Abstract
Percutaneous nephrostomy (PCNL) and retrograde intrarenal surgery (RIRS) are the two main treatments for upper urinary tract stones. The aim of our study was to compare the effectiveness and ...safety of standard PCNL (S-PCNL) and RIRS for the treatment of stones at ureteropelvic junction with high-grade hydronephrosis. The study included 118 patients who underwent surgery for stones at ureteropelvic junction. S-PCNL and RIRS were performed on 66 and 52 patients, respectively. Patient age, sex, body mass index (BMI), stone side, history of urinary tract infection (UTI), history of diabetes, history of ESWL, stone size, Hounsfield unit (HU) values of stones, grade of hydronephrosis, operating time, postoperative hemoglobin loss, narcotic analgesic use, postoperative transfusion rates, stone-free rates (SFRs), length of hospital stay, complication rates and number of secondary interventions were recorded. The comparison of the operative data between the two groups revealed no statistically significant differences in the operative time, SFRs, narcotic analgesic use, postoperative transfusion rate or other postoperative complications defined according to the Clavien system (P > 0.05). The postoperative urinary sepsis rate in the RIRS group was as high as 15.4%, which was much higher than the 1.5% rate observed in the S-PCNL group, and the difference was statistically significant (P < 0.05). A total of 13.5% of the patients in the RIRS group required a second operation due to failure of the placement of the ureteral access sheath. Additionally, S-PCNL had an advantage in operation time, while RIRS in duration of hospital stay and postoperative hemoglobin loss. RIRS and S-PCNL were safe and effective methods for the treatment of stones at ureteropelvic junction with high-grade hydronephrosis. Importantly, S-PCNL had more advantages in terms of the postoperative urinary sepsis rate and secondary surgery rate.
The study aimed to compare the clinicopathological features and prognosis between type I and type II papillary renal cell carcinoma (PRCC) and to investigate whether the subtypes of PRCC would affect ...oncological outcomes. A total of 102 patients with PRCC were recruited, of which 42 were type I PRCC and 60 type II. The clinicopathological features and oncologic outcomes of the patients were evaluated. The type II cases had a higher WHO/ISUP grading (P < 0.001), T (P = 0.003), N (P = 0.010) stage and stage grouping (P = 0.011) than the type I. During a median follow-up period of 61.4 months, 1-year cancer specific survival (CSS) of the type I was 100%, 5-year CSS was 95.2%, the 1-year CSS of the type II was 96.2%, and 5-year CSS was 75.7%. The univariate analysis showed that subtype, symptoms, TNM, stage grouping, WHO/ISUP grading and surgical methods appeared to affect prognosis of the patients with PRCC. However, multivariate analysis revealed that only stage grouping was the independent risk factor. After the stage grouping factor was adjusted for the analysis, there were no statistically significant differences in CSS (P = 0.214) and PFS (P = 0.190) between the localized type I and type II PRCC groups. Compared with type I PRCC, type II had higher pathological T, N stage and WHO/ISUP grading. However, it was the Stage grouping that made a great difference to oncological outcomes, rather than the subtype of PRCC.
To study the relationship between preoperative urine culture, bacterial species and infection after percutaneous nephrolithotomy in patients with upper urinary tract stones, and summarize the ...clinical characteristics of different bacterial infections. From January 2014 and January 2020, 963 patients with upper urinary tract stones who underwent PCNL in the department of urology of Fujian provincial hospital were included in the study. Information included the patient's age, gender, weight, diabetes, chronic disease history, urine routine, preoperative urine culture results, stone size, number of stones, hydronephrosis level, operation time, body temperature, heart rate, blood pressure, breathing rate, hemoglobin, serum creatinine, bilirubin, platelets and whether there was preoperative infection were recorded. 141 patients (14.6%) had a positive urine culture before surgery, and 7 of them had multiple bacterial infections. The most common pathogenic bacteria was Escherichia coli, followed by Enterococcus and Klebsiella pneumoniae. A total of 74 cases (7.7%) of 963 patients with infection after PCNL occurred, 24 cases (32.4%) of infected patients progressed to urinary septic shock. Univariate analysis shown that the probability of infection in patients with long operation time and positive urine culture was significantly higher, and the difference was statistically significant. Further multivariate logistic regression analysis shown that positive urine culture before operation and long operation time were independent risk factors for infection after PCNL. Among the 29 patients with septic shock, 18 cases (62.1%) had a positive urine culture before surgery. The incidence (43.9%) of postoperative infection in Escherichia coli positive patients was significantly higher than that in the negative group, and the difference was statistically significant. The rate of patients with Escherichia coli infection progressing to septic shock was 9 cases (60%). 2 patients with Enterococcus faecium infection and 2 patients with Klebsiella pneumoniae infection all progressed to septic shock. The age of patients with post-PCNL infection caused by Escherichia Coli, Enterococcus faecium and Klebsiella pneumoniae were 58.53 ± 11.73 years, 76.5 years and 74 years.The body temperature of patients with post-PCNL infection caused by Escherichia Coli, Enterococcus faecium and Klebsiella pneumoniae were 39.10 ± 0.25 °C, 39.45 °C and 38.65 °C. The highest pct value of patients with post-PCNL infection caused by Escherichia Coli, Enterococcus faecium and Klebsiella pneumoniae were 80.62 ± 31.45 ng/mL, 24.32 ng/mL and 8.45 ng/mL. The nitrite positive rate of patients with post-PCNL infection caused by Escherichia Coli, Enterococcus faecium and Klebsiella pneumoniae were 64.51%, 16.6% and 0. Postoperative infection of PCNL is significantly correlated with positive preoperative urine culture, and positive preoperative urine culture is an independent risk factor for postoperative infection. The most common pathogen of postoperative infection of PCNL is Escherichia coli, followed by Enterococcus and Klebsiella pneumoniae. Patients with Escherichia coli infection are often positive for nitrite before surgery, mainly manifested by high fever, and PCT is significantly increased (often exceeded 100 ng/ml). Enterococcus faecium and Klebsiella pneumoniae infections mostly occur in elderly patients and often progress to septic shock. Patients with Enterococcus faecium infection have a high fever, and the PCT value is significantly higher (often exceeded 20 ng/ml). Patients with Klebsiella pneumoniae infection have a moderate fever, and the PCT value generally does not exceeded 10 ng/ml. Long operation time is another independent risk factor for PCNL infection.
This study aimed to analyze the infection risk factors for transurethral resection of the prostate (TURP) and establish predictive models to help make personalized treatment plans. Our study was ...designed one-center and retrospectively enrolled 1169 benign prostatic hyperplasia (BPH) patients. Risk factors were explored for postoperative infection. A TURP-postoperative infection (TURP-PI) model with infection prediction values was created. The improved-TURP-PI (I-TURP-PI) model, including extra new factors (pathogens species), was also built to see whether it could optimize the prediction abilities. At last, we developed a nomogram for better clinical application. Operation time, preoperative indwelling urinary catheter (PIUC), and positive preoperative urine culture were independent risk factors (all P < 0.05). Interestingly, pathogens species in pre-surgery urine (P
= 0.014, P
= 0.086) were also independent risk factors. Patients with positive Enterococcus faecium (37.50%) were most likely to have postoperative infection. We built two models with AUC
= 0.709 (95% CI 0.656-0.763) and AUC
= 0.705 (95% CI 0.650-0.760). The nomogram could help improve the prediction ability. To our knowledge, our study is the first to use pathogen species in urine before surgery as risk factors for infection prediction after TURP. TURP-PI and I-TURP-PI models have essential roles in predicting patients' postoperative infections and in better postoperative antibiotic decision-making.
Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new ...classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML.
The expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays.
HOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression.
Taken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype.
IntroductionUpper urinary tract epithelial carcinoma (UTUC) and bladder cancer are both sources of urinary epithelial cell. In our previous study of asymptomatic bladder tumors, we found that most of ...these tumors could be resected through the urethra without radical surgery. This study analyzed the treatment strategies for asymptomatic UTUC. AimTo investigate the clinicopathological features and surgical methods of these patients, thus choosing appropriate surgical treatment. Material and methods136 patients with UTUC were recruited, of whom 21 patients with asymptomatic UTUC were group A, and 115 UTUC patients with hematuria or low back pain were group B. The clinicopathological features, oncologic outcomes, and surgical methods of patients were evaluated. ResultsRadical resection was the main surgical treatment which was included (group A 80.95%, group B 90.43%). Other patients were treated with kidney-retaining surgery. No statistically significant difference was observed in the pathological stage and grade between groups A and B (p > 0.05). During a median follow-up period of 44.3 months, tumor-specific mortality of group A was 7.14%, and that of group B was 5.10%. In the same period, 106 patients with asymptomatic bladder tumor were recruited: 31 patients of them had asymptomatic bladder urothelial carcinoma. The asymptomatic UTUC group had a higher stage and grade of clinicopathological features than the asymptomatic bladder urothelial carcinoma group (p < 0.001). ConclusionsThe principle of asymptomatic UTUC treatment is the same as that of symptomatic UTUC. Risk stratification should be carried out according to clinical staging and other parameters, and the corresponding surgical treatment should be selected.
Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is ...considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients. Keywords: Acute myeloid leukemia, TRAIL, TP53INP2, Venetoclax, Nucleophosmin 1
Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion ...protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. The FABD-deficient adenovirus vectors Ad-BCR/ABLâ³FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright-Giemsa staining and haematoxylin and eosin (HE) staining. We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL.
Acute myeloid leukemia (AML) is a rapidly progressing and often fatal hematopoietic malignancy. Venetoclax (VEN), a recent FDA-approved BCL-2 selective inhibitor, has high initial response rates in ...elderly AML patients, but the majority of patients eventually acquire resistance. Multiple studies have demonstrated that the female sex is associated with better outcomes in patients with AML, which are predominantly attributed to estrogen signaling. As a novel membrane estrogen receptor, G protein-coupled estrogen receptor (GPER)-mediated-rapid estrogen effects have attracted considerable attention. However, whether targeting GPER enhances the antileukemic activity of VEN is unknown. In this study, we first demonstrated that GPER expression was dramatically reduced in AML cells owing to promoter hypermethylation. Furthermore, pharmacological activation of GPER by G-1 combined with VEN resulted in synergistic antileukemic activity in vitro and in vivo. Mechanistically, G-1/VEN combination synergistically triggered concurrent mitochondria-related apoptosis and gasdermin E (GSDME)-dependent pyroptosis by activating p38-MAPK/myeloid cell leukemia 1 (MCL-1) axis. Importantly, leukemic pyroptosis heightened CD8+ T cell immune function by releasing interleukin (IL)-1β/18 into the tumor microenvironment. Our study corroborates that GPER activation shows a synergistic antileukemic effect with VEN, making it a promising therapeutic regimen for AML.
Exosomal long non-coding RNAs (lncRNAs) have emerged as a cell-free biomarker for clinical evaluation of cancers. However, the potential clinical applications of exosomal lncRNAs in acute myeloid ...leukemia (AML) remain unclear. Herein, we attempted to identify plasma exosomal lncRNAs as prospective biomarkers for AML. In this study, plasma exosomes were first successfully extracted from AML patients and healthy donors (HD). Subsequently, the downregulated plasma exosomal lncRNAs (LINC00265, LINC00467, and UCA1) and the upregulated plasma exosomal lncRNA (SNHG1) were identified in AML patients (n=65) compared to HD (n=20). Notably, individual exosomal LINC00265, LINC00467, UCA1, or SNHG1 had a capability for discriminating AML patients from HD, and their combination displayed better efficiency. Furthermore, exosomal LINC00265 and LINC00467 were increased expressed in patients achieving complete remission after chemotherapy. Importantly, there was upregulation of exosomal LINC00265 and downregulation of exosomal SNHG1 upon allogeneic hematopoietic stem cell transplantation. Additionally, these lncRNAs were high stability in plasma exosomes. Exosomal LINC00265, LINC00467, UCA1, and SNHG1 may act as promising cell-free biomarkers for AML diagnosis and treatment monitoring and provide a new frontier of liquid biopsy for this type of cancer.
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