This study aimed to determine whether remnant cholesterol (RC) and its variability can predict the onset of metabolic dysfunction-associated steatotic liver disease (MASLD) independently of low-density lipoprotein cholesterol (LDL-C) levels. A longitudinal cohort study involving 43,065 participants who underwent at least two physical examinations was conducted. This study used Cox proportional hazards models to assess the relationships among RC quartile levels (Q1–Q4), visit-to-visit variability, and the risk of MASLD. This variability was quantified using several metrics: standard deviation (SD), logSD, average real variability (ARV), logARV, mean absolute deviation (MAD), and logMAD. Concurrently, this study utilized a combined analysis of RC and LDL-C groups to assess the independent risk of MASLD associated with RC. During a mean visit-to-visit of 3.19 years (SD 2.06 years), 8374 patients (19.45%) developed MASLD. Compared with Q1, Q4 was associated with a significantly greater risk of MASLD (hazard ratio [HR] 1.309, 95% confidence interval [CI] 1.220–1.403, P < 0.001). The fully adjusted Cox model revealed that the HRs of SD, logSD, ARV, logARV, MAD and logMAD were 1.400 (95% CI 1.305–1.502), 1.278 (95% CI 1.188–1.374), 1.152 (95% CI 1.079–1.229), 1.183 (95% CI 1.140–1.227), 1.578 (95% CI 1.433–1.737) and 1.263 (95% CI 1.175–1.358), respectively. In both LDL-C subgroups (≥ 3.4 mmol/L and < 3.4 mmol/L), high baseline RC was associated with elevated MASLD risk (HR 1.208, 95% CI 1.148–1.270, P < 0.001; HR 1.246, 95% CI 1.129–1.374, P < 0.001). RC levels were independently associated with MASLD in healthy individuals, irrespective of LDL-C level. The variability of RC during visit-to-visit periods provides a predictive marker for identifying individuals at heightened risk of MASLD.

A comprehensive spatial distribution of the proteome in human body and cancers is fundamental for understanding human biology and diseases including cancers. Here, we present an anatomically resolved human proteome derived from 1781 benign and malignant samples from 58 major tissue types encompassing 251 specific tissues and 25 carcinomas. Based on a spectral library covering over 75% of the human protein-coding genes with 208 understudied and 82 missing proteins characterized, we quantified over 13,000 proteins in these samples using data-independent acquisition proteomics. This data resource presents the so far most comprehensive quantitative proteomic landscape of human tissues and common carcinomas. It allows systematic evaluation of tissue-specific drug responses, identification of drug candidates that may be repurposed as antineoplastics, and discovery of novel targets for anticancer therapy. This resource, available as an online knowledgebase, refines our knowledge of spatial distribution of the human proteome and tumor-specific protein modulation. ### Competing Interest Statement T.Guo and Y. Z. are shareholders of Westlake Omics Inc. The other co-authors declare no competing interests. A.I.N. and F.Y. receive royalties from the University of Michigan for the sale of MSFragger and IonQuant software licenses to commercial entities. All license transactions are managed by the University of Michigan Innovation Partnerships office, and all proceeds are subject to university technology transfer policy.

Little is known regarding why a subset of COVID-19 patients exhibited prolonged positivity of SARS-CoV-2 infection. Here, we found that patients with long viral RNA course (LC) exhibited prolonged high-level IgG antibodies and higher regulatory T (Treg) cell counts compared to those with short viral RNA course (SC) in terms of viral load. Longitudinal proteomics and metabolomics analyses of the patient sera uncovered that prolonged viral RNA shedding was associated with inhibition of the liver X receptor/retinoid X receptor (LXR/RXR) pathway, substantial suppression of diverse metabolites, activation of the complement system, suppressed cell migration, and enhanced viral replication. Furthermore, a ten-molecule learning model was established which could potentially predict viral RNA shedding period. In summary, this study uncovered enhanced inflammation and suppressed adaptive immunity in COVID-19 patients with prolonged viral RNA shedding, and proposed a multi-omic classifier for viral RNA shedding prediction.

Radiation-induced damages are difficult to heal than normal wounds. This is because radiation therapy could lead to an imbalanced inflammatory response, oxidative stress response, lack of angiogenesis, and a high risk of bacterial infection, which are considered to be the greatest challenges in radiation-induced damages treatment. Hydrogels are semi-occlusive and are composed of complex hydrophilic polymers with a higher water content. Due to their excellent mechanical and biochemical property (such as adhesiveness, antibacterial, and antioxidant abilities), hydrogels represent a promising strategy that has achieved potent therapeutic efficacy in the treatment of radiation-induced skin and mucosa damages. This review systematically and comprehensively summarizes the recent progress of various types of hydrogels such as natural biopolymer, synthetic polymer, composite hydrogels and commodity dressings for the treatment of radiation-induced skin and mucosa damages.

Subsequently to the publication of the above paper, the authors have reviewed its content and the primary data, and have realized that the western blots selected to show the β‑actin experiments featured in Fig. 4A and Fig. 3C were the same blot, albeit with a different exposure time. The control blots correctly presented for Fig. 3C were inadvertently copied into Fig. 4A owing to an error made during the figure compilation process. The revised version of Fig. 4, containing the correct β‑actin blots for Fig. 4A, is shown below. Note that this error did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors thank the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 10: 2891‑2897, 2014; DOI: 10.3892/mmr.2014.2614].

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.

Purpose: TFEB is a key regulator of autophagy-lysosomal biogenesis pathways, while its dysregulation is highly prevalent in various human cancers, but the specific contribution to breast cancer remains poorly understood. The main purpose of this study is to explore the role of TFEB in breast cancer proliferation, metastasis and maintaining breast cancer stem cells (BCSCs) traits, thus uncovering its underlying mechanism. Methods: Bioinformatics, western blotting and immunohistochemical staining were applied to analyze the expression of TFEB in breast cancer. Stable down-regulation TFEB cells were established in MCF-7 and MDA-MB-231 breast cancer cell lines. MTT, clone formation, wound healing, transwell and 3D tumor invasion assays were used to evaluate the proliferation, migration and invasion ability of breast cancer cells. Mammosphere formation, immunocytochemical (ICC) staining were used to detect the effect of down-regulating TFEB on breast cancer stem cells. Results: we demonstrated that higher expression of TFEB was found in breast cancer. TFEB depletion had inhibitory effects on cellular proliferation, migration and invasion of breast cancer cells. Moreover, knockdown TFEB decreased mammosphere formation ability of BCSCs and expression of cancer stem cell markers. Autophagy-lysosomal related proteins were decreased by down regulation of TFEB. Conclusion: we uncovered a critical role of TFEB in breast cancer proliferation and metastasis, and BCSCs self-renewal and stemness. The underlying mechanisms involve in maintaining BCSCs traits, and dysregulating lysosome functions.

Little is known regarding why a subset of COVID-19 patients exhibited 25 prolonged positivity of SARS-CoV-2 infection. Here, we studied the sera proteomic

Little is known regarding why a subset of COVID-19 patients exhibited prolonged positivity of SARS-CoV-2 infection. Here, we present a longitudinal sera proteomic resource for 37 COVID-19 patients over nine weeks, in which 2700 proteins were quantified with high quality. Remarkably, we found that during the first three weeks since disease onset, while clinical symptoms and outcome were indistinguishable, patients with prolonged disease course displayed characteristic immunological responses including enhanced Natural Killer (NK) cell-mediated innate immunity and regulatory T cell-mediated immunosuppression. We further showed that it is possible to predict the length of disease course using machine learning based on blood protein levels during the first three weeks. Validation in an independent cohort achieved an accuracy of 82%. In summary, this study presents a rich serum proteomic resource to understand host responses in COVID-19 patients and identifies characteristic Treg-mediated immunosuppression in LC patients, nominating new therapeutic target and diagnosis strategy.

BACKGROUND MicroRNAs (miRNAs) have emerged as central regulators of many processes. MiRNA-34 (miR-34) functions as a well-known tumor suppressor. The aim of this study was to investigate the mechanisms underlying how miR-34 participates in vascular disorders. MATERIAL AND METHODS Three miR-34 family members (miR-34a, miR-34b, and miR-34c) were overexpressed or silenced in human vascular smooth muscle cells (VSMCs) and umbilical vein endothelial cells (UVECs), respectively, before the proliferation and apoptosis of cells were detected by using Cell Counting Kit-8 assay and Annexin V- fluorescein isothiocyanate/propidium iodide flow cytometry. The protein expression of apoptosis biomarkers was detected by western blot. Dual-luciferase reporter assay was performed to determine the candidate target of miR-34, and enzyme-linked immune sorbent assay was used to evaluate the effect of miR-34 on the expression of the target gene. RESULTS Overexpression of miR-34 family members repressed proliferation and promoted apoptosis of VSMCs and UVECs, whereas miR-34 knockdown led to the opposite results. In addition, miR-34a inhibited the expression of alpha-1 antitrypsin (AAT), a serine protease inhibitor that suppresses the degradation of extracellular matrix, through a miR-34-binding site within the 3'-UTR of AAT. CONCLUSIONS MiR-34 promoted apoptosis of VSMC and UVEC cells by inhibiting AAT expression. This finding provides an update on the understanding of the clinical value of miR-34, which might assist to uncover novel and effective therapeutic strategies for the treatment of vascular diseases.

Background: Quercetin belongs to the flavonoids family, which has been proven to have extensive pharmacological effects. Nevertheless, the function of quercetin in peripheral arterial disease (PAD) has not yet been reported. In the research, we purposed to disclose the effectiveness of quercetin in the pathogenesis of PAD. Methods: HMEC-1 cells were cultivated in Matrigel for 24 h to observe the tube-formation. Detections of cell viability, migration and apoptosis were through implementing CCK-8, Transwell and flow cytometry methods. Western blot was utilised for measuring angiogenesis-, migration- and apoptosis-correlative factors. MiR-216a expression was examined via qRT-PCR, and its functions in HMEC-1 cells were uncovered after miR-216a mimic transfection. Assessment of JAK2/STAT3 and PI3K/AKT pathways was via implementing western blot. Results: HMEC-1 cells were spontaneously vascularised under Matrigel condition. Quercetin predominantly repressed cell viability, migration, VEGF expression and facilitated apoptosis in HMEC-1 cells. Additionally, suppression of miR-216a was discovered in HMEC-1 cells after quercetin stimulation, meanwhile miR-216a overexpression annulled the functions of quercetin in HMEC-1 cells. Besides, quercetin deactivated PI3K/AKT and JAK/STAT pathways through adjusting miR-216a. Conclusion: The above-mentioned consequences exhibited that quercetin suppressed HMEC-1 cell viability, migration and tube-formation through hindering JAK2/STAT3 and PI3K/AKT pathway via declination of miR-216a.

BACKGROUND:To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression.METHODS:Correlation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, α-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model.RESULTS:It show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/β-catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo.CONCLUSIONS:Stromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ β-catenin signal pathway.

OBJECTIVE:To investigate the correlations between three vascular endothelial growth factor 2 (VEGFR2) gene polymorphisms, +1192C>T, +1719T>A, and -604T>C, and deep venous thrombosis (DVT) in Chinese Han population. METHODS:We conducted a case-control study, between September 2009 and September 2012, in a Chinese Han population with onset of lower extremity DVT. A total of 135 patients were enrolled in the case group and 156 healthy individuals in the control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of the VEGFR2 gene polymorphisms +1192C>T, +1719T>A, and -604T>C. Haplotype analyses were conducted with SHEsis program. Logistic regression was used to detect the risk factors of DVT. Outpatient review and telephone follow-up were conducted to analyze the long-term treatment of DVT patients. RESULTS:The allele and genotype frequencies of -604T>C VEGFR2 polymorphism exhibited significant differences between the case and control groups (both p < 0.05). Haplotype analyses showed remarkable differences between the case and control groups in the distribution frequency of TAC and CTT haplotypes in the VEGFR2 gene (both p < 0.05). Logistic regression analysis showed independent correlation between the incidence of DVT and TAC haplotype in the VEGFR2 gene (p < 0.05). In addition, the TAC haplotype may be a risk factor for DVT treatment failure. CONCLUSION:Our findings suggest that the VEGFR2 gene -604T>C polymorphism and TAC haplotype are associated with DVT, and the TAC haplotype might affect the efficacy of long-term treatment of DVT patients.

Metformin is a first-line used agent for type II diabetes with few side effects. The antineoplastic effect of metformin was widely explored recently. Metformin may also be a prospective chemosensitizer or radiosensitizer in cancer treatment. In the present study, we firstly showed that metformin could effectively enhance the anti-proliferation effect of ionizing radiation (IR) on esophageal cancer (EC) cells ECa109. More potent DNA damage was observed by detection of γH2AX foci. Metformin synergistically induce apoptosis and cell cycle arrest in ECa109 cells with IR. Furthermore, the mechanisms how metformin sensitized ECa109 cells to IR may be targeting the ATM and AMPK/mTOR/HIF-1α pathways. Metformin may be a valuable agent in comprehensive treatment of EC.

The kallikrein-related peptidase 10 (KLK10) gene has tumor-suppressive function in various types of human cancer. However, previous studies showed that KLK10 also acts as an oncogene and is upregulated in gastrointestinal tumors. The role of KLK10 in human esophageal cancer (EC) remains unclear. In the present study, the expression of KLK10 in human esophageal and non-esophageal cancer tissues was investigated by immunohistochemistry. Quantitative RT-PCR and western blot analysis were utilized to detect KLK10 mRNA and protein expression in human esophageal cancer cell lines (TE-1 and Eca-109). Small interference RNA was utilized to specifically knockdown KLK10 expression in Eca-109 and TE-1 cells. Cell proliferation, cell cycle analysis as well as CDDP-dependent apoptosis were determined using a CCK-8 assay and flow cytometry. The results showed that, KLK10 was positive in 67 out of 83 (80.72%) human EC and positive in 3 out of 11 (27.27%) normal tissues (P=0.001). The present study indicated that KLK10 potentially plays a crucial role in Eca-109 cell growth. Additionally, the downregulation of KLK10 induced S-phase arrest and promoted cisplatin-induced apoptosis. The resutls of the present study suggested that KLK10 is a promising novel marker for the diagnostic and therapeutic target of esophageal cancer.

Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose- and time-dependent anti-proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As2O3 by targeting the AMPK/mTOR/HIF-1α/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment.

Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.

[Objective] To profile the expression characteristics and clinical significance of Wnt2 and β-catenin proteins in esophageal carcinoma.[Methods] Nine of normal esophagus tissues,38 precancerous lesions and 83 esophageal carcinomas(EC) were embeded to form tissue array.The expressions of Wnt2 and β-catenin were detected with immunohistochemistry,and the relations of the two protein expressions to invasiveness and metastasis of the carcinoma as well as correlation between Wnt2 and β-catenin were analyzed.[Results] In normal tissue,precancerous lesion and EC,the expression rates of Wnt2 were 22.2%,50.0% and 72.3%,respectively(P0.05),the rates of β-catenin were 33.3%,47.4% and 69.9%,respectively(P0.05).The Wnt2 and β-catenin expression in metastatic LN positive EC group(86.4% and 81.8%)and T3,4 group(81.0% and 82.8%)showed significantly higher expression rate of the two proteins than the LN negative group(56.4% and 56.4%)and T1,2 group(52.0% and 40.0%),P0.05.Statistical significance of Wnt2 expression(82.5% and 62.8%,P0.05) but not β-catenin(62.5% and 76.7%,P0.05) could be established between the III-IV stage group and I-II stage group.(3) Positive correlation between Wnt2 and β-catenin expression could be observed(P0.05,r=0.740).[Conclusion] The expression frequencies of presentation of Wnt signaling,Wnt2 and β-catenin,increase from noncancerous tissues to tumor and show close relationship with EC invasion and metastasis.It indicates that Wnt2 and β-catenin contributes to invasion and progression of EC and of important value as potential biomarker in molecular diagnosis and prognosis prediction.

[Objective] To profile expression of S100A4 during stepwise esophageal carcinogenesis and to analyze the relationship to the series of pathological factors.[Methods] Paraffin embedded tissue array with immunohistochemistry methods were adopted to exam the expression pattern of S100A4 in 83 esophageal carcinomas(EC),38 precancerous lesions and 9 noncancerous esophageal tissues,and the correlations between S100A4 expression and EC invasiveness and metastasis were analyzed.[Results] The expression rates of S100A4 in EC,premalignant and noncancerous tissues twere,59.0% 26.3% and 22.2%,the expression rate of EC was significantly higher than those of noncancerous and precancerous(P0.05),while statistical differences was found between the noncancerous and precancerous group(P0.05).The expression rate of adenocarcinoma(80.0%) was significantly higher than that of squamous cell carcinoma(54.4%),and the rate of female(84.6%) was significantly higher than that of the male(54.3%)(P0.05).The protein expression was not statistically related to patient age and tumor differentiation and size(P0.05).The expression rate of lymph node metastatic group(70.5%) was significantly higher than that of non lymph node metastaticgroup(46.2%),(P0.05).[Conclusions] The expression of S100A4 is an important molecular event in esophageal carcinogenesis,and progression.