Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma.

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.

PiRNA-4447944 promotes castration-resistant growth and metastasis of prostate cancer by inhibiting NEFH expression through forming the piRNA-4447944-PIWIL2-NEFH complex.

Castration-resistant prostate cancer (CRPC) is the leading cause of prostate cancer (PCa)-related death in males, which occurs after the failure of androgen deprivation therapy (ADT). PIWI-interacting RNAs (piRNAs) are crucial regulators in many human cancers, but their expression patterns and roles in CRPC remain unknown. In this study, we performed small RNA sequencing to explore CRPC-associated piRNAs using 10 benign prostate tissues, and 9 paired hormone-sensitive PCa (HSPCa) and CRPC tissues from the same patients. PiRNA-4447944 (piR-4447944) was discovered to be highly expressed in CRPC group compared with HSPCa and benign groups. Functional analyses revealed that piR-4447944 overexpression endowed PCa cells with castration resistance ability in vitro and in vivo, whereas knockdown of piR-4447944 using anti-sense RNA suppressed the proliferation, migration and invasion of CRPC cells. Additionally, enforced piR-4447944 expression promoted in vitro migration and invasion of PCa cells, and reduced cell apoptosis. Mechanistically, piR-4447944 bound to PIWIL2 to form a piR-4447944/PIWIL2 complex and inhibited tumor suppressor NEFH through direct interaction at the post-transcriptional level. Collectively, our study indicates that piR-4447944 is essential for prostate tumor-propagating cells and mediates androgen-independent growth of PCa, which extends current understanding of piRNAs in cancer biology and provides a potential approach for CRPC treatment.

Klotho accelerates the progression of polycystic ovary syndrome through promoting granulosa cell apoptosis and inflammation†.

The morbidity of polycystic ovary syndrome (PCOS) is in highly increasing rate nowadays. PCOS not only affects the fertility in women, but also threatens the health of whole life. Hence, to find the prognostic risk factors is of great value. However, the effective predictors in clinical practice of PCOS are still in blackness. In this study, we found Klotho (KL) was increased in follicular fluid (FF) and primary luteinized granulosa cells (GCs) from PCOS patients with hyperandrogenism. Furthermore, we found follicular KL was negatively correlated with numbers of mature oocytes, and positively correlated with serum testosterone, LH, and LH/FSH levels menstrual cycle and number of total antral follicles in PCOS patients. In primary luteinized GCs, the increased KL was accompanied with upregulation of cell apoptosis and inflammation-related genes. In ovaries of PCOS mice and cultured human KGN cell line, KL was up-regulated and accompanied by apoptosis, inflammation, and mitochondrial dysfunction. Therefore, our findings suggest new mechanisms for granulosa cell injury and revealed to target inhibit KL maybe a new therapeutic strategy for treatment of PCOS.

The PP2A inhibitor LB-100 mitigates lupus nephritis by suppressing tertiary lymphoid structure formation.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ involvement and autoantibody production. Patients with SLE face a substantial risk of developing lupus nephritis (LN), which imposes a substantial burden on both patients and their families. Protein phosphatase 2A (PP2A) is a widely distributed serine/threonine phosphatase that participates in regulating multiple signaling pathways. Inhibition of PP2A has been implicated in the treatment of various diseases. LB-100, a small molecule inhibitor of PP2A, has demonstrated anti-tumor therapeutic effects and high safety profile in preclinical experiments. However, the role of PP2A and its inhibitor has been insufficiently studied in LN. In this study, we assessed the potential effects of LB-100 in both MRL/lpr mice and R848-induced BALB/c mice. Our findings indicated that LB-100 administration led to reduced spleen enlargement, decreased deposition of immune complexes, ameliorated renal damage, and improved kidney function in both spontaneous and R848-induced lupus mouse models. Importantly, we observed the formation of tertiary lymphoid structures (TLSs) in the kidneys of two distinct lupus mouse models. The levels of signature genes of TLS were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokine production and inhibited TLS formation. In addition, we confirmed that inhibition or knockdown of PP2A reduced the production of T cell-related chemokines by renal tubular epithelial cells (RTEC). In summary, our study highlighted the renal protective potential of the PP2A inhibitor LB-100 in two distinct lupus mouse models, suggesting its potential as a novel strategy for treating LN and other autoimmune diseases.

[Impact of different angles of pulmonary surfactant administration on bronchopulmonaryplasia and intracranial hemorrhage in preterm infants: a prospective randomized controlled study]. / ä¸åŒè§’åº¦æ³¨å ¥è‚ºè¡¨é¢æ´»æ€§ç‰©è´¨å¯¹æ—©äº§å„¿æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯å’Œé¢ å† å‡ºè¡€çš„å½±å“ï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. METHODS: A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. RESULTS: The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). CONCLUSIONS: The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants.

Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage-myofibroblast transition.

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-ß and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Identification and validation of cuproptosis and disulfidptosis related genes in colorectal cancer.

Colorectal cancer, the third most prevalent malignant cancer, is associated with poor prognosis. Recent studies have investigated the mechanisms underlying cuproptosis and disulfidptosis in colorectal cancer. However, whether genes linked to these processes impact the prognosis of colorectal cancer patients through analogous mechanisms remains unclear. In this study, we developed a model of cuproptosis and disulfidptosis in colorectal cancer and concurrently explored the role of the pivotal model gene HSPA8 in colorectal cancer cell lines. Our results revealed a positive correlation between cuproptosis and disulfidptosis, both of which are emerging as protective factors for the prognosis of CRC patients. Consequently, a prognostic model encompassing HSPA8, PDCL3, CBX3, ATP6V1G1, TAF1D, RPL4, and RPL14 was constructed. Notably, the key gene in our model, HSPA8, exhibited heightened expression and was validated as a protective prognostic factor in colorectal cancer, exerting inhibitory effects on colorectal cancer cell proliferation. This study offers novel insights into the interplay between cuproptosis and disulfidptosis. The application of the prognostic model holds promise for more effectively predicting the overall survival of colorectal cancer patients.

The Long Noncoding RNA Gall Bladder Cancer-Associated Suppressor of Pyruvate Carboxylase Inhibits the Proliferation, Migration, and Invasion of Colorectal Cancer Cells and Induces Their Apoptosis.

This study aimed to determine the role of the long noncoding RNA (lncRNA) gall bladder cancer-associated suppressor of pyruvate carboxylase (SOD2-1) in the progression of colorectal cancer (CRC). A total of 23 pairs of specimens, including CRC tissues and adjacent normal tissues, were collected, and the expression of lncRNA SOD2-1 (lnc-SOD2-1) was measured. lnc-SOD2-1 function was examined using HCT15 and HCT116 cells. A lnc-SOD2-1 overexpression vector was designed and transfected into both cell lines. MTS and colony formation assays were used to determine cell viability. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays were performed to measure apoptosis. Cell migration and invasion were evaluated using the Transwell assay. Migration and invasion markers were validated using quantitative reverse transcription-polymerase chain reaction and western blot analysis. The results indicated that the expression of lnc-SOD2-1 was downregulated in CRC tissues. lnc-SOD2-1 overexpression evidently decreased cell viability and led to the formation of fewer cell colonies. lnc-SOD2-1 overexpression induced ~ twofold higher apoptosis than the control group. lnc-SOD2-1 overexpression reduced the proportion of migratory and invasive cells to 50% and 75% of the control group, respectively. lnc-SOD2-1 overexpression significantly decreased the expression of matrix metalloproteinase-2 and -9. In conclusion, lnc-SOD2-1 may act as a tumor suppressor that inhibits the proliferation, migration, and invasion of CRC cells and induces their apoptosis.

Olink proteomics analysis uncovers inflammatory proteins in patients with different states of bipolar disorder.

STUDY DESIGN: A prospective study. BACKGROUND: This study aims to investigate the relationship between different states of bipolar disorder (BD) and plasma inflammatory proteins, which may be used as their biomarkers. MATERIALS AND METHODS: We totally collected admission plasma from 16 healthy subjects and 32 BD patients, including 16 patients with BD manic episodes (BD-M) and 16 patients with BD depressive episodes (BD-D). Ten samples in each group were analyzed by proximity extension assays of 92 inflammation-related proteins, and all samples were verified by ELISA. Receiver-operating characteristic (ROC) curve analysis was performed to identify the diagnostic ability and cut-off values of potential biomarkers. RESULTS: Our findings showed that BD patients had significantly higher levels of IL6, MCP-1, TGF-α, IL8, and IL10-RB in comparison with healthy subjects, and their cut-off values were 0.531 pg/ml, 0.531 pg/ml, 0.469 pg/ml, 0.406 pg/ml, and 0.406 pg/ml, respectively. The levels of IL6, MCP-1, TGF-α, and IL8 in BD-M patients were significantly greater than in healthy individuals, and their cut-off values were 0.813 pg/ml, 0.688 pg/ml, 0.438 pg/ml, and 0.625 pg/ml, respectively. Moreover, we found cut-off values of 0.500 pg/mL and 0.688 ng/mL for TGF-α and ß-NGF, respectively, even though the levels in the BD-D group were much higher than in the control group. Furthermore, BD-M patients had significantly higher levels of IL6, FGF-19, IFN-γ, and IL-17C in comparison with BD-D patients. Likewise, 0.687 pg/ml, 0.500 pg/ml, 0.438 pg/ml, and 0.375 pg/ml were their cut-off values, respectively. Our findings also showed that the combination of these proteins had the highest diagnostic accuracy. CONCLUSIONS: Our findings showed that plasma inflammatory proteins were related to BD and its subtypes, which may be utilized as potential biomarkers of different stages of BD. Furthermore, we also found their cut-off values and their combinations to have the highest diagnostic accuracy, providing clinicians with a new method to rapidly differentiate BD and its subtypes and manage early targeted interventions.

Circular RNA circIGF2BP3 Promotes the Proliferation and Differentiation of Chicken Primary Myoblasts.

The quality and quantity of animal meat are closely related to the development of skeletal muscle, which, in turn, is determined by myogenic cells, including myoblasts and skeletal muscle satellite cells (SMSCs). Circular RNA, an endogenous RNA derivative formed through specific reverse splicing in mRNA precursors, has the potential to influence muscle development by binding to miRNAs or regulating gene expression involved in muscular growth at the transcriptional level. Previous high-throughput sequencing of circRNA in chicken liver tissue revealed a circular transcript, circIGF2BP3, derived from the gene encoding insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). In this study, we confirmed the presence of the natural circular molecule of circIGF2BP3 through an RNase R enzyme tolerance assay. RT-qPCR results showed high circIGF2BP3 expression in the pectoral and thigh muscles of Yuexi frizzled feather chickens at embryonic ages 14 and 18, as well as at 7 weeks post-hatch. Notably, its expression increased during embryonic development, followed by a rapid decrease after birth. As well as using RT-qPCR, Edu, CCK-8, immunofluorescence, and Western blot techniques, we demonstrated that overexpressing circIGF2BP3 could promote the proliferation and differentiation of chicken primary myoblasts through upregulating genes such as proliferating cell nuclear antigen (PCNA), cyclin D1 (CCND1), cyclin E1 (CCNE1), cyclin dependent kinase 2 (CDK2), myosin heavy chain (MyHC), myoblast-determining 1 (MyoD1), myogenin (MyoG), and Myomaker. In conclusion, circIGF2BP3 promotes the proliferation and differentiation of myoblasts in chickens. This study establishes a foundation for further investigation into the biological functions and mechanisms of circIGF2BP3 in myoblasts proliferation and differentiation.

Physicochemical Characterization and Oxidative Potential of Iron-Containing Particles Emitted from Xuanwei Coal Combustion.

Respiratory diseases have been proven to be directly related to air pollutants. Xuanwei, located in South China, has been known to have the highest mortality rate for lung cancer in China because of the air pollutants emitted through local coal combustion. However, the mechanism of lung cancer induced by air pollutants is not clear. Based on the fact that a large number of iron-bearing mineral particles was found in Xuanwei coal combustion particles, the iron-containing particles were hypothesized to play important roles in the pathogenesis of the high incidence rate of lung cancer in this area. In this study, raw coal samples were collected from a coal mine in the Xuanwei area. Size-resolved particles emitted from the raw coal samples were collected using an Anderson high-volume sampler. Mineralogical characterization and an assessment of the oxidative potential of the iron-containing particles were conducted using cutting-edge technologies, and the biological activity of the particles were evaluated via DTT assay. Our data showed that the iron-containing minerals accounted for more than 10% of the measured particles emitted from Xuanwei coal combustion samples. The content analysis of ·OH generated from Xuanwei coal combustion particles showed that ·OH content was dependent on the size of particles in the surrogated lung fluid. The concentration of ·OH increased as the particle size decreased. The DTT assay data further demonstrated that when the mass concentration of dissolved irons increased, the oxidation potential of the particles increased. The highest proportion of divalent iron in the total dissolved iron was found in the submicron particles in low pH solution(pH = 1), which indicated that the oxidative potential induced by submicron particles was stronger than that induced by coarse particles and fine particles. Armed with the above data, the toxicological mechanism of the iron-containing mineral particles can be investigated further.

[Platelet-rich Plasma Induces M2 Macrophage Polarization via Regulating AMPK Singling Pathway].

OBJECTIVE: To investigate the role of platelet-rich plasma (PRP) in inducing the M2 macrophage polarization via regulating AMPK singling pathway. METHODS: The expressions of M1 marker CD11c and M2 marker CD206 in macrophages of blank control group, LPS group, LPS+PRP group, and LPS+PRP+Compound C group were detected by flow cytometry. Western blot was used to observe the effects of PRP on the expression of AMPK-mTOR signaling pathway-related proteins at different times (12 h, 18 h and 24 h) after LPS treatment. RNA interference technology was used to silence the expression of AMPK in macrophages, and the expression of TGF-ß protein was subsequently examined by Western blot. RESULTS: LPS significantly reduced the expression of CD206 and increased the expression of CD11c (P <0.05). After the addition of PRP, the expression of CD206 was significantly increased (P <0.05), while the expression of CD11c was significantly decreased (P <0.05). Compared with LPS group, PRP treatment significantly increased the expressions of p-AMPK and p-ULK1 proteins at 12 h, 18 h and 24 h, while significantly decreased the expression of p-mTOR protein (P <0.05). After the addition of AMPK inhibitor Compound C, the expression of CD206 was significantly reduced (P <0.05) and the expression of CD11c was significantly increased compared with LPS+PRP group (P <0.05). After silencing the expression of AMPK in macrophages, the promotion effect of PRP on TGF-ß was significantly reduced (P <0.05). CONCLUSION: PRP can stimulate the transformation of macrophages to M2 type via AMPK signalling pathway.

Ginsenoside Rg3 inhibits the malignant progression of cervical cancer cell by regulating AKT2 expression.

Although ginsenoside Rg3 has been shown to exert anticancer effects in various malignancies, the effects and molecular mechanisms of ginsenoside Rg3 in cervical cancer (CC) remain unclear. This study explored the effect of ginsenoside Rg3 on CC development at the cellular level. The effect of ginsenoside Rg3 on cell proliferation was measured using colony formation and Cell Counting Kit-8 assays. Migration, invasion, and in vitro angiogenesis of CC cells were detected using wound healing, transwell, and tube formation assays, respectively. In addition, we explored the target genes and molecular mechanisms of ginsenoside Rg3 in CC cells overexpressing AKT serine/threonine kinase 2 (AKT2). The results indicated that ginsenoside Rg3 suppressed proliferation, migration, invasion, and tube formation of CC cells in vitro. In addition, ginsenoside Rg3 treatment decreased the expression of AKT2 in CC cells. Moreover, ginsenoside Rg3 treatment partially reversed AKT2 overexpression-mediated reduction in cell proliferation, migration, invasion, and tube formation. In conclusion, the above findings suggested that ginsenoside Rg3 inhibits CC progression via regulation of AKT2 expression, which might provide a potential therapeutic target for tumor therapy.

Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model.

SIGNIFICANCE STATEMENT: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. In this study, we demonstrated in a mouse model that erythrocyte ENT1-AMPD3 is a master energy regulator of the intracellular purinergic hypoxic compensatory response that promotes rapid energy supply from extracellular adenosine, eAMPK-dependent metabolic reprogramming, and O 2 delivery, which combat renal hypoxia and progression of CKD. ENT1-AMPD3-AMPK-BPGM comprise a group of circulating erythroid-specific biomarkers, providing early diagnostic and novel therapeutic targets for CKD. BACKGROUND: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. METHODS: Mice with an erythrocyte-specific deficiency in equilibrative nucleoside transporter 1 ( eEnt1-/- ) and a global deficiency in AMP deaminase 3 ( Ampd3-/- ) were generated to define their function in two independent CKD models, including angiotensin II (Ang II) infusion and unilateral ureteral obstruction (UUO). Unbiased metabolomics, isotopic adenosine flux, and various biochemical and cell culture analyses coupled with genetic studies were performed. Translational studies in patients with CKD and cultured human erythrocytes examined the role of ENT1 and AMPD3 in erythrocyte function and metabolism. RESULTS: eEnt1-/- mice display severe renal hypoxia, kidney damage, and fibrosis in both CKD models. The loss of eENT1-mediated adenosine uptake reduces intracellular AMP and thus abolishes the activation of AMPK α and bisphosphoglycerate mutase (BPGM). This results in reduced 2,3-bisphosphoglycerate and glutathione, leading to overwhelming oxidative stress in eEnt1-/- mice. Excess reactive oxygen species (ROS) activates AMPD3, resulting in metabolic reprogramming and reduced O 2 delivery, leading to severe renal hypoxia in eEnt1-/- mice. By contrast, genetic ablation of AMPD3 preserves the erythrocyte adenine nucleotide pool, inducing AMPK-BPGM activation, O 2 delivery, and antioxidative stress capacity, which protect against Ang II-induced renal hypoxia, damage, and CKD progression. Translational studies recapitulated the findings in mice. CONCLUSION: eENT1-AMPD3, two highly enriched erythrocyte purinergic components that sense hypoxia, promote eAMPK-BPGM-dependent metabolic reprogramming, O 2 delivery, energy supply, and antioxidative stress capacity, which mitigates renal hypoxia and CKD progression.

Effect of perioperative airway management on postoperative outcomes of colorectal cancer patients with sarcopenia.

BACKGROUND: It is common for colorectal cancer patients to have sarcopenia as a comorbidity, which has been shown to have a negative impact on prognosis after surgery. This study explored whether implementing a novel care program could improve postoperative outcomes in colorectal cancer patients with sarcopenia. METHODS: We retrospectively analyzed the clinical data of patients diagnosed with sarcopenia before undergoing radical colorectal cancer surgery. We divided the patients into two groups according to the time point of program implementation and, compared the clinical characteristics and postoperative outcomes of these two groups. RESULTS: A total of 227 patients were included in the study. The baseline clinical characteristics of the two groups were similar. Compared with the control group, patients in the implementation group had a significantly lower rate of total complications (18.5% vs. 30.3%, P = 0.041), a significantly lower rate of pulmonary complications (2.8% vs. 10.9%, P = 0.017), and a significantly shorter postoperative hospital stay (12 days vs. 14 days, P = 0.001). Implementation of perioperative airway management (P = 0.018) was shown to be a protective factor against pulmonary complications in colorectal cancer patients with sarcopenia. CONCLUSION: The perioperative airway management program implemented at our center was easy to perform and can effectively improve short-term postoperative outcomes in colorectal cancer patients with sarcopenia.

Linc00239 Promotes Colorectal Cancer Development via MicroRNA-182-5p/Metadherin Axis.

Long non-coding RNAs (lncRNAs) are associated with colorectal cancer (CRC); however, CRC-related linc00239 functions have not been fully elucidated. Prognostic analysis of patients with CRC with linc00239 overexpression was performed using data from The Cancer Genome Atlas database. Cell Counting Kit-8 and Transwell were used to determine linc00239 functions for CRC cells. The lncRNA-miRNA-mRNA interaction network was used to screen target miRNAs and mRNAs regulated by linc00239. Quantitative real-time polymerase chain reaction and western blotting were used to confirm the miRNA and mRNA expression. Furthermore, a miRNA inhibitor was transfected into CRC cells, and cell function was evaluated. Results indicated a high linc00239 expression in the tumor tissue of patients with CRC. Transfection of linc00239 siRNA into SW480 and LOVO cells decreased cell proliferation, cell migration, and invasion. MiR-182-5p/metadherin (MTDH) axis is a downstream pathway of linc00239. MTDH expression, the activity of cell proliferation, migration, and invasion, which were suppressed by linc00239 siRNA, were partially attenuated when linc00239 siRNA and miR-182-5p inhibitor were co-transfected into the CRC cells. Furthermore, miR-182-5p expression was decreased and MTDH expression was promoted in CRC tissues. Altogether, linc00239 may promote CRC development through the miR-182-5p/MTDH axis.

HLA-DQA1 expression is associated with prognosis and predictable with radiomics in breast cancer.

BACKGROUND: High HLA-DQA1 expression is associated with a better prognosis in many cancers. However, the association between HLA-DQA1 expression and prognosis of breast cancer and the noninvasive assessment of HLA-DQA1 expression are still unclear. This study aimed to reveal the association and investigate the potential of radiomics to predict HLA-DQA1 expression in breast cancer. METHODS: In this retrospective study, transcriptome sequencing data, medical imaging data, clinical and follow-up data were downloaded from the TCIA ( https://www.cancerimagingarchive.net/ ) and TCGA ( https://portal.gdc.cancer.gov/ ) databases. The clinical characteristic differences between the high HLA-DQA1 expression group (HHD group) and the low HLA-DQA1 expression group were explored. Gene set enrichment analysis, Kaplan‒Meier survival analysis and Cox regression were performed. Then, 107 dynamic contrast-enhanced magnetic resonance imaging features were extracted, including size, shape and texture. Using recursive feature elimination and gradient boosting machine, a radiomics model was established to predict HLA-DQA1 expression. Receiver operating characteristic (ROC) curves, precision-recall curves, calibration curves, and decision curves were used for model evaluation. RESULTS: The HHD group had better survival outcomes. The differentially expressed genes in the HHD group were significantly enriched in oxidative phosphorylation (OXPHOS) and estrogen response early and late signalling pathways. The radiomic score (RS) output from the model was associated with HLA-DQA1 expression. The area under the ROC curves (95% CI), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the radiomic model were 0.866 (0.775-0.956), 0.825, 0.939, 0.7, 0.775, and 0.913 in the training set and 0.780 (0.629-0.931), 0.659, 0.81, 0.5, 0.63, and 0.714 in the validation set, respectively, showing a good prediction effect. CONCLUSIONS: High HLA-DQA1 expression is associated with a better prognosis in breast cancer. Quantitative radiomics as a noninvasive imaging biomarker has potential value for predicting HLA-DQA1 expression.

Deep learning for fully automated segmentation and volumetry of Couinaud liver segments and future liver remnants shown with CT before major hepatectomy: a validation study of a predictive model.

Background: Recent reports have shown the potential for deep learning (DL) models to automatically segment of Couinaud liver segments and future liver remnant (FLR) for liver resections. However, these studies have mainly focused on the development of the models. Existing reports lack adequate validation of these models in diverse liver conditions and thorough evaluation using clinical cases. This study thus aimed to develop and perform a spatial external validation of a DL model for the automated segmentation of Couinaud liver segments and FLR using computed tomography (CT) in various liver conditions and to apply the model prior to major hepatectomy. Methods: This retrospective study developed a 3-dimensional (3D) U-Net model for the automated segmentation of Couinaud liver segments and FLR on contrast-enhanced portovenous phase (PVP) CT scans. Images were obtained from 170 patients from January 2018 to March 2019. First, radiologists annotated the Couinaud segmentations. Then, a 3D U-Net model was trained in Peking University First Hospital (n=170) and tested in Peking University Shenzhen Hospital (n=178) in cases with various liver conditions (n=146) and in candidates for major hepatectomy (n=32). The segmentation accuracy was evaluated using the dice similarity coefficient (DSC). Quantitative volumetry to evaluate the resectability was compared between manual and automated segmentation. Results: The DSC in the test data sets 1 and 2 for segments I to VIII was 0.93±0.01, 0.94±0.01, 0.93±0.01, 0.93±0.01, 0.94±0.00, 0.95±0.00, 0.95±0.00, and 0.95±0.00, respectively. The mean automated FLR and FLR% assessments were 493.51±284.77 mL and 38.53%±19.38%, respectively. The mean manual FLR and FLR% assessments were 500.92±284.38 mL and 38.35%±19.14%, respectively, in test data sets 1 and 2. For test data set 1, when automated segmentation of the FLR% was used, 106, 23, 146, and 57 cases were categorized as candidates for a virtual major hepatectomy of types 1, 2, 3, and 4, respectively; however, when manual segmentation of the FLR% was used, 107, 23, 146, and 57 cases were categorized as candidates for a virtual major hepatectomy of types 1, 2, 3, and 4, respectively. For test data set 2, all cases were categorized as candidates for major hepatectomy when automated and manual segmentation of the FLR% was used. No significant differences in FLR assessment (P=0.50; U=185,545), FLR% assessment (P=0.82; U=188,337), or the indications for major hepatectomy were noted between automated and manual segmentation (McNemar test statistic 0.00; P>0.99). Conclusions: The DL model could be used to fully automate the segmentation of Couinaud liver segments and FLR with CT prior to major hepatectomy in an accurate and clinically practicable manner.

Chicken CH25H inhibits ALV-J replication by promoting cellular autophagy.

Autophagy plays an important role in host antiviral defense. The avian leukosis virus subgroup J (ALV-J) has been shown to inhibit autophagy while promoting viral replication. The underlying autophagic mechanisms, however, are unknown. Cholesterol 25-hydroxylase (CH25H) is a conserved interferon-stimulated gene, which converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). In this study, we further investigated the autophagic mechanism of CH25H resistance to ALV-J in chicken embryonic fibroblast cell lines (DF1). Our results found that overexpression of CH25H and treatment with 25HC promoted the autophagic markers microtubule-associated protein 1 light chain 3 II (LC3II) and autophagy-related gene 5(ATG5), while decreased autophagy substrate p62/SQSTM1 (p62) expression in ALV-J infection DF-1 cells. Induction of cellular autophagy also reduces the levels of ALV-J gp85 and p27. ALV-J infection, on the other hand, suppresses autophagic marker protein LC3II expression. These findings suggest that CH25H-induced autophagy is a host defense mechanism that aids in ALV-J replication inhibition. In particular, CH25H interacts with CHMP4B and inhibits ALV-J infection in DF-1 cells by promoting autophagy, revealing a novel mechanism by which CH25H inhibits ALV-J infection. Although the underlying mechanisms are not completely understood, CH25H and 25HC are the first to show inhibiting ALV-J infection via autophagy.

Analysis of interreader agreement in structured reports of pelvic multiparametric magnetic resonance imaging using the METastasis Reporting and Data System for Prostate Cancer guidelines.

PURPOSE: To evaluate interreader agreement on pelvic multiparametric magnetic resonance imaging (mpMRI) interpretation among radiologists using a structured reporting tool based on the METastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines. METHODS: A structured report for follow-up pelvic mpMRI for advanced prostate cancer (APC) patients was formulated based on MET-RADS-P guidelines. In total, 163 paired pelvic mpMRI examinations were performed from December 2017 to February 2021 on 105 patients with APC. These were retrospectively reviewed by two senior and two junior radiologists for metastatic lesion detection and were categorized by these readers using primary/secondary response assessment categories (RACs), with and without the structured report. Interreader agreement regarding metastasis detection and RAC scores was evaluated with Cohen's kappa and weighted Cohen's kappa statistics (K), respectively. RESULTS: The two senior radiologists showed higher agreement with the reference standard for metastasis detection using the structured report (S1: K = 0.83; S2: K = 0.73) compared with the conventional report (S1: K = 0.72; S2: K = 0.61). Junior radiologists showed similar results (J1: 0.66 vs. 0.59; J2: 0.65 vs. 0.57). The overall agreement between the two senior radiologists was excellent for the primary RAC pattern using the structured reports (K = 0.81) and was substantial for secondary RAC categorization (K = 0.75). The interreader agreement of the two junior radiologists was substantial for both primary and secondary RAC values (K = 0.76, 0.68). CONCLUSION: Good interreader agreement was found for the follow-up assessment of APC patients between radiologists, where the pelvic mpMRI was reported using MET-RADS-P guidelines. This improvement applied to both metastatic lesion detection and qualitative RAC assessment.