Three novel QTLs for FHB resistance identified and mapped in spring wheat PI672538 by bulked segregant analysis of the recombinant inbred line.

Introduction: Fusarium head blight (FHB) has a large influence on both the yield and quality of wheat grain worldwide. Host resistance is the most effective method for controlling FHB, but unfortunately, very few genetic resources on FHB resistance are available; therefore, identifying novel resistance genes or quantitative trait loci (QTLs) is valuable. Methods: Here, a recombinant inbred line (RIL) population containing 451 lines derived from the cross L661/PI672538 was sown in four different environments (2019CZa, 2019CZb, 2021QL and 2021WJ). Results: Five QTLs, consisting of two previously reported QTLs (FhbL693a and FhbL693b) and three new QTLs (FhbL693c, FhbL693d and FhbL693e), were identified. Further investigation revealed that FhbL693b, FhbL693c and FhbL693d could be detected in all four environments, and FhbL693a and FhbL693e were detected only in 2019CZb and 2021WJ, respectively. Among the QTLs, the greatest contribution (10.5%) to the phenotypic variation effect (PVE) was FhbL693d in 2021WJ, while the smallest (1.2%) was FhbL693e and FhbL693a in 2019CZb. The selection of 5Dindel-4 for FhbL693d, 4Aindel-7 for FhbL693c and 3Bindel-24 for FhbL693b decreased the number of damaged spikelets by 2.1, and a new line resistant to FHB named H140-2 was developed by marker-assisted selection (MAS). Discussion: These results could help to further improve FHB resistance in the future.

Sequential Reductive Dechlorination of Triclosan by Sediment Microbiota Harboring Organohalide-Respiring Dehalococcoidia.

Aquatic ecosystems represent a prominent reservoir of xenobiotic compounds, including triclosan (TCS), a broad-spectrum biocide extensively used in pharmaceuticals and personal care products. As a biogeochemical hotspot, the potential of aquatic sediments for the degradation of TCS remains largely unexplored. Here, we demonstrated anaerobic biotransformation of TCS in a batch microcosm established with freshwater sediment. The initial 43.4 ± 2.2 µM TCS was completely dechlorinated to diclosan, followed by subsequent conversion to 5-chloro-2-phenoxyphenol, a monochlorinated TCS (MCS) congener. Analyses of community profile and population dynamics revealed substrate-specific, temporal-growth of Dehalococcoides and Dehalogenimonas, which are organohalide-respiring bacteria (OHRB) affiliated with class Dehalococcoidia. Dehalococcoides growth was linked to the formation of diclosan but not MCS, yielding 3.6 ± 0.4 × 107 cells per µmol chloride released. A significant increase in Dehalogenimonas cells, from 1.5 ± 0.4 × 104 to 1.5 ± 0.3 × 106 mL-1, only occurred during the reductive dechlorination of diclosan to MCS. Dehalococcoidia OHRB gradually disappeared following consecutive transfers, likely due to the removal of sediment materials with strong adsorption capacity that could alleviate TCS's antimicrobial toxicity. Consequently, a solid-free, functionally stable TCS-dechlorinating consortium was not obtained. Our results provide insights into the microbial determinants controlling the environmental fate of TCS.

Metagenomic Next-Generation Sequencing as an Effective Diagnostic Tool for Talaromycosis in HIV-Negative Patients.

The diagnosis of Talaromyces marneffei infection in HIV-negative patients remains challenging. There is an urgent need for rapid and convenient methods to diagnose this complicated disease. The aim of this study was to evaluate the diagnostic efficiency of metagenomic next-generation sequencing (mNGS) for talaromycosis in non-HIV-infected patients by comparing mNGS with traditional microbial culture. In total, 66 samples from 57 patients were analyzed via both mNGS and microbial culture. The ROC curve showed a sensitivity for mNGS of 97.22%, which was greater than that of microbial culture (61.11%). Samples from the respiratory tract, infectious skin lesions, and lymph nodes are recommended as routine samples for talaromycosis detection via mNGS. Furthermore, mNGS significantly reduced the diagnostic time compared to microbial culture. Overall, our study demonstrated that mNGS is a promising tool for rapid and accurate pathogenic detection in HIV-negative patients with talaromycosis.

Application value of multi-gene mutation detection in the clinical management of pediatric papillary thyroid carcinoma: a preliminary exploration.

Objectives: Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as BRAF, RAS, and RET/PTC have been widely used in adult PTC. It is currently unclear whether these molecular markers have equivalent potential for application in pediatric patients. This study aims to explore the potential utility of a multi-gene conjoint analysis based on next-generation targeted sequencing for pediatric papillary thyroid carcinoma (PTC). Materials and methods: The patients diagnosed with PTC (aged 18 years or younger) in the pediatrics department of Lishui District Hospital of Traditional Chinese Medicine were retrospectively screened. A targeted enrichment and sequencing analysis of 116 genes associated with thyroid cancer was performed on paraffin-embedded tumor tissues and paired paracancerous tissue of fifteen children (average age 14.60) and nine adults (average age 49.33) PTC patients. Demographic information, clinical indicators, ultrasonic imaging information and pathological data were collected. The Kendall correlation test was used to establish a correlation between molecular variations and clinical characteristics in pediatric patients. Results: A sample of 15 pediatric PTCs revealed a detection rate of 73.33% (11/15) for driver gene mutations BRAF V600E and RET fusion. Compared to adult PTCs, the genetic mutation landscape of pediatric PTCs was more complex. Six mutant genes overlap between the two groups, and an additional seventeen unique mutant genes were identified only in pediatric PTCs. There was only one unique mutant gene in adult PTCs. The tumor diameter of pediatric PTCs tended to be less than 4cm (p<0.001), and the number of lymph node metastases was more than five (p<0.001). Mutations in specific genes unique to pediatric PTCs may contribute to the onset and progression of the disease by adversely affecting hormone synthesis, secretion, and action mechanisms, as well as the functioning of thyroid hormone signaling pathways. But, additional experiments are required to validate this hypothesis. Conclusion: BRAF V600E mutation and RET fusion are involved in the occurrence and development of adolescent PTC. For pediatric thyroid nodules that cannot be determined as benign or malignant by fine needle aspiration biopsy, multiple gene combination testing can provide a reference for personalized diagnosis and treatment by clinical physicians.

Genetic analysis of cervical cancer with lymph node metastasis.

OBJECTIVE: To find out the differences in gene characteristics between cervical cancer patients with and without lymph node metastasis, and to provide reference for therapy. METHODS: From January 2018 to June 2022, recurrent cervical cancer patients 39 cases with lymph node metastasis and 73 cases without lymph node metastasis underwent testing of 1,021 cancer-related genes by next-generation sequencing. Maftools software was used to analyze somatic single nucleotide/insertion-deletion variation mutation, co-occurring mutation, cosmic mutation characteristics, oncogenic signaling pathways. RESULTS: EP300 and FBXW7 were significantly enriched in lymph node-positive patients. Lymph node-positive patients with EP300 or FBXW7 mutations had lower overall survival (OS) after recurrence. Both lymph node-positive and -negative patients had plenty of co-occurring mutations but few mutually exclusive mutations. Lymph node-positive co-occurring mutation number ≥6 had lower OS, while lymph node-negative co-occurring mutation number ≥3 had lower OS after recurrence. The etiology of SBS3 was defects in DNA double strand break repair by homologous recombination, which exclusively exist in lymph node-positive patients. There was no difference in median tumor mutation burden (TMB) between positive and negative lymph nodes, but TMB was significantly associated with PIK3CA mutation. CONCLUSION: The somatic SNV/Indels of EP300 and FBXW7, SBS3 homologous recombination-mediated DNA repair defect were enriched in lymph node-positive patients. For lymph node-positive patients, EP300 or FBXW7 mutations predicted poor prognosis. No matter lymph node-positive or negative, more co-occurring mutation number predicted poor prognosis. PIK3CA mutation may account for the higher TMB and help identify patients who benefit from immunotherapy.

FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.

Objective: To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.Methods: STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.Results: STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation via the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.Conclusions: Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells via the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.

The latest emerging drugs for the treatment of diabetic cardiomyopathy.

INTRODUCTION: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED: In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION: We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.

Microenvironmental Enzyme-Responsive Methotrexate Modified Quercetin Micelles for the Treatment of Rheumatoid Arthritis.

Purpose: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease involving synovial inflammation and joint destruction. Although therapeutic drugs for RA have some efficacy, they usually cause severe side effects and are expensive. RA is characterized by synovial hyperplasia, intra-articular hypoxia, upregulated expression of matrix metalloproteinases, and excessive accumulation of reactive oxygen species. The adverse microenvironment further aggravates activated macrophage infiltration. Therefore, controlling the microenvironment of diseased tissues and targeting the activated macrophages have become new therapeutic targets in RA patients. Methods: Here, microenvironment-targeting micelles (PVGLIG-MTX-Que-Ms) were synthesized using the thin film hydration method. In the inflammatory microenvironment, PVGLIG was cleaved by the highly expressed MMP-2, PEG5000 was eliminated, MTX was exposed, macrophage activation was targeted, and Que enrichment was enhanced. The cytotoxicity, targeting, antioxidant, and anti-inflammatory properties of drug-loaded micelles were tested in vitro. The drug-loaded micelles were used to treat CIA rats. In vivo targeting, expression of serum inflammatory factors, immunohistochemistry of the articular cartilage, and changes in immunofluorescence staining were observed. Results: The developed micelles had a particle size of (89.62 ±1.33) nm and a zeta potential of (-4.9 ±0.53) mV. The IC50 value of PVGLIG-MTX-Que-Ms (185.90 ±6.98) µmol/L was significantly lower than that of free Que (141.10 ±6.39) µmol/L. The synthesized micelles exhibited slow-release properties, low cytotoxicity, strong targeting abilities, and significant anti-inflammatory effects in vitro. In vivo, the drug-loaded micelles accumulated at the joint site for a long time. PVGLIG-MTX-Que-Ms significantly reduced joint swelling, improved bone destruction, and decreased the expression of serum inflammatory factors in CIA rats. Conclusion: The smart-targeting micelles PVGLIG-MTX-Que-Ms with strong targeting, anti-inflammatory, cartilage-protective, and other multiple positive effects are a promising new tool for RA treatment.

[Corrigendum] Bax inhibitor­1 suppresses early brain injury following experimental subarachnoid hemorrhage in rats.

Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 6 on p. 2898, the 'SAH' and 'SAH+NC' data panels contained an apparently overlapping section of data, such that these data appeared to have been derived from the same original source, even though they were intended to show the results from differently performed experiments. The authors have examined their original data, and realize that the 'SAH+NC' data panel had inadvertently been selected incorrectly for this figure. In addition, in response to a further query from the reader, the authors wished to point out that the standard deviations in their study were statistically analysed using GraphPad Prism software version 5.0a. The revised version of Fig. 6, now showing the correct data for the 'SAH+NC' experiment, is shown on the next page. The authors can confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 42: 2891­2902, 2018; DOI: 10.3892/ijmm.2018.3858].

Conditioned Media from Deer Antler Stem Cells Effectively Alleviate Type 1 Diabetes Mellitus Possibly via Inhibiting the NF-κB Signaling Pathway.

BACKGROUND: Type 1 diabetes mellitus (T1D) represents a severe threat to human health. Persistent hyperglycemia and dyslipidemia can lead to damaged liver function, while effective interventions for these complications are currently lacking. Deer antler stem cells (AnSCs), a novel type of adult stem cells, significantly reduced liver injury, which was speculated to be achieved through the paracrine pathway. METHODS: In this study, AnSC-conditioned medium (AnSC-CM) was used to treat C57BL/6 mice with T1D symptoms induced by streptozotocin (STZ). The therapeutic effects of AnSC-CM on T1D were evaluated, and the underlying mechanism was investigated. RESULTS: It was shown that AnSC-CM alleviated the T1D symptom: decreased body weight, increased blood glucose levels and islet lesions, and reduced insulin secretion. Moreover, AnSC-CM treatment improved liver function and mitigated liver injury in T1D mice. Impressively, the therapeutic effects of AnSC-CM on T1D were better than those of bone marrow mesenchymal stem cell-CM (BMSC-CM). The mechanistic study revealed that AnSC-CM significantly downregulated the NF-κB signaling pathway in both pancreatic and liver tissues. CONCLUSIONS: Therapeutic effects of AnSC-CM on STZ-induced T1D and liver injury may be achieved through targeting the NF-κB signaling pathway.

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer.

The Kinesin Family Member C1 (KIFC1) is highly expressed in a variety of tumors. Since it is linked with tumorigenesis and progression, KIFC1 has emerged as a promising candidate for targeted chemotherapies. Thus, this study aims to find out the association between KIFC1 and lung cancer. The original data were assessed from The Cancer Genome Atlas and Gene Expression Omnibus databases. Compared to normal lung tissues, both mRNA and protein levels of KIFC1 were significantly increased in lung cancer tissues. The upregulation of KIFC1 was significantly correlated with sex, pathological stage, and TMN stage. Survival analysis revealed that increased KIFC1 expression was associated with poor overall survival, first-progression survival and post-progression survival in lung cancer. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, we observed that KIFC1 upregulation was linked to enrichment of the cell cycle and TP53 signaling pathway. Additionally, the overexpression of KIFC1 was positively correlated with TP53 mutations in lung cancer. Based on real-world cohort results, western blotting and RT-qPCR showed high-KIFC1 expression in lung cancer, which may be related to the malignancy of lung cancer. Finally, experiments in vitro showed that KIFC1 inhibitor could significantly inhibit the proliferation and invasion of lung cancer cells. In conclusion, KIFC1 is a poor prognostic biomarker, and patients with high-KIFC1 levels may benefit from targeted therapy.

Impact of early rehabilitation therapy on functional outcomes in patients post distal radius fracture surgery: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aims to investigate the efficacy of early rehabilitation on patients who have undergone surgery for distal radius fractures (DRFs) with palmar plating, focusing on multiple outcome measures including upper limb function, wrist function, back extension mobility, pain levels, and complications. METHODS: A rigorous search strategy adhering to the PRISMA guidelines was employed across four major databases, including PubMed, Embase, Web of Science, and the Cochrane Library. Studies were included based on stringent criteria, and data extraction was performed independently by two reviewers. Meta-analysis was conducted employing both fixed-effect and random-effects models as dictated by heterogeneity, assessed by the I2 statistic and chi-square tests. A total of 7 studies, encompassing diverse demographic groups and timelines, were included for the final analysis. RESULTS: The meta-analysis disclosed that early rehabilitation yielded a statistically significant improvement in upper limb function (SMD -0.27; 95% CI -0.48 to -0.07; P < 0.0001) and back extension mobility (SMD 0.26; 95% CI 0.04 to 0.48; P = 0.021). A notable reduction in pain levels was observed in the early rehabilitation group (SMD -0.28; 95% CI -0.53 to -0.02; P = 0.03). However, there were no significant differences in wrist function (SMD -0.13; 95% CI -0.38 to 0.12; P = 0.36) and complications (OR 0.99; 95% CI 0.61 to 1.61; P = 0.96). CONCLUSIONS: Early rehabilitation post-DRF surgery with palmar plating has been found to be beneficial in enhancing upper limb functionality and back extension mobility, and in reducing pain levels. Nevertheless, no significant impact was observed regarding wrist function and complications.

Biologics initiation in moderate versus severe rheumatoid arthritis: real-world experience from a Canadian registry.

OBJECTIVES: To evaluate the treat-to-target experience, and quality of life measures of moderate and severe rheumatoid arthritis (RA) patients initiating a biologic in a real-world setting of a publicly funded payer system. METHODS: Biologic naive RA patients who had initiated their first biologic while enrolled in the Ontario Best Practices Research Initiative registry from 2008 to 2020 were selected if they had moderate (DAS28 >3.2 to ≤5.1) or severe (DAS28 >5.1) RA. Remission, LDA, DAS28, HAQ-DI, fatigue, sleep, drug persistence and characteristics associated with remission were assessed at 12 months post biologic initiation. RESULTS: Overall, 838 patients initiated their first biologic, 264 had moderate RA and 219 had severe RA. After 12 months, 44% moderate RA vs. 21% severe RA achieved remission (p<0.0001), and 59% moderate RA vs. 35% severe RA reached LDA (p<0.0001). Mean change (SD) from baseline in DAS28 was 2.2 (1.5) in severe RA vs. 1.4 (1.3) in moderate RA (p<0.0001), in fatigue score was 1.11 (3.2) in severe RA vs. 0.98 (3.2) in moderate RA (p<0.0001). Moderate disease at a biologic initiation was positively associated with remission (p=0.0016). Female gender (p=0.0170), and a higher HAQ-DI score at baseline (p=0.0042) were negatively associated with remission. Biologic persistence was 77% for moderate, and 73% for severe (p=0.2444). CONCLUSIONS: Severe RA patients had higher mean score improvements in DAS28, sleep and fatigue. Moderate RA was more likely to reach remission or LDA. Both groups had similar biologic persistence at 12 months. These findings highlight the importance of the treat-to-target approach and its potential underutilisation in the real-world setting.

The role of circular RNA in preeclampsia: From pathophysiological mechanism to clinical application.

Preeclampsia (PE) is a common pregnancy-induced hypertension disorder that poses a significant threat to the health of pregnant women and fetuses, and has become a leading cause of maternal, fetal, and neonatal mortality. Currently, the therapy strategy for PE is mainly prevention management and symptomatic treatment, and only delivery can completely terminate PE. Therefore, a deeper understanding of the pathogenesis of PE is needed to make treatment and prevention more effective and targeted. With the deepening of molecular etiology research, circular RNAs (circRNAs) have been found to be widely involved in various processes of PE pathogenesis. As a kind of RNA with a special "head to tail" loop structure, the characteristics of circRNAs enable them to play diverse roles in the pathophysiology of PE, and can also serve as ideal biomarkers for early prediction and monitoring progression of PE. In this review, we summarized the latest research on PE-related circRNAs, trying to elucidate the unique or shared roles of circRNAs in various pathophysiological mechanisms of PE, aiming to provide a whole picture of current research on PE-related circRNAs, and extend a new perspective for the precise screening and targeted therapy of PE.

Identification of a novel genomic variance of BRAF1 in papillary thyroid carcinoma: A case report.

RATIONALE: Papillary thyroid carcinoma (PTC), the predominant subtypes accounting for approximately 85% of thyroid carcinomas, has a rapidly increasing global incidence rate. Statistically, approximately 74.6% PTC patients had the genomic variants of BRAF, especially BRAFV600E mutation, which has been reported to stratify patients and guide clinic-therapies. However, some PTC patients may carry other nonclassical mutation patterns of BRAF, due to the complex of genomic instability. And the spectrum of BRAF mutation was not fully characterized. We reported a novel BRAF mutation pattern of PTC. PATIENT CONCERNS: A 59-year-old woman was admitted to our hospital because of the slight enlargement of bilateral cervical lymph nodes in July 2023. DIAGNOSIS: Ultrasonography revealed that the bilateral thyroid nodules of the patients both presented 1 hypoechoic nodule, which was graded as 3 of the elastic score, and the small calcification in the right lobe (Chinese-Thyroid Imaging Reporting and Data System 4c). Pathological diagnosis showed the interstitial collagen change and focal follicular epithelial papillary hyperplasia with atypical hyperplasia of the bilateral thyroid. Further puncture pathology showed that the patient had a malignant thyroid lesion with the phenotypes of papillary carcinoma and diagnosed with malignancy subsequently. Additionally, the patient harbored a novel insert on BRAF exon 15, a 6-base fragment AGACAG inserting between c.1798 and c.1799. INTERVENTIONS: The patient was undergone on microwave ablation of thyroid carcinoma on July 28, 2023. After the surgery, the patient was treated on anti-infection, cold saline external application of bilateral thyroid swelling supportive treatment. OUTCOMES: No postoperative complications or recurrence and metastasis were found. LESSONS: This is the first case of the novel nonclassical genomic variant of BRAF. Our study extends the spectrum of BRAF mutations. The patient had a favorable response to microwave ablation, indicating that in spite of the association between this mutation and high-grade malignant phenotype, this genomic variant of BRAF did not have a detrimental effect on the response of clinical treatment.

Combined Placental Mesenchymal Stem Cells with Guided Nanoparticles Effective Against Diabetic Nephropathy in Mouse Model.

Background: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and constitutes the primary cause of mortality in affected patients. Previous studies have shown that placental mesenchymal stem cells (PL-MSCs) can alleviate kidney dysfunction in animal models of DN. However, the limited ability of mesenchymal stem cells (MSCs) to home to damaged sites restricts their therapeutic potential. Enhancing the precision of PL-MSCs' homing to target tissues is therefore vital for the success of cell therapies in treating DN. Methods: We developed Fe3O4 coated polydopamine nanoparticle (NP)-internalized MSCs and evaluated their therapeutic effectiveness in a mouse model of streptozotocin- and high-fat diet-induced DN, using an external magnetic field. Results: Our study confirmed that NPs were effectively internalized into PL-MSCs without compromising their intrinsic stem cell properties. The magnetic targeting of PL-MSCs notably improved their homing to the kidney tissues in mice with DN, resulting in enhanced kidney function compared to the transplantation of PL-MSCs alone. Furthermore, the anti-inflammatory and antifibrotic attributes of PL-MSCs played a role in the recovery of kidney function and structure. Conclusion: These results demonstrate that magnetically targeted therapy using PL-MSCs is a promising approach for treating diabetic nephropathy.

ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4.

OBJECTIVE: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, with high morbidity and mortality. N6-methyladenosine (m6A) is an important regulator of LUAD progression. Here, we investigated the potential biological functions of ALKBH5 (a m6A demethylated enzyme) and cell division cycle associated protein 4 (CDCA4) in the progression of LUAD. METHODS: The expressions of CDCA4, METTL3, ALKBH5, FTO, YTHDC2 and YTHDC1 mRNA and proteins in LUAD and adjacent tissues, as well as NCI-H1299 and NCI-H157 cells were detected by RT-qPCR and western blot. Meanwhile, the role of ALKBH5 and CDCA4 in macrophage polarization was explored through tumor formation in Lewis lung carcinoma (LLC) mice and the co-culture system of NCI-H1299 and NCI-H157/THP-1 cells. Cell characterization was further analyzed. The expression of Ki-67 in tumor tissue was tested by immunohistochemistry. The scale of M1 and M2 macrophages was determined by flow cytometry. RESULTS: CDCA4 was significantly overexpressed in NCI-H1299 and NCI-H157 cell lines compared with BEAS-2B cells. The fold enrichment of CDCA4 m6A level in the overexpression (oe)-METTL3 or short hairpin (sh)-ALKBH5 cells was enhanced. Overexpression of CDCA4 promoted the cell viability, proliferation and migration, and inhibited apoptosis, which was reversed by sh-ALKBH5 intervention. Overexpression of YTHDC2 (not YTHDC1) inhibited the effect of CDCA4 on sh-ALKBH5 cells. sh-CDCA4 inhibited tumor growth and weight of LLC cells in mice, and promoted M1/M2 ratio in LLC mice and NCI-H1299/THP-1 and NCI-H157/THP-1 co-culture systems. Oe-CDCA4 promoted the volume and weight of tumor and inhibited the M1/M2 ratio of tumor tissue in LLC mice, but was reversed by sh-ALKBH5 intervention. CONCLUSION: m6A demethylase ALKBH5 promotes the development of LUAD through CDCA4 regulation of malignant characterization and M1/M2 macrophage polarization.

Development of IL-17A inhibitor-induced atopic dermatitis-like rash in psoriasis patients: Insights into immune shift.

Cases of atopic dermatitis (AD)-like rash induced by IL-17A inhibitor secukinumab treatment (SI-AD) have been recently reported in psoriasis patients. To identify immune and inflammatory factors expression in SI-AD. A panel of 15 immune and inflammatory factors in peripheral blood samples from various groups, including patients with patients with SI-AD, psoriasis with secukinumab (S-stable), advanced psoriasis patients (Advanced) and healthy controls (HC). Interleukin-10 (IL-10), IL-4 and IL-17A were detected in skin tissue biopsy samples by immunohistochemistry and real-time quantitative polymerase chain reaction. The immunoglobulin E levels in the SI-AD patients exceeded normal values. The IL-10 levels in SI-AD patients were higher than those in S-stable patients, advanced patients and HC. The IL-4 levels in SI-AD patients were higher than that in S-stable patients and HC. The IL-17A levels in SI-AD patients were higher than those in advanced psoriasis patients and HC, but no significant differences were observed between SI-AD patients and S-stable patients. IL-10 and IL-4 levels were higher in AD-like rashes than in healthy skin, while IL-17A did not differ significantly between the two. Upon discontinuing secukinumab, and switching to oral cyclosporine, antihistamines, Janus kinase 1 inhibitor and topical glucocorticoids, SI-AD patients experienced significant improvement in their skin lesions. Upon reexamination, all 15 immune and inflammatory factors returned to normal levels. Immune shift from Th17 towards Th2 may occur in SI-AD, as indicated by abnormal expression of multiple immune and inflammatory factors observed in peripheral blood and skin tissues.

Lung microvascular occlusion by platelet-rich neutrophil-platelet aggregates promotes cigarette smoke-induced severe flu.

Cigarette smoking is associated with a higher risk of ICU admissions among patients with flu. However, the etiological mechanism by which cigarette smoke (CS) exacerbates flu remains poorly understood. Here, we show that a mild dose of influenza A virus promotes a severe lung injury in mice preexposed to CS but not room air for 4 weeks. Real-time intravital (in vivo) lung imaging revealed that the development of acute severe respiratory dysfunction in CS- and flu-exposed mice was associated with the accumulation of platelet-rich neutrophil-platelet aggregates (NPAs) in the lung microcirculation within 2 days following flu infection. These platelet-rich NPAs formed in situ and grew larger over time to occlude the lung microvasculature, leading to the development of pulmonary ischemia followed by the infiltration of NPAs and vascular leakage into the alveolar air space. These findings suggest, for the first time to our knowledge, that an acute onset of platelet-driven thrombo-inflammatory response in the lung contributes to the development of CS-induced severe flu.