Search

Abstract Multiple myeloma (MM) is a hematological malignancy that is consistently preceded by an asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Disparities by age, gender, and race/ethnicity in both MGUS and MM are well-established. However, it remains unclear whether these disparities can be explained by increased incidence of MGUS and/or accelerated progression from MGUS to MM. Here, we fit a mathematical model to nationally representative data from the United States and showed that the difference in MM incidence can be explained by an increased incidence of MGUS among male and non-Hispanic Black populations. We did not find evidence showing differences in the rate of progression from MGUS to MM by either gender or race/ethnicity. Our results suggest that screening for MGUS among high-risk groups (e.g., non-Hispanic Black men) may hold promise as a strategy to reduce the burden and MM health disparities.

Summary: Chronological age only represents the passage of time, whereas biological age reflects the physiology states and the susceptibility to morbidity and mortality. The association between biological age and lung cancer risk remains controversial. Hence, we conducted a prospective analysis in the UK Biobank study and two-sample Mendelian randomization analysis to investigate this association. Biological aging was evaluated by PhenoAgeAccel, derived from routine clinical biomarkers. Independent of chronological age, PhenoAgeAccel was positively associated with the risk of overall and histological subtypes of lung cancer. There was a joint effect of PhenoAgeAccel and genetics in lung cancer incidence. In Mendelian randomization analysis, the genetically predicted PhenoAgeAccel was associated with the increased risk of overall lung cancer, small cell, and squamous cell carcinoma. Our findings suggest PhenoAgeAccel is an independent risk factor for lung cancer, which could be incorporated with polygenic risk score to identify high-risk individuals for lung cancer.

Abstract Programmed death‐ligand 1 (PD‐L1) is a critical immune checkpoint protein that facilitates tumor immune evasion. While antibody‐based PD‐1/PD‐L1 inhibitors have shown promise, their limitations necessitate the development of alternative therapeutic strategies. This work addresses these challenges by developing a hexapeptide, KFM (Lys‐Phe‐Met‐Phe‐Met‐Lys), capable of both directly downregulating PD‐L1 and self‐assembling into a ROS‐responsive supramolecular hydrogel. This dual functionality allows Gel KFM to function as a localized drug delivery system and a PD‐L1 inhibitor. Loading the hydrogel with mitoxantrone (MTX) and metformin (MET) further enhances the therapeutic effect by combining chemotherapy with PD‐L1 downregulation. In vitro and in vivo studies demonstrate significant tumor growth inhibition, increased CD8+ T cell infiltration, and reduced intratumoral PD‐L1 expression following peritumoral administration. Mechanistically, KFM promotes PD‐L1 degradation via a ubiquitin‐dependent pathway. This “carrier‐free” delivery system expands the role of supramolecular hydrogels beyond passive carriers to active immunotherapeutic agents, offering a promising new strategy for cancer therapy.

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Abstract Tumor heterogeneity and its drivers impair tumor progression and cancer therapy. Single‐cell RNA sequencing is used to investigate the heterogeneity of tumor ecosystems. However, most methods of scRNA‐seq amplify the termini of polyadenylated transcripts, making it challenging to perform total RNA analysis and somatic mutation analysis.Therefore, a high‐throughput and high‐sensitivity method called snHH‐seq is developed, which combines random primers and a preindex strategy in the droplet microfluidic platform. This innovative method allows for the detection of total RNA in single nuclei from clinically frozen samples. A robust pipeline to facilitate the analysis of full‐length RNA‐seq data is also established. snHH‐seq is applied to more than 730 000 single nuclei from 32 patients with various tumor types. The pan‐cancer study enables it to comprehensively profile data on the tumor transcriptome, including expression levels, mutations, splicing patterns, clone dynamics, etc. New malignant cell subclusters and exploring their specific function across cancers are identified. Furthermore, the malignant status of epithelial cells is investigated among different cancer types with respect to mutation and splicing patterns. The ability to detect full‐length RNA at the single‐nucleus level provides a powerful tool for studying complex biological systems and has broad implications for understanding tumor pathology.

High levels of tumor necrosis factor receptor type II (TNFR2) are preferentially expressed by immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs), especially those present in the tumor microenvironment, as initially reported by us. There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses. Furthermore, a broad spectrum of human cancers also expresses TNFR2, while its expression by normal tissue is very limited. We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents. In this study, we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(dl-lactic-co-glycolic acid) (PLGA-PEG) nanodrug delivery system [designated as TNFR2-PLGA-ADR (Adriamycin)]. The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells. Further, upon intravenous injection, TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating Tregs. Compared with ADR and ISO-PLGA-ADR, the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced, which was associated with a decrease of TNFR2+ Tregs and an increase of IFNγ+CD8+ cytotoxic T lymphocytes in the tumor tissue. Therefore, our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.

Designing tactile sensors with high spatial resolution are crucial to manufacture large scale flexible electronics. Here, the authors develop a micro-cage structure by exploiting photo-reticulated strain localization films (prslPDMS), which shows the strain local confinement effect and could be used to prepare ultralow crosstalk sensor arrays.

Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.

Peritrich ciliates are a species-rich group of sessile unicellular eukaryotes, which can be found in various aquatic habitats from all over the world. It is well accepted that there are still many ciliates to be uncovered. During a survey on ciliate biodiversity in the coastal waters of China, three solitary peritrich species were identified as members of the genus Pseudovorticella Foissner & Schiffmann, 1975, including two new species and a rare one. Pseudovorticella zhejiangensis sp. n. differs from its congeners mainly by having a conical-shaped zooid, conspicuous pellicular blisters, one ventral and one dorsal contractile vacuoles, and an infundibular polykinety 3 with three rows of nearly equal length but different beginning positions. Pseudovorticella dalianensis sp. n. can be defined mainly by an obovoid-shaped zooid, one ventral contractile vacuole, and a three-rowed infundibular polykinety 3 with the middle row being the longest. The rare species, Pseudovorticella verrucosa (Dons, 1915) Sun et al., 2009, was redescribed. The small subunit (SSU) rDNA sequences of these three species were sequenced for the first time, the phylogeny of Pseudovorticella species was analyzed, and the results verified the non-monophyly of this genus. This study demonstrates that the morphologic and gene barcoding data are the optimum combination to disclose the biodiversity of ciliates.

Abstract The kernmantle construction, a kind of braiding structure that is characterized by the kern absorbing most of the stress and the mantle protecting the kern, is widely employed in the field of loading and rescue services, but rarely in flexible electronics. Here, a novel kernmantle electronic braid (E‐braid) for high‐impact sports monitoring, is proposed. The as‐fabricated E‐braids not only demonstrate high strength (31 Mpa), customized elasticity, and nice machine washability (>500 washes) but also exhibit excellent electrical stability (>200 000 cycles) during stretching. For demonstration, the E‐braids are mounted to different parts of the trampoline for athletes’ locomotor behavior monitoring. Furthermore, the E‐braids are proved to act as multifarious intelligent sports gear or wearable equipment such as electronic jump rope and respiration monitoring belt. This study expands the kernmantle structure to soft flexible electronics and then accelerates the development of quantitative analysis in modern sports industry and athletes’ healthcare.

ObjectivesThis study is intended to assess the prevalence of depression and anxiety in individuals who had recovered from COVID-19 and been discharged from hospital (RD hereafter) in Wuhan, China, and to explore the factors associated with these mental disorders.MethodsParticipants of this study were the RD who were infected at the beginning of the outbreak from 13 communities in Jianghan District of Wuhan City, Hubei Province, China by convenience sampling in mid-2021. The Generalized Anxiety Disorder Questionnaire, the Patient Health Questionnaire, the Short Version of COVID-19 Stigma Scale, the Peace of Mind Scale, the Resilience Style Questionnaire, and the Perceived Social Support Questionnaire were used to collect relevant information of the participants. Descriptive analyses, Pearson correlation analysis, and logistic regression analysis were used to describe and analyze the data and to examine the factors associated with the mental health status of this population.ResultsIn total, we recruited 1601 participants from 3059 COVID-19 patients, and 1541 participants completed the questionnaire survey, with a response rate of 96.25%. Finally, 1297 participants met the inclusion and exclusion criteria in this study, of whom 28.8% and 37.9% reported mild to severe levels of anxiety and depression symptoms. Perceived better mental health status during hospitalization, higher frequency of alcohol use per week, peace of mind, higher education level, and resilience were negatively associated with anxiety, while stigma and history of psychological or emotional counseling before infection was positively associated with anxiety. More severe clinical classification of COVID-19 and stigma (AOR = 1.057, PConclusionsTailored interventions on reducing stigma, enhancing mindfulness and social support should be taken into account to alleviate anxiety and depression among RD.

We present the experimental realization of tunable honeycomb superlattice plasma photonic crystals (PPCs) in dielectric barrier discharge by utilizing mesh-liquid electrodes. Fast reconfiguration among the simple honeycomb lattice, honeycomb superlattice, and honeycomb-snowflake superlattice is achieved. A dynamic control on the sizes of center scattering elements in the honeycomb superlattice has been realized. A phenomenological activator-inhibitor reaction diffusion model is established to demonstrate the formation and reconstruction of the honeycomb superlattice. The simulations reproduce well the experimental observations. The photonic band diagrams of different honeycomb PPCs are studied by using the finite element method. The addition of large center elements in honeycomb superlattice yields remarkable omnidirectional band gaps that are about 2.5 times larger than in the simple honeycomb lattice. We propose an effective scheme to fabricate spatiotemporally controllable honeycomb lattices that enable great improvement in band gap size and dynamic control of microwave radiations for wide applications.

Media with partisan tendencies publish news articles to support their preferred political parties to guide the direction of public opinion. Therefore, discovering political bias in news texts has important practical significance for national election prediction and public opinion management. Some biased news often has obscure expressions and ambiguous writing styles. By bypassing the language model, the accuracy of methods that rely on news semantic information for position discrimination is low. This manuscript proposes a news standpoint discrimination method based on social background information fusion heterogeneous network. This method expands the judgment ability of creators and topics on news standpoints from external information and fine-grained topics based on news semantics. Multi-attribute features of nodes enrich the feature representation of nodes, and joint representation of heterogeneous networks can reduce the dependence of position discrimination on the news semantic information. To effectively deal with the position discrimination of new news, the design of a multi-attribute fusion heterogeneous network is extended to inductive learning, avoiding the cost of model training caused by recomposition. Based on the Allsides dataset, this manuscript expands the information of its creator’s social background and compares the model for discriminating political positions based on news content. In the experiment, the best transductive attribute fusion heterogeneous network achieved an accuracy of 92.24% and a macro F1 value of 92.05%. The effect is improved based purely on semantic information for position discrimination, which proves the effectiveness of the model design.

Summary: A conceptual framework for understanding abnormal endometrial decidualization, with considerable significance for the diagnosis and treatment of abnormal decidualization-related changes in non-receptive endometrium in implantation failure during early pregnancy is very important. Here, we found the expression levels of miR-29a in endometrial tissues were associated with the menstrual phases and pregnancy outcome. Inhibition of miR-29a led to decreased decidualization of endometrial stromal cells (ESCs) in vitro, whereas Tet methylcytosine dioxygenase 3 (TET3) and its potential demethylation target, the collagen type I alpha 1 chain (Col1A1), were restored. The binding capacity of TET3 to the Col1A1 promoter could be enhanced by the inhibition of miR-29a. Finally, deletion of TET3 rescued the inhibitory effect of the miR-29a antagomir on the proliferation of decidualized ESCs in vitro and embryo implantation in vivo. Thus, loss of miR-29a causes implantation failure because of the limitation of ESCs decidualization-related changes in non-receptive endometrium during early pregnancy.

Abnormal cytoplasmic aggregates of FUS are a hallmark of some forms of amyotrophic lateral sclerosis (ALS). Here, using neurons derived from patients with FUS-ALS, the authors demonstrate that impairment of PARP-dependent DNA damage signaling is an event that occurs upstream of neurodegeneration and cytoplasmic aggregate formation in FUS-ALS.

Abstract The protective effects of Kisspeptin on heat-induced oxidative stress in rats were investigated by using a combination of biochemical parameters and metabonomics. Metabonomic analyses were performed using gas chromatography/mass spectrometry in conjunction with multivariate and univariate statistical analyses. At the end point of the heat stress experiment, histological observation, ultrastructural analysis and biochemical parameters were measured. Metabonomic analysis of liver tissue revealed that Kisspeptin mainly attenuated the alteration of purine metabolism and fatty acid metabolism pathways. Futhermore, Kisspeptin also increased the levels of GSH, T-AOC as well as SOD activities, and upregulated MDA levels. These results provide important mechanistic insights into the protective effects of Kisspeptin against heat-induced oxidative stress.

Secreted Nano-luciferase (secNluc) is a newly engineered secreted luciferase that possesses advantages of high structural stability, long half-life, and glow-type kinetics together with high light emission intensity, and thus would become one of the most valuable tools for bioluminescence assays. However, like other secreted luciferases, secNluc has to mix with the components in the conditioned medium surrounding test cells, or in the biological samples such as blood or urine after being secreted. These components may interfere with secNluc-catalyzed bioluminescence reactions and thus limit the application of the secNluc reporter system. In this study, we first examined the effects of three factors, pH, serum and residual reagents, on secNluc-catalyzed bioluminescence reactions, finding that these factors could interfere with bioluminescence reactions and result in background signal. To resolve these problems, we applied a simple affinity purification strategy in which secNluc was fused with a FLAG-tag, and anti-FLAG magnetic beads were used to catch and transfer the fusion protein to PBST, an optimal buffer for secNluc-catalyzed bioluminescence reactions that was identified in this study. The results indicated that this strategy could not only negate the interferences from serum or residual reagents and enhance the stability of light emission but also greatly increase signal intensity through enzyme enrichment. This strategy may contribute to biomedical studies that utilize secNluc and other secreted luciferases, especially those requiring superior sensitivity, low background noise and high reproducibility.

Sludge dewatering can effectively reduce the volume and mass of sludge for subsequent treatment and disposal. The work validated the potential of Fenton's reagent combined with dodecyl dimethyl benzyl ammonium chloride (DDBAC) in improving sludge dewaterability and proposed the mechanism of joint conditioning. The composite conditioner dosage was optimized using response surface methodology. Results indicated the good conditioning capability of the composite conditioners. The optimum dosages for H2O2, Fe2+, and DDBAC were 44.6, 39.6, and 71.0 mg/g, respectively, at which a sludge cake water content of 59.67% could be achieved. Moreover, a second-order polynomial equation was developed to describe the behavior of joint conditioning. Analysis of the reaction mechanism showed that Fenton oxidation effectively decomposed extracellular polymeric substance (EPS), including loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS), into dissolved organics, such as proteins and polysaccharides. The process facilitated the conversion of the bound water into free water. Furthermore, DDBAC further released the bound water through solubilization of TB-EPS and LB-EPS after the Fenton reaction. The bound water content of the sludge conditioned with Fenton's reagent decreased from 3.15 to 1.36 g/g and further decreased to 1.08 g/g with the addition of DDBAC. High-performance liquid chromatography analysis verified that the composite conditioning could oxidize and hydrolyze EPS into low-molecular-mass organics (e.g., formic and acetic acid), thereby facilitating the release of bound water.

Neuromedin B is one member of a family of bombesin-like peptides, which performs a variety of physiological functions via their receptor (NMBR) in most mammals. However, the genes encoding NMB and NMBR and their functions especially reproduction of the pigs are currently not fully understood. To research the physiological functions of NMB, we cloned and analyzed the NMB and NMBR genes, and systematically investigated the expression levels of NMB and NMBR mRNA using relative real-time PCR and the distribution of NMBR by immunohistochemistry (IHC). Experimental results show that the sequences of the amino acid and gene of NMB and NMBR were highly conservative and homology in many species, Significantly, the relative RT-PCR results revealed that NMB was mainly expressed in the central nervous system (CNS), whereas NMBR is highly expressed in peripheral tissues and organs, such as endocrine tissues, glands and reproductive organs. The IHC results show that NMBR positive cells were widely distributed in the body, such as respiratory and circulatory system, digestive system, urogenital system, in lymphatic organs and in the endocrine system. We also systematically investigated expression levels of NMB and NMBR in the reproductive axis using relative real-time PCR. In sow estrous cycle, the hypothalamic levels of both NMB and NMBR mRAN were similar, but the expression levels of the pituitary were negatively correlated. Expression levels in the ovarian system are lowest in metestrus phases and highest in proestrus and estrus phases. In boar post-natal development stages, the hypothalamic, pituitary and testicular levels of NMB and NMBR mRNAs showed developmental changes on postnatal day 30, 60, 90 and 120. Taken together, this study provided molecular and morphological data necessary for further research of physiological function of NMB/NMBR system in the pigs.

OBJECTIVE:To compare the natural fertility outcomes of salpingotomy and salpingectomy among women treated for tubal pregnancy. METHODS:An online database search including PubMed, Embase, CENTRAL and Web of Science was performed to identify studies comparing salpingotomy and salpingectomy to treat women with tubal pregnancy. The search included papers published after the databases were established until May 2015. Two reviewers independently screened literature according to the inclusion and exclusion criteria and then extracted data and assessed the methodological quality of all of the included studies. The meta-analysis was conducted using RevMan 5.3 software. The registration number is CRD42015017545 in PROSPERO. RESULTS:Two randomized controlled trials (RCTs) and eight cohort studies, including a total of 1,229 patients, were znalyzed. The meta-analysis of the RCT subgroup indicated that there was no statistically significant difference in IUP rates (RR = 1.04, 95% CI = 0.89-1.21, P = 0.61) nor the repeat ectopic pregnancy (REP) rate (RR = 1.30, 95% CI = 0.72-2.38, P = 0.39) between the salpingotomy and salpingectomy group. In contrast, the cohort study subgroup analysis revealed that the IUP rate was higher in the salpingotomy group compared with the salpingectomy group (RR = 1.24, 95% CI = 1.08-1.42, P = 0.002); Salpingotomy also increased the risk of REP rate (RR = 2.27, 95% CI = 1.12-4.58, P = 0.02). The persistent ectopic pregnancy (PEP) occurred more frequently in the salpingotomy group than the salpingectomy group (RR = 11.61, 95% CI = 3.17-42.46, P = 0.0002). An IUP would be more likely to occur after salpingotomy than salpingectomy when the follow-up time was more than 36 months (RR = 1.16, 95% CI = 1.02-1.32, P = 0.03). The IUP rate (RR = 1.13, 95% CI = 1.01-1.26, P = 0.03), and the REP rate (RR = 1.62, 95% CI = 1.02-2.56, P = 0.04) was higher after salpingotomy than salpingectomy among patients from Europe compared with those from America. CONCLUSIONS:Based on the available evidence, we believe that for patients with a healthy contralateral tube operated for tubal pregnancy, the subsequent fertility after salpingectomy and salpingotomy are similar in the long term. The fertility prospects will not be improved via salpingotomy compared with salpingectomy.

Aging, body composition, and body mass index (BMI) are important factors in bone mineral density (BMD). Although several studies have investigated the various parameters and factors that differentially influence BMD, the results have been inconsistent. Thus, the primary goal of the present study was to further characterize the relationships of aging, body composition parameters, and BMI with BMD in Chinese Han males older than 50 years.The present study was a retrospective analysis of the body composition, BMI, and BMD of 358 Chinese male outpatients between 50 and 89 years of age that were recruited from our hospital between 2009 and 2011. Qualified subjects were stratified according to age and BMI as follows: 50-59 (n = 35), 60-69 (n = 123), 70-79 (n = 93), and 80-89 (n = 107) years of age and low weight (BMI: < 20 kg/m2; n = 21), medium weight (20 ≤ BMI < 24 kg/m2; n = 118), overweight (24 ≤ BMI < 28 kg/m2; n = 178), and obese (BMI ≥ 28 kg/m2; n = 41). Dual-energy X-ray absorptiometry (DEXA) was used to assess bone mineral content (BMC), lean mass (LM), fat mass (FM), fat-free mass (FFM), lumbar spine (L1-L4) BMD, femoral neck BMD, and total hip BMD. Additionally, the FM index (FMI; FM/height2), LM index (LMI; LM/height2), FFM index (FFMI; [BMC+LM]/height2), percentage of BMC (%BMC; BMC/[BMC+FM+LM] × 100%), percentage of FM (%FM; FM/[BMC+FM+LM] × 100%), and percentage of LM (%LM; LM/(BMC+FM+LM) × 100%) were calculated. Osteopenia or osteoporosis was identified using the criteria and T-score of the World Health Organization.Although there were no significant differences in BMI among the age groups, there was a significant decline in height and weight according to age (p < 0.0001 and p = 0.0002, respectively). The LMI and FFMI also declined with age (both p < 0.0001) whereas the FMI exhibited a significant increase that peaked in the 80-89-years group (p = 0.0145). Although the absolute values of BMC and LM declined with age (p = 0.0031 and p < 0.0001, respectively), there was no significant difference in FM. In terms of body composition, there were no significant differences in %BMC but there was an increase in %FM (p < 0.0001) and a decrease in %LM (p < 0.0001) with age. The femoral neck and total hip BMD significantly declined with age (p < 0.0001 and p = 0.0027, respectively) but there were no differences in L1-L4. BMD increased at all sites (all p < 0.01) as BMI increased but there were declines in the detection rates of osteoporosis and osteopenia (both p < 0.001). A logistic regression revealed that when the medium weight group was given a BMI value of 1, a decline in BMI was an independent risk factor of osteoporosis or osteopenia, while an increase in BMI was a protective factor for BMD. At the same time, BMD in L1-L4 exhibited a significant positive association with FMI (p = 0.0003) and the femoral neck and total hip BMDs had significant positive associations with FFMI and LMI, respectively (both p < 0.0001).These data indicate that LMI and FFMI exhibited significant negative associations with aging in Chinese Han males older than 50 years, whereas FMI had a positive association. BMD in the femoral neck and total hip declined with age but an increased BMI was protective for BMD. LMI and FFMI were protective for BMD in the femoral neck and total hip.

The gap between the growing demand for available organs and the cadaveric organs facilitates the adoption of living donor liver transplantation. We retrospectively identified and evaluated the post-operative complications as per the modified Clavien classification system in 152 living liver donors at at the First Affiliated Hospital, College of Medicine, Zhejiang University between December, 2006 and June, 2014. Post-operative complications were observed in 61 patients (40.1%) in the present study, but no mortality was reported. Complications developed in 58 (40.0%) right, 1 (33.3%) left, and 2 (66.7%) lateral left hepatectomy donors. The prevalence of re-operation was 1.3%. Grade I and II complications were observed in 38 (25.0%) and 11 (7.2%) donors, respectively. Grade IIIa complications developed in 9 (5.9%) donors and only 3 (2.0%) patients reported grade IIIb complications. The most common complication was pleural effusion that occurred in 31 (20.4%) donors. No significant prognostic baseline factor was identified in this study. In conclusion, living donors experienced various complications, which were usually mild and had a good prognosis.

The specific degradation of type II collagen and aggrecan by matrix metalloproteinase (MMP)-9, -13 and ADAMTS-4 and -5 (aggrecanase-1 and -2) in the cartilage matrix is a critical step in pathology of osteoarthritis (OA). The aims of this study were: i) To investigate the relative contribution of ADAMTS-4 and ADAMTS-5 to cartilage degradation upon catabolic stimulation; ii) To investigate the effect of regulating the activities of key enzymes by mean of broad-spectrum inhibitors.Bovine full-depth cartilage explants stimulated with tumor necrosis factor alpha (TNF-α) and Oncostatin M (OSM) were cultured for 21 days with or without a number of inhibitors targeting different types of proteases. Monoclonal antibodies were raised against the active sites of ADAMTS-4, -5, MMP-9 and -13, and 4 ELISAs were developed and technically validated. In addition, the established AGNxI (ADAMTS-degraded aggrecan), AGNxII (MMP-degraded aggrecan), and CTX-II (MMP-derived type II collagen) were quantified in the explants-conditioned media.We found that: i) Active ADAMTS-4, MMP-9, -13 were released in the late stage of TNF-α/ OSM stimulation, whereas no significant active ADAMTS-5 was detected in either extracts or supernatants; ii) Active ADAMTS-4 was primarily responsible for E373-374A bond cleavage in aggrecan in this setting; and iii) The compensatory mechanism could be triggered following the blockage of the enzyme caused by inhibitors.ADAMTS-4 appeared to be the major protease for the generation of 374ARGS aggrecan fragment in the TNF-α/OSM stimulated bovine cartilage explants. This study addresses the need to determine the roles of ADAMTS-4 and ADAMTS-5 in human articular degradation in OA and hence identify the attractive target for slowing down human cartilage breakdown.

FHL1 is an important tumor-suppressor that is downregulated in multiple tumors by unknown mechanisms. We demonstrated that miR-410 specifically targets the 3'UTR of FHL1. Furthermore, using DNA bisulfite modification and sequencing experiments, we demonstrated that the FHL1 promoter is hypermethylated in cancer cells. FHL1 methylation is increased upon miR-410 expression, suggesting that the regulation of FHL1 by miR-410 occurs by a dual mechanism. Using chromatin immunoprecipitation assays, we observed that miR-410 overexpression results in the increased binding of DNMT3A at the FHL1 promoter, which could explain how miR-410 regulates FHL1 methylation. Importantly, in vitro and in vivo results suggest that miR-410 may have oncogenic properties. Furthermore, both miR-410 and DNMT3A are upregulated in clinical human liver and colorectal tumors cancers. Our results suggest that miR-410 may function as an oncomiR and are consistent with its key function in regulating FHL1 in certain digestive system cancers.

Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of β-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic β-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p' = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, β = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206-1.818, p = 0.013, adjusted OR' = 1.516, 95%CI:1.101-2.006, p' = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6 ± 0.52 vs 5.5 ± 0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p < 0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2-102.3) vs 73.1(49.4-111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre-diabetes in the Chinese Han population.

OBJECTIVE: To investigate the relationship between sex hormones and the risk of vascular disease in elderly men and to evaluate the advantages and disadvantages of testosterone replacement. METHODS: A total of 337 men, aged 60 to 91 years, were enrolled in this single-center, cross-sectional study, and their sex hormone levels were assessed. Linear and logistic regression analyses were utilized to compare the sex hormone levels between patients with and without vascular disease. The nonparametric K-sample test was used for inter-group comparisons. RESULTS: Aging and abnormal metabolism were both significantly associated with an increased risk of vascular diseases and changes in sex hormone levels. Primary linear and logistic regression analyses showed no significant differences in sex hormone concentrations between patients with and without vascular diseases after adjusting for age. Logistic regression with abnormal metabolism as categorical variable showed that free testosterone (FT) and free estradiol (FE2) had significant relationships with CEVD risk (P

As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8(+) CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201(+) acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME(100-108) or PRAME(300-309) peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.