Disease-Associated Q159X Mutant Prion Protein Is Sufficient to Cause Fatal Degenerative Disease in Mice.

PRNP Q160X is one of the five dominantly inheritable nonsense mutations causing familial prion diseases. Till now, it remains unclear how this type of nonsense mutations causes familial prion diseases with unique clinical and pathological characteristics. Human prion protein (PrP) Q160X mutation is equivalent to Q159X in mouse PrP, which produces the mutant fragment PrP1-158. Through intracerebroventricular injection of recombinant adeno-associated virus in newborn mice, we successfully overexpressed mouse PrP1-158-FLAG in the central nervous system. Interestingly, high level PrP1-158-FLAG expression in the brain caused death in these mice with an average survival time of 60 ± 9.1 days. Toxicity correlated with levels of PrP1-158-FLAG but was independent of endogenous PrP. Histopathological analyses showed microgliosis and astrogliosis in mouse brains expressing PrP1-158-FLAG and most of PrP1-158-FLAG staining appeared intracellular. Biochemical characterization revealed that the majority of PrP1-158-FLAG were insoluble and a significant part of PrP1-158-FLAG appeared to contain an un-cleaved signal peptide that may contribute to its cytoplasmic localization. Importantly, an ~10-kDa proteinase K-resistant PrP fragment was detected, which was the same as those observed in patients suffering from this type of prion diseases. To our knowledge, this is the first animal study of familial prion disease caused by Q159X that recapitulates key features of human disease. It will be a valuable tool for investigating the pathogenic mechanisms underlying familial prion diseases caused by nonsense mutations.

Impact of Visceral Fat Area on Intraoperative Complexity and Surgical Approach Decision for Robot-Assisted Partial Nephrectomy: A Comparative Analysis with BMI.

BACKGROUND Optimizing surgical approaches for robot-assisted partial nephrectomy (RAPN) is vital for better patient outcomes. This retrospective study aimed to examine how visceral fat area (VFA) and body mass index (BMI) correlate with intraoperative complexities, thereby guiding the selection of surgical techniques for RAPN. MATERIAL AND METHODS The study analyzed the medical records of 213 Chinese patients diagnosed with a range of benign and malignant renal neoplasms and treated with RAPN in 2020. Visceral fat area was quantified using computed tomography (CT) scans taken at the umbilical level. Various perioperative indicators, such as demographic details, clinicopathological parameters, operation time, estimated blood loss (EBL), warm ischemic time (WIT), and intraoperative complications, were assessed. RESULTS For the retroperitoneal approach, patients with either visceral obesity or general obesity had longer operation times (P<0.001 and P=0.004) and had a tendency for higher EBL (P=0.003 and P=0.001) compared to non-obese patients. In the transperitoneal approach, those with visceral obesity had significantly longer operation times (P=0.008) than their non-viscerally obese counterparts; however, general obesity showed no impact on operation time (P=0.251). Estimated blood loss was higher for patients with visceral obesity (P=0.004), but no significant difference was noted among those with general obesity (P=0.980). CONCLUSIONS VFA appears to offer predictive advantages over BMI in assessing intraoperative complexities for transperitoneal RAPN. When used in conjunction with BMI, it could serve as a valuable tool in selecting the most appropriate surgical approach for RAPN.

One-step fabrication of all-in-one three-dimensional porous polypyrrole/polydopamine structure for efficient solar vapor generation.

High-quality solar evaporators with all-in-one design are highly desirable for vapor generation, but relevant research is scarce. In this study, a three-dimensional (3D) porous polypyrrole/polydopamine (PPY/PDA) structure was fabricated via a simple heating-assisted rapid oxidative polymerization method. The obtained evaporator has multiple features, and can simultaneously provide rapid water transport channels (average pore sizes âˆ¼ 18.37 nm), low thermal conductivity (0.071 W m-1 K-1), high solar absorbance (97.08%), and good mechanical properties. When it is employed as an evaporator, the calculated water evaporation rate is approximately 2.12 kg m-2h-1, which is comparable to other reported 3D evaporators. Additionally, the evaporator displays great potential for purification toward various nonpotable water, as well as reliable pure water yields in an outdoor application (from 8:00 am to 5:00 pm, the evaporator can produce at least 13.95 L of drinkable water for a 1 m2 sample). We believe that the proposed strategy to fabricate all-in-one evaporators has great significance for scientific research and practical applications.

Vesicoprostatic muscle reconstruction: a step further for immediate and early urinary continence.

OBJECTIVES: The vesicoprostatic muscle (VPM) is a longitudinal smooth muscle that originates from the trigone of the bladder or the opening of the ureter and is involved in urination as part of the detrusor apron. We explored the effect of VPM reconstruction on immediate and early recovery of urinary continence in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP). PATIENTS AND METHODS: A total of 523 patients with localized prostate cancer were enrolled from June 2018 to June 2020. All patients were diagnosed in our department based on magnetic resonance imaging and pathological findings on prostate biopsy. After 1:1 propensity score matching, 105 patient pairs were matched. The study was approved by our institutional review board and all surgeries were performed by three experienced high-volume surgeons. Demographic data, total operation time, pathological outcomes, the urinary continence rates of the two groups at different times after RALP, and factors influencing postoperative urinary continence after RALP were recorded. Student's t test was used to compare continuous variables and the Pearson χ2 test to compare categorical variables. Logistic regression analysis was used to identify factors affecting immediate and early postoperative urinary control. RESULTS: VPM reconstruction promoted immediate and early recovery of urinary continence (immediate continence, 66.67 vs. 40.00%, P = 0.000; 3-month continence, 80.95 vs. 64.76%, P = 0.008). CONCLUSIONS: VPM reconstruction improved immediate and early urinary continence in patients who underwent RALP.

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma.

Background: Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance. Methods: Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ2) was used to analyze relationship between clinicopathologic parameters and germline mutations. Results: A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations. Conclusions: To our knowledge, this is the first report of pathogenic germline mutations in the FANCI and FANCM genes and heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.

FDX1 expression predicts favourable prognosis in clear cell renal cell carcinoma identified by bioinformatics and tissue microarray analysis.

Ferredoxin 1 (FDX1), an iron-sulphur protein, is responsible for electron transfer in a range of metabolic redox reactions. Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer characterised by metabolic reprogramming, and FDX1 is a critical regulator of cuproptosis. However, the expression profile and prognostic value of FDX1 associated with clinicopathological features in ccRCC remain largely unelucidated. In this study, we integrated a series of public bioinformatic analysis to explore the mRNA and protein profiles of FDX1 across human cancers and cell lines and validated its expression and prognostic value, especially in ccRCC. In this study, FDX1 mRNA and protein expression were aberrantly downregulated and associated with ccRCC grade, stage, and nodal metastasis, whereas in adjacent non-tumour kidney tissue, it was abundantly expressed and cytoplasmically localised in renal tubular epithelial cells. Multivariate analysis indicated that low FDX1 expression contributed to unfavourable overall and disease-free survival. The functional enrichment of FDX1 co-expressed genes in ccRCC involved mainly mitochondrial dysfunction in various metabolic processes and biological oxidation, besides iron-sulphur cluster biogenesis. Furthermore, FDX1 modulates immunological infiltration to affect prognosis. Thus, FDX1 downregulation is mechanistically because of ccRCC tumourigenesis and is a promising prognostic biomarker to stratify patients with ccRCC.

Histological features suggestive of survival in patients with renal cell carcinoma and tumor thrombus: A single-center experience.

Purpose: To evaluate the impact of histological subtype on the survival of patients with renal cell carcinoma (RCC) and tumor thrombus (TT). Patients and methods: We retrospectively analyzed 350 patients with RCC and TT admitted to Chinese People's Liberation Army General Hospital between January 2006 and June 2021. The patients underwent radical nephrectomy and thrombectomy using robot-assisted laparoscopic, laparoscopic, or open surgery. The clinical and pathological parameters of the patients were taken from their medical records. Survival was calculated with the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic significance of variables on overall survival (OS) and progression-free survival (PFS). Results: TT levels 0-IV were observed in 132 (37.71%), 43 (12.29%), 134 (38.29%), 20 (5.71) and 21 (6.00%) patients, respectively. Papillary (pRCC), clear cell, and other histological subtypes of RCC were detected in 28 (8.00%), 286 (81.71%), and 36 (10.29%) patients, respectively. Compared to the clear cell cohort, collecting systemic invasion (46.43 vs. 25.17%; p = 0.030) and lymph node metastasis (39.29 vs. 11.54%; p < 0.01) were more common in the pRCC cohort. Kaplan-Meier analyses showed that patients with pRCC and other subtypes had significantly worse OS and PFS compared to patients with the clear cell subtype (p < 0.05). Multivariate analyses revealed that histology was independently associated with reduced OS and PFS, including among patients without lymph node and distant metastasis (N0M0). Conclusion: Papillary or other subtypes have a considerably shorter OS and PFS compared to clear cell subtype in RCC patients with TT. Strict follow-up and surveillance should be performed for papillary or other subtypes RCC with TT.

Concurrent Germline and Somatic Mutations in FLCN and Preliminary Exploration of Its Function: A Case Report.

Birt-Hogg-Dube syndrome is an autosomal dominant condition that arises from germline folliculin (FLCN) mutations. It is characterized by skin fibrofolliculomas, lung cysts, pneumothorax, and renal cancer. Here, we present the case of a 36-year-old woman with asymptomatic, multiple renal tumors and a history of spontaneous pneumothorax. Genetic analysis revealed a hotspot FLCN germline mutation, c.1285dupC (p.H429fs), and a novel somatic mutation, c.470delT (p.F157fs). This information and the results of immunohistochemical analysis of the renal tumors indicated features compatible with a tumor suppressor role of FLCN. Two transcription factors, oncogenic TFEB and TFE3, were shown to be regulated by FLCN inactivation, which results in their nuclear localization. We showed that a deficiency in the tumor suppressor FLCN leads to deregulation of the mammalian target of rapamycin signaling (mTOR) pathway. A potential link between FLCN mutation and ciliary length was also examined. Thus, the mutation identified in our patient provides novel insights into the relationship among FLCN mutations, TFEB/TFE3, mTOR, and cilia. However, an in-depth understanding of the role of folliculin in the molecular pathogenesis of renal cancer requires further study.

Survival of Patients With UrAC and Primary BAC and Urothelial Carcinoma With Glandular Differentiation.

Purpose: To investigate the significance of demographic and pathological characteristics on the survival outcomes of urachal adenocarcinoma (UrAC), primary bladder adenocarcinoma (BAC) and urothelial carcinoma with glandular differentiation (UCGD) in China. Materials and Methods: We retrospectively analyzed cases with non-distant metastases (≤ T4M0). Of 106 patients, 30 (28.3%), 40 (37.7%), and 36 (34.0%) met the criteria for UrAC, primary BAC, and UCGD, respectively. Data on patient demographics, tumor pathology, and survival outcomes were collected. The median follow-up was 36 months. Survival was analyzed using multivariate Cox regression. Results: Patients with UrAC were younger (51.87 ± 15.25 years) than those with primary BAC (60.50 ± 12.56 years) and UCGD (63.83 ± 11.60 years) (P<0.001). Patients with UrAC were the most likely to be stage T3-4 (70.0% vs. 40.0% vs. 44.4%; P<0.001), while the primary BAC group had a higher rate of poor differentiation than the UrAC and UCGD groups (57.4% vs. 18.5% vs. 24.1%; P<0.001). The Kaplan-Meier curves showed that the overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) of the primary BAC group were poorer than those of both the UrAC and UCGD groups (P=0.0046,P<0.0001,P=0.0077 respectively). Regarding BAC, patients with mucinous adenocarcinoma tended to have better OS and PFS than those with other histological types (P<0.005,P=0.0245). Multivariate Cox regression analysis revealed that tumor type (P=0.002), T stage (P=0.034), and the age-adjusted Charlson Comorbidity Index (aCCI) scores (P=0.005) predicted the postoperative OS and DSS of the patients. For PFS, the tumor type (P=0.011), grade (P=0.000), and aCCI (P=0.002) scores were predictive. Conclusion: Among UrAC, primary BAC, and UCGD patients, the prognosis was poorest for those with primary BAC. Attempts should be made to diagnose these aggressive tumors early, since patients in whom tumors are detected early appear to survive longer.

Mixed Reality: A Step Further for Planning Complex Renal Tumors (RENAL Nephrometry Score of 7 or Higher).

Objectives: Mixed reality (MR) technology has emerged in recent years and allows three-dimensional visualization, multiangle observation, remote vision, and virtual-real interaction. This study aims to explore the influence of MR technology on the outcomes and strategy planning of robotic surgery for complex renal tumors. Patients and Methods: A total of 92 patients with complex renal tumors were enrolled in this study from June 2018 to June 2020. All patients were found to have tumors by magnetic resonance imaging (MRI) in our department. This trial follows CONSORT guidelines and adopts a single-blind parallel design and randomizes patients with a random number table. The study was approved by the institutional review board, and written informed consent was obtained from each participant. All surgeries were performed by three experienced and high-volume surgeons. The demographic indicators, intraoperative and postoperative complications, renal function outcomes, pathological results, and surgical strategies were recorded. Student's t-test and Wilcoxon rank-sum test were used to compare continuous variables, and Pearson's chi-squared and Fisher's exact tests were used to compare categorical variables. Results: Warm ischemia time (WIT) mainly comprises tumor resection time and reconstruction time, and the reconstruction time accounts for a larger proportion. For urologists treating complex renal tumors, MR technology can help them reduce the warm ischemia time (21.3 ± 4.0 vs 23.6 ± 5.9 minutes, p = 0.031), reconstruction time (15.4 ± 3.8 vs 17.2 ± 4.2 minutes, p = 0.034), estimated blood loss (p = 0.044), operation time (125.7 ± 26.3 vs 144.6 ± 27.9 minutes, p = 0.001), and intraoperative complications (p = 0.030). Conclusions: MR-assisted surgery can reduce the incidence of intraoperative complications and improve perioperative outcomes, and MR may be a good preoperative tool for planning complex renal tumor surgery.

Prevalence and relevant factors of positive RF in brucellosis patients with arthralgia.

BACKGROUND: Brucellosis is a critical zoonotic disease in the world, it is the non-specific arthralgia that make brucellosis patients easily misdiagnosed as rheumatoid arthritis (RA) in endemic regions. Elevated rheumatoid factor (RF) is an essential indicator of RA, and the RF in brucellosis patients is significantly higher than healthy people. Therefore, this study further explored the distribution of RF and the relevant factors of the RF positivity in brucellosis patients with arthralgia, in order to strengthen the recognition of physicians for brucellosis patients with RF positivity, especially in brucellosis-endemic areas, so as to avoid misdiagnosis and untimely treatment that may lead to malignant outcomes. METHODOLOGY AND PRINCIPAL FINDINGS: The medical records of all 572 brucellosis inpatients were collected in the Sixth People's Hospital of Shenyang, China from 2015 to 2016. After excluding 106 patients without arthralgia, 5 patients who unwilling to perform RF testing and 16 patients with diseases that may affect RF, 445 brucellosis inpatients with arthralgia were involved in this retrospective cross-sectional study. 143 (32.1%) patients with RF >10 IU/ml were classified into the RF positive group, with an average level of 16.5[12.2, 34.7] IU/ml, of which 45 (10.1%) patients were high-positive with RF >30 IU/ml. Multivariate logistic regression model was used to further analyze the relevant factors of the RF positivity and found that age, wrist joint pain and elevated C-reactive protein (CRP) were positively associated with RF positivity, with OR of 1.02 (P = 0.024), 8.94 (P = 0.008) and 1.79 (P = 0.019), respectively. CONCLUSION: The prevalence of positive RF in brucellosis patients with arthralgia was critical, nearly one-third of patients had RF positive. Elderly men brucellosis patients with arthralgia, wrist joint pain and elevated CRP were at high risk of positive RF. It is reminded that physicians should focus on differential diagnosis during clinical diagnosis and treatment, especially in brucellosis-endemic regions.

Cervical Artificial Disc Replacement With Discover Prosthesis Does Not Reduce the Midterm Risk of Heterotopic Ossification: Results of a Cohort Study.

STUDY DESIGN: A prospective cohort study with 79 patients. OBJECTIVE: To analyze the midterm incidence of heterotopic ossification (HO) after cervical artificial disc replacement with Discover prosthesis in treatment of cervical degenerative disc disease. MATERIALS AND METHODS: A cohort of 79 patients with 102 Discover prostheses (56 monosegment and 23 bisegments) was evaluated. Clinical and radiographic follow-up was performed. The performance of HO of the operative segments was assessed annually after the operation for 4 years. RESULTS: Early follow-up at 2 years postsurgical treatment showed satisfactory clinical outcomes. No significant changes on the mean Japanese Orthopaedic Association and Visual Analog Scale scores were detected at 3 and 4 years postoperation. The occurrence rate of HO was 5.9% in 1-year follow-up and 17.6% in 2-year follow-up, and then the percentages increased to 49.2% in 3-year follow-up and 65.6% in 4-year follow-up, respectively. No association between the HO grades and the type of the surgical segment was detected by the Fisher exact test (P-value=0.56). No prosthesis subsidence or excursion was identified during the whole follow-up period. CONCLUSIONS: The use of Discover prosthesis resulted in satisfactory clinical outcomes after operation. However, the new prosthesis did not reduce the midterm risk of HO, despite the fact that the observed incidence was relatively low in the early follow-up.

[Research progress in the study of brain microdialysis in glioma].

Glioma is the most common form of brain cancer. Despite recent advances in the treatment of solid tumors, there are few effective treatments for malignant gliomas due to its infiltrative nature. It has important significance to improve the treatment of glioma through in-depth understanding the intracerebral metabolic characteristics and pharmacokinetics of chemotherapeutics. Brain microdialysis (B-MD), an effective method to monitor central nervous system anticancer drug disposition, conditions of drugs through the blood-brain barrier, basic pathophysiologic metabolism, bioactive compounds and the changes of neurotransmitter in brain, provides the unique opportunity to allow the simultaneous determination of unbound concentrations of drugs in several tissues, and directly measure gliomas biochemistry continuously. B-MD has been able to monitor the change of brain drugs, metabolites and neurotransmitters, dynamic analysis of the drug concentration and pharmacological effect after administration, pharmacodynamic interaction between drugs, receptor mechanism of drug transport, as well as feedback information of internal environment. B-MD is expected to provide reference for clinical individual chemotherapy of glioma, but also provide powerful tools for the evaluation of new anticancer drugs in vivo. In this review, a comprehensive overview of B-MD for studies on glioma is elucidated with special emphasis on its application to neurochemistry and pharmacokinetic studies.

Phase transformation of cadmium sulfide under high temperature and high pressure conditions.

Cadmium sulfide (CdS) is one of the most significant wide band gap semiconductors, and knowledge of the phase transformation of CdS under high temperature and pressure is especially important for its applications. The pressure-temperature phase diagram and the phase transformation pathways of CdS have been investigated by using density functional theory combined with quasiharmonic approximation. Our results indicated that under ambient conditions, wz-CdS is a stable phase, while under high temperature and pressure, rs-CdS becomes the stable phase. It is also found that zb-CdS is an intermediate phase in transforming from rs-CdS to wz-CdS. Therefore, although there are no zb-CdS phase regions in the CdS pressure-temperature phase diagram, zb-CdS can be found in some prepared experiments.

Cerebral microdialysis in glioma studies, from theory to application.

Despite recent advances in the treatment of solid tumors, there are few effective treatments for malignant gliomas due to the infiltrative nature, and the protective shield of blood-brain barrier or blood-tumor barriers that restrict the passage of chemotherapy drugs into the brain. Imaging techniques, such as PET and MRI, have allowed the assessment of tumor function in vivo, but they are indirect measures of activity and do not easily allow continuous repeated evaluations. Because the biology of glioma on a cellular and molecular level is fairly unknown, especially in relation to various treatments, the development of novel therapeutic approaches to this devastating condition requires a strong need for a deeper understanding of the tumor's pathophysiology and biochemistry. Cerebral microdialysis, a probe-based sampling technique, allows a discrete volume of the brain to be sampled for neurochemical analysis of neurotransmitters, metabolites, biomarkers, and chemotherapy drugs, which has been employed in studying brain tumors, and is significant for improving the treatment of glioma. In this review, the current concepts of cerebral microdialysis for glioma are elucidated, with a special emphasis on its application to neurochemistry and pharmacokinetic studies.

Sensitive detection of p53 tumor suppressor gene using an enzyme-based solid-state electrochemiluminescence sensing platform.

An enzyme-based solid-state electrochemiluminescence (ECL) sensing platform for sensitive detection of a single point mutation is developed successfully using p53 tumor suppressor gene as a model analyte. A composite of multiwalled carbon nanotubes and Ruthenium (II) tris-(bipyridine) (MWNTs-Ru(bpy)(3)(2+)) was prepared and coated on an electrode surface, which was covered by polypyrrole (PPy) to immobilize ssDNA. Then, the ssDNA recognized the gold nanoparticle (AuNP)-labeled p53 tumor suppressor gene, and produced AuNP-dsDNA electrode with AuNP layer. The surface adsorbed the glucose-dehydrogenase (GDH) molecules for producing ECL signal. This system combined enzyme reaction with ECL detection, and it can recognize sequence-specific wild type p53 sequence (wtp53) and muted type p53 sequence (mtp53) with discrimination of up to 56.3%. The analytic results were sensitive and specific. It holds promise for the diagnosis and management of cancer.

Cycloartane triterpenoids from Kleinhovia hospita.

Four new cycloartane triterpenoids, together with the known gardenolic acid B, were isolated from Kleinhovia hospita. The triterpenoids (1-3) contain a unique 21,23-diacetal side-chain, while compound 4 contains two alpha,beta-unsaturated ketone moieties. Their structures and relative configurations were determined by spectroscopic methods, including 2D NMR and IR. These compounds showed promising hepatoprotective effects on nitrofurantoin-induced cytotoxicity in human liver-derived Hep G2 cells.