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

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.

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.

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.

Objective:To investigate the prognostic value of 18F-fluorodeoxygen-D-glucose-positron emission tomography /computerized tomography ( 18F-FDG-PET-CT) in Hodgkin′s lymphoma (HL) at the end of first-line treatment (PET-end), by comparing the ratio of maximum standardized uptake value (SUV max) of lesion and liver SUV (rLL), SUV max reduction between baseline PET (PET-0) and PET-end (ΔSUV max), and Deauville 5-point scale (5-PS). Methods:Patients with HL newly treated in our hospital from August 2006 to December 2015 were retrospectively analyzed. All the patients enrolled in the study underwent post-treatment FDG PET-CT. The rLL and ΔSUV max were calculated, and all the cases were scored using Deauville 5-PS. The receiver operating characteristic (ROC) approach was applied to identify the optimal cut-point value, and survival curves according to different PET-CT assessment methods were estimated using the Kaplan-Meier analysis. The prognostic efficacy of different PET-CT assessment methods was compared, and DeLong test was used to verify it. Kaplan-Meier method and multivariate analysis using the Cox proportional hazards model were performed to analyze the potential independent risk factors. Results:There were 5 patients progressed within a 3-year follow-up. In the three PET-CT assessment methods, the predictive value of rLL and Deauville 5-PS were significant effective. ROC analysis for rLL as a progression predictor showed an optimal cut-point of 1.29. Deauville 5-PS=4 and rLL=1.29 showed the best prognostic accuracy. The sensitivity of rLL and Deauville 5-PS were both 80.0%, and the specificity of each was 98.0% and 93.7%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of rLL were 66.7% and 98.7%, while the PPV and NPV of 5-PS were 44.4% and 98.7%. The 3-years progression-free survival (PFS) rates of rLL≥1.29 group and rLL<1.29 group were 33.3% and 98.7%, with significant difference ( P<0.001). The 3-years PFS rates of post-treatment Deauville 5-PS<4 group and Deauville 5-PS≥4 group were 98.7% and 55.6%, with significant difference ( P<0.001). The prognostic evaluation efficacy of rLL was positively correlated with that of Deauville 5-PS ( r=0.75, P<0.05). Area under curves (AUC) of rLL and Deauville 5-PS were 0.93 (95% CI: 0.825-1.000) and 0.91 (95% CI: 0.757-1.000), respectively. DeLong test showed the significant difference between the two methods ( P<0.05). The univariate analysis results showed that clinical baseline stage, post-treatment rLL and Deauville 5-PS were associated with the prognoses of HL patients ( P<0.05). The multivariate analysis results showed that post-treatment rLL and Deauville 5-PS were independent prognostic factors of HL ( P<0.05). Conclusions:The rLL and Deauville 5-PS are potential prognostic factors for HL response assessment. The new semi-quantitative method rLL has methodological advantages over visual analysis, and it is a good supplement for Deauville 5-PS. rLL can improve prognostic evaluation accuracy of PET-CT and is useful to early identify patients with HL at a high risk of relapsing after first-line treatment.

Objective:To explore the efficacy and safety of Rivaroxaban in preventing catheter related thrombosis (CRT) in patients with breast cancer who are undergoing central venous catheter chemotherapy, and provide basis for making standardized prevention and treatment strategies.Methods:In this research, a prospective cohort study was adopted, and breast cancer patients who received central venous catheter chemotherapy in Sanhuan Cancer Hospital during September 2020 to March 2022 were selected as a treatment group to take the rivaroxaban anticoagulation therapy with 10 mg.po.qd for one month. The control group got no preventive anticoagulation therapy. Vascular ultrasound examination was taken to confirm the occurrence of CRT, and a chi-square test was done for comparison the disparity between the groups. Logistic regression was applied to analyze the univariate and multivariate factors for the formation of CRT.Results:In the research, a total of 235 patients were selected, and there were a total of 19 035 days of catheterization with 81 days of catheterization on average. While in the control group, the incidence of CRT was 28.0% (33/118), the incidence of CRT in the treatment group was 20.5% (24/117), the difference was no significant ( P=0.183). Subgroup analysis results showed that the peripherally inserted central catheter (PICC) was performed in 165 cases with the CRT incidence of 18.2% (30/165) and thrombosis was mostly seen around axillary vein, accounting for 63.3%. Subclavian vein catheterization was performed in 63 cases with the CRT incidence of 39.7% (25/63), and thrombosis was mostly seen around subclavian vein, accounting for 88.0% (22/25). Implantable venous access port was implanted in 7 cases around subclavian vein and internal jugular vein with the CRT incidence of 28.6% (2/7). The patients who developed CRT within 30 days after catheterization accounted for 54.4% (31/57), 22.8% (13/57) in a period during 30 days and 60 days) and 22.8% (13/57) in a period during 60 days and 180 days). The diagnosed CRT patients had been treated with rivaroxaban 15 mg.bid.po for 3 months. During the 3 months, 100.0% of the thrombosis waned, 71.9% (41/57) of the thrombosis waned within 30 days, 19.3% (11/57) in a period during 30 and 60days and 8.8% (5/57) in a period during 60 days and 90 days. Univariate and multivariate analysis indicated that the risk of CRT in subclavian vein catheterization was higher than that in PICC, respectively ( OR=2.898, 95% CI:1.386-6.056 P=0.005), and the type of catheterization was an independent factor for the formation of thrombosis. Safety analysis result showed that in the prevention of CRT, rivaroxaban treatment did not induce drug-related bleeding, liver function damage, bone marrow suppression or any other side effects. While CRT diagnosed patients were treated with anticoagulation, they kept the central venous catheter, and the infusion was smooth. These patients all finished the anti-tumor treatment as planned, and no abnormalities like new thrombosis or pulmonary embolism were observed. Conclusions:In the mid-term analysis, the proportion of Rivaroxaban in preventing anticoagulant CRT decreases, but it don't reach statistical significance. The sample size should be further increased for observation. Rivaroxaban is proved effective and very safe in the treatment of CRT, and does not affect the concurrent chemotherapy. Medical personnel should carry out the policy of "early prevention, early detection and early treatment" for CRT so as to improve the patients' quality of life.

Abstract Pancreatic cancer is a highly malignant gastrointestinal cancer with a poor prognosis, and early diagnosis remains challenging. The use of reliable biomarkers can significantly enhance the early evaluation and management of this disease. Circulating tumor cells(CTCs) are released into the bloodstream and can be obtained easily through minimally invasive liquid-based biopsy, making them promising candidates for early tumor diagnosis, prognosis assessment, and monitoring therapeutic responses. This paper reviews the advancements in CTCs detection technology and their clinical applications in pancreatic cancer over the past decade, both domestically and internationally, which offer a new perspective on the early diagnosis and prognosis of pancreatic cancer.

Background::Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.Methods::We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (each from three CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. Results::Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. Conclusions::Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.