TR4 worsen urosepsis by regulating GSDMD.

BACKGROUND: Urosepsis is a life-threatening organ disease in which pathogenic microorganisms in the urine enter the blood through the vessels, causing an imbalance in the immune response to infection. The aim of this study was to elucidate the role of testicular orphan receptor 4 (TR4) in urosepsis. METHODS: The role of TR4 in the progression and prognosis of urosepsis was confirmed by analyzing data from online databases and clinical human samples. To mimic urosepsis, we injected E. coli bacteria into the renal pelvis of mice to create a urosepsis model. Hematoxylin and eosin staining was used to observe histopathological changes in urosepsis. The effects of the upregulation or downregulation of TR4 on macrophage pyroptosis were verified in vitro. Chromatin immunoprecipitation assay was used to verify the effect of TR4 on Gasdermin D (GSDMD) transcription. RESULTS: TR4 was more highly expressed in the nonsurviving group than in the surviving group. Furthermore, overexpressing TR4 promoted inflammatory cytokine expression, and knocking down TR4 attenuated inflammatory cytokine expression. Mechanistically, TR4 promoted pyroptosis by regulating the expression of GSDMD in urosepsis. Furthermore, we also found that TR4 knockdown protected mice from urosepsis induced by the E. coli. CONCLUSIONS: TR4 functions as a key regulator of urosepsis by mediating pyroptosis, which regulates GSDMD expression. Targeting TR4 may be a potential strategy for urosepsis treatment.

Immunotherapy with or without targeted therapy for metastatic upper tract urothelial carcinoma: case report and literature review.

Background: Immune checkpoint inhibitors (ICIs) have been proved having a better safety profile compared to platinum-based chemotherapy and have demonstrated encouraging anti-tumor therapeutic effects for patients with metastatic urothelial carcinoma (mUC). However, few studies have evaluated the efficacy of ICIs in patients with metastatic upper tract urothelial carcinoma (mUTUC). Case reports: Case 1 was a 71-year-old male patient diagnosed with left renal pelvic carcinoma, accompanied by a metastasis to the second lumbar spine. As the patient became refractory to chemotherapy, four cycles of camrelizumab, one of the ICIs, were administered, which helped to control the metastases and extend the patient's progression-free survival to five months. Case 2 was an 88-year-old female with middle and lower right ureter carcinoma with right iliac arteriovenous invasion. The patient received five cycles of camrelizumab plus vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors and achieved stable disease. Conclusion: For patients who are ineligible for chemotherapy, immunotherapy might be a feasible treatment, regardless of whether or not they are given VEGFR2 inhibitors.

Combined preoperative prognostic nutritional index and D-dimer score predicts outcome in colorectal cancer.

BACKGROUND: The prognostic nutritional index (PNI) and D-dimer (DD) levels represent useful prognostic indicators in colorectal cancer (CRC); however, a combination of these indicators, namely, the PNI and DD score (PDS) was less addressed. METHODS: A retrospective study with 183 patients after curative surgery was conducted. Patients were divided into 3 subgroups: PDS 0, decreased PNI and increased DD levels; PDS 1, decreased or increased PNI and DD levels; PDS 2, increased PNI and decreased DD levels. The differences in disease-free survival (DFS) and overall survival (OS) were compared among these subgroups, and risk factors for outcome were determined. RESULTS: A total of 56, 65 and 62 patients were assigned to the PDS 0, 1 and 2 subgroups, respectively. PDS was significant in predicting both the DFS (area under the curve (AUC) = 0.68, P < 0.001) and OS (AUC = 0.74, P < 0.001). PDS 0 patients were more likely to be associated with old age (P = 0.032), laparotomy (P < 0.001), elevated CEA (P = 0.001), T3 + T4 (P = 0.001) and advanced TNM stage (P = 0.031). PDS 0 patients had significantly inferior DFS (log rank = 18.35, P < 0.001) and OS (log rank = 28.34, P < 0.001) than PDS 1 or 2 patients. PDS was identified as an independent risk factor for both DFS (PDS 1: HR = 0.54, 95% CI: 0.30-1.00, P = 0.049; PDS 2: HR = 0.40, 95% CI: 0.20-0.79, P = 0.009) and OS (PDS 1: HR = 0.44, 95% CI: 0.22-0.88, P = 0.020; PDS 2: HR = 0.17, 95% CI: 0.06-0.45, P < 0.001). CONCLUSION: The PDS is a useful prognostic indicator for CRC patients after curative surgery, and PDS 0 patients have inferior survival. Additional future studies are needed to validate these findings.

Incidence and risk factors for febrile neutropenia of patients with diffuse large B-cell lymphoma receiving R-CHOP-21 in China.

OBJECTIVE: Febrile neutropenia (FN) is a serious complication of patients with diffuse large B-cell lymphoma (DLBCL) receiving R-CHOP-21. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSFs for patients receiving chemotherapy with FN risk of 20% or 10 to 20% with defined risk factors. However, there are few studies on the incidence and risk factors of FN in patients with DLBCL receiving R-CHOP-21, especially in patients without primary G-CSF prophylaxis. METHODS: We conducted a retrospective analysis for the clinical data of 103 patients with DLBCL who underwent first R-CHOP-21 without primary G-CSF prophylaxis. The objective of the assessment was the incidence and risk factors of FN after the first chemotherapy cycle. RESULTS: After the first chemotherapy cycle, the incidence of FN was 20.4%. Multivariate analysis showed that age ≥ 65 years, bone marrow involvement, albumin < 35 g/L, and average relative dose intensity ≥ 80% were independent risk factors for FN. According to risk factors, we created a risk score system. The incidence of FN in the low-, intermediate- and high-risk groups was 5.6%, 17.2%, and 61.9%, respectively. CONCLUSION: Our data indicated that R-CHOP-21 itself is associated with a high-risk regiment for FN. We recommend that intermediate/high-risk patients should actively consider primary G-CSF prophylaxis to reduce the incidence of FN after chemotherapy.

Acute respiratory distress syndrome secondary to carbon dioxide gas embolism after single-port robotic-assisted perineal radical prostatectomy: a case report.

Background: Single-port robotic-assisted perineal radical prostatectomy (spRAPP) can provide oncologic outcomes similar to those with a traditional approach and is especially indicated for patients with prostate cancer who have a history of major abdominopelvic surgery. Few complications associated with this procedure have been reported. Case Description: A 64-year-old man underwent a spRAPP with a sudden decrease in the percutaneous oxygen saturation (SpO2) and the end-tidal carbon dioxide (ETCO2) partial pressure after accidental injury to the right prostatic venous plexus. And the diagnosis of carbon dioxide (CO2) gas embolism was confirmed by transesophageal echocardiography (TEE). By reducing the pneumoperitoneal pressure, closing the venous rupture, increasing the end-expiratory pressure, and elevating the concentration of inhaled oxygen, the patient's oxygenation improved until the end of the operation. However, he progressed to adult acute respiratory distress syndrome (ARDS) postoperatively. The patient was treated with intensive care and recovered well after treatment with pulmonary protective ventilation. This article reports a case of CO2 embolism confirmed by TEE during spRAPP and resulting in postoperative ARDS, which is the first report in the literature. Conclusions: Anesthesiologists' and surgeons' early detection of CO2 embolism was the key to effective treatment. ARDS secondary to CO2 embolism is rare but cannot be ignored and requires intensive care intervention and comprehensive treatment based on a protective pulmonary ventilation strategy.

Case report: Significant benefits of tislelizumab combined with anlotinib in first-line treatment of metastatic renal pelvic urothelial carcinoma with sarcomatoid carcinoma differentiation.

Background: Renal pelvic urothelial carcinoma with sarcomatoid carcinoma differentiation is a very dangerous malignant tumor and extremely rare in clinical practice. In general, these tumors with a dismal prognosis, and there is no standard treatment. Case presentation: In this case, an 81-year-old male patient was diagnosed with right renal pelvic carcinoma. After an open right radical nephroureterectomy, postoperative pathological examination showed infiltrating urothelial carcinoma with sarcomatoid differentiation. Overexpression of programmed death ligand-1 by immunohistochemistry. The carcinoma recurred 4.5 months after surgery. After informed, tislelizumab combined with anlotinib were used as first-line treatment. The patients showed a clinical partial response that lasted for 20 months. Conclusion: This case demonstrates the efficacy of tislelizumab combined with anlotinib in patients diagnosed with metastatic renal pelvic urothelial carcinoma with sarcomatoid carcinoma differentiation. Moreover, to our knowledge, this is the first application of this treatment.

METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.

Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m6A) is implicated in various stages of cancer development. However, a thorough understanding of m6A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m6A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m6A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m6A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m6A and lncRNA in ccRCC for the first time.

Proteomic Signature of Urosepsis: From Discovery in a Rabbit Model to Validation in Humans.

Urosepsis after upper urinary tract endoscopic lithotripsy (UUTEL) may cause uroseptic shock with high mortality, which can be prevented if early diagnosis and timely intervention are implemented with help of a diagnostic protein panel. The plasma of five rabbits of uroseptic shock and five controls was subjected to exploratory proteomics to search biomarker candidates from proteomic profiles related to uroseptic shock. Then, plasma from 21 nonsepsis and 20 urosepsis patients according to European diagnostic criteria of sepsis was enrolled in the validation study via targeted proteomics. Changes in a massive number of plasma proteins, mainly enriched in immune regulation, coagulation, structural repair, and transport activity, were observed in the rabbit model of septic shock. Fifteen proteins were identified as differential expression proteins between sepsis and nonsepsis patients. A diagnostic model composed of three proteins lipopolysaccharide-binding protein (LBP), clusterin (CLU), and vascular cell adhesion protein 1 (VCAM1) was developed for the early detection (2 hours postoperatively) of urosepsis after UUTEL, with a high area under the receiver operating characteristic (ROC) curve of 0.921. In conclusion, changes in the proteomic profile may reflect the underlying biological mechanisms during the development of urosepsis and produce diagnostic biomarkers for the early detection of urosepsis after UUTEL.

Ligating clip migration after robot-assisted laparoscopic radical prostatectomy: a single-center experience.

BACKGROUND: Ligating clip migration (LCM) after robot-assisted laparoscopic radical prostatectomy (RARP) is a rare but troublesome complication, that may result in calculus formation, bladder neck contracture, and anastomotic stricture. Herein, we describe our experiences with LCM after RARP and explore its risk factors, potential pathogenesis, and preventive measures. METHODS: We retrospectively reviewed patients who underwent RARP at our medical center between December 2015 and June 2019, identifying individuals with LCM. Clinical and surgical data were collected from these patients. RESULTS: Of the 682 patients who underwent RARP at our institution, 26 (3.8%) had LCM. The duration from RARP to the identification of LCM ranged from 1 to 37 (13±10) months. Clips migrated into the urethrovesical anastomosis in 22 patients (84%), prompting cytoscopic extraction to remove the migrated clips. The length of stay after RARP was longer in LCM-positive patients than in LCM-negative patients (13.5 vs. 9.4 days, P=0.034). Additionally, the rates of urine leakage (15% vs. 6%, P=0.046) and anastomotic stenosis (54% vs. 5%, P=0.000) were higher among LCM-positive patients. More positive urethra/apex margins were found in LCM-positive patients (38% vs. 21%, P=0.039). CONCLUSIONS: The incidence of clip migration after RARP may not be as low as previously thought. Cystoscopy is recommended in post-RARP patients with recurrent lower urinary tract symptoms (LUTS) and/or urinary retention. Prolonged length of stay after the first RARP, urine leakage, anastomotic stenosis, and positive urethra/apex margin might be predictors of LCM. We recommend reduced ligating clip usage and electrotome near the urethrovesical anastomosis to reduce clip migration incidence. Meanwhile, more researches are needed to determine the practicality of reducing the risk of clip migration after RARP.

Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression.

Bladder cancer (BCa) belongs to a popular urological malignancy and leads to large numbers of deaths worldwide. Recently, emerging evidences indicate that long noncoding RNAs (lncRNAs) are closely related with BC occurrence and progression. However, the function of lncRNA MAGI2-AS3 remains poorly understood in BC. In this present study, we screened out a novel lncRNA MAGI2-AS3 whose expression was downregulated in BCa tissues. We showed that MAGI2-AS3 downregulation in BCa patients indicated a poor prognosis. Functionally, we showed that MAGI2-AS3 overexpression inhibits proliferation, migration and invasion of BCa cells. Moreover, ectopic expression of MAGI2-AS3 suppresses BCa growth in vivo. Bioinformatics analysis revealed that MAGI2-AS3 could serve as a competing endogenous RNA (ceRNA) for miR-15b-5p. In the meantime, miR-15b-5p directly targeted CCDC19, a tumor suppressor in BCa. Rescue assays demonstrated that knockdown of CCDC19 restored the proliferation, migration and invasion of BCa cells suppressed by MAGI2-AS3 overexpression. In conclusion, this study identified a novel mechanism that MAGI2-AS3/miR-15b-5p/CCDC19 signaling pathway regulates BCa progression.

Uroseptic Shock Can Be Reversed by Early Intervention Based on Leukocyte Count 2 h Post-operation: Animal Model and Multicenter Clinical Cohort Study.

This study investigated whether early intervention based on leukocyte count (WBC) of less than 2.85 × 109/L obtained within 2 h post-operatively may ameliorate the uroseptic shock induced by upper urinary tract endoscopic lithotripsy (UUTEL). Urosepsis was induced in 30 rabbits and assigned to three groups: Control-I, WBC-I, and Shock-I. Control-I: Non-intervention control. WBC-I: Immediate resuscitation when there was a drastic drop of WBC within 2 h post-operatively but without signs or symptoms of shock. Shock-I: Resuscitation only when there were signs or symptoms of shock. In total, 107 patients whose WBC were less than 2.85 × 109/L within 2 h after UUTEL were retrospectively analyzed. Patients were assigned into two groups based on the time of the intervention. Shock-II included 59 patients who were started on the resuscitation bundle when there were signs or symptoms of shock. WBC-II included 48 patients who were started immediately on the resuscitation bundle when the WBC decreased drastically. All Control-I rabbits developed shock within 72 h and died. None of the WBC-I rabbits developed shock and all survived for 72 h. In total, 60% of Shock-I died within 72 h. Overall, 43 patients in Shock-II and six patients in WBC-II experienced uroseptic shock. The average lengths of hospitalization for Shock-II and WBC-II were 17.8 ± 9.7 days and 7 ± 4.2 days, respectively. Six patients in the Shock-II and none in WBC-II died of the uroseptic shock. Early intervention based on WBC measured within 2 h post-operatively might avert the uroseptic shock induced by UUTEL.

Early drastic decrease in white blood count can predict uroseptic shock induced by upper urinary tract endoscopic lithotripsy: a translational study.

PURPOSE: Uroseptic shock is a life threatening complication after upper urinary tract endoscopic lithotripsy. Prompt diagnosis and treatment are paramount for patient survival. We identified a practical predictor of upper urinary tract endoscopic lithotripsy induced uroseptic shock in an animal model. We validated the results by retrospectively reviewing multicenter clinical records. MATERIALS AND METHODS: We ligated the rabbit ureter and injected Escherichia coli solution in the renal pelvis to create a uroseptic shock model. White blood count and other parameters were measured at different intervals and bacterial concentrations. Results were compared with clinical findings in 48 patients who experienced uroseptic shock after upper urinary tract endoscopic lithotripsy at a total of 8 medical centers. We used a ROC curve to evaluate the predictive value of parameters for uroseptic shock. RESULTS: We established a stable rabbit model by injecting 9.0 × 10(8) cfu/ml E. coli in the renal pelvis at a dose of 2 ml/kg. In patients and rabbits with uroseptic shock the white blood count decreased in the first 2 hours after the procedure. The ROC curve showed that the white blood count threshold within the first 2 hours of uroseptic shock was 2.85 × 10(9)/L. Sensitivity and specificity for predicting uroseptic shock were 95.9% and 92.7%, respectively. CONCLUSIONS: The white blood count decreased drastically within the first 2 hours during the development of uroseptic shock. This could be an ideal predictor of uroseptic shock after upper urinary tract endoscopic lithotripsy. In patients with high risk factors for uroseptic shock the white blood count should be measured within 2 hours after upper urinary tract endoscopic lithotripsy.