Associations of Gut and Circulating Microbiota with Circulating Vitamin D3, Type I Interferon, and Systemic Inflammation in Chronic Spontaneous Urticaria Patients.

Objective: To analyze the associations of the gut and circulating microbiota with circulating vitamin D3 (VD3), type I interferon (IFNI), systemic inflammation, and clinical profiles in chronic spontaneous urticaria (CSU) patients. Methods: A total of 36 CSU patients with VD3 insufficiency (VDI; serum 25(OH)VD3 <30 ng/mL) and 36 sex-, age-, and body mass index-matched CSU patients with non-VDI were enrolled. Fecal and serum bacteria were identified through 16S rRNA sequencing, and serum 25(OH)VD3 and inflammation biomarkers were assessed using ELISA kits. IFNI response was determined by measuring the stimulatory activity of serum on IFNI-stimulated response element in HEK293 cells in vitro with luciferase assays. Results: Higher urticarial activity score over 7 days (UAS7), higher frequency of levocetirizine resistance, and more severe proinflammation but weaker IFNI response were observed in VDI than non-VDI patients (all P<0.05). IFNI response was strongly positively associated with serum 25(OH)VD3 level in both groups (P<0.001). Compared to non-VDI patients, abundance of the fecal genera Prevotella 9, Escherichia-Shigella, and Klebsiella was significantly increased, while Bacteroides, Faecalibacterium, and Agathobacter were remarkably reduced in VDI patients (all P<0.05). Burkholderia-Caballeronia-Paraburkholderia (40.95%), Acinetobacter (3.05%), and Aquabacterium (2.37%) were the top three bacteria in sera from VDI patients. Both serum 25(OH)VD3 level and IFNI response were positively associated with fecal Bacteroides in the two groups (P<0.05). In non-VDI patients, there were moderately positive associations between IFNI response and fecal Lachnoclostridium, unclassified_f__Lachnospiraceae, and Phascolarctobacterium and between serum 25(OH)VD3 level and fecal Lachnoclostridium (all P<0.01). Circulating microbiota in VDI patients was closely related only to proinflammation and UAS7 (both P<0.05). Conclusion: Changes in gut but not circulating microbiota composition are associated with serum 25(OH)VD3 insufficiency and impaired IFNI homeostasis, which points to greater disease severity (UAS7) and systemic proinflammation in CSU patients.

The diversity of inhibitory receptor co-expression patterns of exhausted CD8+ T cells in oropharyngeal carcinoma.

Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Prognostic effects of different treatment modalities for hypopharyngeal squamous cell carcinoma: Experience of two tertiary hospitals in Southwestern China.

Background: The prognostic effects of different treatment modalities on patients with hypopharyngeal squamous cell carcinoma (HPSCC) remain unclear. Methods: HPSCC patients diagnosed and treated at either West China Hospital or Sichuan Cancer Hospital between January 1, 2009, and December 31, 2019, were enrolled in this retrospective, real-world study. Survival rates were presented using Kaplan-Meier curves and compared using log-rank tests. Univariable and multivariable Cox proportional hazards regression models were used to identify the predictors of overall survival (OS). Subgroup analyses were conducted for patients with advanced-stage HPSCC (stages III and IV and category T4). Results: A total of 527 patients with HPSCC were included. Patients receiving SRC (surgery, radiotherapy [RT], and chemotherapy) showed the best OS (p < 0.0001). In comparison with RT alone, both surgery alone (all cases: hazard ratio [HR] = 0.39, p = 0.0018; stage IV cases: HR = 0.38, p = 0.0085) and surgery-based multimodality treatment (SBMT; all cases: HR = 0.27, p < 0.0001; stage IV cases: HR = 0.30, p = 0.00025) showed prognostic benefits, while SBMT also showed survival priority over chemoradiotherapy (CRT; all cases: HR = 0.52, p < 0.0001; stage IV cases: HR = 0.59, p = 0.0033). Moreover, patients who underwent surgery alone had comparable OS to those who underwent SBMT (all patients: p = 0.13; stage IV cases: p = 0.34), while CRT yielded similar prognostic outcomes as RT alone (all patients: p = 0.054; stage IV cases: p = 0.11). Conclusions: Surgery alone was comparable to SBMT and superior to RT/CRT in terms of OS in patients with HPSCC. We suggest that surgery should be encouraged for the treatment of HPSCC, even in patients with advanced-stage disease.

Multiobjective tree-based reinforcement learning for estimating tolerant dynamic treatment regimes.

A dynamic treatment regime (DTR) is a sequence of treatment decision rules that dictate individualized treatments based on evolving treatment and covariate history. It provides a vehicle for optimizing a clinical decision support system and fits well into the broader paradigm of personalized medicine. However, many real-world problems involve multiple competing priorities, and decision rules differ when trade-offs are present. Correspondingly, there may be more than one feasible decision that leads to empirically sufficient optimization. In this paper, we propose a concept of "tolerant regime," which provides a set of individualized feasible decision rules under a prespecified tolerance rate. A multiobjective tree-based reinforcement learning (MOT-RL) method is developed to directly estimate the tolerant DTR (tDTR) that optimizes multiple objectives in a multistage multitreatment setting. At each stage, MOT-RL constructs an unsupervised decision tree by modeling the counterfactual mean outcome of each objective via semiparametric regression and maximizing a purity measure constructed by the scalarized augmented inverse probability weighted estimators (SAIPWE). The algorithm is implemented in a backward inductive manner through multiple decision stages, and it estimates the optimal DTR and tDTR depending on the decision-maker's preferences. Multiobjective tree-based reinforcement learning is robust, efficient, easy-to-interpret, and flexible to different settings. We apply MOT-RL to evaluate 2-stage chemotherapy regimes that reduce disease burden and prolong survival for advanced prostate cancer patients using a dataset collected at MD Anderson Cancer Center.

Going the extra mile for patients: Service-oriented high-performance work systems drive nurses' job crafting and extra-role service behaviour.

AIM: This study intends to investigate whether, how and when service-oriented high-performance work systems (SHPWSs) drive nurses' extra-role service behaviour. DESIGN: This was a quantitative cross-sectional study conducted with matched nurse-patient participants. METHOD: We tested hypotheses using data from 284 nurses and their matched 566 patients. The data were collected in 2019. We conducted a set of hierarchical regression analyses to test our hypotheses. RESULTS: The results showed that SHPWSs have a positive impact on job crafting, which, in turn, mediates the link between SHPWSs and extra-role service behaviours. Additionally, the influence of professional identification moderates these relationships. Specifically, SHPWSs are significantly and positively associated with job crafting among highly professionally identified nurses. The indirect effect is significantly positive when nurses strongly identify with their profession but not significant when their professional identification is low. CONCLUSION: The results indicated that SHPWSs can elicit job crafting among higher professional identifiers, which further increases extra-role service behaviours towards patients. IMPACT: Our research emphasizes the significance of HRM themes in the healthcare service industry and their direct impact on healthcare personnel. Shifting from a management-centric to an individual-centric perspective, we focus on the proactive role of nurses. Furthermore, this study enhances the understanding of the boundary conditions for the effectiveness of SHPWSs. PATIENT OR PUBLIC CONTRIBUTION: Nurses and their mated patients from a Chinese hospital contributed to this study by completing the survey.

High-Pressure Electro-Fenton Driving CH4 Conversion by O2 at Room Temperature.

Electrochemical conversion of CH4 to easily transportable and value-added liquid fuels is highly attractive for energy-efficient CH4 utilization, but it is challenging due to the low reactivity and solubility of CH4 in the electrolyte. Herein, we report a high-pressure electro-Fenton (HPEF) strategy to establish a hetero-homogeneous process for the electrocatalytic conversion of CH4 by O2 at room temperature. In combination with elevation of reactant pressure to accelerate reaction kinetics, it delivers an unprecedented HCOOH productivity of 11.5 mmol h-1 gFe-1 with 220 times enhancement compared to that under ambient pressure. Remarkably, an HCOOH Faradic efficiency of 81.4% can be achieved with an ultralow cathodic overpotential of 0.38 V. The elevated pressure not only promotes the electrocatalytic reduction of O2 to H2O2 but also increases the reaction collision probability between CH4 and •OH, which is in situ generated from the Fe2+-facilitated decomposition of H2O2.

Regulation of a novel DsGATA1 from Dunaliella salina on the synthesis of carotenoids under red light.

Dunaliella salina is a high-quality industrial effector for carotenoid production. The mechanism by which red light regulates carotenoid synthesis is still unclear. In this study, a transcription factor of DsGATA1 with a distinct structure was discovered in D. salina. The recognition motif of DsGATA1 was comparable to that of plant and fungal GATA, despite its evolutionary proximity to animal-derived GATA. The expression of DsGATA1 in D. salina was still noticeably decreased when exposed to red light. Analysis of physiological and biochemical transcriptomic data from overexpressed, interfering, and wild-type strains of DsGATA1 revealed that DsGATA1 acts as a global regulator of D. salina carotenoid synthesis. The upregulated genes in the CBP pathway by DsGATA1 were involved in its regulation of the synthesis of carotenoids. DsGATA1 also enhanced carotenoid accumulation under red light by affecting N metabolism. DsGATA1 was found to directly bind to the promoter of nitrate reductase to activate its expression, promoting D. salina nitrate uptake and accelerating biomass accumulation. DsGATA1 affected the expression of the genes encoding GOGAT, GDH, and ammonia transporter proteins. Moreover, our study revealed that the regulation of N metabolism by DsGATA1 led to the production of NO molecules that inhibited carotenoid synthesis. However, DsGATA1 significantly enhanced carotenoid synthesis by NO scavenger removal of NO. The D. salina carotenoid accumulation under red light was elevated by 46% in the presence of overexpression of DsGATA1 and NO scavenger. Nevertheless, our results indicated that DsGATA1 could be an important target for engineering carotenoid production. KEY POINTS: • DsGATA1 with a distinct structure and recognition motif was found in D. salina • DsGATA1 enhanced carotenoid production and biomass in D. salina under red light • DsGATA1 is involved in the regulation of N metabolism and carotenoid synthesis.

Prognostic effects of previous cancer history on patients with major salivary gland cancer.

OBJECTIVES: To explore the prognostic effects of previous cancer history on patients with major salivary gland cancer (SGC). SUBJECTS AND METHODS: SGC patients with (sec-SGC) and without (one-SGC) a previous cancer from the SEER database were identified. Cox proportional hazards regression (CoxPH) models were used to compare the prognosis between sec-SGC and one-SGC patients. Subgroup analyses for sec-SGC patients by gender, previous cancer types, previous cancer histology, and cancer diagnosis interval (CDI) were performed. Two CoxPH models were constructed to distinguish sec-SGC patients with different prognostic risks. RESULTS: 9098 SGC patients were enrolled. Overall, sec-SGC patients (adjusted HR [aHR] = 1.26, p < 0.001), especially those with a CDI ≤ 5 years (aHR = 1.47, p < 0.001), had worse overall survival (OS) than one-SGC patients. In subgroup analysis, only sec-SGC patients with a previous head and neck cancer who were female (aHR = 2.38, p = 0.005), with a CDI ≤ 5 years (aHR = 1.65, p = 0.007) or with a previous squamous cell carcinoma (aHR = 6.52, p < 0.001) had worse OS. Our models successfully differentiated all sec-SGC patients into high-, intermediate- and low-risk groups with different prognosis. CONCLUSIONS: Sec-SGC patients with different previous cancer types, gender, CDI and previous cancer histology had varied prognosis. The models we constructed could help differentiate the prognosis of sec-SGC patients with different risks.

NLRP10 promotes AGEs-induced NLRP1 and NLRP3 inflammasome activation via ROS/MAPK/NF-κB signaling in human periodontal ligament cells.

Diabetes mellitus (DM), characterized by production and accumulation of advanced glycation end products (AGEs), induces and promotes chronic inflammation in tissues, including periodontal tissue. Increasing amount of epidemiological and experimental evidence demonstrated that more extensive inflammatory reaction and bone resorption occurred in periodontal tissues in diabetic patients with periodontitis, which is speculated to be related to NLRP3 inflammasome. NLRP10 is the only NOD-like receptor protein lacking leucine-rich repeats, suggesting that NLRP10 may be a regulatory protein. The aim of this study was to investigate the regulatory role of NLRP10 on NLRP1 and NLRP3 inflammasome in human periodontal ligament cells (HPDLCs) under AGEs treatment. Expression of NLRP10 in HPDLCs stimulated with 100 ug/mL AGEs for 24 h was observed. Detection of TRIM31 is conducted, and in TRIM31-overexpressed HPDLCs, the interaction between NLRP10 with TRIM31 as well as NLRP10 with ubiquitination were explored by immunoprecipitation. Under AGEs stimulation, the activation of reactive oxidative stress (ROS) and inflammatory signaling pathway (NF-κB, MAPK pathway) was detected by biomedical microscope and western blot (WB), respectively. After stimulation with AGEs for 24 h with or without silencing NLRP10, inflammatory cytokines (IL-6 and IL-1ß), NF-κB, MAPK pathway, ROS, and components of inflammasome were assessed. In HPDLCs, we found AGEs induced NLRP10 and inhibited TRIM31. TRIM31 overexpression significantly enhanced interaction between TRIM31 and NLRP10, then induced proteasomal degradation of NLRP10. Moreover, under AGEs stimulation, NLRP10 positively regulates NLRP1, NLRP3 inflammasomes by activating NF-κB, MAPK pathway, and increasing ROS, finally promoting the expression of inflammatory cytokines. Together, we, for the first time, confirmed that NLRP10 could promote inflammatory response induced by AGEs in HPDLCs via activation of NF-κB, and MAPK pathway and increasing ROS.

Low Bone Mineral Density and the Risk of Benign Paroxysmal Positional Vertigo.

OBJECTIVE: This study aimed to comprehensively analyze the relationship between low bone mineral density (BMD) and the risk of benign paroxysmal positional vertigo (BPPV) based on the large prospective population-based UK Biobank (UKB) cohort. STUDY DESIGN: Prospective population-based cohort study. SETTING: The UKB. METHODS: This prospective cohort study included UKB participants recruited between 2006 and 2010 who had information on BMD and did not have BPPV before being diagnosed with low BMD. Univariable and multivariable logistic regression models were constructed to assess the association between low BMD (overall low BMD, osteopenia, and osteoporosis) and BPPV. We further conducted sex and age subgroup analysis, respectively. Finally, the effects of antiosteoporosis and female sex hormone medications on BPPV in participants with osteoporosis were evaluated. RESULTS: In total, 484,303 participants were included in the final analysis, and 985 developed BPPV after a maximum follow-up period of 15 years. Osteoporosis was associated with a higher risk of BPPV (odds ratio [OR] = 1.37, P = .0094), whereas osteopenia was not. Subgroup analyses suggested that the association between osteoporosis and BPPV was significant only in elderly females (≥60 years, OR = 1.51, P = .0007). However, no association was observed between antiosteoporosis or female sex hormone medications and BPPV in the participants with osteoporosis. CONCLUSION: Osteoporosis was associated with a higher risk of developing general BPPV, especially in females aged ≥ 60 years old, whereas osteopenia was not associated with BPPV.

Distribution, characterization, and evolution of heavy metal resistance genes and Tn7-like associated heavy metal resistance Gene Island of Burkholderia.

Introduction: Burkholderia is a rod-shaped aerobic Gram-negative bacteria with considerable genetic and metabolic diversity, which can beused for bioremediation and production applications, and has great biotechnology potential. However, there are few studies on the heavy metal resistance of the Burkholderia genus. Methods: In this paper, the distribution, characteristics and evolution of heavy metal resistance genes in Burkholderia and the gene island of Tn7-like transposable element associated with heavy metal resistance genes in Burkholderia were studied by comparative genomic method based on the characteristics of heavy metal resistance. Results and discussion: The classification status of some species of the Burkholderia genus was improved, and it was found that Burkholderia dabaoshanensis and Burkholderia novacaledonica do not belong to the Burkholderia genus.Secondly, comparative genomics studies and pan-genome analysis found that the core genome of Burkholderia has alarger proportion of heavy metal resistance genes and a greater variety of heavy metalresistance genes than the subsidiary genome and strain specific genes. Heavy metal resistance genes are mostly distributed in the genome in the form of various gene clusters (for example, mer clusters, ars clusters, czc/cusABC clusters). At the same time, transposase, recombinase, integrase and other genes were foundupstream and downstream of heavy metal gene clusters, indicating that heavy metal resistance genes may beobtained through horizontal transfer. The analysis of natural selection pressure of heavy metal resistance genes showed that heavy metal resistance genes experienced strong purification selection under purification selection pressure in the genome.The Tn7 like transposable element of Burkholderia was associated with the heavy metal resistance gene island, and there were a large number of Tn7 transposable element insertion events in genomes. At the same time, BGI metal gene islands related to heavy metal resistance genes of Tn7 like transposable element were found, and these gene islands were only distributed in Burkholderia cepacia, Burkholderia polyvora, and Burkholderia contaminant.

Imaging Structural and Electrical Changes of Aging Cells Using Scanning Ion Conductance Microscopy.

The local charge density and distribution of extracellular membranes play a crucial role in the various cellular processes, such as regulation and localization of membrane proteins, electrophysiological signal transduction, transcriptional control, cell growth, and cell death. In this study, a novel scanning ion conductance microscopy-based method is employed to extracellular membrane mapping. This method allows to not only visualize the dynamic topography and surface charge distribution around individual cells, but also distinguish the charge difference. To validate the accuracy and effectiveness of this method, the charge density on model sample surfaces are initially manipulated and the charge sensing mechanism using finite element modeling (FEM) is explored subsequently. By applying this method, both the extracellular charge distributions and topography structures of normal and senescent human dental pulp stem cells (hDPSCs) are able to monitor. Interestingly, it is observed that the surface charge became significantly more negative after cellular senescence. This innovative approach enables us to gain valuable insights into surface charge changes during cellular senescence, which can contribute to a better understanding of the underlying mechanisms and potential therapeutic strategies for age-related diseases.

[Effects of Tomato Planting Years on Soil Physical and Chemical Properties and Microbial Communities].

Long-term continuous cropping of facility soils could influence soil properties; however, the differences in soil properties among different continuous cropping years are still not well understood. The objective of this study was to explore the effects of continuous cropping years of tomato on the physical and chemical properties and biological characteristics of facility soil. Conventional analysis, high-throughput sequencing, and other methods were used to examine the soil physicochemical properties, soil microbial community diversity, and enzyme activities in facility soil after continuous tomato cropping for 1-3 years, 5-7 years, and more than 10 years. As the continuous tomato cropping years increased, soil bulk density and pH decreased; soil maximal water holding capacity increased; and organic matter, total nitrogen, and total phosphorus accumulated. As continuous cropping years increased, the total salt and EC value decreased with continuous cropping for 5-7 years and increased from 5-7 years to more than 10 years continuous cropping and showed a trend of secondary soil salinization. There was a significant increase in alkaline phosphatase for 1-3 years to 5-7 years continuous tomato cropping. There were significant differences in fungal community abundance among different cropping years. The Simpson index and Shannon index of fungi showed a trend of increasing first and then decreasing with the extension of continuous cropping years and reached the maximum value at 5 years of continuous cropping. The Chao1 index decreased continuously following the cropping years. As continuous cropping years increased, Streptomyces became the dominant bacteria, and Aspergillus and Pseudaleuria became the dominant fungi. The key factors affected by continuous cropping years were available potassium and available nitrogen based on the redundancy analysis. The results of this study lay the foundation for future research on the influence of continuous cropping years on the health of facility soil.

A Comparative Study on the Mechanical Properties of Open-Hole Carbon Fiber-Reinforced Thermoplastic and Thermosetting Composite Materials.

In this paper, the damage initiation/propagation mechanisms and failure modes of open-hole carbon fiber-reinforced thermoplastic composites and thermosetting composites with tension, compression, and bearing loads are investigated, respectively, by experiments and finite element simulations. The experimental evaluations are performed on the specimens using the Combined Loading Compression (CLC) test method, the tensile test method, and the single-shear test method. The differences in macroscopic damage initiation, evolution mode, and damage characteristics between thermoplastic composite materials and thermosetting composite material open-hole structures are obtained and analyzed under compressive load. Based on scanning electron microscope SEM images, a comparative analysis is conducted on the micro-failure modes of fibers, matrices, and fiber/matrix interfaces in the open-hole structures of thermoplastic and thermosetting composites under compressive load. The differences between thermoplastic and thermosetting composites were analyzed from the micro-failure mechanism. Finally, based on continuum damage mechanics (CDM), a damage model is also developed for predicting the initiation and propagation of damage in thermoplastic composites. The model, which can capture fiber breakage and matrix crack, as well as the nonlinear response, is used to conduct virtual compression tests, tensile test, and single-shear test, respectively. Numerical simulation results are compared with the extracted experimental results. The displacement-load curve and failure modes match the experimental result, which indicates that the finite element model has good reliability.

A Population-Based Outcome-Wide Association Study of the Comorbidities and Sequelae Following COVID-19 Infection.

BACKGROUND: Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection. METHODS: In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%). CONCLUSION: In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period.

mRNA-LNP vaccination-based immunotherapy augments CD8+ T cell responses against HPV-positive oropharyngeal cancer.

Although mRNA vaccines are known as potent activators of antigen-specific immune responses against infectious diseases, limited understanding of how they drive the functional commitment of CD8+ T cells in tumor microenvironment (TME) and secondary lymphoid organs hinders their broader application in cancer immunotherapy. Here, we systematically evaluated the immunological effects of a lipid nanoparticle (LNP)-encapsulated mRNA vaccine that encodes human papillomavirus E7 protein (HPV mRNA-LNP), a tumor-specific antigen of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). HPV mRNA-LNP vaccination activated overall and HPV-specific CD8+ T cells, as well as differentially drove the functional commitment of CD8+ T cells through distinct IFN-response and exhaustion trajectories in the spleen and TME, respectively. Combination therapies of HPV mRNA-LNP vaccination with immune checkpoint blockades boosted HPV-specific CD8+ T cells while maintaining their anti-tumor function, thus further promoting tumor regression. Our results showed that the HPV mRNA-LNP vaccination combined with immune checkpoint blockade is a promising approach for immunotherapy of HPV-positive OPSCC.

Comparative effectiveness and safety of drug therapy for chronic urticaria: a network meta-analysis and risk-benefit assessment.

BACKGROUND: Chronic urticaria (CU) is a prevalent chronic skin condition characterized by recurrent wheals. Clinical guidelines recommend multiple drugs for CU treatment. Our study aims to compare the effectiveness and safety of drug therapy for CU. METHODS: We conducted a comprehensive search of randomized controlled trials (RCTs) and real-world studies (RWSs) in PubMed, EMBASE, and Cochrane. A network meta-analysis (NMA) was conducted to assess the response rate, decline in Urticaria Activity Score over 7 Days (UAS7), Dermatology Life Quality Index (DLQI), and adverse event rates of standard-dose and high-dose H1 antihistamine (H1AH), omalizumab (OMA) 75, 150, and 300 mg, cyclosporine and placebo. The risk-benefit assessment was conducted by probabilistic simulation and stochastic multicriteria acceptability analysis (SMAA). RESULTS: A total of 39 studies were identified, including 37 RCTs and 2 RWSs. OMA 300 mg and 150 mg both had significantly higher response rate than standard-dose H1AH (p < 0.05, respectively). OMA 300 mg and 150 mg both consistently led to a huge drop in UAS7 and DLQI compared to standard-dose H1AH and high-dose H1AH (p < 0.05). CONCLUSION: Regarding risk-benefit assessment, OMA 300 mg emerges as the optimal pharmacological intervention for CU, while OMA 150 mg stands as a secondary alternative compared to H1 antihistamines and cyclosporine.

Associations between immune-mediated diseases (IMDs) and the risk of HPV-associated diseases: a UK Biobank cohort analysis.

OBJECTIVES: To systematically assess the associations between various immune-mediated diseases (IMDs) and human papillomavirus (HPV)-associated diseases. DESIGN: Retrospective cohort study. SETTING: UK Biobank. PARTICIPANTS: A total of 500 371 subjects aged 40-69 years were eligible for the analysis, after excluding those with prevalent HPV-associated diseases at baseline and those who had withdrawn their informed consent or lacked information on sex. EXPOSURE: Eighty IMDs (involving allergic/atopic diseases, autoimmune diseases, immunodeficiency diseases, etc) were identified in the UK Biobank. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome was the incidence of HPV-associated diseases (including warts and malignancies of the cervix, oropharynx, anus, penis, vulva and vagina). Cox proportional hazards model was used to estimate HRs and 95% CIs with particular adjustment for sexual behaviours. We also conducted subgroup analyses based on benign and malignant status, and anatomical sites of HPV-associated diseases, respectively. RESULTS: During a median of 12.0 years of follow-up, 2244 cases out of 500 371 subjects developed HPV-associated diseases. Overall, participants with IMDs had a higher risk of HPV-associated diseases than their controls after adjustment for sexual behaviours and other potential confounders (female: HR=1.90, 95% CI=1.66 to 2.17, p<0.001; male: HR=1.66, 95% CI=1.41 to 1.97, p<0.001). Additionally, eight individual IMDs in women (eg, asthma: HR=1.76, 95% CI=1.47 to 2.11, p<0.001) and three in men (eg, chronic nephritic syndrome: HR=6.05, 95% CI=3.32 to 11.04, p<0.001) were associated with increased risk of HPV-associated diseases. Subgroup analyses revealed significant IMD differences between benign and malignant subgroups as well as between oropharyngeal and anogenital subgroups. CONCLUSION: In this large retrospective cohort study, IMDs were significantly associated with an elevated risk of HPV-associated diseases. Besides, gender-specific and region-specific associations were also observed between individual IMDs and HPV-associated diseases.

Zyxin inhibits the epithelial-mesenchymal transition process in gastric cancer by upregulating SIRT1.

Tumor development relies on the stemness of cancer stem cells, which is regulated by environmental cues. Previous studies have shown that zyxin can inhibit the expression of genes for embryonic stem cell status. In the present study, the expression levels of zyxin protein in cancer tissues and adjacent noncancerous tissues from 73 gastric cancer patients with different clinical stages were analyzed by Western blot. We showed that the relative expression levels of zyxin in gastric cancer tissues (cancer tissues/adjacent tissues) were significantly downregulated in advanced clinical stages. Overexpression of zyxin inhibited the stemness and epithelial-mesenchymal transition (EMT) processes in gastric cancer cells. Zyxin also inhibited the proliferation, migration, and invasion but increased the sensitivity of cancer cells to drugs. Overexpression of zyxin in MKN45 cells inhibited tumor growth in nude mice. We show that the interactions between zyxin and SIRT1 led to the upregulation of SIRT1, reduced acetylation levels of histone H3 K9 and K23, decreased transcription levels of SNAI 1/2, and inhibition of the EMT process. This study demonstrated that zyxin negatively regulates the progression of gastric cancer by inhibiting the stemness of cancer stem cells and EMT. Our findings shed new light on the pathogenesis of gastric cancer.

F-box and leucine-rich repeat protein 16 controls tamoxifen sensitivity via regulation of mitochondrial respiration in estrogen receptor-positive breast cancer cells.

Tamoxifen is one of the most effective therapeutic tools for estrogen receptor-positive (ER +) breast cancer. However, the intrinsic insensitivity and resistance to tamoxifen remains a significant hurdle for achieving optimal responses and curative therapy. In this study, we report that F-box and leucine-rich repeat protein 16 (FBXL16) is located in the mitochondria of ER + breast cancer cells. The mitochondrial FBXL16 plays an essential role in sustaining mitochondrial respiration and thereby regulates the sensitivity of ER + breast cancer cells to tamoxifen treatment. Importantly, high FBXL16 expression is significantly correlated with poor overall survival of ER + breast cancer patients. Moreover, mitochondrial inhibition phenocopies FBXL16 depletion in terms of sensitizing the ER + breast cancer cells to tamoxifen treatment. Together, our study demonstrates that FBXL16 acts as a novel regulator of tamoxifen sensitivity. Thus, targeting FBXL16 may serve as a promising approach for improving the therapeutic efficacy of tamoxifen in ER + breast cancer cells.