Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model.

BACKGROUND: Ovarian ageing is one of the major issues that impacts female fertility. Mesenchymal stem cell (MSC)-based therapy has made impressive progress in recent years. However, the efficacy and safety of MSCs, as nonautologous components, remain to be further verified. METHODS: Two common sources of MSCs, umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (AD-MSCs), were orthotopically transplanted into a mouse model of ovarian ageing to evaluate their therapeutic effects. The safety of the treatment was further evaluated, and RNA sequencing was performed to explore the underlying mechanisms involved. RESULTS: After orthotopic transplantation of MSCs into the ovary, the oestrous cycle, ovarian weight, number and proportion of primary follicles, granulosa cell proliferation, and angiogenesis were improved. The effects of AD-MSCs were superior to those of UC-MSCs in several indices, such as post-transplant granulosa cell proliferation, ovarian weight and angiogenesis. Moreover, the tumorigenesis, acute toxicity, immunogenicity and biodistribution of MSCs were evaluated, and both AD-MSCs and UC-MSCs were found to possess high safety profiles. Through RNA sequencing analysis, enhancement of the MAPK cascade was observed, and long-term effects were mainly linked to the activation of immune function. CONCLUSIONS: Orthotopic transplantation of MSCs displays significant efficacy and high safety for the treatment of ovarian ageing in mice.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

A Network Pharmacology-based Study on the Anti-aging Properties of Traditional Chinese Medicine Sisheng Bulao Elixir.

BACKGROUND: Traditional Chinese Medicine (TCM) has a rich history of use in preventing senescence for millennia in China. Nonetheless, a systematic method to study the antiaging properties and the underlying molecular mechanism of TCM remains absent. OBJECTIVE: The objective of this study is to decipher the anti-aging targets and mechanisms of Sisheng Bulao Elixir (SBE) using a systematic approach based on a novel aging database and network pharmacology. METHODS: Bioactive compounds and target proteins in SBE were identified via the Traditional Chinese Medicine System Pharmacology (TCMSP) database. Aging-related proteins were uncovered through alignment with the Ageing Alta database. A compound-target (CT) protein network analysis highlighted key flavonoids targeting aging. Core aging-related proteins were extracted through protein-protein interaction (PPI) network analysis. Molecular docking validated binding activities between core compounds and aging-related proteins. The antioxidant activity of SBE was confirmed using an in vitro senescent cells model. RESULTS: A total of 39 active compounds were extracted from a pool of 639 compounds in SBE. Through a matching process with the Aging Alta, 88 target proteins associated with the aging process were identified. Impressively, 80 out of these 88 proteins were found to be targeted by flavonoids. Subsequently, an analysis using CT methodology highlighted 11 top bioactive flavonoids. Notably, core aging-related proteins, including AKT1, MAPK3, TP53, VEGFA, IL6, and HSP90AA1, emerged through the PPI network analysis. Moreover, three flavonoids, namely quercetin, kaempferol, and luteolin, exhibited interactions with over 100 aging-related proteins. Molecular docking studies were conducted on these flavonoids with their shared three target proteins, namely AKT1, HSP90AA1, and IL6, to assess their binding activities. Finally, the antioxidant properties of SBE were validated using an in vitro model of senescent cells. CONCLUSION: This study offers novel insights into SBE's anti-aging attributes, providing evidence of its molecular mechanisms. It enhances our understanding of traditional remedies in anti-aging research.

Stem cells from human exfoliated deciduous teeth rejuvenate the liver in naturally aged mice by improving ribosomal and mitochondrial proteins.

BACKGROUND AIMS: Aging is accompanied by a decline in cellular proteome homeostasis, mitochondrial, and metabolic function. Mesenchymal stromal cell (MSC) therapies have been reported to extend lifespan and delay some age-related pathologies, yet the anti-aging rate and mechanisms remain unclear. Here, we investigated the effects and mechanism by transplantation of stem cells from human exfoliated deciduous teeth (SHED) into the naturally aged mice model. METHODS: SHED were cultured in vitro and injected into mice by caudal vein. The in vivo imaging uncovered that SHED labeled by DiR dye mainly migrated to the liver, spleen, and lung organs of wild-type mice. As the main metabolic organ and SHED homing place, the liver was selected for proteomics and aging clock algorithm (LiverClock) analysis, which was constructed to estimate the proteomic pattern related to liver age state. RESULTS: After 6 months of continuous SHED injections, the liver proteomic pattern was reversed from senescent (∼30 months) to a youthful state (∼3 months), accompanied with upregulation of hepatocytes marker genes, anti-aging protein Klotho, a global improvement of liver functional pathways proteins, and a dramatic regulation of ribosomal and mitochondrial proteins, including upregulation of translation elongation and ribosome-sparing proteins Rpsa and Rplp0; elongation factors Eif4a1, Eef1b2, Eif5a; protein-folding chaperones Hsp90aa and Hspe1; ATP synthesis proteins Atp5b, Atp5o, Atp5j; and downregulation of most ribosomal proteins, suggesting that the proteome homeostasis destruction and mitochondria dysfunction in the aged mice liver might be relieved after SHED treatment. CONCLUSIONS: SHED treatment could dramatically relieve the senescent state of the aged liver, affect ribosome component proteins and upregulate the ribosomal biogenesis proteins in the aged mice liver. These results may help understand the improvements and mechanisms of SHED treatment in anti-aging.

Simultaneous thulium laser resection of the prostate and transperineal prostate biopsy in clinically diagnosed metastatic prostate cancer with bladder outlet obstruction.

Metastatic prostate cancer (mPCa) patients complicated with bladder outlet obstruction (BOO) are often referred to a urologist. Androgen deprivation therapy (ADT) combined with indwelling catheter usually be the initial management. To retrospectively analysis the safety and efficacy of simultaneous thulium laser resection of the prostate (TmLRP) and transperineal prostate biopsy in metastatic prostate cancer with bladder outlet obstruction. From January 2016 to December 2021, 67 clinically diagnosed mPCa with BOO patients were included in this study. All patients were preoperatively assessed with international prostate symptom score (IPSS), QoL, serum prostate-specific antigen (PSA), prostate volume evaluation by transrectal ultrasound, postvoid residual urine volume (PVR), and maximum flow rate (Qmax). Preoperative and perioperative parameters at 1-, 3-, and 6-month follow-up were also evaluated. All complications were recorded. Simultaneous TmLRP and transperineal prostate biopsy had obvious advantages for clinically diagnosed mPCa patients with BOO, including short overall operation time (52 ± 23.3 min), little hemoglobin decrease (0.6 ± 0.7 g/l), and short hospital stay (average 3.8 days). In addition, simultaneous TmLRP and transperineal prostate biopsy also brought them significant improvement on IPSS, QoL score, Qmax, and PVR volume (P < 0.001) at 1-, 3-, and 6-month follow-up after operation compared to preoperative parameters. Complications were in a low incidence. Simultaneous TmLRP and transperineal prostate biopsy is a bloodless operation with immediate effect and little perioperative complication. Importantly, it is a promising technology in the diagnosis and treatment of clinically diagnosed mPCa patients with BOO.

Rapamycin and Low-dose IL-2 Mediate an Immunosuppressive Microenvironment to Inhibit Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

Efficacy of Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With ROS1-Rearranged Advanced Lung Adenocarcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) exert robust antitumor activity in non-small-cell lung cancer (NSCLC) without actionable mutations. Apart from isolated case reports, the efficacy of PD-1 blockade in ROS1-rearranged NSCLC is currently unknown. METHODS: This retrospective cohort study included 23 patients with ROS1-rearranged advanced lung adenocarcinoma who received ICI plus chemotherapy regardless of the treatment setting. ICI plus chemotherapy was received as a later-line regimen by 14 patients, as the first-line regimen by six patients, and after chemoradiotherapy by three patients. RESULTS: All three patients who received chemoradiotherapy followed by ICI plus chemotherapy achieved partial response (PR) and had a progression-free survival (PFS) of >17.9 months. Of the six patients who received first-line ICI plus chemotherapy, five patients achieved PR and one had stable disease (SD), with a median PFS of 24.3 months (95% CI, 4.9 to 43.7). Of the 14 previously treated patients who received later-line ICI plus chemotherapy, the Objective Response Rate (ORR) was 28.6%, the Disease Control Rate (DCR) was 92.9%, and the median PFS was 5.8 months (95% CI, 0.2 to 9.4). The median time on ICI therapy was 10.0 months (95% CI, 1.5 to 32.5). The duration of response was 24.3 months (95% CI, 5.4 to 43.2) and 4.8 months (95% CI, 2.3 to 12.7) for first-line (n = 5) and subsequent-line (n = 4) ICI plus chemotherapy, respectively. Of the 10 patients with brain metastasis before receiving ICI plus chemotherapy, four patients achieved intracranial PR and five patients achieved intracranial SD, achieving an intracranial ORR of 40.0% and an intracranial DCR of 90.0%. CONCLUSION: Our retrospective study provides real-world clinical evidence that ROS1-rearranged NSCLCs benefit from ICI plus chemotherapy in any treatment setting, including patients who present with brain metastasis.

Recyclable Magnetic Iron Immobilized onto Chitosan with Bridging Cu Ion for the Enhanced Adsorption of Methyl Orange.

Chitosan (CS) is a natural and low-cost adsorbent for capturing metal ions and organic compounds. However, the high solubility of CS in acidic solution would make it difficult to recycle the adsorbent from the liquid phase. In this study, the CS/Fe3O4 was prepared via Fe3O4 nanoparticles immobilized onto a CS surface, and the DCS/Fe3O4-Cu was further fabricated after surface modification and the adsorption of Cu ions. The meticulously tailored material displayed the sub-micron size of an agglomerated structure with numerous magnetic Fe3O4 nanoparticles. During the adsorption of methyl orange (MO), the DCS/Fe3O4-Cu delivered a superior removal efficiency of 96.4% at 40 min, which is more than twice the removal efficiency of 38.7% for pristine CS/Fe3O4. At an initial MO concentration of 100 mg L-1, the DCS/Fe3O4-Cu exhibited the maximum adsorption capacity of 144.60 mg g-1. The experimental data were well explained by the pseudo-second-order model and Langmuir isotherm, suggesting the dominant monolayer adsorption. The composite adsorbent still maintained a large removal rate of 93.5% after five regeneration cycles. This work develops an effective strategy to simultaneously achieve high adsorption performance and convenient recyclability for wastewater treatment.

Astrocyte-derived hepcidin controls iron traffic at the blood-brain-barrier via regulating ferroportin 1 of microvascular endothelial cells.

Brain iron dysregulation associated with aging is closely related to motor and cognitive impairments in neurodegenerative diseases. The regulation of iron traffic at the blood-brain barrier (BBB) is crucial to maintain brain iron homeostasis. However, the specific mechanism has not been clarified in detail. Using various conditional gene knockout and overexpression mice, as well as cell co-culture of astrocyte and bEND.3 in the transwell, we found that astrocyte hepcidin knockdown increased the expression of ferroportin 1 (FPN1) of brain microvascular endothelial cells (BMVECs), and that it also induced brain iron overload and cognitive decline in mice. Moreover, BMVECs FPN1 knockout decreased iron contents in the cortex and hippocampus. Furthermore, hepcidin regulates the level of FPN1 of BMVECs with conditional gene overexpression in vivo and in vitro. Our results revealed that astrocytes responded to the intracellular high iron level and increased the secretion of hepcidin, which in turn diminished iron uptake at BBB from circulation through directly regulating FPN1 of BMVECs. Our results demonstrate that FPN1 of BMVECs is a gateway for iron transport into the brain from circulation, and the controller of this gateway is hepcidin secreted by astrocyte at its endfeet through physical contact with BMVECs. This regulation is indeed the major checkpoint for iron transport from the blood circulation to the brain. This study delineates the pathway and regulation of iron entry into the brain, providing potential therapeutic targets for iron dysregulation-related neurological diseases.

Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model.

BACKGROUND AIMS: Stem cell therapy is a novel therapy being explored for AD. The molecular mechanism of its effect is still unclear. The authors investigated the effects and mechanism by injection of SHEDs into an AD mouse model. METHODS: SHEDs were cultured in vitro and injected into AD SAMP8 mice by caudal vein, and SHEDs labeled via synthetic dye showed in vivo migration to the head. The cognitive ability of SAMP8 mice was evaluated via Barnes maze and new object recognition. The pathological indicators of AD, including Tau, amyloid plaques and inflammatory factors, were examined at the protein or RNA level. Next, macro-proteomics analysis and weighted gene co-expression network analysis (WGCNA) based on protein groups and behavioral data were applied to discover the important gene cluster involved in the improvement of AD by SHEDs, which was further confirmed in an AD model in both mouse and cell lines. RESULTS: SHED treatment improved the cognitive ability and pathological symptoms of SAMP8 mice. Proteomics analysis indicated that these improvements were tightly related to the mitochondria, which was proved through examination of the shape and function of mitochondria both in vivo (SAMP8 brain) and in vitro (SH-SY5Y cells). Finally, the core targets of SHEDs in the mitochondrial pathway, Hook3, Mic13 and MIF, were screened out and confirmed in vivo. CONCLUSIONS: SHED treatment significantly relieved AD symptoms, improved cognitive ability and reversed memory loss in an AD mouse model, possibly through the recovery of dysfunctional mitochondria. These results raise the possibility that SHED may ease the symptoms of AD by targeting the mitochondria.

Stem Cells from Human Exfoliated Deciduous teeth Promote Hair Regeneration in Mouse.

Stem cells in different types may interact with each other to maintain homeostasis or growth and the interactions are complicated and extensive. There is increasing evidence that mesenchymal-epithelial interactions in early morphogenesis stages of both tooth and hair follicles show many similarities. In order to explore whether stem cells from one tissue could interact with cells from another tissue, a series of experiments were carried out. Here we successfully extracted and identified stem cells from human exfoliated deciduous teeth (SHED) of 8-12 years old kids, and then found that SHED could promote hair regeneration in a mouse model. In vitro, SHED shortened the hair regeneration cycle and promoted the proliferation and aggregation of dermal cells. In vivo, when SHED and skin cells of C57 mice were subcutaneously co-transplanted to nude mice, more hair was formed than skin cells without SHED. To further explore the molecular mechanism, epidermal and dermal cells were freshly extracted and co-cultured with SHED. Then several signaling molecules in hair follicle regeneration were detected and we found that the expression of Sonic Hedgehog (Shh) and Glioma-associated oncogene 1 (Gli1) was up-regulated. It seems that SHED may boost the prosperity of hairs by increase Shh/Gli1 pathway, which brings new perspectives in tissue engineering and damaged tissue repairing.

Proteomic profile of human stem cells from dental pulp and periodontal ligament.

Background The study of molecular profiling of dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) contributes to understanding the high proliferation ability and multi-lineage differentiation potential. Objectives The aim of the study was to compare the protein abundance and specific markers of DPSCs and PDLSCs by protein profiles. Material and methods The DPSCs and PDLSCs extracted from the same tooth were lysed with 3 biological replicates and the protein was collected. Two-dimensional electrophoresis technology and TMT proteomics were used to separate and identify proteins. The data are available via ProteomeXchange with identifier PXD021997. The RT-qPCR detection of mRNA expression revealed a special marker for distinguishing two kinds of dental stem cells. Results Compared with PDLSCs, 962 differential proteins (DAPs) were up-regulated, and 127 were down-regulated in DPSCs. In the up-regulated DAPs, two high-scoring sub-networks were detected for neural-related molecules, which encode cell vesicle transport and mitochondrial energy transfer to regulate cell proliferation and secretion factors. A large number of cell adhesion molecules were distinguished among the highly expressed molecules of PDLSCs, supporting that stem cells provide cell attachment functions. It was interpreted ENPL, HS90A and HS90B were highly expressed in DPSCs, while CKB was highly abundant in PDLSCs. Another cell group confirmed that these molecules can be used as special biomarkers to identify and distinguish between DPSCs and PDLSCs. Conclusions This study can promote the basic research and clinical application of dental stem cells. Significance The high-throughput protein profiles were tested by combining two-dimensional gel proteomics and TMT-based proteomics. The proteomics of DPSCs and PDLSCs without individual difference demonstrated an accurate and comprehensive molecular expression profiles and interpretation of neural application potential, this study promotes the basic research of dental stem cells and clinical application.

A Modified Technique of Thulium Laser Enucleation for Benign Prostatic Hyperplasia With Non-morcellator Approach.

Background: Until recently, most enucleation techniques of the prostate were performed with the application of morcellator. We introduce a modified enucleation technique of thulium laser with non-morcellator approach, which is about incising and vaporizing remaining prostate tissue instead of a morcellator. Methods: A retrospective evaluation of 223 patients undergoing ThuLEP from January 2014 to December 2015 was performed in our institution. One hundred five of the patients used morcellator while the other 118 used non-morcellator approach. All patients were assessed with the International Prostate Symptom Score (IPSS), quality of life (Qol), ultrasonography, serum prostate-specific antigen (PSA), maximal urine flow rate (Qmax), and postvoid residual urine volume (PVR). We reassessed these parameters at 1-, 3-, 6-, and 12-months after operation. Operative time, perioperative, and postoperative complications were also recorded. Results: Significant improvement was noted in the IPSS, QoL, Qmax, and PVR in both groups at the 12-month follow-up, and assessment showed no differences in these parameters between the two groups. Comparisons of the total operation time and enucleation time demonstrated no significant differences between the two groups. Our non-morcellator approach needed more time to incise and vaporize the enucleated tissue compared to morcellation when the prostate volume was about 40-80 ml (p < 0.05), while it showed a significant lower rate of superficial bladder injury than using morcellator (p < 0.05). There were no significant differences in other complications between the two groups (p > 0.05). Conclusions: Our modified technique is a safe and effective procedure for the treatment of BPH avoiding the potential complications caused by morcellator.

Targeting ADT-Induced Activation of the E3 Ubiquitin Ligase Siah2 to Delay the Occurrence of Castration-Resistant Prostate Cancer.

Siah2 is an E3 ubiquitin ligase that targets androgen receptor (AR) and plays an important role in the development of castration-resistant prostate cancer (CRPC). However, the regulation of Siah2 in prostate cancer (PCa) is largely unknown. In this study, we used AR-dependent and -independent cells lines to investigate the cellular roles of AR and androgen deprivation therapy (ADT) on Siah2 protein levels and E3 ligase activity using Western blotting and co-immunoprecipitation. We also validated our findings using patient samples taken before and after ADT. Finally, we used xenograft tumor models to test the effects of ADT combined with vitamin K3 (Vit K3) on tumor growth in vivo. Our results showed that AR stabilizes Siah2 protein by attenuating its self-ubiquitination and auto-degradation, likely by blocking its E3 ubiquitin ligase activity. Conversely, ADT decreased Siah2 protein expression but enhanced its E3 ligase activity in PCa cells. Notably, the findings that ADT decreasing Siah2 protein expression were verified in a series of paired PCa samples from the same patient. Additionally, we found that ADT-induced Siah2 activation could be abolished by Vit K3. Strikingly, ADT combined with Vit K3 treatment delayed the occurrence of CRPC and dramatically inhibited the growth of tumor xenografts compared with ADT treatment alone. AR is an inhibitor of Siah2 in PCa, and ADT leads to the continuous activation of Siah2, which may contribute to CRPC. Finally, ADT+Vit K3 may be a potential approach to delay the occurrence of CRPC.

ERgene: Python library for screening endogenous reference genes.

In gene expression analysis, sample differences and experimental operation differences are common, but sometimes, these differences will cause serious errors to the results or even make the results meaningless. Finding suitable internal reference genes efficiently to eliminate errors is a challenge. Aside from the need for high efficiency, there is no package for screening endogenous genes available in Python. Here, we introduce ERgene, a Python library for screening endogenous reference genes. It has extremely high computational efficiency and simple operation steps. The principle is based on the inverse process of the internal reference method, and the robust matrix block operation makes the selection of internal reference genes faster than any other method.

Maternal exposure to Di-n-butyl phthalate (DBP) aggravate gestational diabetes mellitus via FoxM1 suppression by pSTAT1 signalling.

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.

Thulium laser enucleation versus thulium laser resection of the prostate for prevention of bladder neck contracture in a small prostate: a prospective randomized trial.

PURPOSE: To compare the safety and efficacy of thulium laser enucleation of the prostate (ThuLEP) versus thulium laser resection of the prostate (TmLRP) in small prostates (≤ 30 g) and to test the validity of ThuLEP for bladder neck contracture (BNC). METHODS: A total of 115 patients with benign prostatic hyperplasia (BPH) (prostate size ≤ 30 g) were randomly assigned to ThuLEP (n = 56) or TmLRP (n = 59). All patients were evaluated preoperatively and at 1, 3, 6, and 12 months after surgery. Baseline characteristics of the patients, perioperative data, postoperative outcomes and complications were assessed. RESULTS: Comparisons of the baseline and perioperative data demonstrated no significant differences between the ThuLEP and TmLRP groups. Significant improvement was noted in the International Prostate Symptom Score, quality of life, maximal urinary flow rate (Qmax) and post-void residual volume (PVR) in both groups at the 12-month follow-up, and assessment showed no differences in these parameters between the two groups. The TmLRP group showed a significantly higher rate (13.6%) of BNC than the ThuLEP group (1.8%; P = 0.045). There were no significant differences in other complications between the two groups (P > 0.05). CONCLUSIONS: ThuLEP and TmLRP are both safe and efficient procedures for the treatment of patients with small prostate volume, while ThuLEP can significantly reduce the risk of BNC in patients with a small prostate because the procedure enucleates adenomas without thermal damage to the bladder neck.

Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3.

LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.

FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation, and migration in prostate cancer cells.

BACKGROUND: ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor in the prostate. However, the mechanisms underlying tumor suppressive function of EAF2 are still largely unknown. Identification of factors capable of modulating EAF2 function will help elucidate the mechanisms underlying EAF2 tumor suppressive function. METHODS: Using eaf-1(the ortholog of EAF2) mutant C. elegans model, RNAi screen was used to identify factors on the basis of their knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans. In human cells, the interaction of EAF2 with FOXA1 and the effect of EAF2 on the FOXA1 protein levels were determined by co-immunoprecipitation and protein stability assay. The effect of EAF2 and/or FOXA1 knockdown on the expression of AR-target genes was determined by real-time RT-PCR and luciferase reporter assays. The effect of EAF2 and/or FOXA1 knockdown on LNCaP human prostate cancer cell proliferation and migration was tested using BrdU assay and transwell migration assay. RESULTS: RNAi screen identified pha-4, the C. elegans ortholog of mammalian FOXA1, on the basis of its knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans causing sterility. EAF2 co-immunoprecipitated with FOXA1. EAF2 knockdown enhanced endogenous FOXA1 protein level, whereas transfected GFP-EAF2 down-regulated the FOXA1 protein. Also, EAF2 knockdown enhanced the expression of AR-target genes, cell proliferation, and migration in LNCaP cells. However, FOXA1 knockdown inhibited the effect of EAF2 knockdown on AR-target gene expression, cell proliferation, and migration in LNCaP cells, suggesting that FOXA1 can modulate EAF2 regulation of AR transcriptional activation, cell proliferation, and migration. CONCLUSIONS: These findings suggest that regulation of the AR signaling pathway, cell proliferation, and migration through FOXA1 represents an important mechanism of EAF2 suppression of prostate carcinogenesis.

Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition.

Androgen receptor (AR) has been indicated to be involved in bladder cancer progression. We showed androgen induced epithelial-mesenchymal transition (EMT) in AR-positive bladder cancer cells and promoted tumor metastasis in xenograft models. We subsequently identified that Slug was the mediator of EMT induced by androgen. Furthermore, upregulation of Slug was due to activation of Wnt/ß-catenin signaling in response to androgen. Finally, expression of AR showed strong correlation with loss of E-cadherin, higher expression of Slug and nuclear accumulation of ß-catenin in bladder tumor tissues. Taken together, our results suggest AR signaling promotes bladder cancer metastasis through Slug mediated EMT.