomes were shown as P-score. Results: Within this network meta-analysis, mineral trioxide aggregate (MTA) had superior effects among all root-end filling materials at 12-months follow-up. (MTA: OR, 2.03; 95% CI, 0.84-4.91; P-score, 0.86; reference material, gutta-percha). In further sensitivity analyses, MTA, calcium silicate-based root repair material (RRM) and super EBA cement (Super EBA) were associated with significantly higher success rates at 12-months follow-up. (MTA: OR, 5.62; 95% CI, 1.58-19.99; P-score, 0.88; RRM: OR, 5.23; 95% CI, 1.05-25.98; P-score, 0.74; Super EBA: OR, 3.99; 95% CI, 1.06-15.04; P-score, 0.54; reference material, gutta-percha). Conclusion: MTA remains the best choice for root-end filling materials of modern surgical endodontic treatment at the 12-month follow-up. Comparative randomized clinical trials in the long-term follow-up are warranted in future investigations.

Premorbid Steatohepatitis Increases the Seriousness of Dextran Sulfate Sodium-induced Ulcerative Colitis in Mice.

Background and Aims: The concurrence of nonalcoholic steatohepatitis (NASH) and ulcerative colitis (UC) is increasingly seen in clinical practice, but the underlying mechanisms remain unclear. This study aimed to develop a mouse model of the phenomenon by combining high-fat high-cholesterol diet (HFHCD)-induced NASH and dextran sulfate sodium (DSS)-induced UC, that would support mechanistic studies. Methods: Male C57BL/6 mice were randomly assigned to two groups receiving either a chow diet or HFHCD for 12 weeks of NASH modeling. The mice were the divided into four subgroups for UC modeling: (1) A control group given a chow diet with normal drinking water; (2) A colitis group given chow diet with 2% DSS in drinking water; (3) A steatohepatitis group given HFHCD with normal drinking water; and (4) A steatohepatitis + colitis group given HFHCD with 2% DSS in drinking water. Results: NASH plus UC had high mortality (58.3%). Neither NASH nor UC alone were fatal. Although DSS-induced colitis did not exacerbate histological liver injury in HFHCD-fed mice, premorbid NASH significantly increased UC-related gut injury compared with UC alone. It was characterized by a significantly shorter colon, more colonic congestion, and a higher histopathological score (p<0.05). Inflammatory (tumor necrosis factor-alpha, interleukin 1 beta, C-C motif chemokine ligand 2, and nuclear factor kappa B) and apoptotic (Bcl2, Bad, Bim, and Bax) signaling pathways were significantly altered in distal colon tissues collected from mice with steatohepatitis + colitis compared with the other experimental groups. Conclusions: Premorbid steatohepatitis significantly aggravated DSS-induced colitis and brought about a lethal phenotype. Potential links between NASH and UC pathogeneses can be investigated using this model.

Relationship Between Sporadic Renal Cysts and Renal Function Detected by Isotope Renography in Type 2 Diabetes.

Purpose: This study aimed to reveal the relationship between the volume of sporadic renal cysts and renal function in patients with type 2 diabetes (T2D). Materials and Methods: One hundred and seventy-one patients that underwent renal imaging and other routine examinations at the Shanghai Pudong Hospital were included in this study. The Gates' method of glomerular filtration rate (GFR) was measured by 99mTc-DTPA renal dynamic imaging in addition to the eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results: Our results showed that BMI, total iGFR, and eGFR showed significant differences between patients with T2D with or without SRC (p < 0.05). Spearman correlation analysis showed that cyst volume was positively correlated with Scr and gender but not iGFR (p > 0.05). The total iGFR positively correlated with eGFR (r = 0.83, p < 0.0001) and negatively with Scr (r = -0.78, p < 0.0001), age (r = -0.43, p < 0.0001), duration of T2D (r = -0.25, p = 0.001), and BMI (r = -0.21, p = 0.006) but not gender (r = -0.03, p = 0.668). The multilinear regression model revealed that gender (ß = 0.346, p < 0.001), iGFR (ß = -0.705, p < 0.001), and serum uric acid (ß = 0.195, p = 0.032) were independent predictors of Scr. Moreover, we observed a significant increase in Scr in males (p < 0.05). Finally, we found that the split kidney function reflected by iGFR and related parameters such as time to peak (PTT) and half time of excretion (excrete t1/2) did not mutually distinguish from each other significantly whether they are measured in patients with renal cysts or in those without renal cysts (p > 0.05). Conclusion: Our preliminary results suggest that in T2D, SRCs may be a renal complication of diabetic nephropathy. Although we found that the patients with renal cysts may display reduced iGFR, the volume of simple cysts seems not to exacerbate renal insufficiency. Isotope renography is a useful tool to evaluate the split kidney functions in diabetic patients who acquire single-side cysts.

Xanthan gum enhances peripheral blood CIK cells cytotoxicity in serum-free medium.

As a water-soluble macromolecule polysaccharide, xanthan gum (XG) has several biological activities, such as antitumor, antiviral, and immunomodulatory function. However, the effect of XG on the proliferation and cytotoxicity of cytokines induced killer (CIK) cells is rarely studied. In this study, the effect of XG on CIK cells derived from peripheral blood was investigated by analyzing the expansion fold of total cells, phenotype, cytotoxicity, degranulation, and apoptosis in serum-free medium. The results showed that the expansion fold of total cells with 100 µg/ml XG which molecule weight is 2.95 × 106 Da reached 4534.0 folds, significantly higher than that without XG (1299.0 folds, p < 0.05). The percentage of main effector cells-CD3+ CD56+ cells increased to 25.5% and the cytotoxic activity of CIK cells increased to 45.3%. The cell proportions of expression granzyme B and perforin that related to cytotoxicity in CIK cells reached 53.6% and 48.3%, respectively, significantly higher than 27.5% and 37.5% in the group without XG (p < 0.05). Collectively, XG could stimulate the ex vivo expansion of CIK cells and enhance the cytotoxicity of expanded CIK cells. The above results provide technical support for optimizing the expansion process of CIK cells ex vivo.