Adrenomedullin/FOXO3 enhances sunitinib resistance in clear cell renal cell carcinoma by inhibiting FDX1 expression and cuproptosis.

Cuproptosis, a new type of copper-induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib-resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM-regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.

[Correlation of environment temperature with the incidence of testicular torsion].

Objective： To explore the influence of environment temperature on the incidence of testicular torsion. METHODS: We collected the clinical data on 172 cases of testicular torsion diagnosed in the Second Hospital of Hebei Medical University from December 2013 to December 2020. According to the local environment temperature on the day of onset, we divided the patients into groups A (below 0℃), B (0－10℃), C (10－20℃) and D (above 20℃), and compared the incidence rates of testicular torsion among the four groups, followed by correlation analysis. RESULTS: The incidence rate of testicular torsion was 12.8% (n = 22) in group A, 35.5% (n = 61) in B, 34.9% (n = 60) in C and 16.9% (n = 29) in D, the highest at 0－10℃ in group B, with statistically significant difference among the four groups (χ2 = 29.07, P <0.001). Spearman correlation analysis indicated that the incidence of testicular torsion was negatively correlated with the environment temperature (r = －0.261, P <0.01), with no statistically significant difference among different seasons (χ2 = 5.349, P >0.05), but higher in autumn and winter than in the other two seasons. CONCLUSION: The incidence of testicular torsion is negatively correlated with the environment temperature, elevated when the temperature decreases, but has no statistically significant difference among different seasons, though relatively higher in autumn and winter.

[Application of Intraoperative Transesophageal Echocardiography in the Treatment of Renal Cell Carcinoma with Inferior Vena Cava Tumor Thrombus].

Objective To investigate the value of intraoperative transesophageal echocardiography (TEE) in the diagnosis and treatment of renal cell carcinoma with inferior vena cava tumor thrombus. Methods Ten patients of renal cell carcinoma with inferior vena cava tumor thrombus treated in the Second Hospital of Hebei Medical University from January 2017 to January 2021 were selected.TEE was employed to locate the position of the tumor thrombus,determine the occlusion point of the inferior vena cava,count the intraoperative tumor thrombus shedding rate,examine the tumor thrombus resection integrity,and measure blood loss and other indicators,on the basis of which the application value of TEE in the operation of renal cell carcinoma with inferior vena cava tumor thrombus was evaluated. Results All the 10 patients had completed the operations successfully,including 8 patients of open operation and 2 patients of laparoscopic operation.TEE showed tumor thrombi clearly,and all the tumor thrombi were completely removed.There was no tumor thrombus shedding during the operation.The blood loss varied within the range of 300-800 ml,with the mean of (520.0±193.2) ml.The grade III tumor thrombi in 2 patients and the grade I tumor thrombus in 1 patient diagnosed before operation were reduced to grade Ⅱ and upgraded to grade Ⅱ,respectively,by TEE.One patient had no floating tumor thrombus at the end of tumor thrombus before operation,and the blocking position was adjusted in time with the assistance of TEE to avoid the shedding of the floating tumor thrombus. Conclusion TEE can accurately determine and dynamically monitor the location and shape of inferior vena cava tumor thrombus,which provides an important reference and has a significant clinical value in the operation of renal cell carcinoma with inferior vena cava tumor thrombus.

Clinical application of directional dilation in transurethral columnar balloon dilation of the prostate.

Objectives: To investigate the clinical efficacy and safety of directional dilation in transurethral columnar balloon dilation of the prostate (TUCBDP), and summarize relevant experience. Methods: Retrospective analysis was performed on the clinical data of 38 patients with prostatic hyperplasia admitted to the Department of Urology, The Second Hospital of Hebei Medical University from October 2017 to January 2020 who underwent TUCBDP with directional dilation (12 o'clock direction). Complications related to surgery including hemorrhage, urinary incontinence and pain were analyzed. Moreover, patients were followed up for six months postoperatively, and their preoperative and postoperative maximum urine flow rate (Qmax), residual bladder volume (PVR), international prostate symptom score (IPSS), and quality of life score (QoL) were compared. Results: Thirty-eight patients underwent TUCBDP successfully, with dilation positions all in the 12 o'clock direction and no ectopic dilation point. All patients had no severe hematuria postoperatively. Numeric rating scales (NRS) was utilized twice at 8h and 24hour postoperatively to score the pain degree, with no statistically significant difference (P=0.157). Hb was reexamined on the first day postoperatively, with no statistically significant difference compared with that preoperatively (P>0.05). The bladder irrigation time was 1-2 Day postoperatively, while the urethra was removed five days postoperatively, with no severe hematuria in all patients. Two patients developed mild urinary incontinence, which disappeared on the 2nd and 5th day after extubation, respectively, while no patients had dysuria and urinary retention. All 38 patients were detected for Qmax and PVR after urethral removal, with a statistically significant difference compared with those preoperatively (P<0.001), and were reexamined three months postoperatively for Qmax and PVR, with a statistically significant difference compared with those postoperatively (P<0.001); IPSS and QoL were significantly different from those preoperatively with statistically significance (P<0.001). At the follow-up six months postoperatively, Qmax, PVR and IPSS showed statistically significant differences compared with that at three months postoperatively (P<0.05), while QoL showed no statistically significant differences compared with that at 3 months postoperatively (P=0.088). Conclusion: Directional dilation is improved in TUCBDP as having the advantages of safety and effectiveness, and it is worthy of clinical promotion.

A comparative study on the Efficacy of Retroperitoneoscopic Pyeloplasty and Open Surgery for Ureteropelvic Junction Obstruction in Children.

OBJECTIVES: To compare the therapeutic effect of retroperitoneoscopic dismembered pyeloplasty and open ureteropelvic junction plasty on the ureteropelvic junction obstruction (UPJO) in children. METHODS: After the retrospective analysis of clinical data, 78 children with ureteropelvic junction stenosis treated from January, 2012 to June, 2018 were divided into two groups: OP (open pyeloplasty) group (38 cases) and LP (laparoscopic dismembered pyeloplasty) group (40 cases) according to the surgical methods. The operation time, intraoperative bleeding volume, postoperative length of stay (LOS), postoperative complication rate, postoperative hydronephrosis improvement and other indicators were compared between the two groups. RESULTS: All patients underwent surgery successfully, without conversion to open surgery in LP group. The incidence of postoperative urine leakage and the recovery of hydronephrosis between LP group and OP group 12 months after operation showed no statistically significant difference (P>0.05). The intraoperative bleeding volume, the incidence of postoperative retroperitoneal hematoma, and the postoperative LOS in LP group were lower than those in OP group, while the operation time was longer than that in the OP group, with statistically significant difference (P<0.05). CONCLUSION: Retroperitoneoscopic dismembered pyeloplasty had similar effect with open dismembered pyeloplasty, but faster recovery and fewer complications, so it has become the preferred treatment method for UPJO in children.

Effect of tadalafil combined with atorvastatin on hemodynamics and sexual function in middle-aged and elderly patients with hyperlipidemia complicated with erectile dysfunction.

OBJECTIVE: To evaluate the effect and clinical significance of tadalafil combined with atorvastatin on hemodynamics and sexual function in middle-aged and elderly patients with hyperlipidemia complicated with Erectile dysfunction (ED). METHODS: Eighty patients with hyperlipidemia complicated with ED who were treated at The Second Hospital of Hebei Medical University from January 2019 to June 2020 were selected. Using a completely randomized design experimental method, these 80 patients were randomly divided into two groups: the experimental group and the control group, with 40 cases in each group. The control group was treated with a single drug, atorvastatin calcium, while the experimental group was given tadalafil orally on the basis of the control group for 3 months. Changes in the levels of inflammatory factors such as IL-6, TNF and CRP, adverse drug reactions, changes in hemodynamic indicators such as HSV, LSV, PSV, HCT and ESR before and after treatment, as well as changes in sexual function after treatment were compared and analyzed between the two groups. RESULTS: TNF-a, CRP and IL-6 in the experimental group were significantly lower than those in the control group after treatment, with statistically significant differences (p<0.05). There was no significant difference in the incidence of adverse drug reactions between the two groups (p=0.18). After treatment, hemodynamic indexes and sexual function indexes of the experimental group were significantly improved compared with those in the control group, with statistically significant differences (p<0.05). CONCLUSION: A significant improvement effect can be achieved by tadalafil combined with atorvastatin on hemodynamics and sexual function in middle-aged and elderly patients with hyperlipidemia complicated with ED. At the same time, the combination of the two has synergism on inflammatory factors and blood rheology, and the incidence of adverse reactions is not significantly increased.

[Transumbilical single-port laparoscopy combined with improved double hernia needles for pediatric hydrocele].

OBJECTIVE: To compare the clinical effect of transumbilical single-port laparoscopy combined with improved double hernia needles with that of traditional open surgery in the treatment of hydrocele in children. METHODS: We retrospectively analyzed 35 cases (54 sides) of pediatric hydrocele treated by transumbilical single-port laparoscopy combined with improved double hernia needles (laparoscopy group). We recorded the operation time, intraoperative blood loss, hospital stay, scrotal edema, and postoperative complications and compared them with those of another 46 cases (58 sides) treated by traditional open surgery (open surgery group) during the same period. RESULTS: The laparoscopy group showed a significantly shorter operation time, less intraoperative blood loss, milder scrotal edema, and fewer hospital days than the open surgery group (all P<0.05). However, no statistically significant difference was found in the incidence of postoperative complications between the two groups (P>0.05). Subcutaneous emphysema developed in 2 patients in the laparoscopy group, which disappeared after 1－3 days of oxygen inhalation and other symptomatic treatment, while scrotal hematoma occurred in 1 and incision fat liquefaction in 2 patients in the open surgery group 3 days postoperatively, which healed after debridement suture and daily dressing, respectively. The patients were followed up for 3－6 months, which revealed no late complications in the laparoscopy group but 1 case of unilateral recurrence and 2 cases of offside recurrence in the open surgery group, all cured by laparoscopic internal ring ligation. CONCLUSIONS: Transumbilical single-port laparoscopy combined with improved double hernia needles is superior to traditional open surgery for the treatment of pediatric hydrocele and therefore deserves clinical generalization.

No genetic causal relationship between acne and prostate cancer through Mendelian randomization combined with meta-analysis.

Background: Previous observational studies regarding the relationship between acne and prostate cancer have reported inconsistent results. As such studies are prone to biases, we conducted this Mendelian randomization (MR) analysis to better explore the causal association between acne and prostate cancer. Methods: The genetic data for assessing acne were acquired from the largest genome-wide association study (GWAS) of acne by far, and the genetic data for assessing prostate cancer were acquired from the FinnGen consortium, UK Biobank, European Bioinformatics Institute, and IEU OpenGWAS project. We performed two-sample MR analyses using data from these GWASs followed by a meta-analysis to provide an overall evaluation. The primary MR methods used included inverse variance weighted, MR-Egger, and weighted median. Leave-one-out sensitivity tests, Cochran's Q tests, and MR-Egger intercept tests were used to bolster the robustness of the MR results. Results: Through MR combined with meta-analysis, our study found no genetic causal relationship between acne and prostate cancer (p=0.378; odds ratio=0.985; 95% confidence interval, 0.954-1.018). Sensitivity tests ensured the robustness of this result. Conclusion: Acne should not be considered as a morbidity hazard factor for prostate cancer.

Efficacy and safety of laparoendoscopic single-site adrenalectomy versus conventional laparoscopic adrenalectomy: an updated systematic review and meta-analysis.

INTRODUCTION: Laparoendoscopic single-site adrenalectomy (LESSA) has the advantages of early recovery and better cosmetic appearance. However, there are still debates on the efficacy and safety of LESSA and conventional laparoscopic adrenalectomy (CLA). AIM: To reevaluate the efficacy and safety of LESSA vs CLA for adrenal lesions. MATERIAL AND METHODS: A systematic literature research of PubMed, Ovid, Scopus (up to February 2021), and citation lists was performed to identify eligible studies. All studies comparing LESSA versus CLA were included. Data were analyzed using the RevMan 5.4 software. RESULTS: Overall, eighteen studies including 1307 patients (LESSA 520; CLA 787) were included. LESSA was associated with smaller mean tumor size (weighted mean difference (WMD) = 0.53 cm, 95% CI: -0.81 to -0.24; p < 0.001). The operative time for LESSA was longer than CLA (WMD = 13.86 min, 95% CI: 4.43 to 23.30; p = 0.004). LESSA had a better visual analog scale (VAS) score (WMD = -0.56, 95% CI: -1.01 to -0.11; p = 0.02), shorter return to diet time (WMD = -0.27 days, 95% CI: -0.52 to -0.03; p = 0.03), shorter length of hospital stay (WMD = -0.56 days, 95% CI: -1.01 to -0.11; p = 0.01), and comparable postoperative complications (OR = 0.98, 95% CI: 0.56 to 1.70; p = 0.93). The wound size of LESSA was definitely smaller (WMD = -2.72 cm, 95% CI: -3.50 to -1.94; p < 0.001). The subgroup analysis of studies via the transperitoneal approach showed reasonable results. CONCLUSIONS: LESSA is significantly better in terms of postoperative pain, time to diet, length of hospital stay and wound size, but the operative time is significantly longer.

Quantum dots assembly enhanced and dual-antigen sandwich structured lateral flow immunoassay of SARS-CoV-2 antibody with simultaneously high sensitivity and specificity.

Exploring reliable and highly-sensitive SARS-CoV-2 antibody diagnosis by point-of-care (POC) manner, holds great public health significance for extensive COVID-19 screening and controlling. Unfortunately, the currently applied gold based lateral flow immunoassay (GLFIA) may expose both false-negative and false-positive interpretations owing to the sensitivity and specificity limitations, which may cause significant risk and waste of public resources for large population screening. To simultaneously overcome the drawbacks of GLFIA, a novel fluorescent LFIA based on signal amplification and dual-antigen sandwich structure was established with largely improved sensitivity and specificity. The compact three-dimensional incorporation of hydrophobic quantum dots within dendritic affinity templates and multilayer surface derivation guaranteed a high and robust fluorescence of single label, which lowered the false negative rate of GLFIA prominently. A dual-antigen sandwich structure using labeled/immobilized SARS-CoV-2 spike receptor binding domain antigen for capturing total human SARS-CoV-2 antibody was developed, instead of general indirect antibody capturing approach, to reduce the false positive rate of GLFIA. Over 300 cases of COVID-19 negative and 97 cases of COVID-19 positive samples, the current assay revealed a 100% sensitivity and 100% specificity confirmed by both polymerase chain reaction (PCR) and chemiluminescence immunoassay (CLIA), compared with the considerable misinterpretation cases by currently applied GLFIA. The quantitative results verified by receiver operating characteristic curve and other statistical analysis indicated a well-distinguished positive/negative sample groups. The proposed strategy is highly sensitive towards low concentrated SARS-CoV-2 antibody serums and highly specific towards serums from COVID-19 negative persons and patients infected by other viruses.

Contrast-enhanced ultrasound targeted versus conventional ultrasound guided systematic prostate biopsy for the accurate diagnosis of prostate cancer: A meta-analysis.

BACKGROUND: Conventional transrectal ultrasonography (TRUS) guided prostate biopsy is the standard method for accurate diagnosis of prostate cancer (PCa). However, the limitations of this technique in terms of missed diagnosis cannot be ignored. Based on previous studies, contrast-enhanced ultrasound (CEUS) may be able to more distinctly detect malignant lesions with increased microvessels. Therefore, to evaluate the diagnostic efficiency and clinical application prospects of CEUS-guided prostate biopsy for patients with suspected PCa, we performed a meta-analysis comparing CEUS-targeted with TRUS-guided systematic biopsy. METHODS: A systematic search of PubMed, Web of Science, Embase and CNKI was performed up to March, 2022 for the relevant published studies. After data extraction and quality assessment, meta-analysis was performed using the RevMan 5.3 software. RESULTS: The results showed that the overall sensitivity was higher for CEUS targeted biopsy than systematic biopsy (P = .03), so was the accuracy (P = .03). However, significant heterogeneity and inconsistent results from certain subgroup analyses challenged the validity of the results. Meanwhile, CEUS yielded a much higher sensitivity in patients with prostate specific antigen (PSA) level of 4 to 10 ng/mL (P = .007). On the other hand, the positive rate of each core (P < .001) and the detection rate of clinically significant PCa (P = .006) were significantly improved using CEUS. CONCLUSION: CEUS showed the advantage of a higher detection rate of clinically significant PCa, which might provide more specific indications for subsequent treatment. More feasible, real-time data are required to confirm our findings.

Identification of a potentially functional circRNA-miRNA-mRNA ceRNA regulatory network in bladder cancer by analysis of microarray data.

BACKGROUND: Circular RNAs (circRNAs) have received increasing attention in cancer development. However, a substantial number of circRNAs still require characterization. The purpose of this study is to uncover novel circRNAs and their molecular mechanism in bladder cancer (BCa). METHODS: A combinative strategy of extensive data mining and computational biology was employed to identify BCa-related circRNAs and explore their potential mechanisms of action. RESULTS: Three differentially expressed circRNAs (has_circ_0023642, has_circ_0047322, has_circ_0041151) were obtained from the microarray dataset (GSE92675). Four miRNAs (miR-616, miR-515-5p, miR-647, miR-1178) with potential binding sites with these three circRNAs were identified. Pathway analysis demonstrated that all four miRNAs were closely associated with some cancer-related pathways. Survival analysis indicated that these miRNAs might potentially play a role in tumor-suppressive functions in BCa. Subsequently, 181 overlapping genes were identified from 472 up-regulated genes in BCa (TCGA database), and 10,017 predicted target genes of the four miRNAs obtained. A circRNA-miRNA-mRNA network was constructed on the identified three circRNAs, four miRNAs, and 181 overlapping genes. Besides, six hub genes (CENPA, HIST1H2BJ, HIST1H2BO, HIST1H3H, HIST1H3B, HIST1H3F) were identified from establishing a protein-protein interaction (PPI) network on the same overlapping genes. Furthermore, a circRNA-miRNA-hub gene sub-network was built to delineate the links among the differential circRNAs, miRNA, and hub genes. CONCLUSIONS: Our study provided significant insights into the molecular mechanisms that regulate the progression of BCa from the circRNA-miRNA-mRNA network view.

Adrenomedullin blockade suppresses sunitinib-resistant renal cell carcinoma growth by targeting the ERK/MAPK pathway.

PURPOSE: To evaluate the mechanisms underlying sunitinib resistance in RCC and to identify targets that may be used to overcome this resistance. RESULTS: Reanalysis of transcriptome microarray datasets (GSE64052 and GSE76068) showed that adrenomedullin expression was increased in sunitinib-resistant tumors. And adrenomedullin expression was increased in sunitinib-resistant tumor xenografts, accompanied by upregulation of phospho-ERK levels. However, blocking adrenomedullin inhibited sunitinib-resistant tumor growth. Treatment of RCC cells with sunitinib and ADM22-52 was superior to monotherapy with either agent. Additionally, adrenomedullin upregulated cAMP and activated the ERK/MAPK pathway, promoting cell proliferation, while knockdown of adrenomedullin inhibited RCC cell growth and invasion in vitro. MATERIALS AND METHODS: We searched the Gene Expression Omnibus (GEO) database to find data regarding sunitinib-resistant RCC. These data were subsequently reanalyzed to identify targets that contribute to sunitinib resistance, and adrenomedullin upregulation was found to mediate sunitinib resistance in RCC. Then, we created an RCC mouse xenograft model. Mice were treated with sunitinib, an adrenomedullin receptor antagonist (ADM22-52), a MEK inhibitor (PD98059) and different combinations of these three drugs to investigate their effects on tumor growth. RCC cells (786-0) were cultured in vitro and treated with an ADM22-52 or PD98059 to determine whether adrenomedullin activates the ERK/MAPK pathway. Adrenomedullin was knocked down in 786-0 cells via siRNA, and the effects of this knockdown on cell were subsequently investigated. CONCLUSIONS: Adrenomedullin plays an important role in RCC resistance to sunitinib treatment. The combination of sunitinib and an adrenomedullin receptor antagonist may result in better outcomes in advanced RCC patients.

Bioconversion of phenylpyruvate to phenyllactate: gene cloning, expression, and enzymatic characterization of D- and L1-lactate dehydrogenases from Lactobacillus plantarum SK002.

Two DNA fragments containing the entire coding sequences of lactate dehydrogenase (LDH; ldhL1 and ldhD), whose enzymes have high activity for bioconversion of phenylpyruvate (PPA) to phenyllactate (PLA), were amplified from Lactobacillus plantarum SK002 using PCR. Sequencing showed open reading frames of 963 bp (ldhL1) and 999 bp (ldhD) encoding putative proteins of 320 and 332 amino acid residues, respectively. The LDH genes were cloned into an expression vector pET-22b(+) and expressed in Escherichia coli BL21(DE3). The purified recombinant L1-LDH and D-LDH had approximate (SDS-PAGE) molecular weights of 35 and 40 kDa, respectively. L1-LDH and D-LDH had PPA bioconversion specific activities of 71.06 and 215.84 U/mg with K (m) values of 3.96 and 5.4 mM, respectively. The rL1-LDH and rD-LDH showed maximum enzyme activity at 30 and 40 degrees C while both had optimum activity at pH 6.0. L1-LDH exhibited a higher pH and temperature stability than D-LDH. The results show that the his-tagged L. plantarum SK002 D- and L1-LDHs are efficient catalysts for bioconversion of PPA to PLA.

Production of 4-hydroxyphenyllactic acid by Lactobacillus sp. SK007 fermentation.

The production of 4-hydroxyphenyllactic acid (4-HO-PLA), a novel antifungal compound, was studied in Lactobacillus sp. SK007 growth. When grown in MRS broth, the strain could produce 75 microg/ml HO-4-PLA, which was the highest reported so far. Tyrosine and 4-hydroxyphenylpyruvic acid (HO-4-PPA) supplements during fermentation could both increase the HO-4-PLA production yield, and the effect of HO-4-PPA on HO-4-PLA production was remarkably better than that of tyrosine. Using HO-4-PPA as substrate could effectively produce HO-4-PLA, which reached 1.26 mg/ml.

3-Phenyllactic acid production by substrate feeding and pH-control in fed-batch fermentation of Lactobacillus sp. SK007.

3-Phenyllactic acid (PLA), which is produced by some strains of lactic acid bacteria (LAB), is a known antimicrobial agent with a broad spectrum. Batch and fed-batch fermentation by the strain Lactobacillus sp. SK007 for PLA production have been reported. With batch fermentation without pH-control, PLA production yield was 2.42 g L(-1). When fed-batch fermentation by Lactobacillus sp. SK007 was conducted in 3 L initial volume with pH-control at 6.0 and intermittent feeding, which was developed after fermentation for 12 h and every 2 h with 120 mL 100 g L(-1) PPA phenylpyruvic acid (PPA) and 50 mL 500 g L(-1) glucose each time, PLA production yield reached 17.38 g L(-1). The final conversion ratio of PPA to PLA was 51.1%, and the PLA production rate was 0.241 g L(-1) h(-1). This indicated that PPA was the ideal substrate for PLA fermentation production, and fed-batch fermentation with intermittent PPA feeding and pH-control was an effective approach to improve PLA production yield.