Analysing the causal relationship between potentially protective and risk factors and cutaneous melanoma: A Mendelian randomization study.

BACKGROUND: Previous observational studies reported altered melanoma risks in relation to many potential factors, such as coffee intake, smoking habits and photodamage-related conditions. Considering the susceptibility of epidemiological studies to residual confounders, there remains uncertainty about the actual causal roles of these reported factors in melanoma aetiology. OBJECTIVES: This study aims to investigate the causal association between cutaneous melanoma (CM) and previously reported factors: coffee intake, alcohol consumption, lifetime smoking, socioeconomic status (SES), ease of skin tanning, childhood sunburn and facial ageing, providing insight into its underlying aetiology and preventative strategies. METHODS: We utilized a two-sample MR analysis on data from the largest meta-analysis summary statistics of confirmed cutaneous melanoma including 30,134 patients. Genetic instrumental variables were constructed by identifying single nucleotide polymorphisms (SNPs) that associate with corresponding factors. Inverse variance weighted (IVW) was the primary MR method. For sensitivity and heterogeneity, MR Egger, weighted median, simple mode, weighted mode and MR Egger intercept tests were examined. RESULTS: Cutaneous melanoma risks were found to be elevated in association with a predisposition towards ease of skin tanning (IVW: OR = 2.842, 95% CI 2.468-3.274, p < 0.001) and with childhood sunburn history (IVW: OR = 6.317, 95% CI 4.479-8.909, p < 0.001). Repeated MR after removing potential confounders and outliers demonstrated resolved horizontal pleiotropy and statistically significant results that closely mirrored the initial findings. Other potential factors, such as coffee intake, alcohol consumption, smoking and socioeconomic status (SES), indicated insignificant effects on melanoma risk in the analysis, and therefore, our Mendelian randomization study does not support their roles in modifying melanoma risks. CONCLUSIONS: Our extensive MR analysis provides strong evidence of the causative role of ease of skin tanning and childhood sunburn history in elevating melanoma risk. Curtailing ultraviolet radiation (UVR) exposure may be the single best preventative strategy to reduce melanoma risk.

Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis.

OBJECTIVES: Co-infection of syphilis and HIV remains hard to manage and its morbidity shows a rising tendency. Syphilis has been associated with increased risk of HIV acquisition in high-risk groups, especially in men who have sex with men (MSM). This systematic review and meta-analysis estimates the effect of syphilis infection on subsequent HIV acquisition, and assesses its difference between MSM and other high-risk populations. METHODS: Five electronic databases were searched for literature published to 21 September 2019 without language restrictions. Longitudinal studies that enrolled key populations to compare the incidence of HIV with and without syphilis exposure were included. We used a random-effects model to estimate the effect of syphilis infection on HIV acquisition among high-risk populations, which include MSM, sex workers, serodiscordant couples, people who inject drugs and attendees of STD clinics. RESULTS: A total of 17 cohorts and 5 case-control studies involving 65 232 participants were included. HIV incidence showed a two-time increase after syphilis exposure, compared with a control group (relative risk (RR) 2.67 (95% CI 2.05 to 3.47); p<0.05 for prevalence; RR 3.21 (95% CI 2.26 to 4.57); p=0.419 for incidence). No significant differences were observed between MSM and other high-risk groups in syphilis infection prevalence (RR 2.60 (95% CI 1.78 to 3.80); p<0.05 vs RR, 2.98 (95% CI 2.15 to 4.14); p<0.05; ratio of relative risk 0.76 (95% CI 0.49 to 1.17)). CONCLUSIONS: Syphilis infection increases the risk of HIV acquisition in high-risk populations. There is no evidence to suggest MSM are at greater risk than other high-risk populations. Prompt diagnosis, timely treatment, preventive interventions against syphilis infection would be a worthwhile investment for reducing HIV incidence. Strategies to combat stigma and discrimination targeted at MSM are pragmatically needed.

The Great Imitator: Atypical Cutaneous Manifestations of Primary Syphilitic Chancre.

Objective To analyze the reasons of misdiagnosis of primary syphilitic chancre and strengthen the understanding of atypical features of this disease. Methods A case series of twenty-seven challenging primary syphilis patients who were not immediately recognized as chancre was included in our study. The clinical data including the patients' age, sex, skin lesions, HIV status, syphilis serologic test results, treatment, and follow-up results were collected. Hematoxylin-eosin and immunohistochemistry staining of skin biopsy sections were reviewed. Results Four female cases with extragenital chancres presenting as erythema or erosive skin lesions on the nipple were misdiagnosed as Paget's disease or eczema. The disorder of missed or misdiagnosed male cases manifested as syphilitic balanitis or multiple chancres on the penis root and adjacent pubis rather than coronal sulcus or frenum. Patients with nonreactive nontreponemal tests at initial presentation were also easily missed or misdiagnosed. Conclusion Primary syphilis presenting as multiple lesions rather than a single chancre, at atypical locations, or with a nonreactive nontreponemal test result, tends to be missed or misdiagnosed.

Peripheral blood mononuclear cell microRNA profiles in syphilitic patients with serofast status.

Syphilis is a chronic sexually transmitted disease caused by infection with Treponema pallidum, which can invade various system organs, leading to clinical manifestations such as neurosyphilis, ocular syphilis, and cardiovascular syphilis and seriously endangering human health. Serofast status is a common outcome after syphilis treatment that presents an important clinical problem. At present, the etiology of serofast status remains unknown. A systematic investigation of the microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with serofast status or secondary syphilis and of healthy control subjects was conducted using small RNA-seq. The expression of miRNAs was further confirmed by real-time fluorescence quantitative PCR (qPCR) assays. The data reveal a specific miRNA expression profile that was displayed in cells from patients with serofast status. Known and novel predicted (np)-miRNAs were also identified and verified, such as miR-338-5p, np-miR-163, np-miR-128, np-miR-244, and np-miR-5, which together may be used as indicators for treatment evaluation. The functions of genes targeted by the miRNAs differentially expressed in serofast status patients were further analyzed; these genes were found to be involved in various biological functions, such as T-cell receptor signaling pathways, metabolism, and growth. Our study presents the first systematic landscape of miRNAs in PBMCs from patients with serofast status and proposes specific miRNAs linked with serofast status. Our results provide further evidence that serofast status is closely related to host immune function. Additionally, the miRNA expression profile in PBMCs of patients with serofast status generated by this work offers insight into the complex immune network in humans. We hope our results can provide new insights into the pathogenesis of serofast status.

Risk Factors for the Co-infection with HIV, Hepatitis B and C Virus in Syphilis Patients.

Syphilis, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes. Syphilis infection can increase the risk of acquiring and transmitting HIV in key populations. The aims of this study were to investigate the risk factors and co-infection patterns for HIV, HBV and HCV in patients with syphilis. A retrospective study was conducted of 2,412 patients with syphilis (1,922 (79.68%) with latent syphilis, 336 (13.93%) with secondary syphilis, 78 (3.23%) with primary syphil-is, 72 (2.99%) with tertiary syphilis, and 4 (0.17%) with congenital syphilis). Positive results were odserved in 8.21% (134/1,620) of patients tested for HIV, 5.75% (82/1,427) for HBV, and 1.02% (14/1,374) for HCV, respectively. Multivariate logistic regression analysis found that male sex (adjusted odds ratio (AOR) 26.03; 95% confidence interval (CI) 10.37-65.36), age <55 years, especially age group 25-34-years (AOR 8.06; 95% CI 4.16-15.61), diagnosed at the Department of Infectious Disease (AOR 19.16; 95% CI 9.74-37.69), patients from Southern China, which is a geographical area south of the Qinling-Huaihe line (AOR 1.86; 95% CI 1.06-3.26) and having a rapid plasma reagin titre ≥1:32 (AOR 1.88; 95% CI 1.12-3.15) were independently associated with HIV infection. Risk factors for HBV co-infection in patients with syphilis, including male sex (AOR 1.78; 95% CI 1.12-2.83) and living in Southern China (AOR 4.66; 95% CI, 2.36-9.17) were also identified.

Clinicopathological characteristics and prognosis of amelanotic acral melanoma: A comparative study with pigmented acral melanoma.

We compared the clinicopathological features and prognosis between 16 amelanotic acral melanomas versus 56 pigmented acral melanomas. Amelanotic acral melanomas showed a thicker Breslow thickness (all had a Breslow thickness > 1 mm), more frequent ulceration (15/16, 93.7%) and lower HMB-45 positive rate than pigmented acral melanomas. However, a significant difference in survival was not observed.

NOVA1 acts as an oncogene in melanoma via regulating FOXO3a expression.

Increasing studies have suggested that dysregulation of RNA-binding proteins (RBPs) contributes to cancer progression. Neuro-oncological ventral antigen 1 (NOVA1) is a novel RBP and plays an important role in tumour development. However, the expression and role of NOVA1 in melanoma remain unknown. In this study, we indicated that NOVA1 expression was up-regulated in melanoma samples and cell lines. Moreover, we demonstrated that knockdown of NOVA1 suppressed melanoma cell proliferation, migration and invasion in both A375 and A875 cell lines. In addition, we showed that suppressed expression of NOVA1 enhanced forkhead box O3a (FOXO3a) expression while inhibited AKT expression in melanoma cell. Furthermore, we demonstrated that inhibited expression of FoxO3A rescued NOVA1-mediated cell proliferation, migration and invasion in melanoma cell line A375. These results suggested that NOVA1 acted as an oncogene in the development of melanoma partly through regulating FoxO3A expression.

HULC: an oncogenic long non-coding RNA in human cancer.

Highly up-regulated in liver cancer (HULC) was originally identified as the most overexpressed long non-coding RNA in hepatocellular carcinoma. Since its discovery, the aberrant up-regulation of HULC has been demonstrated in other cancer types, including gastric cancer, pancreatic cancer, osteosarcoma and hepatic metastasis of colorectal cancer. Recent discoveries have also shed new light on the upstream molecular mechanisms underlying HULC deregulation. As an oncogene, HULC promotes tumorigenesis by regulating multiple pathways, such as down-regulation of EEF1E1, promotion of abnormal lipid metabolism, and up-regulation of sphingosine kinase 1. Pertinent to clinical practice, a genetic variant in the HULC gene has been found to alter the risk for hepatocellular carcinoma and oesophageal cancer, whereas cancer patients with high or low expression of HULC exhibit different clinical outcome. These findings highlighted the pathogenic role and clinical utility of HULC in human cancers. Further efforts are warranted to promote the development of HULC-directed therapeutics.

Upregulation of SYF2 is associated with neuronal apoptosis caused by reactive astrogliosis to neuroinflammation.

SYF2, known as CCNDBP1-interactor or p29, is likely involved in pre-mRNA splicing and cell cycle progression. The present study was designed to elucidate dynamic changes in SYF2 expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that SYF2 expression was induced strongly in active astrocytes after LPS injection. In vitro studies showed that the upregulation of SYF2 might be involved in the activation of C6 cells after LPS challenge and the neuronal apoptosis after conditioned media challenge. In addition, with silencing of SYF2 in C6 and PC12 cells by siRNA, the results indicated that SYF2 was required for astrocyte activation and neuronal apoptosis induced by LPS. Our findings on the cellular signaling pathway may provide a new therapeutic strategy against neuroinflammation in the CNS.

Localized pagetoid reticulosis (Woringer-Kolopp disease) completely response to NB-UVB combined with IFN.

A cutaneous lymphoproliferative disorder, localized pagetoid reticulosis (LPR), is rare but distinctive in its clinical and histopathological manifestations. Without an evidence-based medicine treatment guideline because of extremely low incidence, LPR poses a therapeutic challenge. We describe a 67-year-old Chinese woman with LRP who showed complete response to narrow-band ultraviolet B combined with intramuscular interferon alpha-2b.

[Combined therapy of psoralen plus ultraviolet A followed by narrow band ultraviolet B photochemotherapy for early stage mycosis fungoides].

OBJECTIVE: Only a few clinical reports in the treatment of early mycosis fungoides (MF)(IA, IB, IIA stage) are available in the literature. The purpose of this study was to compare the efficacy and safety of narrow-band UVB and psoralen plus ultraviolet A (PUVA) photochemoterapy in 24 patients with early-stage MF, and explore a new approach for the treatment of early mycosis fungoides. METHODS: A total of 24 identified early mycosis fungoides patients received PUVA, NB-UVB and a combined therapy of PUVA followed by NB-UVB (n = 9/6/9) irradiation. A retrospective study was carried out to analyze the sex, age of onset, TNM stage, treatment, and duration of treatment, and times of treatment, duration of maintenance treatment, effective and recurrence in these patients. The data were analyzed using SPSS 17.0 and a two-sided test at the α = 0.05 level of significance was conducted. RESULTS: Of the 24 patients studied, the average treatment was 104.5 (95% CI, 75.71-133.29) times. The average duration of treatment was 12.88 (95% CI, 9.90-15.85) months. The average maintenance treatment time was 11.08 (95% CI, 2.13-20.04) months. The effective rate (CR+PR) of PUVA treatment was 88.9%, recurrence rate was 11.1% (n = 9). In the NB-UVB treatment group, the effective rate was 100.0%, and the recurrence rate was 33.3% (n = 6). In the PUVA followed by NB-UVB (combination therapy) treatment group, the effective rate was 77.8% and the recurrence rate was 55.6% (n = 9). There were no significant differences among the three groups in terms of number of treatments, treatment duration, maintenance treatment duration, effective rate and recurrence rate (P > 0.05). CONCLUSIONS: PUVA and NB-UVB are effective and safe in the targeted therapy of early stage mycosis fungoides. The combined therapy of PUVA followed by NB-UVB can reduce the total PUVA dose and risk of developing skin cancer.

[Detection of polA gene in whole blood samples and preliminary observations with molecular subtyping of Treponema pallidum].

OBJECTIVE: To detect Treponema pallidum (T.pallidum) DNA with polymerase chain reaction (PCR) in whole blood samples of syphilis patients and analyze their features of sub-genotypes. METHODS: The clinical data of patients were collected from July 2012 to February 2013. And polA gene of syphilis was detected by PCR. The arp and tpr genes of polA gene-positive samples were analyzed by the established genotyping system.Statistical analyses were performed to compare different clinical courses and features to examine their correlations. RESULTS: The common treponemal gene target (polA) of 35 samples were detected in whole blood by PCR in 181 samples. A total of 24 cases (35.8%) were positive in 67 patients with newly diagnosed non-latent syphilis untreated patients;26 cases of latent syphilis were negative;7 cases (9.7%) were positive in 72 subsequent visit patients;4 cases (25.0%) were positive in 16 patients with sero-resistant. There were 4 subtypes of 14a (n = 7), 14b (n = 10), 13c (n = 4) and 14d (n = 14). Among those positive samples, there were 4 sero-resistant samples of 3 subtypes 14d and 1 subtype 14b. CONCLUSIONS: The feasibility of peripheral blood is confirmed. Although the positive rate of whole blood detection of T.pallidum gene is low, the method is both simple and reliable for patients with sero-resistant syphilis.

[Retrospective analysis of 50 cases of senile syphilis].

OBJECTIVE: To summarize the epidemiological features of senile syphilis. METHOD: The clinical data of 50 elderly (>60 years) patients with syphilis who were treated in the Clinic of Sexually Transmitted Diseases of Peking Union Medical College Hospital were retrospectively analyzed. RESULTS: There were 31 men and 19 women (male to female ratio:1.6:1). Non-marital sexual intercourse was the main route of transmission. The disease was mainly found before surgeries. Among these 50 syphilis cases, 3 were primary syphilis, 13 were secondary syphilis, 10 were early latent syphilis, 12 were late latent syphilis, and 12 were latent syphilis of unknown duration. Co-morbidities with other sexually transmitted diseases were found in 4 patients. The rate of sero-resistance was 40%. CONCLUSIONS: The incidence of syphilis in the senile population is higher than we expected. Routine serological screening for syphilis is required in clinical settings. The underlying diseases, human hosts-related spirochetes, and laboratory testing techniques are important reasons for the false positive findings in senile patients.

Post-marketing safety concerns with abrocitinib: a real-world pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: Abrocitinib was newly approved for treatment of moderate-to-severe atopic dermatitis. The present study was to assess abrocitinib-related adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of abrocitinib-related AEs. RESULTS: A total of 3,177,744 reports of AEs were collected from the FAERS database, of which 1370 reports were identified with abrocitinib as the primary suspect drug. Abrocitinib-induced adverse events (AEs) occurred across 27 system organ classes (SOCs). A total of 68 preferred terms (PTs) with significant disproportionality, meeting the criteria of all four algorithms simultaneously, were identified. Unexpected significant AEs, such as increased blood cholesterol, venous embolism, hypoacusis, cellulitis, and tuberculosis, might also occur. The median onset time for abrocitinib-associated AEs was 182 days (interquartile range [IQR] 47-527 days). CONCLUSIONS: The results of this study were consistent with clinical observations. Additionally, unexpected safety signals for abrocitinib were identified, which provided supportive information for the safety profile of abrocitinib. Prospective clinical studies are warranted to validate these findings.

Diagnosing Tabes Dorsalis in HIV-Negative Patients: Clinical Features, Neuroimaging, and Laboratory Insights in the Modern Antibiotic Era.

Background: Tabes dorsalis is a late manifestation of neurosyphilis, characterized by progressive ataxia, lightning pains, loss of proprioception, and urinary incontinence. The absence of a definitive diagnostic standard and the non-specific clinical manifestations have led to a significant rate of misdiagnoses. Methods: Hospitalized patients with tabes dorsalis at Peking Union Medical College Hospital between January 2010 and December 2023 were reviewed. Results: A total of 13 patients were included, with 10 males and 3 females. The median age was 50 years (range, 34-64). The most frequent initial symptoms were limb numbness (30.8%) and lightning pains (30.8%). Eleven patients (84.6%) received misdiagnoses prior to the final diagnosis. The most frequently observed physical sign was positive Romberg's sign (84.6%). Notably, Argyll Robertson pupil was presented in 7 subjects (53.8%). Serological tests revealed positive rapid plasma regain (RPR) and Treponema pallidum particle agglutination (TPPA) for all patients. All CSF samples were TPPA-reactive. Intramedullary hyperintensity on T2-weighted imaging of spinal MRI was found in 5 patients (38.5%). All patients received anti-syphilitic treatment, with effective treatment recorded in five cases. Conclusion: This study underscores the importance of neurological symptoms and signs in diagnosing tabes dorsalis. Individuals with progressive ataxia and positive Romberg's sign should be closely monitored for potential neurosyphilis. Integrating clinical features, laboratory tests, and neuroimaging could reduce misdiagnosis and expedite the initiation of anti-syphilitic therapy.

Large-Scale Proteome Profiling Identifies Biomarkers Associated with Suspected Neurosyphilis Diagnosis.

Neurosyphilis (NS) is a central nervous system (CNS) infection caused by Treponema pallidum (T. pallidum). NS can occur at any stage of syphilis and manifests as a broad spectrum of clinical symptoms. Often referred to as "the great imitator," NS can be easily overlooked or misdiagnosed due to the absence of standard diagnostic tests, potentially leading to severe and irreversible organ dysfunction. In this study, proteomic and machine learning model techniques are used to characterize 223 cerebrospinal fluid (CSF) samples to identify diagnostic markers of NS and provide insights into the underlying mechanisms of the associated inflammatory responses. Three biomarkers (SEMA7A, SERPINA3, and ITIH4) are validated as contributors to NS diagnosis through multicenter verification of an additional 115 CSF samples. We anticipate that the identified biomarkers will become effective tools for assisting in diagnosis of NS. Our insights into NS pathogenesis in brain tissue may inform therapeutic strategies and drug discoveries for NS patients.

Up-regulation of NFATc4 involves in neuronal apoptosis following intracerebral hemorrhage.

Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcriptional factor, is involved in the control about the flow of genetic information and the modulation of diverse cellular activities. Accumulating evidence has demonstrated that NFATc4 exerted a pro-apoptotic effect in multiple diseases. Here, we explored the NFATc4's roles during the pathophysiological processes of intracerebral hemorrhage (ICH). An ICH rat model was built and evaluated according to behavioral testing. Using Western blot, immunohistochemistry, and immunofluorescence, significant up-regulation of NFATc4 was found in neurons in brain areas surrounding the hematoma following ICH. Increasing NFATc4 expression was found to be accompanied by the up-regulation of Fas ligand (FasL), active caspase-8, and active caspase-3, respectively. Besides, NFATc4 co-localized with active caspase-3 in neurons, indicating its role in neuronal apoptosis. Our in vitro study, using NFATc4 RNA interference in PC12 cells, further confirmed that NFATc4 might exert its pro-apoptotic function in neuronal apoptosis through extrinsic pathway. Thus, NFATc4 may play a role in promoting the brain secondary damage following ICH.

Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study.

RESULTS: The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.

Clinical and Laboratory Characteristics, Neuroimaging Alternations and Treatment Response of 25 HIV-Negative General Paresis Patients.

Purpose: General paresis is a common type of neurosyphilis featuring progressive cognitive deterioration. The lack of a golden standard of diagnosis and its nonspecific clinical manifestations resulted in a high rate of misdiagnoses. This study aims to investigate the clinical, laboratory and radiological presentations of general paresis and enrich its knowledge for timely diagnoses. Patients and methods: The study collected hospitalized patients admitted for general paresis from September 2002 to November 2022. Their socio-demographical and medical status, clinical presentations, cognitive assessments, laboratory and radiographical manifestations and treatment information were collected retrospectively. Results: A total of 20 males and 5 females were included. Patients' ages ranged from 30 to 66 years (average 50.3 years). The average and median time for diagnosing general paresis was 14.1 months and 10.0 months respectively. The most frequent initial symptom is memory deterioration (68.0%). Impaired calculative ability and memory deterioration were the most frequent cognitive anomalies, as found in 50% and 45.4% of subjects during examination. The mean and median scores of MoCA was 16.7 and 17 respectively. Serological tests revealed positive TPPA for all patients and a median RPR titer at 1:64 positive. All CSF samples with TPPA and FTA-ABS results reported positivity. The MRI manifestations of general paresis include patchy or speckled hyperintensities (70.8%) and cerebral atrophy (45.8%). The most common lesioned sites in MRI were the ventricular and paraventricular area (50.0%) and temporal lobes (45.8%). For treatment, penicillin-based anti-syphilitic plans were adopted in 17 patients (68.0%). Conclusion: The clinical features and radiological alternations of general paresis patients often exhibited diverse and nonspecific alternations. However, some specific clinical manifestations and auxiliary examinations can provide meaningful clues for the identification and differential diagnosis of this disease.