LncRNA GAS5 restrains ISO-induced cardiac fibrosis by modulating mir-217 regulation of SIRT1.

Considering the effect of SIRT1 on improving myocardial fibrosis and GAS5 inhibiting occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating mir-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-ß1 were used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with mir-217 mimics and mir-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1ß and SIRT1 were conducted. The findings indicated that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1ß and SIRT1 in ISO treated mice and TGF-ß1 treated MCFs. However, this effect was significantly weakened after mir-217 overexpression, but was further enhanced after knockdown of mir-217. mir-217 down-regulates the expression of SIRT1, leading to increased activation of the NLRP3 inflammasome and subsequent pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced via regulating mir-217/SIRT1 pathway.

An enigmatic Cretaceous beetle with possible affinity to Erotylidae (Coleoptera: Cucujiformia).

The morphology of beetles of the recently defined superfamilies Erotyloidea, Nitiduloidea and Cucujoidea is varied. Determining the systematic positions of Mesozoic fossils within these groups can often be challenging. Here we describe and illustrate a puzzling cucujiform beetle, Isocryptophilus exilipunctus Li & Cai gen. & sp. nov., based on an individual from mid-Cretaceous Burmese amber. While we cannot definitively pinpoint the exact phylogenetic position of Isocryptophilus, its possible affinity to Erotylidae is discussed in light of our phylogenetic analyses. A broader-sampled morphological matrix, coupled with a robust molecular phylogeny of these groups, will be promising for clarifying the systematic placement of the fossil.

Comprehensive improvements in the emergency laboratory test process based on information technology.

OBJECTIVE: To explore the application effects of information technology (IT) on emergency laboratory testing procedures. METHODS: In this study, IT-based optimisation of the emergency laboratory testing process was implemented between October and December 2021. Thus, the emergency laboratory test reports from January to September 2021 were placed into the pre-optimised group, while those from January to September 2022 were categorised into the post-optimised group. Besides, the emergency laboratory test report time, emergency laboratory test report time limit coincidence rate, error rate, and employee and patient satisfaction levels in individual months and across the whole period were described. Moreover, changes in the above indicators before and after the implementation of IT-based optimisation were explored and the application effects of IT-based optimisation were also evaluated. RESULTS: The emergency laboratory test report times after the implementation of IT-based optimisation were shorter than those before IT-based optimisation (P < 0.05). The total number of laboratory test items before and after information optimization amounted to 222,139 and 259,651, respectively. Also, IT-based optimisation led to an increase in the emergency laboratory test report time limit coincidence rate from 98.77% to 99.03% (P < 0.05), while the emergency laboratory test report error rate fell from 0.77‱ to 0.15‱ (P < 0.05). Additionally, IT-based optimisation resulted in increases in both employee satisfaction, from 80.65% to 93.55% (N = 31, P > 0.05), and patient satisfaction, from 93.06% to 98.44% (P < 0.05). CONCLUSION: The automation and IT-based optimisation of the emergency laboratory testing process significantly reduces the emergency laboratory test report time and error rate. Additionally, IT-driven optimization enhances the alignment of emergency laboratory test report deadlines and enhances the overall quality and safety of emergency laboratory testing.

Regular gastroscopy and colonoscopy during the evaluation of urachal cancer: do we really need them?

PURPOSE: Urachal cancer is similar to gastrointestinal adenocarcinoma in histology, and gastroscopy/colonoscopy is often administered during perioperative evaluation. However, gastroscopy and colonoscopy have corresponding disadvantages. This study discusses whether gastroscopy/colonoscopy is truly necessary for patients with urachal cancer. PATIENTS AND METHODS: A total of 166 bladder adenocarcinoma cases diagnosed at Sun Yat-sen University Cancer Center were retrospectively reviewed and divided into two groups (urachal cancer and nonurachal cancer), and perioperative evaluations were retrieved. RESULTS: There were 78 patients with urachal cancer, the median age was 48 years, and 59 were male. Perioperative gastroscopy/colonoscopy revealed 5 intestinal polyps and 1 adenoma during these evaluations, and no primary gastrointestinal cancer was found. Meanwhile, preoperative imaging evaluation did not detect significant gastrointestinal lesions. For 88 patients with nonurachal cancer, including primary bladder adenocarcinoma and metastatic tumors from gastrointestinal cancer, the median age was 56 years, and 64 were male. Preoperative imaging evaluation demonstrated 36 cases of gastrointestinal lesions, and 32 were confirmed by gastroscopy/colonoscopy; the other 4 were negative. Another 4 cases of colon cancer were detected by regular colonoscopy for suspected primary bladder adenocarcinoma. In all, 35 cases of colon cancer and 1 case of gastric cancer were identified by endoscopic examination. The diagnostic consistency of imaging and gastrointestinal endoscopy was favorable (P < 0.001), and the negative predictive value and diagnostic efficiency of imaging were 96.9% and 94.6%, respectively. CONCLUSIONS: The vast majority of gastrointestinal cancer cases can be identified by assessment of the patient's clinical symptoms, meticulous physical examination, and imaging evaluation. We recommend that gastroscopy/colonoscopy only be applied to patients with urachal cancer when the above examinations are positive.

Optimal interval timing between transurethral resection of bladder tumors and Bacillus Calmette-Guerin perfusion.

OBJECTIVE: There is no consensus regarding the best interval time between transurethral resection of a bladder tumor and Bacillus Calmette-Guerin (BCG) perfusion. This study was to explore whether the interval time has an impact on the prognosis and adverse effects. METHODS: We retrospectively reviewed the clinical data of patients who received BCG intravesical perfusion at Sun Yat-sen University Cancer Center (SYSUCC) from September 2015 to October 2021. Recurrence-free survival (RFS) and progression-free survival were the primary endpoints. Cox regression was used to explore independent predictors. The association between interval time and adverse effect grade was detected by logistic regression. Propensity score matching (PSM) was performed. RESULTS: A total of 403 patients were enrolled, the median interval time was 24 days (6-163 days), and the follow-up was 28 months (7-82 months). Eighty-eight (20.9%) patients relapsed, and 40 patients (10.0%) suffered progression. The multivariate Cox regression analysis confirmed that interval time was an independent predictor of RFS (p = 0.017). Notably, when the interval time was less than or equal to 26 days, there was a trend toward better RFS, PSM resulted in 65 matched pairs in each group, and Kaplan-Meier analysis showed that there was a significant difference in RFS between groups (p = 0.009). The logistic regression analysis showed that there was no correlation between interval time and adverse effects and their grades (p > 0.05). CONCLUSIONS: We considered that the first BCG perfusion could be performed within 2-4 weeks after surgery.

[Mechanism of Zhenwu Decoction in improving renal inflammatory injury in mice with DN of spleen-kidney Yang deficiency syndrome by regulating ROCK/IKK/NF-κB pathway].

To investigate the intervention effect and mechanism of Zhenwu Decoction on diabetic nephropathy(DN) mice of spleen-kidney Yang deficiency syndrome based on the Rho-associated coiled-coil kinase(ROCK)/IκB kinase(IKK)/nuclear factor-κB(NF-κB) pathway. Ninety-five 7-week-old db/db male mice and 25 7-week-old db/m male mice were fed adaptively for one week. The DN model of spleen-kidney Yang deficiency syndrome was induced by Dahuang Decoction combined with hydrocortisone by gavage, and then the model was evaluated. After modeling, they were randomly divided into a model group, high-dose, medium-dose, and low-dose Zhenwu Decoction groups(33.8, 16.9, and 8.45 g·kg~(-1)·d~(-1)), and an irbesartan group(25 mg·kg~(-1)·d~(-1)), with at least 15 animals in each group. The intervention lasted for eight weeks. After the intervention, body weight and food intake were measured. Serum crea-tinine(Scr), blood urea nitrogen(BUN), fasting blood glucose(FBG), urinary albumin(uALb), and urine creatinine(Ucr) were determined. The uALb/Ucr ratio(ACR) and 24 h urinary protein(UTP) were calculated. Renal pathological morphology was evaluated by HE staining and Masson staining. The levels of key molecular proteins in the ROCK/IKK/NF-κB pathway were detected by Western blot. Enzyme-linked immunosorbent assay(ELISA) was used to detect interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-8(IL-8), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Compared with the blank group, the model group showed increased content of BUN, uALb, and SCr, increased values of 24 h UTP and ACR, decreased content of Ucr(P<0.05), enlarged glomeruli, thickened basement membrane, mesangial matrix proliferation, inflammatory cell infiltration, and collagen fiber deposition. The protein expression of ROCK1, ROCK2, IKK, NF-κB, phosphorylated IKK(p-IKK), phosphorylated NF-κB(p-NF-κB), and phosphorylated inhibitor of NF-κB(p-IκB) increased(P<0.05), while the protein expression of inhibitor of NF-κB(IκB) decreased(P<0.05). The levels of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α increased(P<0.05), while the level of IL-10 decreased(P<0.05). Compared with the model group, the groups with drug treatment showed decreased levels of BUN, uALb, SCr, 24 h UTP, and ACR, increased level of Ucr(P<0.05), and improved renal pathological status to varying degrees. The high-and medium-dose Zhenwu Decoction groups and the irbesartan group showed reduced protein expression of ROCK1, ROCK2, IKK, NF-κB, p-IKK, p-NF-κB, and p-IκB in the kidneys(P<0.05), increased protein expression of IκB(P<0.05), decreased levels of serum inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α(P<0.05), and increased level of IL-10(P<0.05). Zhenwu Decoction can significantly improve renal function and renal pathological damage in DN mice of spleen-kidney Yang deficiency syndrome, and its specific mechanism may be related to the inhibition of inflammatory response by down-regulating the expression of key molecules in the ROCK/IKK/NF-κB pathway in the kidney.

Combining clinical parameters and multiparametric magnetic resonance imaging to stratify biopsy-naïve men for an optimum diagnostic strategy with prostate-specific antigen 4 ng ml-1 to 10 ng ml-1.

We attempted to perform risk categories based on the free/total prostate-specific antigen ratio (%fPSA), prostate-specific antigen (PSA) density (PSAD, in ng ml-2), and multiparametric magnetic resonance imaging (mpMRI) step by step, with the goal of determining the best clinical diagnostic strategy to avoid unnecessary tests and prostate biopsy (PBx) in biopsy-naïve men with PSA levels ranging from 4 ng ml-1 to 10 ng ml-1. We included 439 patients who had mpMRI and PBx between August 2018 and July 2021 (West China Hospital, Chengdu, China). To detect clinically significant prostate cancer (csPCa) on PBx, receiver-operating characteristic (ROC) curves and their respective area under the curve were calculated. Based on %fPSA, PSAD, and Prostate Imaging-Reporting and Data System (PI-RADS) scores, the negative predictive value (NPV) and positive predictive value (PPV) were calculated sequentially. The optimal %fPSA threshold was determined to be 0.16, and the optimal PSAD threshold was 0.12 for %fPSA ≥0.16 and 0.23 for %fPSA <0.16, respectively. When PSAD <0.12 was combined with patients with %fPSA ≥0.16, the NPV of csPCa increased from 0.832 (95% confidence interval [CI]: 0.766-0.887) to 0.931 (95% CI: 0.833-0.981); the detection rate of csPCa was similar when further stratified by PI-RADS scores (P = 0.552). Combining %fPSA <0.16 with PSAD ≥0.23 ng ml-2 predicted significantly more csPCa patients than those with PSAD <0.23 ng ml-2 (58.4% vs 26.7%, P < 0.001). Using PI-RADS scores 4 and 5, the PPV was 0.739 (95% CI: 0.634-0.827) when further stratified by mpMRI results. In biopsy-naïve patients with PSA level of 4-10 ng ml-1, stratification of %fPSA and PSAD combined with PI-RADS scores may be useful in the decision-making process prior to undergoing PBx.

Robotic versus laparoscopic total mesorectal excision for rectal cancer: a meta-analysis of long-term survival and urogenital functional outcomes.

INTRODUCTION: Robotic surgical technology has been widely introduced and applied in various fields of surgery. The aim of this study was to analyze long-term oncological and urogenital functional outcomes following laparoscopic/robotic total mesorectal excision (TME) in rectal cancer surgery. EVIDENCE ACQUISITION: We identified studies that compared oncological and functional outcomes following laparoscopic TME (LTME) and robotic TME (RTME) for treatment of rectal cancer over the past 16 years. Data related to overall survival (OS), disease-free survival (DFS), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF) were subjected to meta-analysis. EVIDENCE SYNTHESIS: There was no difference in long-term OS and DFS in the pooled data. Compared with LTME, there were significant differences in the score of IPSS at 3, 6 and 12 months for RTME, in the pooled data for male patients. There were significant differences in IIEF score for male patients at 3 and 6 months. CONCLUSIONS: Compared with LTME, RTME has better preservation of urinary and sexual functions and comparable long-term oncological outcome in rectal cancer.

Profiling of gene fusion involving targetable genes in Chinese gastric cancer.

BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

A new marsh beetle from mid-Cretaceous amber of northern Myanmar (Coleoptera: Scirtidae).

As one of the earliest-diverging lineage of the megadiverse beetle suborder Polyphaga, marsh beetles (Scirtidae) are crucial for reconstructing the ancestor of all polyphagan beetles and the ecomorphological underpinnings of their remarkable evolutionary success. The phylogeny of marsh beetles has nonetheless remained challenging to infer, not least because of their fragmentary Mesozoic fossil record. Here we describe a new scirtid beetle genus and species, Varcalium lawrencei gen. et sp. nov., preserving internal tissue, from Albian-Cenomanian Kachin amber (ca 99 Ma), representing the second member of this family known from the deposit. Based on a formal morphological phylogenetic analysis, Varcalium is recovered within the crown-group of Scirtinae, forming a clade with other genera that possess subocular carinae. The finding suggests that the crown-group of Scirtinae has already diversified by the mid-Cretaceous.

The role of prostate-specific antigen density and negative multiparametric magnetic resonance imaging in excluding prostate cancer for biopsy-naïve men: clinical outcomes from a high-volume center in China.

This study aimed to assess the role of prostate-specific antigen density (PSAD) and negative multiparametric magnetic resonance imaging (mpMRI) in predicting prostate cancer for biopsy-naïve men based on a large cohort of the Chinese population. From a prostate biopsy database between March 2017 and July 2021, we retrospectively identified 240 biopsy-naïve patients with negative prebiopsy mpMRI (Prostate Imaging Reporting and Data System version 2 [PI-RADS v2] score <3). Logistic regression analysis was performed to select the potential predictors for clinically significant prostate cancer (csPCa). Receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) were performed to assess the diagnostic accuracy. The negative predictive values of mpMRI in excluding any cancer and csPCa were 83.8% (201/240) and 90.8% (218/240), respectively. ROC curve analysis indicated that PSAD was the most promising predictor, with an AUC value of 0.786 (95% confidence interval [CI]: 0.699-0.874), and multiparametric logistic regression analysis confirmed that higher PSAD remained a significant marker for predicting csPCa (odds ratio [OR]: 10.99, 95% CI: 2.75-44.02, P < 0.001). Combining negative mpMRI and PSAD below 0.20 ng ml-2 obviously increased the predictive value in excluding PCa (91.0%, 101/111) or csPCa (100.0%, 111/111). If a PSAD below 0.20 ng ml-2 was set as the criterion to omit biopsy, nearly 46.3% of patients (463 per 1000) with negative mpMRI could safely avoid unnecessary biopsy, with approximately 4.2% of patients (42 per 1000) at risk of missed diagnosis of PCa and no patients with csPCa missed. A PI-RADS v2 score <3 and a PSAD <0.20 ng ml-2 could be potential criteria for the Chinese population to omit prompt biopsy safely.

PSEN1 G417S mutation in a Chinese pedigree causing early-onset parkinsonism with cognitive impairment.

Presenilin 1 (PSEN1) mutations are a major cause of familial Alzheimer's disease. The pathogenic variant, PSEN1 p.G417S, has been reported to be associated with spastic paraparesis and cotton wool plaques in Japan. Here, we report a 3 generation Chinese pedigree that included 10 patients presenting with early-onset and rapid progression of parkinsonism with cognitive impairment in their third or fourth decade of life. Three additional living patients developed different degrees of cognitive impairment, without movement disorders. Magnetic resonance imaging of the brain showed white matter hyperintensities, multiple microbleeds, and enlarged perivascular spaces. Whole exome sequencing analysis of the proband detected the mutation, p.G417S, in PSEN1, which was completely co-segregated with the disease phenotype within the family by Sanger sequencing. 3D protein structures predicted that the mutation might influence contact with the lipid membrane and the interaction with beta-catenin. Our study provides insights into the heterogeneity in clinical presentation and imaging associated with mutations in PSEN1.

Efficacy of Lauromacrogol Injection for Ablation of Benign Predominantly Cystic Thyroid Nodules and Related Factors: A Prospective Study.

OBJECTIVE: To prospectively evaluate the efficacy of lauromacrogol injection for ablation (LIA) of benign predominantly cystic thyroid nodules and its related factors. MATERIALS AND METHODS: A total of 142 benign predominantly cystic thyroid nodules (median volume, 12.5 mL; range, 0.4-156 mL) in 137 patients (male:female sex ratio, 36:101; mean age ± standard deviation [SD], 49 ± 13 years) were treated with LIA after being confirmed as benign via cytology. The volume reduction rate (VRR) of the nodules and cosmetic score were evaluated during follow-up at 1, 3, and 6 months after treatment and every 6 months thereafter. A VRR of ≥ 50% at the 12-month follow-up was considered to indicate effective treatment. The associations between the clinical factors and nodular ultrasound features, including the initial nodule volume, proportion of solid components, vascularity grade and ineffective treatment (VRR of < 50% at the 12-month follow-up), and regrowth were analyzed. RESULTS: All patients completed follow-up for at least 12 months. The average ± SD follow-up period was 32 ± 11 months (range, 12-54 months). The effective treatment rate was 73.2% (104/142), while the regrowth rate was 12.0% (17/142) at the last follow-up. Grade 2-3 intranodular vascularity in the solid components of the nodules was the only independent factor associated with ineffective treatment, with an odds ratio (reference category, grade 0-1) of 3.054 (95% confidence interval, 1.148-8.127) (p = 0.025). CONCLUSION: LIA is an effective treatment for predominantly cystic thyroid nodules. Grade 2-3 intranodular vascularity in the solid components of nodules is the only independent risk factor for ineffective LIA.

Genomic insight into the scale specialization of the biological control agent Novius pumilus (Weise, 1892).

BACKGROUND: Members of the genus Novius Mulsant, 1846 (= Rodolia Mulsant, 1850) (Coleoptera, Coccinellidae), play important roles in the biological control of cotton cushion scale pests, especially those belonging to Icerya. Since the best-known species, the vedalia beetle Novius cardinalis (Mulsant, 1850) was introduced into California from Australia, more than a century of successful use in classical biological control, some species of Novius have begun to exhibit some field adaptations to novel but related prey species. Despite their economic importance, relatively little is known about the underlying genetic adaptations associated with their feeding habits. Knowledge of the genome sequence of Novius is a major step towards further understanding its biology and potential applications in pest control. RESULTS: We report the first high-quality genome sequence for Novius pumilus (Weise, 1892), a representative specialist of Novius. Computational Analysis of gene Family Evolution (CAFE) analysis showed that several orthogroups encoding chemosensors, digestive, and immunity-related enzymes were significantly expanded (P < 0.05) in N. pumilus compared to the published genomes of other four ladybirds. Furthermore, some of these orthogroups were under significant positive selection pressure (P < 0.05). Notably, transcriptome profiling demonstrated that many genes among the significantly expanded and positively selected orthogroups, as well as genes related to detoxification were differentially expressed, when N. pumilus feeding on the nature prey Icerya compared with the no feeding set. We speculate that these genes are vital in the Icerya adaptation of Novius species. CONCLUSIONS: We report the first Novius genome thus far. In addition, we provide comprehensive transcriptomic resources for N. pumilus. The results from this study may be helpful for understanding the association of the evolution of genes related to chemosensing, digestion, detoxification and immunity with the prey adaptation of insect predators. This will provide a reference for future research and utilization of Novius in biological control programs. Moreover, understanding the possible molecular mechanisms of prey adaptation also inform mass rearing of N. pumilus and other Novius, which may benefit pest control.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

GPNMB overexpression is associated with extensive bone metastasis and poor prognosis in renal cell carcinoma.

Glycoprotein non-metastatic protein B (GPNMB) promotes bone metastasis (BM) in various types of cancer. However, GPNMB expression and its function in patients with renal cell carcinoma (RCC) and BM is still unknown. Therefore, the clinical significance of GPNMB and its biological function in RCC with BM was investigated in the present study. A total of 31 patients with RCC and BM were retrospectively collected. The association between GPNMB protein expression level on the primary tumor and the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier analysis was used to investigate the association between GPNMB expression and the prognosis of the patients. The effects of GPNMB inhibition on cell proliferation, migration and invasion in RCC cells were investigated using short hairpin (sh)RNA. High GPNMB expression level was significantly associated with the number (P=0.001) and the extent of BM (P=0.001), Fuhrman grade (P=0.037), and ERK expression level (P=0.003) of the primary tumor. In addition, GPNMB overexpression was significantly associated with poor prognosis with respect to overall survival time (P=0.001). Furthermore, a specific shRNA sequence targeting the GPNMB gene was constructed and transduced into the ACHN cell line, using a lentivirus vector to obtain a stable cell line with low mRNA expression level of GPNMB. Low GPNMB expression level inhibited RCC cell proliferation, which was measured using a Cell Counting Kit-8 assay. Cell migration and invasion ability was significantly decreased in GPNMB knockdown RCC cells compared with that in cells transduced with the negative control shRNA. In addition, the protein expression levels of phosphorylated ERK were lower in the GPNMB shRNA-transduced ACHN cells compared with those in the control cells. Therefore, these results suggested that GPNMB plays an important role in tumor progression in RCC with BM. Furthermore, it might serve as a predictive marker for BM and as a poor prognostic factor in RCC with BM. GPNMB downregulation suppressed the proliferation, migration and invasion of the RCC cells, which may be mediated through the inhibition of the ERK signaling pathway.

Constructing Prediction Models for Freezing of Gait by Nomogram and Machine Learning: A Longitudinal Study.

Objectives: Although risk factors for freezing of gait (FOG) have been reported, there are still few prediction models based on cohorts that predict FOG. This 1-year longitudinal study was aimed to identify the clinical measurements closely linked with FOG in Chinese patients with Parkinson's disease (PD) and construct prediction models based on those clinical measurements using Cox regression and machine learning. Methods: The study enrolled 967 PD patients without FOG in the Hoehn and Yahr (H&Y) stage 1-3 at baseline. The development of FOG during follow-up was the end-point. Neurologists trained in movement disorders collected information from the patients on a PD medication regimen and their clinical characteristics. The cohort was assessed on the same clinical scales, and the baseline characteristics were recorded and compared. After the patients were divided into the training set and test set by the stratified random sampling method, prediction models were constructed using Cox regression and random forests (RF). Results: At the end of the study, 26.4% (255/967) of the patients suffered from FOG. Patients with FOG had significantly longer disease duration, greater age at baseline and H&Y stage, lower proportion in Tremor Dominant (TD) subtype, a higher proportion in wearing-off, levodopa equivalent daily dosage (LEDD), usage of L-Dopa and catechol-O-methyltransferase (COMT) inhibitors, a higher score in scales of Unified Parkinson's Disease Rate Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Rating Scale (HDRS)-17, Parkinson's Fatigue Scale (PFS), rapid eye movement sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK), Epworth Sleepiness Scale (ESS), and a lower score in scales of Parkinson's Disease Sleep Scale (PDSS) (P < 0.05). The risk factors associated with FOG included PD onset not being under the age of 50 years, a lower degree of tremor symptom, impaired activities of daily living (ADL), UPDRS item 30 posture instability, unexplained weight loss, and a higher degree of fatigue. The concordance index (C-index) was 0.68 for the training set (for internal validation) and 0.71 for the test set (for external validation) of the nomogram prediction model, which showed a good predictive ability for patients in different survival times. The RF model also performed well, the C-index was 0.74 for the test set, and the AUC was 0.74. Conclusions: The study found some new risk factors associated with the FOG including a lower degree of tremor symptom, unexplained weight loss, and a higher degree of fatigue through a longitudinal study, and constructed relatively acceptable prediction models.

LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis.

Reactive oxygen species (ROS) which are continuously generated mainly by mitochondria, have been proved to play an important role in the stress signaling of cancer cells. Moreover, pentatricopeptide repeat (PPR) proteins have been suggested to take part in mitochondrial metabolism. However, the mechanisms integrating the actions of these distinct networks in urothelial carcinoma of the bladder (UCB) pathogenesis are elusive. In this study, we found that leucine rich pentatricopeptide repeat containing (LRPPRC) was frequently upregulated in UCB and that it was an independent prognostic factor in UCB. We further revealed that LRPPRC promoted UCB tumorigenesis by regulating the intracellular ROS homeostasis. Mechanistically, LRPPRC modulates ROS balance and protects UCB cells from oxidative stress via mt-mRNA metabolism and the circANKHD1/FOXM1 axis. In addition, the SRA stem-loop interacting RNA binding protein (SLIRP) directly interacted with LRPPRC to protect it from ubiquitination and proteasomal degradation. Notably, we showed that LRPPRC modulated the tumorigenesis of UCB cells in a circANKHD1-FOXM1-dependent manner. In conclusion, LRPPRC exerts critical roles in regulating UCB redox homeostasis and tumorigenesis, and is a prognostic factor for UCB; suggesting that LRPPRC may serve as an exploitable therapeutic target in UCB.

Lauric acid alleviates deoxynivalenol-induced intestinal stem cell damage by potentiating the Akt/mTORC1/S6K1 signaling axis.

Intestinal stem cell (ISC)-driven intestinal homeostasis is subjected to dual regulation by dietary nutrients and toxins. Our study investigated the use of lauric acid (LA) to alleviate deoxynivalenol (DON)-induced intestinal epithelial damage. C57BL/6 mice in the control, LA, DON, and LA + DON groups were orally administered PBS, 10 mg/kg BW LA, 2 mg/kg BW DON, and 10 mg/kg BW LA + 2 mg/kg BW DON for 10 days. The results showed that LA increased the average daily gain and average daily feed intake of the mice exposed to DON. Moreover, the DON-triggered impairment of jejunal morphology and barrier function was significantly improved after LA supplementation. Moreover, LA rescued ISC proliferation, inhibited intestinal cell apoptosis, and promoted ISC differentiation into absorptive cells, goblet cells, and Paneth cells. The jejunum crypt cells from the mice in the LA group expanded into enteroids, resulting in a significantly greater enteroid area than that in the DON group. Furthermore, LA reversed the DON-mediated inhibition of the Akt/mTORC1/S6K1 signaling axis in the jejunum. Our results indicated that LA accelerates ISC regeneration to repair intestinal epithelial damage after DON insult by reactivating the Akt/mTORC1/S6K1 signaling pathway, which provides new implications for the function of LA in ISCs.