Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Caveolin-1 (Cav-1), a main structural protein of caveolae, orchestrates key cellular processes including endocytosis, lipid transport, and signal transduction by serving as a platform. However, its specific role in AKI remains unclear. Here, we report that Cav-1 is upregulated in distal tubule epithelial cells (TECs) in both AKI patients and mouse models induced by ischemia/reperfusion injury (IRI) and lipopolysaccharide (LPS). Global and distal TEC-specific Cav1 knockout exacerbates IRI and LPS-induced AKI. RNA-seq reveals that Cav-1 deficiency exacerbates intracellular calcium ion (Ca2+) homeostasis imbalance and endoplasmic reticulum (ER) stress in injured kidney tissues. Mechanistically, Cav-1 interacts with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), a key regulator of intracellular Ca2+ homeostasis, through its scaffolding domain, promoting SERCA2 deubiquitination and stability in the ER, thereby maintaining intracellular Ca2+ homeostasis and suppressing ER stress in distal TECs. Furthermore, supplementation with a cell-permeable Cav-1 scaffolding domain peptide (CSP) or activation of SERCA2 with a small-molecule agonist CDN1163 alleviates IRI- and LPS-induced AKI, while distal TEC-specific SERCA2 knockdown abrogates CSP's therapeutic effect. Together, these findings reveal a novel Cav-1-mediated pathway and highlight its potential as a therapeutic target for AKI.

INTRODUCTION:Cellular calcium homeostasis is essential for maintaining kidney function. Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), the primary calcium pump responsible for transporting cytosolic calcium ions back into the endoplasmic reticulum, is a key regulator of endoplasmic reticulum stress and intracellular calcium balance. However, its specific role in acute kidney injury (AKI) and the underlying regulatory mechanisms remain poorly understood. METHODS:SERCA2 expression was measured in biopsies of patients with AKI, animal models, and cellular assays. AKI models were established using SERCA2 conditional knockdown and overexpression mice, HK-2 cells and primary kidney tubular epithelial cells in vitro. To investigate the underlying mechanisms, we integrated approaches including RNA-sequencing, transmission electron microscopy, immunofluorescence, and Seahorse analyses. RESULTS:Transcriptomic and histopathological analyses revealed reduced SERCA2 expression in proximal tubules of both patient AKI biopsies and murine models. Proximal tubule-specific SERCA2 knockdown exacerbated kidney dysfunction and tubular injury in murine AKI, while SERCA2 allosteric activation with CDN1163 or its overexpression attenuated these injuries. Mechanistically, SERCA2 deficiency disrupted endoplasmic reticulum calcium homeostasis, leading to endoplasmic reticulum stress and promoting voltage dependent anion channel 1 (VDAC1) oligomerization through impaired mitochondria-associated endoplasmic reticulum membranes. These changes led to mitochondrial permeability transition pore opening, mitochondrial calcium overload, oxidative stress, and ferroptosis. Importantly, stopping VDAC1 oligomerization with small molecule inhibitor VBIT-4 or blocking ferroptosis with ferrostatin-1 restored mitochondrial function and mitigated ferroptosis in SERCA2-deficient models. CONCLUSIONS:Our study identifies the SERCA2-VDAC1 axis as a critical regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in AKI. Both SERCA2 activation and inhibition of VDAC1 oligomerization conferred substantial renoprotection, highlighting this pathway as a promising therapeutic target for attenuating tubular damage in AKI.

Growth differentiation factor 15 (GDF-15) has been implicated in multiple biological functions. However, the role of GDF15 in silicosis remains unclear. In this study, the serum level of GDF-15 was investigated in 46 patients with silicosis by ELISA and results showed it was higher than that of control patients. The effects of exogenous GDF15 on mRNA and miRNA expression profiles of MRC5 cells were analyzed by RNA sequencing. GDF15 activated human embryonic lung fibroblast MRC5 cells with upregulation of col1a and α-SMA. GDF15 reduced miR-338 expression and increased STAT1 expression in MRC5 cells. The results of the luciferase reporter assay and bioinformatics analysis indicated that STAT1 was a direct target of miR-338. miR-338 mimics down-regulated col1a and α-SMA expression induced by GDF15 with STAT1 overexpression, whereas miR-338 inhibitor up-regulated col1a and α-SMA expression induced by GDF15 with STAT1 knockdown. Those results indicated GDF15 activated MRC5 cells through the miR-338/STAT1 pathway and GDF-15 may play an important role in silicosis.

The molecular mechanisms underlying sex differences in acute kidney injury (AKI) remain incompletely understood. In a study recently published in Nature, Tonnus et al. reported that 17β-estradiol (E2) induces an anti-ferroptotic state in renal tubules through both genomic and non-genomic mechanisms, thereby providing renal protection against AKI.

Damage-associated molecular patterns (DAMPs) are a cause of Crohn’s disease (CD). Peroxiredoxin 1 (Prdx1), a newly identified DAMP, plays a critical role in organ injury with its potent proinflammatory properties. However, its specific role in CD remains unclear. Here, we identify serum Prdx1 as a DAMP involved in CD. Serum Prdx1 levels were significantly increased and positively correlated with the severity of intestinal inflammation in both CD patients and mice with experimental colitis. Genetic knockout of Prdx1 or administration of a Prdx1-neutralizing antibody attenuated colitis in mice, as evidenced by restoration of the colonic epithelium, improved disease activity, and reduced colonic inflammation. These protective effects were impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, Prdx1 exacerbated intestinal inflammation by promoting macrophage infiltration and subsequent cytokine production. Depletion of macrophages abolished the rPrdx1-mediated exacerbation of colitis. Further, rPrdx1 was internalized by macrophages, leading to lysosomal disruption and subsequent activation of the NLRP3 inflammasome. Pharmacological inhibition of NLRP3 effectively abrogated rPrdx1-induced exacerbation of colitis. In conclusion, serum Prdx1 promotes intestinal inflammation in CD at least in part by activating the NLRP3 inflammasome through lysosomal disruption in macrophages. These findings highlight the pathogenic role of Prdx1 in CD and reveal therapeutic potential of managing CD via neutralization of circulating Prdx1.

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation (LPO), has emerged as a promising target in cancer therapy. In this study, we detected elevated levels of glutathione (GSH) peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in human gastric adenocarcinoma tissues, indicating a suppression of ferroptosis in gastric cancer (GC). Apatinib (Apa), a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, was found to induce ferroptosis through the classical SLC7A11/GSH/GPX4 pathway. However, long-term administration of high-dose Apa is associated with adverse side effects and the risk of drug resistance. To address these limitations, we developed a novel drug delivery system (DDS) using hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles for targeted co-delivery of Apa and chitosan-coated silver nanoparticles (Chi-Ag). Our results demonstrated that the combination of Apa and Chi-Ag exerted a synergistic cytotoxic effect against GC cells. This co-delivery system evidently increased oxidative stress at the tumor site and effectively promoted ferroptosis via modulation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway. In summary, we present a targeted nanoplatform that enhances the antitumor efficacy of Apa at lower dosages by leveraging ferroptosis induction. This strategy holds promise for improving the clinical outcomes in patients with GC.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Background: Silicosis is a severe occupational disease induced by silica inhalation. It is characterized by chronic persistent pulmonary inflammation and progressive widespread interstitial lung fibrosis with worldwide prevalence. The purpose of this study was to elucidate whether fluorofenidone (AKF-PD), a newly developed anti-fibrotic chemical, can prevent pulmonary fibrosis and inflammation induced by silica. Methods: Male C57BL/6J mice were used to develop a silicosis model and randomly divided into three groups: the control group (abbreviated as Control), the silica-treated group (abbreviated as Silica), and the silica plus AKF-PD treated group (abbreviated as AKF-PD). Pathological changes in the tissue of the lungs were examined using Hematoxylin and eosin (HE) and Masson's trichrome staining methods. Western blot analysis was used to assess the expression levels of alpha-smooth muscle actin (alpha-SMA), fibronectin, caspase-1, pro-caspase-1, and pro-interleukin (IL)-1 beta in lung tissues. Moreover, the levels of inflammatory cytokines were determined using their corresponding Enzyme-linked Immunosorbent Assay (ELISA) kits. Before the stimulation with 100 mu g/mL nano-silica, the THP-1 cells were pre-treated with either AKF-PD (400 mu g/mL) or serum-free RPMI-1640 medium. Additionally, we evaluated the proteins involved in the assembly of the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes in the cell and the production of inflammatory cytokines in the cell medium. Moreover, we assessed the expression levels of phosphorylated NLRP3, phosphorylated apoptosis-associated speck-like protein containing with CARD domain (ASC), and the proteins involved in the assembly of the NLRP3 inflammasomes in the lung tissues mice. Results: We observed that AKF-PD treatment significantly reduced alveolitis (p < 0.001), lung fibrosis (p < 0.01), and collagen III distribution (p < 0.0001) in the silica-induced silicosis model mice. AKF-PD decreased the expression levels of fibronectin (p < 0.05), alpha-smooth muscle actin (p < 0.05), interleukin-1 beta and transforming growth factor-beta (p < 0.05), as well as the levels of interleukin-6 and tumor necrosis factor-alpha (p < 0.01) compared to the silica group. The AKF-PD treatment significantly reduced the silica-induced elevated levels of caspase-1 in lung tissues (p < 0.05), but did not reduce the expression of pro-caspase-1 and pro-IL-1 beta. However, AKF-PD treatment attenuated the expression levels of interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and caspase-1 (p < 0.05) in silica-treated THP-1 cells, whereas did not reduce the expression of pro-IL-1 beta and pro-caspase-1 in these cells. Additionally, it was observed that AKF-PD treatment did not reduce the silica-induced elevated expressions of NLRP3 and ASC. However, it reduced the expression levels of phosphorylated NLRP3 (p-NLRP3) (p < 0.05), and phosphorylated ASC induced by silica (p < 0.05). Moreover, a similar trend in the data was observed in mouse lung tissue homogenates analysis. Conclusions: In summary, AKF-PD exhibits anti-inflammatory and anti-fibrotic effects in silicosis, reducing pulmonary inflammation and fibrosis while decreasing the release of IL-1 beta and the activation of NLRP3 inflammasome. These findings suggest AKF-PD as a potential therapy for silicosis-induced fibrosis.

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/-mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-KB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.

Background. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disorder with a high rate of postoperative recurrence. SERPINB10 is a proinflammatory cytokine expressed on epithelial cells, but its role in CRSwNP has not been described. This study is aimed at exploring the SERPINB10 expression in CRSwNP and its relationship with postoperative recidivation. Methods. We recruited 140 individuals, consisting of 60 patients with CRSwNP, 40 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 40 healthy controls (HCs). Tissue specimens were collected during the surgery, and SERPINB10 expression was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence. We determined the tissue SERPINB10 expression levels in CRSwNP and examined its clinical value in predicting postoperative recurrence. Results. We determined that tissue SERPINB10 mRNA and protein levels were increased in the CRSwNP group, especially in the recurrent CRSwNP group, compared with the CRSsNP and HC groups ( p < 0.05 ), and SERPINB10 mRNA levels were correlated with peripheral and tissue eosinophil counts and percentages ( p < 0.05 ). Binary logistic regression analysis and receiver operating characteristic (ROC) curves suggested that the expressions of tissue SERPINB10 mRNA were significantly linked to postoperative recurrence in CRSwNP patients ( AUC = 0.741 , p < 0.001 ). Conclusion. Elevated local SERPINB10 levels in patients with CRSwNP were related to tissue eosinophilic inflammation and disease recurrence. These data suggested that SERPINB10 might contribute to the eosinophilic inflammation in CRSwNP and appeared to be a potential biomarker for the prediction of relapse after surgery.

Background:Chronic rhinosinusitis with polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinuses with a high rate of postoperative recurrence. In this study, we aim to investigate the expression of B7-H4 in CRSwNP and its association with postoperative recurrence.Methods:A total of 80 CRSwNP patients, including 40 primary CRSwNP (pCRSwNP) patients and 40 recurrent CRSwNP (rCRSwNP) patients, 27 chronic rhinosinusitis without polyps (CRSsNP) and 32 healthy controls (HC) were enrolled in this study, and the serum, nasal polyps and middle turbinate tissue samples were collected. Peripheral and tissue B7-H4 expressions were detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence, and their clinical values in predicting postoperative recurrence of CRSwNP were evaluated.Results:We identified significantly higher tissue B7-H4 mRNA levels in the CRSwNP group than in the HC group, and elevated B7-H4 levels were associated with tissue eosinophil count and percentage (r = 0.469, P < 0.001; r = 0.521, P < 0.001). B7-H4 mRNA and protein levels were significantly higher in the rCRSwNP group than the pCRSwP group. Multivariate analysis and receiver operating characteristic (ROC) curves showed that tissue B7-H4 levels were associated with postoperative recurrence in patients with CRSwNP (P < 0.05). In addition, serum B7-H4 levels were significantly increased in the CRSwNP group than the CRS and HC groups, especially in the rCRSwNP group (P < 0.05), and the ROC curve presented a predictive ability of serum B7-H4 in predicting postoperative recurrence.Conclusion:Our results indicated that B7-H4 level was clearly enhanced in CRSwNP patients and associated with postoperative recurrence. Serum B7-H4 might serve as a simple and convenient biomarker for early predicting postoperative recurrence in CRwNP patients.

Gastric cancer (GC) is a highly heterogeneous disease with a dismal prognosis at both phenotypical and molecular levels.1 The Lauren type is currently the most useful and widely used in GC.2 However, the prognosis and molecular characteristics of Lauren type have not been fully described. Additionally, although several molecular classifications have been proposed,3, 4 clinically-relevant subtypes are still urgently needed. Here, we systematically investigated the molecular landscape and evolution features of 169 primary GC samples among Lauren type. We identified a prognostic-relevant subtype based on clone number (CN). Patients with high CN showed high tumour mutation burden (TMB) and significantly enriched in Adherens junction, ERBB2 regulates cell motility, and signaling by WNT pathway, indicating CN may have potential risk of tumour metastasis and benefit from immunotherapy. Our findings may inform the exploration of patient stratification and personalized therapy, as well as new clinical trials designed for the selection of combination therapy strategies. We enrolled 169 patients with formalin-fixed paraffin-embedded samples of matched tumour and adjacent tissue, including extended Lauren type: intestinal type (IT, n = 26), mixed type (MT, n = 35), non-signet ring diffuse type (NSRD, n = 77), and signet ring type (SRT, n = 31) with signet ring cells accounting for more than 10%.5 The median sequencing depth was 747× (range, 373–1186×) for tumour and was 428× (range, 221–960×) for adjacent tissue (Figure S1). We obtained 2847 Single Nucleotide Variations (SNVs) and 44 indels. The median TMB was 10.56 per Mb (mean 16.43 per Mb). The most recurrent mutant genes included TP53 (39.1%), CDH1 (28.4%), ARID1A (24.9%), TTN (24.3%), and MUC16 (19.5%), which was consistent with previous studies (The Cancer Genome Atlas (TCGA): 48.1%, 8.4%, 25.8%, 54.9%, 33.9%; ACRG: 40%, 4%, 17.8%, 38.2%, 25.8%; oncosg: 47.6%, 9.5%, 13.6%, 38.1%, 19.7%; respectively. Figure S2A).3, 4, 6 MUC16- and TTN-mutated samples showed higher TMB value (Figure S2B,C,E). Only Adenomatous Polyposis Coli (APC) (p = .038) showed significant difference (Figure 1, Figures S3–S4), suggesting high-frequency mutated genes have similar variation pattern in the four types. There was no significant difference in sex, age, venous invasion, perineural invasion, treatment regimen, TNM stage, tumour site, tumour size, and MSI status except CEA(p = .0221) and CA199 index (p = .03) (Table S1, Figure S5C,D). Patients with high tumour markers generally have worse prognosis (Figure S5A,B). However, we found only patients in NSRD with CEA-high or CA199-high had significantly shorter outcomes (Figure S5E,F), suggesting the importance of stratified management for patient care. The mutational signature analysis also showed only signature 3 and signature 17 were not enriched in NSRD and SRT, respectively (Figure 1, Figure S6). In terms of comprehensive indicators, we compared the TMB score, mutant-allele tumour heterogeneity (MATH) score,7 and variant allele frequency (VAF) from three dimensions: mutational burden, mutation heterogeneity, and allelic mutation frequency. We found no significant difference in TMB and MATH values between the four types except VAF (Figure 2A–C), suggesting VAF may influence histological types. We then preformed pyclone analysis.8 We defined the highest cell prevalence cluster as clone and the other as subclone. Pyclone inferred 379 clones (IT, 59, 13.9%; MT, 70, 9.9%; NSRD, 176, 12.9%; SRT, 74, 18.8%) and 2514 subclones (IT, 366, 86.1%; MT, 640, 90.1%; NSRD, 1188, 87.1%; SRT, 320, 81.2%). The median CN was 7 (range, 1–54). Highly specific clonal genes were observed in each type (unique ratio: IT, 30.5%; MT, 22.9%; NSRD, 32.9%; SRT, 28.4%) (Figure 2D), and subclonal gene has similar phenomenon (Figure 2E). The results indicated the differences of gene mutation process among the four types. To clarify the functional role of clonal and subclonal genes, we performed pathway enrichment analysis. The result showed clonal genes in IT were significantly enriched in TP53 regulates transcription of DNA repair genes pathway, and subclonal genes were in DNA repair pathways. We also found clonal and subclonal genes in MT were enriched in the PI3K-Akt signaling pathway and c-type lectin receptor signaling pathway, respectively. Several classical tumour-related pathways were enriched in the NSRD, such as pre-NOTCH transcription and translation, Ras signaling pathway, and p53 signaling pathway. Additionally, signaling by receptor tyrosine kinases and ErbB signaling were significantly enriched in the SRT, respectively (Figure 2F). The different functional enrichment features among the four types suggest the clonal evolution patterns may be related to histological phenotypes. To evaluate the clonal heterogeneity process, the distribution of high-frequently mutant genes was tested. We found that the same gene can be either a clone gene or a subclone gene in different samples, indicating gene clonal heterogeneity (Figure 3A). Furthermore, CN was significantly correlated with the maximum VAF (Figure 3B). To further illustrate the clinical relevance of CN, we observed the characteristics distribution of CN with the overall survival data (Figure 3C) and patients with CN ≥ 7 was associated with poor outcomes (Figure 3D). Besides, CN stratification remained significantly associated with survival in the multivariate setting of Cox model (Figure 4A). We further excluded the interference of phenotype and stage on CN stratification by statistical test (Figure 4B,C). CN may be an independent prognostic factor in GC. Detailed mutational landscape analysis of CN stratification showed the mutation frequencies of ARID1A, TTN, MUC16, MLL4, MLL2, GRIN2A, NRG1, ERBB2, SPTA1, SLIT2, and RHOA genes were significantly higher in CN-high group (Figure 4D). Higher TMB was also observed in CN-high group (Figure 4E). Patients with high CN may benefit from immunotherapy. Functional enrichment analysis showed that Adherens junction, ERBB2 regulates cell motility, and signaling by WNT were significantly enriched in CN-high group (Figure 4F), indicating patients with high CN may have a high risk of metastasis. We also found the prognosis of IT CN ≥ 7 subgroup was significantly worse than that of CN < 7 subgroup, and consistent trend was observed in NSRD and SRT (Figure 4G). Thus, combining CN and histological phenotype may be an actionable marker for clinical prognosis stratification. In summary, we highlight the molecular, evolutionary and prognostic heterogeneity of GC phenotype at multi-dimensionally levels. The clonal evolution patterns of the four histological types showed different characteristics, and CN may be a molecular classification indicator for patient stratification. The authors would like to thank the patients, their families and caregivers, data managers and all study investigators for their contributions to study conduct. This study was supported by the National Natural Science Foundation of China (grant number: 8197103463) and the Hunan Natural Science Foundation (grant number: 2012FJ6088). The authors declare there is no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Purpose: To explore the molecular mechanism of promoting cervical cancer by HSF1 in vivo and in vitro. Methods: The expression of HSF1 in 110 paraffin-embedded cervical cancer sections of different grades was examined via immunohistochemistry analyses. Expression of HSF1 downstream targets Metadherin (MTDH), VEGF-C and CD31 were studied using immunohistochemistry analyses. HSF1 transcriptional activity in the MTDH promoter region was detected by EMSA, CHIP and luciferase. Cell proliferation and clonality were detected by MTT and clonal formation assay. Cell migration and invasion ability were investigated by scratch analysis and transwell assay. HSF1-mediated tumorigenesis in vivo was examined in xenograft models. Results: HSF1 expression of cervical cancer cell line was increased compared to normal human cervical tissues. HSF1 enhanced the expression of MTDH, VEGF-C and CD31. HSF1 can combine with MTDH promoter to promote the expression of MTDH. HSF1 enhanced HeLa cell proliferation and clone formation. Furthermore, HSF1 increased HeLa cells migration and invasion in vitro. In the transplanted tumor model, HSF1 inhibited tumor growth in vivo after interference, and reduced the expression of MTDH, VEGF-C and CD31. Discussion: HSF1 can promote the proliferation, metastasis and invasion of cervical cancer.

如何发挥党建引领在医疗扶贫工作中的作用?根据病理学专业的特点,结合病理学专业的实际情况,针对基层医院出现的病理诊断问题,讨论了如何通过主题党日活动、数字远程病理诊断、"健康中国"建设、医联体专科联盟的建设等方式实现医疗扶贫,发挥基层党组织的战斗堡垒作用,阐述了党建引领在开展医疗扶贫工作中的具体措施,探讨了在开展医疗扶贫工作中如何充分发挥基层党组织的作用,并就如何进一步提升党建引领在医疗扶贫中的质量提出了自己的建议.

推进"双带头人"培育工程,坚持双向提升,把符合条件的学术带头人培养选拔为党支部书记,把有条件的教师党支部书记培养为学术带头人,确保高校教师党支部书记履职尽责、管理监督、示范带动等机制更加健全,使党支部建设质量显著提升,党支部主体作用有效发挥,实现基层党建和教学、科研、医疗诊断工作的双融合、双促进、双提高.通过三年的整体推进与实施,"双带头人"培育工程基本实现了全覆盖,实现了党建及学术双丰收.

Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO2-Exos) were collected and cocultured with fibroblasts. The expression of collagen I and alpha-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2 alpha were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-alpha, IL-1 beta and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and alpha-SMA was up-regulated after treatment with SiO2-Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2 alpha. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-alpha, IL-1 beta and IL-6 in BALF. These results suggested that SiO2-Exos are profibrogenic and that the facilitating effect is dependent on ER stress.

远程病理诊断平台很少应用于病理学基础与临床教学.经过中南大学湘雅基础医学院病理学系的持续探索和改革病理教学方法与手段,运用远程病理诊断平台开展病理教学资源库建设、病理综合讨论课教学、课程思政教育、实验教学考核,从而完善了教学手段,极大提高了教学质量.

Suitable and efficient treatments for Henoch-Schonlein purpura nephritis (HSPN) with proteinuria remains unclear. Whether steroids combined with immunosuppressive agents improves prognosis compared to steroid therapy alone also remains controversial. This study explored whether combined therapy reduces proteinuria in HSPN patients with different pathological features. Chinese patients (n = 84) diagnosed with HSPN with proteinuria by renal biopsy between 2010 and 2019 were retrospectively studied. Patients were grouped into the steroid group (control) or the combined steroid and immunosuppressant group. Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m(2)/y) and proteinuria were measured. The primary outcome progression was analyzed using Kaplan-Meier survival curves. The effect of the combined therapy on renal outcome was analyzed by multivariable Cox regression. Propensity score matching and sensitivity analysis were used to explore whether pathological features impacted prognosis. Patients who received combined steroid and immunosuppressant therapy were more likely to recover from HSPN and had proteinuria < 3 g/24 h (P = 0.02) or 1 g/24 h (P = 0.03). Multiple Cox regression analysis confirmed that this decrease was independent of renin-angiotensin system blockers. Further sensitivity analysis showed that combined therapy was effective in patients with crescents (P = 0.02). However, combined steroid and immunosuppressant therapy was not more effective in patients with endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T), or segmental sclerosis (S). Combined steroid and immunosuppressant therapy was significantly associated with HSPN remission, and more effectively decreased proteinuria during the initial disease phase.

The mortality rate of ovarian cancer is the highest among gynaecological cancers, primarily due to metastatic symptoms. Recent studies have shown that HOX genes are crucial in tumour progression, but the underlying mechanisms remain unclear. Here, HOXC10 expression was examined in ovarian cancer tissues. The function of HOXC10 in ovarian cancer metastasis was investigated in vitroand via intraperitoneal injection in vivo. A total of 158 ovarian cancer patients with adequate records were enrolled for analysis. HOXC10 was associated with metastasis and poor prognosis in ovarian cancer. In vitro, HOXC10 overexpression promoted ovarian cancer cell migration. Moreover, HOXC10 positively regulated Slug expression, altering the migration ability of cancer cells. Furthermore, our study showed that miR-222-3p was a suppressor of HOXC10. In vivo, a decrease in hepatic metastasis was seen in xenograft mice harbouring tumours with stable HOXC10 overexpression after miR-222-3p agomir (an overexpression reagent) injection. This study provides the first evidence that HOXC10 promotes ovarian cancer metastasis by regulating the transcription of the EMT-related gene Slug. Moreover, we found that HOXC10 is regulated by miR-222-3p. These data highlight the crucial role of HOXC10 in enhancing ovarian cancer metastasis and may provide a therapeutic target for ovarian cancer.

Idiopathic interstitial pulmonary fibrosis is a common diffuse interstitial lung disease and has poor prognosis. And one of the pathological features of it is persistent fibroblast activation. It was reported that microRNA‐30a was down‐regulated in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis patients. But whether miR‐30a is involved in fibroblast activation and its specific mechanism is unclear. In this study, we aimed to investigate the role of miR‐30a in fibroblast activation induced by TGF‐β1. We found miR‐30a could targetedly suppress FAP‐α expression. In MRC5 cells, miR‐30a was not only involved in regulating the expression of FAP‐α, col1a and α‐SMA induced by TGF‐β1 but also had a role in cell proliferation with or without TGF‐β1 treatment via regulating FAP‐α expression. Thus, the results indicated that miR‐30a alleviated fibroblast activation by regulating the expression of FAP‐α.