Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis.

OBJECTIVE: The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl-/H+-exchange activity is crucial for the biological role of ClC-6. METHODS: We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6-/- mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6. RESULTS: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6-/- mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6-/- brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. INTERPRETATION: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl- transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024.

Prediction of Vasoactive-Inotropic Score on Prolonged Mechanical Ventilation in Adult Congenital Heart Disease Patients After Surgical Treatment Combined with Coronary Artery Bypass Grafting.

INTRODUCTION: This study aimed to investigate the predictive value of the vasoactive-inotropic score (VIS) at different time points for postoperative prolonged mechanical ventilation (PMV) in adult congenital heart disease patients undergoing surgical treatment combined with coronary artery bypass grafting. METHODS: Patients were divided into two groups that developed PMV or not. The propensity score matching method was applied to reduce the effects of confounding factors between the two groups. VIS at different time points (VIS at the end of surgery, VIS6h, VIS12h, and VIS12h max) after surgery were recorded and calculated. The value of VIS in predicting PMV was analyzed by the receiver operating characteristic (ROC) curve, and multivariate logistic regression was used to analyze independent risk factors. RESULTS: Among 250 patients, 52 were in the PMV group, and 198 were in the non-PMV group. PMV rate was 20.8%. After propensity score matching, 94 patients were matched in pairs. At each time point, the area under the ROC curve predicted by VIS for PMV was > 0.500, among which VIS at the end of surgery was the largest (0.805). The optimal cutoff point for VIS of 6.5 could predict PMV with 78.7% sensitivity and 72.3% specificity. VIS at the end of surgery was an independent risk factor for PMV (odds ratio=1.301, 95% confidence interval 1.091~1.551, P<0.01). CONCLUSION: VIS at the end of surgery is an independent predictor for PMV in patients with adult congenital heart disease surgical treatment combined with coronary artery bypass grafting.

Optimizing the prognostic capacity of baseline 18F-FDG PET/CT metabolic parameters in extranodal natural killer/T-cell lymphoma by using relative and absolute thresholds.

Objectives: To investigate the prognostic capacity of baseline 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in extranodal natural killer/T-cell lymphoma (ENKTCL), and the influence of relative thresholds (RT) and absolute thresholds (AT) selection on prognostic capacity. Materials and methods: Metabolic tumor volume (MTV)-based parameters were defined using RTs (41 % or 25 % of maximum standardized uptake value [SUVmax]), ATs (SUV 2.5, 3.0, 4.0, or mean liver uptake) in 133 patients. Metabolic parameters were classified into avidity-related parameters (SUVmax, mean SUV [SUVmean], standard deviation of SUV [SUVsd]), volume-related parameters (RT-MTV), and avidity- and volume-related parameters (total lesion glycolysis [TLG] and AT-MTV). The prognostic capacity of the metabolic parameters and the effects of different threshold types (RT vs. AT) were evaluated. Results: All metabolic parameters were moderately associated with prognosis. However, the area under the receiver operating characteristic curve of MTV and TLG was slightly higher than that of avidity-related parameters for predicting 5-year progression-free survival (PFS) (0.614-0.705 vs. 0.563-0.609) and overall survival (OS) (0.670-0.748 vs. 0.562-0.593). Correlations of MTV and avidity-related parameters differed between RTs (r < 0.06, P = 0.324-0.985) and ATs (r 0.56-0.84, P ≤ 0.001). AT-MTV was the optimal predictor for PFS and OS, while RT-TLG was the optimal predictor for PFS, and the combination of RT-MTV with SUVmax was the optimal predictor for OS. Conclusion: The incorporation of volume and avidity significantly improved the prognostic capacity of PET in ENKTCL. Composite parameters that encompassed both avidity and volume were recommended.

Prediction of Vasoactive-Inotropic Score on Prolonged Mechanical Ventilation in Adult Congenital Heart Disease Patients After Surgical Treatment Combined with Coronary Artery Bypass Grafting

ABSTRACT Introduction: This study aimed to investigate the predictive value of the vasoactive-inotropic score (VIS) at different time points for postoperative prolonged mechanical ventilation (PMV) in adult congenital heart disease patients undergoing surgical treatment combined with coronary artery bypass grafting. Methods: Patients were divided into two groups that developed PMV or not. The propensity score matching method was applied to reduce the effects of confounding factors between the two groups. VIS at different time points (VIS at the end of surgery, VIS6h, VIS12h, and VIS12h max) after surgery were recorded and calculated. The value of VIS in predicting PMV was analyzed by the receiver operating characteristic (ROC) curve, and multivariate logistic regression was used to analyze independent risk factors. Results: Among 250 patients, 52 were in the PMV group, and 198 were in the non-PMV group. PMV rate was 20.8%. After propensity score matching, 94 patients were matched in pairs. At each time point, the area under the ROC curve predicted by VIS for PMV was > 0.500, among which VIS at the end of surgery was the largest (0.805). The optimal cutoff point for VIS of 6.5 could predict PMV with 78.7% sensitivity and 72.3% specificity. VIS at the end of surgery was an independent risk factor for PMV (odds ratio=1.301, 95% confidence interval 1.091~1.551, P<0.01). Conclusion: VIS at the end of surgery is an independent predictor for PMV in patients with adult congenital heart disease surgical treatment combined with coronary artery bypass grafting.

Ovarian Metastasis From Diffuse Epithelioid Malignant Mesothelioma Revealed by 18 F-FDG PET/CT.

ABSTRACT: Diffuse epithelioid malignant mesothelioma (MM) with metastasis to the ovary is rare. We reported FDG PET/CT findings in a 39-year-old woman with ovarian metastasis from diffuse epithelioid MM. The ultrasound findings at the external hospital revealed multiple masses in the hepatic hilus. FDG PET/CT examination was recommended to evaluate the nature of the lesions. It showed that 2 hypodense lesions in the perihepatic space had intense activity, and there was an additional FDG lesion in the right ovary, which was later confirmed as diffuse epithelioid MM with ovarian metastasis by pathological examination.

Unlocking the Nucleophilicity of Strong Alkyl C-H Bonds via Cu/Cr Catalysis.

Direct functionalization of inert C-H bonds is one of the most attractive yet challenging strategies for constructing molecules in organic chemistry. Herein, we disclose an unprecedented and Earth abundant Cu/Cr catalytic system in which unreactive alkyl C-H bonds are transformed into nucleophilic alkyl-Cr(III) species at room temperature, enabling carbonyl addition reactions with strong alkyl C-H bonds. Various aryl alkyl alcohols are furnished under mild reaction conditions even on a gram scale. Moreover, this new radical-to-polar crossover approach is further applied to the 1,1-difunctionalization of aldehydes with alkanes and different nucleophiles. Mechanistic investigations reveal that the aldehyde not only acts as a reactant but also serves as a photosensitizer to recycle the Cu and Cr catalysts.

The Humeral Metastasis as the Initial Presentation of Lung Adenocarcinoma Revealed by 18F-FDG PET/CT.

ABSTRACT: Lung adenocarcinoma with humeral metastasis as the initial presentation is rare. We reported FDG PET/CT findings of solitary humeral metastasis from adenocarcinoma of the lung in a 57-year-old man with the right upper arm pain as the initial presentation. MRI showed bone destruction of the right humerus with a soft tissue mass, suggesting the possibility of malignancy. FDG PET/CT showed that the right humeral mass had strong activity, and there were additional FDG lesions in the right armpit, left apical lung, and left adrenal gland, which was later confirmed as humeral metastasis from lung adenocarcinoma by pathological examination.

[Factors influencing the efficacy of initial adrenocorticotropic hormone therapy for infantile epileptic spasms syndrome]. / é¦–æ¬¡ä¿ƒè‚¾ä¸Šè ºçš®è´¨æ¿€ç´ æ²»ç–—å©´å„¿ç™«ç—«ç—‰æŒ›ç»¼åˆå¾ç–—æ•ˆçš„å½±å“å› ç´ åˆ†æž.

OBJECTIVES: To study the factors influencing the short-term (28 days) efficacy of initial adrenocorticotropic hormone (ACTH) therapy for infantile epileptic spasms syndrome (IESS), as well as the factors influencing recurrence and prognosis. METHODS: The clinical data were collected from the children with IESS who received ACTH therapy for the first time in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from April 2008 to January 2018 and were followed up for ≥2 years. The multivariate logistic regression analysis was used to evaluate the factors influencing the short-term efficacy of ACTH therapy, recurrence, and long-term prognosis. RESULTS: ACTH therapy achieved a control rate of seizures of 55.5% (111/200) on day 28 of treatment. Of the 111 children, 75 (67.6%) had no recurrence of seizures within 12 months of follow-up. The possibility of seizure control on day 28 of ACTH therapy in the children without focal seizures was 2.463 times that in those with focal seizures (P<0.05). The possibility of seizure control on day 28 of ACTH therapy in the children without hypsarrhythmia on electroencephalography on day 14 of ACTH therapy was 2.415 times that in those with hypsarrhythmia (P<0.05). The possibility of recurrence within 12 months after treatment was increased by 11.8% for every 1-month increase in the course of the disease (P<0.05). The possibility of moderate or severe developmental retardation or death in the children without seizure control after 28 days of ACTH therapy was 8.314 times that in those with seizure control (P<0.05). The possibility of moderate or severe developmental retardation or death in the children with structural etiology was 14.448 times that in those with unknown etiology (P<0.05). CONCLUSIONS: Presence or absence of focal seizures and whether hypsarrhythmia disappears after 14 days of treatment can be used as predictors for the short-term efficacy of ACTH therapy, while the course of disease before treatment can be used as the predictor for recurrence after seizure control by ACTH therapy. The prognosis of IESS children is associated with etiology, and early control of seizures after ACTH therapy can improve long-term prognosis.

Intradermal delivery of an angiotensin II receptor blocker using a personalized microneedle patch for treatment of hypertrophic scars.

High-quality postoperative rehabilitation is the focus of most patients currently, and hypertrophic scar (HS) greatly reduces the patient's quality of life due to the symptom of severe itching. Traditional HS therapies are associated with limitations, such as poor drug delivery efficiency for topical administration and severe pain for intralesional injection. In this study, we developed a personalized microneedle patch system for minimally invasive and effective treatment of HSs. The microneedle patches were personalized designed and fabricated with 3D printing in order to adapt to individual HS. The optimized microneedle patches were composed of dissolving gelatin and starch and loaded with losartan. Losartan, as a drug class of angiotensin II receptor blockers (ARBs), can effectively inhibit the proliferation and migration of hypertrophic scar fibroblasts (HSFs) and downregulate the gene expression related to scar formation in HSFs. The dissolving microneedle patches exhibited strong mechanical strength, effectively penetrated the stratum corneum of HSs and increased the losartan delivery into HSs upon dissolution of gelatin and starch. Together, the losartan-loaded microneedle patches effectively inhibited the formation of HSs in rabbit ears with reduced scar elevation index (SEI), and decreased fibrosis and collagen deposition in HSs. This personalized microneedle patch system increases the drug delivery efficiency into HSs with minimal invasion, and opens a new window for personalized management and treatment of skin diseases.

Accelerometer-measured physical activity and sample-based frailty in older women: does pattern really matter?

Background: The relationship between the patterns of physical activity (PA) and frailty, including its various subdomains, remains poorly understood. Therefore, this study aims to investigate the correlations between the patterns of physical activity and frailty and its various subdomains in community-dwelling older women. Methods: A cross-sectional study investigated the association between physical activity and frailty in 1,099 women aged between 60 to 70 years. Triaxial accelerometers were used to measure bouted PA (a minimum duration of 10 min) and sporadic PA (a duration of <10 min). Fried's frailty phenotype was utilized to evaluate the status of frailty. Data were analyzed using logistic regression and the receiver operating characteristic (ROC) curve. Results: Bouted moderate-to-vigorous PA (MVPA) and sporadic MVPA were associated with decreased odds of being prefrail and frail, and the optimal cutoff values were 6 and 19.7 for the prefrail stage and 6.6 and 19.4 min/day for the frail stage, respectively. Bouted light PA (LPA) was associated with decreased odds of being prefrail, and the optimal cutoff value was 170.2 min/day. Additionally, bouted and sporadic MVPA were associated with decreased odds of being slow and their optimal cutoff values were 5 and 19.1 min/day, respectively. Sporadic MVPA was associated with decreased odds of exhaustion, and the cutoff was 19.7 min/day. Bouted MVPA and LPA were associated with decreased odds of having low PA, and the cutoff values were 4.4 and 163.2 min/day, respectively. Conclusion: Any MVPA, regardless of bout duration, could be used as a suitable PA program to improve and prevent frailty in older women, such as bouted MVPA (4-5 times/week) or sporadic MVPA (20 min/day). The improvement effect of bouted and sporadic MVPA on the frailty of older people may not be affected by the subdomain. Additionally, bouted LPA was suitable for the management of prefrailty.

Worm-like porous and defect-structured cadmium stannate photoanodes for enhanced solar water oxidation.

The work aims to elucidate the importance of hybrid microwave annealing technology (HMA) in ultrafast fabrication of deficient cadmium stannate (Cd2SnO4) photoanodes with a worm-like porous structure and significant enhancement of solar water oxidation performance and stability. Comparison of three synthetic routes and experimental characterization revealed that relative to conventional thermal annealing (CTA) or even with extra HMA for 5 min (optimal), direct HMA for only 8 min can form cubic Cd2SnO4 thin films of unique worm-like and highly porous nanostrucures with a large interfacial surface area, high degree of phase crystallinity and high-concentration defects. The obtained results from the photoluminescence spectra and the charge efficiency measurements collaboratively verified that compared to using CTA treatment solely, the HMA treatment is effective in significantly improving charge separation, recombination and transfer processes, mainly by an over 13.5-fold increase in the bulk charge separation efficiency. Benefiting from these merits, under optimized conditions the HMA treated Cd2SnO4 film exhibited a remarkable 6-fold and 2-fold solar photocurrent enhancement compared with those of the CTA treated one and the combined CTA-HMA treated one, respectively, and an IPCE of 39% at 300 nm and 18% at 350 nm at 1.7 V versus RHE. Despite a high external bias required in this case, the study provides a simple route for synthesis of ideal Cd2SnO4 photoanodes which can be further extended to doping engineering and non-noble metal cocatalyst deposition.

Etiologic Classification of 541 Infantile Spasms Cases: A Cohort Study.

Objective: To explore the etiology of infantile spasms (IS) in a large Chinese cohort based on the United States National Infantile Spasms Consortium (NISC) classification. Methods: In the present study, we recruited IS patients diagnosed at a single center (Xiangya Hospital, Central South University) between Jan 2010 and Aug 2019. Thereafter, we collected their clinical and genetic information retrospectively. Their underlying etiologies were classified according to the NISC classification and then compared in different scenarios to understand their distribution. Results: A total of 541 patients with IS from 18 provinces were included in this study. The underlying etiology was identified in 53.2% of the cases: structural-acquired, 25.3%; genetic, 12.9%; genetic-structural, 7.2%; structural-congenital, 5.0%; metabolic, 2.4%; infections, 0.4% and immune, 0%. Whole-exome sequencing (WES) provided the highest diagnostic yield (26.9%). In structural-acquired IS, the proportion of hypoglycemic brain injuries was significant, second only to hypoxic-ischemic encephalopathy. There was no patient discovered to have Down syndrome. STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1 were the most frequently implicated genes. Genetic causes were found to be the most common cause of IS in the early onset group, while structural-acquired etiologies were common in males and preterm babies. Patients with pre-spasm seizures were associated with a higher proportion of identified causes than those without. Non-acquired structural etiologies were more common in patients without hypsarrhythmia than in those with hypsarrhythmia. Significance: The most prevalent cause of IS was structural acquired followed by genetic causes. When brain MRI fails to detect the etiology, we propose WES as the next step. Structural-acquired IS and cases with genetic disorders are characteristic of the Chinese cohort, however, the etiology differs with the patient's age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia.

Electrochemical Borylation of Alkyl Halides: Fast, Scalable Access to Alkyl Boronic Esters.

Herein, a fast, scalable, and transition-metal-free borylation of alkyl halides (X = I, Br, Cl) enabled by electroreduction is reported. This process provides an efficient and practical access to primary, secondary, and tertiary boronic esters at a high current. More than 70 examples, including the late-stage borylation of natural products and drug derivatives, are furnished at room temperature, thereby demonstrating the broad utility and functional-group tolerance of this protocol. Mechanistic studies disclosed that B2cat2 serves as both a reagent and a cathodic mediator, enabling electroreduction of difficult-to-reduce alkyl bromides or chlorides at a low potential.

The phycobilisome core-membrane linkers from Synechocystis sp. PCC 6803 and red-algae assemble in the same topology.

The phycobilisomes (PBSs) of cyanobacteria and red-algae are unique megadaltons light-harvesting protein-pigment complexes that utilize bilin derivatives for light absorption and energy transfer. Recently, the high-resolution molecular structures of red-algal PBSs revealed how the multi-domain core-membrane linker (LCM ) specifically organizes the allophycocyanin subunits in the PBS's core. But, the topology of LCM in these structures was different than that suggested for cyanobacterial PBSs based on lower-resolution structures. Particularly, the model for cyanobacteria assumed that the Arm2 domain of LCM connects the two basal allophycocyanin cylinders, whereas the red-algal PBS structures revealed that Arm2 is partly buried in the core of one basal cylinder and connects it to the top cylinder. Here, we show by biochemical analysis of mutations in the apcE gene that encodes LCM , that the cyanobacterial and red-algal LCM topologies are actually the same. We found that removing the top cylinder linker domain in LCM splits the PBS core longitudinally into two separate basal cylinders. Deleting either all or part of the helix-loop-helix domain at the N-terminal end of Arm2, disassembled the basal cylinders and resulted in degradation of the part containing the terminal emitter, ApcD. Deleting the following 30 amino-acids loop severely affected the assembly of the basal cylinders, but further deletion of the amino-acids at the C-terminal half of Arm2 had only minor effects on this assembly. Altogether, the biochemical data are consistent with the red-algal LCM topology, suggesting that the PBS cores in cyanobacteria and red-algae assemble in the same way.

Electrochemical C-C bond cleavage of cyclopropanes towards the synthesis of 1,3-difunctionalized molecules.

Electrochemistry has a lot of inherent advantages in organic synthesis and many redox reactions have been achieved under electrochemical condition. However, the electrochemical C-C bond cleavage and functionalization reactions are less studied. Here we develop electrochemical C-C bond cleavage and 1,3-difuntionalization of arylcyclopropanes under catalyst-free and external-oxidant-free conditions. 1,3-difluorination, 1,3-oxyfluorination and 1,3-dioxygenation of arylcyclopropanes are achieved with a high chemo- and regioselectivity by the strategic choice of nucleophiles. This protocol has good functional groups tolerance and can be scaled up. Mechanistic studies demonstrate that arylcyclopropane radical cation obtained from the anode oxidation and the subsequently generated benzyl carbonium are the key intermediates in this transformation. This development provides a scenario for constructing 1,3-difunctionalized molecules.

The patterns of response of 11 regimens for infantile spasms.

Infantile spasms (ISs) is a devastating form of an early infantile epileptic encephalopathy. The patterns of response of multiple regimens, and the difference in response rates for the cases who receive first-line therapies on time versus those who receive them after non-first-line therapies are unknown. We performed a study involving 314 ISs cases aiming to investigate the patterns of response of 11 regimens, and the difference in response rates for the cases received first-line therapies as first two regimens versus those who received other drugs prior to first-line options. As a result, the efficacy of each regimen was: the foremost two regimens; 36.99%, third; 10.27%, fourth; 6.16%, fifth; 5.48%, and from the sixth regimen onwards, each additional regimen added ≤ 2% probability of seizure freedom. There was a statistically significant difference in seizure freedom rates between cases received first-line therapies as first or second regimen versus those who received them later. Our study revealed for the first time that in ISs cases, seizure freedom is likely to be observed within the first five regimens, and an early administration of first-line therapies is superior to non-first-line options. These results will aid in management of ISs cases.

Balloon versus Amplatz for tract dilation in fluoroscopically guided percutaneous nephrolithotomy: a systematic review and meta-analysis.

OBJECTIVE: To compare the safety and efficacy of balloon and Amplatz for tract dilation in fluoroscopically guided percutaneous nephrolithotomy (PCNL). METHOD: EMBASE, PUBMED, MEDLINE and the Cochrane Central Register of Controlled Trials were searched for pertinent studies up until 30 October 2019. Pooled effects were calculated as ORs with 95% CIs or mean differences (MD) with 95% CIs. Endpoints included postoperative decrease in haemoglobin, transfusion rate, complication rate, successful dilation rate, stone-free rate, fluoroscopy time, access time, total operation time and length of postoperative hospitalisation (LPH). Bonferroni's correction was intercalated to reduce the likelihood of making a meta-analytical false positive. RESULTS: One randomised controlled trial and five controlled clinical trials were included, which involved 1317 patients in total. We found a lower drop in postoperative haemoglobin for patients receiving balloon dilation compared with those in the Amplatz group (MD=-0.21, 95% CI -0.33 to 0.09, p=0.0005; Bonferroni correction a=0.005). Access time in the balloon group was also, on average, 2.61 min shorter than the Amplatz group (MD=-2.61, 95% CI -4.20 to 1.01, p=0.001; Bonferroni correction a=0.005). No significant differences were identified between the two dilation methods in terms of transfusion rate, complication rate, successful dilation rate, stone-free rate, fluoroscopy time, total operation time and LPH. CONCLUSION: Balloon dilation is a safe and effective tract dilation technique for access creation during fluoroscopically guided PCNL. Both of methods have similar success rates although balloon dilation is associated with significantly less postoperative haemoglobin decline and shorter access time. Therefore, balloon dilation appears to be the superior tract dilation technique, but further confirmatory research is required to confirm these findings.

[Mutations in aminoacyl-tRNA synthetase genes: an analysis of 10 cases].

OBJECTIVE: To study the clinical features of the diseases associated with aminoacyl-tRNA synthetases (ARS) deficiency. METHODS: A retrospective analysis was performed of the clinical and gene mutation data of 10 children who were diagnosed with ARS gene mutations, based on next-generation sequencing from January 2016 to October 2019. RESULTS: The age of onset ranged from 0 to 9 years among the 10 children. Convulsion was the most common initial symptom (7 children). Clinical manifestations included ataxia and normal or mildly retarded intellectual development (with or without epilepsy; n=4) and onset of epilepsy in childhood with developmental regression later (n=2). Some children experienced disease onset in the neonatal period and had severe epileptic encephalopathy, with myoclonus, generalized tonic-clonic seizure, and convulsive seizure (n=4); 3 had severe delayed development, 2 had feeding difficulty, and 1 had hearing impairment. Mutations were found in five genes: 3 had novel mutations in the AARS2 gene (c.331G>C, c.2682+5G>A, c.2164C>T, and c.761G>A), 2 had known mutations in the DARS2 gene (c.228-16C>A and c.536G>A), 1 had novel mutations in the CARS2 gene (c.1036C>T and c.323T>G), 1 had novel mutations in the RARS2 gene (c.1210A>G and c.622C>T), and 3 had novel mutations in the AARS gene (c.1901T>A, c.229C>T, c.244C>T, c.961G>C, c.2248C>T, and Chr16:70298860-70316687del). CONCLUSIONS: A high heterogeneity is observed in the clinical phenotypes of the diseases associated with the ARS deficiency. A total of 14 novel mutations in 5 genes are reported in this study, which enriches the clinical phenotypes and genotypes of the diseases associated with ARS deficiency.

MicroRNA-34a inhibits bladder cancer cell migration and invasion, and upregulates PTEN expression.

MicroRNA-34a (miR-34a) serves as a tumor suppressor in a number of different types of cancer. The present study was performed to investigate the involvement of miR-34a in bladder cancer. In the present study, miR-34a was downregulated in patients with bladder cancer compared with the healthy controls in bladder biopsies and plasma. Downregulation of miR-34a distinguished between patients with bladder cancer and the healthy controls. miR-34a expression was associated with tumor metastasis; however, not with tumor size. Transfection of miR-34a mimics upregulated the expression of phosphatase and tensin homolog (PTEN) in bladder cancer cells, and decreased cell migration and invasion. miR-34a may inhibit bladder cancer cell migration and invasion by upregulating PTEN. miR-34a may additionally serve as a potential therapeutic target for bladder cancer.

[Evaluation and Comparison of SHA.LIN,S.T.O.N.E.Nephrolithometry Scoring System,and Clinical Research Office of the Endourological Society Nephrolithometry Nomogram for Predicting Stone Free Rate and Postoperative Outcomes after Percutaneous Nephrolithotomy].

To compare the accuracy of SHA.LIN,S.T.O.N.E.nephrolithometry scoring system,and Clinical Research Office of the Endourological Society(CROES)nephrolithometry nomogram in predicting percutaneous nephrolithotomy(PCNL)outcomes including stone free rate(SFR)and perioperative status. Methods The clinical data of 90 patients with nephrolithiasis undergoing PCNL in department of urology,China-Japan Friendship Hospital from January 2015 to March 2018 were retrospectively analyzed.The general data,stone characteristics,operation approaches,and perioperative variables were recorded.SHA.LIN,S.T.O.N.E.score,and CROES nomogram were assigned according to the computed tomography(CT)findings before surgery.Stone free status was evaluated by kidney-ureter-bladder one month after PCNL.The relationships of SHA.LIN score,S.T.O.N.E.score,and CROES score with SFR,postoperative complications,operation time(OT),length of hospital stay(LOS),estimated blood loss(EBL),and decrease of hemoglobin was evaluated.Receiver operating characteristic(ROC)curves were used to analyze the predictive accuracy. Results The SFR was 72.2%(65/90)and postoperative complications occurred in 33 cases(36.7%).The mean OT was(103.1±39.6)min,the mean EBL was(46.1±53.0)ml,the mean LOS was(15.3±5.2)d,the mean postoperative LOS was(8.5±3.4)d,and the mean decrease of hemoglobin was(16.1±10.2)g/L.Stone-free patients had significantly lower SHA.LIN score(8.23 vs. 10.36,P=0.000)and S.T.O.N.E.score(7.05 vs.8.16,P=0.000)and significantly higher CROES score(188.50 vs. 143.89,P=0.000)compared to patients with residual fragments.All these scores were not significantly associated with complications(P>0.05).On the other hand,all these scores were significantly correlated with OT,EBL,and decrease of hemoglobin(SHA.LIN:POT=0.006,PEBL=0.028,Pdecrease of hemoglobin=0.014;S.T.O.N.E.:POT=0.012,PEBL=0.047,Pdecrease of hemoglobin=0.011;and CROES:POT=0.040,PEBL=0.045,Pdecrease of hemoglobin=0.013).SHA.LIN(P=0.001)and S.T.O.N.E.(P=0.005)scores were associated with LOS.Logistic regression analysis revealed that SHA.LIN(OR=2.491),S.T.O.N.E.(OR=3.030),and CROES(OR=0.973)scores were significantly associated with stone-free status.ROC curves in predicting SFR showed that there was significant difference in the areas under the curves(AUC)for the SHA.LIN vs. S.T.O.N.E.score [0.808(95% CI=0.711-0.905)vs. 0.748(95% CI=0.632-0.864),P=0.047].AUC for the CROES score [0.770(95% CI=0.664-0.877)] showed no significantly different for the SHA.LIN score or the S.T.O.N.E.score(P>0.05). Conclusions All these three scoring systems have good predictive accuracy for SFR.SHA.LIN is more precise than S.T.O.N.E.in predicting SFR.However,they can not predict postoperative complications.