In this study, the rescue effect of receptor activator for nuclear factor-kappaB ligand (RANKL) on zoledronate acid (ZOL) induced inhibition of osteoclastogenesis and gene expression of NF-kappaB p50 and c-Jun was investigated. Mice calvarial osteoblasts (OBs) were harvested and co-cultured with RAW264.7 cells and the cells were divided into 4 groups and received treatment with ZOL and RANKL, either single or combined. The formation of multi-nucleated osteoclast (OC) was examined and gene expression of NF-kappaB p50 and c-Jun was detected. Group B (ZOL) showed least multi-nucleated OC and resorption lacunae among the 4 groups (P < 0.05 or P < 0.01) and it was followed by group C (ZOL+RANKL). Group D (RANKL) showed highest OC and resorption lacunae while it was similar to Group A (control) (P > 0.05). Gene expression of NF-kappaB p50 and c-Jun was the lowest in group B (P < 0.05 or P < 0.01) among the four groups and was significantly increased in group C when compared with group B (P < 0.05). Group A and D showed highest gene expression and they were similar to each other (P > 0.05). This study suggest that RANKL might partly rescue ZOL induced inhibition of osteoclastogenesis, and the effect of RANKL and ZOL on osteoclastogenesis may be mediated by NF-kappaB p50 and c-Jun.
Animals ; Bone Resorption ; drug therapy ; Cell Line ; Diphosphonates ; pharmacology ; Gene Expression ; Imidazoles ; pharmacology ; Mice ; NF-kappa B p50 Subunit ; metabolism ; Osteoblasts ; drug effects ; Osteoclasts ; drug effects ; Proto-Oncogene Proteins c-jun ; metabolism ; RANK Ligand ; pharmacology

Total 967 patients with diabetes mellitus treated in Morindawa People's Hospital from June 2012 to June 2014 were included in the study,among them 425 (44.0％) were of Daur nationality and 542 (56.0％) were of Han nationality.The clinical data and laboratory tests were analyzed and compared between two groups.Compared with Han nationality,Daur patients presented a younger average age[(55 ± 1 1) y vs.(58 ± 1 0) y,P=0.000],an earlier age of onset[(50±10)y vs.(53 ± 1 1) y,P=0.000],a higher percentage of males (54.8％ vs.46.9％,P =0.008),a higher percentage of rural residents (42.1％ vs.36.2％,P =0.034),a lower level of fasting blood-glucose (FBG) [(9.25 ± 3.37) mmol/L vs.(10.28 ±4.33) mmol/L,P =0.000],higher levels of HbA1c [(7.61 ± 1.71)％ vs.(7.29 ± 1.63)％,P=0.008],triglyceride (TG) [(2.91 ±2.06) mmol/L vs.(2.36 ±2.13) mmol/L,P =0.008],low density lipoprotein cholesterol (LDL-C) [(3.22 ± 1.06) mmol/L vs.(3.01 ±0.92)mmol/L,P=0.020],systolic blood pressure (SBP) [(139.48 ± 21.58) mmHg (1 mmHg =0.133 kPa) vs.(136.37 ± 23.44) mmHg,P =0.002],diastolic blood pressure (DBP) [(87.23 ± 12.59) mmHg vs.(85.32 ± 12.52) mmHg,P =0.019],blood uric acid [(324.97 ± 106.45) μmol/L vs.(285.32 ± 98.69) μmol/L,P =0.000] and the ratio of urine microalbumin to urine creatinine [(2.29 ±5.57) mg/g vs.(0.12 ±0.98) mg/g,P =0.000].The results show that Daur diabetic patients are.younger in age,with more severe disorders in HbA1 c,blood pressure,blood uric acid and lipids levels,which increase the probability of renal damage or cardiovascular diseases in these patients.

Purpose　To investigate the significance of tumor suppressor gene p15 and p16 expression in soft tissue leiomyosarcoma(LMS) and leiomyoma(LM). Methods　Expressions of p15 and p16 was studied in 38 cases of LMS and 20 LM with immunohistochemical method. Results　The abnormal expression rates of p15 and p16 in LMS were 18.4% and 42.1% respectively, and were significantly different. p15 abnormal expression rate in LM was 60%, significantly higher than in LMS. The total abnormal expression rate of p15 and p16 was 52.6% in LMS studied. Grade Ⅰ tumor had the significantly higher abnormal expression rate than that of grade Ⅱ or Ⅲ tumor. Fifteen cases of LMS were followed. The abnormal expression rate of p15 and p16 in recurrent group was 75%, significantly higher than that in non recurrent group. Conclusions　Loss of expression of p16 protein is more frequent in LMS than that of p15, whereas deletion of p15 protein is more frequent in LM than in LMS. Loss of functions of p15 together with p16 participates in the tumorigenesis and progression of LMS, and is correlated with pathologic grading and prognosis of LMS.

OBJECTIVETo study the pattern of CGG repeat instability within germline cells derived from two male fetuses affected with Fragile X syndrome (FXS).

METHODSThe length and methylation status of CGG repeats within the testes of a fetus carrying a full FXS mutation and another fetus carrying mosaicism FXS mutation were analyzed with Southern blotting and AmplideX FMR1 PCR. Immunohistochemistry was also applied for the measurement of FMR1 protein (FMRP) expression within the testes.

RESULTSFor the fetus carrying the full mutation, Southern blotting analysis of the PCR product has detected an expected band representing the full mutation in its brain and a premutation band of > 160 CGG repeats in its testis. Whereas the pattern of premutation/full mutation in mosaic testis was similar to that in peripheral blood and no sign of contracted fragment was found other than a band of about 160 CGG repeats. Immunohistochemistry assay with a FMRP-specific antibody demonstrated a number of FMRP-positive germ cells, which suggested a contraction from full mutation to premutation alleles.

CONCLUSIONThis study has clarified the instability pattern of CGG repeat and expression of FMRP protein within the testes of fetuses affected with FXS, confirming that the CGG repeat can contract progressively within the germline. The FMRP expression in the testis is consistent with spermatogonium proliferation, and thus the contraction from full mutation to unmethylated premutations may occur for the requirement of FMRP expression during spermatogenesis. The better understanding of FMRP function during germ cell proliferation may elucidate the mechanism underlying the contraction of full FXS mutation in male germline.

Abortion, Eugenic ; Blotting, Southern ; Brain ; embryology ; metabolism ; DNA Methylation ; Fatal Outcome ; Fetus ; cytology ; metabolism ; Fragile X Mental Retardation Protein ; genetics ; metabolism ; Fragile X Syndrome ; diagnosis ; genetics ; Humans ; Immunohistochemistry ; Male ; Mosaicism ; Mutation ; Polymerase Chain Reaction ; Spermatozoa ; metabolism ; Testis ; cytology ; embryology ; metabolism ; Trinucleotide Repeat Expansion ; genetics

Objective:To explore the efficacy and safety of in-class transition from proteasome inhibitor bortezomib to ixazomib in the treatment of newly-treated patients with multiple myeloma (MM).Methods:The clinical data of 63 newly-treated MM patients in Shenzhen Second People's Hospital from January 2018 to December 2020 were retrospectively analyzed. They were divided into transition group (23 cases) and bortezomib group (40 cases). Both groups were treated with bortezomib-containing regimen as the first-line treatment regimen. In case of intolerable adverse reactions, patients in the transition group were treated with ixazomib instead of bortezomib, while the patients in the bortezomib group did not undergo drug transition. The curative effect and progression-free survival (PFS) were compared between the two groups.Results:In the transition group, the overall response rate (ORR) before in-class transition was 95.7% (22/23), the rate of ≥ very good partial remission (VGPR) was 52.2% (12/23); the ORR after transition was 95.7% (22/23), and the rate of ≥ VGPR was 82.6% (19/23). In the bortezomib group, ORR was 90.0% (36/40), and the rate of ≥ VGPR was 72.5% (29/40). There was no significant difference in ORR and the rate of ≥VGPR between the two groups ( χ2 = 0.64, P=0.424; χ2 = 0.82, P = 0.364). The median number of cycles of PI therapy in the transition group was 9, and the median PFS time was not reached. The median number of cycles of PI therapy in the bortezomib group was 7.5, and the median PFS time was 30.0 months (95% CI 19.1-40.9 months), there was no significant difference in PFS between the two groups ( P = 0.275). In the bortezomib group, 12 patients discontinued bortezomib due to adverse reactions, the median PFS time was 20.0 months (95% CI 12.6-27.4 months), and the PFS of patients who discontinued PI in the transition group and the bortezomib group was compared, the difference was statistically significant ( P = 0.043). In the transition group, 21 patients (21/23, 91.3%) developed peripheral neuropathy, and the incidence of ≥grade 3 adverse reactions was 13.0% (3/23); in the bortezomib group, 22 patients (22/40, 55.0%) developed peripheral neuropathy, and the incidence of ≥grade 3 adverse reactions was 12.5% (5/40). Conclusions:For newly-treated MM patients, the transition from bortezomib to ixazomib can improve the depth of remission and reduce the recurrence caused by the discontinuation of PI.

Advanced glycation end-products (AGEs) are stable and toxic by-products of non-enzymatic metabolic reaction of proteins,lipids and nucleotides.The elevated serum AGEs level in pregnant women is strongly associated with hyperglycemia,oxidative stress and insulin resistance and may be one of the cause for the onset and development of the gestational diabetes mellitus(GDM).This review mainly focuses on the pathogenesis of AGEs and GDM.

Humans ; Transcranial Magnetic Stimulation ; Pain Management ; Psychotic Disorders/therapy* ; Depressive Disorder, Major ; Treatment Outcome ; Transcranial Direct Current Stimulation

Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS