Clinical efficacy of modified sacral fixation under Leonardo da Vinci robot laparoscopy for pelvic organ prolapse.

OBJECTIVE: The aim of this study was to analyze the clinical efficacy of modified sacral fixation under Leonardo da Vinci robot laparoscopy for pelvic organ prolapse (POP). PATIENTS AND METHODS: Sixty POP patients admitted to our hospital from January 2020 to December 2021 were picked and divided into Group A (laparoscopic Y-mesh, n = 20), Group B (laparoscopic sacrovaginal fixation, n = 20), and Group C (da Vinci robotic sacral fixation, n = 20). These three groups were compared in terms of the perioperative indexes, such as operation time, intraoperative blood loss, postoperative indwelling catheter days, anal exhaust time, postoperative hospitalization days, etc. The occurrence of short-term and long-term complications in the three groups was compared. The changes of the following index values in the POP quantification system (POP -Q) staging before and 1 year after surgery were recorded and compared among the three groups. It mainly includes the midline of the anterior vaginal wall at 3 cm from the hymenal margin (Aa), the farthest point of the anterior vaginal vault from point Aa (Ba), the farthest point of the ectocervix (C), the location of the posterior vaginal vault or rectal uterine trap (D), the midline of the posterior vaginal wall at 3 cm from the hymenal margin (Ap), and the reflection of the posterior vaginal vault at the farthest point from the Ap point (Bp) values. The changes in Pelvic Floor Distress Inventory-Short Form 20 (PFDI-20) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) were recorded and compared before and 1 year after the operation. RESULTS: The patients in Group C had significantly lower intraoperative bleeding, postoperative indwelling catheter days, anal exhaust time, and postoperative hospitalization days compared with those in Group A and Group B (p < 0.05). There existed no statistical difference in the incidence of short-term and long-term complications between Group B and Group C (p > 0.05), but both were much lower than Group A (p < 0.05). The differences in POP-Q staging, PFDI-20 scale, and PISQ-12 scale were not statistically significant among the three groups before surgery (p > 0.05), and the POP-Q staging Aa, Ba, C, D, Ap, and Bp values, PFDI-20 scale, and PISQ-12 scale were strongly improved in three groups after the surgery (p < 0.05). However, the POP-Q staging, PFDI-20 scale, and PISQ-12 scale among the three groups had no obvious difference after the surgery (p > 0.05). CONCLUSIONS: The efficacy of modified sacral fixation under Leonardo da Vinci robot laparoscopy for POP was comparable to that of laparoscopic Y-mesh treatment and laparoscopic sacral vaginal fixation. However, da Vinci's robotic sacral fixation had the advantages of less intraoperative bleeding and faster postoperative recovery, which helped patients recover quickly and improved their quality of life.

Application of B-flow imaging and its enhanced mode in perforator mapping.

AIM: To explore the value of B-flow (B-mode blood flow) imaging and its enhanced mode in perforator mapping. MATERIALS AND METHODS: Before surgery, B-flow imaging, enhanced B-flow imaging, colour Doppler flow imaging (CDFI), and contrast-enhanced ultrasound (CEUS) were used to detect the skin-perforating vessels and small vessels in the fat layer of the donor site. Taking the intra-operative results as the reference standard, the diagnostic consistency and efficiency of the four modes were compared. Statistical analysis was performed using the Friedman M-test, Cochran's Q-test, and the Z-test. RESULTS: Thirty flaps were excised, with 34 skin-perforating vessels and 25 non-skin-perforating vessels, as confirmed during surgery. In order of the number of skin-perforating vessels detected, the results showed that enhanced B-flow imaging detected more vessels than B-flow imaging and CDFI (all p<0.05), CEUS detected more vessels than B-flow imaging and CDFI (all p<0.05), B-flow imaging detected more vessels than CDFI (p<0.05). All four modes had remarkable and satisfactory diagnostic consistency and effectiveness, but B-flow imaging was the best (sensitivity 100%, specificity 92%, Youden index 0.92). In order of the number of small vessels in the fat layer detected, the results showed that enhanced B-flow imaging detected more vessels than CEUS, B-flow imaging, and CDFI (all p<0.05). CEUS detected more vessels than B-flow imaging and CDFI (all p<0.05). CONCLUSION: B-flow imaging is an alternative method for perforator mapping. Enhanced B-flow imaging can reveal the microcirculation of flaps.

Evaluation of miR-429 as a novel serum biomarker for pancreatic ductal adenocarcinoma and analysis its tumor suppressor function and target genes.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. Various microRNAs have been identified to play an important role in PDAC. The study aimed to explore the role of miR-429 in PDAC. PATIENTS AND METHODS: The expression and prognostic value of miR-429 were first analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Next, miR-429 expression was evaluated in the tissues and serum of 90 patients with PDAC. CCK8, SRB, wound healing and transwell assays were used to determine the effect of miR-429 on the proliferation, invasion, and migration of PDAC cells, respectively. Weighted gene co-expression network analysis (WGCNA), correlation analysis, TargetScan, and miRDB databases were used to screen and identify the target genes of miR-429. RESULTS: The results revealed that the expression of miR-429 was downregulated in PDAC tissues and the serum compared with those in normal tissues and the serum of healthy volunteers, respectively. The decreased expression of miR-429 was significantly associated with shorter overall survival. The overexpression of miR-429 significantly inhibited the proliferation, invasion, and migration of PDAC cells. Potential target genes of miR-429 were identified using WGCNA and bioinformatics analysis, and the results showed that cadherin 11 (CDH11), inositol polyphosphate-4-phosphatase type I (INPP4A), laminin gamma 1 (LAMC1), low density lipoprotein receptor-related protein 1 (LRP1), and quaking (QKI) were potential target genes of miR-429 in PDAC. Lower expression of CDH11 and QKI was associated with a more favorable prognosis in patients with PDAC. The overexpression of miR-429 could inhibit the expression of CDH11 and QKI. A nomogram model, involving miR-429, CDH11, and QKI, was subsequently constructed to determine their ability to accurately predict overall and disease-free survival in patients with PDAC. CONCLUSIONS: Taken together, miR-429 is involved in the development and progress of PDAC. MiR-429 could be recommended as a prognostic biomarker and therapeutic indicator in PDAC diagnosis.

Associations between body composition and vertebral fracture risk in postmenopausal women.

INTRODUCTION: Osteoporosis is a metabolic bone disease with low bone mineral density (BMD) and high incidence of vertebral fractures (VFs). Postmenopausal women with osteoporosis have decreased total fat and lean mass. This study aimed to investigate the associations between body composition and VF risk and explore the potential predictor of VF risk in postmenopausal women. METHODS: Enrolled 731 postmenopausal women were referred by various departments and outpatient clinics to assess vertebral status between October 2016 and November 2017. The main measures were total body lean mass, fat mass, and BMD. Patients were divided into osteopenia, osteoporosis, and normal groups based on T-scores. Logistic regression analyses were performed to evaluate associations between body composition parameters and VF. RESULTS: VF was significantly associated with increased age, lower height, and lighter weight in all participants, and higher BMI was observed in VF participants. Participants in the osteoporosis group were older and had lower height, weight, and BMD than those in normal and osteopenia groups. Femoral and total hip T-scores as well as T-scores for lumbar spine were significantly lower in participants with VF than in non-VF participants. Percentage of bone mass was also significantly lower in VF participants compared to that of non-VF participants. Women with increased BMD and lower bone mass had reduced odds for VF occurrence. Bone mass was significantly able to identify VF occurrence. CONCLUSIONS: Body composition analysis discerns differences in the bone status of postmenopausal women with and without VF. The cutoff value of the bone mass might be used effectively as an indicator of risk for VF occurrence.

Is heritability of alopecia areata sex-specific? A nationwide population-based cohort study.

Previous studies have demonstrated the heritability of alopecia areata (AA). However, whether the heritability of AA is sex-specific has not been examined. A nationwide population-based retrospective cohort study was performed using the Taiwan Maternal and Child Health Database from 2004 to 2017. We examined the heritability of AA in offspring of parents with and without AA, and determined whether the transmission of AA from parents to the next generation may occur in opposite directions depending on sex. We found that the risk ratio (RR) for heritability of AA between parents with and without AA was approximately two-fold. In addition, for fathers with AA, the risk of AA in offspring tended to be higher in girls than in boys (RR: 2.97; 95% confidence interval: 0.94, 9.31). Therefore, the present study confirms the heritability of AA, and further studies examining the sex-specific heritability of AA with a larger sample are warranted.

Study on the effects of quercetin on brain cell apoptosis and HMGB-1 and TLR-4 level in rats with encephalitis.

OBJECTIVE: To explore the therapeutic effects of quercetin on rats with encephalitis, especially on cell apoptosis, and the levels of HMGB-1 and TLR-4. MATERIALS AND METHODS: 32 healthy rats were equally assigned into ZC group (healthy group), NY group (encephalitis group), DJ group (60 ml quercetin group), and GJ group (240 ml quercetin group) followed by analysis of cell apoptosis, brain tissue water content, neurons, HMGB-1, TLR-4 and other inflammatory factors. RESULTS: The ZC group showed normal neuron volume and equitable staining; compared with ZC group, NY group showed neuron volume shrinkage and chromatin condensation; the neuron and color in DJ group were slightly better than NY group; the neuron volume in GJ group increased significantly and chromatin is distributed evenly. TLR-4, IL-4, IL-6, HMGB-1 in ZC and DJ group were significantly lower than those in NY group (p<0.05); IL-4, IL-6, HMGB-1 in GJ group significantly decreased compared with DJ group (p<0.05); MMP-9 enzyme activity in ZC and DJ group was significantly lower than NY group (p<0.05) with lower level in GJ group than DJ group (p<0.05). The water content was higher in brain tissue of NY group than ZC group (p<0.05) and lower in DJ group than NY group (p<0.05) with lower level in GJ group than DJ and NY group (all p<0.05). The hippocampal neurons and cortical neurons in ZC and DJ group were higher than those in NY group (p<0.05) and elevated in GJ group compared with DJ group and NY group (p<0.05). CONCLUSIONS: Quercetin is effective in treating encephalitis rats possibly through inhibition of neuronal cell apoptosis and level of HMGB-1 and TLR-4.

Hemogram-based decision tree for predicting the metabolic syndrome and cardiovascular diseases in the elderly.

BACKGROUND: This study aimed to build a hemogram-based decision tree to evaluate the association between current probability of metabolic syndrome (MetS) and prediction of future hypertension, type 2 diabetes and cardiovascular diseases (CVD) risk. METHODS: A total of 40 395 elder participants (≥60 years) were enrolled in a standard health examination program in Taiwan from January 1999 to December 2014. A decision tree classification of the presence or absence of MetS at baseline, using age, sex and hemogram (white blood cell, hemoglobin and platelet) as independent variables, was conducted for the randomly assigned training (70%) and validation (30%) groups. Participants without MetS at baseline (n = 25 643) were followed up to observe whether they developed MetS, hypertension, type 2 diabetes or CVD in the future. RESULTS: Modest accuracy of the decision tree in the training and validation groups with area under the curves of 0.653 and 0.652, respectively, indicated an acceptable generalizability of results. The predicted probability of baseline MetS was obtained from decision tree analysis. Participants without MetS at baseline were categorized into three equally sized groups according to the predicted probability. Participants in the third tertile had significantly higher risks of future MetS (hazard ratio 1.40, 95% confidence interval 1.25-1.58); type 2 diabetes (1.46, 1.17-1.83); hypertension (1.14, 1.01-1.28); and CVD (1.21, 1.01-1.44), compared with those in the first tertile. CONCLUSIONS: Execution of hemogram-based decision tree analysis can assist in early identification and prompt management of elderly patients at a high risk of future hypertension, type 2 diabetes and CVD.

MIIP inhibits malignant progression of hepatocellular carcinoma through regulating AKT.

OBJECTIVE: This study was aimed to investigate the expression characteristics of MIIP in hepatocellular carcinoma (HCC), and to further explore whether it can inhibit the malignant progression of this disease via regulating AKT expression. PATIENTS AND METHODS: Real-time quantitative PCR (qRT-PCR) was performed to examine the expression of MIIP in tumor and paracancerous tissue specimens of 39 patients with HCC, and to analyze the interplay between MIIP expression and clinical indicators and prognosis of HCC patients. At the same time, in HCC cell lines, the expression of MIIP was further verified using qRT-PCR. In addition, MIIP overexpression and knockdown models were constructed using lentivirus in HCC cell lines (Bel-7402 and Hep3B), and the influence of MIIP on the biological function of HCC cells was analyzed through CCK-8 and transwell migration assays. Finally, luciferase reporting assay and cell reverse experiments were applied to further explore the potential molecular mechanism and the interaction between MIIP and AKT. RESULTS: The results of qRT-PCR showed that the expression level of MIIP in HCC tissue samples was remarkably lower than that in adjacent ones, with a statistically significant difference. Compared with patients with high expression of MIIP, patients with low MIIP expression had a higher occurrence of distant metastasis and a lower overall survival rate. Similarly, compared with control group, the proliferation and migration ability of HCC cells in MIIP knockdown group (sh-MIIP) was remarkably enhanced, while the opposite result was observed in MIIP overexpression group. In addition, qRT-PCR results also revealed that AKT and MIIP were negatively correlated in HCC tissues. At the same time, the results of luciferase reporter gene assay demonstrated that MIIP can be targeted by AKT through certain binding site. Additionally, cell reverse experiment found that there might exist a mutual regulation between MIIP and AKT, thereby jointly regulating the malignant progression of HCC. CONCLUSIONS: MIIP expression is remarkably decreased both in HCC tissues and cell lines; meanwhile, the low expression of MIIP is positively correlated with the occurrence of distant metastasis and poor prognosis of patients with HCC. In addition, MIIP may be able to inhibit the malignant progression of HCC by modulating AKT expression.

Clinical outcomes of patients undergoing a cardiac implantable electronic device implantation following a recent non-device-related infection.

BACKGROUND: Clinical outcomes of patients undergoing a cardiac implantable electronic device (CIED) implantation following a recent non-device related infection are unknown. AIM: To evaluate the clinical outcomes of patients with recent infection before CIED implantation. METHODS: Consecutive patients (N = 1237) were classified as patients with recent infection (N = 72) and without recent infection (N = 1165). A recent infection was established by reviewing medical records, including symptoms and clinical manifestations, diagnosis of systemic inflammatory response syndrome, and quick Sequential Organ Failure Assessment (qSOFA) score. Multiple stepwise logistic regression analysis was used to identify independent predictors of in-hospital all-cause mortality. FINDINGS: During nearly three years of follow-up, 17 patients had CIED infection (1.4%), and the incidence of CIED infection did not significantly differ between patients with and without recent infection according to symptoms and clinical manifestations (2.8% vs 1.3%, respectively; not significant). However, patients with recent infection had a significantly higher in-hospital mortality rate compared to those without recent infection (22.2% vs 0.9%, respectively; P < 0.05). In multivariate analysis, predictors of in-hospital mortality were recent infection before CIED implantation (odds ratio: 20.3; 95% confidence interval: 8.4-49.3; P < 0.001) and end-stage renal disease (4.3; 1.4-12.8; P = 0.009). CONCLUSION: A CIED implantation is feasible in patients with recent infection if the patient is afebrile and has received an adequate duration of antibiotic therapy. Participants in shared decision-making before implant should be advised that recent infection increases in-hospital mortality risk, especially in patients with a qSOFA score of ≥2.

Bundled skin antiseptic preparation for complex cardiac implantable electronic device infection: a propensity-score matching cohort study.

BACKGROUND: Cardiac implantable electronic device (CIED) infection, a major complication of a CIED implant procedure, can prolong hospitalization and cause mortality. AIM: To evaluate the efficacy of a bundled skin antiseptic preparation for preventing infection after implantation of a complex CIED. METHODS: This study analysed 1163 consecutive patients who had received a bundled skin antiseptic preparation before CIED implantation from July 2012 to December 2017. According to the complexity of the CIED implant procedure, the patients were divided into a complex CIED group (N = 370) and a non-complex CIED group (N = 793). A complex procedure was defined as a pacemaker replacement, implantation of implantable cardioverter defibrillator and cardiac resynchronization therapy, device upgrade, or lead revision. FINDINGS: During a mean follow-up of 2.9 ± 1.7 years, CIED infection developed in 15 patients (1.3%), and the incidence of minor and major infection was 1.1% and 0.2%, respectively. The incidence of CIED infection did not significantly differ between the complex CIED group and the non-complex CIED group (1.1% vs 1.4%, respectively; non-significant). Multivariate analysis indicated that procedural complexity was not an independent predictor of CIED infection. After 2:1 propensity score matching, the matched non-complex CIED group and the matched complex CIED group still showed no significant difference in the incidence of CIED infection. CONCLUSION: Bundled skin antiseptic preparation is an effective and widely applicable strategy for decreasing infection risk after a complex CIED implantation.

Impact of Positive Donor-Specific HLA Antibodies Crossmatch on Graft Survival in ABO-Incompatible Liver-Kidney Transplantation: A Case Report.

We present a patient with positive donor-specific antibodies (DSA) and crossmatch of ABO-incompatible (ABOi) combined liver and kidney transplantation (CLKT). Antibody-mediated rejection did not occur and the graft had survived for over one year at the time of writing without infectious complications. A 56-year-old man with positive DSA and positive crossmatch underwent living donor CLKT. The preoperative protocol for ABOi consisted of a single dose of rituximab and total plasma exchange (TPE). The result of anti-B antibody titer for IgG was 1:32. The evaluations of complement-dependent cytotoxicity and flow cytometry cross-match revealed a change from T+/B+ to T-/B+. The patient required adult living donor CLKT. Acute rejection episodes were treated using antithymocyte globulin, and the kidney required 7 days' treatment to recover. No further rejection and infectious episodes have been observed in past 13 months since the transplant. DSA and crossmatches are important for antibody detection and analysis. In the rituximab era, TPE can be used to achieve a successful decrease in antibody titer. In countries with a severe shortage of cadaveric organ donors, it may be possible to select ABOi candidate donors with positive DSA and crossmatch.

Downregulated miR-328 suppressed cell invasion and growth in hepatocellular carcinoma via targeting PTEN.

OBJECTIVE: To investigate the regulatory effect of miR-328 on biological behaviors of hepatocellular carcinoma (HCC) cells, such as invasion and proliferation. PATIENTS AND METHODS: The expressions of miR-328 were detected in 48 pairs of HCC tissue samples and matched adjacent tissues, as well as in 3 kinds of HCC cell lines via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Further, we analyzed the effects of miR-328 inhibition on cell invasion, proliferation, cell apoptosis, and cell cycle. Dual-luciferase activity assay was performed to examine the potential target gene PTEN which was predicted by an online database. Protein levels were detected using Western blot assay. RESULTS: The expression of miR-328 was significantly increased in HCC tissue samples. Decreased miR-328 in HCC cells significantly attenuated cell invasion and proliferation capacities, promoted cell apoptosis and induced cell cycle arrest at G0/G1 phase. Moreover, PTEN was verified as a target gene of miR-328 by dual-luciferase activity assay, qRT-PCR and Western blot. Furthermore, the silence of PTEN neutralized the suppressive effect of decreased miR-328 on cell growth and metastasis. CONCLUSIONS: MiR-328 is involved in the development of HCC via regulating PTEN, which might provide a new target for HCC diagnosis and therapy.

A modification and validation of quantitative morphometry classification system for osteoporotic vertebral compressive fractures in mainland Chinese.

This study described a modified quantitative morphometry (mQM) system adapted to specific reference values for Mainland Chinese population. The mQM system is validated using the Genant Semiquantative system and is sensitive for detecting vertebral height changes and predicting cement leakage after percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compressive fracture (OVCF). INTRODUCTION: OVCF is a manifestation of osteoporosis. To improve clinical management of osteoporosis, the quantitative morphometry (QM) system has been widely used for the early diagnosis and precise classification of OVCF in developed countries. Here, we present an mQM system and validated its use in detecting OVCF in Mainland Chinese. METHODS: Using our mQM system, the pre- and post-operative values of vertebral heights were measured and evaluated in 309 Mainland Chinese who received percutaneous kyphoplasty (PKP) as OVCF treatment. Measurements and classification of fractures from the mQM system were validated by comparing to values obtained by the Genant semiquantative (SQ) method. Moreover, we evaluated the sensitivity of the mQM system by its ability to detect restoration of vertebral heights and predict cement leakage after PKP. RESULTS: The five classification of fractures, No deformity (ND), anterior wedge (AW), posterior wedge (PW), biconcavity (BC), and compression (CP), evaluated by the mQM method shared similar distribution characteristics compared to those obtained by the SQ method. In addition, mQM evaluation showed that the vertebra height of all fracture types showed significant restoration after PKP. The incidence of cement leakage was most common in CP (37.5%), followed by AW (31.6%), BC (26.5%), ND (23.7%), and PW (0.0%). CONCLUSIONS: Our mQM system is suitable for classification of fractures, detection of vertebral height restoration, and correlation of cement leakage after PKP in Mainland Chinese population.

Immune imbalance of global gene expression, and cytokine, chemokine and selectin levels in the brains of offspring with social deficits via maternal immune activation.

The murine maternal immune activation (MIA) offspring model enables longitudinal studies to explore aberrant social behaviors similar to those observed in humans. High levels of cytokines, chemokines and cell adhesion molecules (CAM) have been found in the plasma and/or brains of psychiatric patients. We hypothesized that upregulation of the systemic or brain immune response has an augmenting effect by potentially increasing the interplay between the neuronal and immune systems during the growth of the MIA offspring. In this study, a C57BL/6j MIA female offspring model exhibiting social deficits was established. The expression of fetal interferon (IFN)-stimulated (gbp3, irgm1, ifi44), adolescent immunodevelopmental transcription factor (eg, r2, tfap2b), hormone (pomc, hcrt), adult selectin (sell, selp) and neuroligin (nlgn2) genes was altered. Systemic upregulation of endogenous IL-10 occurred at the adult stage, while both IL-1ß and IL-6 were increased and persisted in the sera throughout the growth of the MIA offspring. The cerebral IL-6 levels were endogenously upregulated, but both MCP-1 (macrophage inflammatory protein-1) and L-selectin levels were downregulated at the adolescent and/or adult stages. However, the MIA offspring were susceptible to lipopolysaccharide (LPS) stimulation. After reinjecting the MIA offspring with LPS in adulthood, a variety of sera and cerebral cytokines, chemokines and CAMs were increased. Particularly, both MCP-1 and L-selectin showed relatively high expression in the brain compared with the expression levels in phosphate-buffered saline (PBS)-treated offspring injected with LPS. Potentially, MCP-1 was attracted to the L-selectin-mediated immune cells due to augmentation of the immune response following stimulation in MIA female offspring.

Regulation of DNA methylation and tumor suppression gene expression by miR-29b in leukemia patients and related mechanisms.

OBJECTIVE: Leukemia is characterized as a kind of malignant clonal disease in hematological stem cells. The study showed an abnormal level of DNA methylation in leukemia cells, which further led to an abnormal expression of hematological genes. This study investigated the role of miR-29b on the modulation of DNA methylation and tumor suppressor gene expression in leukemia patients. PATIENTS AND METHODS: A total of 21 leukemia patients were recruited for the collection of monocytes. Methylation levels of promoter sequence of ESR1 and p15 genes were analyzed by methylation assay kit combined with DHPLC. DNA microarray and qRT-PCR were used to measure microRNA expressional profile, and bioinformatics plus luciferase reporter assay confirmed target gene of miR-29b. After transfection with miR-29b, promoter methylation levels of ESR1 and p15 gene were measured. Protein expressions of DNMT1 DNA (cytosine-5)-methyltransferase 1 (DNMT1), DNA (cytosine-5)-methyltransferase 3A (DNMT3A) and DNA (cytosine-5)-methyltransferase 3B (DNMT3B) were quantified. RESULTS: The methylation levels of the promoter region of ESR1 and p15 genes in monocytes of leukemia patient were significantly elevated (p < 0.05). DNA microarray and qRT-PCR confirmed the down-regulation of miR-29b (p < 0.05). Luciferase reporter assay revealed DNMT1, DNMT3A and DNMT3B as target genes of miR-29b. MiR-29b transfection inhibited the expressions of DNMT3A and DNMT3B in Kasumi-1 cells (p < 0.05), and promoter methylation levels of estrogen Receptor 1 (ESR1) and p15 gene were decreased (p < 0.05). CONCLUSIONS: In leukemia cells, hyper- methylation existed in the promoter region of tumor suppressor gene. The methylation was enhanced in gene DNMT1, DNMT3A and DNMT3B via the reduction of miR-29b in leukemia tumor cells.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation.

Aberrant protein glycosylation could be a distinct surface-marker of cancer cells that influences cancer progression and metastasis because glycosylation can regulate membrane protein folding which alters receptor activation and changes epitope exposure for antibody (Ab) recognition. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol-anchored protein, is a heavily glycosylated tumor antigen. However, the clinical significance and biological effect of CEACAM6 glycosylation has not been addressed in cancers. We recently developed an anti-CEACAM6 Ab (TMU) from an immune llama library which can be engineered to a single-domain (sd)Ab or a heavy-chain (HC)Ab. The TMU HCAb specifically recognized glycosylated CEACAM6 compared to the conventional antibodies. Using the TMU HCAb, we found that glycosylated CEACAM6 was a tumor marker associated with recurrence in early-stage OSCC (oral squamous cell carcinoma) patients. CEACAM6 promoted OSCC cell invasion, migration, cytoskeletal rearrangement, and metastasis via interaction with epidermal growth factor (EGF) receptor (EGFR) and enhancing EGFR activation, clustering and intracellular signaling cascades. These functions were modulated by N-acetylglucosaminyltransferase 5 (MGAT5) which mediated N-glycosylation at Asn256 (N256) of CEACAM6. Finally, the TMU sdAb and HCAb treatment inhibited the migration, invasion and EGF-induced signaling in CEACAM6-overexpressing cells. In conclusion, the complex N-glycosylation of CEACAM6 is critical for EGFR signaling of OSCC invasion and metastasis. Targeting glycosylated CEACAM6 with the TMU sdAb or TMU HCAb could be a feasible therapy for OSCC.

A stress-induced cellular aging model with postnatal neural stem cells.

This corrects the article DOI: 10.1038/cddis.2014.82.

The Role of Uric Acid for Predicting Future Metabolic Syndrome and Type 2 Diabetes in Older People.

OBJECTIVE: Although it is known that high uric acid (UA) level is associated with type 2 diabetes (T2DM) and metabolic syndrome (MetS), most of the previous studies were focused on adults. Since aging becomes a major problem for many societies, in this longitudinal study, we investigated the role of UA in future T2DM and MetS in a large cohort of people who were older than 65 years. DESIGN: A cross-sectional and longitudinal study. SETTING/PARTICIPANTS: 18,907 elderly (9,732 men, 9,175 women) aged above 65 years, enrolled from health check-up centers, were classified into three subgroups by 10-year intervals (young old 65-74 years, YO; old old 75-84 years, OO; and oldest old 85-94 years, ODO), with the average follow-up period of 4.3 years. MEASUREMENTS: The optimal cut-off values (CoVs) of baseline UA to predict future MetS and T2DM were determined by receiving operating characteristic (ROC) curve analysis. Using these CoVs of UA, the participants were divided into normal- and high-level groups of UA. Cox proportional hazard analysis was used to calculate hazard ratios (HRs) for the subjects with a high level of UA for the risk of future MetS and T2DM. In addition, Kaplan-Meier plots and log rank test were used to evaluate the time effect on the incidence of developing MetS and T2DM between the two groups. RESULTS: In ROC curve analysis, the optimal CoVs of baseline UA were 6.0, 6.3 and 6.7 mg/dl in YO, OO, and ODO men, respectively; 5.5 and 4.9 mg/dl in YO and OO women, respectively (all p < 0.05). However, the CoVs of UA in ODO women (6.1 mg/dl) failed to show its discriminant power (p = 0.13). The Cox regression analysis showed the YO subjects with a higher baseline level of UA had a higher risk of developing MetS (HRs 1.56 and 1.58 for men and women, respectively, both p < 0.001); as for T2DM the HRs were 1.39 and 1.57. In OO men, the HRs was 1.89 for developing future MetS. However, no significant findings could be noted in the ODO group. Kaplan-Meier plots and log rank test also showed the same findings. CONCLUSION: Our study showed that old subjects with high levels of UA will have a higher chance to have MetS and T2DM, particularly in the YO group (6.0 mg/dl for men and 5.5 mg/dl for women, respectively). Using UA as one of the metabolic biomarkers may help clinicians to early detect and prevent MetS and diabetes.

Betel Nut Chewing Is Associated With Reduced Tacrolimus Concentration in Taiwanese Liver Transplant Recipients.

PURPOSE: Studies have shown that arecoline, the major alkaloid component of betel nuts, alters the activity of enzymes in the cytochrome P450 (CYP-450) family. Tacrolimus, an immunosuppressant that protects against organ rejection in transplant recipients, not only is mainly metabolized by CYP3A enzymes but also has a narrow therapeutic range. We aimed to investigate whether dose-adjusted blood trough levels of tacrolimus differed over time between betel nut-chewing and non-betel nut-chewing liver transplant recipients. METHODS: In this retrospective case-control study, 14 active betel nut-using liver recipients were matched at a 1:2 ratio to 28 non-betel nut-using liver recipients by sex, age, graft source, duration of follow-up after liver transplantation, and estimated glomerular filtration rate. Differences in liver function index, renal function index, and dose-adjusted blood trough levels of tacrolimus over an 18-month period were compared between the 2 groups by using the Generalized Estimating Equation approach. RESULTS: Dose-adjusted blood trough levels of tacrolimus tended to be significantly (P = .04) lower in betel nut chewers (mean = 0.81, medium = 0.7, 95% confidence interval [CI] = 0.73 to 0.90) than in nonchewers (mean = 1.12, medium = 0.88, 95% CI = 1.03 to 1.22) during the 18-month study period. However, there was no significant difference in renal and liver function index between the 2 groups. CONCLUSION: Liver transplant recipients receiving tacrolimus tend to have lower blood trough levels of the drug over time if they chew betel nuts.