lncTIMP3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells via miR-214/Smad4 axis to relieve postmenopausal osteoporosis.

BACKGROUND: Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. METHODS: The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. RESULTS: The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. CONCLUSION: lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.

CircMYO1C silencing alleviates chondrocytes inflammation and apoptosis through m6A/HMGB1 axis in osteoarthritis.

Circular RNAs (circRNAs) are involved in osteoarthritis (OA) progression. This study aimed to investigate the role and molecular mechanisms of circMYO1C in OA. CircMYO1C was upregulated in OA- and interleukin-1ß (IL-1ß)-exposed chondrocytes. The results indicated that circMYO1C knockdown repressed the inflammatory factors (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], interleukin-8 [IL-8], etc.) and apoptosis of chondrocytes following IL-1ß exposure. CircMYO1C was an N6-methyladenosine (m6A)-modified circRNA with m6A characteristics. High mobility group box 1 (HMGB1) was a target of circMYO1C. IL-1ß exposure increased the stability and half-life (t1/2) of HMGB1 mRNA, while silencing circMYO1C reduced HMGB1 mRNA stability. Taken together, circMYO1C targets the m6A/HMGB1 axis to promote chondrocyte apoptosis and inflammation. The present study demonstrates that the circMYO1C/m6A/HMGB1 axis is essential for OA progression, highlighting a novel potential therapeutic target for clinical OA.

Immunologic derangement caused by intestinal dysbiosis and stress is the intrinsic basis of reactive arthritis.

Reactive arthritis (ReA) is defined as arthritis resulting from infections in other body parts, such as the gastrointestinal and urogenital tracts. The primary clinical manifestations involve acute-onset and self-limiting asymmetric large joint inflammation in the lower limbs. Although bacterial or chlamydia infections have long been recognized as playing a pivotal role in its pathogenesis, recent studies suggest that antibiotic treatment may perpetuate rather than eradicate chlamydia within the host, indicating an involvement of other mechanisms in Reactive arthritis. Reactive arthritis is currently believed to be associated with infection, genetic marker (HLA-B27), and immunologic derangement. As an autoimmune disease, increasing attention has been given to understanding the role of the immune system in Reactive arthritis. This review focuses on elucidating how the immune system mediates reactive arthritis and explores the roles of intestinal dysbiosis-induced immune disorders and stress-related factors in autoimmune diseases, providing novel insights into understanding reactive arthritis.

miR-15b-5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer.

MicroRNAs (miRNAs) have been reported to participate in many biological behaviours of multiple malignancies. Recent studies have shown that miR-15b-5p (miR-15b) exhibits dual roles by accelerating or blocking tumour progression. However, the molecular mechanisms by which miR-15b contributes to prostate cancer (PCa) are still elusive. Here, miR-15b expression was found significantly up-regulated in PCa in comparison with the normal samples and was positively correlated with age and Gleason score in patients with PCa. Notably, PCa patients with miR-15b high expression displayed a higher recurrence rate than those with miR-15b low expression (P = 0.0058). Knockdown of miR-15b suppressed cell growth and invasiveness in 22RV1 and PC3 cells, while overexpression of miR-15b reversed these effects. Then, we validated that RECK acted as a direct target of miR-15b by dual-luciferase assay and revealed the negative correlation of RECK with miR-15b expression in PCa tissues. Ectopic expression of RECK reduced cell proliferation and invasive potential and partially abrogated the tumour-promoting effects caused by miR-15b overexpression. Additionally, miR-15b knockdown inhibited tumour growth activity in a mouse PCa xenograft model. Taken together, our findings indicate that miR-15b promotes the progression of PCa cells by targeting RECK and represents a potential marker for patients with PCa.

Calycosin, a Phytoestrogen Isoflavone, Induces Apoptosis of Estrogen Receptor-Positive MG-63 Osteosarcoma Cells via the Phosphatidylinositol 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway.

BACKGROUND Osteosarcoma is the most common primary bone malignancy and often presents at an early age. Calycosin is a phytoestrogen isoflavone, which has previously been reported to inhibit tumor cell growth. The aim of this study was to investigate the effects of calycosin on apoptosis of estrogen receptor (ER)-positive and ER-negative human osteosarcoma cell lines and tumor xenografts in mice. MATERIAL AND METHODS Cultured ER-positive MG-63 human osteosarcoma cells and ER-negative U2-OS human osteosarcoma cells were treated with increasing doses of calycosin (0, 25, 50, and 100 µm). Cell viability and apoptosis were studied by an MTT assay and flow cytometry. Western blot measured the expression levels of the apoptosis-related protein p-PI3K, p-Akt, and p-mTOR in MG-63 cells, with and without pretreatment with the PI3K inhibitor, LY294002, the AKT inhibitor, MK-2206, or the mTOR inhibitor, rapamycin. MG-63 tumor-bearing nude mice were used to evaluate the effects of treatment with calycosin. RESULTS Calycosin treatment inhibited proliferation and induced apoptosis in MG-63 cells, but had no effect on U2-0S cells. In MG-63 cells, calycosin treatment increased the expression of the PI3K/AKT/mTOR pathway proteins; inhibitor assays showed that expression of the PI3K protein was most strongly associated with the antitumor effects of calycosin. In the nude mouse MG-63 tumor xenografts, calycosin inhibited tumor growth and regulated the expression levels of apoptosis-related PI3K/AKT/mTOR pathway proteins. CONCLUSIONS The phytoestrogen, calycosin, induced apoptosis of cells of the ER-positive osteosarcoma cell line, MG-63, via the PI3K/AKT/mTOR pathway, with these effects being mainly due to PI3K.

Triptorelin relieves lower urinary tract symptoms in Chinese advanced prostate cancer patients: a multicenter, non-interventional, prospective study.

BACKGROUND: Although triptorelin is increasingly used in China for biochemical castration, its effects on primary prostate cancer symptoms remain unclear. This study aimed to assess the prevalence of lower urinary tract symptoms (LUTS) in Chinese prostate cancer patients and the effectiveness of triptorelin on LUTS. METHODS: In this 48-week multicenter, non-interventional, prospective study, we enrolled patients with locally advanced or metastatic prostate cancer. Patients received triptorelin (15 mg) intramuscularly at baseline and at weeks 12, 24, and 36 with symptom assessment using the International Prostate Symptoms Score (IPSS). The primary endpoints were the prevalence of LUTS at baseline per IPSS categories and the percentage of patients with moderate to severe LUTS (IPSS > 7) at baseline, having at least a 3-point reduction of IPSS score at week 48. RESULTS: A total of 398 patients were included; 211 (53.0%) and 160 (40.2%) among them had severe and moderate LUTS, respectively. Of the patients with IPSS scores available at baseline and at week 48 (n = 213), 81.2% achieved a reduction in IPSS of at least 3 points. Of the patients with moderate to severe LUTS at baseline and IPSS scores available at baseline and at week 48 (n = 194), 86.6% achieved a total IPSS reduction of at least 3 points. CONCLUSIONS: The vast majority of Chinese patients with locally advanced or metastatic prostate cancer scheduled to receive triptorelin as part of their standard treatment have severe or moderate LUTS. Triptorelin therapy resulted in sustained improvement of LUTS in these patients.

MicroRNA-146b acts as a potential tumor suppressor in human prostate cancer.

PURPOSE: MicroRNAs (miRs) act as either tumor suppressors or oncogenes and are frequently deregulated in cancers. Although downregulation of miR-146b has been reported in various cancers, its role in prostate cancer is totally unknown. METHODS: The miR-146b expression in 18 human prostate cancer lines with case-matched adjacent normal tissues was measured by quantitative RT-PCR. Furthermore, the expression levels of miR-146b in normal prostate and prostate cancer cell lines were assessed. Cell proliferation, apoptosis, migration and invasion assays were performed in overexpressing or knockdown miR-146b cells. RESULTS: miR-146b expression was significantly reduced in all prostate tumor tissues. Furthermore, miR-146b was significantly decreased in prostate cancer cells as compared to normal prostate cells. Loss-of-function and gain-of-function showed that miR-146b induced apoptosis and suppressed cell proliferation, migration and invasion of the prostate cancer cell lines. CONCLUSION: Our results demonstrated that miR-146b expression is downregulated in prostate tumor tissues and is a potential tumor suppressor miR, suggesting that miR-146b might be a potential clinical marker and therapeutic target for prevention and treatment of prostate cancer.

[Effects of administration and local application of epimedium on the fracture healing in osteoporosis rats].

OBJECTIVE: To study the effects of administration or local application of epimedium on the fracture healing in osteoporosis rats. METHODS: Eighty-two 4-month old clean female rats, 210-250 g, were randomly divided into the experimental group (n = 75) and the control group (n = 7). The bilateral ovaries were resected in the experimental group, while only little fat tissue around the ovary was resected in the control group. Ten weeks after operation the osteoporosis model was successfully established verified by bone densitometry and scanning electron microscopy (SEM). The femur fracture models were established in the rest 72 rats of the experimental group. They were randomly divided into 3 groups, 24 in each group, i.e., the calcium phosphate cement (CPC) group (Group A), the CPC-epimedium group (Group B), and the epimedium administration group (Group C). The serum alkaline phosphatase (ALP) levels of the 3 groups were determined 2, 4, 8, and 12 weeks after surgery. The vitodynamical test and observation of the histological section were performed. RESULTS: The serum ALP levels increased to some extent in the 3 groups 2, 4, and 8 weeks after bone fracture surgery. But the increase was more obvious in Group B with statistical difference shown when compared with Group A and C (P < 0.05). The ALP level in Group B decreased to the normal range till the 12th week. The bone fracture had not completely healed in Group C and A. Their ALP levels decreased to some extent, but were still maintained to a comparatively higher level, showing statistical difference when compared with that of Group B (P < 0.05). These results were agreeable with the results of the histological observation. Better bone activity promoting results were shown in Group B. The vitodynamical test results of the femur of Group B were all higher than those of Group A and C at each time point (P < 0.05). CONCLUSIONS: Local application of epimedium could accelerate the fracture healing in osteoporosis rats. It showed better effects when compared with oral administration at the same dose.

Human umbilical cord Wharton's jelly-derived mesenchymal stem cell transplantation could improve diabetic intracavernosal pressure.

Mesenchymal stem cells (MSCs) secrete various cytokines with angiogenic and neuroprotective effects. This study aimed to assess the effects of human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on diabetes-related intracavernosal pressure (ICP) impairment in rats. hWJ-MSCs were isolated from human umbilical cord Wharton's jelly and transplanted into the corpus cavernosum of streptozotocin (STZ)-induced diabetic rats by unilateral injection. The erectile function was evaluated at 4 weeks, as well as the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS), and insulin-like growth factor 1 (IGF1). STZ-induced diabetic rats showed impaired ICP, which was significantly improved by hWJ-MSC treatment. VEGF, eNOS, IGF1, and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats. These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors, highlighting a novel potential therapeutic option for erectile dysfunction.

Comparison of the short-term effects of lumbar endoscopic and microscopic tubular unilateral laminotomy with bilateral decompression in the treatment of elderly patients with lumbar spinal stenosis.

OBJECTIVE: To compare the clinical efficacy of lumbar endoscopic Delta large channel and microscopic tubular Quadrant channel unilateral laminotomy with bilateral decompression in the treatment of elderly patients with lumbar spinal stenosis. METHODS: A total of 40 patients aged above 75 years with lumbar spinal stenosis admitted from June 2019 to August 2021 were reviewed, in which the observation group was treated with the Delta large channel technique and the control group was treated with Quadrant channel open decompression. The general data, duration of illness, operation time, intraoperative bleeding, VAS score preoperatively, 3 days postoperatively, 3 months postoperatively and 6 months postoperatively, and ODI index of the two groups were recorded in the two groups. RESULTS: The observation group had significantly shorter operation time (59.93 ± 10.46 min vs 77.66 ± 12.44 min, P < 0.001) and less intraoperative bleeding (21.06 ± 4.59 mL vs 51.00 ± 10.02 mL, P < 0.001) than the control group. There were no significant differences between the two groups in the duration of illness (11.85 ± 5.08 years vs 13.80 ± 7.40 years, P = 0.337), VAS score preoperatively (6.05 ± 1.19 vs 6.40 ± 1.47, P = 0.412), 3 days postoperatively (1.90 ± 0.85 vs 2.00 ± 1.08, P = 0.746), 3 months postoperatively (1.10 ± 0.31 vs 1.20 ± 0.41, P = 0.389) and 6 months postoperatively (1.25 ± 0.44 vs 1.30 ± 0.57, P = 0.759), and ODI index preoperatively (0.78 ± 0.07 vs 0.74 ± 0.07, P = 0.09), 3 months postoperatively (0.28 ± 0.06 vs 0.30 ± 0.05, P = 0.189) and 6 months postoperatively (0.21 ± 0.07 vs 0.22 ± 0.04, P = 0.444) (P > 0.05). The ODI index 3 days postoperatively in the observation group was significantly lower than that in the control group (0.33 ± 0.06 vs 0.37 ± 0.05, P = 0.022). CONCLUSION: Both surgical methods had good clinical outcomes for the treatment of lumbar spinal stenosis. However, Delta large channel endoscopy had a clearer vision, less trauma and lower incidence of early postoperative back pain than that of Quadrant channel open decompression.

Icariin Exerts Estrogen-Like Actions on Proliferation of Osteoblasts in Vitro via Membrane Estrogen Receptors-Mediated Non-nuclear Effects.

Background: According to reports, icariin (ICA) is a bone anabolic agent able to prevent osteoporosis in both ovariectomized rats and postmenopausal women. However, its effect on osteoblast proliferation remains to be determined, and the underlying mechanism remains to be elucidated. Methods: Icariin-bovine serum albumin (BSA) conjugates were purified by Sephadex G-25 gel chromatography technology. Primary osteoblasts from neonatal rats were used to evaluate the effects of ICA, ICA-BSA, ICA-BSA + ICI182780, and ICA-BSA + PD98059. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and propidium iodide (PI)-staining assays were used to detect the proliferation of osteoblasts after drug exposure. The intracellular calcium ions were detected using a confocal microscope with Fluo-3/AM as the fluorescent indicator. Western blot was capitalized on to measure the relative content of phospho-extracellular signal-regulated kinase (p-ERK). Results: Primary osteoblasts in culture were detected by histochemical staining of alkaline phosphatase, and calcified nodules were obtained by sequential digestion. Icariin and bovine serum albumin could form conjugate, which could be purified by Sephadex G-25 gel chromatography technology. MTT and flow cytometry results show that ICA-BSA conjugate significantly facilitated the proliferation of osteoblasts (P < 0.05). The intracellular calcium ions also ascended vastly in the cells treated with ICA-BSA conjugate (P < 0.01). Icariin-bovine serum albumin exposure rapidly activated the extracellular signal-regulated kinase (ERK) signaling. Furthermore, ICA- and ICA-BSA-mediated actions on osteoblasts were signally alleviated after dealing with ERK inhibitor PD98059 or estrogen receptor (ER) antagonist ICI182780, which might have a relation to the repression of ERK phosphorylation. Conclusions: Icariin could serve as estrogen in osteoblast cells by the rapid nongenomic ER signaling pathway independent of ligand and estrogen response element (ERE) and mediated by mitogen-activated protein kinase (MAPK).

Long-term prognosis and prognostic factors of brachytherapy and propensity score matched comparisons of the outcomes between brachytherapy and radical prostatectomy: a retrospective cohort study.

Background: To report outcomes of patients undergoing brachytherapy (BT), investigate factors associated with biochemical progression-free survival (bPFS) and to compare its long-term prognosis with that of radical prostatectomy (RP) in localized prostate cancer. Methods: The clinical data of 87 elderly patients with localized prostate cancer who underwent BT at Huadong Hospital affiliated to Fudan University from January 2009 to December 2016 were retrospectively analyzed. Patient prognoses and associated factors were investigated using univariate and multivariate Cox regression models. The clinical data of the 142 patients with localized prostate cancer who underwent RP during the same period were also collected. By using propensity score matching (PSM), the 42 patients who underwent BT were matched to 42 patients who underwent RP, and the differences in the survival curves were investigated using the Kaplan-Meier method. Results: The median follow-up period of the patients who underwent BT was 101 months. The 5- and 10-year overall survival (OS) rates of the patients who underwent BT were 82.8% and 64.0%, respectively, while the 5- and 10-year bPFS rates were 97.2% and 87.5%, respectively. The preoperative clinical Tumor (T) stage was identified as a prognostic factor of bPFS, as patients who underwent BT whose clinical stage was T3 had a worse prognosis than those whose clinical stage was T1-T2 (HR =0.097, P=0.049). After PSM, the average follow-up time of the BT group was 90 months and that of the RP group was 94 months. No significant differences in bPFS or cause-specific survival were observed between the 2 groups. The OS of the RP group was significantly higher than that of the BP group (P=0.030). Among the patients with a prostate volume >35 mL, those who underwent BT had significantly higher pPFS than those who underwent RP (P=0.041). Conclusions: In the localized prostate cancer, BT and RP offered similar oncological control in the localized prostate cancer. Stage T3 prostate cancer who undergo BT was associated with worse biochemical failure and was the only variable significantly predictive of biochemical recurrence.

Cedrol alleviates the apoptosis and inflammatory response of IL-1ß-treated chondrocytes by promoting miR-542-5p expression.

Cedrol has been shown to exert anti-tumor, anti-inflammatory, and anti-oxidative effects, but its role in osteoarthritis (OA) is unclear. This study aimed to explore the effect of cedrol in OA. Chondrocytes were isolated from newborn rats and cultured in Dulbecco's modified Eagle's medium (DMEM). Then, Alcian blue staining was used to identify the chondrocytes. IL-1ß and cedrol were used to treat chondrocytes. Cell viability and apoptosis were measured by MTT and flow cytometry assays, respectively. The expressions of miR-542-5p, miR-26b-5p, miR-572, miR-138-5p, miR-328-3p, miR-1254, Bcl-2, Bax, iNOS, COX-2, and MMP-13 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot. NO and PGE2 levels were detected by ELISA. All the cells extracted from the newborn rats were dyed blue, indicating that the cells were chondrocytes. IL-1ß could reduce the viability and promote apoptosis and inflammatory response of chondrocytes, while cedrol could reverse the effect of IL-1ß. In addition, cedrol could significantly increase the expression of miR-542-5p in IL-1ß-treated chondrocytes. Moreover, miR-542-5p inhibitor could partly reverse the effect of cedrol in the apoptosis and inflammation response of chondrocytes. Cedrol alleviated IL-1ß-induced apoptosis and inflammatory response of chondrocytes by promoting miR-542-5p expression.

Cervical sagittal alignment in patients with dropped head syndrome.

BACKGROUND: Dropped head syndrome (DHS) can be divided into two types, the positive sagittal vertical axis (SVA) type and the negative SVA type. However, the cervical sagittal alignment of DHS including global sagittal spinal alignment and the typical cervical alignment of the types of DHS is still unclear. The purpose of this study was to clarify the character of cervical sagittal alignment of DHS and analyze the relationship between cervical sagittal alignment and global sagittal spinal alignment. METHODS: The subjects were 35 DHS patients (10 men, 25 women, mean 71.1 years old). They were divided into two groups: negative DHS (N-DHS group, SVA < 0 mm) and positive DHS group (P-DHS group, SVA ≥ 0 mm). As control, 28 age-matched cervical spondylosis patients (CS, 21 men, 7 women, mean 67.4 years old) were analyzed. The following parameters were measured on lateral global-spine standing radiographs: cervical SVA (C2-C7SVA), O-C2A (O-C2 angle), C2 slope (C2S), C2-7A (C2-7 angle), T1 slope (T1S) and C7SVA. RESULTS: The results of measurements of each of the averaged sagittal alignment parameters were (CS, P-DHS, N-DHS): C2-7SVA(26.2 mm, 47.3 mm, 44.5 mm), O-C2 angle (35.0°, 37.1°, 39.3°), C2S (16.5°, 31.4°, 33.8°), C2-7A (9.3°, 9.9°, -16.6°), T1S (22.9°, 39.7°, 25.7°), C7SVA (35.3 mm, 51.0 mm, -43.1 mm). C2-C7SVA and C2S were significantly larger in both types of DHS compared to CS. Comparing P-DHS with N-DHS, C2-C7A and T1S were significantly smaller in N-DHS. CONCLUSIONS: O-C2A did not differ significantly among CS, P-DHS and N-DHS. In DHS patients, C2-7SVA and C2S were significantly larger than those of CS regardless of the type of DHS. The typical cervical sagittal alignment of DHS was different between P-DHS and N-DHS. In P-DHS, C2-7A and T1S were larger than those in N-DHS and the imbalance of thoraco-lumbar alignment should be noted.

Quercetin suppresses inflammatory cytokine production in rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic, progressive and systemic autoimmune disease mainly characterized by symmetric multijoint synovitis. Quercetin has anti-inflammatory, anti-oxidation and immune regulation activities, and therefore shows high medicinal value. The present study aimed to observe the effect of quercetin on fibroblast-like synoviocytes (FLSs) in RA. Rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) were pretreated with 50 nmol/l quercetin for 2 h and were then stimulated using TNF-α for 24 h for subsequent experiments. RAFLSs were transfected with short interfering (si)-X-inactive specific transcript (XIST), microRNA (miR)-485 mimic, miR-485 inhibitor or si-PSMB8 or combination. ELISA, PCR and western blotting was used to evaluate the effect of quercetin on RAFLSs treated with TNF-α. It was revealed that quercetin inhibited the production of inflammatory cytokines and the expression of XIST in RAFLSs induced by TNF-α. Bioinformatics analysis indicated that XIST acted as a sponge for miR-485 and that proteasome subunit ß type-8 (PSMB8) was a direct target of miR-485. Moreover, PSMB8 functioned as a suppressor in inflammatory cytokine production of RAFLSs induced by TNF-α. Overall, quercetin was observed to inhibit the production of inflammatory cytokines and the expression of XIST in RAFLSs induced by TNF-α. Moreover, XIST-silencing could suppress the inflammatory reaction by sponging miR-485 in cells treated with TNF-α. Altogether, quercetin could suppress the development of RA in vitro.

Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for a Pediatric Ph-Like B-ALL Patient That Relapsed After CART-Cell and Haplo-HSCT Therapy: A Case Report and Review of Literature.

Pediatric Philadelphia chromosome-like (Ph-like) acute B-lymphoblastic leukemia (B-ALL), a high-risk subset of B-ALL characterized by a gene expression profile similar to that of Ph-positive ALL, has extremely poor outcome after a relapse following autologous chimeric antigen receptor (CAR)-T and haploidentical (haplo) hematopoietic stem cell transplantation(HSCT)therapy. with very limited treatment options. Donor-derived CAR T-cell therapy, the most vital advanced anticancer technology, may be a promising salvage strategy for patients with Ph-like B-ALL. Here, we presented a relapsed and refractory case of a child with Ph-like B-ALL after autologous anti-CD19 CAR T-cell therapy followed by haplo-HSCT. She successfully achieved the fourth complete remission (CR4) and maintained CR for five months after the sequential infusion of donor-derived anti-CD22 and anti-CD19 CAR T cells, with mild CRS side effects and no obvious graft-versus-host disease. A donor-derived anti-CD22 and -CD19 CAR T-cell therapy combined with a sequential infusion strategy may provide a promising alternative treatment strategy as effective and safe salvage therapy for children with recurrent and refractory Ph-like B-ALL after autologous CD19-directed CAR T-cell therapy followed by haplo-HSCT.

Allogeneic Donor-Derived Anti-CD19 CAR T Cell Is a Promising Therapy for Relapsed/Refractory B-ALL After Allogeneic Hematopoietic Stem-Cell Transplantation.

INTRODUCTION: Currently, effective and safe salvage therapies are limited among patients with relapsed acute lymphoblastic leukemia after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Anti-CD19 chimeric antigen receptor T (CAR T) cell is a promising treatment. PATIENTS AND METHODS: We studied 11 patients with B-cell acute lymphoblastic leukemia that relapsed after allo-HSCT between September 2017 and October 2019. Patients were treated with a dose of single-infusion donor-derived anti-CD19 CAR T cells. RESULTS: Eight patients (72.7%) experienced morphologic remissions. Seven (63.6%) experienced minimal residual disease-negative remission. The ongoing complete remission (CR) duration of 2 patients reached 22 months. The median overall survival was 9 months (range, 2-22 months). Only one patient with grade 1 acute graft-versus-host disease was observed. Two patients (18.2%) developed grade 3/4 cytokine release syndrome. CONCLUSION: This prospective study showed allogeneic donor-derived anti-CD19 CAR T-cell therapy is an effective and safe salvage regimen for patients with relapsed/refractory B-cell acute lymphoblastic leukemia after allo-HSCT. Further randomized and multicenter investigations are needed to evaluate their potential role in relapsed acute lymphoblastic leukemia therapies after allo-HSCT.

[A comparative study on different doses of cernilton for preventing the clinical progression of benign prostatic hyperplasia].

OBJECTIVE: To compare the efficacy and safety of different doses of cernilton in preventing the clinical progression of benign prostatic hyperplasia (BPH). METHODS: A total of 240 BPH patients with the International Prostate Symptom Score (IPSS) >7 were equally allocated to an experimental and a control group and treated with oral cernilton (Prostate), the former at the dose of 750 mg, the latter at 375 mg, both twice a day for 4 years. Changes, of IPSS, prostate volume, postvoid residual urine, maximum flow rate (Qmax), prostate specific antigen (PSA), the incidence of urine retention and the rate of surgery were compared between the two groups after the treatment. RESULTS: In the experimental group, the IPSS, prostate volume, postvoid residual urine and Qmax were 10.5 +/- 5.6, (29.2 +/- 9.5) ml, (15.2 +/- 3.1) ml and (16.2 +/- 4.5) ml/s after the treatment, as compared with 20.1 +/- 4.1, (37.8 +/- 12.5) ml, (42.5 +/- 6.6) ml and (10.0 +/- 3.5) mVs before the treatment, while in the control group, the four indexes were 14.9 +/- 4.3 vs 19.2 +/- 3.8, (34.7 +/- 9.8) ml vs (37.1 +/- 11.9) ml, (25.6 +/- 4.6) ml vs (41.8 +/- 6.1) ml and (13.5 +/- 4.1) ml/s vs (10.2 +/- 3.8) ml/s, with a more obvious improvement in the experimental group than in the control after the 4-year treatment (P < 0.0001). Compared with pre-treatment, the IPSS and Qmax were improved 3 months (16.7 +/- 3.9, P < 0. 000 1) and 6 months ([13.2 +/- 4.1] ml/s, P < 0. 0001) respectively after the treatment in the experimental group, compared with 6 months (17.6 +/- 3.3, P = 0.0010) and 9 months ([12.0 +/- 3.7] ml/s, P = 0.0005) in the control; the prostate volume was improved 1 year after the treatment in the former ( [ 15.6 +/- 3.2 ] ml,P = 0.0487) but not at 4 years in the latter ([25.6 +/- 4.6] ml,P = 0.1040). The postvoid residual urine was improved at 3 months in both the experimental ([38.7 +/- 6.1] ml, P < 0.000 1) and the control group ([40.2 +/- 5.5] ml, P = 0.0422). The incidence of urine retention was lower in the former than in the latter (5 vs 16 person-times, P = 0.0147), and so was the rate of surgery (2 vs 8 person-times, P = 0.046 2). There were no significant differences in PSA between the pre-and post-treatment either in the experimental (P = 0.349 6) or in the control group (P = 0.3805). No toxical and adverse effects were observed. CONCLUSION: Long-term administration of cernilton at the dose of 750 mg may achieve faster and more obvious efficacy than at 375 mg in improving symptomatic BPH and preventing the clinical progression of BPH, with no adverse events.

Secretome analysis of rat osteoblasts during icariin treatment induced osteogenesis.

Osteoporosis is a serious public health problem and icariin (ICA) is the active component of the Epimedium sagittatum, a traditional Chinese medicinal herb. The present study aimed to investigate the effects and underlying mechanisms of ICA as a potential therapy for osteoporosis. Calvaria osteoblasts were isolated from newborn rats and treated with ICA. Cell viability, apoptosis, alkaline phosphatase activity and calcium deposition were analyzed. Bioinformatics analyses were performed to identify differentially expressed proteins (DEPs) in response to ICA treatment. Western blot analysis was performed to validate the expression of DEPs. ICA administration promoted osteoblast viability, alkaline phosphatase activity, calcium deposition and inhibited osteoblast apoptosis. Secretome analysis of ICA­treated cells was performed using two­dimensional gel electrophoresis and matrix­assisted laser desorption/ionization time­of­flight mass spectrometry. A total of 56 DEPs were identified, including serpin family F member 1 (PEDF), protein disulfide isomerase family A, member 3 (PDIA3), nuclear protein, co­activator of histone transcription (NPAT), c­Myc and heat shock protein 70 (HSP70). These proteins were associated with signaling pathways, including Fas and p53. Bioinformatics and western blot analyses confirmed that the expression levels of the six DEPs were upregulated following ICA treatment. These genes may be directly or indirectly involved in ICA­mediated osteogenic differentiation and osteogenesis. It was demonstrated that ICA treatment promoted osteogenesis by modulating the expression of PEDF, PDIA3, NPAT and HSP70 through signaling pathways, including Fas and p53.

SOX2 Is a Marker for Stem-like Tumor Cells in Bladder Cancer.

It has been reported that functionally distinct cancer stem cells (CSCs) exist in human bladder cancer (BCa). Here, we found that Sox2, a transcription factor that is well characterized as a marker for stem cells, is upregulated in both mouse and human BCa. Sox2 expression is absent in normal urothelial cells, but it begins to be expressed in pre-neoplastic bladder tumors and continues to be expressed in invasive mouse BCa. Using s as a reporter of Sox2 transcriptional expression, we demonstrated that Sox2-expressing cells mark a subpopulation of tumor cells that fuel the growth of established BCa. SOX2-positive cells also expressed other previously reported BCa CSC markers, including Keratin14 (KRT14) and CD44v6. Ablation of Sox2-expressing cells within primary invasive BCa led to enhanced tumor regression, supporting the essential role of SOX2-positive cells in regulating BCa maintenance and progression. Our data show that Sox2 is a marker of bladder CSCs and indicate it as a potential clinical target for BCa therapy.