SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-type Palmoplantar Keratoderma.

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

Immune micro-environment analysis and drug screening for ovarian endometriosis.

BACKGROUND: Patients of ovary endometriosis have an abnormal immune micro-environment, leading to endometrial tissue that from retrograde menstruation evade immune surveillance and subsequently develop into ectopic lesions. OBJECTIVE: This study aims to elucidate the crucial immune cells and molecular pathways that are associated with an aberrant immune micro-environment of endometriosis. METHOD: In this study, we identified differentially expressed genes between ovarian ectopic endometrial tissue (OVE) and eutopic endometrial tissue from patients with endometriosis (PE) and non-endometriosis patients (CON) by analyzing the mRNA sequencing data. Additionally, we used WGCNA(Weighted Gene Co-expression Network Analysis) to screen for key genes related to immune cell infiltration and compared the sub-types of infiltrating immune cells using CIBERSORT(cell-type identification by estimating relative subsets of RNA transcript). Subsequently, we conducted a single-cell analysis on the identified key genes. Furthermore, we analyzed potential drugs suitable for ovarian endometriosis treatment using pRRophertic. RESULTS: Seven key genes associated with immune cell infiltration were screened out. The expression of these genes in OVE was significantly lower than that in PE and CON. These key genes were mainly enriched in the NK cell-mediated cytotoxicity pathway, especially for CD16 + CD56dim NK. Moreover, NK cells infiltration in ovarian endometriosis was significantly reduced compared with PE and CON, while M2 macrophage shown the opposite. Results of the single-cell analysis showed that the expression of the seven key genes in NK cells and monocyte-macrophages in OVE was significantly lower than that in PE or CON. Additionally, we identified potential drugs suitable for ovarian endometriosis treatment. CONCLUSION: The decreased infiltration of NK cells and increased infiltration of M2 macrophages contribute to the evasion of immune surveillance against endometrial tissue, promoting the progression of OVE. Therefore, potential strategies for the treatment of OVE include increasing NK cell activation and decreasing M2 macrophage polarization.

Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation.

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1ß, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.

METTL14 affects UVB-induced human dermal fibroblasts photoaging via miR-100-3p biogenesis in an m6A-dependent manner.

Exposure to ultraviolet radiation can lead to skin photoaging, which increases the risk of skin tumors. This study aims to investigate how microRNA m6A modification contributes to skin photoaging. This study found that skin fibroblasts exposed to a single UVB dose of 30 mJ/cm2 exhibited characteristics of photoaging. The m6A level of total RNA decreased in photoaged cells with a down-regulated level of METTL14, and overexpression of METTL14 displayed a photoprotective function. Moreover, miR-100-3p was a downstream target of METTL14. And METTL14 could affect pri-miR-100 processing to mature miR-100-3p in an m6A-dependent manner via DGCR8. Furthermore, miR-100-3p targeted at 3' end untranslated region of ERRFI1 mRNA with an inhibitory effect on translation. Additionally, photoprotective effects of overexpression of METTL14 were reversed by miR-100-3p inhibitor or overexpression of ERRFI1. In UVB-induced photoaging of human skin fibroblasts, METTL14-dependent m6A can regulate miR-100-3p maturation via DGCR8 and affect skin fibroblasts photoaging through miR-100-3p/ERRFI1 axis.

Association between single nucleotide polymorphisms, TGF-ß1 promoter methylation, and polycystic ovary syndrome.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disease in women. Hyperandrogenaemia (HA) and insulin resistance (IR) are the basic pathophysiological characteristics of PCOS. The aetiology of PCOS has not been fully identified and is generally believed to be related to the combined effects of genetic, metabolic, internal, and external factors. Current studies have not screened for PCOS susceptibility genes in a large population. Here, we aimed to study the effect of TGF-ß1 methylation on the clinical PCOS phenotype. METHODS: In this study, three generations of family members with PCOS with IR as the main characteristic were selected as research subjects. Through whole exome sequencing and bioinformatic analysis, TGF-ß1 was screened as the PCOS susceptibility gene in this family. The epigenetic DNA methylation level of TGF-ß1 in peripheral blood was detected by heavy sulfite sequencing in patients with PCOS clinically characterised by IR, and the correlation between the DNA methylation level of the TGF-ß1 gene and IR was analysed. We explored whether the degree of methylation of this gene affects IR and whether it participates in the occurrence and development of PCOS. RESULTS: The results of this study suggest that the hypomethylation of the CpG4 and CpG7 sites in the TGF-ß1 gene promoter may be involved in the pathogenesis of PCOS IR by affecting the expression of the TGF-ß1 gene. CONCLUSIONS: This study provides new insights into the aetiology and pathogenesis of PCOS.

Gasdermin D-mediated keratinocyte pyroptosis as a key step in psoriasis pathogenesis.

Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role remains unclear in psoriasis as one chronic inflammatory skin disorder with high prevalence. We found that N-terminal GSDMD (N-GSDMD) was aberrantly expressed in epidermis of skin lesion in psoriasis patients and imiquimod-induced psoriasis-like dermatitis (IIPLD) mice. In epidermis of IIPLD mice and M5 (simulating psoriatic inflammatory challenge)-treated keratinocytes cultured in vitro, cleavage products of caspase-1, GSDMD and IL-1ß were increased. M5-stimulated keratinocyte presented typical pyroptosis morphology accompanied with PI-staining. Gsdmd-/- keratinocytes could not present pyroptosis morphology while stimulated with M5. Electroporation of recombinant N-GSDMD could make the pyroptosis morphology reappear. In Gsdmd-/- mice or keratinocyte-specific Gsdmd conditional knockout mice, we observed the alleviation of psoriatic inflammation and epidermal aberrant expression of Ki-67 and differentiation markers (loricrin and keratin 5) after imiquimod stimulation. Transplanting skin tissue from control mice to Gsdmd-/- mice can evoke the response to imiquimod stimulation in the background of Gsdmd-/- mice (not limited in transplanting area). In M5-stimulated keratinocytes, disulfiram or GSDMD siRNA transfection can inhibit pyroptosis and eliminate disproportionate increases of Ki-67 and PI. We further validated that topically application of disulfiram (pyroptosis inhibitor) also alleviated IIPLD in mice. These findings indicate a novel mechanism that GSDMD-mediated keratinocyte pyroptosis facilitates hyperproliferation and aberrant differentiation induced by immune microenvironment in psoriatic skin inflammation, which contributes to pathogenesis of psoriasis. Our study provides an innovative insight that targeting pyroptosis can be considered as a therapeutic strategy against psoriasis.

A Systematic Review and Meta-Analysis of Interventions to Promote Adjuvant Endocrine Therapy Adherence Among Breast Cancer Survivors.

PURPOSE: Adjuvant endocrine therapy (AET) adherence among breast cancer survivors is often suboptimal, leading to higher cancer recurrence and mortality. Intervention studies to promote AET adherence have burgeoned, more than doubling in number since this literature was last reviewed. The current aim is to provide an up-to-date systematic review and meta-analysis of interventions to enhance AET adherence and to identify strengths and limitations of existing interventions to inform future research and clinical care. METHODS: Systematic searches were conducted in three electronic databases. Studies were included in the systematic review if they examined an intervention for promoting AET adherence among breast cancer survivors. Studies were further included in the meta-analyses if they examined a measure of AET adherence (defined as compliance or persistence beyond initiation) and reported (or provided upon request) sufficient information to calculate an effect size. RESULTS: Of 5,045 unique records, 33 unique studies representing 375,951 women met inclusion criteria for the systematic review. Interventions that educated patients about how to manage side effects generally failed to improve AET adherence, whereas policy changes that lowered AET costs consistently improved adherence. Medication reminders, communication, and psychological/coping strategies showed varied efficacy. Of the 33 studies that met the inclusion criteria for the systematic review, 25 studies representing 367,873 women met inclusion criteria for the meta-analysis. The meta-analysis showed statistically significant effects of the adherence interventions overall relative to study-specified control conditions (number of studies [k] = 25; odds ratio, 1.412; 95% CI, 1.183 to 1.682; P = .0001). Subgroup analyses showed that there were no statistically significant differences in effect sizes by study design (randomized controlled trial v other), publication year, directionality of the intervention (unidirectional v bidirectional contact), or intervention type. CONCLUSION: To our knowledge, this is the first known meta-analysis to demonstrate a significant effect for interventions to promote AET adherence. The systematic review revealed that lowering medication costs and a subgroup of psychosocial and reminder interventions showed the most promise, informing future research, policy, and clinical directions.

Effect of longitudinal-bending elliptical ultrasonic vibration assistance on electrosurgical cutting and hemostasis.

Electrosurgical devices are widely used for tissue cutting and hemostasis in minimally invasive surgery (MIS) for their high precision and low trauma. However, tissue adhesion and the resulting thermal injury can cause infection and impede the wound-healing process. This paper proposes a longitudinal-bending elliptical ultrasonic vibration-assisted (EUV-A) electrosurgical cutting system that incorporates an ultrasonic vibration in the direction of the cut by introducing an elliptical motion of the surgical tip. Compared with a solely longitudinal ultrasonic vibration-assisted (UV-A) electrosurgical device, the EUV-A electrode contacts the tissue intermittently, thus allowing for a cooler cut and preventing tissue accumulation. The experimental results reveal that the EUV-A electrode demonstrates better performance than the UV-A electrode for both anti-adhesion and thermal injury through in vitro experiments in porcine samples. The tissue removal mechanism of EUV-A electrosurgical cutting is modeled to investigate its anti-adhesion effect. In addition, lower adhesion, lower temperature, and faster cutting are demonstrated through in vivo experiments in rabbit samples. Results show that the EUV-A electrode causes lower thermal injury, indicative of faster postoperative healing. Finally, efficacy of the hemostatic effect of the EUV-A electrode is demonstrated in vivo for vessels up to 3.5 mm (equivalent to that of electrocautery). The study reveals that the EUV-A electrosurgical cutting system can achieve safe tissue incision and hemostasis.

Identification of immune cell infiltration and effective biomarkers of polycystic ovary syndrome by bioinformatics analysis.

BACKGROUND: Patients with polycystic ovary syndrome (PCOS) exhibit a chronic inflammatory state, which is often accompanied by immune, endocrine, and metabolic disorders. Clarification of the pathogenesis of PCOS and exploration of specific biomarkers from the perspective of immunology by evaluating the local infiltration of immune cells in the follicular microenvironment may provide critical insights into disease pathogenesis. METHODS: In this study, we evaluated immune cell subsets and gene expression in patients with PCOS using data from the Gene Expression Omnibus database and single-sample gene set enrichment analysis. RESULTS: In total, 325 differentially expressed genes were identified, among which TMEM54 and PLCG2 (area under the curve = 0.922) were identified as PCOS biomarkers. Immune cell infiltration analysis showed that central memory CD4+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, γδ T cells, and type 17 T helper cells may affect the occurrence of PCOS. In addition, PLCG2 was highly correlated with γδ T cells and central memory CD4+ T cells. CONCLUSIONS: Overall, TMEM54 and PLCG2 were identified as potential PCOS biomarkers by bioinformatics analysis. These findings established a basis for further exploration of the immunological mechanisms of PCOS and the identification of therapeutic targets.

Association of urinary nickel levels with diabetes and fasting blood glucose levels: A nationwide Chinese population-based study.

Some epidemiological studies support a relationship between nickel exposure and diabetes in the general population. To address this, we tested the association of nickel exposure with diabetes in 10,890 adults aged ≥ 18 years old from the China National Human Biomonitoring study conducted in 2017-2018. Urinary nickel concentrations and fasting blood glucose (FBG) were measured, and lifestyle and demographic data were collected. Weighted logistic and linear regressions were used to estimate the associations of urinary nickel levels with diabetes prevalence and FBG. Restricted cubic splines (RCS) were used to test for the dose-response relationship. The odd ratio (95% confidence interval [CI]) of diabetes for the highest versus lowest quartiles of urinary nickel concentrations was 1.74 (1.28, 2.36) in the multivariate model (p trend =0.001). Each one-unit increase in log-transformed urinary nickel concentrations was associated with a 0.36 (0.17, 0.55) mmol/L elevation in FBG. The RCS curves showed a monotonically increasing dose-response relationship of urinary nickel with diabetes as well as FBG levels, and then tended to flatten after about 4.75 µg/L of nickel exposure. The nickel-diabetes association was stronger in individuals with lower than those with higher rice consumption (OR: 2.39 vs. 1.72). Our study supports a positive association between nickel exposure and diabetes prevalence in Chinese adults, especially in individuals with lower rice consumption. Further large-scale prospective studies are needed to validate our findings.

Reduction of miR-133a-3p contributes to apoptosis and gasdermin E-mediated pyroptosis of keratinocytes in skin exposed to ultraviolet B radiation.

Engagement of regulated cell death in keratinocytes plays a crucial role in the pathogenesis and development of skin disorders associated with UV radiation. However, it remains unclear how microRNAs (miRNAs) participate in the regulation of UV-caused keratinocyte death. In this study, we found that miR-133a-3p was decreased in the epidermis of UVB-challenged mice and UVB-irradiated keratinocyte cell line HaCaT cells. The intradermal injection of agomir miR-133a-3p ameliorated skin damage of UVB-challenged mice, especially epidermal necrosis. Meanwhile, the injection inhibited apoptosis indicator PARP cleavage and pyroptosis indicator GSDME cleavage in the epidermis. In UVB-challenged HaCaT cells, transfection of miR-133a-3p mimic or inhibitor alleviated or aggravated UVB-induced apoptosis and GSDME-mediated pyroptosis respectively. miR-133a-3p was also involved in the effects of metformin treatment on alleviating skin damage in UVB-challenged mice and on inhibiting apoptosis and GSDME-mediated pyroptosis in UVB-irradiated HaCaT cells. We confirmed that CYLD is a target gene of miR-133a-3p and participates in the protective effects of miR-133a-3p on inhibiting UVB-caused apoptosis and GSDME-mediated pyroptosis in keratinocytes. This study indicates a pivotal role for miR-133a-3p of keratinocytes in UVB-caused skin damage. Alleviating skin photodamage by restoring the decrease of miR-133a-3p can be considered a potential therapeutic approach.

Association of low cadmium and mercury exposure with chronic kidney disease among Chinese adults aged ≥80 years: A cross-sectional study.

BACKGROUND: The heavy metals cadmium (Cd) and mercury (Hg) are known to be widespread environmental contaminants and high occupational exposure adversely affects the risk of chronic kidney disease (CKD). However, evidence from epidemiological studies linking low Cd and Hg exposure (or non-industrial) to the risk of progression to CKD are conflicting. This study aimed to explore the association of low Cd and Hg exposure with the risk of CKD in Chinese adults aged ≥80 years. METHODS: The participants were recruited for the Healthy Aging and Biomarkers Cohort Study in 2017, an ongoing perspective survey conducted in longevity areas in China initially involving 3016 older adults. We used logistic regression models to estimate odds ratios (ORs) with 95% confidence intervals of CKD setting Cd and Hg as categorical variables. Logistic regression with restricted cubic spline was used to characterize a dose-response relationships between Cd or Hg concentrations and the risk of CKD in the study population. RESULTS: The ORs for the risk of CKD comparing the fourth to the first quartile of blood Cd, blood Hg, urine Cd, and urine Hg were 1.77, 1.57, 2.03, and 1.50, respectively. Restricted cubic spline models showed that blood Cd and urine Hg were significantly linearly correlated with the risk of CKD, while blood Hg and urine Cd were non-linearly correlated with the risk of CKD with a steeper slope at concentrations <2.30 µg/L and 3.30 µg/g creatinine. CONCLUSIONS: Our findings suggest that even low Cd and Hg exposure (or non-industrial) were associated with increased risk of CKD in Chinese oldest old, although we did not find a significant multiplicative and additive interaction between Cd and Hg levels in relation to the risk of CKD.

Urinary Creatinine Concentrations and Its Explanatory Variables in General Chinese Population: Implications for Creatinine Limits and Creatinine Adjustment.

Objective: The study aimed to analyze the applicability of the World Health Organization's exclusionary guidelines for Urinary creatinine (Ucr) in the general Chinese population, and to identify Ucr related factors. Methods: We conduct a cross-sectional study using baseline data from 21,167 participants in the China National Human Biomonitoring Program. Mixed linear models and restricted cubic splines (RCS) were used to analyze the associations between explanatory variables and Ucr concentration. Results: The geometric mean and median concentrations of Ucr in the general Chinese population were 0.90 g/L and 1.01 g/L, respectively. And 9.36% samples were outside 0.3-3.0 g/L, including 7.83% below the lower limit and 1.53% above the upper limit. Middle age, male, obesity, smoking, higher frequency of red meat consumption and chronic kidney disease were associated significantly with higher concentrations of Ucr. Results of the RCS showed Ucr was positively and linearly associated with body mass index, inversely and linearly associated with systolic blood pressure, diastolic blood pressure, triglycerides level, and glomerular filtration rate, and were non-linearly associated with triiodothyronine. Conclusion: The age- and gender-specific cut-off values of Ucr that determine the validity of urine samples in the general Chinese population were recommended. To avoid introducing bias into epidemiologic associations, the potential predictors of Ucr observed in the current study should be considered when using Ucr to adjust for variations in urine dilution.

GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils.

Gasdermin E (GSDME)-mediated pyroptosis is induced in keratinocytes of UVB-challenged skin. The role of GSDME in UVB-caused skin damage remains unknown. To explore the role of GSDME in UVB-induced skin inflammation. We compared differences in skin appearance, histological features, keratinocyte death modalities, infiltration of immune cells, and levels of some inflammatory cytokines between Gsdme-/- mice and wild type (WT) mice after UVB exposure. We explored whether keratinocytes contribute to GSDME deficiency-caused aggravation of UVB-induced skin inflammation in GSDME knockdown keratinocyte cultured in vitro and keratinocyte-specific Gsdme conditional knockout mice. We used anti-Ly6G antibody to deplete neutrophils and explore their role in UVB-caused skin damage. Skin damage and neutrophils infiltration were aggravated in UVB-challenged Gsdme-/- mice, compared with UVB-challenged WT mice. Apoptosis and necroptosis, which were initiated together with GSDME-mediated pyroptosis in UVB-challenged WT mice, were not enhanced in UVB-challenged Gsdme-/- mice. Neutrophils activation indicators and its recruiting cytokines were increased in skin tissue of UVB-challenged Gsdme-/- mice. However, GSDME knockdown did not lead to the further increase of mRNA and secretion of TNF-α and IL-6 in UVB-challenged keratinocytes. Skin damage was not aggravated in UVB-challenged Gsdme cKO mice. Neutrophils depletion alleviated UVB-caused skin damage in WT mice and Gsdme-/- mice, and eliminated its aggravation in Gsdme-/- mice. This study demonstrates that GSDME plays a restrictive role in UVB-induced skin damage through inhibiting excessive recruitment and activation of neutrophils in the immune microenvironment in UVB-caused skin inflammation. However, keratinocytes might not contribute to this restrictive function.

Clinical guideline for the diagnosis and treatment of cutaneous warts (2022).

AIM: Cutaneous warts caused by human papillomavirus are benign proliferative lesions that occur at any ages in human lives. Updated, comprehensive and systematic evidence-based guidelines to guide clinical practice are urgently needed. METHODS: We collaborated with multidisciplinary experts to formulate this guideline based on evidences of already published literature, focusing on 13 clinical questions elected by a panel of experts. We adopted Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to form classification of recommendations as well as the improved Delphi method to retain respective recommendations with a consensus degree of over 80%. RESULTS: Our guideline covered aspects of the diagnosis and treatment of cutaneous warts such as diagnostic gold standard, transmission routes, laboratory tests, treatment principle, clinical cure criterion, definitions, and treatments of common warts, flat warts, plantar warts, condyloma acuminatum, and epidermodysplasia verruciformis. Recommendations about special population such as children and pregnant women are also listed. In total, 49 recommendations have been obtained. CONCLUSIONS: It is a comprehensive and systematic evidence-based guideline and we hope this guideline could systematically and effectively guide the clinical practice of cutaneous warts and improve the overall levels of medical services.

Abelson tyrosine kinase controls BCR signalling and B-cell differentiation by promoting B-cell metabolism.

As a nonreceptor tyrosine kinase, Abelson tyrosine kinase (c-Abl) was first studied in chronic myelogenous leukaemia, and its role in lymphocytes has been well characterised. c-Abl is involved in B-cell development and CD19-associated B-cell antigen receptor (BCR) signalling. Although c-Abl regulates different metabolic pathways, the role of c-Abl is still unknown in B-cell metabolism. In this study, B-cell-specific c-Abl knockout (KO) mice (Mb1Cre+/- c-Ablfl/fl ) were used to investigate how c-Abl regulates B-cell metabolism and BCR signalling. We found that the levels of activation positive BCR signalling proximal molecules, phosphorylated spleen tyrosine kinase (pSYK) and phosphorylated Bruton tyrosine kinase (pBTK), were decreased, while the level of key negative regulator, phosphorylated SH2-containing inositol phosphatase 1 (pSHIP1), was increased in Mb1Cre+/- c-Ablfl/fl mice. Furthermore, we found c-Abl deficiency weakened the B-cell spreading, formation of BCR signalosomes, and the polymerisation of actin during BCR activation, and also impaired the differentiation of germinal center (GC) B-cells both in quiescent condition and after immunisation. Moreover, B-cell mitochondrial respiration and the expression of B-cell metabolism-regulating molecules were downregulated in c-Abl deficiency mice. Overall, c-Abl, which involved in actin remodelling and B-cell metabolism, positively regulates BCR signalling and promotes GC differentiation.

Trehalose Protects Keratinocytes against Ultraviolet B Radiation by Activating Autophagy via Regulating TIMP3 and ATG9A.

Trehalose, a natural disaccharide, is synthesized by many organisms when cells are exposed to stressful stimuli. On the basis of its ability to modulate autophagy, trehalose has been considered an innovative drug for ameliorating many diseases, but its molecular mechanism is not well described. Previous findings demonstrated that trehalose plays a photoprotective role against ultraviolet (UV) B-induced damage through autophagy induction in keratinocytes. In this study, coimmunoprecipitation, label-free quantitative proteomic and parallel reaction monitoring, and western blot analysis demonstrated that trehalose promotes the interaction between tissue inhibitor of metalloproteinase (TIMP) 3 and Beclin1. Western blot and immunofluorescence staining analysis suggested that trehalose increases ATG9A localization in lysosomes and decreases its localization in the endoplasmic reticulum. Furthermore, in the presence or absence of UVB radiation, we evaluated the influence of TIMP3 and ATG9A small interfering RNA (siRNA) on the effect of trehalose on autophagy, cell death, migration, or interleukin-8 expression in keratinocytes, including HaCaT, A431, and human epidermal keratinocytes. The results revealed that in HaCaT cells, TIMP3 and ATG9A siRNA resulted in attenuation of trehalose-induced autophagy and inhibited cell death. In A431 cells, TIMP3 and ATG9A siRNA led to attenuation of trehalose-induced autophagy and cell death and inhibited migration. In human epidermal keratinocytes, trehalose-induced autophagy and inhibition of the interleukin-8 expression were blocked by ATG9A but not TIMP3 siRNA. In addition, the results of quantitative real-time PCR and immunohistochemistry analysis demonstrated the abnormal expression of TIMP3 and ATG9A in actinic keratosis and cutaneous squamous cell carcinoma skin tissues. These findings suggest the protective effects of trehalose in normal keratinocytes and its inhibitory effects on cancerous keratinocytes, possibly mediated by activation of autophagy and regulation of TIMP3 and ATG9A, providing the mechanistic basis for the potential use of trehalose in the prevention or treatment of UVB-induced skin diseases.

Single nucleotide polymorphisms in binding site of miRNA-135a and targeted gene IRS2 are correlated with multiple clinical features of PCOS: A study in Chinese women.

BACKGROUND: The etiology of polycystic ovary syndrome (PCOS) remains unclear with highly heterogeneous clinical manifestations, recently growing evidence revealing genetic variants play a crucial part in its pathogenesis. OBJECTIVE: This study aimed to examine the correlation between SNPs in miRNA-135a's binding site of targeted gene IRS2 and clinical manifestations of PCOS in Chinese females. METHOD: A total of 126 Chinese women with PCOS and 109 healthy women were enrolled, divided into 4 groups based on different clinical features of hyperandrogenemia (HA), insulin resistance (IR), polycystic ovary morphology (PCOM) and obesity. We analyzed 2 single nucleotide polymorphisms (SNPs) of the IRS2 gene (rs2289046 and rs1865434) and clinical features' laboratory measurements such as sex hormone, fasting plasma glucose (FPG), fasting plasma insulin (FINS). RESULTS: Located in miRNA-135a binding site of IRS2 gene, the rs2289046's triple genotypes distribution showed a significant difference between PCOS/control group and PCOM/non-PCOM group (P< 0.05) while the rs1865434's triple genotype distribution showed a significant difference between obesity/non-obesity group (P< 0.05). CONCLUSION: The results revealed the two SNPs as rs2289046 and rs1865434 in the IRS-2 binding region of miRNA-135a have correlations with the clinical features of PCOS in Chinese population.

Effectiveness of Using Mean Corpuscular Volume and Mean Corpuscular Hemoglobin for Beta-thalassemia Carrier Screening in the Guangdong Population of China.

Beta (ß)-thalassemia is one of the most common hemoglobinopathies worldwide, creating major public health problems and social burdens in many regions. Screening for ß-thalassemia carriers is crucial for controlling this condition. To investigate the effectiveness of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) for screening ß-thalassemia, retrospective data were analyzed for 6,779 ß-thalassemia carriers subjected to genetic testing following thalassemia screening in Guangdong province between January 2018 and December 2019. Prevalent mutations observed included CD41/42 (-TTCT) (38.43%), IVS-II-654 (C > T) (25.71%), -28 (A > G) (15.78%), CD17 (AAG > TAG) (10.03%), and ß E (GAG > AAG) (3.13%). In the ß 0, ß +, and HbE groups, MCV values were 63.8 ± 4.2 fL, 67.0 ± 5.5 fL, and 75.8 ± 5.6 fL, while MCH values were 20.1 ± 1.4 pg, 21.2 ± 1.9 pg, and 24.8 ± 2.0 pg, respectively. Among ß-thalassemia carriers, 85 (1.25%) and 28 (0.41%) individuals had MCV ≥ 80 fL and MCH ≥ 27 pg, respectively. Using a combination of MCV and MCH reduced the number of false negative screenings to 15 (0.22%). Therefore, evaluating both MCV and MCH is strongly recommended for screening ß-thalassemia carriers.

Evaluation of IGRT-Induced Imaging Doses and Secondary Cancer Risk for SBRT Early Lung Cancer Patients In Silico Study.

OBJECTIVES: This study performed dosimetry studies and secondary cancer risk assessments on using electronic portal imaging device (EPID) and cone beam computed tomography (CBCT) as image guided tools for the early lung cancer patients treated with SBRT. METHODS: The imaging doses from MV-EPID and kV-CBCT of the Edge accelerator were retrospectively added to sixty-one SBRT treatment plans of early lung cancer patients. The MV-EPID imaging dose (6MV Photon beam) was calculated in Pinnacle TPS, and the kV-CBCT imaging dose was simulated and calculated by modeling of the kV energy beam in TPS using Pinnacle automatic modeling program. Three types of plans, namely PlanEPID, PlanCBCT and Planorigin, were generated with incorporating doses of EPID, CBCT and no imaging, respectively, for analysis. The effects of imaging doses on dose-volume-histogram (DVH) and plan quality were analyzed, and the excess absolute risk (EAR) of secondary cancer for ipsilateral lung was evaluated. RESULTS: The regions that received less than 50 cGy were significantly impacted by the imaging doses, while the isodose lines greater than 1000 cGy were barely changed. The DVH values of ipsilateral lung increased the most in PlanEPID, followed by PlanCBCT. Compared to Planorigin on the average, the estimated EAR of ipsilateral lung in PlanEPID increased by 3.43%, while the corresponding EAR increase in PlanCBCT was much smaller (about 0.4%). Considering only the contribution of the imaging dose, the EAR values for the ipsilateral lung due to the MV-EPID dose in 5 years,10 years and 15 years were 1.49 cases, 2.09 cases and 2.88 cases per 104PY respectively, and those due to the kV-CBCT dose were about 9 times lower, correspondingly. CONCLUSIONS: The imaging doses produced by MV-EPID and kV-CBCT had little effects on the target dose coverage. The secondary cancer risk caused by MV-EPID dose is more than 8.5 times that of kV-CBCT.