Search

Abstract Background Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease; most ALS patients die within 3 to 5 years after symptom onset, usually as a consequence of respiratory failure. In the present study, we aim to screen the survival-related pulmonary function parameters, and to explore the predictive value of peak expiratory flow (PEF) in disease severity and prognosis in patients with ALS. Methods The discovery cohort included 202 ALS patients, and the demographic and clinical characteristics of eligible patients were collected and pulmonary function tests were performed using MS-PFT spirometer. In the validation cohort, 62 newly diagnosed ALS patients performed the pulmonary function test by MS-PFT spirometer and household peak flow meter (KOKA) simultaneously. Results Among 12 pulmonary function parameters, FVC, FEV1, PEF, MEF75%, and MVV were identified to be independent predictive factors for survival. PEF was highly correlated with FVC (r = 0.797), MVV (r = 0.877), FEV1 (r = 0.847), and MEF75% (r = 0.963). Besides, the values of PEF were positively associated with disease severity (ALSFRS-R score, rs = 0.539, P

Experimental autoimmune prostatitis (EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus (PVN). However, the mechanism has not yet been elucidated. Herein, we screened out the target prostate-derived inflammation cytokines (PDICs) by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid (CSF) between EAP rats and their controls. After identifying the target PDIC, qualified males in initial copulatory behavior testing (CBT) were subjected to implanting tubes onto bilateral PVN. Next, they were randomly divided into four subgroups (EAP-1, EAP-2, Control-1, and Control-2). After 1-week recovery, EAP-1 rats were microinjected with the target PDIC inhibitor, Control-1 rats were microinjected with the target PDIC, while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF (aCSF). Results showed that only interleukin-1β(IL-1β) had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls (P < 0.001) and significantly higher protein concentrations in both the serum (P = 0.001) and CSF (P < 0.001) of the EAP groups compared to the Control groups. Therefore, IL-1β was identified as the target PDIC which crosses the blood-brain barrier, thereby influencing the central nervous system. Moreover, the EAP-1 subgroup displayed a gradually prolonged ejaculation latency (EL) in the last three CBTs (all P < 0.01) and a significantly lower expression of NMDA NR1 subunit in the PVN (P = 0.043) compared to the respective control groups after a 10-day central administration of IL-1β inhibitors. However, the Control-1 subgroup showed a gradually shortened EL (P < 0.01) and a significantly higher NR1 expression (P = 0.004) after homochronous IL-1β administration. Therefore, we identified IL-1β as the primary PDIC which shortens EL in EAP rats. However, further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1β upregulates NMDA expression.

Abstract Background Ferroptosis, a novel form of regulated cell death, has been implicated in the pathogenesis of cancers. Nevertheless, the potential function and prognostic values of ferroptosis in bladder urothelial carcinoma (BLCA) are complex and remain to be clarified. Therefore, we proposed to systematically examine the roles of ferroptosis-associated genes (FAGs) in BLCA. Methods According to The Cancer Genome Atlas (TCGA) database, differently expressed FAGs (DEFAGs) and differently expressed transcription factors (DETFs) were identified in BLCA. Next, the network between DEFAGs and DETFs, GO annotations and KEGG pathway analyses were performed. Then, through univariate, LASSO and multivariate regression analyses, a novel signature based on FAGs was constructed. Moreover, survival analysis, PCA analysis, t-SNE analysis, ROC analysis, independent prognostic analysis, clinicopathological and immune correlation analysis, and experimental validation were utilized to evaluate the signature. Results Twenty-eight DEFAGs were identified, and four FAGs (CRYAB, TFRC, SQLE and G6PD) were finally utilized to establish the FAGs based signature in the TCGA cohort, which was subsequently validated in the GEO database. Moreover, we found that immune cell infiltration, immunotherapy-related biomarkers and immune-related pathways were significantly different between two risk groups. Besides, nine molecule drugs with the potential to treat bladder cancer were identified by the connectivity map database analysis. Finally, the expression levels of crucial FAGs were verified by the experiment, which were consistent with our bioinformatics analysis, and knockdown of TFRC could inhibit cell proliferation and colony formation in BLCA cell lines in vitro. Conclusions Our study identified prognostic ferroptosis-associated genes and established a novel FAGs signature, which could accurately predict prognosis in BLCA patients.

Abstract Objective To explore the associations between serum creatinine and creatine kinase (CK) levels with survival in male and female ALS patients. Methods A prospective cohort study was carried out including 346 ALS patients with repeated serum creatinine and CK measurements. Kaplan Meier analysis and multivariable Cox regression were used to perform survival analysis. Results There were 218 male and 128 female patients, and the males had significantly higher baseline serum creatinine and CK levels than females. After multivariable Cox regression analysis, lower baseline serum creatinine levels were associated with a short survival in both male (≤61 μmol/L, HR: 1.629; 95%CI: 1.168–2.273) and female ALS patients (≤52 μmol/L, HR: 1.677; 95%CI: 1.042–2.699), whereas, the serum CK levels were not correlated with survival. Besides, creatinine levels were positively associated with ALSFRS‐R scores, and inversely with the decline rate of ALSFRS‐R per month. During follow‐up, serum creatinine levels tended to be decreased along with the disease progression, and the higher decline rate of creatinine per month (>1.5) showed significantly shorter survival, compared to the lower group (≤1.5) (30.0 months vs. 65.0 months, Chi square = 28.25, P

Abstract Objective Amyotrophic lateral sclerosis (ALS) is an adult‐onset fatal neurodegenerative disease which lacks identified biological markers. A label‐free plasma surface‐enhanced Raman spectroscopy (SERS) method was developed to explore a simple and noninvasive test for ALS. Methods ALS patients were enrolled serially and plasma samples were collected at the time of diagnosis prior to the start of ALS treatment. SERS spectra were recorded using a Renishaw micro‐Raman system. Results To exclude the interference by varying disease severity, we enrolled three groups of ALS patients, including ALS‐1 (n = 60; ALSFRS‐R ≥ 42 and time interval ≤ 12 months), ALS‐2 (n = 61; ALSFRS‐R 12 months). The SERS spectra were analyzed using principal component analysis (PCA), which showed that ALS‐1, ALS‐2, ALS‐3, and control groups were separated significantly. Then, decision tree (DT) models and receiver operating characteristic curves were employed and identified that bands at 722 and 739 cm−1, and ratios of 635–722 cm−1 and 635–739 cm−1 were able to distinguish ALS from controls significantly. Finally, we highlighted six metabolism pathways correlated with ALS, including phenylalanine‐tyrosine‐tryptophan biosynthesis, aminoacyl‐tRNA biosynthesis, phenylalanine metabolism, pantothenate and CoA biosynthesis, porphyrin and chlorophyll metabolism, and pyrimidine metabolism. Interpretation: Plasma SERS could be a promising tool for the detection of ALS. The bands at 722 and 739 cm−1, and the ratios of 635–722 cm−1 and 635–739 cm−1 could serve as potential indicator for ALS.

Abstract Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta‐analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta‐analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients (CCND2: pooled HR = 2.21, 95% CI: 1.67‐2.93; CCND3: pooled HR = 2.29, 95% CI: 1.05‐5.03). In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer (HR = 2.20, 95% CI: 1.66‐2.92), whereas it might be a tumor suppressor in NSCLC (HR = 0.28, 95% CI: 0.12‐0.64). In addition, CCND3 was correlated to reduced OS in breast cancer patients (HR = 1.64, 95% CI: 1.07‐2.52) and shorter DFS/PFS/RFS in bladder cancer patients (HR = 4.60, 95% CI: 1.89‐12.57). Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms.

Immune checkpoint blockade (ICB) therapies have significantly improved the prognosis and shown considerable promise for cancer therapy; however, differences in ICB treatment efficacy between the elderly and young are unknown. We analyzed the studies enrolled in the meta-analysis using the deft approach, and found no difference in efficacy except melanoma patients receiving anti–PD-1 therapy. Similarly, higher treatment response rate and more favorable prognosis were observed in elderly patients in some cancer types (e.g., melanoma) with data from published ICB treatment clinical trials. In addition, we comprehensively compared immunotherapy-related molecular profiles between elderly and young patients from public trials and The Cancer Genome Atlas (TCGA), and validated these findings in several independent datasets. We discovered a divergent age-biased immune profiling, including the properties of tumors (e.g., tumor mutation load) and immune features (e.g., immune cells), in a pancancer setting across 27 cancer types. We believe that ICB treatment efficacy might vary depending on specific cancer types and be determined by both the tumor internal features and external immune microenvironment. Considering the high mutational properties in elderly patients in many cancer types, modulating immune function could be beneficial to immunotherapy in the elderly, which requires further investigation.

Objective: To explore the associations between serum uric acid levels with survival in male and female ALS patients.Methods: A longitudinal cohort study was carried out including 313 sporadic and 16 familial ALS patients with repeated serum uric acid measurements. Multivariate Cox regression models were used to evaluate the survival-related factors.Results: There were 207 male and 122 female, and the mean age of onset was 55.7 ± 11.2 years old. The male patients had significantly higher baseline uric acid levels than that in female patients (342.4 ± 91.4 vs. 279.3 ± 71.4 μmol/L; p < 0.0001). The uric acid levels were inversely associated with the decline rate of ALSFRS-R per month (ΔALSFRS-R). After multivariate Cox regression analysis, a survival advantage was found in male, but not female, with higher serum uric acid levels. In males, a shorter diagnostic delay (≤10 m), lower BMI at baseline (≤18.70 kg/m2), faster disease progression (ΔALSFRS-R > 0.63), and lower baseline uric acid levels (≤292 μmol/L, HR: 1.936; 95% CI: 1.334–2.810) were associated with a shorter survival. During follow-up, the serum uric acid levels were not significantly altered over time.Conclusion: There is an inverse correlation between baseline serum uric acid levels and risk of death, prominently in male ALS patients.

Background. Cutaneous melanoma is defined as one of the most aggressive skin tumors in the world. An increasing body of evidence suggested an indispensable association between immune-associated gene (IAG) signature and melanoma. This article is aimed at formulating an IAG signature to estimate prognosis of melanoma. Methods. 434 melanoma patients were extracted from The Cancer Genome Atlas (TCGA) database, and 1811 IAGs were downloaded from the ImmPort database in our retrospective study. The Cox regression analysis and LASSO regression analysis were utilized to establish a prognostic IAG signature. The Kaplan-Meier (KM) survival analysis was performed, and the time-dependent receiver operating characteristic curve (ROC) analysis was further applied to assess the predictive value. Besides, the propensity score algorithm was utilized to balance the confounding clinical factors between the high- and low-risk groups. Results. A total of six prognostic IAGs comprising of INHA, NDRG1, IFITM1, LHB, GBP2, and CCL8 were eventually filtered out. According to the KM survival analysis, the results displayed a shorter overall survival (OS) in the high-risk group compared to the low-risk group. In the multivariate Cox model, the gene signature was testified as a remarkable prognostic factor (HR=45.423, P

Objective: This study aims to explore the association between median nerve-neurophysiological index (NI) and survival of patients with amyotrophic lateral sclerosis (ALS).Methods: A retrospective case series with a prospective follow-up study was performed in 238 patients with ALS. Their clinical profiles and NI were recorded. Kaplan-Meier curves and Cox regression were adopted to perform survival analysis.Results: The median survival time of all ALS cases was 33.0 months. Multivariate analysis showed that older age of onset, shorter diagnostic delay, higher ΔALSFRS-R, and faster progression {NI ≤ 2.15; hazard ratio [HR] = 1.543 [95% confidence interval (CI), 1.136–2.094]} were associated with short survival. NI was correlated with ALSFRS-R at baseline (rs = 0.3153; p < 0.0001) and ALSFRS-R at different time points of follow-up (rs = 0.5127; p < 0.0001). The higher NI slope of decline (> 0.25) showed shorter survival compared with the lower group (≤ 0.25; 34.0 vs. 52.0 months; p = 0.0003). A predictive model was constructed based on the age of onset, diagnostic delay, median nerve NI, and ΔALSFRS-R. The higher predictive score (> 14) showed significantly shorter survival compared with the lower group (≤ 14; HR = 3.907, 95% CI, 2.857–5.342).Conclusion: Median nerve NI and its slope of decline were predictive of survival of ALS.

Abstract Background Incidence of simultaneous renal cyst with calyceal diverticula in contralateral kidney is rare in children. A minimally invasive procedure in different sittings is often recommended. Case presentation A Chinese 15-month-old boy presented to the Urology department of a tertiary care center with right flank pain. He was subjected to magnetic resonance urography and was diagnosed as having right renal cyst and contralateral calyceal diverticula. He underwent robotic cyst decortication and calyceal diverticulectomy using da Vinci robot. His postoperative period was uneventful. He was discharged on fifth postoperative day. Histopathology was consistent with simple renal cyst. Conclusions Robotic combined cyst decortication and contralateral diverticulectomy is feasible in selected small children. However, it demands adequate technical skill and experience.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China. Methods Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients. Results Two TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 ± 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 ± 41.8 months (n = 8). Conclusions We found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival.

Background: Mitochondrial dysfunction is linked to the pathogenesis of Parkinson′s disease (PD). However, the precise role of mitochondrial DNA (mtDNA) variations is obscure. On the other hand, mtDNA haplogroups have been inconsistently reported to modify the risk of PD among different population. Here, we try to explore the relationship between mtDNA haplogroups and sporadic PD in a Han Chinese population. Methods: Nine single-nucleotide polymorphisms, which define the major Asian mtDNA haplogroups (A, B, C, D, F, G), were detected via polymerase chain reaction-restriction fragment length polymorphism or denaturing polyacrylamide gel electrophoresis in 279 sporadic PD patients and 510 matched controls of Han population. Results: Overall, the distribution of mtDNA haplogroups did not show any significant differences between patients and controls. However, after stratification by age at onset, the frequency of haplogroup B was significantly lower in patients with early-onset PD (EOPD) compared to the controls (odds ratio [OR] =0.225, 95% confidence interval [CI]: 0.082-0.619, P = 0.004), while other haplogroups did not show significant differences. After stratification by age at examination, among subjects younger than 50 years of age: Haplogroup B also showed a lower frequency in PD cases (OR = 0.146, 95% CI: 0.030-0.715, P = 0.018) while haplogroup D presented a higher risk of PD (OR = 3.579, 95% CI: 1.112-11.523, P = 0.033), other haplogroups also did not show significant differences in the group. Conclusions: Our study indicates that haplogroup B might confer a lower risk for EOPD and people younger than 50 years in Han Chinese, while haplogroup D probably lead a higher risk of PD in people younger than 50 years of age. In brief, particular Asian mtDNA haplogroups likely play a role in the pathogenesis of PD among Han Chinese.

Objective To investigate the value of multiplex ligation⁃dependent probe amplification (MLPA) method in the prenatal diagnosis of spinal muscular atrophy (SMA). Methods Six SMA pedigrees, which included 7 patients, 12 parents and 6 fetuses, were admitted in our hospital. MLPA was used to detect the survival motor neuron (SMN) and other modifier genes, according to steps of hybridization, ligation, PCR reaction, fragment separation by capillary electrophoresis and peak pattern evaluation. Synchronously, the deletion of SMN1 gene was detected by polymerase chain reaction⁃restriction fragment length polymorphism (PCR⁃RFLP). The DNA samples of fetuses were collected by centrifuging the amniotic fluid as well as derived from amniotic cell culture. Results According to MLPA, 7 patients and 1 fetus were detected to carry homozygous deletion of survival motor neuron 1 (SMN1) gene, which was also detected by PCR⁃PFLP. In addition, 11 parents and 5 fetuses carried one copy of SMN1 gene, while 1 parent who was also a carrier of SMA carried two copies of SMN1 gene. Furthermore, after being analyzed by MLPA, 10 cases carried one copy of SMN2 gene, while 15 cases had two copies of SMN2 gene. After detecting the neuronal apoptosis inhibitory protein (NAIP) gene, 3 cases had the deletion of NAIP gene while others showed normal. Conclusion MLPA can detect the deletion and quantify the copy numbers of SMN and other modifier genes, improving the efficiency and stability of genetic diagnosis. It is adequate for detecting patients and carriers of SMA, as well as providing reliable evidence for genetic counseling. DOI：10.3969/j.issn.1672⁃6731.2012.03.012

BackgroundPost-stroke depression (PSD) , a common complication in stroke patients, may increase the disability and mortality, however, its pathogenesis is unknown yet.ObjectiveTo observe the white matter fiber bundle alterations by diffusion tensor tractography (DTT) , and to explore its correlation with depression in patients with PSD.MethodsParticipants were selected from the First Affiliated Hospital of Jinzhou Medical University from September 2019 to September 2020, involving 40 inpatients with first-episode ischemic stroke (20 were found with PSD, and 20 without) , and 20 physical examinees as healthy controls. DTT was performed in all participants, fractional anisotropy (FA) and number of fiber bundles in regions of interest (ROIs) were compared across PSD and non-PSD inpatients and healthy controls. Pearson correlation analysis was performed to analyze the correlations of FA and number of fiber bundles on the side of stroke in the ROIs with 24-item Hamilton Rating Scale for Depression (HAMD-24) in PDS inpatients.ResultsIn PSD inpatients, the FA of inferior fronto-occipital fascicles, corticospinal tract, frontopontine tract, cingulum bundle and uncinate fasciculus on the side of the stroke was significantly lower than those on the contralateral side (P

This study aimed to investigate the functional and morphological changes in the corpus cavernosum after cavernous nerve (CN) injury or neurectomy and then reveal whether treatment with the angiotensin II Type 1 receptor antagonist losartan would improve erectile function as well as its potential mechanisms. A total of 48 10-week-old Sprague-Dawley male rats, weighing 300-350 g, were randomly divided into the following four groups (n = 12 per group): sham operation (Sham) group, bilateral cavernous nerve injury (BCNI) group, losartan-treated BCNI (BCNI + Losartan) group, and bilateral cavernous neurectomy (Neurectomy) group. Losartan was administered once daily by oral gavage at a dose of 30 mg kg-1 day-1 for 4 weeks starting on the day of surgery. The BCNI and the Neurectomy groups exhibited decreases in erectile response and increases in apoptosis and oxidative stress, compared with the Sham group. Treatment with losartan could have a modest effect on erectile function and significantly prevent corporal apoptosis and oxidative stress. The phospho-B-cell lymphoma 2 (Bcl-2)-associated death promoter (p-Bad)/Bad and phospho-the protein kinase B (p-AKT)/AKT ratios were substantially lower, while the Bcl-2-associated X protein (Bax)/Bcl-2 ratio, nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1), transforming growth factor-β 1 (TGF-β1) and heme oxygenase-1 (HO-1) levels, and caspase-3 activity were higher in the BCNI and Neurectomy groups than in the Sham group. After 4 weeks of daily administration with losartan, these expression levels were remarkably attenuated compared with the BCNI group. Taken together, our results suggested that early administration of losartan after CN injury could slightly improve erectile function and significantly reduce corporal apoptosis and oxidative stress by inhibiting the Akt/Bad/Bax/caspase-3 and Nrf2/Keap-1 pathways. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a lethal childhood neurodegenerative disorder that is caused by the homozygous deletion of survival motor neuron 1 (SMN1). To date, no effective treatments are available. In the current study, urine cells taken from SMA patients were cultured and the application of patient-derived urine cells was determined in drug intervention. A total of 13 SMA patient-derived urine cell lines and 40 control cell lines were established. SMN was highly expressed in the nucleus and cytoplasm. Patient-derived urine cells expressed low levels of SMN protein compared with controls, they exhibited good tolerance to chemical and electrical damage. SMN expression was upregulated following treatment with histone deacetylase inhibitors and the effect was greater in groups treated with morpholino modified antisense oligo, which targets ISS-N1 in SMN2 intron 7. The results of the current study indicated that SMA patient-derived urine cells may be useful in the initial screening of potential compounds and drugs to treat SMA. [ABSTRACT FROM AUTHOR]