STAS: New explorations and challenges for thoracic surgeons.

Spread through air spaces (STAS) represents a relatively novel concept in the pathology of lung cancer, and it specifically refers to the dissemination of tumour cells into the parenchymal air spaces adjacent to the primary tumour. In 2015, the World Health Organization (WHO) classified STAS as a new invasive form of lung adenocarcinoma (LUAD). Many studies investigated the role of STAS and revealed its association with the prognosis of LUAD and its influence on the outcomes of other malignant pulmonary neoplasms. Additionally, the underlying mechanisms and predictive models of STAS have received considerable attention in recent years. This paper provides a comprehensive overview of the research advancements and prospects of STAS by examining it from multiple perspectives.

Inverted U-Shaped relationship Between Systemic Immune-Inflammation Index and Pulmonary Function: A Large Population-Based Study in US Adults.

Background: Systemic immune-inflammation index (SII) is a novel comprehensive inflammatory marker. Inflammation is associated with impaired lung function. We aimed to explore the possible relationship between SII and lung function to examine the potential of SII in predicting lung function decline. Methods: A cross-sectional survey was conducted using the data of the NHANES from 2007 to 2012. Multiple linear regression models were used to analyze the linear relationship between SII and pulmonary functions. Sensitivity analyses, subgroup analyses, and interaction tests were used to examine the robustness of this relationship across populations. Fitted smooth curves and threshold effect analysis were used to describe the nonlinear relationships. Results: A total of 10,125 patients were included in this study. After adjusting for all covariates, multiple linear regression model analysis showed that high Log2-SII level was significantly associated with decreased FVC(ß, -23.4061; 95% CI, -42.2805- -4.5317), FEV1(ß, -46.7730; 95% CI, -63.3371- -30.2089), FEV1%(ß, -0.7923; 95% CI, -1.1635- -0.4211), FEV1/FVC(ß, -0.6366; 95% CI, -0.8328- -0.4404) and PEF(ß, -121.4468; 95% CI,-164.1939- -78.6998). The negative correlation between Log2-SII and pulmonary function indexes remained stable in trend test and stratified analysis. Inverted U-shaped relationships between Log2-SII and FVC, FEV1, FEV1%, and PEF were observed, while a negative linear correlation existed between FEV1/FVC and Log2-SII. The cutoff values of the nonlinear relationship between Log2-SII and FVC, FEV1, FEV1%, PEF were 8.3736, 8.0688, 8.3745, and 8.5255, respectively. When SII exceeded the critical value, the lung function decreased significantly. Conclusion: This study found a close correlation between SII and pulmonary function indicators. This study investigated the SII threshold when lung functions began to decline in the overall population. SII may become a promising serological indicator for predicting lung function decline. However, prospective studies were needed further to establish the causal relationship between these two factors.

Diagnostic efficacy of the contrast-enhanced ultrasound thyroid imaging reporting and data system classification for benign and malignant thyroid nodules.

Background: The contrasted-enhanced ultrasound thyroid imaging reporting and data system (CEUS TI-RADS) is the first international risk stratification system for thyroid nodules based on conventional ultrasound (US) and CEUS. This study aimed to evaluate the diagnostic efficacy of CEUS TI-RADS for benign and malignant thyroid nodules and to assess the related interobserver agreement. Methods: The study recruited 433 patients who underwent thyroid US and CEUS between January 2019 and June 2023 at the Affiliated Hospital of Guangdong Medical University. A retrospective analysis of 467 thyroid nodules confirmed by fine-needle aspiration (FNA) and/or surgery was performed. Further, a CEUS TI-RADS classification was assigned to each thyroid nodule based on the CEUS TI-RADS scoring criteria for the US and CEUS features of the nodule. The nodules were grouped based on their sizes as follows: size ≤1 cm, group A; size >1 and ≤4 cm, group B; and size >4 cm, group C. Multivariate logistic regression was used to analyze independent risk factors for malignant thyroid nodules. Pathological assessment was the reference standard for establishing the sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) of CEUS TI-RADS in diagnosing malignant thyroid nodules. The area under the curve (AUC) in the receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficacy of the scoring system in predicting malignancy in three groups of nodules. The intragroup correlation coefficient (ICC) was adopted to assess the interobserver agreement of the CEUS TI-RADS score. Results: Out of the 467 thyroid nodules, 262 were malignant and 205 were benign. Logistic regression analysis revealed that the independent risk factors for malignant thyroid nodules included punctate echogenic foci (P<0.001), taller-than-wide shape (P=0.015), extrathyroidal invasion (P=0.020), irregular margins/lobulation (P=0.036), hypoechoicity on US (P=0.038), and hypoenhancement on CEUS (P<0.001). The AUC for the CEUS TI-RADS in diagnosing malignant thyroid nodules was 0.898 for all nodules, 0.795 for group A, 0.949 for group B, and 0.801 for group C, with the optimal cutoff values of the CEUS TI-RADS being 5 points, 6 points, 5 points, and 5 points, respectively. Among these groups of nodules, group B had the highest AUC, with the SEN, SPE, ACC, PPV, and NPV for diagnosing malignant nodules being 95.9%, 88.1%, 92.8%, 92.6%, and 93.2%, respectively. The ICC of the CEUS TI-RADS classification between senior and junior physicians was 0.862 (P<0.001). Conclusions: In summary, CEUS TI-RADS demonstrated significant efficacy in distinguishing thyroid nodules. Nonetheless, there were variations in its capacity to detect malignant nodules across diverse sizes, and it demonstrate optimal performance in 1- to 4-cm nodules. These findings may serve as important insights for clinical diagnoses.

Predictive factors of stress response of nursing student repeaters under the background of abolishing the final supplementary examination in China.

BACKGROUND: Academic pressure and frustration stimulation are significant stressors in college students, and response to the prolonged stimuli would cause adverse mental and physical outcomes. However, more is needed to know about the stress response and its predictors among undergraduate nursing students retaking failed course under the background of the abolition of the Final Supplementary Examination in China. This study aimed to investigate the stress response and its predictive factors of nursing student repeaters who are retaking at least one failed course. METHODS: A cross-sectional study was conducted, utilizing convenience sampling to recruit 120 nursing student repeaters from four 4-year undergraduate medical universities in China between September 2020 and May 2021. Data collection instruments included a general information questionnaire, a stress response questionnaire, the Connor-Davidson resilience scale, a self-control scale, and a academic self-efficacy questionnaire. The data were analyzed using descriptive statistics, Pearson correlation coefficients, t-tests, analysis of variance (ANOVA), and multiple linear regression. RESULTS: The average scores of the total stress response, emotional response, physical response, and behavioral response were 58.07 ± 26.72, 86.97 ± 17.12, 57.69 ± 9.75, 67.16 ± 9.22, respectively. Stress response was predicted by psychological resilience, self-control ability, academic self-efficacy and the number of retaking courses. CONCLUSIONS: The stress response among nursing student repeaters is relatively active. Higher psychological resilience, self-control ability, and academic self-efficacy predict lower levels of stress response. In order to help nursing students with failing and repeating course release their psychological stress and maintain well-being, nursing educators could adopt self-control promotion strategies and emphasize the cultivation of psychological resilience and academic self-efficacy as parts of health promotion programs for this particular student group.

The urinary microbiota composition and functionality of calcium oxalate stone formers.

Background: Accumulated evidences indicate that dysbiosis of the urinary microbiota is associated with kidney stone formation. In the present study, we aimed to investigate the urinary microbiota composition and functionality of patients with calcium oxalate stones and compare it with those of healthy individuals. Method: We collected bladder urine samples from 68 adult patients with calcium oxalate stones and 54 age-matched healthy controls by transurethral catheterization. 16S rRNA gene and shotgun sequencing were utilized to characterize the urinary microbiota and functionality associated with calcium oxalate stones. Results: After further exclusion, a total of 100 subjects was finally included and analyzed. The diversity of the urinary microbiota in calcium oxalate stone patients was not significantly different from that of healthy controls. However, the urinary microbiota structure of calcium oxalate stone formers significantly differed from that of healthy controls (PERMANOVA, r = 0.026, P = 0.019). Differential representation of bacteria (e.g., Bifidobacterium) and several enriched functional pathways (e.g., threonine biosynthesis) were identified in the urine of calcium oxalate stone patients. Conclusion: Our results showed significantly different urinary microbiota structure and several enriched functional pathways in calcium oxalate stone patients, which provide new insight into the pathogenesis of calcium oxalate stones.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Association Study of Pleural Mesothelioma and Oncogenic Simian Virus 40 in the Crocidolite-Contaminated Area of Dayao County, Yunnan Province, Southwest China.

Background: In Dayao County, Chuxiong Yi Autonomous Prefecture, Yunnan Province, Southwest China, 5% of the surface is scattered with blue asbestos, which has a high incidence of pleural mesothelioma (PMe). Simian virus 40 (SV40) is a small circular double-stranded DNA polyomavirus that can cause malignant transformation of normal cells of various human and animal tissue types and promote tumor growth. In this study, we investigate whether oncogenic SV40 is associated with the occurrence of PMe in the crocidolite-contaminated area of Dayao County, Yunnan Province, Southwest China. Methods: Tumor tissues from 51 patients with PMe (40 of whom had a history of asbestos exposure) and pleural tissues from 12 non-PMe patients (including diseases such as pulmonary maculopathy and pulmonary tuberculosis) were collected. Three pairs of low-contamination risk primers (SVINT, SVfor2, and SVTA1) were used to detect the gene fragment of SV40 large T antigen (T-Ag) by polymerase chain reaction (PCR). The presence of SV40 T-Ag in PMe tumor tissues and PMe cell lines was detected by Western blotting and immunohistochemical staining with SV40-related antibodies (PAb 101 and PAb 416). Results: PCR, Western blotting, and immunohistochemical staining results showed that the Met5A cell line was positive for SV40 and contained the SV40 T-Ag gene and protein. In contrast, the various PMe cell lines NCI-H28, NCI-H2052, and NCI-H2452 were negative for SV40. PCR was negative for all three sets of low-contamination risk primers in 12 non-PMe tissues and 51 PMe tissues. SV40 T-Ag was not detected in 12 non-PMe tissues or 51 PMe tissues by immunohistochemical staining. Conclusion: Our data suggest that the occurrence of PMe in the crocidolite-contaminated area of Yunnan Province may not be related to SV40 infection and that crocidolite exposure may be the main cause of PMe. The Clinical Trial Registration number: 2020-YXLL20.

Biological and physiological effects in Bemisia tabaci feeding on tomatoes endophytically colonized by Beauveria bassiana.

BACKGROUND: Entomopathogenic fungi (EPF) treatment of plants may affect the survival and feeding preferences of herbivorous pests. However, comprehensive studies on the fitness across their entire life cycle, feeding behavior, and physiological changes in herbivores consuming EPF-treated plants within the tripartite interactions of EPF, plants, and pests are still limited. In this study, we utilized life tables, electrical penetration graph (EPG), and metabolomics to uncover the biological and physiological characteristics of Bemisia tabaci on tomato plants inoculated with Beauveria bassiana through root irrigation. RESULTS: Our study indicated that Beauveria bassiana Bb252 can penetrate the entire tissue from the point of inoculation, primarily colonizing the intercellular spaces and vascular tissue. However, this colonization is temporary, lasting no more than 35 days. Moreover, the population fitness and feeding behavior of Bemisia tabaci on tomato plants treated with Beauveria bassiana via root irrigation were significantly affected, showing a substantial 41.4% decrease in net reproductive rate (R0), a notable reduction in watery salivation, and shortened phloem ingestion. Lastly, we observed a significant decrease in hormones and amino acids of whiteflies that fed on Beauveria bassiana-treated tomato plants by root irrigation. CONCLUSIONS: Our results indicated that the endophyte, Beauveria bassiana Bb252, reduced demographic fitness of Bemisia tabaci by altering its hormones and amino acids levels. These findings enhance our understanding of multitrophic interactions in integrated pest management. © 2024 Society of Chemical Industry.

Historical trends of breast cancer burden attributable to metabolic factors among Chinese women, 1990-2019: A population-based epidemiological study.

BACKGROUND:  This study aims to analyze breast cancer burden attributable to high body mass index (BMI) and high fasting plasma glucose (FPG) in China from 1990 to 2019. METHODS: Data were obtained from the Global Burden of Disease (GBD) study 2019. Deaths and disability-adjusted life years (DALYs) were used for attributable burden, and age-period-cohort (APC) model was used to evaluate the independent effects of age, period and birth cohort. RESULTS: In 2019, the age-standardized mortality and DALY rates of breast cancer attributable to high BMI were 1.107 (95% UI: 0.311, 2.327) and 29.990 (8.384, 60.713) per 100 000, and mortality and DALY rates attributable to high FPG were 0.519 (0.095, 1.226) and 13.662 (2.482, 32.425) per 100 000. From 1990 to 2019, the age-standardized mortality and DALY rates of breast cancer attributable to high BMI increased by 1.192% and 1.180%, and the trends of high FPG were not statistically significant. The APC results showed that the age effects of high BMI and high FPG-mortality and DALY rates increased, with the highest rates in the age group over 80 years. The birth cohort effects of high BMI showed "inverted V" shapes, while high FPG showed downward trends. CONCLUSIONS: Age was the main reason for the increase of attributable burden, and postmenopausal women were the high-risk groups. Therefore, targeted prevention measures should be developed to improve postmenopausal women's awareness and effectively reduce the prevalence of obesity and diabetes, thereby reducing the breast cancer burden caused by metabolic factors in China.

Epidemiological and transcriptome data identify shared gene signatures and immune cell infiltration in type 2 diabetes and non-small cell lung cancer.

BACKGROUND: Numerous previous studies have reported an association between type 2 diabetes mellitus (T2DM) and lung cancer risk, but the underlying mechanism of the interaction remains unclear. This study aimed to investigate the shared genetic features and immune infiltration processes between lung cancer and T2DM. METHODS: Epidemiological data from the National Health and Nutrition Examination Survey (NHANES) 2000-2018 was used to explore the relationship between lung cancer and diabetes systematically. In addition, we also used bioinformatics methods to analyze the transcriptome data from the Gene Expression Omnibus (GEO) to explore the potential functional mechanisms from the perspective of genes and immune infiltration. RESULTS: Logistic regression analysis showed that prediabetes (OR = 3.289,95%CI 1.231, 8.788, p = 0.01760, model 3)and type 2 diabetes (OR = 3.032 95%CI,1.015, 9.054, p = 0.04689) were significantly associated with an increased risk of lung cancer after adjusting for multiple covariates. Data from NHANES showed an inverted U-shaped relationship between fasting blood glucose and glycosylated haemoglobin and the risk of lung cancer (P for non-linear < 0.001). Transcriptome data showed that we screened 57 co-DEGs, of which 25 were up-regulated co-DEGs and 32 were down-regulated. Ten core DEGs were identified by bioinformatics analysis, which were SMC6, CDC27, CDC7, RACGAP1, SMC4, NCF4, NCF1, NCF2, SELPLG and CFP. Correlation analysis showed that some core DEGs were significantly associated with simultaneous dysregulation of immune cells. CONCLUSION: The identified core genes of NSCLC and T2DM are associated with dysregulated immune cells, which provides a potential research avenue for diagnosing and treating lung cancer combined with diabetes.

CPT1A Protects Podocytes From Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo.

Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.

Deficiency of Nuclear Receptor Coactivator 3 Aggravates Diabetic Kidney Disease by Impairing Podocyte Autophagy.

Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR-γ dependent way. Podocyte-specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis.

BACKGROUND: Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. METHODS: An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. RESULTS: An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. CONCLUSIONS: The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.

LncRNA expression profiling in exosomes derived from synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: To identify the long non-coding RNA (lncRNA) expression profiling in exosomes derived from synovial fluid of rheumatoid arthritis (RA) patients, and carry out bioinformatics analysis on target genes of differentially expressed lncRNAs. METHODS: Exosomes were isolated from synovial fluid via ultracentrifugation. RNAs were extracted from exosomes by using HiPure Liquid RNA/miRNA kits, followed by lncRNA sequencing. Differentially expressed lncRNAs in RA were screened, and bioinformatics analysis of their target genes was carried out. qRT-PCR was used to verify the lncRNA expression levels. RESULTS: Compared with osteoarthritis (OA), 347 lncRNAs were found differentially expressed in RA. Compared with gout, 805 lncRNAs were found differentially expressed in RA. Compared with both OA and gout, 85 lncRNAs were found specially expressed in RA (65 were upregulated (including ENST00000433825.1)). Functional analysis of target genes of the specially expressed lncRNAs revealed significant enrichment of "autophagy" and "mTOR signaling pathway". The qRT-PCR results indicated that ENST00000433825.1 was highly expressed in RA, compared with both OA and gout (P < 0.05), which matched the lncRNA sequencing results. Correlation analysis showed that the level of ENST00000433825.1 in RA patients was significantly and positively correlated with the level of C-reactive protein (CRP) (P < 0.001). CONCLUSIONS: The lncRNA expression profiling in exosomes derived from synovial fluid of RA was significantly different from OA and gout. ENST00000433825.1 was highly and uniquely expressed in RA and significantly and positively correlated with CRP, which might provide a diagnostic and therapeutic biomarker for RA.

Efficient healing of diabetic wounds by MSC-EV-7A composite hydrogel via suppression of inflammation and enhancement of angiogenesis.

Diabetes mellitus (DM) is characterized by prolonged hyperglycemia, impaired vascularization, and serious complications, such as blindness and chronic diabetic wounds. About 25% of patients with DM are estimated to encounter impaired healing of diabetic wounds, often leading to lower limb amputation. Multiple factors are attributed to the non-healing of diabetic wounds, including hyperglycaemia, chronic inflammation, and impaired angiogenesis. It is imperative to develop more efficient treatment strategies to tackle healing difficulties in diabetic wounds. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising for diabetic wound healing considering their anti-inflammatory, pro-angiogenic and pro-proliferative activities. A histone deacetylase 7 (HDAC7)-derived 7-amino-acid peptide (7A) was shown to be highly effective for angiogenesis. However, it has never been investigated whether MSC-EVs are synergistic with 7A for the healing of diabetic wounds. Herein, we propose that MSC-EVs can be combined with 7A to greatly promote diabetic wound healing. The combination of EVs and 7A significantly improved the migration and proliferation of skin fibroblasts. Moreover, EVs alone significantly suppressed LPS-induced inflammation in macrophages, and notably, the combination treatment showed an even better suppression effect. Importantly, the in vivo study revealed that the combination therapy consisting of EVs and 7A in an alginate hydrogel was more efficient for the healing of diabetic wounds in rats than monotherapy using either EV or 7A hydrogels. The underlying mechanisms include suppression of inflammation, improvement of skin cell proliferation and migration, and enhanced collagen fiber disposition and angiogenesis in wounds. In summary, the MSC-EV-7A hydrogel potentially constitutes a novel therapy for efficient healing of chronic diabetic wounds.

Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation.

Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.

Enhanced cartilage regeneration by icariin and mesenchymal stem cell-derived extracellular vesicles combined in alginate-hyaluronic acid hydrogel.

OBJECTIVE: Osteoarthritis (OA) is characterized by progressive cartilage degeneration and absence of curative therapies. Therefore, more efficient therapies are compellingly needed. Both mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) and Icariin (ICA) are promising for repair of cartilage defect. This study proposes that ICA may be combined to potentiate the cartilage repair capacity of MSC-EVs. MATERIALS AND METHODS: MSC-EVs were isolated from sodium alginate (SA) and hyaluronic acid (HA) composite hydrogel (SA-HA) cell spheroid culture. EVs and ICA were combined in SA-HA hydrogel to test therapeutic efficacy on cartilage defect in vivo. RESULTS: EVs and ICA were synergistic for promoting both proliferation and migration of MSCs and inflammatory chondrocytes. The combination therapy led to strikingly enhanced repair on cartilage defect in rats, with mechanisms involved in the concomitant modulation of both cartilage degradation and synthesis makers. CONCLUSION: The MSC-EVs-ICA/SA-HA hydrogel potentially constitutes a novel therapy for cartilage defect in OA.

Moon-forming impactor as a source of Earth's basal mantle anomalies.

Seismic images of Earth's interior have revealed two continent-sized anomalies with low seismic velocities, known as the large low-velocity provinces (LLVPs), in the lowermost mantle1. The LLVPs are often interpreted as intrinsically dense heterogeneities that are compositionally distinct from the surrounding mantle2. Here we show that LLVPs may represent buried relics of Theia mantle material (TMM) that was preserved in proto-Earth's mantle after the Moon-forming giant impact3. Our canonical giant-impact simulations show that a fraction of Theia's mantle could have been delivered to proto-Earth's solid lower mantle. We find that TMM is intrinsically 2.0-3.5% denser than proto-Earth's mantle based on models of Theia's mantle and the observed higher FeO content of the Moon. Our mantle convection models show that dense TMM blobs with a size of tens of kilometres after the impact can later sink and accumulate into LLVP-like thermochemical piles atop Earth's core and survive to the present day. The LLVPs may, thus, be a natural consequence of the Moon-forming giant impact. Because giant impacts are common at the end stages of planet accretion, similar mantle heterogeneities caused by impacts may also exist in the interiors of other planetary bodies.

ALOX5AP is a new prognostic indicator in acute myeloid leukemia.

BACKGROUND: The overexpression of ALOX5AP has been observed in many types of cancer and has been identified as an oncogene. However, its role in acute myeloid leukemia (AML) has not been extensively studied. This study aimed to identify the expression and methylation patterns of ALOX5AP in bone marrow (BM) samples of AML patients, and further explore its clinical significance. METHODS: Eighty-two de novo AML patients and 20 healthy donors were included in the study. Meanwhile, seven public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were included to confirm the alteration of ALOX5AP. Receiver operating characteristic (ROC) curve analysis was applied to determine the discriminative capacity of ALOX5AP expression to discriminate AML. The prognostic value of ALOX5AP was identified by the Kaplan-Meier method and log-rank test. It was further validated in four independent cohorts (n = 1186). Significantly different genes associated with ALOX5AP expression were subsequently compared by LinkedOmics, and Metascape database. RESULTS: The level of ALOX5AP expression was significantly increased in bone marrow cells of AML patients compared with healthy donors (P < 0.05). ROC curve analysis suggested that ALOX5AP expression might be a potential biomarker to discriminate AML from controls. ALOX5AP overexpression was associated with decreased overall survival (OS) in AML according to the TCGA data (P = 0.006), which was validated by other four independent cohorts. DNA methylation levels of ALOX5AP were significantly lower in AML patients compared to normal samples (P < 0.05), as confirmed in the Diseasemeth database and the independent cohort GSE63409. ALOX5AP level was positively associated with genes with proleukemic effects such as PAX2, HOX family, SOX11, H19, and microRNAs that act as oncogenes in leukemia, such as miR125b, miR-93, miR-494, miR-193b, while anti-leukemia-related genes and tumor suppressor microRNAs such as miR-582, miR-9 family and miR-205 were negatively correlated. CONCLUSION: ALOX5AP overexpression, associated with its hypomethylation, predicts poorer prognosis in AML.