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Psoriasis is a chronic inflammatory skin disease. Emerging evidence shows that neurogenic inflammation, induced by nociceptive neurons and T helper 17 cell (Th17) responses, has a fundamental role in maintaining the changes in the immune system due to psoriasis. Nociceptive neurons, specific primary sensory nerves, have a multi-faceted role in detecting noxious stimuli, maintaining homeostasis, and regulating the immunity responses in the skin. Therefore, it is critical to understand the connections and interplay between the nociceptive neurons and the immune system in psoriasis. Here, we review works on the altered innervation that occurs in psoriasis. We examine how these distinct sensory neurons and their signal transducers participate in regulating inflammation. Numerous clinical studies report the dysfunction of nociceptive neurons in psoriasis. We discuss the mechanism behind the inconsistent activation of nociceptive neurons. Moreover, we review how neuropeptides, involved in regulating Th17 responses and the role of nociceptive neurons, regulate immunity in psoriasis. Understanding how nociceptive neurons regulate immune responses enhances our knowledge of the neuroimmunity involved in the pathogenesis of psoriasis and may form the basis for new approaches to treat it.

BET bromodomain inhibitors (BETi), such as JQ1, have been demonstrated to effectively kill multiple types of cancer cells. However, the underlying mechanisms for BETi resistance remain largely unknown. Our evidences show that JQ1 treatment evicts BRD4 from the FOXD3-localized MIR548D1 gene promoter, leading to repression of miR-548d-3p. The loss of miRNA restores JunD expression and subsequent JunD-dependent transcription of RPS6KA2 gene. ERK1/2/5 kinases phosphorylate RSK3 (RPS6KA2), resulting in the enrichment of activated RSK3 and blockade of JQ1 killing effect. Dual inhibition of MEKs/ERKs or single EGFR inhibition are able to mimic the effect of JunD/RSK3-knockdown to reverse BETi resistance. Collectively, our study indicates that loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance, which can be reversed by targeting EGFR-MEK1/2/5-ERK1/2/5 signalling. The clinical use of BET inhibitors (BETi) is limited by primary and acquired resistance. Here, the authors report that BETi resistance is determined by JunD/RSK3 signalling activation induced by the loss of BRD4/Foxd3/miR-548d-3p, which can be reverted by targeting the EGFR-MEK-ERK pathway.

Background This scoping review maps population-based surveys and mental health literacy (MHL) interventions undertaken in China during 1997–2018 in order to identify research gaps. Method Following Arksey and O’Malley’s framework for a scoping review, five English databases (Medline, PsycINFO, Cochrane library, Web of Science and CINAHL) and two Chinese ones (CNKI and WanFang) were systematically searched, identifying both reports of surveys and evaluation of interventions from Jan 1997 to Oct 2018. Results MHL research has developed rapidly in China in terms of numbers of studies and geographic coverage over the past two decades. There were 350 peer-reviewed publications included in this review, covering diverse settings and participants. Of these publications, 313 (89.4%) were published in Chinese-language journals and 37 in English-language journals; 303 (86.6%) reported on survey findings and 47 reported on the evaluation of MHL interventions. MHL research in China has mainly focused on the assessment of mental health-related knowledge and beliefs. Much less attention has been given to developing and evaluating relevant interventions. MHL related to general mental health and suicide were most commonly studied, with less focus on specific disorders, although some studies covered depression, psychosis and anxiety disorders. The majority of MHL tools utilized in the studies reported in this review were developed in China ( n  = 97, 80.2% ) and almost half of these studies (57.8%) did not provide enough details concerning psychometrics. Conclusions More interventions targeting the general public and aiming to improve MHL and promote behaviour change, are needed in China. These should be evaluated with high-quality study designs, such as randomised controlled trials. Proper validation of tools used for measuring MHL should also be addressed in future studies.

Alzheimer's disease (AD), a prevalent neurodegenerative disease, is primarily characterized by progressive neuron loss and memory impairment. NOD-like receptors (NLRs) are crucial for immune regulation and maintaining cellular homeostasis. Recently, NLRs have been identified as important contributors to neuroinflammation, thus presenting a potential approach for reducing inflammation and slowing AD progression. We use quantitative RT-PCR to detect levels of NLR family members in AD mouse model. Additionally, we use immunofluorescence to detect NLRP3 expressions in microglia surrounding Aβ plaques in AD mouse model and human AD patients. In this study, we examined the expression of NLR family members in the human AD database, and found increased levels of CIITA, NOD1, NLRC5, NLRP1, NLRP3, NLRP7, NLRP10, NLRP12, and NLRP13 in hippocampus tissue in patients with AD, along with increased levels of NOD1, NLRC5, NLRX1, NLRP3, and NLRP7 levels in frontal cortex tissue. Furthermore, through detecting their levels in AD mouse model, we found that NLRP3 levels were significantly increased. Additionally, we found that NLRP3 expressions were mainly elevated in microglia surrounding Aβ plaques in AD mouse model and human AD patients. These findings highlight the potential important role of NLRP3 in AD pathology, offering new therapeutic targets and interventions.

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer. The molecular mechanism underlying the resistance of AKT inhibitors in breast cancer is still elusive. Here, the authors demonstrate that BRD4/FOXO3a axis upregulates CDK6 promoter activity to promote resistance to AKT inhibition in breast cancer cells and that blocking the action of CDK6 re-sensitizes resistant cancer cells to growth inhibition.

Depressive symptoms erode both physical and mental aspects of health-related quality of life (HRQoL). Social support (SS) may improve HRQoL through its direct effects or buffering effects. The association among depressive symptoms, SS, and HRQoL has been studied in specific groups, but research in the general adult population remains limited. This study examined the association among depressive symptoms, SS, and HRQoL, including exploring whether SS (including its three dimensions: subjective SS, objective SS and support utilization) mediated or moderated the relationship between depressive symptoms and HRQoL among community-based adults. We conducted a cross-sectional survey in six communities in Shanghai, China, and 1642 adult participants with complete information on depressive symptoms and/or SS, and HRQoL were included. Linear regression analysis was used to investigate the association among depressive symptoms, SS, and HRQoL. In addition, we explored the mediating and moderating role of SS in the relationship between depressive symptoms and HRQoL. More depressive symptoms were associated with lower physical HRQoL (B = −0.64, p < .001) and lower mental HRQoL (B = −0.83, p < .001). SS (B = 0.07, p = .02), specifically subjective SS (B = 0.09, p = .03), was positively related to mental HRQoL. After adjusting for covariates, we found no evidence for a mediating role of SS in the relationship between depressive symptoms and HRQoL, while SS (subjective SS and objective SS) moderated the association between depressive symptoms and mental HRQoL. Due to the low voluntary participation rate of employees, participants represented approximately 50% of the individuals approached, thus limiting the generalizability of our findings. Data collected through self-report scales could lead to information bias. SS does not appear to underlie the relationship between depressive symptoms and HRQoL. However, interventions to increase SS (in particular, subjective SS and objective SS) should be studied to determine whether they may be beneficial in alleviating the adverse impact of depressive symptoms on mental HRQoL. •Depressive symptoms eroded health-related quality of life (HRQoL).•Social support (SS) and subjective SS were positively associated with mental HRQoL.•SS did not mediate the association between depressive symptoms and HRQoL.•SS moderated the association between depressive symptoms and mental HRQoL.

The management of patients with isolated gamma-glutamyltransferase (GGT) elevation during statin therapy remains a common clinical dilemma due to the unclear relevance to hepatotoxicity. We report a case of a patient with coronary artery disease who developed persistent isolated GGT elevation (> 100 U/L) while on atorvastatin, with normal alanine and aspartate aminotransferase levels. Critically, the elevated GGT persisted after statin withdrawal, and a comprehensive workup revealed uncontrolled cardiometabolic risk factors. We conclude that isolated GGT elevation in this context is more likely a biomarker of underlying cardiovascular risk than of statin-induced liver injury. Based on this case analysis, we propose a stepwise decision framework to guide evaluation and management in such scenarios. Through literature review and case analysis, we conclude that isolated GGT elevation is not a reliable indicator of statin hepatotoxicity and may be associated with cardiovascular risk. Therefore, clinicians should not hastily discontinue statins. Instead, a comprehensive assessment should be initiated to identify potential causes and personalize treatment.

Psoriasis is a chronic immune-mediated inflammatory skin disease driven by dysregulation of the IL-23/IL-17 axis and influenced by genetic and environmental factors. The role and molecular mechanisms of the environmental pollutant dibenzo-p-dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in psoriasis remain unclear. An integrative strategy combining network toxicology, machine learning, bioinformatics analysis, molecular simulation, and keratinocyte qRT-PCR validation was employed to systematically investigate the potential toxicity and molecular mechanisms of TCDD in psoriasis. Eighty-seven overlapping genes were identified between TCDD-related targets and psoriasis-associated genes and were mainly enriched in IL- 17-, chemokine-, MAPK/ ERK-, and GPCR-related signaling pathways. Machine learning identified five core target genes-LCK, MMP9, CXCR2, PTAFR, and CCNB1-which were significantly upregulated in psoriatic lesions, showed strong diagnostic performance within the analyzed datasets, and were associated with local immune infiltration patterns. Structural analyses supported potential interactions between TCDD and these core targets, with CXCR2 showing the most favorable predicted docking score. A 24-h keratinocyte TCDD-response signature showed significant concordance with psoriatic lesional transcriptomes, and keratinocyte qRT-PCR validation showed increased expression of LCK, MMP9, CXCR2, and PTAFR, whereas CCNB1 showed only a modest change. In biologic-therapy cohorts, core genes were downregulated after 12 weeks, and higher baseline MMP9 was associated with poorer clinical improvement and may have potential relevance to treatment response. Our integrative analyses identify TCDD-associated genes and pathways potentially involved in psoriasis immune dysregulation. Structural modeling supports the plausibility of TCDD engaging CXCR2, while transcriptomic concordance and keratinocyte qRT-PCR findings support dysregulation of several core genes in epidermal cells. Baseline MMP9 was associated with week-12 treatment response in biologic-therapy cohorts. Nevertheless, the link between environmental TCDD exposure and psoriasis remains inferential because the study relied mainly on analyses without individual-level exposure data; therefore, further validation in well-designed cohort studies is needed.

Background Clinical research suggests that posttraumatic stress disorder (PTSD) patients exposed to multiple traumatic events (TEs) rather than a single TE have increased morbidity and dysfunction. Although epidemiological surveys in the United States and Europe also document high rates of multiple TE exposure, no population‐based cross‐national data have examined this issue. Methods Data were analyzed from 20 population surveys in the World Health Organization World Mental Health Survey Initiative (n = 51,295 aged 18+). The Composite International Diagnostic Interview (3.0) assessed 12‐month PTSD and other common DSM‐IV disorders. Respondents with 12‐month PTSD were assessed for single versus multiple TEs implicated in their symptoms. Associations were examined with age of onset (AOO), functional impairment, comorbidity, and PTSD symptom counts. Results 19.8% of respondents with 12‐month PTSD reported that their symptoms were associated with multiple TEs. Cases who associated their PTSD with four or more TEs had greater functional impairment, an earlier AOO, longer duration, higher comorbidity with mood and anxiety disorders, elevated hyperarousal symptoms, higher proportional exposures to partner physical abuse and other types of physical assault, and lower proportional exposure to unexpected death of a loved one than cases with fewer associated TEs. Conclusions A risk threshold was observed in this large‐scale cross‐national database wherein cases who associated their PTSD with four or more TEs presented a more “complex” clinical picture with substantially greater functional impairment and greater morbidity than other cases of PTSD. PTSD cases associated with four or more TEs may merit specific and targeted intervention strategies.

Background To evaluate the safety, efficacy, and the refractive outcomes of single-step transepithelial photorefractive keratectomy (TransPRK) for the correction of mild, moderate, and high myopia. Methods This study consecutively recruited 32 high myopic eyes, 32 mild myopic and 32 moderate myopic eyes. Eyes with myopia that had undergone TransPRK treatment. Pre- and post-operative visual and refractive data, corneal Higher Order Aberration (HOA) as well as safety and efficacy indices were analyzed at 6 months postoperatively. Results Six months after TransPRK, the manifest refraction spherical equivalent (SE) was not significantly between high myopia group and moderate myopia group ( p = 0.636). No eyes lost ≥2 lines of corrected distant visual acuity (CDVA) in high myopic eyes. The uncorrected distance visual acuity (UDVA) was significantly higher in low and moderate myopia groups than the high myopia group ( P < 0.001; P = 0.002). The CDVA was not significantly different between moderate and high myopia groups ( P  = 0.057). There was no significant difference in mean safety index between high myopia group (1.01 ± 0.14) and mild myopia group (1.08 ± 0.15) ( P > 0.05). The mean safety index was significantly higher in the moderate myopia group (1.16 ± 0.23) than in the high myopia group (1.01 ± 0.14) ( P = 0.002). The efficacy index was significantly higher in the moderate myopia group (1.05 ± 0.20) than in the high myopia group (0.89 ± 0.17) ( P = 0.02), and there was no significant difference between the high myopia group (0.89 ± 0.17) and the low myopia group (0.96 ± 0.16) ( P  = 0.14). Conclusions The mean safety index was over 1.0 in the three groups. TransPRK showed acceptable safety and efficacy in the moderate myopic eyes, as well as mild and high myopic eyes. High myopic eyes got very similar refractive results with moderate myopic eyes six months postoperatively. The safety and efficacy indexes were not significantly different between the high myopia group and the low myopia group.