Melittin inhibits tumor cell migration and enhances cisplatin sensitivity by suppressing IL-17 signaling pathway gene LCN2 in castration-resistant prostate cancer.

BACKGROUND: Melittin is a small molecule polypeptide extracted from the abdominal cavity of bees, which is used to treat inflammatory diseases and relieve pain. However, the antitumor effect of melittin and its mechanisms remain unclear, especially in castration-resistant prostate cancer (CRPC). METHODS: Through CCK-8 assay, colony formation assay, wound healing assay and Transwell migration assay, we explored the effect of melittin on CRPC cell lines. In addition, with microarray analysis, gene ontology analysis and kyoto encyclopedia of genes and genomes analysis, this study identified key genes and signaling pathways that influence the growth of PC-3 cells. Meanwhile, the effect of melittin on CRPC was also verified through subcutaneous tumor formation experiments. Finally, we also tested the relevant indicators of human prostate cancer (PCa) specimens through immunohistochemistry and H＆E stating. RESULTS: Here, melittin was verified to inhibit the cell proliferation and migration of CPRC. Moreover, RNA-sequence analysis demonstrated that Interleukin-17 (IL-17) signaling pathway gene Lipocalin-2 (LCN2) was downregulated by melittin treatment in CRPC. Further investigation revealed that overexpression of LCN2 was able to rescue tumor suppression and cisplatin sensitivity which melittin mediated. Interestingly, the expression of LCN2 is highly related to metastasis in PCa. CONCLUSIONS: In brief, our study indicates that LCN2 plays an oncogenic role in CRPC and melittin may be selected as an attractive candidate for CRPC therapy.

Sasanquasaponin inhibited epithelial to mesenchymal transition in prostate cancer by regulating the PI3K/Akt/mTOR and Smad pathways.

CONTEXT: Sasanquasaponin (SQS) is a commonly used traditional Chinese medicine proved to have a wide range of pharmacological functions. OBJECTIVE: The objective of this study is to explore the effect and underlying mechanism of SQS in the treatment of prostate cancer (PC). MATERIALS AND METHODS: PC cell lines (22Rv1 and PC-3) were treated with SQS (0, 0.5, 1, 2, and 4 µM) for 12 or 24 h. The viability of cells was evaluated, while the mRNA and protein levels of epithelial to mesenchymal transition (EMT)-related genes in PC cell lines were measured (Groups: Control, TGF-ß1, TNF-α, TGF-ß1 + TNF-α, and TGF-ß1 + TNF-α + SQS). The migration and invasion abilities of PC cell lines were evaluated (Groups: Control, SQS). Finally, the antitumour effect of SQS (25, 50,100, and 200 mg/kg) in BALB/c nude mice (6 weeks, 18-20 g) was evaluated (Groups: Control, Vehicle, 25, 50,100, and 200 mg/kg SQS). The study duration was 1 month. RESULTS: SQS inhibited the viability and the number of colonies of 22Rv1 or PC-3 cells. The IC50 of SQS of 12 and 24 h in these two cells was 3.25, 1.82, 4.76, and 4.70 µM, respectively. SQS inhibited the adhesion, migration, and invasion of PC cells. It also inhibited the expression of EMT-related markers of PC cells. The PI3K/Akt/mTOR and Smad2/3 signalling pathways were activated in the process of EMT, and SQS could significantly reduce the activation of the PI3K/Akt/mTOR and Smad2/3 pathways. Finally, SQS inhibited the growth of xenograft tumours in vivo. CONCLUSIONS: SQS inhibited EMT in PC by regulating the PI3K/Akt/mTOR and Smad pathways.

[comIdiopathic scrotal calcinosis: A report of 10 cases and review of the literature].

OBJECTIVE: To investigate the clinical features, pathogenesis, diagnosis and scrotal reconstruction in the treatment of idiopathic scrotal calcinosis (ISC). METHODS: From March 2007 to October 2018, 10 ISC patients, aged 28－79 (mean 45) years and with a disease course of 6－497 (mean 128.4) months, were treated in our hospital. We retrospectively analyzed their clinical data and reviewed related literature. RESULTS: All the patients underwent physical examination and biochemical and parathyroid function tests. None of them had a history of endocrine or metabolic disease, or trauma, or a family member with similar diseases, and none had subjective symptoms except local pruritus in 1 case. All were treated surgically and post-operative follow-up revealed no recurrence. Histopathological examination of the excised lesion confirmed it to be ISC. CONCLUSIONS: ISC is a rare localized benign disease, of which surgery seems an effective option for the definite diagnosis and treatment. Occasionally scrotal reconstruction may be required in case of extensive involvement of the scrotal skin.

[Surgical repair of the tunica albuginea for penis fracture: Selection of incision].

OBJECTIVE: To investigate the diagnosis and management of penile fracture. METHODS: From June 1993 to May 2017, 46 cases of penile fracture were treated in our hospital, averaging 33.5 (25－42) years of age and 3.45 (1－10) hours in duration, of which 41 occurred during sexual intercourse, 4 during masturbation and 1 during prone sleeping, 4 with hematuria, but none with dysuria or urethral bleeding. Hematoma was confined to the penis. Emergency surgical repair was performed for all the patients, 45 under spinal anesthesia and 1 under local anesthesia, 16 by coronal proximal circular incision and the other 30 by local longitudinal incision according to the rupture location on ultrasonogram. The tunica albuginea ruptures averaged 1.31 (0.5－2.5) cm in length, which were sutured in the "8" pattern for 6 cases and with the 3－0 absorbable thread for 18 cases. The skin graft or negative pressure drainage tube was routinely placed, catheters indwelt, and gauze used for early pressure dressing. In the recent few years, elastic bandages were employed for 3－5 days of pressure dressing and antibiotics administered to prevent infection. The stitches and catheter were removed at 7 days after surgery. RESULTS: Short-term postoperative foreskin edema occurred in 14 of the 16 cases of circular degloving incision, but no postoperative complications were observed in any of the cases of local incision. Twenty-eight of the patients completed a long-term follow-up of 49.4 (10－125) months, which revealed good erectile function, painless erection, and satisfactory sexual intercourse. CONCLUSIONS: For most penile fractures, local longitudinal incision is sufficient for successful repair of the tunica albuginea, with mild injury, no influence on the blood supply or lymph reflux, and a low rate complications. It therefore is obviously advantageous over circular degloving incision except when the cavernous body of urethra is to be explored, which necessitates circular degloving incision below the coronal groove.

Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert.

BACKGROUND: Erectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion. METHODS: In this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum. RESULTS: EXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle. CONCLUSIONS: These findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.

Simvastatin attenuates diabetes mellitus erectile dysfunction in rats by miR-9-5p-regulated PDCD4.

DMED is a common complication of diabetes, for which new treatment methods are urgently required. Focused on DMED, the pharmacological mechanism of simvastatin (Sim) was probed. A model of DMED was made in rats with streptozotocin and orally medicated with Sim. Lentiviral vectors that interfere with miR-9-5p or PDCD4 were injected, and the erectile function, histopathology of cavernous tissue, and α-SMA expression were evaluated. Cavernous smooth muscle cells (CMSCs) obtained from DMED rats were treated with Sim and transfected with the plasmid vector that interferes with miR-9-5p or PDCD4 to observe cell viability and apoptosis. The binding relationship between miR-9-5p and PDCD4 was checked. After 8-week treatment with Sim, erectile function was improved and the corpus cavernosum injury was alleviated. Upregulating miR-9-5p or downregulating PDCD4 further improved erectile function and cavernous injury in rats. miR-9-5p targeted regulation of PDCD4. In vitro cell experiment results showed that Sim induced proliferation and reduced apoptosis of CSMCs by enhancing miR-9-5p-targeted regulating PDCD4 in vitro. Sim attenuates DMED in rats via miR-9-5p/PDCD4.

Analysis of the effect of holmium laser flexible ureteroscopic intrapelvic drainage in the treatment of parapelvic renal cysts.

Objective: To explore the efficacy, safety, and feasibility of holmium laser flexible ureteroscopic intrapelvic drainage in the treatment of parapelvic renal cysts. Methods: From September 2012 to February 2019, a total of 18 patients, aged from 28 to 62 (mean±standard deviation [SD]: 46.50±9.14) years, were diagnosed with parapelvic renal cysts and treated by holmium laser flexible ureteroscopic intrapelvic drainage. There were 10 males and eight females. All of the parapelvic renal cysts were unilateral, and two cases were complicated with pyelolithiasis. The diameters of the cysts ranged from 4.1 cm to 8.2 cm. Results: All the patients completed the operation successfully in one stage without conversion to open surgery; in two cases, it was difficult to find the cysts during the operation, and the localization was completed by B-ultrasound and percutaneous injection of methylene blue. The mean operative time was 33.89 (SD: 9.68; range: 22-54) min, and the mean hospitalization time was 2.67 (SD: 0.91; range: 2-5) days. Three months and 6 months of follow-up were performed after surgery. The cysts disappeared in 13 (72%) cases, and the diameter of the cysts in five (28%) cases decreased by more than 50%. Conclusion: Holmium laser flexible ureteroscopic intrapelvic drainage in the treatment of parapelvic renal cysts is simple, safe, and effective, and can be used as the first choice for the treatment of parapelvic renal cysts.

Structural and molecular insights into the mechanism of resistance to enzalutamide by the clinical mutants in androgen receptor (AR) in castration-resistant prostate cancer (CRPC) patients.

Androgen receptor (AR) is a key contributing element in the prostate cancer (PCa) instigation, progression and it is among the vastly discovered target for prostate cancer. Numerous mechanisms trigger the expansion of CRPC among which the aberrant AR gene is considered as the prime factor. Recently three essential substitutions H875Y, F877L, and T878A are reported to cause resistance to Enzalutamide. However, no detailed study is available to explore the key events that contribute to the resistance. Hence, considering the applicability of structural bioinformatics and molecular simulation-based methods in the current study, we assessed the impact of these mutations on the binding of Enzalutamide. Using a long-run simulation approach the binding stability, residues flexibility, hydrogen bonding, and protein compactness for each complex were determined to reveal the dynamic variations induced by these mutations. We discovered that the binding mode of Enzalutamide is altered by these mutations which misstarget the key residues required for the antagonistic activity. Molecular simulation of each complex revealed that the wild type H11 and H12 are more flexible moving outside and provides more volume for the ligand optimization. In the mutant complexes, the H12 remained tighter pushing out enzalutamide from the key residues which then essentially misstarget the correct orientation for the antagonist activity. The binding free energy (BFE) for the wild type was computed to be -59.92 ± 0.18 kcal/mol, for H875Y the BFE was -55.92 ± 0.18 kcal/mol, -54.82 ± 0.15 kcal/mol for F877L and -53.87 ± 0.18 kcal/mol for T878A, which further demonstrate that these mutations have destabilized the binding of enzalutamide. The proteins' motion and FEL further validated the aforementioned findings where the wild type reported different dynamic features than the mutant complexes. In conclusion, this study provides a structural basis for the resistance to Enzalutamide, which can be used to design novel effective drugs using structure-based and rationale approaches.

A protein coupling and molecular simulation analysis of the clinical mutants of androgen receptor revealed a higher binding for Leupaxin, to increase the prostate cancer invasion and motility.

Recently a novel coactivator, Leupaxin (LPXN), has been reported to interact with Androgen receptor (AR) and play a significant role in the invasion and progression of prostate cancer. The interaction between AR and LPXN occurs in a ligand-dependent manner and has been reported that the LIM domain in the Leupaxin interacts with the LDB (ligand-binding domain) domain AR. However, no detailed study is available on how the LPXN interacts with AR and increases the (prostate cancer) PCa progression. Considering the importance of the novel co-activator, LPXN, the current study also uses state-of-the-art methods to provide atomic-level insights into the binding of AR and LPXN and the impact of the most frequent clinical mutations H874Y, T877A, and T877S on the binding and function of LPXN. Protein coupling analysis revealed that the three mutants favour the robust binding of LPXN than the wild type by altering the hydrogen bonding network. Further understanding of the binding variations was explored through dissociation constant prediction which demonstrated similar reports as the docking results. A molecular simulation approaches further revealed the dynamic features which reported variations in the dynamics stability, protein packing, hydrogen bonding network, and residues flexibility index. Furthermore, we also assessed the protein motion and free energy landscape which also demonstrated variations in the internal dynamics. The binding free energy calculation revealed -32.95 ± 0.17 kcal/mol for the wild type, for H874Y the total binding energy (BFE) was -36.69 ± 0.11 kcal/mol, for T877A the BFE was calculated to be -38.78 ± 0.17 kcal/mol while for T877S the BFE -41.16 ± 0.12 kcal/mol. This shows that the binding of LPXN is increased by these mutations which consequently increase the PCa invasion and motility. In conclusion, the current study helps in understanding the protein networks and particular the coupling of AR-LPXN in prostate cancer and is of great interest in deciphering the molecular mechanism of disease and therapeutics developments.

A Modified Bilateral Scrotal Flap for Penile Skin Defect Repair.

Skin shortages and scar contractures are common complications following penile trauma and tumor surgery, resulting in significant pain and erectile dysfunction. Currently, skin grafts and scrotal flaps are widely used to reconstruct skin shortages. However, various limitations still exist; for instance, the skin graft may cause severe scarring in patients, and the traditional scrotal flap usually requires a two-stage procedure due to the large skin defect. To treat the shortage of foreskin, a modified bilateral scrotal pedicled flap is used. In this procedure, flaps located on each side of the midline of the scrotum, which was pedicled from the anterior scrotal artery, are harvested. Subsequently, these bilateral scrotal flaps, like a butterfly, can successfully cover the foreskin defect. In this study, seven patients underwent this procedure, and satisfactory outcomes were obtained. Only two patients developed necrosis in some small areas of the flaps, which were recovered after wound care. Postoperative penile length significantly increased compared to the preoperative status in both flaccid and erectile states. We believe that modified bilateral scrotal flaps are a simple and effective solution to penile skin shortages and scar contractures.

METTL3-Mediated m6A Modification of lncRNA MALAT1 Facilitates Prostate Cancer Growth by Activation of PI3K/AKT Signaling.

Accumulating data show that N6-methyladenosine (m6A) methyltransferase METTL3 and long noncoding RNA MALAT1 act pivotal roles in multiple malignancies including prostate cancer (PCa). However, the role and molecular mechanism underlying METTL3-mediated m6A modification of MALAT1 in PCa remain undocumented. The association of METTL3 and MALAT1 expression with clinicopathological characteristics and prognosis in patients with PCa was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and public The Cancer Genome Atlas (TCGA) dataset. The in vitro and in vivo experiments were executed to investigate the role of METTL3 in PCa. m6A dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated m6A modification of MALAT1. The effects of METTL3 on MALAT1-mediated PI3K/AKT pathway were assessed by Western blot analysis. As a result, we found that METTL3 was significantly upregulated in PCa tissues and high expression of METTL3 was associated with Gleason score and tumor recurrence in patients with PCa. Knockdown of METTL3 markedly repressed growth and invasion of PCa cells in vitro and in vivo, whereas ectopic expression of METTL3 showed the opposite effects. Moreover, knockdown of METTL3 decreased the total m6A levels of PCa cells as well as the MALAT1 m6A levels, leading to reduced MALAT1 expression. Overexpression of MALAT1 reversed METTL3 knockdown-induced antitumor effects and PI3K/AKT signaling inactivation. MALAT1 harbored a positive correlation with METTL3 expression and tumor recurrence in PCa. In conclusion, our findings demonstrate that METTL3-mediated m6A modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.

Exosomes derived from miR-301a-3p-overexpressing adipose-derived mesenchymal stem cells reverse hypoxia-induced erectile dysfunction in rat models.

BACKGROUND: Erectile dysfunction (ED) has often been observed in patients with obstructive sleep apnea (OSA). Research on adipose-derived mesenchymal stem cell (ADSC)-derived exosomes has shown that they have significant therapeutic effects in many diseases including ED. METHODS: In this study, ED was induced in Sprague Dawley (SD) rats using chronic intermittent hypoxia (CIH) exposure. CIH-mediated influences were then measured in the corpus cavernous smooth muscle cells (CCSMCs). RESULTS: Our data showed that miR-301a-3p-enriched exosome treatment significantly recovered erectile function in rats and CCSMCs by promoting autophagy and inhibiting apoptosis. The treatment also significantly recovered the level of alpha smooth muscle actin (α-SMA) in rats and CCSMCs. Bioinformatics predicted that phosphatase and tensin homolog (PTEN) and Toll-like receptor 4 (TLR4) might be targets of miR-301a-3p. CONCLUSIONS: Our results indicate that PTEN-overexpression vectors or TLR4-overexpression vectors reverse the therapeutic effects achieved by miR-301a-3p in CCSMCs indicating that PTEN/hypoxia-inducible factor-1 alpha (HIF-1α) and TLR4 signaling pathways play key roles in the progression of ED. The findings in this study suggest that miR-301a-3p should be considered a new therapeutic target for treating ED associated with OSA.

A novel spherical-headed fascial dilator is feasible for second-stage ultrasound guided percutaneous nephrolithotomy: A pilot study.

OBJECTIVE: In second-stage percutaneous nephrolithotomy (PCNL), because the hydronephrosis has been decompressed, the dilated renal pelvis has resolved and the space is small. Consequently, introduction of the tip of the Amplatz dilator can cause injury to the opposite side of the renal-pelvic mucosa. In this study, we report the experimental and initial clinical performance of a spherical-headed fascial dilator developed specifically for second-stage PCNL. METHODS: The novel spherical-headed dilator was compared with existing tapered-headed dilators in configuration and in puncture resistance utilizing a static puncture test. Subsequently, a pilot clinical study was conducted during which patients scheduled to undergo second-stage PCNL from June 2019 to October 2019 in our center were enrolled. A typical ultrasound guided PCNL procedure was performed with the exception that the new spherical-headed fascial dilator was substituted for a tapered-headed one. RESULTS: Experimentally, stab resistance against polyethylene film was significantly increased using the novel spherical-headed dilator compared to the traditional tapered-headed dilators (p<0.005). In the clinical study, the novel dilators were successfully introduced into the renal pelvis and passed down the collecting system in all eight second-stage PCNL cases. There were no cases of renal pelvic perforation or brisk hemorrhage nor need for transfusion. CONCLUSION: The design of the novel spherical-headed fascial dilator avoided the concentration of pressure at the tapered tip of the current Amplatz dilator by increasing the contact area and uniformly distributing and diffusing the pressure. Therefore, it is feasible to use the spherical-headed fascial dilator for second-stage PCNL.

Effects of Hand Holding on Anxiety and Pain During Prostate Biopsies: A Pilot Randomized Controlled Trial.

BACKGROUND: Effective pain management is limited for patients during prostate biopsy (PBx). Touch support, such as hand holding, has stress-buffering benefits and effective analgesic effects. We conducted a prospective, single-center randomized clinical trial to assess whether hand holding can reduce patient anxiety, pain, and dissatisfaction during PBx. METHODS: Between April 2020 and October 2020, 120 male patients were randomized into three groups: a hand holding with relatives (HR) group, a hand holding with strangers (HS) group and a control group. A visual analog scale (VAS) was used for self-assessments of pain and satisfaction. Anxiety levels were quantified according to the State-Trait Anxiety Inventory (STAI). Hemodynamic changes were also measured. RESULTS: The degree of pain and anxiety in the hand-holding groups was significantly better than that in the control group (P<0.001), and the patients were more willing to undergo repeat PBx (P=0.017). The anxiety levels in the HR group were significantly lower than those in the HS group (P=0.019). During PBx, the changes in systolic blood pressure and heart rate in the hand-holding groups were more stable than those in the control group (P<0.01), and the fluctuations in heart rate in the HR group were smaller than those in the HS group (P<0.01). CONCLUSION: Hand holding, especially with relatives, can promote incremental reductions in anxiety, pain and dissatisfaction in patients during PBx. Hence, we recommend hand holding with relatives as an effective adjunct during PBx.

Is 10/12 Fr Ureteral Access Sheath more Suitable for Flexible Ureteroscopic Lithotripsy?

PURPOSE: To choose the ideal ureteral access sheath (UAS) size for an unstented ureter in flexible ureteroscopic lithotripsy (FURL). MATERIALS AND METHODS: A retrospective study was conducted in patients treated with FURL for renal calculi from 2005 to 2020. The patients were divided into two groups: smaller (10/12 Fr) vs. larger (12/14 Fr) calibre UAS. The outcomes were the insertion success rate, systemic inflammatory response syndrome (SIRS) complication rate after the operation, ureteral wall injury, operative time, and stone-free rate. RESULTS: Of the 1573 patients enrolled, 10/12 Fr UAS was used in 957 patients (Group A), and 12/14 Fr UAS was used in the remaining patients (Group B). The insertion success rate was significantly better in Group A (91.2% vs. 86.9%, P = .006), with no significant difference between the groups regarding the stone-free rate, postoperative pain, operative time or hospital stay. The severity of visible ureteral lesions with 10/12 Fr UAS was significantly lower than that with larger UASs (80.1% vs 85.2%, P < .001). Despite the lack of a significant difference in the incidence of SIRS between the two groups, the incidence of SIRS in the 10/12 Fr group showed a sharp increase with stones > 2 cm (17.0% vs. 8.5%, P = 0.037). CONCLUSION: The use of 10/12 Fr UAS was beneficial with respect to insertion success rate, avoiding ureteral wall injury and not increasing postoperative infectious complications in FURL. We recommend the use of a smaller calibre (10/12 Fr) UAS in patients with renal calculi < 2 cm.

It is efficient to monitor the status of implanted ureteral stent using a mobile social networking service application.

Forgotten ureteral stents (FUS) is a great threat to both patients and doctors. Applications on smartphones can significantly reduce the incidence of FUS. But existing applications do not have instant notification and consultation functions. To implement those function, we developed a ureteral stent tracking system embedded in a social networking service application, WeChat. "Ureteral Stent Tracking System" was developed on WeChat, a social media application using by 1.4 million active users. The study consecutively enrolled patients who underwent ureteral stent installation from April 2018 to July 2018. Each patient's information was recorded on the smartphone by the urologists to create a document immediately after the surgery. The system sends notifications twice a week to both patients and clinicians via the message function of WeChat. A total of 183 patients were enrolled. The most senior patient enrolled was 73 years old. 156 (85.2%) patients underwent stent extraction before the scheduled time. 22 did not undergo stent extraction before the scheduled time because of urinary tract infection or stone residue. They underwent stent extraction within 1 month after the scheduled time. Two patients did not come to the hospital until we had made a phone call to them, though they had received notification from the online system. During the study, no patient was lost-to-follow up. In bilateral stents cases, no stent was forgotten after extraction surgery. A total of 85 (46.4%) patients consulted 132 issues in the system. 52 (39.4%) patients complained about hematuria. 36 (27.3%) patients reported lower urinary tract symptoms. All the consultations were answered within 24 h. "Ureteral Stent Tracking System" implement instant notification and consultation functions via WeChat. It helps urologists to manage indwelling ureteral stents and to reduce the incidence of FUS efficiently.

Circular RNA_PDHX Promotes the Proliferation and Invasion of Prostate Cancer by Sponging MiR-378a-3p.

The dysregulation of circular RNAs (circRNAs) is implicated in the pathogenesis of prostate cancer (PCa). However, the underlying mechanisms by which hsa_circ_0003768 (circPDHX) contributes to PCa remain elusive. The differentially expressed circRNAs between PCa and normal tissues were identified by Gene Expression Omnibus dataset. The association of circPDHX and miR-378a-3p expression with the clinicopathological parameters and prognosis in patients with PCa was analyzed by fluorescence in situ hybridization and The Cancer Genome Atlas dataset. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assays as well as a xenograft tumor model were used to assess the role of circPDHX in PCa cells. circPDHX-specific binding with miR-378a-3p was validated by bioinformatic analysis, luciferase gene reporter, and RNA immunoprecipitation assays. As a result, we found that increased expression of circPDHX was associated with Gleason score (P = 0.001) and pathogenic T stage (P = 0.01) and acted as an independent prognostic factor of poor survival (P = 0.036) in patients with PCa. Knockdown of circPDHX inhibited cell proliferation and invasion in vitro and in vivo, but ectopic expression of circPDHX reversed these effects. Furthermore, circPDHX could sponge miR-378a-3p to promote cell proliferation, but miR-378a-3p counteracted circPDHX-induced cell proliferation and insulin-like growth factor 1 receptor (IGF1R) expression in PCa cells. In conclusion, our findings demonstrated that circPDHX facilitated the proliferation and invasion of PCa cells by sponging miR-378a-3p.

LPCAT1 enhances castration resistant prostate cancer progression via increased mRNA synthesis and PAF production.

Our previously study shown that Lysophosphatidylcholine Acyltransferase1 (LPCAT1) is overexpressed in castration resistant prostate cancer (CRPC) relative to primary prostate cancer (PCa), and androgen controls its expression via the Wnt signaling pathway. While highly expressed in CRPC, the role of LPCAT1 remains unclear. In vitro cell experiments referred to cell transfection, mutagenesis, proliferation, migration, invasion, cell cycle progression and apoptosis, Western blotting, Pulse-chase RNA labeling. BALB/c nude mice were used for in vivo experiments. We found that LPCAT1 overexpression enhanced the proliferation, migration, and invasion of CRPC cells both in vitro and in vivo. Silencing of LPCAT1 reduced the proliferation and the invasive capabilities of CRPC cells. Providing exogenous PAF to LPCAT1 knockdown cells increased their invasive capabilities; however platelet activating factor acetylhydrolase (PAF-AH) and the PAFR antagonist ABT-491 both reversed this phenotype; proliferation of CRPC cells was not affected in either model. LPCAT1 was found to mediate CRPC growth via nuclear re-localization and Histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates. We also found that LPCAT1 overexpression led to CRPC cell resistance to treatment with paclitaxel. LPCAT1 overexpression in CRPC cells drives tumor progression via increased mRNA synthesis and PAF production. Our results highlight LPCAT1 as a viable therapeutic target in the context of CRPC.

Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells.

ELK3, an ETS domain-containing transcription factor, participates in various physiological and pathological processes including cell proliferation, migration, angiogenesis, and malignant progression. However, the role of ELK3 in prostate cancer cells and its mechanism are not fully understood. The contribution of ELK3 to prostate cancer progression was investigated in the present study. We showed that silencing of ELK3 by siRNA in prostate cancer cell DU145 induced S-M phase arrest, promoted apoptosis, inhibited cell proliferation and migration in vitro, and suppressed xenograft growth in mice in vivo. In accordance with its ability to arrest cells in S-M phase, the expression of cyclin A and cyclin B was downregulated. In addition, the expression of p53 was upregulated following ELK3 knockdown, while that of antiapoptotic Bcl-2 was decreased. The migration inhibition may partly due to upregulation of SERPINE1 (a serine protease inhibitor) followed ELK3 knockdown. Consistently, downregulation of SERPINE1 resulted in a modest elimination of migration inhibition resulted from ELK3 knockdown. Furthermore, we found that the AKT signaling was activated in ELK3 knockdown cells, and treatment these cells with AKT inhibitor attenuated SERPINE1 expression induced by ELK3 silencing, suggesting that activation of AKT pathway may be one of the reasons for upregulation of SERPINE1 after ELK3 knockdown. In conclusion, modulation of ELK3 expression may control the progression of prostate cancer partly by regulating cell growth, apoptosis, and migration.

Performance of Modified Early Warning Score (MEWS) and Circulation, Respiration, Abdomen, Motor, and Speech (CRAMS) score in trauma severity and in-hospital mortality prediction in multiple trauma patients: a comparison study.

BACKGROUND: With an increasing number of motor vehicle crashes, there is an urgent need in emergency departments (EDs) to assess patients with multiple trauma quickly, easily, and reliably. Trauma severity can range from a minor to major threats to life or bodily function. In-hospital mortality and trauma severity prediction in such cases is crucial in the ED for the management of multiple trauma and improvement of the outcome of these patients. Previous studies have examined the performance of Modified Early Warning Score (MEWS) or Circulation, Respiration, Abdomen, Motor, and Speech (CRAMS) score based solely on mortality prediction or injury severity prediction. However, to the best of our knowledge, the performances of both scoring systems on in-hospital mortality and trauma severity prediction have not been compared previously. This retrospective study evaluated the value of MEWS and CRAMS score to predict in-hospital mortality and trauma severity in patients presenting to the ED with multiple traumatic injuries. METHODS: All study subjects were multiple trauma patients. Medical data of 1,127 patients were analyzed between January 2014 and April 2018. The MEWS and CRAMS score were calculated, and logistic regression and receiver operating characteristic curve analysis were conducted to investigate their performances regarding in-hospital mortality and trauma severity prediction. RESULTS: For in-hospital mortality prediction, the areas under the receiver operating characteristic curve (AUROCs) for MEWS and CRAMS score were 0.90 and 0.91, respectively, indicating that both of them were good in-hospital mortality predictors. Further, our study indicated that the CRAMS score performed better in trauma severity prediction, with an AUROC value of 0.84, which was higher than that of MEWS (AUROC = 0.77). For trauma severity prediction, the optimal cut-off value for MEWS was 2, while that of the CRAMS score was 8. CONCLUSIONS: We found that both MEWS and CRAMS score can be used as predictors for trauma severity and in-hospital mortality for multiple trauma patients, but that CRAMS score was superior to MEWS for trauma severity prediction. CRAMS score should be prioritized in the prediction of trauma severity due to its excellence as a multiple trauma triage tool and potential contribution to rapid emergency rescue decisions.