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OBJECTIVE: To observe the anticancer effects of the granular preparation of Tenglong Buzhong decoction (藤龙补中汤,TBD), i.e Tenglong Buzhong granules (藤龙补中颗粒, TBG), in human SW620 colon cancer. METHODS: BALB/c nude mice were subcutaneously transplanted with SW620 cells, and treated with TBG (2.56 g/kg, once per day) and/or 5-Fu (104 mg/kg, once per week) for 21 d. Apoptosis, Caspase activities and cellular senescence were measured by commercial kits. The protein expression and phosphorylation were detected by Western blot or immunohistochemistry. RESULTS: TBG and 5-Fu inhibited tumor growth. The tumor inhibition rate of the TBG, 5-Fu, and TBG+5-Fu groups was 42.25%, 51.58%, and 76.08%, respectively. Combination of TBG and 5-Fu showed synergetic anti-cancer effects. TBG and 5-Fu induced apoptosis, activated caspase-3, -8, and -9, increased SMAC expression, inhibited XIAP expression. TBG induced cellular senescence, upregulated cyclin-dependent kinase inhibitor 1a (CDKN1a) and cyclin-dependent kinase inhibitor 2a (CDKN2a) expression, and inhibited phosphorylation of retinoblastoma-associated protein (RB) and expression of cyclin E1 (CCNE1) and cyclin-dependent kinases (CDK) 2. TBG also inhibited angiogenesis accompanied by downregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). CONCLUSIONS: TBG inhibits SW620 colon cancer growth, induces apoptosis via SMAC-XIAP-Caspases signaling, induces cellular senescence through CDKN1a/CDKN2a-RB-E2F signaling, inhibits angiogenesis by down-regulation of HIF-1α and VEGF, and enhances the effects of 5-Fu.

Background MCM3AP-AS1 is a recently characterized lncRNA playing an oncogenic role in several cancers. However, its role in lung cancer remains unknown. Here, we aimed to explore the functions of MCM3AP-AS1 in small cell lung cancer (SCLC) and the possible underlying mechanisms. Methods MCM3AP-AS1 and ROCK1 levels in SCLC patients were analyzed by qPCR. RNA pull-down and luciferase assays were performed to analyze the interaction between MCM3AP-AS1 and miR-148a. ROCK1 mRNA and protein levels were detected by qPCR and Western blot, respectively. Cell invasion and migration were analyzed by Transwell assays. Results MCM3AP-AS1 was upregulated in patients with SCLC, and a high MCM3AP-AS1 level was accompanied by a low survival rate. The binding of MCM3AP-AS1 to miR-148a predicted by bioinformatics analysis was verified by RNA pull-down and luciferase assays. However, MCM3AP-AS1 and miR-148a did not affect each other’s expression. ROCK1 was upregulated in SCLC tissues and positively correlated with MCM3AP-AS1. In SCLC cells, MCM3AP-AS1 overexpression increased ROCK1 and promoted cancer cell invasion and migration, while miR-148a overexpression showed the opposite effects and attenuated the effects of MCM3AP-AS1 overexpression on ROCK1 expression and cell behaviors. Conclusions MCM3AP-AS1 sponges miR-148a, thereby increasing SCLC cell invasion and migration via upregulating ROCK1 expression.

Objective The aim of the present study was to retrospectively evaluate the toxicity and efficacy of post-operative small pelvic intensity-modulated radiotherapy in early-stage cervical cancer patients with intermediate-risk factors. Methods Between 2012 and 2016, 151 patients who had cervical cancer (International Federation of Gynecology and Obstetrics stage I–IIA) with intermediate-risk factors were treated with post-operative small pelvic intensity-modulated radiotherapy. The median dose of 50.4 Gy in 28 fractions with small pelvic intensity-modulated radiotherapy was prescribed to the planning target volume. The intensity-modulated radiotherapy technique used was conventional fixed-field intensity-modulated radiotherapy or helical tomotherapy. Results The median follow-up was 37 months. The 3-year disease-free survival and overall survival rates were 89 and 96%, respectively. A total of 144 patients (95.3%) were alive at the last follow-up. In total, 6 patients (3.9%) had recurrence: locoregional recurrence in 3 patients (2%), distant metastasis in 2 (1.3%), and both in 1 (0.6%). Diarrhoea was the most common acute toxicity. There were no patients suffering from acute or late grade ≥ 3 toxicity. Only 4 patients (2.6%) had late grade 2 toxicities. Conclusions For early-stage cervical cancer patients with intermediate-risk factors, post-operative small pelvic intensity-modulated radiotherapy was safe and well tolerated. The rates of acute and late toxicities were quite satisfactory.

Enterovirus A71 (EV-A71) is an important pathogen of severe hand, foot, and mouth disease (HFMD) in young children. This study aimed to retrospectively analyze the molecular epidemiology and recombination of EV-A71 in mainland China during 1987–2017. Phylogenetic tree showed that besides the previously reported subgenotypes A, B5, C0, C2, C3, and C4, a new subgenotype C6 emerged in mainland China. Recombination analysis indicated that C4 EV-A71 was derived from a common ancestor as a “double-recombinant” virus by intertypic recombination between C EV-A71 and CVA4, CVA5, CVA14, and CVA16 strains in P3 region and intratypic recombination between C and B EV-A71 strains in P2 region. The B5 EV-A71 shared high similarity with C EV-A71 in P1 region while it contained an unidentified sequence in P2 and P3 regions with two possible recombination patterns: one occurred between C4 EV-A71 and CVA3, CVA5, CVA6, CVA10, and CVA12 stains with one breakpoint in 3C, and the other occurred between C1, C2, C3, and C5 EV-A71 and CVA4, CVA5, CVA14, and CVA16 strains with two breakpoints in the 2A/2B junction and 3C. The C2 EV-A71 was probably a recombinant virus between C4 EV-A71 and CVA8 strains with two breakpoints located in the 5′UTR and 2A/2B junction. Moreover, an incredible recombination of C6 EV-A71 occurred between C4 and C2 EV-A71 with multiple breakpoints. Thus, continuous studies on EV-A71 genome characteristics are still useful and essential for monitoring emergence of new viruses and preventing HFMD outbreaks. Supplementary Information The online version contains supplementary material available at 10.1007/s10123-021-00164-2.

Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.

Rectal cancer is the most common malignant tumor in the digestive system with rapidly metastasis and highly recurrence. Agrin (AGRN) is a proteoglycan involving in a large number of human cancers. However, how AGRN regulates the progression of rectal cancer remains largely unknown. We aimed to determine the biological role of AGRN and its mechanism in rectal cancer. AGRN expression in rectal cancer tissues was detected based on TCGA. The survival curve was plotted using the Kaplan-Meier method. qRT-PCR and western blot were utilized to examine the expression level of AGRN in cells. Cell proliferation, clonogenic ability, invasion, and migration of rectal cancer cells were analyzed by CCK-8, colony formation and transwell experiments. GSEA was employed for the analysis of the potential pathways-related with AGRN in rectal cancer. The activity of WNT pathway was determined by western blot. AGRN expression was dramatically increased in rectal cancer, and its up-regulation was associated with poorer prognosis of rectal cancer patients. AGRN expression was an independent factor for the prognosis of rectal cancer. AGRN inhibition suppressed rectal cancer cell growth, invasion, and migration, whereas AGRN overexpression facilitated these behaviors of rectal cancer cells

Objective: Hyperglycemia-mediated cardiomyocyte damage is associated with inflammation and AMPK inactivation.Aim: The aim of our study is to explore the protective effects exerted by liraglutide on AMPK pathway and glucagon-like peptide 1 receptor in diabetic cardiomyopathy.Methods: Cardiomyocytes were treated with high-glucose stress and cardiomyocyte viability was determined via (3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide assay. Besides, LDH release, immunofluorescence, and qPCR were used to verify the influence of liraglutide on hyperglycemia-treated cardiomyocytes.Results: Hyperglycemia treatment caused inflammation response and oxidative stress were significantly elevated in cardiomyocytes. This alteration could be reversed by liraglutide. Besides, cell viability was reduced whereas apoptosis was increased after exposure to high glucose treatment. However, liraglutide treatment could attenuate apoptosis and reverse cell viability in cardiomyocyte. Further, we found that AMPK pathway was also activated and glucagon-like peptide 1 receptor expression was increased in response to liraglutide treatment.Conclusions: Liraglutide could attenuate hyperglycemia-mediated cardiomyocyte damage through reversing AMPK pathway and upregulating glucagon-like peptide 1 receptor.

Objective: The goal of this study was to confirm the clinical value of pretreatment serum squamous cell carcinoma antigen (SCC-Ag) in the administration of consolidation chemotherapy in patients with cervical cancers undergoing postoperative extended-field radiotherapy (EFRT) and concurrent chemotherapy (CCRT). Methods: Between 2007 and 2018, a total of 113 patients were treated with postoperative extended-field intensity-modulated radiotherapy (EF-IMRT) and CCRT. There were 63 patients receiving extended-field concurrent chemoradiotherapy (EF-CCRT) and consolidation chemotherapy, while another 50 patients underwent EF-CCRT alone. For the planning target volume, the prescribed dose was 45 to 50.4Gy/25 to 28 fractions. The consolidation chemotherapy regimen contained docetaxel and cisplatin. Results: For the patients with high pretreatment SCC-Ag, the addition of consolidation chemotherapy significantly improved their treatment outcomes and they had better 5-year overall survival (OS) (81.02% vs 63.44%, P = .018) and disease-free survival (DFS) (76.95% vs 61.12%, P = .007) than those without it. Meanwhile, the patients with consolidation chemotherapy had a lower rate of distant metastasis (8.8% vs 34.8%, P = .001). For the patients with low pretreatment SCC-Ag, there was no difference in prognosis between patients receiving consolidation chemotherapy and those not receiving consolidation. In multivariate analysis, consolidation chemotherapy was found to be a factor significantly associated with DFS ( P = .035, 95% confidence interval (CI): 0.304-0.977) and distant metastasis ( P = .009, 95% CI: 0.125-0.841). Conclusion: The patients who received consolidation chemotherapy showed significantly better DFS. Furthermore, pretreatment serum SCC-Ag > 6.5 ng/mL may be a predictive factor for the use of consolidation chemotherapy in cervical cancer patients treated with postoperative EF-CCRT.

Objective Irisin is a myokine that greatly affects energy expenditure and systemic metabolism. While thyroid hormone is likely associated with irisin, a direct relationship remains to be fully elucidated. This study aimed to investigate plasma irisin levels in Chinese patients with hypothyroidism. Methods A total of 155 subjects were divided into the hypothyroidism group or the control group. Fifty-seven patients in the hypothyroidism group received levothyroxine treatment. Baseline irisin levels were measured in the two groups and post-treatment levels were measured in the hypothyroidism group. Results Irisin levels were significantly lower in the hypothyroidism group than in the control group. In the hypothyroidism group, irisin levels were positively associated with free triiodothyronine and free thyroxine levels, and negatively associated with thyrotropin levels. In the hypothyroidism group, irisin levels were significantly increased after levothyroxine treatment. Multiple linear regression models showed that total cholesterol and free thyroxine levels were the only significant predictors of serum irisin levels. Conclusions Irisin levels are decreased in patients with hypothyroidism. Our results suggest that decreased irisin levels are directly associated with reduced thyroid hormone levels. These values may be restored after levothyroxine treatment in Chinese patients with hypothyroidism.

Mesenchymal stem cell (MSC) is an absorbing candidate for cell therapy in treating spinal cord injury (SCI) due to its great potential for multiple cell differentiation, mighty paracrine secretion as well as vigorous immunomodulatory effect, of which are beneficial to the improvement of functional recovery post SCI. However, the therapeutic effects of MSC on SCI have been limited because of the gradual loss of MSC stemness in the process of expanding culture. Therefore, in this study, we aimed to maintain those beneficial properties of MSC via three-dimensional spheroid cell culture and then compared them with conventionally-cultured MSCs in the treatment of SCI both in vitro and in vivo with the aid of two-photon microscope. We found that 3D human placenta-derived MSCs (3D-HPMSCs) demonstrated a significant increase in secretion of anti-inflammatory factors and trophic factors like VEGF, PDGF, FGF via QPCR and Bio-Plex assays, and showed great potentials on angiogenesis and neurite morphogenesis when co-cultured with HUVECs or DRGs in vitro. After transplantation into the injured spinal cord, 3D-HPMSCs managed to survive for the entire experiment and retained their advantageous properties in secretion, and exhibited remarkable effects on neuroprotection by minimizing the lesion cavity, inhibiting the inflammation and astrogliosis, and promoting angiogenesis. Further investigation of axonal dieback via two-photon microscope indicated that 3D-HPMSCs could effectively alleviate axonal dieback post injury. Further, mice only treated with 3D-HPMSCs obtained substantial improvement of functional recovery on electrophysiology, BMS score, and Catwalk analysis. RNA sequencing suggested that the 3D-HPMSCs structure organization-related gene was significantly changed, which was likely to potentiate the angiogenesis and inflammation regulation after SCI. These results suggest that 3D-HPMSCs may hold great potential for the treatment of SCI.

Background In mid-March 2020, the World Health Organization declared that COVID-19 was to be characterised as a pandemic. The purpose of this article is to recommend emergency management procedures for dental clinics during this public health emergency. Materials and methods We have implemented a series of emergency management measures to prevent cross-infection in our dental clinic during the COVID-19 pandemic, including personnel scheduling, division of the clinic into functional areas, limitation or delay of non-emergency patients, staff protection and infection controls, clinical environmental disinfection, and the use of online consultation services, among others. Results Due to public health policy and dental emergency management, the number of dental visitors to our clinic dropped sharply, and no COVID-19 suspected cases or high-risk patients received treatment. There have been no reports of infection of dental staff or patients during dental treatment in China to date. Conclusion These public health policies and dental emergency management measures were effective in controlling cross-infection of COVID-19 in the dental clinic. Practical implications We share control measures for COVID-19, and hope that they will be helpful for dental professionals worldwide to continue to provide dental care in a safe and orderly manner.

Background Neoantigen-based personal vaccines and adoptive T cell immunotherapy have shown high efficacy as a cancer treatment in clinical trials. Algorithms for the accurate prediction of neoantigens have played a pivotal role in such studies. Some existing bioinformatics methods, such as MHCflurry and NetMHCpan, identify neoantigens mainly through the prediction of peptide-MHC binding affinity. However, the predictive accuracy of immunogenicity of these methods has been shown to be low. Thus, a ranking algorithm to select highly immunogenic neoantigens of patients is needed urgently in research and clinical practice. Results We develop TruNeo, an integrated computational pipeline to identify and select highly immunogenic neoantigens based on multiple biological processes. The performance of TruNeo and other algorithms were compared based on data from published literature as well as raw data from a lung cancer patient. Recall rate of immunogenic ones among the top 10-ranked neoantigens were compared based on the published combined data set. Recall rate of TruNeo was 52.63%, which was 2.5 times higher than that predicted by MHCflurry (21.05%), and 2 times higher than NetMHCpan 4 (26.32%). Furthermore, the positive rate of top 10-ranked neoantigens for the lung cancer patient were compared, showing a 50% positive rate identified by TruNeo, which was 2.5 times higher than that predicted by MHCflurry (20%). Conclusions TruNeo, which considers multiple biological processes rather than peptide-MHC binding affinity prediction only, provides prioritization of candidate neoantigens with high immunogenicity for neoantigen-targeting personalized immunotherapies.

Background This study aims to investigate clinical significance of HMGB1 in neonatal patients with necrotizing enterocolitis (NEC). Methods This observational study enrolled a total of 106 stage II-III NEC neonatal patients, who were admitted in our hospital from March 2014 to March 2019. In addition, 99 suspected NEC patients and 200 healthy controls were included. The serum levels of HMGB1, I-FABP, and inflammatory factors CRP, IL-1β, IL-6 and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). Then, the demographic data and clinical characteristics of all patients were collected. Statistical analysis was conducted to determine the correlation between HMGB1 and the clinical characteristics. Results No significant difference was found in the basic characteristics of NEC patients and healthy controls, except for birth weight and gestational age. The expression levels of HMGB1, I-FABP, and inflammatory factors IL-1β, IL-6 and TNF-α were significantly higher in NEC patients, when compared to healthy controls. The serum levels of HMGB1, I-FABP, IL-1β and IL-6 markedly increased in stage II-III NEC patients, when compared to stage I NEC patients. The Pearson’s analysis revealed a positive correlation between HMGB1 and I-FABP, HMGB1 and IL-1β, and HMGB1 and IL-6. The ROC curve revealed that both HMGB1 and I-FABP can potentially be used as diagnostic factors for NEC. The logistic multivariate regression revealed that I-FABP, IL-1β and IL-6 are independent risk factors for mortality in neonatal NEC patients. Conclusions Serum HMGB1 levels are upregulated in neonatal NEC patients, and these are correlated with the patient’s prognosis.

Rheumatoid arthritis (RA) is a chronic inflammatory syndrome designated by synovial joint inflammation leading to cartilage degradation and bone damage as well as progressive disability. Synovial inflammation is promoted through the infiltration of mononuclear immune cells, dominated by CD4+ T cells, macrophages and dendritic cells (DCs), together with fibroblast‐like synoviocytes (FLS), into the synovial compartment. Berberine is a bioactive isoquinoline alkaloid compound showing various pharmacological properties that are mainly attributed to immunomodulatory and anti‐inflammatory effects. Several lines of experimental study have recently investigated the therapeutic potential of berberine and its underlying mechanisms in treating RA condition. The present review aimed to clarify determinant cellular and molecular targets of berberine in RA and found that berberine through modulating several signalling pathways involved in the joint inflammation, including PI3K/Akt, Wnt1/β‐catenin, AMPK/lipogenesis and LPA/LPA1/ERK/p38 MAPK can inhibit inflammatory proliferation of FLS cells, suppress DC activation and modulate Th17/Treg balance and thus prevent cartilage and bone destruction. Importantly, these molecular targets may explore new therapeutic targets for RA treatment.

Studies have shown that α-enolase ENO1 is involved in the regulation of cancer cell proliferation and metastasis. However, the role of ENO1 is yet to be explored in breast cancer. This study was undertaken to explore the role and therapeutic potential of ENO1 in breast cancer.Expression analysis was carried out by qRT-PCR. Transfections were performed by Lipofectamine 2000 reagent. WST-1 assay was used for cell viability. Wound healing assay was used for cell migration analysis. Western blot analysis was used to determine protein expression.The results showed that the expression of ENO1 was significantly upregulated in breast cancer by up to 4-fold. Silencing of ENO1 caused significant decline in the proliferation rate and colony formation of the SK-BR-3 breast cancer cells. The decrease in the proliferation rate of the ENO1 cells was due to the induction of apoptosis as revealed by DAPI staining. Annexin V/propidium iodide (PI) showed a significant increase in the apoptotic SK-BR-3 cells. The apoptosis percentage was 2.17 in si-NC and 23.1% in si-ENO1 transfected SK-BR-3 cells. The apoptosis induction was also accompanied by increase in Bax and decrease in Bcl-2 expression. ENO1 silencing also resulted in the arrest of the SK-BR-3 cells in the G2/M phase of the cell cycle which was also associated with depletion of Cdc2, Cdc25 and cyclin B1 expression levels. ENO1 silencing also caused decrease in the migration and invasion of the SK-BR-3 cells as revealed by the wound healing and transwell assays.These findings suggest that ENO1 has oncogenic properties in breast cancer which can be exploited in breast cancer treatment.

OBJECTIVE: We aimed to evaluate the association between platelet (PLT) count and the risk and progression of hand, foot, and mouth disease (HFMD). METHODS: In total, 122 HFMD patients and 40 healthy controls were enrolled in the study. The differences between variables among the different subgroups were compared. Logistic regression analyses were performed to assess the relationship between various parameters and HFMD risk/progression. Sensitivity analysis was conducted by detecting the trend of the association between PLT count quartiles and HFMD risk/progression. A generalized additive model was used to identify the nonlinear relationship between PLT count and HFMD risk/progression. The relationship between gender and PLT count as well as the risk/progression of HFMD was detected using a stratified logistic regression model. RESULTS: Significant differences were observed in terms of age, male/female ratio, white blood cell (WBC) count, and PLT count between patients with stage I-II, III-IV HFMD and healthy controls. Moreover, the alanine aminotransferase and magnesium levels between patients with stage I-II and III-IV HFMD significantly differed. Moreover, a significant difference was noted in the male/female ratio among the different PLT groups. The group with a low PLT count had a lower risk of HFMD progression than the group with a high PLT count (Q4) (p=0.039). Lower age, male gender, and WBC count were found to be associated with HFMD risk. Meanwhile, PLT count was correlated to HFMD progression. The sensitivity analysis yielded a similar result using the minimally adjusted model (p for trend=0.037), and minimal changes were observed using the crude and fully adjusted model (p for trend=0.054; 0.090). A significant nonlinear relationship was observed between PLT count and HFMD progression after adjusting for age, gender, and WBC (p=0.039). CONCLUSIONS: PLT was independently associated with HFMD progression in a nonlinear manner.

An accurate interpretation of immunohistochemistry (IHC) staining results is crucial for precise disease diagnosis. In this study, we present a novel scoring method for interpreting and reporting of IHC staining assay results for the nuclear-type molecule. On the basis of the histologic characteristics, the samples were subdivided into 3 basic structural units and tissue subtypes including covered, mosaic, and mesenchymal subtypes. A cut-off of moderate-positive (2+) cells and 10% as the differential expression were applied to stratify the results into 11 grade scoring system (0 to X level). The observer can directly identify and count the number and percentage of positive cells from IHC staining data. Furthermore, Ki67 staining results in 88 carcinoma specimens were re-evaluated to determine the ease, reliability, reproducibility, and variance among different observers. The results indicated the consistency ratio of 68.0% for the mosaic subtype and 80% for the mesenchymal subtype, and 68.2% for the covered subtype by 5 experienced pathologists independently. Using 10% as the cut-off threshold, the consistency ratio of 92.5%, 96.8%, and 92.9% was noted for mosaic, mesenchymal, and covered subtypes, respectively. Besides, the correlation of counts revealed excellent agreement among the 5 independent pathologists. Overall, the proposed IHC scoring method is a novel, simple, reliable, and reproducible grading system for accurate interpretation of IHC staining data. Furthermore, the presented practical grading approach has the potential to improve the clinical evaluation of the IHC staining data for personalized therapy.

Background: Studies determining which patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB disease benefit from prophylactic extended-field irradiation (EFRT), which can reduce para-aortic lymph node (PALN) failure rates, are limited. The study was designed to evaluate the value of the controlling nutritional status (CONUT) score as a risk factor for predicting PALN recurrence and identifying potential indications of prophylactic EFRT. Methods: From 2010 to 2015, a retrospective review was conducted among patients with FIGO stage IIIB cervical cancer who were treated with definitive pelvic radiotherapy or concurrent chemoradiotherapy. We analyzed para-aortic lymph node metastasis-free survival (PALNMFS) using Kaplan-Meier curves. Multivariate analyses were performed using Cox regression models. Results: A total of 116 patients with FIGO stage IIIB cervical cancer were included in the study and the median follow-up was 42.2 months (range: 3.5-104.2 months). Multivariate analysis revealed that the CONUT score (HR: 3.141; 95% CI: 2.321-5.436; P

Recent studies have shown that the use of mesenchymal stem/stromal cells (MSCs) may be a promising strategy for treating spinal cord injury (SCI). This study aimed to explore the effectiveness of human umbilical cord-derived MSCs (hUC-MSCs) with different administration routes and dosages on SCI rats. Following T10-spinal cord contusion in Sprague-Dawley rats (N = 60), three different dosages of hUC-MSCs were intrathecally injected into rats (SCI-ITH) after 24 h. Intravenous injection of hUC-MSCs (SCI-i.v.) and methylprednisolone reagent (SCI-PC) were used as positive controls (N = 10/group). A SCI control group without treatment and a sham operation group were injected with Multiple Electrolyte Injection solution. The locomotor function was assessed by Basso Beattie Bresnahan (BBB) rating score, magnetic resonance imaging (MRI), histopathology, and immunofluorescence. ELISA was conducted to further analyze the nerve injury and inflammation in the rat SCI model. Following SCI, BBB scores were significantly lower in the SCI groups compared with the sham operation group, but all the treated groups showed the recovery of hind-limb motor function, and rats receiving the high-dose intrathecal injection of hUC-MSCs (SCI-ITH-H) showed improved outcomes compared with rats in hUC-MSCs i.v. and positive control groups. Magnetic resonance imaging revealed significant edema and spinal cord lesion in the SCI groups, and significant recovery was observed in the medium and high-dose hUC-MSCs ITH groups. Histopathological staining showed that the necrotic area in spinal cord tissue was significantly reduced in the hUC-MSCs ITH-H group, and the immunofluorescence staining confirmed the neuroprotection effect of hUC-MSCs infused on SCI rats. The increase of inflammatory cytokines was repressed in hUC-MSCs ITH-H group. Our results confirmed that hUC-MSC administered via intrathecal injection has dose-dependent neuroprotection effect in SCI rats.

BACKGROUND Degenerative spinal disorders have adverse impacts on patients' quality of life. Because the main objectives of any surgical intervention are to improve health-related quality of life and to reduce disability, instruments capable of measuring patient-oriented outcomes are now increasingly used. The aim of this study was to evaluate the use of the Short Form 36 Health Survey Questionnaire (SF36) for assessing patient-oriented outcomes of degenerative cervical myelopathy surgery. MATERIAL AND METHODS A literature search was conducted in electronic databases (Google Scholar, Ovid SP, PubMed, Science Direct, and Springer). Studies were included if they reported SF36 scores by following patients for at least 12 months. Random effects meta-analyses were performed to estimate changes in SF36 physical/mental component summary (SF36-PCS/MCS), SF36 dimensional, Japanese Orthopedics Association (JOA)/modified JOA (mJOA), and Neck Disability Index (NDI) scores by latest follow-up. RESULTS Fourteen studies (1966 patients; age 58.2 years [95% confidence interval (CI), 56.6 to 59.9]; 60% males [95% CI, 55 to 64]; follow-up 24.8 months [95% CI, 20.9 to 28.7]) were included in meta-analysis. SF36-PCS (6.60 [95% CI, 4.91 to 8.28]; p

Rationale: Limited knowledge is available regarding solitary fibrous tumors (SFTs), about 15% of which are malignant. In particular, the long-term survival of patients with malignant SFTs (mSFTs), the disease course, and the potential for recurrence of second primary tumors or distant metastases are largely undetermined. Patient concerns: We report a rare case in which an mSFT was found at the main bronchus of the right lung of a 37-year-old man. Diagnosis: The tumor cells of mSFT were spindle-shaped and expressed antigen Ki-67, B-cell lymphoma 2, cluster of differentiation 31, and vimentin. Interventions: A total pneumonectomy was performed. Outcomes: The patient developed fibrosarcoma of the small intestine at 6 months, as well as extensive pleural and peritoneal metastases at 1 year, after removal of the primary mSFT from the right main bronchus. Lessons: From these findings, we expect that patients with primary mSFT, especially of the lung, have a high potential to develop second tumors or distant metastases. Close monitoring after surgery is necessary to improve the outcomes of these patients.

// Simon-Peter Williams 1 , Annie Ogasawara 1 , Jeff N. Tinianow 1 , Judith E. Flores 1 , David Kan 1 , Jeffrey Lau 1 , MaryAnn Go 1 , Alexander N. Vanderbilt 1 , Herman S. Gill 1 , Li Miao 1 , Joshua Goldsmith 1 , Bonnee Rubinfeld 1 , Weiguang Mao 1 , Ron Firestein 1 , Shang-Fan Yu 1 , Jan Marik 1 , Anton G.T. Terwisscha van Scheltinga 1, 2 1 Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA 2 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, 9700RB, The Netherlands Correspondence to : Simon-Peter Williams, e-mail: williams.simon@gene.com Keywords: antibody-drug conjugates, immunoPET, TENB2, STEAP1, zirconium-89 Received: December 10, 2015 Accepted: March 04, 2016 Published: March 26, 2016 ABSTRACT The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo . 89 Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with 111 In-mAbs and gamma counting or with 89 Zr-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that 89 Zr-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload.

Objective To evaluate the efficacy and fertility outcomes of progestin treatment for complex atypical hyperplasia (CAH)/grade I endometrial cancer (G1EC) in Chinese patients (≤40years old). Methods Women ≤40years old who were treated with progestin for CAH or G1EC were identified from 9 provinces of China. The time to achieve complete response (CR) and the time from CR to recurrence or pregnancy were censored for patients without events and were analyzed for associations between patient and treatment characteristics. Results Thirty-two patients were included: 13 with CAH and 19 with G1EC. Nine patients exhibited elevated serum HbA 1 C before treatment. After a mean follow-up of 32.5months, the CR rate was 84.4%. Patients who exhibited elevated HbA 1 C were more likely to experience CR, while those with polycystic ovarian syndrome (PCOS) exhibited the opposite outcome (p=0.01, 0.03). Nine of 21 patients experienced clinical pregnancies. Eight patients underwent assisted reproductive technology (ART). Five patients had newborn infants. Patients undergoing ART were more likely to become pregnant (p=0.04). Conclusion Oral progestin is an effective fertility-sparing treatment for women with CAH/G1EC in China. Patients with elevated HbA 1 C receiving both metformin and progestin were more likely to achieve CR, whereas those with PCOS were not. ART is a good choice for clinical pregnancy after treatment.

Purpose Microbial ecosystems interact with the human body and affect human health. The microbial community on the ocular surface remains an underexplored territory despite its importance as the first line of defense barrier that protects the eye and ultimately sight. We investigated how age and sex affected human ocular surface microbiome, and in the present study wanted to understand how geographic difference shaped the microbiome in the ocular surface. Methods We collected conjunctival specimens of 172 eyes from 86 healthy volunteers living in three Chinese cities, namely, Guangzhou, Wenzhou, and Beijing. Using the direct metagenomic shotgun sequencing approach, we characterized how geographic difference affected the human ocular microbiome. Results We surveyed the taxonomic composition and metabolic function of the microbiota on human ocular surface. We showed that the ocular surface microbiota was composed of bacteria, viruses, and fungi. A geographical difference in both composition and function of the conjunctival microbiome suggests that the environment people lived in shapes their conjunctival microbiome, especially the dominate species. Conclusions Our study provides a reference catalog of the healthy conjunctival metagenome and raises a concern for environmental influences on the ocular surface microbiome.

To explore the effect of IL-8 on the epithelial-to-mesenchymal transition (EMT) in ovarian cancer,which will provide experimental basis for revealing related molecular mechanism in malignant metastasis of ovarian cancer.The migration of ovarian cancer cell line SKOV3 cells was explored with Real time label free cell analysis (RTCA) after treatment with recombinant human IL-8.SKOV3 cells were co-cultured with IL-8 for 48 h,proteins involved in EMT were investigated via Western blot to explore the effect of IL-8 on the activation of the EMT. Invasion of SKOV3 cells after treatment with IL-8 were evaluated by transwell assay.According to the results of RTCA,after treatment with IL-8 for 48 h,the migration of SKOV3 cells was in platform phase. The treatment of IL-8 unregulated vimentin and snail and downregulated E-cadherin,which suggested that IL-8 induced EMT in ovarian cancer. The results of transwell test showed that invasive ability of IL-8 pretreated SKOV3 cells was enhanced (IL-8 can induce the EMT of ovarian cancer and enhance the invasion and migration of ovarian cancer.

An efficient heterotrophic nitrifying/aerobic denitrifying strain, Photobacterium sp. NNA4 was isolated from a recirculating aquaculture system (RAS). NNA4 was capable of utilizing ammonia, nitrate or nitrite as sole N-source with maximal removal rates of 12.5 mg/L/h for NH4+ N, 16.4 mg/L/h for NO3--N, and 4.5 mg/L/h for NO2--N, respectively. Optimal nitrification conditions were: sodium succinate as C-source, 30–37°C, NaCl 1–4%, pH 7.0–8.0, dissolved oxygen 5.89 mg/L, C/N > 10. Gas chromatography/mass spectrometry and gas chromatography/isotope ratio mass spectrometry analyses showed that N2 and N2O were aerobic denitrification products of nitrite and nitrate. NNA4 could tolerate high concentration of hydroxylamine and displayed efficient hydroxylamine-transforming capability. Hydroxylamine oxidoreductase activity using potassium ferricyanide as electron acceptor was 0.042 U. Results revealed that strain NNA4 could oxidize NH2OH directly to N2O at aerobic conditions. In view of its high removal ability of inorganic nitrogen pollutants and broad salinity tolerance range, NNA4 has great potential in denitrification treatment of types of wastewater with either low salinity (e.g., municipal facilities) or high salinity (e.g., aquaculture, seafood processing).

To mine the medication rules of herbal prescriptions for gout caused by heat-damp accumulation syndrome, and explore the possible mechanism of the core herbs, we collected the relevant literature of gout caused by heat-damp accumulation syndrome in CNKI, medication rules of herbal prescriptions are analyzed by using TCMISS(V2.5) software, and the compatibility of core drugs and new prescriptions were mined.KEGG pathway analysis was performed by BATMAN-TCM, an online analysis tool, and the potential signaling pathways of core drugs compatibility to treat gout caused by heat-damp accumulation syndrome were revealed. The results showed that six core drugs and three new prescriptions were found out of the 136 prescriptions. The core compatibility herbs in clinical treament of gout caused by heat-damp accumulation syndrome, Phellodendri Chinrnsis Cortex, Achyranthis Bidentatae Radix and Achyranthis Bidentatae Radix, which potential signaling pathways were purine metabolic pathway and neura activity ligand receptor interaction signaling pathway. Therefore, for gout caused by heat-damp accumulation syndrome, the mainly used therapies of TCM were clearing heat and drying dampness,inducing diuresis for removing edema, dispeling wind and eliminating dampness. The mechnisms of core compatibility herbs may be achieved through the intervention of purine metabolic pathway and neural activity ligand receptor interaction signaling pathway.

Purpose A growing body of evidence suggests that the microbiome of the ocular surface confers potent immunoregulatory functions and has a key role in the physiologic maintenance of healthy eyes and in the pathogenesis of ocular diseases. Although the microbiome is known to be affected by age and sex, the influence of these factors on ocular surface microbiota in healthy adults remains largely unknown. Methods Ocular surface microbiome samples were obtained from the inferior bulbar conjunctiva of 48 young and 42 old adults at Zhongshan Ophthalmic Center. Using metagenomic shotgun sequencing, we characterized the sex- and age-differences in conjunctival microbiome profiles of healthy adults. Results Male and female groups differed only in the β diversity of bacterial communities, while there were significant differences in bacterial composition, metabolic functions, and the abundance of antibiotic resistance genes between young and old adult groups. Conclusions Our findings suggest that age and sex collectively shape the conjunctival microbiome, and may change the immune homeostasis of the ocular surface through alterations of its commensal microbiome.

Homocysteine suppresses hepatic apolipoprotein AI synthesis in mice. We assessed the relationship between homocysteine and apolipoprotein AI levels in patients with impaired glucose tolerance. A total of 217 participants, including 95 impaired glucose tolerance patients and 122 healthy subjects, were classified as normal control subjects without hyperhomocysteinaemia, control subjects with hyperhomocysteinaemia, impaired glucose tolerance patients without hyperhomocysteinaemia (n-IGT) and impaired glucose tolerance patients with hyperhomocysteinaemia (H-IGT). The impaired glucose tolerance patients had higher plasma levels of homocysteine and homeostasis model assessment index of insulin resistance values, and lower plasma apolipoprotein AI levels than the normal control and control subjects with hyperhomocysteinaemia (all p

Sight threatening immune responses that damage the eye characterize intraocular inflammatory diseases. These diseases including uveitis and age-related macular degeneration are worryingly common and quality of life shattering. Genetic studies in past decades significantly advanced our understanding of the etiology of these devastating diseases. Unfortunately, patient genetics alone failed to adequately explain disease origin, susceptibility, and progression. Non-genetic factors such as the epigenetic regulation of ocular diseases and the environmental factors triggering intraocular inflammation offer new insight into intraocular inflammatory disorders. Importantly, mounting evidence is signaling that dysbiosis of human microbiota leads to rapid epigenomic reprograming of host cells and results in the onset of many diseases. In this review, we discuss how epigenetic mechanisms and microbiota may cooperate to initiate and perpetuate ocular inflammation. Lastly, we propose that the discovery of intraocular microbiota presents a significant shift in thought affecting current approaches to the diagnosis, treatment, and prevention of intraocular inflammatory diseases such as uveitis and age-related macular degeneration. The geographical and genetic background difference in both disease presentation and genetic association of intraocular inflammatory diseases may be due to the variation of intraocular microbiota.

Interleukin-12 (IL-12) is a proinflammatory cytokine, and its increased level correlates with the severity of periodontitis. However, its role in the pathogenesis of tooth periapical lesions is controversial and has not been completely clarified. The present study aimed to investigate whether IL-12 affects the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human periodontal ligament fibroblasts (hPDLFs). After treatment with IL-12 for different times, real-time PCR and Western blotting were used to determine the mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, and TIMP-2, respectively. ELISA was applied to measure MMPs and TIMPs secretion production. The results indicated that IL-12 significantly increased the mRNA and protein expression levels of MMP-1, MMP-3, and MMP-13, but down-regulated MMP-2 and MMP-9 mRNA and protein expression in the hPDLFs. Furthermore, IL-12 (10 ng/ml) enhanced the secreted protein production of MMP-1, MMP-3, and MMP-13, and conversely lowered MMP-2 and MMP-9 secretion levels. However, IL-12 treatment did not exert a significant effect on the mRNA and protein levels of TIMP-1 and TIMP-2 and their secreted production. Additionally, IL-12 increased the phosphorylated levels of IκBα and nuclear factor-κB P65 (NF-κB P65), and promoted NF-κB P65 subunit nuclear translocation. Pretreatment with NF-κB inhibitor not only attenuated IL-12-induced IκBα and NF-κB P65 phosphorylation and inhibited NF-κB P65 subunit into nucleus, but also antagonized IL-12-mediated MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13 expression in the hPDLFs. These findings indicate that NF-κB-dependent activation is possibly indispensable for IL-12-mediated MMP expression in hPDLFs.

In China, the majority of ovarian cancer patients (80%–90%) are women who are diagnosed with epithelial ovarian cancer. The SYNPO2 gene has recently been reported to be associated with epithelial ovarian cancer in Europeans. To investigate the association of common variants of SYNPO2 gene with epithelial ovarian cancer in Han Chinese individuals, we designed a case–control study with 719 epithelial ovarian cancer patients and 1568 unrelated healthy controls of Han Chinese descent. A total of 49 tagging single-nucleotide polymorphisms were genotyped; single-single-nucleotide polymorphism association, imputation, and haplotypic association analyses were performed. The single-nucleotide polymorphism rs17329882 was found to be strongly associated with serous epithelial ovarian cancer and with ages ≤49 years, consistent with the pre-menopausal status of analyzed epithelial ovarian cancer cases. Odds ratios and 95% confidence intervals provided evidence of the risk effects of the C allele of the single-nucleotide polymorphism on epithelial ovarian cancer. Imputation analyses also confirmed the results with a similar pattern. Additionally, haplotype analyses indicated that the haplotype block that contained rs17329882 was significantly associated with epithelial ovarian cancer risk, specifically with the serous epithelial ovarian cancer subtype. In conclusion, our results show that SYNPO2 gene plays an important role in the etiology of epithelial ovarian cancer, suggesting that this gene may be a potential genetic modifier for developing epithelial ovarian cancer.

Streptococcus suis serotype 2 (SS2) is a major porcine and human pathogen which causes arthritis, meningitis, and septicemia. Streptococcus suis nuclease A (SsnA) is a recently discovered deoxyribonuclease (DNase), which has been demonstrated to contribute to escape killing in neutrophil extracellular traps (NETs). To further determine the effects of ssnA on virulence, the ssnA deletion mutant (ΔssnA) and its complemented strain (C-ΔssnA) were constructed. The ability of ΔssnA mutant to interact with human laryngeal epithelial cell (Hep-2) was evaluated and it exhibited dramatically decreased ability to adhere to and invade Hep-2 cells. This mutation was found to exhibit significant attenuation of virulence when evaluated in CD1 mice, suggesting ssnA plays a critical role in the pathogenesis of SS2. Finally, we found that immunization with the ΔssnA mutant triggered both antibody responses and cell-mediated immunity, and conferred 80% protection against virulent SS2 challenge in mice. Taken together, our results suggest that ΔssnA represents an attractive candidate for designing an attenuated live vaccine against SS2.

Background Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. Objective To identify recurrent somatic mutations with prognostic significance in patients with CRC. Method Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. Results Seven significantly mutated genes, including four reported ( APC , TP53 , KRAS and SMAD4 ) and three novel recurrently mutated genes ( CDH10 , FAT4 and DOCK2 ), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature ( CDH10 , COL6A3 , SMAD4 , TMEM132D , VCAN ) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. Conclusions The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.

The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified fibroblast growth factor 16 (FGF16) as a potent inducer of several physical and transcriptional characteristics analogous to those of both "classical" BAT and iBAT. Overexpression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically the significant induction of the Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 overexpression in vivo were not the result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake, combined with feces replete with lipid and bile acid, indicated a phenotype more akin to that of starvation and intestinal malabsorption. Gene expression analysis of the liver and ileum indicated alterations in several steps of bile acid metabolism, including hepatic synthesis and reabsorption. Histological analysis of intestinal tissue revealed profound abnormalities in support of this conclusion. The in vivo data, together with FGF receptor binding analysis, indicate that the in vivo outcome observed is the likely result of both direct and indirect mechanisms and probably involves multiple receptors. These results highlight the complexity of FGF signaling in the regulation of various metabolic processes.

Loss of GGPPS from childhood mumps infection or deletion in mice results in constitutively activated MAPK and NF-kB signaling that induces spermatogonium apoptosis, macrophage invasion into seminiferous tubules, and sterility., Mumps commonly affects children 5–9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell–only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients’ fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-κB signaling pathways were constitutively activated in GGPPS−/− Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS−/− Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.

To investigate the expression of PIGF and its receptor Flt-1 in patients with multiple myeloma, and to analyze their correlation with the efficacy of thalidomide-based chemotherapy so as to provide further theoretical basis for individualized treatment.A total of 35 patients diagnosed as multiple myeloma from June 2012 to March 2013 in our hospital and 15 non-tumor patients as controls were enrolled in this study. MM patients were treated with thalidomide-based chemotherapy for 3 months, and then were grouped according to the curative effecacy. The expression levels of PIGF and Flt-1 were detected in bone marrow of control and MM patient group by RT-PCR and Western blot before and after chemotherapy, their correlation with chemotherapeutic efficacy was analyzed. Serum concentrations of PITG and Flt-1 were detected in control and MM patients before and after chemotherapy by ELISA and their correlation with the chemotherapeutic efficacy was analyzed.The effective rate of three-months-thalidomide-based chemotherapy was 54.3% in MM patients. The expression levels of PIGF and Flt-1 in MM patients' bone marrow were obviously higher than those in controls. After chemotherapy, PIGF and Flt-1 expression levels significantly reduced and the decline level was positively correlated with curative effecacy(r=0.71). The serum concentrations of PIGF and Flt-1 in MM patients' bone marrow were obviously higher than those in control. After chemotherapy, serum concentrations of PIGF and Flt-1 were significantly decreased and the decline level positively correlated with curative effecacy(r=0.87).PIGF and FLT-1 are highly expressed in patients with multiple myeloma, and their expression levels positively correlates with curative effecacy of thalidomide-based chemotherapy.

Background Hypothyroidism (HO) can significantly impair lipid metabolism and increase cardiovascular disease risk. Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Our previous study demonstrated that HHcy significantly induced insulin resistance and impaired coronary artery endothelial function in patients with either hypertension or HO. In the present study, we studied whether plasma levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) were altered in patients with HO, and if so, whether this change was mediated by HHcy. Methods A total of 258 subjects were enrolled and divided into the following three groups: control group (n = 94), HO group (n = 73), and subclinical hypothyroidism (SHO) group (n = 91). Additionally, all groups were subdivided based on the subjects’ Hcy levels into HHcy (plasma Hcy level over 15 μmol/l) and normal Hcy subgroups. The plasma levels of lipid indexes were measured. Statistical analyses were performed to evaluate the correlations between groups. Results The plasma Hcy levels were significantly higher in the HO group than in the SHO or control groups (all p

Background: The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. Aims: This research aimed to determine the clinical and virological features of the rare pattern. Methods: A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. Results: The amino acid variability within major hydrophilic region, especially the “a” determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the “a” determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. Conclusions: In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence. Keywords: Chronic hepatitis B, Coexistence of HBsAg and anti-HBs, S gene, Reverse transcriptase

Wnt signaling is important for normal cell proliferation and differentiation, and mutations in pathway components are associated with human cancers. Recent studies suggest that altered wnt ligand/receptor interactions might also contribute to human tumorigenesis. Therefore, agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. We have generated a soluble wnt receptor comprising the Frizzled8 cysteine-rich domain (CRD) fused to the human Fc domain (F8CRDhFc) that exhibits favorable pharmacologic properties in vivo. Potent antitumor efficacy was shown using the mouse mammary tumor virus-Wnt1 tumor model under dosing conditions that did not produce detectable toxicity in regenerating tissue compartments. In vitro, F8CRDhFc inhibited autocrine wnt signaling in the teratoma cell lines PA-1, NTera-2, Tera-2, and NCCIT. In vivo, systemic administration of F8CRDhFc significantly retarded the growth of tumor xenografts derived from two of these cell lines, PA-1 and NTera-2. Pharmacodynamic markers of wnt signaling, identified by gene expression analysis of cultured teratoma cells, were also modulated in the tumor xenografts following treatment with F8CRDhFc. Additionally, these markers could be used as indicators of treatment efficacy and might also be useful in identifying patients that would benefit from the therapeutic agent. This is the first report showing the efficacy of a soluble wnt receptor as an antitumor agent and suggests that further development of wnt antagonists will have utility in treating human cancer. [Cancer Res 2007;67(11):5371–9]

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator of energy metabolism. Thyroid hormone has been shown to regulate hepatic FGF21 expression in rodents. The goal of this study was to evaluate the plasma FGF21 levels in participants with normal thyroid function, subclinical hypothyroidism, or overt hypothyroidism and to investigate the change of plasma FGF21 levels in patients with overt hypothyroidism after levothyroxine treatment.A total of 473 drug-naive participants were recruited, including 250 healthy control subjects, 116 patients with subclinical hypothyroidism, and 107 patients with overt hypothyroidism. Thirty-eight patients with overt hypothyroidism were assigned to receive levothyroxine treatment.The overt hypothyroidism group had decreased FGF21 levels compared with the control and subclinical hypothyroidism groups (P0.01). Levothyroxine treatment markedly attenuated the increased circulating levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hsCRP), and homeostasis model assessment index of insulin resistance (HOMA-IR) in patients with overt hypothyroidism. A significant increase in plasma FGF21 levels was observed after levothyroxine treatment (P0.01). The change in FGF21 levels was correlated with the increase of FT3 and FT4 after levothyroxine treatment (FT3: r=0.44; FT4: r=0.53; all P0.05).Levothyroxine treatment ameliorated metabolic disorders and restored the decreased circulating FGF21 levels in patients with overt hypothyroidism. The increase in FGF21 levels after levothyroxine treatment might be partly associated with the amelioration of metabolic disorders in patients with hypothyroidism.

Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer’s disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.

Primary retroperitoneal liposarcoma is generally regarded as a genetic disorder. We have retrospectively genotyped 8 single nucleotide polymorphisms (SNPs) in 6 candidate genes (MDM2, CDK4, CDC27, FPGS, IGFN1 and PRAMEF13) in 138 patients and 131 healthy control subjects to evaluate the effects of genetic factors on individual susceptibility to primary retroperitoneal liposarcoma in Chinese population. Three SNPs (rs2870820, rs1695147, rs3730536) of MDM2 showed significant differences in single-loci genotypes and allele frequencies between case and control groups (p < 0.05). The minor allele G of SNP rs10760502 in FPGS (folylpolyglutamate synthase) gene was significantly associated with increased risk for primary retroperitoneal liposarcoma, compared with major allele A. Our data suggest that FPGS variant in Chinese population may affect individual susceptibility to primary retroperitoneal liposarcoma.