Associations between 25 hydroxyvitamin D concentration and spontaneous abortion.

BACKGROUND: Spontaneous abortion is a common complication of pregnancy that can lead to adverse physical and psychological outcomes for women. Vitamin D is reported to be associated with reproductive functions, whereas its casual effects on abortion remains unclear. MATERIALS AND METHODS: In this study, a two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between serum 25 hydroxyvitamin D [25(OH)D] concentration and the risk of spontaneous abortion. GWAS summary data of 25(OH)D were used as exposure, and data of spontaneous abortion was considered as outcome. A retrospective study was additionally conducted to verify the MR results. RESULTS: MR estimates showed that a higher 25(OH)D level was potentially associated with decreased risk of spontaneous abortion (IVW, OR = 0.98, 95%CI = 0.90-1.06; MR Egger, OR = 0.94, 95%CI = 0.84-1.05; Weighted median, OR = 0.93, 95%CI = 0.82-1.06; Weighted mode, OR = 0.93, 95%CI = 0.84-1.03), though the P-value was not statistically significant. The retrospective study also produced consistent result of Vitamin D's protective role to spontaneous abortion. The P-value was very close to statistical significance (P = 0.053). CONCLUSIONS: This study reports the potential protective role of serum 25(OH)D concentration to spontaneous abortion, suggesting that increased vitamin D levels may decrease the risk of abortion. Further larger prospective studies and/or even randomized controlled trials are needed to confirm causal relationship between vitamin D and abortion.

Proteome-wide analysis reveals potential therapeutic targets for Colorectal cancer: a two-sample mendelian randomization study.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting an unmet clinical need for more effective therapies. This study aims to evaluate the causal relationship between 4,489 plasma proteins and CRC to identify potential therapeutic targets for CRC. METHODS: We conducted two-sample Mendelian randomization (MR) analysis to examine the causal effects of plasma proteins on CRC. Mediation analysis was performed to assess the indirect effects of plasma proteins on CRC through associated risk factors. In addition, we conducted a phenome-wide association study using the UK Biobank dataset to examine associations between these plasma proteins and other phenotypes. RESULTS: Out of 4,489 plasma proteins, MR analysis revealed causal associations with CRC for 23 proteins, including VIMP, MICB, TNFRSF11B, C5orf38 and SLC5A8. Our findings also confirm the associations between reported risk factors and CRC. Mediation analysis identified mediating effects of proteins on CRC outcomes through risk factors. Furthermore, MR analysis identified 154 plasma proteins are causally linked to at least one CRC risk factor. CONCLUSIONS: Our study evaluated the causal relationships between plasma proteins and CRC, providing a more complete understanding of potential therapeutic targets for CRC.

NSD1 promotes esophageal cancer tumorigenesis via HIF1α signaling.

Unlike angiogenesis in normal tissues, tumor angiogenesis is typically dysregulated, during which the HIF1/VEGFA signaling pathway plays a pivotal role. Solid tumors generate immature vessels, which promote tumor progression and treatment resistance. NSD1 can di-methylate histone 3 lysine 36 and regulate transcription factors binding to the promoters of various genes. However, the role of NSD1 in tumorigenesis remains elusive. Here, we evaluated the relationship between NSD1 signaling and HIF1 signaling. It was found that NSD1 transcriptionally regulates HIF1α expression by recruiting STAT3 molecule into the HIF1α promoter. In vivo xenograft experiments further confirmed that HIF1α and STAT3 maintenance is essential for NSD1-mediated tumor progression and angiogenesis. Therefore, the NSD1/STAT3/HIF1α signaling pathway may be a novel and effective treatment target for ESCA.

Contrast-enhanced 3D-T2-weighted SPACE sequence for MRI detection and localization of adrenocorticotropin (ACTH)-secreting pituitary microadenomas.

OBJECTIVE: Cushing disease is a potentially fatal endocrine disorder caused by adrenocorticotropin (ACTH)-secreting microadenomas in the pituitary gland. Accurate detection and localization of the adenomas is the key to clinical treatment. This study analysed the value of contrast-enhanced Sampling Perfection with Application-optimized Contrasts using different flip angle Evolutions (SPACE) sequence in magnetic resonance imaging (MRI) assessment of ACTH-secreting pituitary microadenomas. DESIGN AND PATIENTS: We carried out a retrospective study in which 45 patients with ACTH-secreting pituitary microadenomas were enrolled. Dynamic contrast-enhanced (DCE) coronal T1-SE sequence was performed. A contrast-enhanced coronal SPACE sequence was added immediately after DCE MRI finished. Two independent observers assessed the tumour existence and location, then the results were compared with surgical findings. RESULTS: Twenty-four lesions (53.3%) were detected by the DCE T1-SE sequence alone, while 35 lesions (80.0%) were detected with the addition of contrast-enhanced SPACE sequence. The sensitivity (58.5% vs. 85.3%; p < .05) and best diagnostic accuracy (62.0% vs. 84.4%; p < .05) were significantly better for addition with SPACE sequence than DCE-SE images alone in detection of ACTH-secreting pituitary microadenomas. For lesions <5 mm, the detected numbers were 4 (16.6%) versus 10 (27.8%) by DCE T1-SE sequence and combined DCE T1-SE with SPACE sequence. CONCLUSIONS: A combination of contrast-enhanced SPACE with DCE T1-SE sequence could improve the detection of ACTH-secreting pituitary microadenomas. Contrast-enhanced SPACE sequence could be a supplementary sequence for imaging of ACTH-secreting pituitary adenomas when T1-SE sequence provides negative or equivocal findings.

Double-lumen tube versus bronchial blocker in lymphadenectomy along the left recurrent laryngeal nerve for esophageal cancer: a propensity-matched analysis.

BACKGROUND: Lymph node (LN) dissection along left recurrent laryngeal nerve (RLN) is challenging in esophagectomy for esophageal cancer, and double-lumen endotracheal tube (DLT) impedes the exposure of this area. The aim of this study was to determine whether bronchial blockers (BB) could be a better choice for this procedure. METHODS: The clinical characteristics of patients who received McKeown esophagectomy with radical lymph node dissection in Wuhan Tongji Hospital between August 2017 and July 2019 were retrospectively analyzed. The 1:1 propensity score match analysis was performed to compare the short-term effectiveness, the numbers of lymph nodes dissected, and the patterns of recurrence and survival between the two groups. RESULTS: A total of 294 patients (192 and 102 in the DLT and BB group, respectively) were enrolled in the study. After matching, 204 patients (102 pairs) who underwent one-lung ventilation with DLT or BB displayed no significant variance in baseline characteristics. The BB group had higher number of LNs resected along left RLN (1.8 ± 2.3 vs. 2.5 ± 2.5, P = 0.001). For patients with metastatic left RLN LN, the BB group had longer medium survival time (15 vs. 32 months, P = 0.045), and tended to have longer medium recurrence-free survival time (6 vs. 15 months, P = 0.079), and lower rate of upper mediastinal and cervical LN recurrence (30.00% vs. 66.67%, P = 0.198). The postoperative complications were similar in both groups. CONCLUSIONS: Compared with DLT, using BB in esophagectomy may allow more radical lymphadenectomy along left RLN.

ATF5 and HIF1α cooperatively activate HIF1 signaling pathway in esophageal cancer.

BACKGROUND: Esophageal cancer (ESCA) is one of the most common cancers worldwide and has a very poor prognosis. Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a critical role in tumorigenesis and is therefore considered a potential therapeutic target in the treatment of many cancers. Activating transcription factor 5 (ATF5) facilitates the expression of various genes and has been extensively studied for its potential role in cancer treatment. METHODS: The expression level of ATF5 in clinic sample was detected by quantitative real time PCR and immunohistochemistry. ATF5 biological function was investigated by western blot, cell cycle analysis, cell viability assay, luciferase reporter assays, colony formation assay, transwell assay, wound healing assay, tube formation assay, and ELISA assay. CHIP and Re-CHIP assay, GST-pulldown, and RNA-sequencing were used to study the cross-talks between ATF5 and HIF1 complex. Mouse xenograft study was utilized to study the correlation of ATF5 and tumor growth in vivo. Student's t-test or Chi-square test was used for statistical analysis. RESULTS: Here, we first found ATF5 was dramatically upregulated in ESCA cancer and related with poor survival time. Next, we found that the expression level of ATF5 had a positive relationship with the proliferation, migration, and invasion ability of ESCA cells. Besides, we innovatively found that ATF5 functions as a novel coactivator in HIF1 transcription complex by binding to HIF1α. Further, we demonstrated that silencing ATF5 phenocopies HIF1α knockdown in tumorigenic properties in vitro and inhibited ESCA tumor angiogenesis and proliferation in vivo. CONCLUSION: Herein, we found ATF5 as a novel component of the HIF1 transcription complex. The findings of the present study may provide new insights into the development of a novel and more efficient therapeutic strategy against ESCA. Video abstract.

Pretreatment clamping of pulmonary artery during uniportal thoracoscopic lobectomy.

BACKGROUND: Intraoperative pulmonary artery (PA) hemorrhage is one of the leading reasons for conversion from uniportal VATS to open thoracotomy, especially for the small incision (≤3 cm) uniportal VATS performed by our department. So, We designed a technology called pretreatment clamping of the pulmonary artery, which may be helpful to solve the problem. METHODS: A retrospective analysis of 19 patients who had pulmonary artery bleeding during uniportal thoracoscopic lobectomy in which one group had undergone preventive pulmonary artery clamping, the clamping group (n = 11), and one group which did not receive preventive clamping, the non-clamping group (n = 8). We compared the rates of conversion from the uniportal VATS approach to open thoracotomy or multi-incision operation, duration of pulmonary artery repair, blood loss, length of postoperative hospital stay and postoperative complications of the two groups. RESULTS: Compared to the non-clamping group, the clamping group had lower rates of conversion to open thoracotomy (0% vs 62.5%, p < 0.05) and lower rates of conversion to multi-incision operations (18.2% of non-clamping converted to 2-port approach vs 12.5% of clamping converted to 2-port approach and 12.5% converted to 3-port approach, p < 0.05). Duration of pulmonary artery repair was reduced in the clamping group (10.1 ± 3.2 min vs 18.3 ± 5.5 min, p < 0.05). The clamping group also had decreased blood loss (23.6 ± 11.2 ml vs 47.5 ± 14.9 ml, p<0.05). There were no significant differences in postoperative hospital stay and postoperative complications between the two groups. CONCLUSION: Pretreatment clamping of the pulmonary artery in VATS lobectomy can decrease conversion rates, decrease blood loss, shorten repairing time of the pulmonary artery, and feasibly can be applied in uniportal thoracoscopic lobectomy.

[Comparison of Recovery Phase CT Features between Mild/moderate and Severe/critical Coronavirus Disease 2019 Patients].

Objective To investigate the computed tomographc(CT)features of mild/moderate and severe/critical cases of coronavirus disease 2019(COVID-19)in the recovery phase. Methods Totally 63 discharged patients in Wuhan,China,who underwent both chest CT and reverse transcription-polymerase chain reaction(RT-PCR)from February 1 to February 29,2020,were included.With RT-PCR as a gold standard,the performance of chest CT in diagnosing COVID-19 was assessed.Patients were divided into mild/moderate and severe/critical groups according to the disease conditions,and clinical features such as sex,age,symptoms,hospital stay,comorbidities,and oxygen therapy were collected.CT images in the recovery phase were reviewed in terms of time from onset,CT features,location of lesions,lobe score,and total CT score. Results There were 37 patients in the mild/moderate group and 26 in the severe/critical group. Compared with the mild/moderate patients,the severe/critical patients had older age [(43±16) years vs. (52±16) years; t=2.10, P=0.040], longer hospital stay [(15±6)d vs. (19±7)d; t=2.70, P=0.009], higher dyspnea ratio (5.41% vs. 53.85%; χ2=18.90, P<0.001), lower nasal oxygen therapy ratio (81.08% vs. 19.23%;χ2=23.66, P<0.001), and higher bi-level positive airway pressure ventilation ratio (0 vs. 57.69%; χ2=25.62, P<0.001). Time from onset was (23±6) days in severe/critical group, significantly longer than that in mild/moderate group [(18±7) days] (t=3.40, P<0.001). Severe/critical patients had significantly higher crazy-paving pattern ratio (46.15% vs.10.81%;χ2=4.24, P=0.039) and lower ground-glass opacities ratio (15.38% vs. 67.57%; χ2=16.74, P<0.001) than the mild/moderate patients. The proportion of lesions in peripheral lung was significantly higher in mild/moderate group than in severe/critical group (78.38% vs.34.61%; χ2=13.43, P<0.001), and the proportion of diffusely distributed lesions was significantly higher in severe/critical group than in mild/moderate group (65.38% vs.10.81%; χ2=20.47, P<0.001). Total CT score in severe/critical group was also significantly higher in severe/critical group than in mild/moderate group [11 (8,17) points vs. 7 (4,9) points; Z=3.81, P<0.001]. Conclusions The CT features in the recovery stage differ between mild/moderate and severe/critical COVID-19 patients.The lung infiltration is remarkably more severe in the latter.

Adsorption and Desorption Performance and Mechanism of Tetracycline Hydrochloride by Activated Carbon-Based Adsorbents Derived from Sugar Cane Bagasse Activated with ZnCl2.

Adsorption and desorption behaviors of tetracycline hydrochloride by activated carbon-based adsorbents derived from sugar cane bagasse modified with ZnCl2 were investigated. The activated carbon was tested by SEM, EDX, BET, XRD, FTIR, and XPS. This activated carbon exhibited a high BET surface area of 831 m2 g-1 with the average pore diameter and pore volume reaching 2.52 nm and 0.45 m3 g-1, respectively. The batch experimental results can be described by Freundlich equation, pseudo-second-order kinetics, and the intraparticle diffusion model, while the maximum adsorption capacity reached 239.6 mg g-1 under 318 K. The effects of flow rate, bed height, initial concentration, and temperature were studied in fixed bed adsorption experiments, and adsorption data were fitted with six dynamic adsorption models. The results of characterizations and the batch experiments were analyzed to study the adsorption and desorption mechanisms. Tetracycline hydrochloride and activated carbon were bonded together by π-π interactions and cation-π bonds. Ethanol was used as an eluent which bonded with 10 hydrogen bond acceptors on tetracycline hydrochloride to form a complex by hydrogen bonding to achieve recycling.

IFN-γ-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling.

IFN-γ plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-γ might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN-γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-γ and PD-L1 have the best prognosis compared to those with tumors expressing IFN-γ or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-γ display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD-L1+ but not PD-L1- tumors. The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)-mediated anti-tumor progression. However, our data indicate that PD-L1 expression in the presence of IFN-γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-γ-induced activation of JAK2-STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-γ. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-γ, suggesting that blockade of PI3K might maximize the IFN-γ-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

Effect of a microbial phytase on growth performance, plasma parameters and apparent ileal amino acid digestibility in Youxian Sheldrake fed a low-phosphorus corn-soybean diet.

OBJECTIVE: This study investigated the effect of microbial phytase supplementation on growth performance, tibia ash, plasma parameters, apparent ileal digestibility (AID) of amino acid (AA) and apparent digestibility of nutrients in Youxian Sheldrakes fed with low-phosphorus (P) corn-soybean diets. METHODS: A total of 350 Youxian Sheldrakes (7d old) were randomly divided into 5 treatment groups: positive control (PC) group has adequate available P diet (0.42% and 0.38%, starter and grower), negative control (NC) group were deficient in available P (0.32% and 0.28%, starter and grower) and NC diet was supplemented with 3 levels of microbial phytase (500, 750, and 1,000 U/kg). RESULTS: Dietary supplementation of phytase in NC diet improved the average daily gain, increased the levels of serum calcium (Ca), tibia Ca and P, AID of AA and apparent digestibility of energy and Ca in starter stage (p<0.05). There was an increased (p<0.001) in the utilization of P from 17.3% to 23.9%. Phytase supplementation (1,000 U/kg) has shown that the AID of His, Thr, Val, indispensable AA, Glu, Pro, and dispensable AA was higher (p<0.05) than that of NC. Moreover, phytase supplementation improved (p<0.05) serum and tibia Ca and P, AID of AA and apparent digestibility of dry matter, crude protein, energy, P and Ca, and reduced (p<0.05) feed to gain ratio (F/G) and the levels of serum alkaline phosphatase in grower stage. Likewise, an increase (p<0.001) in the utilization of P was noticed from 12.6% to 17.2%. Supplement phytase at 750 U/kg improved the AID of His, Thr, Asp, Cys, Pro, and Ser (p<0.05). CONCLUSION: The microbial phytase supplement could improve growth performance, AID of some AA and apparent utilization of other nutrients in Youxian Sheldrakes, and reduce excreta P load to environment.

Genetic variants in the ITGB6 gene is associated with the risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy.

The αvß6 integrin is a cell surface adhesion molecule that plays critical roles in the injury and inflammation processes. We hypothesized that polymorphisms in αvß6 integrin genes (ITGAV and ITGB6) might be associated with the risk of radiation pneumonitis (RP) in lung cancer patients treated with thoracic radiation. We genotyped three potentially functional αvß6 integrin single-nucleotide polymorphisms (rs1839123 and rs4129787 in ITGAV, and rs4665162 in ITGB6) and found that the genotypes of rs4665162 single-nucleotide polymorphisms were predictors of RP development (for grade ≥2 RP, HR = 1.505, 95 % CI 1.069-2.119, P = 0.019; for grade ≥3 RP, HR = 3.006, 95 % CI 1.431-6.313, P = 0.004). Our results showed that AG/GG genotypes of ITGB6 rs4665162 gene were associated with a higher risk of RP in patients with lung cancer receiving radiotherapy and thus may serve as a reliable predictor of RP. Further studies will be needed to confirm these findings.

Immunohistochemistry with a novel mutation-specific monoclonal antibody as a screening tool for the EGFR L858R mutational status in primary lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutation status is the best predictor of patient response to treatments with tyrosine kinase inhibitors in primary lung adenocarcinoma and is typically analyzed by DNA-based techniques, such as direct DNA sequencing and allele-specific PCR. Recently, however, two mutation-specific antibodies against delE746-A750 in exon 19 and L858R in exon 21 have opened the door for a more convenient and more efficient strategy to determine EGFR mutation status. To evaluate the clinical application of a new mutation-specific mouse monoclonal antibody for EGFR (L858R), we performed immunohistochemistry (IHC) studies with tumor samples from primary lung adenocarcinoma in retrospective and validation settings. A total of 215 cases of primary lung adenocarcinoma were examined and compared using a combination of DNA-based techniques (direct DNA sequencing and/or allele-specific PCR) and protein-based IHC. IHC staining was assessed on a 0 to 3+ score scale, and a cutoff value of 2+ was used as positive by IHC. In the retrospective setting, statistical analyses of the data showed that the sensitivity of IHC was 90.9% and the specificity was 96.8%. Findings from the validation study demonstrated that the sensitivity and specificity of IHC were 88.2% and 100%, respectively. IHC with the novel mutation-specific antibody could be used as a screening method to assess the EGFR L858R mutation status in primary lung adenocarcinoma.

Multiple metallic foreign bodies accidentally detected in different body cavities: a case report.

We accidentally found an unusual case of a middle aged Tibetan woman who had eight metallic foreign bodies (eight needles) in her head, chest and abdomen. These needles were not related to any surgical intervention or trauma. The diagnosis "metallic foreign bodies" cannot usually be made in an acute setting. Some patients may present chronic symptoms, such as infection or pain. However, in some cases, the patients do not have any symptoms.

Type B thymomas in patients with myasthenia gravis display a distinctive pattern of αß TCR and IL-7 receptor α expression on CD4+CD8+ thymocytes.

Thymoma is closely associated with myasthenia gravis (MG). However, due to the heterogeneity of thymoma and the intricate pathogenesis of MG, it remains unclear why some patients with thymoma develop MG and others do not. In this study, we conducted a comparative phenotype analysis of thymocytes in type B thymomas in patients with MG (MG (+) thymomas) and without MG (MG (-) thymomas) via fluorescence-activated cell sorting (FACS). Our results show that the developmental stages defined by the expression of CD3, CD4, and CD8 were largely maintained in both MG (+) and MG (-) thymomas, with CD4+CD8+ cells constituting the majority of thymocytes in type B thymoma, and no significant difference between this cell population was observed in MG (+) and MG (-) thymomas.We discovered that CD4+CD8+ thymocytes in MG (+) thymomas expressed low levels of αß TCR and high levels of IL-7 receptor α (IL-7Rα), whereas in MG (-) thymomas, CD4+CD8+ thymocytes exhibited the opposite pattern of αß TCR and IL-7Rα expression. These results suggest that the positive and negative selection processes of CD4+CD8+ thymocytes might differ between MG (+) thymomas and MG (-) thymomas. The expression of the Helios transcription factor is induced during negative selection and marks a group of T cells that have undergone negative selection and are likely to be deleted due to strong TCR binding with self-peptides/MHC ligands. We observed that the percentage of Helios-positive CD4SP T cells was greater in MG (-) than in MG (+) thymomas. Thus, the differentially regulated selection process of CD4+CD8+ thymocytes, which involves TCR and IL-7/IL-7Rα signaling, is associated with the presence of MG in type B thymomas.

Proteomic analysis reveals potential therapeutic targets for childhood asthma through Mendelian randomization.

BACKGROUND: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets. METHODS: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset. RESULTS: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes. CONCLUSION: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.

Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses.

Purpose: NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Methods: Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Results: Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Conclusions: Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.

Trio-based whole-exome sequencing reveals mutations in early-onset high myopia.

PURPOSE: Myopia, especially high myopia (HM), represents a widespread visual impairment with a globally escalating prevalence. This study aimed to elucidate the genetic foundations associated with early-onset HM (eoHM) while delineating the genetic landscape specific to Shaanxi province, China. METHODS: A comprehensive analysis of whole-exome sequencing was conducted involving 26 familial trios displaying eoHM. An exacting filtration protocol identified potential candidate mutations within acknowledged myopia-related genes and susceptibility loci. Subsequently, computational methodologies were employed for functional annotations and pathogenicity assessments. RESULTS: Our investigation identified 7 genes and 10 variants associated with HM across 7 families, including a novel mutation in the ARR3 gene (c.139C>T, p.Arg47*) and two mutations in the P3H2 gene (c.1865T>C, p.Phe622Ser and c.212T>C, p.Leu71Pro). Pathogenic mutations were found in syndromic myopia genes, notably encompassing VPS13B, TRPM1, RPGR, NYX and RP2. Additionally, a thorough comparison of previously reported causative genes of syndromic myopia and myopia risk genes with the negative sequencing results pinpointed various types of mutations within risk genes. CONCLUSIONS: This investigation into eoHM within Shaanxi province adds to the current understanding of myopic genetic factors. Our results warrant further functional validation and ocular examinations, yet they provide foundational insights for future genetic research and therapeutic innovations in HM.

Genetic variation in a miR-335 binding site in BIRC5 alters susceptibility to lung cancer in Chinese Han populations.

Polymorphisms in 3' untranslated region (UTR) of cancer-related genes might affect their regulation by microRNAs (miRNAs) and thereby contribute to carcinogenesis. In this study, we screened single nucleotide polymorphisms (SNPs) in 3' UTR of cancer-related genes and investigated their effects on risk of lung cancer. First, we genotyped seven SNPs in a Chinese Han population with 600 lung cancer patients and 600 matched healthy controls and found that compared with the TT genotype of rs2239680 in 3' UTR of baculoviral IAP repeat containing 5 (BIRC5), C allele was associated with a significantly increased risk of lung cancer and advanced pathologic stage, with the odds ratio for participants carrying the CT or CC genotype being 1.50 [95% confidence interval (CI) 1.20-1.89, P<0.01] and 2.29 (95% CI 1.64-3.18, P<0.01), respectively. These results were further replicated and confirmed in another independent population with 1000 lung cancer cases and 1000 matched healthy controls. In support of the postulation that the 3' UTR SNP may directly affect miRNA-binding site, reporter gene assays indicated BIRC5 was a direct target of miR-335, and the rs2239680 T>C change resulted in altered regulation of BIRC5 expression. Moreover, BIRC5 was over expressed in lung cancer tissues compared with the normal lung tissues, and the protein levels of BIRC5 correlated with SNP genotypes in normal lung tissues. Our findings defined a 3' UTR SNP in human BIRC5 oncogene that may increase individual susceptibility to lung cancer probably by attenuating the interaction between miR-335 and BIRC5.

Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns.

Diabetic wound is a great threat to patient's health and lives. The refractory diabetic wound shows spatial inflammation patterns, in which the early-wound pattern depicts a deprived acute inflammatory response, and the long-term non-healing wound pattern delineates an excessive and persistent inflammation due to the delayed immune cell infiltration in a positive feedback loop. In this work, we give points to some strategies to normalize the dysregulated immune process based on the spatial inflammation pattern differences in diabetic wound healing. First of all, inhibiting inflammatory response to avoid subsequent persistent and excessive immune infiltration for the early diabetic wound is proposed. However, diabetic wounds are unperceptive trauma that makes patients miss the best treatment time. Therefore, we also introduce two strategies for the long-term non-healing diabetic wound. One strategy is about changing chronic wounds to acute ones, which aims to rejuvenate M1 macrophages in diabetic wounds and make spontaneous M2 polarization possible. To activate the controllable proinflammatory response, western medicine delivers proinflammatory molecules while traditional Chinese medicine develops "wound-pus promoting granulation tissue growth theory". Another strategy to solve long-term non-healing wounds is seeking switches that target M1/M2 transition directly. These investigations draw a map that delineates strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns systematically.