Improved bone and renal safety in younger tenofovir disoproxil fumarate experienced chronic hepatitis B patients after switching to tenofovir alafenamide or entecavir.

INTRODUCTION AND OBJECTIVES: Renal and bone impairment has been reported in chronic hepatitis B (CHB) patients receiving long-term tenofovir disoproxil fumarate (TDF) therapy. This study aimed to assess the incidence of renal and bone impairment in CHB patients with long-term TDF therapy and to identify the changes in bone mineral density (BMD) and renal function in these patients after switching to entecavir (ETV) or tenofovir alafenamide (TAF). MATERIALS AND METHODS: This retrospective study collected clinical data from CHB patients who received TDF monotherapy over 96 weeks. The changes in BMD and renal function were analyzed after 96 weeks of switching antiviral regimens (ETV or TAF) or maintenance TDF. RESULTS: At baseline, 154 patients receiving TDF monotherapy over 96 weeks were enrolled, with a younger median age of 36.75 years, 35.1% (54/154) of patients experienced elevated urinary ß2 microglobulin and 20.1% (31/154) of patients had reduced hip BMD (T<-1). At week 96, among the 123 patients with baseline normal BMD, patients who maintained TDF (n=85) had experienced a decrease in hip BMD, while patients who switched antiviral regimens (n=38) experienced an increase (-13.97% vs 2.34%, p<0.05). Among patients with a baseline reduced BMD (n=31), the alterations in BMD were similar in patients who maintained TDF (n=5) and those who switched antiviral regimens (n=26) (-15.81% vs 7.35%, p<0.05). Irrespective of baseline BMD status, renal function decreased significantly in patients who maintained TDF and improved in patients who switched antiviral regimens. CONCLUSIONS: Younger CHB patients on long-term TDF therapy are at high risk for bone and renal impairment, with the risk being reduced when switched to ETV or TAF.

Edaravone Improves the Post-traumatic Brain Injury Dysfunction in Learning and Memory by Modulating Nrf2/ARE Signal Pathway.

OBJECTIVES: To investigate the molecular mechanism of edaravone (EDA) in improving the post-traumatic brain injury (TBI) dysfunction in learning and memory. METHODS: In vitro and in vivo TBI models were established using hydrogen peroxide (H2O2) treatment for hippocampal nerve stem cells (NSCs) and surgery for rats, followed by EDA treatment. WST 1 measurement, methylthiazol tetrazolium assay, and flow cytometry were performed to determine the activity, proliferation, and apoptosis of NSCs, and malondialdehyde (MDA), lactic dehydrogenase (LDH), and reactive oxygen species (ROS) detection kits were used to analyze the oxides in NSCs. RESULTS: Following EDA pretreatment, NSCs presented with promising resistance to H2O2-induced oxidative stress, whereas NSCs manifested significant increases in activity and proliferation and a decrease in apoptosis. Meanwhile, for NSCs, EDA pretreatment reduced the levels of MDA, LDH, and ROS, with a significant upregulation of Nrf2/antioxidant response element (ARE) signaling pathway, whereas for EDA-treated TBI rats, a significant reduction was observed in the trauma area and injury to the hippocampus, with improvement in memory and learning performance and upregulation of Nrf2/ARE signaling pathway. CONCLUSIONS: EDA, by regulating the activity of Nrf2/ARE signal pathway, can improve the TBI-induced injury to NSCs and learning and memory dysfunction in rats.

Edaravone improves the post-traumatic brain injury dysfunction in learning and memory by modulating Nrf2/are signal pathway

OBJECTIVES: To investigate the molecular mechanism of edaravone (EDA) in improving the post-traumatic brain injury (TBI) dysfunction in learning and memory. METHODS: In vitro and in vivo TBI models were established using hydrogen peroxide (H2O2) treatment for hippocampal nerve stem cells (NSCs) and surgery for rats, followed by EDA treatment. WST 1 measurement, methylthiazol tetrazolium assay, and flow cytometry were performed to determine the activity, proliferation, and apoptosis of NSCs, and malondialdehyde (MDA), lactic dehydrogenase (LDH), and reactive oxygen species (ROS) detection kits were used to analyze the oxides in NSCs. RESULTS: Following EDA pretreatment, NSCs presented with promising resistance to H2O2-induced oxidative stress, whereas NSCs manifested significant increases in activity and proliferation and a decrease in apoptosis. Meanwhile, for NSCs, EDA pretreatment reduced the levels of MDA, LDH, and ROS, with a significant upregulation of Nrf2/antioxidant response element (ARE) signaling pathway, whereas for EDA-treated TBI rats, a significant reduction was observed in the trauma area and injury to the hippocampus, with improvement in memory and learning performance and upregulation of Nrf2/ARE signaling pathway. CONCLUSIONS: EDA, by regulating the activity of Nrf2/ARE signal pathway, can improve the TBI-induced injury to NSCs and learning and memory dysfunction in rats.

Relationship between Neutrophil-to-Lymphocyte Ratio and Systemic Lupus Erythematosus: A Meta-analysis.

Systemic lupus erythematosus (SLE) is a chronic systematic autoimmune disease. Current methods of diagnosing SLE or evaluating its activity are complex and expensive. Numerous studies have suggested that neutrophil-to-lymphocyte ratio (NLR) is closely correlated with the presence of SLE and its activity, suggesting that it may serve as a diagnostic and monitoring indicator for SLE. Therefore, we performed a meta-analysis to systematically assess the association between NLR and SLE. We performed a literature search until 12 April 2019 in the PubMed, Web of Science, and China National Knowledge Infrastructure databases. Cross-sectional studies comparing the NLR of SLE patients versus those of healthy controls, of active versus inactive SLE patients, and of SLE patients with versus without lupus nephritis were considered for inclusion. Mean intergroup NLR differences were estimated using standardized mean differences and their 95% confidence intervals. Study quality was assessed using the Agency for Healthcare Research and Quality instrument for cross-sectional studies. Fourteen studies with 1,781 SLE patients and 1,330 healthy controls were included in this meta-analysis. The pooled results showed that the NLR was significantly higher in SLE patients than in healthy controls, in active SLE patients than in inactive SLE patients, and in SLE patients with lupus nephritis than in those without lupus nephritis. NLR may be an indicator for monitoring disease activity and reflecting renal involvement in SLE patients. Nevertheless, more high-quality studies are warranted to further validate our findings.

Mothers' parenting knowledge and its sources in five societies: Specificity in and across Argentina, Belgium, Italy, South Korea, and the United States.

In a cross-society comparison, we assessed the state of mothers' knowledge of child rearing and child development. The study included 1,077 mothers from five countries on four continents: Argentina, Belgium, Italy, South Korea, and the United States. A criteria-referenced instrument, the Knowledge of Infant Development Inventory, was used to assess parenting knowledge after being adapted for cross-society comparison using item response theory and the alignment optimization approach for testing between-sample measurement invariance. Levels of mothers' parenting knowledge varied across the five societies and were associated with different sociodemographic factors and personal and non-personal supports.

Relationship between neutrophil-to-lymphocyte ratio and systemic lupus erythematosus: a meta-analysis

Systemic lupus erythematosus (SLE) is a chronic systematic autoimmune disease. Current methods of diagnosing SLE or evaluating its activity are complex and expensive. Numerous studies have suggested that neutrophil-to-lymphocyte ratio (NLR) is closely correlated with the presence of SLE and its activity, suggesting that it may serve as a diagnostic and monitoring indicator for SLE. Therefore, we performed a meta-analysis to systematically assess the association between NLR and SLE. We performed a literature search until 12 April 2019 in the PubMed, Web of Science, and China National Knowledge Infrastructure databases. Cross-sectional studies comparing the NLR of SLE patients versus those of healthy controls, of active versus inactive SLE patients, and of SLE patients with versus without lupus nephritis were considered for inclusion. Mean intergroup NLR differences were estimated using standardized mean differences and their 95% confidence intervals. Study quality was assessed using the Agency for Healthcare Research and Quality instrument for cross-sectional studies. Fourteen studies with 1,781 SLE patients and 1,330 healthy controls were included in this meta-analysis. The pooled results showed that the NLR was significantly higher in SLE patients than in healthy controls, in active SLE patients than in inactive SLE patients, and in SLE patients with lupus nephritis than in those without lupus nephritis. NLR may be an indicator for monitoring disease activity and reflecting renal involvement in SLE patients. Nevertheless, more high-quality studies are warranted to further validate our findings.

Intermittent vibrations accelerate fracture healing in sheep.

PURPOSE: To investigate the effect of intermittent vibration at different intervals on bone fracture healing and optimize the vibration interval. METHODS: Ninety sheep were randomized to receive no treatment (the control group), incision only (the sham control group), internal fixation with or without metatarsal fracture (the internal fixation group), and continuous vibration in addition to internal fixation of metatarsal fracture, or intermittent vibration at 1, 2, 3, 5, 7 and 17-day interval in addition to internal fixation of metatarsal fracture (the vibration group). Vibration was done at frequency F=35 Hz, acceleration a=0.25g, 15 min each time 2 weeks after bone fracture. Bone healing was evaluated by micro-CT scan, bone microstructure and mechanical compression of finite element simulation. RESULTS: Intermittent vibration at 7-day interval significantly improved bone fracture healing grade. However, no significant changes on microstructure parameters and mechanical properties were observed among sheep receiving vibration at different intervals. CONCLUSIONS: Clinical healing effects should be the top concern. Quantitative analyses of bone microstructure and of finite element mechanics on the process of fracture healing need to be further investigated.

Intermittent vibrations accelerate fracture healing in sheep

Purpose: To investigate the effect of intermittent vibration at different intervals on bone fracture healing and optimize the vibration interval. Methods: Ninety sheep were randomized to receive no treatment (the control group), incision only (the sham control group), internal fixation with or without metatarsal fracture (the internal fixation group), and continuous vibration in addition to internal fixation of metatarsal fracture, or intermittent vibration at 1, 2, 3, 5, 7 and 17-day interval in addition to internal fixation of metatarsal fracture (the vibration group). Vibration was done at frequency F=35 Hz, acceleration a=0.25g, 15 min each time 2 weeks after bone fracture. Bone healing was evaluated by micro-CT scan, bone microstructure and mechanical compression of finite element simulation. Results: Intermittent vibration at 7-day interval significantly improved bone fracture healing grade. However, no significant changes on microstructure parameters and mechanical properties were observed among sheep receiving vibration at different intervals. Conclusions: Clinical healing effects should be the top concern. Quantitative analyses of bone microstructure and of finite element mechanics on the process of fracture healing need to be further investigated.(AU)

Intermittent vibrations accelerate fracture healing in sheep

Abstract Purpose: To investigate the effect of intermittent vibration at different intervals on bone fracture healing and optimize the vibration interval. Methods: Ninety sheep were randomized to receive no treatment (the control group), incision only (the sham control group), internal fixation with or without metatarsal fracture (the internal fixation group), and continuous vibration in addition to internal fixation of metatarsal fracture, or intermittent vibration at 1, 2, 3, 5, 7 and 17-day interval in addition to internal fixation of metatarsal fracture (the vibration group). Vibration was done at frequency F=35 Hz, acceleration a=0.25g, 15 min each time 2 weeks after bone fracture. Bone healing was evaluated by micro-CT scan, bone microstructure and mechanical compression of finite element simulation. Results: Intermittent vibration at 7-day interval significantly improved bone fracture healing grade. However, no significant changes on microstructure parameters and mechanical properties were observed among sheep receiving vibration at different intervals. Conclusions: Clinical healing effects should be the top concern. Quantitative analyses of bone microstructure and of finite element mechanics on the process of fracture healing need to be further investigated.

Negative Predictive Value and Significance of Benign-Appearing Endometrial Cells in Papanicolaou Tests.

OBJECTIVES: Reporting benign-appearing endometrial cells (nEMCs) in Papanicolaou (Pap) smears of women 40 years and older, introduced in The Bethesda System 2001, may be interpreted as an abnormal finding and lead to unnecessary endometrial biopsies. To our knowledge, this is the first study on the negative predictive value (NPV) of this cytology finding. METHODS: An 11-year database with 1,036,629 Pap test reports and 121,079 surgical pathology reports identified reports of nEMCs in women 40 years and older with follow-up endometrial histopathology within 6 months. Endometrial carcinoma and atypical endometrial hyperplasia were chosen as relevant outcomes. NPVs were calculated. Bayesian modeling assessed the impact of age, bleeding, and postmenopausal status on risk. RESULTS: NPVs for patients aged 40 to 44 years and 45 to 49 years (99.5% and 99.3%, respectively) were not significantly different. NPVs for patients aged 50 to 54 years, 55 to 59 years, and 60 years and older (97.1%, 95.3%, and 94.5%, respectively) were lower than the NPV for patients aged 40 to 49 years. Bayesian modeling indicated that asymptomatic patients in all age groups 40 years and older have very low risk. Bleeding history increased risk in all age groups, especially in women 50 years and older. CONCLUSIONS: nEMCs in Pap test reports of women 40 years and older are a normal cytology finding in premenopausal women, which may result in unnecessary endometrial biopsies. The NPV associated with this finding for women aged 40 to 49 years exceeded 99%.

Immunohistochemical profile of breast cancer with respect to estrogen receptor and HER2 status.

There are a few studies that have evaluated a panel of stains on a single large data set of breast cancers, which is required for direct comparison between antibodies. The immunohistochemical panel in this study was chosen to include breast-specific markers and markers that are expressed in tumors resembling breast cancer. The individual marker positivity in decreasing order was 95% (177/186) for GATA-3, 92% (172/186) for cytokeratin (CK)7, 80% (151/189) for AR, 80% for estrogen receptor (158/198), 69% for progesterone receptor (137/198), 55% (105/190) for NY-BR-1, 52% (99/189) for mammaglobin, 31% (59/191) for vimentin, 26% (51/195) for GCDFP-15, 0.5% (1/186) for CK20, and 0% (0/188) for PAX-8. When tumors were categorized based on estrogen receptor and HER2 status; a total of 45 profiles were identified. In addition, some tumors showed an unconventional profile-although the majority of breast carcinomas were CK7-positive/CK20-negative, a CK7-negative/CK20-negative profile was seen in ∼8% of the cases. Such a profile can create confusion in investigation of a carcinoma of unknown origin. The results define the individual sensitivity of each marker and establish a baseline diagnostic profile of breast cancer in a large data set. In addition, the results support the use of immunohistochemical panel for confirming or determining breast as the source of metastasis.

Microsymbionts of Phaseolus vulgaris in acid and alkaline soils of Mexico.

In order to investigate bean-nodulating rhizobia in different types of soil, 41 nodule isolates from acid and alkaline soils in Mexico were characterized. Based upon the phylogenetic studies of 16S rRNA, atpD, glnII, recA, rpoB, gyrB, nifH and nodC genes, the isolates originating from acid soils were identified as the phaseoli symbiovar of the Rhizobium leguminosarum-like group and Rhizobium grahamii, whereas the isolates from alkaline soils were defined as Ensifer americanum sv. mediterranense and Rhizobium radiobacter. The isolates of "R. leguminosarum" and E. americanum harbored nodC and nifH genes, but the symbiotic genes were not detected in the four isolates of the other two species. It was the first time that "R. leguminosarum" and E. americanum have been reported as bean-nodulating bacteria in Mexico. The high similarity of symbiotic genes in the Rhizobium and Ensifer populations showed that these genes had the same origin and have diversified recently in different rhizobial species. Phenotypic characterization revealed that the "R. leguminosarum" population was more adapted to the acid and low salinity conditions, while the E. americanum population preferred alkaline conditions. The findings of this study have improved the knowledge of the diversity, geographic distribution and evolution of bean-nodulating rhizobia in Mexico.

Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates.

To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH) clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs) of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX), intermediate resistant to Levofloxacin (LVX) and Sparfloxacin (SFX), and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

BACKGROUND: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. CONCLUSION: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients.

AIM: This study was designed to explore the genetic polymorphism of IL-10 (-1082A/G, -592A/C, -819T/C), TNF-α (-308G/A) with susceptibility to docetaxel-induced liver injury (DILI) in Chinese breast cancer patients. METHODS: The targeted genetic polymorphisms of IL10-1082G/A, IL10-592A/C, IL10-819T/C, TNF-308G/A from 40 patients with DILI were assayed by matrix-assisted laser desorption/ionization-time of flight of Sequenom. RESULTS: AA genotype of IL10-592 and TT of IL10-819 significantly increased incidence of DILI (P = 0.005, OR = 3.137). No differences of TNF gene polymorphism between the two groups were seen. CONCLUSION: The genetic polymorphism of the IL10-592A/C AA genotype and IL10-819T/C TT genotype was predominantly conferred to the incidence of docetaxel-induced liver injury.

Recombinant human endostatin could eliminate the pro-angiogenesis priority of SP cells sorted from non-small cell lung cancer cells.

PURPOSE: To ascertain the biologic significance of lung cancer Side population (SP) cells, which represent putative cancer stem cells (CSC) in the absence of consensus biomarkers for tumor-specific CSC. MATERIALS AND METHODS: We sorted and analyzed the angiogenic features of SP cells, isolated from tumor cell lines based on the exclusion of the DNA dye Hoechst 33342, from the NSCLC cell lines A549 and H460. RESULTS: Compared with non-SP cells, mRNA of vascular endothelial growth factor (VEGF)-A, VEGF-B, angiopoietin (ang)-1, ang-2, fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8) were over-expressed in SP cells accompanied by over-expression of ABCG2 and MDR1 mRNA. The supernatant of cultured SP cells could significantly induce migration of human umbilical vein endothelial cells, while recombinant human endostatin (Endostar 25(®)) could inhibit the migration. CONCLUSIONS: This study revealed that the NSCLC SP cells might represent CSCs and possess pro-angiogenic properties, and antiangiogenesis represent a potential therapy.

Clinical safety of induced CTL infusion through recombinant adeno-associated virus-transfected dendritic cell vaccination in Chinese cancer patients.

AIM: The aim of the study is to explore the safety of cytotoxic T lymphocytes (CTLs) infusion by transfected dendritic cells (DCs) with recombinant adeno-associated virus vector (rAAV) carrying CEA cDNA among advanced cancer patients. PATIENTS AND METHODS: A total of 27 cancer patients with tumor tissue expression positivity and/or sera-elevated level of CEA were subsequently divided into cohort A and B resulted from the ex vivo expansion number of CTLs generated from co-culture of specific transfected DCs with autologous T lymphocytes. Based on the variations of infused number of specific CTL derived from different yields of individualized patients who had experienced various anti-cancer treatments, we compared the patients of low number of CTL cells (2-8 × 10(8) infused, cohort A, 6 cases) with those of higher number (above 8 × 10(8) infused, cohort B, 21 cases) to testify the possible adverse reactions caused by amount of infused CTLs. This study resembled a phase I study aiming for setting up clinical trial of adoptive cellular therapy that conceptually comes from conventional cytotoxic drugs. RESULTS: The results showed that one case from the each cohort had experienced moderate fever, and four cases with fatigue were seen in cohort B. The symptoms were transient without serious adverse events. For the consideration of clinical response 2 partial remission (8.0 %, 2/25), 1 minor remission, and 9 stable disease (40 %, 10/25) were observed in 25 patients eligible for evaluation. Sera levels of CEA assay were lowered in six patients. During a median follow-up of 8.1 months, we could not observe severe or chronic adverse reactions related to rAAV-DC infusions. Meanwhile, the variation of number of CTLs infused in this setting did not alter the status of peripheral lymphocyte population. CONCLUSIONS: These preliminary data suggest that the rAAV-DC immunotherapy is well-tolerated and showed no severe adverse reactions in cancer patients.

Murine bone marrow stromal cells pulsed with homologous tumor-derived exosomes inhibit proliferation of liver cancer cells.

BACKGROUND: Increasing evidence shows that bone marrow stromal cells (BMSCs) have antitumor activities both in vitro and in animal models. Further studies fleshed out the supportive data that the antitumor activity of BMSCs could be markedly enhanced by cytokines such as IL-2 and IFN-ß (interferon). However, powerful strategies to activate BMSCs other than by genetically engineering interventions are still required. METHODS: In this study, new methods of generating antitumor activities of murine marrow-originated MSCs pulsed with homologous tumor-derived exosomes (TEX) were explored to yield potent immune effectors against hepatocellular carcinoma cells in vitro. RESULTS: The results showed that BMSCs pulsed with exosomes and IFN-γ exhibited increased migration ability with a result of 163.22 ± 26.90 versus 129.89 ± 29.28 cells/HP by transwell determination (p < 0.05). The inhibition of homologous hepatocellular carcinoma cells line H(22) cells by exosomes pulsed BMSCs was significantly increased by 41.9 % compared with control (p < 0.05), and flow cytometry analysis showed that the cell cycle of H(22) cells was arrested in G(0)/G(1) phase. Meanwhile, western blot analysis showed that PCNA protein expression in the supernatant of H(22) cells was significantly decreased. CONCLUSIONS: This study demonstrated that BMSCs pulsed with TEX could enhance its antitumor activities, which might be regarded as a novel promising antitumor treatment.