Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases.

Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.

Memory/active T cell activation is associated with immunotherapeutic response in fumarate hydratase-deficient renal cell carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for metastatic patients. RESULTS: In the localized setting, we found that a cell cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS: 17.3 vs. 9.6 months, P=0.016) and OS (median OS: not reached vs. 25.7 months, P=0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

CL-K1 Promotes Complement Activation and Regulates Opsonophagocytosis of Macrophages with CD93 Interaction in a Primitive Vertebrate.

Collectin is a crucial component of the innate immune system and plays a vital role in the initial line of defense against pathogen infection. In mammals, collectin kidney 1 (CL-K1) is a soluble collectin that has recently been identified to have significant functions in host defense. However, the evolutionary origins of immune defense of CL-K1 and its mechanism in clearance of pathogenic microorganisms remain unclear, especially in early vertebrates. In this study, the Oreochromis niloticus CL-K1 (OnCL-K1) protein was purified and identified, which was capable of binding to two important pathogens of tilapia, Streptococcus agalactiae and Aeromonas hydrophila. Interestingly, OnCL-K1 exhibited direct bactericidal activity by binding to lipoteichoic acid or LPS on cell walls, disrupting the permeability and integrity of the bacterial membrane in vitro. Upon bacterial challenge, OnCL-K1 significantly inhibited the proliferation of pathogenic bacteria, reduced the inflammatory response, and improved the survival of tilapia. Further research revealed that OnCL-K1 could associate with OnMASPs to initiate and regulate the lectin complement pathway. Additionally, OnCD93 reduced the complement-mediated hemolysis by competing with OnMASPs for binding to OnCL-K1. More importantly, OnCL-K1 could facilitate phagocytosis by collaborating with cell surface CD93 in a lectin pathway-independent manner. Moreover, OnCL-K1 also promoted the formation of phagolysosomes, which degraded and killed ingested bacteria. Therefore, this study reveals the antibacterial response mechanism of CL-K1 in primitive vertebrates, including promoting complement activation, enhancing opsonophagocytosis, and killing of macrophages, as well as its internal links, all of which provide (to our knowledge) new insights into the understanding of the evolutionary origins and regulatory roles of the collectins in innate immunity.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Functional connectivity alterations in the frontoparietal network and sensorimotor network are associated with behavioral heterogeneity in blepharospasm.

Objective: Primary blepharospasm (BSP) is a clinically heterogeneous disease that manifests not only as spasmodic closure of the eyelids but also sometimes with apraxia of eyelid opening (AEO). This cross-sectional study aimed to investigate differences in the neural mechanisms of isolated BSP and BSP-associated AEO subtypes, which may reveal the pathophysiology underlying different phenotypes. Methods: A total of 29 patients manifested as isolated BSP, 17 patients manifested as BSP associated with AEO, and 28 healthy controls underwent resting-state functional near-infrared spectroscopy (fNIRS). We assessed functional connectivity (FC) between regions of interest (ROIs) in the fronto-parietal control network (PFCN) and sensorimotor network (SMN). We also examined the relationship between altered FC and behavioral data. Results: In the FPCN, ROI- analyses showed decreased FC between the left premotor cortex and supramarginal gyrus in the BSP with AEO group compared to the isolated BSP group. In the SMN, both subgroups showed hypoconnectivity of the left premotor cortex with the right primary motor cortex, primary sensory cortex, and somatosensory association cortex. This hypoconnectivity was positively correlated with the total number of botulinum toxin A treatments, which suggests that long-term botulinum toxin A treatment may modulate motor sequence planning and coordination. Conclusion: These findings showed different connectivity alterations in neural networks associated with motor and cognitive control among different behavioral phenotypes of BSP. The identification of specific alterations in various networks that correspond to clinical heterogeneity may inform the identification of potential biomarkers for early diagnosis and personalized neuromodulation targets for treating different BSP subphenotypes.

Brain nuclei and neural circuits in neuropathic pain and brain modulation mechanisms of acupuncture: a review on animal-based experimental research.

Neuropathic pain (NP) is known to be associated with abnormal changes in specific brain regions, but the complex neural network behind it is vast and complex and lacks a systematic summary. With the help of various animal models of NP, a literature search on NP brain regions and circuits revealed that the related brain nuclei included the periaqueductal gray (PAG), lateral habenula (LHb), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC); the related brain circuits included the PAG-LHb and mPFC-ACC. Moreover, acupuncture and injurious information can affect different brain regions and influence brain functions via multiple aspects to play an analgesic role and improve synaptic plasticity by regulating the morphology and structure of brain synapses and the expression of synapse-related proteins; maintain the balance of excitatory and inhibitory neurons by regulating the secretion of glutamate, γ-aminobutyric acid, 5-hydroxytryptamine, and other neurotransmitters and receptors in the brain tissues; inhibit the overactivation of glial cells and reduce the release of pro-inflammatory mediators such as interleukins to reduce neuroinflammation in brain regions; maintain homeostasis of glucose metabolism and regulate the metabolic connections in the brain; and play a role in analgesia through the mediation of signaling pathways and signal transduction molecules. These factors help to deepen the understanding of NP brain circuits and the brain mechanisms of acupuncture analgesia.

Long-chain pentraxin 3 possesses agglutination activity and plays a role in host defense against bacterial infection in Oreochromis niloticus.

Pentraxin 3 (PTX3) is a soluble pattern recognition molecule in the innate immune system that has multiple functions. It is involved in resisting pathogen infection. However, the functions of PTX3 in teleost fish are not well understood. In this study, we identified and characterized PTX3 in Nile tilapia (Oreochromis niloticus) (OnPTX3). The open reading frame of OnPTX3 was found to be 1305 bp, encoding 434 aa. We conducted spatial mRNA expression analysis and found that the expression of OnPTX3 was significantly increased after infection with Streptococcus agalactiae and Aeromonas hydrophila, both in vivo and in vitro. We also observed that recombinant OnPTX3 protein could bind and agglutinate bacterial pathogen. Furthermore, OnPTX3 enhanced the phagocytosis of bacteria (S. agalactiae and A. hydrophila) by head kidney macrophages. Additionally, OnPTX3 was found to influence the expression of inflammatory cytokines, suggesting its involvement in the regulation of the inflammatory response. Moreover, OnPTX3 was shown to promote complement-mediated hemolysis and possess antibacterial activity. In conclusion, our research demonstrates that OnPTX3 has bacterial binding and agglutination activities, enhances phagocytosis, and regulates inflammation. It plays a crucial role in the defense of Nile tilapia against pathogenic bacteria, providing valuable insights for the prevention and control of aquatic diseases in the future.

Mannose-binding lectin suppresses macrophage proliferation through TGF-ß1 signaling pathway in Nile tilapia.

Mannose-binding lectin (MBL) is a multifunctional pattern recognition molecule, which not only mediates the recognition of pathogenic microorganisms and their products, playing an important role in innate immune defense, but also participates in adaptive immune responses of mammalian. However, it's related immune mechanism remains limited, especially the regulation of cell proliferation in early vertebrates. In this study, OnMBL was found to bind to kidney macrophages (MФ) from Nile tilapia (Oreochromis niloticus). Interestingly, OnMBL was able to reduce the proliferation of activated-MФ by regulating the cell cycle, arresting a large number of cells in the G0/G1 phase, and increasing the probability of apoptosis. More importantly, we found that the inhibition of cell proliferation by OnMBL was closely related to the evolutionarily conserved canonical transforming growth factor-beta 1 (TGF-ß1) signaling pathway. Mechanistically, OnMBL could significantly increase the expression of TGF-ß1, activate and regulate the downstream Smad-dependent pathway to reduce the MФ proliferation, thereby maintaining cellular homeostasis in the body's internal environment. This study represents the first description regarding the regulatory mechanisms of the MBL on cell proliferation in teleost fish, which provides a novel perspective on the understanding of the multiple function and evolutionary origins of C-type lectins in the immune system.

Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase-deficient renal cell carcinoma.

BACKGROUND: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear. METHODS: In this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions. RESULTS: Paired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci. CONCLUSIONS: Overall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.

Corrigendum: Elucidation of the mechanism underlying impaired sensorimotor gating in patients with primary blepharospasm using prepulse inhibition.

[This corrects the article DOI: 10.3389/fneur.2023.1105483.].

C9 regulates the complement-mediated cell lysis in association with CD59 to resist bacterial infection in a primary animal.

Complement component 9 (C9), as an essential component of terminal membrane attack complex of complement system, plays an important role in innate immune defense. However, the function and regulatory mechanism of C9 in the antimicrobial immune response of teleost fish remain unclear. In this study, the open reading frame of Nile tilapia (Oreochromis niloticus) C9 (OnC9) gene was amplified. The mRNA and protein expression of OnC9 were significantly changed upon infection with Streptococcus agalactiae and Aeromonas hydrophila in vivo and in vitro. Upon bacterial challenge, the OnC9 knockdown could lead to rapid proliferation of the pathogenic bacteria, ultimately resulting in tilapia death. However, the phenotype was rescued by re-injection of OnC9, which restored the healthy status of the knockdown tilapia. Further, the OnC9 was an essential component in complement-mediated cell lysis and associated with OnCD59 to regulate the efficiency of lysis. Overall, this study indicates that OnC9 is involved in host defense against bacterial infection, and provides a valuable reference for further exploration of the molecular regulatory mechanism of C9 in innate immune defense in a primary animal.

Neuroendocrine differentiation predicts the therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.

PURPOSE: We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. METHODS: We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). RESULTS: NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients' survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. CONCLUSION: For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients' outcomes and optimizing treatment decisions.

Elucidation of the mechanism underlying impaired sensorimotor gating in patients with primary blepharospasm using prepulse inhibition.

Objective: We aimed to analyze prepulse inhibition (PPI) impairment of the blink reflex in patients with primary blepharospasm (BSP). Methods: We recruited 30 BSP patients and 20 gender- and age-matched healthy controls (HCs). Weak electrical stimulation was applied to the right index finger at interstimulus intervals (ISIs) of 120, 200, and 300 ms before the supraorbital nerve stimulation to investigate PPI size [PPI size = (1 - R2 area at prepulse trials/R2 area at baseline trials) × 100%]. Results: The prepulse stimulus significantly inhibited the R 2 component at the three ISIs in both groups, but less inhibition was shown in the BSP group (p < 0.05). In HCs, the prepulse stimulus induced prolonged R 2 and R 2c latencies at the three ISIs and increased the R 1 amplitude at ISIs of 120 ms; these changes were absent in BSP patients. In the BSP group, patients with sensory tricks showed better PPI than patients without sensory tricks. Disease duration and motor symptom severity showed no significant correlation with PPI size. Conclusion: In BSP patients, PPI was impaired while R 1 facilitation was absent. PPI size did not correlate with the motor symptom severity and disease duration. Patients with sensory tricks showed better PPI than those without sensory tricks.

Correlation and underlying brain mechanisms between rapid eye movement sleep behavior disorder and executive functions in Parkinson's disease: an fNIRS study.

Purpose: Rapid eye movement sleep behavior disorder (RBD) affects 30%-40% of patients with Parkinson's disease (PD) and has been linked to a higher risk of cognitive impairment, especially executive dysfunction. The aim of this study was to investigate the brain activation patterns in PD patients with RBD (PD-RBD+) compared to those without RBD (PD-RBD-) and healthy controls (HCs), and to analyze the correlation between changes in cerebral cortex activity and the severity of RBD. Methods: We recruited 50 PD patients, including 30 PD-RBD+, 20 PD-RBD-, and 20 HCs. We used functional near infrared spectroscopy during a verbal fluency task (VFT-fNIRS) and clinical neuropsychological assessment to explore the correlation between PD-RBD+ and executive function and changes in neural activity. Results: The VFT-fNIRS analysis revealed a significant reduction in activation among PD-RBD+ patients across multiple channels when compared to both the PD-RBD- and HC groups. Specifically, PD-RBD+ patients exhibited diminished activation in the bilateral dorsolateral prefrontal cortex (DLPFC) and the right ventrolateral prefrontal cortex (VLPFC) relative to their PD-RBD- counterparts. Furthermore, compared to the HC group, PD-RBD+ patients displayed reduced activation specifically in the right DLPFC. Significantly, a noteworthy negative correlation was identified between the average change in oxygenated hemoglobin concentration (ΔHbO2) in the right DLPFC of PD-RBD+ patients and the severity of their RBD. Conclusion: Our study offers compelling evidence that RBD exacerbates cognitive impairment in PD, manifested as executive dysfunction, primarily attributed to reduced prefrontal activation. These aberrations in brain activation may potentially correlate with the severity of RBD.

Complement C3 Regulates Inflammatory Response and Monocyte/Macrophage Phagocytosis of Streptococcus agalactiae in a Teleost Fish.

The complement system is composed of a complex protein network and is pivotal to innate immunity. Complement 3 (C3) is a critical protein in the complement cascade and participates in complement activation and immune defense. In this study, C3 from Nile tilapia (Oreochromis niloticus) was cloned and its function in resisting pathogen infection was characterized. The full length of OnC3 open reading frame is 4974 bp, encoding 1657 aa, and the predicted protein mass weight is 185.93 kDa. The OnC3 amino acid sequence contains macroglobulin domains. The expression pattern of OnC3 mRNA in the tissues of healthy fish was detected, with the highest in the liver and the lowest in the muscle. After challenged with Streptococcus agalactiae and Aeromonas hydrophila, the expression of OnC3 mRNA was significantly up-regulated in the liver, spleen, and head kidney. Further, the recombinant OnC3 protein alleviated the inflammatory response and pathological damage of tissues after infected with S. agalactiae. Moreover, the OnC3 promoted the phagocytosis of monocytes/macrophages to S. agalactiae. The data obtained in this study provide a theoretical reference for in-depth understanding of C3 in host defense against bacterial infection and the immunomodulatory roles in teleost fish.

Atypical metanephric adenoma: Shares similar histopathological features and molecular changes of metanephric adenoma and epithelial-predominant Wilms' tumor.

Background: Metanephric adenomas (MAs) are rare, benign renal tumors. Wilms' tumors (WTs) are malignant embryonic tumors that originated from nephrogenic blastemal cells. However, some tumors have similar morphology to both MA and epithelial-predominant WT, which makes differential diagnosis difficult. We aimed to analyze the morphological, immunophenotypic and molecular changes in overlapping cases to explore their attribution. Methods and results: Twenty MAs, ten WTs, and nine cases with MA/WT overlapping histological features were studied. Twenty tumors demonstrated the typical morphological spectrum of MA with high cellularity and were composed of tightly packed small, uniform, round acini with a lower Ki67 index. Almost all MAs (94.7%, 18/19) were detected with BRAF V600E mutation. The ten WTs were epithelial-predominant WTs with glands, rosettes and glomerular structures, which also showed a higher Ki-67 index (up to 60%), invasive growth patterns, and a lack of BRAF mutation. However, the other nine overlapping cases showed two components: typical MA-like areas and epithelial WT-like areas. The cells of the WT-like areas were tubular, columnar and showed marked cytological atypia, with a Ki-67 proliferative index of up to 30%. The immunophenotype of these overlapping lesions was not significantly different from that of typical MA and they positively expressed WT1 and CD57. The BRAF V600E mutation was detected in both WT-like and MA-like areas in nine overlapping tumors. The follow-up data of 31 patients were analyzed, with a median follow-up time of 66 months (range, 8-45 months). Even though most patients with WT underwent radiotherapy or chemotherapy after surgery, two died, and one had liver metastasis. No MA or overlapping cases showed any evidence of recurrence or metastasis after surgery. Conclusions: The molecular changes in tumors with overlapping morphological features were the same as those of typical MA; thus, we think that these tumors should be classified as MA and further called atypical MA. It is important to note that atypical MA is not a neglected subtype of MA. It possesses different histological morphology and a higher Ki-67 index but has the common imaging characteristics, immunophenotype and gene expression as typical MA, and patients usually have a good prognosis.

Survival in patients with Parkinson's disease: a ten-year follow-up study in northern China.

BACKGROUND: A thorough understanding of the factors that influence patient survival in Parkinson's disease (PD) will aid in prognosis prediction and provide a new direction for disease modification treatment. Currently, there are no standardized mortality ratio (SMR) data for PD patients in the northern Chinese mainland. The main focus of this study was to determine which factors in the prospectively collected baseline characteristics can affect the survival of PD patients. In addition, for the first time, we investigated the SMR of PD patients in northern China. METHODS: Between 2009 and 2012, 218 PD patients were continuously recruited from the movement disorder clinic of the First Affiliated Hospital of Dalian Medical University and followed up until death or May 31, 2021. The prespecified prognostic variables were demographics, clinical features, lifestyle factors, and drug dose prospectively collected at baseline. To determine the independent predictors of survival during follow-up, the Cox proportional hazards model was used. Kaplan-Meier analysis was applied to estimate the overall survival curve and to compare survival between layers based on statistically significant predictors. The SMR of this northern Chinese mainland PD cohort was calculated. RESULTS: After a mean follow-up of 9.58 ± 2.27 years, 50 patients (22.90%) died. Factors that could individually predict shortened survival during follow-up included older age at onset (hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.06-1.15), Hoehn and Yahr (H&Y) stage ≥ 3 (HR 9.36, 95% CI 2.82-31.03) and severe cognitive impairment (HR 6.18, 95% CI 2.75-13.88). Univariate Cox regression revealed that a certain amount of physical activity was associated with better survival (HR 0.41, 95% CI 0.22-0.74), while fatigue was associated with an increased risk of death (HR 2.54, 95% CI 1.37-4.70). The overall SMR was 1.32 (95% CI 0.98-1.74). CONCLUSIONS: Older age at onset, higher baseline H&Y stage, and severe cognitive impairment have a negative impact on survival. The 10-year survival of PD patients is not significantly different from that of the general population in China.

The roles of mutated SPINK1 gene in prostate cancer cells.

SPINK1-positive prostate cancer (PCa) has been identified as an aggressive PCa subtype. However, there is a lack of definite studies to elucidate the underlying mechanism of the loss of SPINK1 expression in most PCa cells except 22Rv1 cells, which are derived from a human prostatic carcinoma xenograft, CWR22R. The aim of this study was to investigate the mechanisms of SPINK1 protein positive/negative expression and its biological roles in PCa cell lines. SPINK1 mRNA was highly expressed in 22Rv1 cells compared with LNCaP, C4-2B, DU145, and PC-3 cells, and the protein was only detected in 22Rv1 cells. Among these cell lines, the wild-type SPINK1 coding sequence was only found in 22Rv1 cells, and two mutation sites, the c.194G>A missense mutation and the c.210T>C synonymous mutation, were found in other cell lines. Our further research showed that the mutations were associated with a reduction in SPINK1 mRNA and protein levels. Functional experiments indicated that SPINK1 promoted PC-3 cell proliferation, migration, and invasion, while knockdown of SPINK1 attenuated 22Rv1 cell proliferation, migration, and invasion. The wild-type SPINK1 gene can promote the malignant behaviors of cells more than the mutated ones. Cell cycle analysis by flow cytometry showed that SPINK1 decreased the percentage of cells in the G0/G1 phase and increased the percentage of S phase cells. We demonstrated that the c.194G>A and c.210T>C mutations in the SPINK1 gene decreased the mRNA and protein levels. The wild-type SPINK1 gene is related to aggressive biological behaviors of PCa cells and may be a potential therapeutic target for PCa.

The tumor-repressing effect of CYP27A1 on renal cell carcinoma by 27-HC arising from cholesterol metabolism.

As a key approach to mediate cholesterol metabolism, the role of the CYP27A1/27-HC axis in renal cell carcinoma (RCC) remains unclear. Analysis of CYP27A1 expression from public databases and metastatic cases in our center suggested that CYP27A1 was obviously downregulated in RCC tissues, and survival analysis further showed its correlation with favorable clinicopathological features and prognosis. In vitro, up and downregulation of CYP27A1 expression in RCC cell lines could definitely illustrate its anticipation involving apoptosis, proliferation, invasion, migration, and clonality. This could be achieved through upregulation of 27-HC concentration, which mediates the activation of signaling pathways of apoptosis and cell cycle arrest. Further, recovery of CYP27A1 expression could definitely inhibit the proliferation of RCC tumors in vivo. This is the first study to explore the role of the CYP27A1/27-HC axis in RCC. Attempts to maintain the normal function of the axis may be a potential strategy in the treatment of RCC, and the predictive value of CYP27A1 detection on the efficacy of targeted therapy in metastatic RCC is also worthy of attention.