Ultrasound-guided extracorporeal shock wave lithotripsy with minimal x-ray exposure prevented genitourinary tract injury patients with urolithiasis in Taiwan.

BACKGROUND: This study investigated the use of ultrasound-guided extracorporeal shock wave lithotripsy (ESWL) to break stones in the genitourinary tract and prevent genitourinary injury. Our goals were to achieve accurate focusing and minimal X-ray exposure for the benefit of the patients. METHODS: The LiteMed LM-9200 lithotripter with ultrasonography and fluoroscopy was used for two different procedures: autoaimed and autoperiodical. These procedures enabled dual focusing on stone localization and tracking. RESULTS: Out of 108 patients who underwent autoperiodical procedures, 29 had no gross hematuria. Among the 335 patients who received autoaimed procedures, 194 had no gross hematuria. The average duration of X-ray exposure during autoperiodical and autoaimed procedures was 120 and 50 s, respectively. CONCLUSION: The ultrasound-guided ESWL with minimal X-ray exposure was found to be useful in treating genitourinary upper-tract urolithiasis in the autoaimed procedure. Patients who underwent the autoaimed procedure experienced less gross hematuria compared to those who underwent the autoperiodical procedure.

Comparison of balloon dissection and telescopic dissection of the preperitoneal space in laparoscopic totally extraperitoneal hernia repair: a systematic review and meta-analysis.

PURPOSE: Safety in creating a preperitoneal space is crucial in laparoscopic totally extraperitoneal (TEP) hernia repairs. In this systematic review and meta-analysis, we compared the outcomes of balloon dissection and telescopic dissection in patients with inguinal or femoral hernias who underwent TEP hernia repair. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane databases for randomized controlled trials (RCTs) and prospective and retrospective studies published from inception to July 2022. Meta-analysis was performed using a random-effects model. The treatment outcome was measured using operation time, incidence of intraoperative hemorrhage, peritoneal laceration, conversion to other approaches, surgical site infection (SSI), hematoma, seroma formation, hernia recurrence, and postoperative pain. RESULTS: Five RCTs, one prospective study, and two retrospective studies (in total, 936 patients) were included. No significant between-group differences were noted in operation time, SSI, hematoma, seroma, recurrence rate, and postoperative pain on days 1 and 7. The conversion rate was significantly lower in the balloon group than in the telescopic group (odds ratio, 0.34; 95% confidence interval, 0.15-0.81). CONCLUSIONS: Both balloon dissection and telescopic dissection are viable techniques for creating preperitoneal space in laparoscopic TEP hernia repair and have similar operation time, complication rate, and postoperative pain. Nevertheless, the conversion rate was lower in patients undergoing balloon dissection than in those undergoing telescopic dissection.

Chronic exposure to IQOS results in impaired pulmonary function and lung tissue damage in mice.

The use of IQOS brand heated tobacco products (HTPs) is increasing worldwide; however, little is known about the long-term effects of HTPs aerosol exposure on the lungs. Herein, we exposed C57BL/6 J mice for 24 weeks to clean air, IQOS aerosol, or cigarette smoke, and determined pulmonary function, lung tissue pathology, inflammation, and oxidative stress. Compared with the control group mice, IQOS group mice showed substantially decreased weight and lung function. Levels of IL-6 and TNF-a, as well as oxidative stress markers, were comparable to those found in the cigarette group. In addition, hematoxylin and eosin staining showed that the alveolar space was enlarged and that emphysema had formed in the IQOS group. Masson staining showed that collagen deposition areas were substantially increased in the airway walls in the IQOS group than in the control group. Immunohistochemical staining showed epithelial-mesenchymal transition in the airways of mice in the IQOS group. In conclusion, chronic exposure to IQOS aerosol results in impaired pulmonary function and lung tissue damage; hence, concern should be raised regarding the long-term safety of this product.

miR-137 represses migration and cell motility by targeting COX-2 in non-small cell lung cancer.

Background: Lung cancer is a common malignant tumor, with, non-small cell lung cancer (NSCLC) accounting for about 80-85% of cases. This study investigated the expression of miR-137 in NSCLC tissues and cells and its effects on the migration and invasion of NSCLC cells and related mechanisms. Methods: We collected the neoplastic and paracancerous tissues of NSCLC patients, detected the expression of miR-137 in NSCLC tissues and cell lines by real-time quantitative polymerase chain reaction (RT-qPCR), and analyzed the correlation between miR-137 expression and the clinicopathological features and survival of NSCLC. Following transfection with miR-137 mimic or inhibitor in NSCLC cell lines (A549 or H1299) to upregulate or downregulate the expression of miR-137, transwell assay was employed to detect the effects of miR-137 on migration or invasion. Online software was employed to predict and analyze the target gene of miR-137, and luciferase reporter gene system was adopted to validate it. The effects of miR-137 on the expressions of COX-2 and Epithelial-Mesenchymal Transition (EMT) related proteins were investigated by Western blot. Results: Compared to paracancerous tissues and BEAS-2B cells, the expressions of miR-137 in NSCLC tissues, A549 and H1299 cells were dramatically down-regulated (P<0.01). After transfection with miR-137 mimic or inhibitor in A549 and H1299 cells, the miR-137 expressions were markedly up-regulated or down-regulated (P<0.01), respectively. The number of migrating or invading cells was observably decreased or increased (P<0.01) after transfected with mimic or inhibitor, respectively, while relative luciferase activity was evidently decreased in cells co-transfected with miR-137 mimic and wild type recombined vector of 3'UTR of COX-2. While the expressions of COX-2 and E-cadherin were both substantially reduced in A549 cells treated with miR-137 mimic, that of vimentin was substantially raised. The expression of miR-137 correlated with smoking history, lymph node metastasis, and TNM clinical stage, and patients with high miR-137 expression had apparent longer survival. Conclusions: The expression of miR-137 was significantly down-regulated in NSCLC tissues and cells, and correlated with NSCLC progress. miR-137 suppressed the migration and invasion of NSCLC cells through regulating EMT relative proteins by targeting COX-2. miR-137 is expected to become a novel biomarker and therapeutic target of NSCLC.

[Analysis of HPRT1 gene variant and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome but no specimen from affected probands].

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome (LNS) but no specimen from the affected probands. METHODS: All affected individuals in this pedigrees were male and had deceased during childhood, with no biological specimen left. Based on their typical neurological dysfunction and tendency for self-mutilation, the diagnosis of LNS was suspected. Sanger sequencing was carried out to detect potential variant of the HPRT1 gene among female members from the pedigree. Following the identification of the pathogenic variant, prenatal diagnosis was provided for a high-risk fetus. RESULTS: The proband's mother and three other females were found to harbor heterozygous c.500_501delGGinsC (p.Arg167fs*23) variant of the HPRT1 gene, which was unreported previously. Prenatal diagnosis showed that the fetus was a male and had inherited the same pathogenic variant. CONCLUSION: The c.500_501delGGinsC variant of the HPRT1 gene probably underlay the LNS in this pedigree. Above finding has provided a basis for prenatal diagnosis and genetic counseling for this pedigree.

The PDE5 inhibitor, vardenafil, ameliorates progressive pathological changes in a focal segmental glomerulosclerosis mouse model.

AIMS: Phosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5'-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model. MATERIALS AND METHODS: FSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 µg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions. KEY FINDINGS: In this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-ß-induced fibroblast-to-myofibroblast transdifferentiation. SIGNIFICANCE: Our data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.

A Safe and Effective Two-Step Tract Dilation Technique in Totally Ultrasound-Guided Percutaneous Nephrolithotomy.

PURPOSE: To evaluate the safety and the efficacy of a radiation-free 2-step tract dilation technique in totally ultrasound-guided percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: From Oct 2018 to Mar 2020, we prospectively and consecutively enrolled 18 patients with 19 kidney units with urolithiasis. The nephrostomy tract was established by the following four steps: 1) ultrasound-guided renal puncture, 2) first-stage serial dilation to 16 Fr with Amplatz dilators, 3) check and adjustment of the partially dilated tract with a ureteroscope, 4) second-stage dilation with a 24-Fr balloon dilator. RESULTS: The median age was 62.0 [IQR 11.0] years, and 11 (61.1%) were male. The median stone size was 3.3 [3.6] cm2, and stone laterality was almost equal over both sides. Successful tract establishment on the first attempt without fluoroscopy was achieved in 18 (94.7%) operations. The median tract establishment time was 10.4 [4.9] mins, and the median operation time was 67.0 [52.2] mins. The median hemoglobin drop was 1.0 [1.1] g/dL, and none required blood transfusion. Three (15.8%) developed fever. Pleural injury occurred in two (10.5%) operations (both had supracostal puncture), and one required drainage with pigtail. Stone-free status was achieved in 15 (77.8%) operations at 3 months postoperatively. CONCLUSIONS: Herein we present a radiation-free 2-step tract dilation technique, which is characterized by ureteroscopic check of the partially dilated tract in between the first dilation with serial fascial dilators and the second dilation with balloon. Our data suggest that it is a safe and effective method.

The intraureteral placement of the stent's distal end decreases stent-related urinary symptoms: a prospective randomized clinical trial.

PURPOSE: We compared intraureteral stent placement (CIU-SP) with conventional stent placement (C-SP) regarding the stent-related symptoms. METHODS: We randomized patients who underwent ureteroscopic lithotripsy into two groups. In CIU-SP group, a 16-cm or 18-cm stent was placed with its distal end above the ureterovesical junction. In C-SP group, a 22-cm or 24-cm stent was placed in a conventional method. Stent-related symptoms were assessed with the Ureteral Stent Symptom Questionnaire (USSQ) before the stent was removed, around 7 days after the operation. The primary outcome was the urinary symptoms; the secondary outcomes included postoperative pain and quality of life. RESULTS: We randomized 103 patients, of which 91 (45 in CIU-SP and 46 in C-SP) entered the final analysis. Regarding the primary endpoint, the CIU group had less urinary symptoms; the mean USSQ urinary symptom score was significantly lower in the CIU-SP versus C-SP group (25.5 ± 6.3 vs 31.7 ± 5.9, P < 0.001). The CIU-SP group also had more favorable profiles in the following outcomes: lower USSQ body pain score (15.5 ± 5.3 vs 20.1 ± 5.2, P < 0.001), lower overall pain score (3.2 ± 2.2 vs 5.7 ± 2.3, P < 0.001), less number of pain site (1.0 ± 0.9 vs 1.7 ± 0.9, P = 0.001, lower USSQ general health score (10.4 ± 3.7 versus 13.9 ± 3.4, P < 0.001), and lower USSQ work performance score (5.2 ± 3.3 versus 6.7 ± 2.8, P = 0.033). In either group, there was no complication of Clavien-Dindo Class 2 or greater. CONCLUSION: The complete intraureteral placement significantly decreases stent-related urinary symptoms and pain. It is also associated with better postoperative general health condition and is less likely to limit physical activity and work ability.

Efficacy of Penile Low-Intensity Shockwave Therapy and Determinants of Treatment Response in Taiwanese Patients with Erectile Dysfunction.

BACKGROUND: Erectile dysfunction (ED) remains an emotional wrench to patients and a therapeutic challenge to urologists in andrology clinics worldwide. This is, in part, related to refraction to, or transient effect of phosphodiesterase 5 inhibitors (PDE5i), coupled with patients' dissatisfaction with this treatment modality. Low-intensity extracorporeal shockwave therapy (Li-ESWT) is an evolving treatment option, with promising curative potential. Current international guidelines are inconclusive, bear weak recommendation strength, and lack ethnogeographic consensus. OBJECTIVES: This study evaluated the safety, efficacy, and effect duration of Li-ESWT, as well as exploring disease-associated determinants of treatment success in Taiwanese males with ED. METHODS: A cohort of 69 eligible cases treated with 12 sessions of Li-ESWT and followed up for at least 12 months after treatment, between January 2018 and December 2019 at our medical facility, was used. The present single-center, retrospective, non-randomized, single-arm study employed standardized erectile function evaluation indices, namely, the five-item International Index of Erectile Function (IIEF-5) and Erection Hardness Score (EHS). Clinicopathological analyses of selected variables and comparative analyses of time-phased changes in the EF indices relative to baseline values were performed. Evaluation of treatment success was based on minimal clinically important difference (MCID), using a binomial logistic regression model. RESULTS: The median age and duration of ED for our Taiwanese cohort were 55 years and 12 months, respectively, and an average of 31.3% presented with co-morbidities. The mean improvement in IIEF-5, EHS, and quality of life (QoL) domain scores relative to the baseline values was statistically very significant (p < 0.001) at all indicated follow-up time-points. When stratified, Taiwanese patients with severe and moderate ED benefited more from Li-ESWT, compared with those in the mild or mild-to-moderate group. Patients' pre-Li-ESWT PDE5i response status was not found to significantly influence Li-ESWT response. Univariate analysis showed that age > 45 years (p = 0.04), uncontrolled diabetes mellitus (p = 0.04), and uncontrolled hyperlipidemia (p = 0.01) were strongly associated with Li-ESWT efficacy; however, only age > 45 years (p = 0.04) and uncontrolled hyperlipidemia (p = 0.03) were found to be independent negative predictors of Li-ESWT success by the multivariate logistic model. Follow-up was uneventful, with no treatment-related adverse events or side effects reported. Of the treated patients, 86.1% indicated satisfaction with the treatment regimen, and over 90% indicated they would recommend the same therapy to others. CONCLUSIONS: Li-ESWT is a safe and efficacious therapeutic modality for Taiwanese patients with ED. Uncontrolled hyperlipidemia and age > 45 years are independent negative predictors of treatment success for this cohort.

Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2).

BACKGROUND: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. OBJECTIVE: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. METHODS: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. RESULTS: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1-TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. CONCLUSION: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Extracorporeal Shockwave Therapy (ESWT) Alleviates Pain, Enhances Erectile Function and Improves Quality of Life in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), affecting over 90% of patients with symptomatic prostatitis, remains a therapeutic challenge and adversely affects patients' quality of life (QoL). This study probed for likely beneficial effects of ESWT, evaluating its extent and durability. PATIENTS AND METHODS: Standardized indices, namely the pain, urinary, and QoL domains and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL_US were employed in this study of patients with CP/CPPS who had been refractory to other prior treatments (n = 215; age range: 32-82 years; median age: 57.5 ± 12.4 years; modal age: 41 years). RESULTS: For CP symptoms, the mean pre-ESWT NIH-CPSI total score of 27.1 ± 6.8 decreased by 31.3-53.6% over 12 months after ESWT. The mean pre-ESWT NIH-CPSI pain (12.5 ± 3.3), urinary (4.98 ± 2.7), and QoL (9.62 ± 2.1) domain scores improved by 2.3-fold, 2.2-fold, and 2.0-fold, respectively, by month 12 post-ESWT. Compared with the baseline IPSS of 13.9 ± 8.41, we recorded 27.1-50.9% amelioration of urinary symptoms during the 12 months post-ESWT. For erectile function, compared to pre-ESWT values, the IIEF-5 also improved by ~1.3-fold by month 12 after ESWT. This was corroborated by EHS of 3.11 ± 0.99, 3.37 ± 0.65, 3.42 ± 0.58, 3.75 ± 0.45, and 3.32 ± 0.85 at baseline, 1, 2, 6, and 12 months post-ESWT. Compared to the mean pre-ESWT QoL score (4.29 ± 1.54), the mean QoL values were 3.26 ± 1.93, 3.45 ± 2.34, 3.25 ± 1.69, and 2.6 ± 1.56 for months 1, 2, 6, and 12 after ESWT, respectively. CONCLUSIONS: This study shows ESWT, an outpatient and easy-to-perform, minimally invasive procedure, effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with refractory CP/CPPS.

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer.

Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein-protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through "SRD5A1 withdrawal" or "SHBG induction" is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

[Analysis of DFNA5 gene variant in a Chinese pedigree affected with late-onset non-syndromic hearing loss].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with autosomal dominant late-onset non-syndromic hearing loss (NSHL). METHODS: Clinical data of the pedigree were collected. Genomic DNA was extracted from peripheral blood samples of the proband and other family members. Trio whole exome sequencing was carried out for 19 396 genes to identify potential pathogenic variants. Sanger sequencing was carried out to verify the candidate variant in the pedigree. RESULTS: The proband and his father were found to carry a c.1183+1delG p.? variant of the DFNA5 gene. The variant was confirmed to be co-segregating with the disease phenotype in the pedigree. CONCLUSION: The c.1183+1delG p.? variant of the DFNA5 gene probably underlay the late onset NSHL in this pedigree. Above finding has enabled accurate genetic counseling for this pedigree.

MED10 Drives the Oncogenicity and Refractory Phenotype of Bladder Urothelial Carcinoma Through the Upregulation of hsa-miR-590.

BACKGROUND: Dysfunctional transcription machinery with associated dysregulated transcription characterizes many malignancies. Components of the mediator complex, a principal modulator of transcription, are increasingly implicated in cancer. The mediator complex subunit 10 (MED10), a vital kinase module of the mediator, plays a critical role in bladder physiology and pathology. However, its role in the oncogenicity, metastasis, and disease recurrence in bladder cancer (BLCA) remains unclear. OBJECTIVE: Thus, we investigated the role of dysregulated or aberrantly expressed MED10 in the enhanced onco-aggression, disease progression, and recurrence of bladder urothelial carcinoma (UC), as well as the underlying molecular mechanism. METHODS: Using an array of multi-omics big data analyses of clinicopathological data, in vitro expression profiling and functional assays, and immunocytochemical staining, we assessed the probable roles of MED10 in the progression and prognosis of BLCA/UC. RESULTS: Our bioinformatics-aided gene expression profiling showed that MED10 is aberrantly expressed in patients with BLCA, is associated with high-grade disease, is positively correlated with tumor stage, and confers significant survival disadvantage. Reanalyzing the TCGA BLCA cohort (n = 454), we showed that aberrantly expressed MED10 expression is associated with metastatic and recurrent disease, disease progression, immune suppression, and therapy failure. Interestingly, we demonstrated that MED10 interacts with and is co-expressed with the microRNA, hsa-miR-590, and that CRISPR-mediated knockout of MED10 elicits the downregulation of miR-590 preferentially in metastatic UC cells, compared to their primary tumor peers. More so, silencing MED10 in SW1738 and JMSU1 UC cell lines significantly attenuates their cell proliferation, migration, invasion, clonogenicity, and tumorsphere formation (primary and secondary), with the associated downregulation of BCL-xL, MKI67, VIM, SNAI1, OCT4, and LIN28A but upregulated BAX protein expression. In addition, we showed that high MED10 expression is a non-inferior biomarker of urothelial recurrence compared with markers of cancer stemness; however, MED10 is a better biomarker of local recurrence than any of the stemness markers. CONCLUSION: These data provide preclinical evidence that dysregulated MED10/MIR590 signaling drives onco-aggression, disease progression, and recurrence of bladder UC and that this oncogenic signal is therapeutically actionable for repressing the metastatic/recurrent phenotypes, enhancing therapy response, and shutting down stemness-driven disease progression and relapse in patients with BLCA/UC.

AMPK α1 Downregulates ROS Levels Through Regulating Trx Leading to Dysfunction of Apoptosis in Non-Small Cell Lung Cancer.

PURPOSE: AMP-activated protein kinase α1 (AMPK α1) associates closely with cancers. However, the relationship between AMPK α1 and non-small cell lung cancer (NSCLC) is not fully understood. In this study, we aim to explore the role and mechanism of AMPK α1 in NSCLC initiation and progression. MATERIALS AND METHODS: A total of 165 clinical NSCLC specimens were included in the formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays. The expression levels of AMPK α1 and thioredoxin (Trx) in NSCLC cancer tissues and adjacent non-tumor lung tissues were measured through using immunohistochemistry. MTT assay was used to detect cell proliferation. Intracellular ROS levels were measured by using H2DCFDA reagent. Lentiviruses including LV-PRKAA1-RNAi, LV-PRKAA1 and a negative LV-control were used to infect A549 cells to modulate AMPK α1 expression in vitro. Immunoblotting was used to determine the modulation relationship between AMPK α1 and Trx. Log rank test and Kaplan-Meier survival analysis were performed to evaluate the significances of AMPK α1 and Trx expression levels on NSCLC patients' prognoses. RESULTS: AMPK α1 was highly expressed in NSCLC cancer tissues and correlated with poor prognosis in patients with NSCLC. In A549 cells, overexpression of AMPK α1 promoted proliferation, suppressed ROS levels and inhibited apoptosis. Moreover, inhibition of AMPK α1 expression achieved the opposite effects. Trx was significantly overexpressed in NSCLC cancer tissues; furthermore, Trx expressed much more in cytoplasm when compared with cell nucleus. Trx expression levels were positively correlated with AMPK α1 expression levels in NSCLC tissues. AMPK α1 could regulate Trx in A549 cells. No significant correlations were observed between Trx expression variances and prognoses in NSCLC patients. Combination of AMPK α1 and Trx had no advantage in predicting prognoses of NSCLC patients. CONCLUSION: These results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of Trx expression, and thus represents a potential treatment target in patients with NSCLC.

[Genetic analysis of a pedigree affected with congenital split-hand/foot malformation].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with split hand/foot malformation (SHFM). METHODS: Genomic DNA of the proband and other affected members was extracted from peripheral blood samples. Chromosomal microarray analysis was employed to detect genome-wide copy number variations (CNVs). RESULTS: A 400 kb microduplication was identified in the 10q24.31-q24.32 region among all affected individuals. The microduplication has involved four genes, namely LBX1, BTRC, POLL and DPCD, in addition with part of FBXW4 gene. CONCLUSION: The 10q24.31-q24.32 microduplication has segregated with the disease phenotype in this pedigree and probably underlay the SHFM malformation in the patients.

Association between interleukin-8 rs4073 polymorphism and prostate cancer: A meta-analysis.

BACKGROUND/PURPOSE: Interleukin-8 (IL-8) is an inflammatory cytokine and plays important role in development of cancers. We conducted a meta-analysis to explore the association between IL-8 rs4073 polymorphism and risk of prostate cancer. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched for only case-control studies published before February 2019. The methodological quality assessment of included studies was performed based on Newcastle-Ottawa Quality Scale (NOS). Based on the heterogeneity, we conducted a meta-analysis using random-effect models. Pooled odds ratios (ORs) with a 95% confidence interval (CI) were calculated using the allele (T vs. A), homozygous (TT vs. AA), heterozygous (TA vs. AA), dominant (TT + TA vs. AA), and recessive (TT vs. TA + AA) genetic models to assess the strength of the relationship between IL-8 rs4073 polymorphism and prostate cancer risk. In addition, the stability of our analysis was evaluated by heterogeneity, sensitivity, subgroup of ethnicity and study design, and publication bias analysis. RESULTS: We included 6 case-control studies with a total of 1752 cases and 1982 controls. Significantly higher prostate cancer risk of 1.12 (95% CI = 1.01-1.25), 1.26 (95% CI = 1.03-1.55), and 1.20 (95% CI = 1.02-1.41) were found for the allele, homogeneous, and recessive model, respectively. Though there was no statistical association with other genetic models in our meta-analyses, a tendency of higher prostate cancer risk was observed in all five genetic models. CONCLUSION: The major findings of this meta-analysis suggested that IL-8 rs4073 polymorphism is significantly associated with risk of prostate cancer.

The demographic and treatment options for patients with large cell neuroendocrine carcinoma of the lung.

INTRODUCTION: Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive tumor, for which the optimal treatment strategies for LCNEC have not yet been established. In order to explore how to improve the outcome of prognosis for patients with LCNEC, this study investigated the effect of different treatments based on the data obtained from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: A total of 2594 LCNEC cases with conditional information were extracted from SEER database. Propensity Score Matching (PSM) method was conducted to reduce possible bias between groups. One-way ANOVA was used to test the differences of characteristics between groups. Univariate and multivariate Cox proportional hazard models were applied to identify prognostic factors. RESULTS: Clinicopathologic characteristics including gender, age, TNM stage, T stage, N stage, and M stage were all identified as independent prognostic factors. Surgery benefited stage I, II, and III LCNEC patients' prognoses. The combination treatment that surgery combining with chemotherapy was the optimal treatment for stage I, II, and III LCENC patients. Compared with palliative treatment, stage IV patients obtained better prognoses with the treatment of radiation, chemotherapy, or chemoradiation. When comparing the effect of the three treatments (radiation, chemotherapy, and chemoradiation) in achieving better prognosis for stage IV patients, chemotherapy alone was better than the other treatments. CONCLUSION: Surgery combining with chemotherapy was the optimal treatment for stage I, II, and III LCNEC patients; chemotherapy alone achieves more benefit than the other treatments for stage IV patients.

MicroRNA­144­3p may participate in the pathogenesis of preeclampsia by targeting Cox­2.

Preeclampsia remains a major cause of maternal mortality and morbidity worldwide. It is generally accepted that the development of the placenta, including spiral artery remodelling, normal trophoblast cells function and maternal­fetal inflammation­immune interactions, is critical for the pathogenesis of preeclampsia. Several investigations have demonstrated that microRNAs (miRNAs/miRs) in the placenta may be potential molecular markers for diagnosis of preeclampsia. In the current study, the aim was to investigate the expression of miR­144­3p in the placenta of patients with preeclampsia and normal placentas, and to explore the potential target genes. miRNA microarray analysis was performed using three paired placentas (preeclampsia and normal) in order to find differential expression of miRNAs. Following this, miR­144­3p was selected as a differentially expressed miRNA and validated using in situ hybridization to determine the clinical significance in placentas with preeclampsia. A potential target gene of miR­144­3p, cyclooxygenase­2 (Cox­2), was identified by bioinformatics, luciferase reporter assay and western blotting. The expression of Cox­2 was also examined by immunohistochemical staining of samples of placenta from patients with preeclampsia and normal placenta. Western blot analysis was performed to investigate the effect of miR­144­3p on the expression of Cox­2 in HTR­8/SVneo cells in vitro. miR­144­3p was decreased in placentas from patients with preeclampsia. A luciferase reporter assay demonstrated that Cox­2 was a potential miR­144­3p target gene and the result was verified by western blotting. A negative correlation was observed between miR­144­3p and Cox­2 in preeclamptic placenta by immunohistochemical staining and in situ hybridization. Western blot analysis demonstrated that overexpression of miR­144­3p decreased Cox­2 expression by 38.2% in HTR­8/SVneo cells. Understanding the differential expression of miR­144­3p and its association with Cox­2 may aid the exploration of the pathogenesis of preeclampsia, and contribute to the development of miRNA­based therapies in the future.

Modified U-Shaped ileal neobladder designed for facilitating neobladder-urethral anastomosis in extracorporeal reconstruction after robotic-assisted radical cystectomy.

BACKGROUND/OBJECTIVE: To report the initial experience and the early outcomes of a modified U-shaped ileal neobladder, which was developed to facilitate the neobladder-urethral anastomosis by minimizing the anastomotic tension. PATIENTS AND METHODS: Between June 2015 and December 2016, two male and two female patients (median age: 65.5 years, range: 43-72 years) underwent the modified U-shaped ileal neobladder after robotic-assisted radical cystectomy (RARC). The most mobile and dependent ileal segment was first selected intracorporeally as the site for later neobladder-urethral anastomosis. The neobladder was formed extracorporeally, and the previously selected ileal segment formed the most dependent portion of the neobladder. The neobladder-urethral anastomosis was completed after robotic redocking. RESULTS: The median follow-up was 8 months (3-21 months). The median operative time, console time, and extracorporeal reconstruction time were 620 min (534-674 min), 372 min (314-420 min), and 151 min (128-215 min), respectively. In all patients, the neobladder-urethral anastomosis was completed intracorporeally with minimal tension. The median hospital time after the surgery was 14.5 days (14-19 days). Postoperatively, the median peak flow rate and void volume were 10 ml/s (4-35 ml/s) and 258 ml (88-775 ml). The median postvoid residual was 20 ml (10-53 ml). At daytime, two were completely continent; the other two reported mild (1-2 pads) and moderate (>2 pads) incontinence at the postoperative 3 and 4 months, respectively. Three reported nocturnal enuresis. CONCLUSIONS: Our initial experience demonstrated that the modified U-shaped neobladder designed for minimizing the anastomotic tension is safe and feasible with its satisfactory functional outcomes.