Peak expiratory flow is a reliably household pulmonary function parameter correlates with disease severity and survival of patients with amyotrophic lateral sclerosis.

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 < 0.0001), and negatively associated with progression rate (ΔALSFRS-R, rs = -0.316, P < 0.0001). Finally, we also confirmed that the values of KOKA-measured PEF were highly correlated with the ones measured using MS-PFT spirometer (r = 0.9644, p < 0.0001). CONCLUSIONS: Our work emphasizes the critical role of PFTs in predicting prognosis of ALS patients. PEF is an easily available pulmonary function index, which is also a promising indicator in predicting disease severity and survival for ALS patients.

A novel signature constructed by ferroptosis-associated genes (FAGs) for the prediction of prognosis in bladder urothelial carcinoma (BLCA) and associated with immune infiltration.

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.

Abnormal Thalamic Metabolism in Patients With Lifelong Premature Ejaculation.

BACKGROUND: Although some recent neuroimaging studies have indicated the abnormal brain structure or function in patients with lifelong premature ejaculation (LPE), whether and how the abnormal thalamic function participates in processing sexual behavioral information are still unclear in patients with LPE. AIM: The aim of this study was to assess the changes in the thalamus metabolism and structural integrity in patients with LPE. METHODS: We performed a multimodal magnetic resonance approach in a 3.0 T system, including proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging, and volumetric analysis to detect the differences in thalamic metabolism and structure between 20 patients with LPE and 15 healthy controls. OUTCOMES: We analyzed and correlated the clinical symptoms of the subjects with significant 1H-MRS-based features. Peak areas of N-acetylaspartate, choline, creatine (Cr), and glutamate/glutamine (Glu) were calculated with the LCModel software. RESULTS: Diffusion tensor imaging and volumetric analysis of thalami showed no differences between the 2 groups. On the contrary, 1H-MRS study disclosed that both Glu concentrations and Glu/Cr ratio values in the thalami of patients with LPE were remarkably increased when compared with healthy controls (P < .01 for both variables). In addition, both the intravaginal ejaculatory latency time score and Chinese Index of Sexual Function for Premature Ejaculation-5 score were negatively related to increased Glu concentrations and Glu/Cr ratio values. CLINICAL IMPLICATIONS: Glutamatergic activity changes of thalamus may be an underlying indicator for evaluating sensory conduction efficiency in patients with LPE. STRENGTHS & LIMITATIONS: The present study first found the abnormal thalamic metabolism in patients with LPE and contributed to a better understanding of the LPE etiology. Limitations include a cross-sectional study design with small samples and no examination of other brain areas. CONCLUSION: Our findings show that the increase in glutamatergic activity of thalamus is related to LPE, suggesting that the increased Glu neurotransmission in the thalamus may contribute to the development of premature ejaculation. Xia J-D, Chen F, Zhang Q-J, et al. Abnormal Thalamic Metabolism in Patients With Lifelong Premature Ejaculation. J Sex Med 2021;18:275-283.

m6A RNA methylation regulators correlate with malignant progression and have potential predictive values in clear cell renal cell carcinoma.

N6-methyladenosine (m6A) has been reported to be involved in several biological processes in tumors. In this study, we found that most of the m6A RNA methylation regulators were not only differentially expressed between clear cell renal cell carcinoma (ccRCC) and normal but also among ccRCC stratified by different clinicopathologic characters. Two ccRCC subgroups, cluster 1 and 2, were identified using consensus clustering based on the expression of m6A methylation regulators. Although no obvious differences were observed between two subgroups regarding clinicopathologic characters, except gender, patients in cluster 1 had a relatively more favorable survival rate than cluster 2. Moreover, we established a risk signature with two m6A methylation regulators, METTL3 and METTL14, which was not only of great value for prognosis prediction but also closely associated with clinicopathological features. In conclusion, m6A RNA methylation regulators play an important role in ccRCC progression and are potentially favorable for prognostic stratification.

[Stem cell therapy for erectile dysfunction: An update].

Erectile dysfunction (ED) is a common andrological disorder, and traditional oral drugs often fail to achieve satisfactory therapeutic effects. As a new field of biomedicine, stem cell therapy (SCT) has seen a significantly increasing number of researches on its treatment of ED in recent years. Preclinical animal models for the study of ED mainly include the models of diabetes mellitus-, aging-, cavernous nerve injury-, and Peyronie's disease-related ED. Previous studies indicated that SCT improved erectile function through paracrine and was more effective when combined with other therapies than used alone in restoring ED-induced pathological changes. Although clinical trials on SCT have partially proved its safety and effectiveness for the treatment of ED, they were still in the early stages and with relatively small sample sizes. This article summarizes the latest advances in the treatment of ED by SCT.

[Changes of psychological, erectile and urinary functions of the patients with penile fracture after surgical treatment].

OBJECTIVE: To investigate the impacts of surgical treatment of penile fracture on the short- and long-term psychological, erectile and urinary functions of the patient. METHODS: Fifty patients with penile fracture underwent surgical treatment in the Emergency Department of our hospital from June 2010 to December 2015. Using the Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), IIEF-5 and IPSS, we evaluated the psychological, erectile and urinary functions of the patients at 1 day, 6 months and 18 months after surgery, and analyzed the relationship between psychological and erectile functions as well as the possible factors affecting erectile function postoperatively. RESULTS: Compared with the baseline, significant increases were observed at 6 months after surgery in the SDS score (30.3 ± 4.1 vs 50.7 ± 6.5, P < 0.01) and SAS score (29.9 ± 5.9 vs 55.4 ± 7.7, P < 0.01) but a remarkable decrease in the IIEF-5 score (22.4 ± 1.3 vs 18.4 ± 2.1, P < 0.01). At 18 months, neither SDS (50.7 ± 10.0) or SAS score (54.1 ± 8.7) showed any statistically significant difference from that at 6 months (P > 0.05), but the IIEF-5 score (21.1 ± 2.2) was markedly lower than the baseline (P < 0.01), though higher than that at 6 months (P < 0.01). The IPSS scores at 6 and 18 months exhibited were not significantly different from that preoperatively (P > 0.05). Both the SDS and SAS scores were evidently higher in the patients with severe than in those with mild ED. The body mass index (BMI) and waiting time for surgery were significantly negatively correlated with short- and long-term erectile function of the patients after surgery. CONCLUSIONS: Patients with penile fracture may have decreased erectile function after surgery, accompanied with anxiety and depression. The risk factors for ED include BMI and waiting-for-surgery time.

Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats.

BACKGROUND: Although abnormal sympathetic nerve system (SNS) activity has been demonstrated in the pathogenesis of ejaculation disorders, few data are available on its underlying mechanism. AIM: To investigate whether differences in ejaculatory behavior of rats were associated with the state of SNS activity and gamma-aminobutyric (GABA) receptor expressions in the paraventricular nucleus (PVN) of the hypothalamus and the effects of GABA receptors in the PVN on ejaculatory behavior. METHODS: Based on ejaculatory performance, Sprague-Dawley rats were divided into "sluggish," "normal," and "rapid" ejaculators. PVN microinjection was performed to evaluate the role of GABA receptors on sexual behavior. OUTCOMES: The outcomes include differences in expression and distribution of GABA receptors and norepinephrine level among the 3 groups and changes in copulation behavior parameters after PVN microinjection. RESULTS: Compared with "normal" rats, the "rapid" group ejaculated more times with shorter latency (P < .001, P < .001) and had lower expression and distribution of both GABA-A and GABA-B receptors, while the opposed results appeared in the "sluggish" group. The norepinephrine level was successively increased among "sluggish," "normal," and "rapid" rats (P < .001) and correlated with ejaculation frequency (r = 0.896, P < .001) and ejaculation latency (r = -0.835, P < .001). In addition, bilateral microinjection of the GABA-A and GABA-B receptor agonist (isoguvacine and baclofen) into the PVN both significantly prolonged the intromission latency and inhibited ejaculation, which could be blocked by antagonist gabazine and CGP-35348, respectively. Vigabatrin, the GABA-transaminase inhibitor, caused a significantly reduced ejaculation frequency and extended ejaculation latency in rats, which could be offset by simultaneous injections of gabazine and CGP-35348. CLINICAL IMPLICATIONS: Our findings provide new understanding about GABA receptors in the PVN on sexual behavior and enhance the comprehension of neurobiological mechanisms involved in premature ejaculation. STRENGTHS & LIMITATIONS: Our results have indicated that GABA receptors in the PVN may inhibit ejaculation through restraining the activity of SNS. However, our study did not analyze the changes of GABA receptors in other brain areas, which needs further study. CONCLUSION: Ejaculation behaviors in male rats are associated with SNS activity and could be regulated by GABA receptors in the PVN, which may be of assistance in the treatment of ejaculation disorders in the future. Zhang QJ, Yang BB, Yang J, et al. Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats. J Sex Med 2020;17:614-622.

[Mu-opioid receptors in the paraventricular nucleus regulate ejaculatory behaviors via the sympathetic nerve system in male rats].

OBJECTIVE: To explore the effects of the mu-opioid receptor (MOR) in the paraventricular nucleus (PVN) on the ejaculatory behaviors of male rats and its potential mechanisms. METHODS: Male SD rats with normal ejaculation ability were mated with female ones in hormone-induced estrus. After bilateral PVN microinjection of D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) with an inserted catheter, the male animals were observed for mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL), ejaculation frequency (EF), post-ejaculation interval (PEI), and intromission ratio (IR). The lumbar sympathetic nerve activity (LSNA) of the rats was recorded using the PowerLab data acquisition hardware device, and the levels of norepinephrine (NE) in the peripheral plasma were measured by ELISA following microinjection of saline or different doses of DAGO or CTAP. RESULTS: Neither CTAP nor DGAO significantly affected the ML of the male rats (P > 0.05). DGAO remarkably increased IF (P < 0.01) and MF (P < 0.01), prolonged IL (P < 0.01), EL (P < 0.01) and PEI (P < 0.01), and reduced EF (P <0.01) and IR (P < 0.05). On the contrary, CTAP markedly decreased IF (P < 0.01) and MF (P < 0.01), shortened IL (P < 0.01), EL (P < 0.01) and PFI (P < 0.01), and elevated EF (P < 0.01) and IR (P < 0.01). Additionally, DAGO decreased LSNA in a dose-dependent manner and reduced the NE level in the peripheral plasma. CTAP, however, not only offset the effects of DAGO on LSNA, but also significantly increased LSNA. CONCLUSIONS: MOR in PVN inhibits ejaculatory behaviors in male rats by weakening LSNA, which has provided some theoretical evidence for the use of highly selective opioids in the treatment of premature ejaculation.

[Glans-preserving surgery for superficial penile squamous cell carcinoma ≥2 cm in diameter].

OBJECTIVE: To explore the feasibility of glans-preserving surgery (GPS) in the treatment of superficial penile squamous cell carcinoma (PSCC) with the lesion diameter of ≥2 cm. METHODS: We retrospectively analyzed the clinical data on 69 cases of superficial PSCC (≤T1aN0) treated by GPS (n = 36) or radical surgery (total or partial penectomy, n = 33) from July 2007 to July 2017. RESULTS: The mean tumor diameter and depth of invasion were 3.16 (2.0－6.0) cm and 0.89 (0.5－2.0) cm in the GPS group and 3.56 (2.0－6.0) cm and 1.89 (0.6－4.0) cm respectively in the radical surgery group. The patients were followed up for 10－102 (mean 42) months, during which, 5 patients in the GPS group developed local recurrence at 40 days and 2, 4, 7 and 9 months postoperatively, again underwent gansectomy, partial penectomy or GPS, and experienced no more recurrence during the follow-up of 54, 34, 39, 66 and 70 months. No local recurrence was observed in the radical surgery group, and none of the 69 patients experienced lymph node metastasis or died during the follow-up. CONCLUSIONS: GPS is safe and efficient for the treatment of superficial PSCC with the lesion diameter of ≥2 cm.

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis.

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.

[Neurophysiological mechanisms of ejaculation].

The sexual behavior of the male can be described as a series of behavioral transitions eventually leading to ejaculation and sexual satisfaction. The ejaculation itself is extensively regulated by different ejaculation generators. The "spinal ejaculation generator" receives genito-sensory signals through afferent fibers and then informs the brainstem and forebrain via ascending fiber projections. Conversely, the supraspinal areas restrict ejaculations to the optimal moments and circumstances through descending afferent fibers. The messages ascending from the spinal cord reach the interconnected thalami, hypothalami, limbic system and cerebral cortex and are integrated with olfactory information. These brain areas are all related to ejaculation, but the exact facilitatory and inhibitory mechanisms involved have not yet been elucidated hitherto. Both the medial preoptic nucleus and brainstem areas play an important role in the "downward" mechanisms underlying the spinal "release" of an ejaculation. The medial preoptic nucleus is also precisely related to the "sexual rewarding" coming with an ejaculation. Meanwhile, the roles of several neurotransmitters are discussed considering their remarkable effects on ejaculation. This review focuses on the ejaculation-related circuits and neurotransmitters for the purpose of gaining a deeper insight into the mechanisms of ejaculation and providing some theoretical evidence for the study and treatment of ejaculation-related diseases.

Novel mutations of PDGFRB cause primary familial brain calcification in Chinese families.

Four causative genes, including solute carrier family 20 member 2 (SLC20A2), platelet-derived growth factor receptor b (PDGFRB), platelet-derived growth factor b (PDGFB)and xenotropic and polytropic retrovirus receptor 1 (XPR1), have been identified to cause primary familial brain calcification (PFBC). However, PDGFRB mutations seem to be quite rare and no PDGFRB mutations have been reported in Chinese PFBC patients. A total of 146 PFBC patients including 12 families and 134 sporadic patients were recruited in this study. All of them were previously tested negative for the SLC20A2. Mutational analyses of the entire exons and exon-intron boundaries of PDGFRB were carried out by direct gene sequencing. In silico analyses of the identified variants were conducted using Mutation Taster, PolyPhen-2 and Sorts Intolerant From Tolerant. Two heterozygous variants, c.3G>A and c.2209G>A, of the PDGFRB gene were revealed in two PFBC families, respectively. These two variants were not observed in 200 healthy controls. The variant c.3G>A was located in exon 2 and affected the initiation codon of the PDGFRB gene. The variant c.2209G>A resulted in amino-acid substitutions of aspartic acid to asparagine at position 737. Both of these two variants co-segregated with the disease phenotype (variant carriers in Family 1: I1, II2 and II3; variant carriers in Family 2: I2 and II8), suggesting a pathogenic impact of these variants. The prevalence of PDGFRB mutations in Chinese PFBC patients seems to be quite low, indicating that PDGFRB is not a major causative gene of PFBC in Chinese population.

[Epigenetics of male infertility: An update].

Epigenetic factors play an important role in male infertility though about 60%－65% of the disease is idiopathic and its underlying causes are not yet clear. Many studies have indicated that epigenetic modifications, including DNA methylation, histone tail modifications, chromatin remodeling, and non-coding RNAs, may be involved in idiopathic male infertility. Abnormal methylation is associated with decreased sperm quality and fertility. It is known that 1 881 miRNAs are related to male fertility and such non-coding RNAs as piRNA, IncRNA, and circRNA play a regulating role in male reproduction. This review focuses on the value of epigenetics in the etiology and pathogenesis of male infertility, aiming to provide some evidence for the establishment of some strategies for the treatment and prediction of the disease.

Orexin receptors in paraventricular nucleus influence sexual behavior via regulating the sympathetic outflow in males.

BACKGROUND: Orexins are hypothalamic neuropeptides associated with various neurophysiological activities such as sleep, arousal, and reward. However, there are few studies investigating the relationships between orexin receptors in the paraventricular nucleus and sexual behaviors. OBJECTIVES: To explore the roles of orexin receptors in the paraventricular nucleus on sexual behaviors and uncover its potential mechanisms in males. MATERIALS AND METHODS: Orexin A, orexin 1 receptor antagonist SB334867, and orexin 2 receptor antagonist TCS-OX2-29 were microinjected into the paraventricular nucleus to investigate the effects of orexin receptors on copulatory behavior testing of C57BL/6 mice. To explore if ejaculation could activate orexin 1 receptor-expressing neurons in the paraventricular nucleus, fluorescence immunohistochemical double staining was utilized. The levels of serum norepinephrine were measured and the lumbar sympathetic nerve activity was recorded to reflect the sympathetic nervous system activity. Moreover, the bulbospongiosus muscle-electromyogram was recorded and analyzed. To test whether perifornical/lateral hypothalamic area orexinergic neurons directly projected to the paraventricular nucleus, virus retrograde tracing technology was utilized. RESULTS: Orexin A significantly enhanced sexual performance by shortening the intromission and ejaculation latencies, and increasing the mount and intromission frequencies, while the opposite outcomes appeared with SB334867. However, TCS-OX2-29 had no significant effects on sexual behaviors. Moreover, orexin A increased lumbar sympathetic nerve activity and the levels of serum norepinephrine, while SB334867 decreased lumbar sympathetic nerve activity and norepinephrine, which caused a significant decrease in sympathetic nervous system outflow. Meanwhile, a robust increase in the bulbospongiosus muscle-electromyogram activity was identified after microinjecting orexin A. Furthermore, cFos immunopositive cells were increased and double stained with orexin 1 receptor-expressing neurons in the mating group. Additionally, the retrograde tracing results demonstrated that orexinergic neurons in the perifornical/lateral hypothalamic area directly projected to the paraventricular nucleus. CONCLUSIONS: Orexin 1 receptor in the paraventricular nucleus could influence the ejaculatory reflex via mediating the sympathetic nervous system activity, which might be of great importance in the treatment of premature ejaculation in the future.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Prostate-derived IL-1ß upregulates expression of NMDA receptor in the paraventricular nucleus and shortens ejaculation latency in rats with experimental autoimmune prostatitis.

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-1ß(IL-1ß) 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-1ß 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-1ß 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-1ß administration. Therefore, we identified IL-1ß 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-1ß upregulates NMDA expression.

Decreased serum creatinine levels predict short survival in amyotrophic lateral sclerosis.

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 < 0.0001). INTERPRETATION: Serum creatinine could be a reliable and easily accessible prognostic chemical marker for ALS, and decreased baseline creatinine levels could predict a poor prognosis and a short survival in both male and female ALS patients.

Serum Uric Acid Levels Predict Mortality Risk in Male Amyotrophic Lateral Sclerosis Patients.

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.

Age-Related Differences in Molecular Profiles for Immune Checkpoint Blockade Therapy.

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.

The Identification and Validation of a Robust Immune-Associated Gene Signature in Cutaneous Melanoma.

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 < 0.001). Additionally, the ROC curve analyses were performed which demonstrated our IAG signature was superior to four known biomarkers mentioned in the study. Moreover, the IAG signature was significantly related to immunotherapy-related biomarkers. CONCLUSION: Our study demonstrated that the six IAG signature played a critical role in the prognosis and immunotherapy of melanoma, which might help clinicians predict patients' survival and provide individualized treatment.