Age was a protective factor for unexpected malignant diagnoses in patients with vertebral compression fracture.

OBJECTIVE: The purpose was to investigate the risk factors for unexpected malignant diagnoses in patients with vertebral compression fractures (VCF). METHODS: The clinical data were retrospectively collected from 1396 patients who underwent vertebral augmentation and biopsy between 2012 and 2022. According to the imaging results, the preoperative diagnoses were benign VCF (BVCF) in all these cases. Based on the histological findings, the patients were divided into two groups. In group A, unexpected malignant VCF (MVCF) was identified, while benign VCF (BVCF) was verified in group B. Logistic regression analysis was performed to analyze the risk and protective factors for unexpected malignant diagnoses. RESULTS: There were 44 patients in group A and 1352 in group B. The incidence of unexpected MVCF was 3.2 %. Age was significantly lower in group A compared to group B. Additionally, none of the patients in group A were older than 75. Age was associated with unexpected malignant diagnoses, according to the univariate logistic analysis. The multivariate logistic analysis showed that age was a protective factor for unexpected malignant diagnoses (odds ratio = 0.849, 95 % confidence interval: 0.809-0.891, p < 0.01). CONCLUSION: Age was a protective factor for unexpected malignant diagnoses in patients with preoperative diagnosis of BVCF. A routine biopsy is recommended to be performed during vertebral augmentation in young patients without preoperative imaging evidence of MVCF.

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review.

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

Du-moxibustion ameliorates depression-like behavior and neuroinflammation in chronic unpredictable mild stress-induced mice.

BACKGROUND: Neuroinflammation is involved in the advancement of depression. Du-moxibustion can treat depression. Here, we explored whether Du-moxibustion could alleviate neuroglia-associated neuro-inflammatory process in chronic unpredictable mild stress (CUMS) mice. METHODS: C57BL/6J mice were distributed into five groups. Except for the CON group, other four groups underwent CUMS for four consecutive weeks, and Du-moxibustion was given simultaneously after modeling. Behavioral tests were then carried out. Additionally, Western blot was conducted to measure the relative expression levels of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). Immunofluorescence was employed to evaluate the positive cells of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were analyzed using an ELISA assay. RESULTS: We found that CUMS induced depression-like behaviors, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, decreased the time in open arms and prolonged immobility. Furthermore, versus the CON group, the expression of HMGB1, TLR4, MyD88, NF-κB, positive cells of Iba-1, IL-1ß and TNF-α were increased but positive cells of GFAP were decreased in CUMS group. However, the detrimental effects were ameliorated by treatment with CUMS+FLU and CUMS+DM. LIMITATIONS: A shortage of this study is that only CUMS model of depression were used, while other depression model were not included. CONCLUSIONS: Du-moxibustion alleviates depression-like behaviors in CUMS mice mainly by reducing neuroinflammation, which offers novel insights into the potential treatment of depression.

The Main Mechanisms of Mesenchymal Stem Cell-Based Treatments against COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has a clinical manifestation of hypoxic respiratory failure and acute respiratory distress syndrome. However, COVID-19 still lacks of effective clinical treatments so far. As a promising potential treatment against COVID-19, stem cell therapy raised recently and had attracted much attention. Here we review the mechanisms of mesenchymal stem cell-based treatments against COVID-19, and provide potential cues for the effective control of COVID-19 in the future. METHODS: Literature is obtained from databases PubMed and Web of Science. Key words were chosen for COVID- 19, acute respiratory syndrome coronavirus 2, mesenchymal stem cells, stem cell therapy, and therapeutic mechanism. Then we summarize and critically analyze the relevant articles retrieved. RESULTS: Mesenchymal stem cell therapy is a potential effective treatment against COVID-19. Its therapeutic efficacy is mainly reflected in reducing severe pulmonary inflammation, reducing lung injury, improving pulmonary function, protecting and repairing lung tissue of the patients. Possible therapeutic mechanisms might include immunoregulation, anti-inflammatory effect, tissue regeneration, anti-apoptosis effect, antiviral, and antibacterial effect, MSC - EVs, and so on. CONCLUSION: Mesenchymal stem cells can effectively treat COVID-19 through immunoregulation, anti-inflammatory, tissue regeneration, anti-apoptosis, anti-virus and antibacterial, MSC - EVs, and other ways. Systematically elucidating the mechanisms of mesenchymal stem cell-based treatments for COVID-19 will provide novel insights into the follow-up research and development of new therapeutic strategies in next step.

Elevated expression of LCN13 through FXR activation ameliorates hepatocellular lipid accumulation and inflammation.

BACKGROUND: Lipocalin 13 (LCN13) is a member of the lipocalin family that consists of numerous secretory proteins. LCN13 high-expression has been reported to possess anti-obesity and anti-diabetic effects. Although metabolic dysfunction-associated steatotic liver diseases (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) are frequently associated with obesity and insulin resistance, the functional role of endogenous LCN13 and the therapeutic effect of LCN13 in MASH and related metabolic deterioration have not been evaluated. METHODS: We employed a methionine-choline deficient diet model and MASH cell models to investigate the role of LCN13 in MASH development. We sought to explore the effects of LCN13 on lipid metabolism and inflammation in hepatocytes under PA/OA exposure using Western blotting, real-time RT-PCR, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, oil red O staining. Using RNA sequencing, chromatin immunoprecipitation assay, and luciferase reporter assays to elucidate whether farnesoid X receptor (FXR) regulates human LCN13 transcription as a transcription factor. RESULTS: Our study found that LCN13 was down-regulated in MASH patients, MASH mouse and cell models. LCN13 overexpression in hepatocyte cells significantly inhibited lipid accumulation and inflammation in vitro. Conversely, LCN13 downregulation significantly exacerbated lipid accumulation and inflammatory responses in vivo and in vitro. Mechanistically, we provided the first evidence that LCN13 was transcriptionally activated by FXR, representing a novel direct target gene of FXR. And the key promoter region of LCN13 binds to FXR was also elucidated. We further revealed that LCN13 overexpression via FXR activation ameliorates hepatocellular lipid accumulation and inflammation in vivo and in vitro. Furthermore, LCN13-down-regulated mice exhibited aggravated MASH phenotypes, including increased hepatic lipid accumulation and inflammation. CONCLUSION: Our findings provide new insight regarding the protective role of LCN13 in MASH development and suggest an innovative therapeutic strategy for treating MASH or related metabolic disorders.

CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.

BACKGROUND: Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH. METHODS AND RESULTS: Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (P<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (P=0.0315). Patients with lower circALMS1 levels had higher risk of death (P=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (P<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (P<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (P<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (P<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (P=0.9721). CONCLUSIONS: Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.

IGF2BP2-m6A-circMMP9 axis recruits ETS1 to promote TRIM59 transcription in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is a common malignancy of the head and neck. Recently, circular RNA (circRNA) has been studied extensively in multisystem diseases. However, there are few research on biological functions and molecular mechanisms of circRNAs in LSCC. CircRNA array was used to detect the differentially expressed circRNAs. Kaplan-Meier and cox regression analysis were used to identify survival based on circMMP9. The qRT-PCR, RNase R treatment, sanger sequencing and in situ hybridization were used to verify circMMP9 expression, characteristics and localization in LSCC tissues and cells. Functionally, colony formation, MTS, transwell and in vivo assays were proceeded to detect the biological function of circMMP9 in LSCC progression. The RNA-seq was conducted to identify the molecular targets of circMMP9. Mechanically, MeRIP, RNA Immunoprecipitation (RIP), RNA pulldown, Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried on to verify the regulatory mechanism of circMMP9. CircMMP9 was discovered upregulated in LSCC tissues and cells, and high level of circMMP9 was associated with poor prognosis, low degree of pathological grading, high TNM stage and lymph node metastasis of LSCC. CircMMP9 knockdown prevented LSCC progression both in vitro and in vivo, whereas, circMMP9 overexpression had the opposite effect. CircMMP9 was stabilized by IGF2BP2 in m6A-dependent manner. TRIM59 was identified as downstream target of circMMP9. CircMMP9 recruited ETS1 to stimulate TRIM59 transcription. Moreover, TRIM59 accelerated LSCC progression via activating the PI3K/AKT signal pathway. Our findings offered a unique regulatory mechanism for circMMP9 in LSCC, as well as a novel proof that circMMP9 may be utilize as a diagnostic marker and therapeutic target for LSCC patients.

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.

Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs) and senomorphics (compounds that alter intercellular communication and modulate the behavior of SnCs) have become hot research topics in the field of anti-aging. In addition, strategies such as combination therapies and immune-based approaches have also made significant progress in the field of anti-aging therapy. In this article, we discuss the latest research on anti-aging targeting SnCs and gain a deeper understanding of the mechanism of action and impact of different anti-aging strategies on aging and age-related diseases, with the aim of providing more effective references and therapeutic ideas for clinical anti-aging treatment in the face of the ever-grave challenges of aging and age-related diseases.

Association of serum oleic acid level with depression in American adults: a cross-sectional study.

BACKGROUND: As the most abundant fatty acid in plasma, oleic acid has been found to be associated with multiple neurological diseases; however, results from studies of the relationship between oleic acid and depression are inconsistent. METHODS: This cross-sectional study analyzed 4,459 adults from the National Health and Nutrition Examination Survey 2011-2014. The following covariates were adjusted in multivariable logistic regression models: age, sex, race/ethnicity, education level, marital status, body mass index, physical activity, smoking status, alcohol status, metabolic syndrome, omega-3 polyunsaturated fatty acids, and total cholesterol. RESULTS: Serum oleic acid levels were positively associated with depression. After adjusting for all covariates, for every 1 mmol/L increase in oleic acid levels, the prevalence of depression increased by 40% (unadjusted OR: 1.35, 95%CI: 1.16-1.57; adjusted OR: 1.40, 95% CI: 1.03-1.90). CONCLUSIONS: Our study suggests that oleic acid may play a role in depression. Further research is needed to investigate the potential benefits of changing oleic acid levels for the treatment and prevention of depression.

CircCDK1 blocking IGF2BP2-mediated m6A modification of CPPED1 promotes laryngeal squamous cell carcinoma metastasis via the PI3K/AKT signal pathway.

BACKGROUND: Circular RNA (circRNA) is a novel noncoding RNA (ncRNA) that plays a critical role in various cancers. However, the clinical significance, biological function, and molecular mechanisms of circRNAs in laryngeal squamous cell carcinoma (LSCC) remain unclear. METHODS: A circRNA array was performed to identify the differentially expressed circRNAs. In vitro and in vivo assays were proceeded to verify the biological function of circCDK1 in LSCC. RNA pulldown assays and RNA immunoprecipitation (RIP) were used to confirm the binding between circCDK1 and insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2). The MeRIP assay was then used to identified the N6-methyladenisine (m6A) methylation of calcineurin like phosphatase domain containing1 (CPPED1). RESULTS: Hsa_circ_0005774 (circCDK1) was found upregulated in LSCC tissues compared to adjacent normal tissues. The level of circCDK1 was positively correlated with poor prognosisof LSCC patients. In vitro and in vivo, circCDK1 promoted migration and invasion of LSCC cells. Mechanistically, eukaryotic translation initiation factor4A3(EIF4A3) induced biogenesis of circCDK1 by binding to its flanking. By competitively binding to IGF2BP2, circCDK1 blocked the m6A modification of CPPED1 in IGF2BP2-dependent manner. Moreover, the circCDK1-mediated decrease of CPPED1 activated the PI3K/AKT signal pathway to facilitate progression of LSCC. CONCLUSIONS: Our findings demonstrated that EIF4A3-induced upregulation of circCDK1 promoted LSCC metastasis via EIF4A3-circCDK1-IGF2BP2-CPPED1 to activate PI3K-AKT signal pathway. CircCDK1 might serve as a new diagnostic and prognostic marker or potential therapeutic target for LSCC.

SHFL inhibits enterovirus A71 infection by triggering degradation of viral 3Dpol protein via the ubiquitin-proteasome pathway.

Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.

Association between dietary caffeine intake and severe headache or migraine in US adults.

The relationship between current dietary caffeine intake and severe headache or migraine is controversial. Therefore, we investigated the association between dietary caffeine intake and severe headaches or migraines among American adults. This cross-sectional study included 8993 adults (aged ≥ 20 years) with a dietary caffeine intake from the National Health and Nutrition Examination Surveys of America from 1999 to 2004. Covariates, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglycerides, were adjusted in multivariate logistic regression models. In US adults, after adjusting for potential confounders, a 100 mg/day increase in dietary caffeine intake was associated with a 5% increase in the prevalence of severe headache or migraine (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.07). Further, the prevalence of severe headache or migraine was 42% higher with caffeine intake of ≥ 400 mg/day than with caffeine intake of ≥ 0 to < 40 mg/day (OR 1.42, 95% CI 1.16-1.75). Conclusively, dietary caffeine intake is positively associated with severe headaches or migraines in US adults.

Whole-Transcriptome Sequencing Reveals a ceRNA Regulatory Network Associated with the Process of Periodic Albinism under Low Temperature in Baiye No. 1 (Camellia sinensis).

The young shoots of the tea plant Baiye No. 1 display an albino phenotype in the early spring under low environmental temperatures, and the leaves re-green like those of common tea cultivars during the warm season. Periodic albinism is precisely regulated by a complex gene network that leads to metabolic differences and enhances the nutritional value of tea leaves. Here, we identified messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) to construct competing endogenous RNA (ceRNA) regulatory networks. We performed whole-transcriptome sequencing of 12 samples from four periods (Bud, leaves not expanded; Alb, albino leaves; Med, re-greening leaves; and Gre, green leaves) and identified a total of 6325 differentially expressed mRNAs (DEmRNAs), 667 differentially expressed miRNAs (DEmiRNAs), 1702 differentially expressed lncRNAs (DElncRNAs), and 122 differentially expressed circRNAs (DEcircRNAs). Furthermore, we constructed ceRNA networks on the basis of co-differential expression analyses which comprised 112, 35, 38, and 15 DEmRNAs, DEmiRNAs, DElncRNAs, and DEcircRNAs, respectively. Based on the regulatory networks, we identified important genes and their interactions with lncRNAs, circRNAs, and miRNAs during periodic albinism, including the ceRNA regulatory network centered on miR5021x, the GAMYB-miR159-lncRNA regulatory network, and the NAC035-miR319x-circRNA regulatory network. These regulatory networks might be involved in the response to cold stress, photosynthesis, chlorophyll synthesis, amino acid synthesis, and flavonoid accumulation. Our findings provide novel insights into ceRNA regulatory mechanisms involved in Baiye No. 1 during periodic albinism and will aid future studies of the molecular mechanisms underlying albinism mutants.

Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

PKMYT1 inhibits lung adenocarcinoma progression by abrogating AKT1 activity.

PURPOSE: AKT hyperactivation drives malignant phenotypes in lung cancer via promoting tumor cell proliferation and survival. However, the relationship between dysregulation of cell cycle progression and AKT1 kinase activity is still not clear. METHODS: Following the expression level of PKMYT1 in lung cancer, we performed cell proliferation, migration, invasion, and xenograft assays to determine the function of PKMYT1. We used RNA-seq to explore the anti-tumor mechanism of PKMYT1 and examined the effect of PKMYT1 on AKT1 activity. RESULTS: In this study, we report that PKMYT1 is downregulated in lung adenocarcinoma (LUAD) tissues and its low expression predicts a poor prognosis in LUAD patients. PKMYT1 exerts potent tumor-suppressive functions in LUAD cells by inhibiting AKT1 activation and thereby repressing cell cycle progression, which depends on its tyrosine and threonine protein kinase activity. Interestingly, PKMYT1 could directly bind AKT1 to abrogate AKT1 activation. Moreover, silencing AKT1 and inhibitors targeting the AKT pathway effectively reverse the promoting effects of PKMYT1 knockdown on proliferation, migration and invasion of LUAD cells. CONCLUSION: This work reveals the anti-tumor effect of PKMYT1 in LUAD and provides evidence to clarify the dual roles of PKMYT1 in tumor progression. Moreover, our findings broaden the current understandings on AKT1 activation and identify PKMYT1 as a potential negative regulator of AKT1 kinase activity, providing further insights into targeting the AKT pathway in LUAD.

ncRNA-mediated overexpression of ubiquitin-specific proteinase 13 contributes to the progression of prostate cancer via modulating AR signaling, DNA damage repair and immune infiltration.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer, and the molecular mechanism driving mCRPC progression has not yet been fully elucidated. Immunotherapies such as chimeric antigen receptor, T-cell therapy and immune checkpoint blockade have exerted promising antitumor effects in hematological and solid tumor malignancies; however, no encouraging responses have been observed against mCRPC. The deubiquitinase USP13 functions as a tumor suppressor in many human cancers, as it sustains the protein stability of PTEN and TP53; however, its role in prostate cancer (PCa) and involvement in DNA damage and AR signaling remain unclear. In the current study, we explored the prognostic value of USP13 in PCa based on the TCGA database, and we analyzed the expression of USP13 in PCa tissues and adjacent normal tissues based on TCGA and our cohort. The results suggested that USP13 is overexpressed in PCa tumors and has the potential to be an independent biomarker for the overall survival of PCa patients. Additionally, enrichment analysis indicated that USP13 may participate in the AR pathway and PI3k/Wnt signaling, which are closely related to PCa progression. We also observed a significant correlation between the expression of USP13 and AR-related genes, DDR genes and mismatch repair genes based on the TCGA_PRAD dataset, which further supported the critical role of USP13 in AR activation and the DNA damage response of PCa. USP13 was also found to be enriched in protein neddylation, and expression of USP13 was significantly associated with infiltration of immune cells and expression of immunomodulators. Taken together, our study revealed a key role of USP13 in contributing to PCa progression by participating in multiple oncogenic signaling pathways, the DNA damage response and the immunosuppressive tumor microenvironment. Targeting USP13 may inhibit tumor growth and provide additional benefits in cooperation with DDR inhibitors and immunotherapy.

A Novel Nomogram for Prediction of Post-Hepatectomy Liver Failure in Patients with Resectable Hepatocellular Carcinoma: A Multicenter Study.

Objective: To develop a nomogram for predicting post-hepatectomy liver failure (PHLF) in patients with resectable hepatocellular carcinoma (HCC) based on portal hypertension, the extent of resection, ALT, total bilirubin, and platelet count. Methods: Patients with HCC hospitalized from January 2015 to December 2020 were included in a retrospective cohort study. 595 HCC patients were divided into a training cohort (n=416) and a validation cohort (n=179) by random sampling. Univariate and multivariable analyses were performed to identify the independent variables to predict PHLF. The nomogram models for predicting the overall risk of PHLF and the risk of PHLF B+C were constructed based on the independent variables. Comparisons were made by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) with traditional models, such as FIB-4 score, APRI score, CP class (Child-Pugh), MELD score (model of end-stage liver disease), and ALBI score (albumin-bilirubin) to analyze the accuracy and superiority of the nomogram. Results: We discovered that portal hypertension (yes vs no) (OR=1.677,95% CI:1.817-4.083, p=0.002), the extent of liver resection (OR=1.872,95% CI:3.937-47.096, p=0.001), ALT (OR=1.003,95% CI:1.003-1.016, P=0.003), total bilirubin (OR=1.036,95% CI:1.031-1.184, p=0.005), and platelet count (OR= 1.004, 95% CI:0.982-0.998, p=0.020) were independent risk factors for PHLF using multifactorial analysis. The nomogram models were constructed using well-fit calibration curves for each of these five covariates. When compared to the FIB4, ALBI, MELD, and CP score, our nomogram models have a better predictive value for predicting the overall risk of PHLF or the risk of PHLF B+C. The validation cohort's results were consistent. DCA also confirmed the conclusion. Conclusion: Our models, in the form of static nomogram or web application, were developed to predict PHLF overall risk and PHLF B+C risk in patients with HCC, with a high prediction sensitivity and specificity performance than other commonly used scoring systems.

Integrative Analysis and Experimental Validation Indicated That SNHG17 Is a Prognostic Marker in Prostate Cancer and a Modulator of the Tumor Microenvironment via a Competitive Endogenous RNA Regulatory Network.

The incidence of prostate cancer (PC) is growing rapidly worldwide, and studies uncovering the molecular mechanisms driving the progression and modulating the immune infiltration and antitumor immunity of PC are urgently needed. The long noncoding RNA SNHG family has been recognized as a prognostic marker in cancers and contributes to the progression of multiple cancers, including PC. In this study, we aimed to clarify the prognostic values and underlying mechanisms of SNHGs in promoting the progression and modulating the tumor microenvironment of PC through data mining based on The Cancer Genome Atlas (TCGA) database. We identified that within the SNHG family, SNHG17 was most correlated with the overall survival of PC patients and could act as an independent predictor. Moreover, we constructed a competitive endogenous RNA (ceRNA) network by which SNHG17 promotes progression and potentially inhibits the immune infiltration and immune response of prostate cancer. By interacting with miR-23a-3p/23b-3p/23c, SNHG17 upregulates the expression of UBE2M and OTUB1, which have been demonstrated to play critical roles in the tumorigenesis of human cancers, more importantly promoting cancer cell immunosuppression and resistance to cytotoxic stimulation. Finally, we examined the correlation between SNHG17 expression and the clinical progression of PC patients based on our cohort of 52 PC patients. We also verified the SNHG17/miR-23a/OTUB1 axis in RV-1 and PC-3 cells by dual luciferase and RIP assays, and we further identified that SNHG17 promoted cellular invasive capacity by modulating OTUB1. In summary, the current study conducted a ceRNA-based SNHG17-UBE2M/OTUB1 axis and indicated that SNHG17 might be a novel prognostic factor associated with the progression, immunosuppression, and cytotoxic resistance of PC.

Neomycin inhibits Megalocytivirus infection in fish by antagonizing the increase of intracellular reduced glutathione.

Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the Megalocytivirus genus that infects a number of marine and freshwater fishes, causing huge economic losses in aquaculture. The ISKNV infection leads to increase of reducing power in cells. As the antibiotic neomycin can promote the production of reactive oxygen species (ROS) in animal cells, in the current study, the potential therapeutic effect of neomycin on ISKNV infection was explored. We showed that neomycin could decrease the reducing power in cultured MFF-1 cells and inhibit ISKNV infection by antagonizing the shift of the cellular redox balance toward reduction. In vivo experiments further demonstrated that neomycin treatment significantly suppresses ISKNV infection in mandarin fish. Expression of the major capsid protein (MCP) and the proportion of infected cells in tissues were down-regulated after neomycin treatment. Furthermore, neomycin showed complex effects on expression of a set of antiviral related genes of the host. Taking together, the current study suggested that the viral-induced redox imbalance in the infected cells could be used as a target for suppressing ISKNV infection. Neomycin can be potentially utilized for therapeutic treatment of Megalocytivirus diseases by antagonizing intracellular redox changes.

NIR-II-Responsive CeO2-x@HA Nanotheranostics for Photoacoustic Imaging-Guided Sonodynamic-Enhanced Synergistic Phototherapy.

The therapeutic effect of photothermal therapy (PTT) and photodynamic therapy (PDT) is severely limited because of the shallow tissue penetration depth of the first near-infrared (NIR-I) light. Multifunctional nanotheranostics irradiated by the second near-infrared (NIR-II) light have received wide interest with respect to deeper tissue penetration, and sonodynamic therapy (SDT) synergistic phototherapy can achieve the complete elimination of tumors. Herein, we successfully constructed a single NIR-II light-induced nanotheranostic using cerium oxide (CeO2-x) with abundant oxygen vacancies for photoacoustic imaging-guided SDT-enhanced phototherapy for the first time. CeO2-x with surface crystalline disorder showed extensive NIR-II region absorption and an outstanding photothermal conversion ability. In addition, the CeO2-x layer with numerous oxygen defects can promote the separation of holes and electrons by ultrasound irradiation, which can remarkably enhance the efficacy of phototherapy to achieve high-efficiency tumor ablation. CeO2-x was surface modified with hyaluronic acid (HA) to prepare CeO2-x@HA to allow active tumor targeting efficiency. Both cell and animal experiments confirmed that all-in-one CeO2-x@HA exhibited a high therapeutic efficacy of SDT-enhanced PDT/PTT under 1064 nm laser irradiation, which achieved complete tumor eradication without systemic toxicity. This study significantly broadened the application of NIR-II-responsive CeO2-x for photoacoustic imaging-mediated SDT-enhanced phototherapy to the highly efficient and precise elimination of tumors.