Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers.

This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.

Causal association between sleep traits and autoimmune arthritis: Evidence from a bidirectional Mendelian randomization study.

OBJECTIVE: To explore whether there is a genetic causal relationship between sleep traits and the risk of autoimmune arthritis (AA). METHODS: Univariable and multivariable Mendelian randomization was employed using genome-wide association studies data to assess sleep traits' associations with AAs, including rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. The inverse-variance weighted method served as the primary analysis, supplemented by the CAUSE method to improve power and mitigate false positives. Mediation Mendelian randomization was used to quantify direct and indirect effects. RESULTS: Significant associations were shown between insomnia symptoms and increased risk of overall RA (odds ratio = 2.75, 95% confidence interval 1.45-5.22) and seronegative RA (odds ratio = 6.95, 95% confidence interval 2.47-19.56). CAUSE results revealed an association of insomnia symptoms with overall RA and seronegative RA, as well as the sleep duration with overall RA. After the adjustment for body mass index, alcohol status, smoking status, and physical activity levels, multivariable analyses revealed that genetic predisposition to insomnia symptoms and prolonged sleep duration showed independent negative associations with the risk of overall RA and seropositive RA. In the reversed multivariable analyses, a borderline negative association was shown in the overall RA-sleep duration and a positive association of seropositive RA with the risk of insomnia symptoms. CONCLUSION: This study demonstrated a potential bidirectional causal relationship that genetic predisposition to insomnia symptoms and shorter sleep duration was associated with the risk of AA, especially RA. Genetic predisposition to RA was also associated with decreased sleep duration, as well as increased insomnia symptom risk.

Childhood sunburn and risk of melanoma and non-melanoma skin cancer: a Mendelian randomization study.

Previous evidence has suggested that childhood sunburn could be a risk factor for cutaneous malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, existing observational studies could not reveal the causal associations genetically. This study aimed to investigate whether there was a genetic causal relationship between childhood sunburn and skin cancers. Univariable Mendelian randomization (MR) and Causal Analysis Using Summary Effect analysis was carried out for causal estimates and evaluation for the horizontal pleiotropy. Multivariable MR and the mediation effects analysis were used to test whether the causal associations were mediated by potential confounders. A suggestively significant causal association between childhood sunburn and MM was indicated (OR = 4.74; 95% CI: 1.31-17.19; p = 1.79E-02). Genetically predicted childhood sunburn was significantly associated with increased risk of overall melanoma in situ (MIS) (OR = 4.02; 95% CI: 2.00-8.08; p = 9.40E-05), MIS of face (OR = 18.28; 95% CI: 5.28-63.35; p = 4.59E-06), and MIS of trunk (OR = 7.05; 95% CI: 2.06-24.13; p = 1.88E-03). Similar trends were found for childhood sunburn and NMSC (OR = 8.16; 95% CI: 6.07-10.99; p = 1.53E-20), including both basal cell carcinoma (BCC) (OR = 3.76; 95% CI:2.96-4.77; p = 2.19E-08) and squamous cell carcinoma (SCC) (OR = 7.44; 95% CI: 5.09-10.87; p = 2.19E-08). After adjustment for hair and skin color, facial ageing, vitamin D levels, body mass index, alcohol consumption, and smoking status, childhood sunburn showed an independent association with MIS, MIS of face, MIS of trunk, as well as NMSC, including both BCC and SCC. Mediation analysis showed no significant mediation effect. This study demonstrated a causal relationship between childhood sunburn and the risk of both MM and NMSC, which suggested that enhanced screening and prevention for childhood sunburn could contribute to the early detection and decreased risk of MM and NMSC.

Causal association of leisure sedentary behavior with arthritis: A Mendelian randomization analysis.

OBJECTIVES: This study aimed at exploring the potential causal effects of leisure sedentary behavior (LSB) on common types of arthritis. METHOD: Two-sample Mendelian randomization (MR), including both univariable MR (UVMR) and multivariable MR (MVMR) analysis, was performed to explore the effects of LSB on the risk of several common types of arthritis, including osteoarthritis, rheumatoid arthritis (RA), and psoriatic arthritis (PsA). Genetic variants from genome-wide association studies (GWAS) of LSBs for time spent on television watching, computer use, and driving were obtained from the UK Biobank. Summarized GWAS data of OA [overall, OA of the hip (HOA), and OA of the knee (KOA)], RA [overall, seronegative RA (nRA) and seropositive RA], and PsA was also acquired from the FinnGen Biobank Analysis. Causal Analysis Using Summary Effect Estimates (CAUSE) were further applied to verify the causality. RESULTS: UVMR results provided evidence for the causal relationship of time spent on watching TV with overall OA [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.45-2.23], KOA (OR = 1.86, 95% CI = 1.45-2.39) and HOA (IVW-fixed: OR = 1.65, 95% CI =1.20-2.26). Similar associations were observed in the TV-overall RA and TV-pRA, and TV-PsA, but the CAUSE method results only supported the causal association of time spent TV watching with OA and KOA. Moreover, MVMR results showed indicated an independent causal effect of TV watching on OA (overall, KOA, and HOA). CONCLUSION: This study demonstrated the genetic causal association of prolonged TV watching time with overall OA and KOA risks.

The causal association of polyunsaturated fatty acids with allergic disease: A two-sample Mendelian randomization study.

Objectives: Previous studies have reported a potential association of polyunsaturated fatty acids (PUFAs) levels with allergic disease risk and the possible benefit of PUFAs supplementation on allergic disease prevention. This study was performed to estimate the genetic association between PUFAs and allergic diseases using the method of both univariable and multivariable two-sample Mendelian randomization (MR). Methods: As indicators of the PUFAs levels, we included the omega-3, omega-6, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA), and the ratio of omega-6 to omega-3 (omega-6:3). Summarized statistics of genome-wide association studies (GWASs) for these PUFAs were obtained from the United Kingdom Biobank and the Twins United Kingdom cohort. Genetic data relating to allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), allergic urticaria (AU) and asthma, were accessed from the FinnGen biobank analysis. Odds ratios and 95% CIs were used to express the impact. Results: The MR results denoted a genetic association between the genetically determined increase in omega-3 levels and the decreased risk of some allergic diseases including AD (OR: 0.863; 95% CI: 0.785 to 0.949; p = 3.86E-03), AC (OR:0.720; 95% CI: 0.547 to 0.947; p = 1.87E-02) and AU (OR:0.821; 95% CI: 0.684 to 0.985; p = 3.42E-02), while omega-6 and DHA level was only found to have negatively correlation with risk of AC with ORs of 0.655 (95% CI: 0.445 to 0.964; p = 3.18E-02) and 0.671 (95% CI 0.490 to 0.918; p = 1.25E-02), respectively. Omega-6:3 were causally significantly associated with the increased risk of AD (OR:1.171; 95% CI: 1.045 to 1.312; p = 6.46E-03) and AC (IVW: OR:1.341; 95% CI: 1.032 to 1.743; p = 2.83E-02). After adjustment of age, economic level, BMI, smoking and alcohol behaviors in the multivariable MR analysis, a direct causal protective effect of omega-3 on AD and AC, as well as a direct causal association between DHA and AD were observed. Omega-6:3 was also found to be directly associated with an increased risk of AD and AC. No association was found of EPA or LA with allergic diseases. Conclusion: Higher PUFA concentrations (omega-3, omega-6, DHA) and lower omega-6:3 ratios were genetically associated with a lower risk of some allergic diseases.

Optimal administration strategies of tranexamic acid to minimize blood loss during spinal surgery: results of a Bayesian network meta-analysis.

BACKGROUND: Tranexamic acid (TXA) has been widely used for bleeding reduction in spinal surgery. Available evidence is insufficient to inform clinical decisions making and there remains a lack of comprehensive comparisons of dose regimens and delivery routes. This study is aimed to assess and compare different strategies regarding the involvement of TXA in spinal surgery for the optimal pathway of efficacy and safety. MATERIALS AND METHODS: Cochrane Library, PubMed, Embase, Scopus and CNKI were searched for the period from January 1990 to October 2021. A random-effect model was built in the Bayesian network meta-analysis. The surface under the cumulative ranking analysis (SUCRA) and clustering rank analysis was performed for ranking the effects. RESULTS: The current network meta-analysis incorporated data from 33 studies with 3302 patients. Combination administration showed superior effects on reducing intraoperative bleeding (SUCRA 78.78%, MD -129.67, 95% CI [(-222.33, -40.58)]) than placebo, and was ranked as top in reducing postoperative bleeding (SUCRA 86.91%, MD -169.92, 95% CI [(-262.71, -83.52)]), changes in haemoglobin (SUCRA 97.21%, MD -1.28, 95% CI [(-1.84, -0.73)]), and perioperative blood transfusion (SUCRA 93.23%, RR 0.10, 95% CI [(0.03, 0.25)]) simultaneously, and was shown as the best effectiveness and safety (cluster-rank value for IBL and VTE: 4057.99 and for TRF and VTE: 4802.26). CONCLUSIONS: Intravenous (IV) plus topical administration of TXA appears optimal in the reduction of perioperative bleeding and blood transfusion, while the local infiltration administration is not effective for blood conservation. Further studies are required to verify the current findings.

Optimal Biologic Drugs for the Treatment of Ankylosing Spondylitis: Results from a Network Meta-Analysis and Network Metaregression.

Background: Ankylosing spondylitis (AS) is a common immune-related systemic chronic inflammatory osteoarthropathy. Previous studies have proven that biologic agents, including IL-17A inhibitors (IL17Ai), TNF-α inhibitor FC fusion protein (TNFiFCP), or fully human monoclonal antibody (TNFiNMA) and JAK inhibitor (JAKi), are effective for AS treatment. Our study is aimed at comparing the clinical efficacy, tolerability, and safety of different biological agents, including novel IL-6 inhibitor (IL6i), IL-23 inhibitor (IL23i), and IL-17 A/F dual variable domain inhibitor (IL17AFi) in AS. Method: PubMed, Scopus, Embase, CNKI, and the Cochrane Library were systematically searched. A frequentist framework network meta-analysis with a random-effects model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and cluster-rank analysis. Results: IL17AFi reported both the highest ASAS40 (SUCRA = 91.4%) and ASAS20 (SUCRA = 92.5%) response, while IL6i and IL23i reported the lowest responses (SUCRA = 6.6% and 19.9%, respectively). With the exceptions of IL6i (RR 0.60, 95% CI (0.22 to 1.67) for ASAS40 and 1.36 (0.71 to 2.58) for ASAS20) and IL23i (0.98 (0.68 to 1.40) for ASAS40 and 0.91 (0.70 to 1.19) for ASAS20), all biological drugs demonstrated statistically superior ASAS responses than placebo. TNFiFMA performed best in the suppression of disease activity (SUCRA = 77.4%, SMD 2.35, and 95% CI (1.11 to 3.59)) and functional improvement (SUCRA = 68.8%, SMD 1.67, and 95% CI (0.59 to 2.74)). There were no significant differences in tolerability or safety between biologic drugs and placebo. Conclusions: The novel IL-17 A/F dual variable domain inhibitor, bimekizumab, may be an ideal future treatment choice for AS, while IL-23 and IL-6 inhibitors demonstrate little potential in the treatment of AS. For patients with rapid disease progression and severe functional limitation, TNF-α inhibitors, especially infliximab, are safe and effective and could be a first-line treatment choice.

Causal Association Between Inflammatory Bowel Disease and Psoriasis: A Two-Sample Bidirectional Mendelian Randomization Study.

Background: Previous observational studies have found an association between inflammatory bowel disease (IBD) and psoriasis. Using the mendelian randomization (MR) approach, we aim to determine whether there was a causal association between IBD and psoriasis. Methods: We performed a two-sample MR with the genetic instruments identified for IBD and its main subtypes, Crohn's disease (CD) and ulcerative colitis (UC), from a genome-wide association study (GWAS) involving 25,042 cases with an IBD diagnosis and 34,915 controls. Summarized data for psoriasis were obtained from different GWAS studies which included 4510 cases and 212,242 controls without psoriasis. Causal estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results: The overall outcome of MR analysis was to demonstrate that genetic predisposition to IBD was associated with an increased risk of psoriasis (OR: 1.1271; 95% CI: 1.0708 to 1.1864). Psoriatic arthritis (PsA) had a significant association with total IBD (OR: 1.1202; 95% CI: 1.0491 to 1.1961). Casual relationship was also identified for CD-psoriasis (OR: 1.1552; 95% CI: 1.0955 to 1.2182) and CD-PsA (OR: 1.1407; 95% CI: 1.0535 to 1.2350). The bidirectional analysis did not demonstrate that a genetic predisposition to psoriasis was associated with total IBD, although psoriasis showed association with CD (OR: 1.2224; 95% CI: 1.1710 to 1.2760) but not with UC. A genetic predisposition to PsA had a borderline association with IBD (OR: 1.0716; 95% CI: 1.0292 to 1.1157) and a suggestive association with CD (OR: 1.0667; 95% CI: 1.0194 to 1.1162). Conclusion: There appears to be a causal relationship between IBD and psoriasis, especially for PsA, but for psoriasis and IBD, only total psoriasis and PsA were associated with CD. Understanding that specific types of psoriasis and IBD constitute mutual risk factors facilitates the clinical management of two diseases.

Assessment of efficacy and safety of UV-based therapy for psoriasis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have proven that ultraviolet (UV)-based phototherapy, including UVB or psoralen UVA (PUVA), and their combination therapies, is effective for psoriasis treatment. OBJECTIVE: To compare the clinical efficacy and adverse events (AEs) of different UV-based phototherapy in psoriasis. METHODS: PubMed, Cochrane Library, Scopus and Embase were systematically searched. A random-effect model network meta-analysis with frequentist framework was performed, and results were reported as risk ratios (RRs) with 95% CI. The main variable for assessing effectiveness and safety are PASI 75 response and withdrawal due to AEs. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA). RESULTS: Thirty-two studies involving a total of 2120 psoriasis patients were included in this network meta-analysis. Overall, no significant difference was reported with respect to withdrawal due to AEs or incidence of erythema. The relatively safest strategy was combined adjuvant therapy with PUVA (cPUVA), especially PUVA combined with calcium/vitamin D derivatives (RR 0.98, 95% CI [0.30-3.17], SUCRA = 80.8%). Both cPUVA (RR 1.39, 95% CI [1.00- 1.94]) and combined adjuvant therapy with UVB (cUVB) (RR 1.27, 95% CI [1.03-1.57]) showed a superior effect than the monotherapy of UVA or UVB, respectively. PUVA combined with vitamin D and its derivatives (PAVD) ranked highest concerning clinical effect and safety (clusterank value = 7393.2). CONCLUSIONS: The efficacy of all the combination therapy regimens was significantly superior to that of UV monotherapy, without significant differences in tolerability and safety. cUVB and cPUVA, and particularly the combination of UVA with calcium/vitamin D derivatives, was ranked as the overall safest and most effective phototherapy method.

Mesenchymal Stem Cells: A New Choice for Nonsurgical Treatment of OA? Results from a Bayesian Network Meta-Analysis.

OBJECTIVE: Osteoarthritis (OA) is the most common degenerative joint disease, causing joint pain, stiffness, and even disability. Guidelines recommend intra-articular injections as an alternative treatment to relieve OA symptoms for patients who demonstrate poor tolerability or compliance to oral administration of drugs. Mesenchymal stem cells (MSCs) are a potential treatment for of OA. We conducted this network meta-analysis to comprehensively compare the efficacy and safety between hyaluronic acid (HA), corticosteroids (GCs), platelet-rich plasma (PRP), and MSCs. DESIGN: Systematic review and Bayesian network meta-analysis. Data Sources. Relevant studies, published from January 2000 to January 2020, in the PubMed, Cochrane library, EMBASE, and CKNI databases. METHODS: Bayesian network and conventional meta-analyses were conducted. Pain relief, functional improvement, improvement in joint stiffness, and risk of adverse effects (AEs) were assessed. RESULTS: Twenty-five articles with 4642 patients were included. Overall, MSC therapy was the most effective treatment for pain relief (standardized mean difference compared with placebo = 3.61, 95% CI [1.87 to 5.35]). Both MSC and PRP therapies improved every symptom of OA effectively and have an advantage over HA and GCs which are recommended by guidelines. MSCs, PRP, HA, and GCs are tolerated well for patients in long-term treatment of OA compared with placebo. CONCLUSIONS: The results show that MSCs relieve pain, stiffness, and dysfunction due to OA better than PRP, HA, and GCs and are not statistically correlated with greater safety concerns. More high-quality trials are needed to reconfirm the findings of this study, however, standardization of preparation of MSCs and PRP should be investigated in the future.

Tussilagone Inhibits Osteoclastogenesis and Periprosthetic Osteolysis by Suppressing the NF-κB and P38 MAPK Signaling Pathways.

BACKGROUND: Aseptic prosthetic loosening is one of the main factors causing poor prognosis of limb function after joint replacement and requires troublesome revisional surgery. It is featured by wear particle-induced periprosthetic osteolysis mediated by excessive osteoclasts activated in inflammatory cell context. Some natural compounds show antiosteoclast traits with high cost-efficiency and few side effects. Tussilagone (TUS), which is the main functional extract from Tussilago farfara generally used for relieving cough, asthma, and eliminating phlegm in traditional medicine has been proven to appease several RAW264.7-mediated inflammatory diseases via suppressing osteoclast-related signaling cascades. However, whether and how TUS can improve aseptic prosthetic loosening via modulating osteoclast-mediated bone resorption still needs to be answered. METHODS: We established a murine calvarial osteolysis model to detect the preventative effect of TUS on osteolysis in vivo. Micro-CT scanning and histomorphometric analysis were used to determine the variation of bone resorption and osteoclastogenesis. The anti-osteoclast-differentiation and anti-bone-resorption bioactivities of TUS in vitro were investigated using bone slice resorption pit evaluation, and interference caused by cytotoxicity of TUS was excluded according to the CCK-8 assay results. Quantitative polymerase chain reaction (qPCR) analysis was applied to prove the decreased expression of osteoclast-specific genes after TUS treatment. The inhibitory effect of TUS on NF-κB and p38 MAPK signaling pathways was testified by Western blot and NF-κB-linked luciferase reporter gene assay. RESULTS: TUS better protected bones against osteolysis in murine calvarial osteolysis model with reduced osteoclasts than those in the control group. In vitro studies also showed that TUS exerted antiosteoclastogenesis and anti-bone-resorption effects in both bone marrow macrophages (BMMs) and RAW264.7 cells, as evidenced by the decline of osteoclast-specific genes according to qPCR. Western blotting revealed that TUS treatment inhibited IκBα degradation and p38 phosphorylation. CONCLUSIONS: Collectively, our studies proved for the first time that TUS inhibits osteoclastogenesis by suppressing the NF-κB and p38 MAPK signaling pathways, therefore serving as a potential natural compound to treat periprosthetic osteolysis-induced aseptic prosthetic loosening.

Oxygen embolism after hydrogen peroxide irrigation during hip arthroscopy: a case report.

BACKGROUND: Hydrogen peroxide has been widely used in Orthopaedics including Orthopaedic oncology, trauma and joint surgeries. However, we encountered an oxygen embolism and myoglobinuria after hydrogen peroxide was used to irrigate a septic hip arthroscopically. CASE PRESENTATION: A 61-year-old male patient with right hip septic arthritis underwent an arthroscopic hip washout and debridement. During the operation, the surgeon used 100 ml of 3% hydrogen peroxide to irrigate the joint cavity. Two minutes after irrigation, there was a transient decrease in oxygen saturation, heart rate and blood pressure, with significant subcutaneous emphysema around the wound. Concentrated urine was drained out 8 h after operation which resolved the following day. Post-operatively, the patient was managed in the intensive care unit for a pulmonary embolism and discharged without further complications. CONCLUSION: Medical staff should be aware of the risk of oxygen embolism and be extremely careful when using hydrogen peroxide in patient care. Oxygen embolism following hydrogen peroxide use is rare, however, once encountered, it may bring serious consequences. Therefore, the use of hydrogen peroxide in closed spaces or arthroscopic procedures should be discontinued.

Prognostic relevance of SMC family gene expression in human sarcoma.

OBJECTIVE: To explore the prognostic value of the expression of genes encoding structural maintenance of chromosomes (SMCs) in human sarcoma. RESULTS: We found that the levels of SMC1A, SMC2, SMC3, SMC4, SMC5 and SMC6 mRNA were all higher in most tumors compared to normal tissues, and especially in sarcoma. According to the Cancer Cell Line Encyclopedia (CCLE), SMC1A, SMC2, SMC3, SMC4, SMC5 and SMC6 are also highly expressed in sarcoma cell lines. Results of Gene Expression Profiling Interactive Analysis (GEPIA) indicated that high expression of SMC1A was significantly related to poor overall survival (OS) (p<0.05) and disease-free survival (DFS) in sarcoma (p<0.05). Additionally, strong expression of SMC2 was significantly related to poor OS in sarcoma (p<0.05). In contrast, SMC3, SMC4, SMC5, and SMC6 expression had no significant impact on OS or DFS in sarcoma. CONCLUSIONS: Expression of SMC family members is significantly different in sarcoma relative to normal tissues, and SMC1A and SMC2 may be useful as prognostic biomarkers. METHODS: We performed a detailed comparison of cancer and normal tissues regarding the expression levels of mRNA for SMC family members in various cancers including sarcoma through ONCOMINE and GEPIA (Gene Expression Profile Interactive Analysis) databases.