[The impact of donor human leukocyte antigen-Bw4 allele on natural killer cell reconstitution and transplant-related mortality in haploidentical transplantation].

Objective: To investigate the impact of donor human leukocyte antigen (HLA) -Bw4 expression on natural killer (NK) cell reconstitution and transplant outcomes in recipients undergoing haploidentical hematopoietic stem cell transplantation (HSCT) from maternal or related donors without ex vivo T-cell depletion. Methods: This study prospectively enrolled 32 patients who received T-replete haploidentical HSCT from maternal or collateral donors (cohort 1) to evaluate the facilitating effect of donor HLA-Bw4 expression on NK cell reconstitution. Furthermore, a retrospective analysis was conducted on 278 patients who underwent T-replete haploidentical HSCT from maternal or collateral donors (cohort 2) to analyze the impact of donor HLA-Bw4 expression on HSCT outcomes. Thus, a comparison was made between the effects of donor HLA-Bw4 expression on HSCT outcomes in patients receiving or not receiving post-transplant cyclophosphamide (PT-Cy) conditioning. Results: Donors expressing HLA-Bw4 alleles facilitated NK cell reconstitution and functional recovery, which remained unaffected by PT-Cy. Donors with HLA-Bw4 expression were associated with reduced transplant-related mortality (TRM), particularly mortality related to infections. The use of PT-Cy did not impact the ability of donor HLA-Bw4 to decrease TRM. Conclusion: In haploidentical HSCT from maternal or related donors without ex vivo T-cell depletion, the presence of donor HLA-Bw4 expression promotes rapid NK cell reconstitution and functional recovery and is significantly associated with lower TRM, especially infection-related mortality. These findings underscore the clinical significance of donor HLA-Bw4 expression in patients who underwent HSCT. Hence, the consideration of donor HLA-Bw4 in recipient selection and HSCT strategies holds important clinical implications.

[Cross-sectional study on clinic behavior and therapeutic status of patients with psoriatic arthritis in multi-center].

OBJECTIVE: To investigate and analyse the features of treatment behavior and standardized therapeutic status of patients with psoriatic arthritis (PsA). METHODS: Out patients diagnosed with PsA in People's Hospital of Peking University, Haidian Hospital, People's Hospital of Jianyang City, Central Hospital of Xinxiang City, Integrated Traditional Chinese and Western Medicine Hospital of Cangzhou City, The Third Hospital of Hebei Medical University from February to June 2018 were enrolled in this investigation. The data including gender, age of onset, course of disease, site of first consulting department, time of the first visit and definite diagnosis, follow-up interval, and use of conventional disease modifying anti-rheumatic drugs (cDMARDs) and biological DMARDs (BioDMARDs) were collected and analyzed. RESULTS: In the cross-sectional study, 133 PsA patients were investigated. The mean age of onset was (47±11) years, the male to female ratio was 1.3:1, and mean disease duration was (16±8) years. Rheumatology department was the most common site of first hospital visit (37.6%, 50/133). Orthopedics department and dermatological department were visited by 24.1% (32/133) and 23.3% (31/133), respectively. Ratio of definite diagnosis was the highest in rheumatology department which was 78% (39/50). The ratio of definite diagnosis of dermatological department was the second highest, which was 19.4% (6/31). The mean definite diagnosed time was 7.6 months since the first visit of PsA patients, and diagnosed time was the shortest in rheumatology department, which had statistical significance. 37% PsA patients were treated appropriately in 3 months, 17.3% PsA patients were treated in 3-6 months and 40.2% patients with PsA visited their doctor more than once a year. 48.8% patients hadn't received standardized treatment before visit, and one third patients never received the therapy of DMARDs. Methotrexate was the most commonly used cDMARDs (58.3%), followed by leflunomide (20.5%) and BioDMARDs (19.7%), and biologicals were tumor necrosis factor antagonists. CONCLUSION: In this multi-center study, the first visit department of PsA patients was widely distributed, and most patients were definitely diagnosed in Rheumatology Department. The time of their first visit and definite diagnosis were delayed due to multi factors. Nearly half of the patients did not receive standardized treatment.

[The efficacy and safety of salvage surgery for local recurrent nasopharyngeal carcinoma: a systematic review and Meta-analysis].

Objective: To assess the current evidence regarding the efficacy, safety, and potential advantages of endoscopic compared with open salvage surgery for patients with local recurrent nasopharyngeal carcinoma. Methods: A systematic search of Pubmed/Medline, Embase, and Cochrane databases ranged between 2000 and 2017 was conducted. Included studies reported specific residual or local recurrent nasopharyngeal cancer survival data. Proportional Meta-analysis was performed on both outcomes with a random-effects model and the 95% confidential intervals were calculated by Stata 12.0 software. Results: A total of 24 case series studies were included in the Meta-analysis.The pooled 2-year overall survival rates of endoscopic and open group were 84% (95%CI:72%-93%), 68%(95%CI:59%-77%),respectively.The pooled 2-year disease-free survival rates of endoscopic and open group were 68%(95%CI:53%-81%), 65%(95%CI:54%-75%),respectively. The pooled 5-year overall survival rates of endoscopic and open group were 72%(95%CI:37%-97%), 48% (95%CI:40%-56%),respectively.The pooled 5-year disease-free survival rates of endoscopic and open group were 65%(95%CI:29%-93%), 50%(95%CI:43%-57%),respectively.The combined outcome of endoscopic was higher than open procedure. In addition, less severe complications, lower local recurrence rates(27%vs32%).The 2-year overall survival rates of endoscopic was higher than open procedure in the staging of rT1, rT2, and rT3 (93%vs87%; 77%vs63%; 67%vs53%) , but was equal to open in the staging for rT4 (35%vs35%) .Meta-regression showed that the heterogeneity was correlated with advanced tumor ratio. Conclusions: The present Meta-analysis reveals that endoscopic approach offers a safe and efficient alternative to open approach with better short-term outcome and fewer postoperative complications in selecting patients strictly.

[Clinicopathological features and prognosis of 488 patients with neuroendocrine tumors].

Objective: To investigate the clinicopathological features and prognosis of patients with neuroendocrine tumors (NETs). Methods: The clinicopathologic data of enrolled patients with NETs between October 2012 and October 2017 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Results: Among the 488 NETs patients, the average age was (51.0±15.8) years, and the sex ratio (male/female) was 1∶1.1. Of the NETs, 370 were located in the digestive system (75.8%), 63 were pulmonary (12.9%), 14 were mediastinal (2.9%), 7 were of unknown primary origin (1.4%), and 34 were located in other sites (7.0%). Among the NETs, the pancreas, rectum and stomach were the most common sites. In the digestive system NETs, the most common tumor grade was G1 (190 cases, 51.4%), followed by G2 (143 cases, 38.6%) and NET-G3 (37 cases, 10.0%). In pulmonary NETs, typical and atypical carcinoid tumors was 47.6% and 52.4%, respectively. There were 310 patients at stage Ⅰ/Ⅱ, 53 at stage Ⅲ, 69 at stage Ⅳ and 56 at stage undiagnosed, respectively. The relationships among age, stage, grade, metastasis, treatment and prognosis were analyzed. All these factors could influence the survival rate of NET patients. Multivariate Cox analysis showed that age (>50 years old) (HR=2.831, 95%CI:1.414-7.029, P=0.025) and distant metastasis (HR=10.208, 95%CI:4.110-25.355, P<0.001) were independent risk factors. Conclusions: The most common primary sites of NETs are the pancreas, rectum, and stomach. Age and distant metastasis are independent risk factors for the prognosis of NETs.

CT-guided core needle biopsy of small (≤20 mm) subpleural pulmonary lesions: value of the long transpulmonary needle path.

AIM: To evaluate the accuracy and complications of computed tomography (CT)-guided core needle biopsy (CNB) of small (≤20 mm) subpleural pulmonary lesions with the use of the long transpulmonary needle path. MATERIALS AND METHODS: A retrospective study was undertaken comprising 235 patients who underwent CT-guided CNB of small (≤20 mm) subpleural pulmonary lesions. One of two needle paths was used: a long (≥10 mm) transpulmonary needle path (n=164, group A) or a short (<10 mm) transpulmonary needle path (n=71, group B). Diagnostic accuracy, pneumothorax, and bleeding rates were compared between the two groups. RESULTS: The diagnostic accuracy in group A was significantly higher than that in group B (93.9% versus 81.7%, p=0.004), particularly in patients with 5-10 mm lesions (89.2% versus 53.3%, p=0.013). The mean length of the transpulmonary needle path was 23.9 mm in group A and 5.9 mm in group B (p<0.001). The mean number of pleural punctures in group A was 1.01 and 1.11 in group B (p=0.016), but for patients with more than one puncture, the short transpulmonary path was not associated with a higher accuracy rate. The incidence of bleeding was 22% in group A and 9.9% in group B (p=0.028). CONCLUSION: Diagnostic accuracy for small subpleural pulmonary lesions with the use of the long transpulmonary needle path was higher than that with the use of the short transpulmonary needle path, especially for 5-10 mm lesions; however, the long transpulmonary needle path was associated with a higher rate of bleeding.

Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance.

AIMS/HYPOTHESIS: Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. METHODS: We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. RESULTS: Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. CONCLUSIONS/INTERPRETATION: These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.

In vitro study on the influence of strontium-doped calcium polyphosphate on the angiogenesis-related behaviors of HUVECs.

Angiogenesis is of great importance in bone tissue engineering, and has gained large attention in the past decade. Strontium-doped calcium polyphosphate (SCPP) is a novel biodegradable material which has been proved to be able to promote in vivo angiogenesis during bone regeneration. An in vitro culture system was developed in the present work to examine its influence on angiogenesis-related behaviors of human umbilical vein endothelial cells (HUVECs), including cell adhesion, spreading, proliferation and migration. The effects of microtopography, chemical property and the ingredients in the degradation fluid (DF) on cell behaviors were discussed. The results showed that cells attached and spread better on SCPP scaffold than on calcium polyphosphate (CPP), which might partially result from the less rough surface of SCPP scaffold and the less hydrogel formed on the surface. In addition, cell proliferation was significantly improved when treated with SCPP DF compared with the treatment with CPP DF. Statistical analysis indicated that Sr(2+) in SCPP DF might be the main reason for the improved cell proliferation. Moreover, cell migration, another important step during angiogenesis, was evidently stimulated by SCPP DF. The improved in vivo angiogenesis by SCPP might be assigned to its better surface properties and strontium in the DF. This work also provides a new method for in vitro evaluation of biodegradable materials' potential effects on angiogenesis.

Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Balpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen.

Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-terminal leucine 309 are two important mechanisms by which protein phosphatase 2A (PP2A) can be regulated. In this study, both genetic and biochemical approaches were used to investigate regulation of regulatory subunit binding by C subunit methylation. Monoclonal antibodies selectively recognizing unmethylated C subunit were used to quantitate the methylation status of wild-type and mutant C subunits. Analysis of 13 C subunit mutants showed that both carboxy-terminal and active site residues are important for maintaining methylation in vivo. Severe impairment of methylation invariably led to a dramatic decrease in Balpha subunit binding but not of striatin, SG2NA, or polyomavirus middle tumor antigen (MT) binding. In fact, most unmethylated C subunit mutants showed enhanced binding to striatin and SG2NA. Certain carboxy-terminal mutations decreased Balpha subunit binding without greatly affecting methylation, indicating that Balpha subunit binding is not required for a high steady-state level of C subunit methylation. Demethylation of PP2A in cell lysates with recombinant PP2A methylesterase greatly decreased the amount of C subunit that could be coimmunoprecipitated via the Balpha subunit but not the amount that could be coimmunoprecipitated with Aalpha subunit or MT. When C subunit methylation levels were greatly reduced in vivo, Balpha subunits were found complexed exclusively to methylated C subunits, whereas striatin and SG2NA in the same cells bound both methylated and unmethylated C subunits. Thus, C subunit methylation is critical for assembly of PP2A heterotrimers containing Balpha subunit but not for formation of heterotrimers containing MT, striatin, or SG2NA. These findings suggest that methylation may be able to selectively regulate the association of certain regulatory subunits with the A/C heterodimer.

Inducible overexpression of Bak sensitizes HCC-9204 cells to apoptosis induced by doxorubicin.

AIM: To investigate the role of overexpression of Bak in apoptotic pathways and drug susceptibility using doxorubicin and vinorelbine in human HCC-9204 cells. METHODS: An inducible system, MT-II regulatory system which allowed controlled expression of protein upon addition of ZnSO4(100 mumol/L) as an external inducer was used. Stable transfection of pMD-Bak gene was performed on HCC-9204 cells. Apoptotic cells were measured by morphological criteria, as well as by TUNEL assay and flow cytometry. The ability of Bak to decrease clonogenic cell survival was studied by colony-forming assays, while decrease in cell viability was assessed by MTT assay. RESULTS: Cells overexpressing Bak showed extensive cell death with nucleus fragmentation detected by TUNEL assay. FACS analyses showed that Bak could induce significant G1 accumulation and apoptosis in 19.29% cells 24 h after induction. Bak significantly decreased the clonogenic survival following exposure to adriamycin, but not vinorelbine. Furthermore, the time-course of cell viability rates following exposure of HCC-9204/Bak cells to adriamycin and vinorelbine was in agreement with the above findings. Bak selectively sensitized HCC-9204 cells to death induced by adriamycin while resisted to vinorelbine. CONCLUSION: Bak may prolong cell cycle in G1 phase, leading to apoptosis and decrease clonogenic survival of HCC-9204 cells in a drug-specific manner.

UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells.

Uncoupling proteins (UCPs) are a family of mitochondrial transporter proteins that have been implicated in thermoregulatory heat production and maintenance of the basal metabolic rate. We have identified and partially characterized a novel member of the human uncoupling protein family, termed uncoupling protein-4 (UCP4). Protein sequence analyses showed that UCP4 is most related to UCP3 and possesses features characteristic of mitochondrial transporter proteins. Unlike other known UCPs, UCP4 transcripts are exclusively expressed in both fetal and adult brain tissues. UCP4 maps to human chromosome 6p11.2-q12. Consistent with its potential role as an uncoupling protein, UCP4 is localized to the mitochondria and its ectopic expression in mammalian cells reduces mitochondrial membrane potential. These findings suggest that UCP4 may be involved in thermoregulatory heat production and metabolism in the brain.