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.

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.

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 common mechanisms between endometriosis and ovarian cancer.

PURPOSE: To determine common molecular markers between endometriosis and ovarian cancer. METHODS: Patients included women who underwent laparoscopic excision of ovarian endometriotic lesions (n = 7), healthy non-pregnant women with normal pelvises, who underwent excision of normal peritoneum (n = 7). Two epithelial ovarian cancer (EOC) cell lines were also utilized. Expression of transforming growth factor (TGF)-ß1, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), estrogen receptor (ER)-1α, progesterone receptor (PR), androgen receptor (AR), and aromatase was evaluated by real-time RT-PCR. RESULTS: Endometriosis and EOC cells manifested significantly higher mRNA levels of TGF-ß1, COX-2, VEGF, ER-1α, AR, and aromatase, while they expressed significantly lower mRNA levels of PR. CONCLUSIONS: Increased TGF-ß1, COX-2, VEGF, ER-1α, AR, and aromatase and decreased PR in endometriotic as well as EOC cells suggests a potential association between these two disease processes. This association is important, as it may reveal common mechanisms for both diseases.

Study of Microbiomes in Aseptically Collected Samples of Human Breast Tissue Using Needle Biopsy and the Potential Role of in situ Tissue Microbiomes for Promoting Malignancy.

Mounting evidence suggests that changes in microbiome are linked to development of cancer and its aggressiveness. Microbiome profiles in human breast tissue previously presumed to be sterile, have recently been characterized using high-throughput technologies. Recent findings of microbiome variation between benign and malignant disease provides a rationale for exploring microbiomes associated with cancer during tumor progression. We assessed microbiomes of aseptically collected human breast tissue samples in this study, using needle biopsy from patients with benign and malignant tumors of different histological grading, using 16S rRNA gene amplicon sequencing. This is consistent with previous studies, and our results identified distinct microbiome profiles in breast tissues from women with cancer as compared to women with benign breast disease in Chinese cohorts. The enriched microbial biomarkers in malignant tissue included genus Propionicimonas and families Micrococcaceae, Caulobacteraceae, Rhodobacteraceae, Nocardioidaceae, Methylobacteriaceae, which appeared to be ethno-specific. Further, we compared microbiome profiles in malignant tissues of three different histological grades. The relative abundance of family Bacteroidaceae decreased and that of genus Agrococcus increased with the development of malignancy. KEGG pathways inferred by PICRUSt showed that biotin and glycerophospholipid metabolism had significant differences in all three grades. Glycerophospholipid and ribosome biogenesis increased in grade III tissue as compared to grades I and II. Flavonoid biosynthesis significantly decreased in grade III tissue. The specific correlation of these potential microbial biomarkers and indicated pathways with advanced disease could have broad implications in the diagnosis and staging of breast cancer. Further large-cohort investigation of the breast cancer microbiome and its potential mechanism in breast cancer development are essential.

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.

PADI2 is significantly associated with rheumatoid arthritis.

Citrullination, a posttranslational modification of peptidyl arginine to citrulline, plays an essential role in rheumatoid arthritis (RA). Citrullination is catalyzed by a group of peptidylarginine deiminases (PADs) including PADI 1, 2, 3, 4 and 6. Many studies have indicated that the gene encoding PADI4 is a factor in susceptibility to RA. Some studies have detected PADI2 expression in RA synovial tissues, suggesting that PADI2 also plays an important role in the disease. This study evaluated the possible association between the PADI2-encoding gene and RA. Seventeen tag SNPs across the PAD locus were genotyped using a custom-designed Illumina 96-SNP VeraCode microarray. Peripheral blood samples were collected from patients with RA (n = 267), ankylosing spondylitis (AS, n = 51) and healthy controls (n = 160). The results of genotyping were verified using Sequenom MassARRAY in an independent cohort of 307 patients with RA, 324 patients with AS and 509 healthy controls. A western blot analysis was performed using synovial tissue from patients with RA (n = 7), osteoarthritis (OA, n = 7) and AS (n = 5) to determine the levels of expression of PADI2. A microarray analysis revealed a significant association between three selected PADI2 SNPs (rs2235926, rs2057094, rs2076616) and the presence of RA. The increased susceptibility to RA associated with rs2235926 (OR = 1.706733, 95% CI = [1.576366-1.866587], p = 0.000839) and rs2057094 (OR = 1.360432, 95% CI = [1.065483-1.869482], p = 0.003291) was further confirmed by the Sequenom MassARRAY. No tag SNPs in the PADI2 locus showed a significant association with AS. Increased expression of PADI2 was detected in RA synovial tissues compared with samples from patients with OA and AS. PADI2 is significantly associated with RA and may be involved in the pathogenesis of the disease.