[Effect of TLK2 Expression Regulated by MiR-21 on Proliferation and Apoptosis of Acute Myeloid Leukemia Cells].

OBJECTIVE: To investigate the effect of TLK2 expression regulated by miR-21 on proliferation and apoptosis of acute myeloid leukemia cells. METHODS: Seventy patients with AML admitted to our hospital from January 2019 to July 2022 were selected, while 30 patients with iron deficiency anemia were selected as the control group. Bone marrow mononuclear cells (BMMNCs) of the patients were obtained using Ficoll density gradient centrifugation. RT-qPCR was used to determine the expression levels of miR-21 and TLK2 mRNA in BMMNCs. Mimics-miR-21, mimics-NC, inhibitor-miR-21, inhibitor-NC and NC were transfected into HL-60 cells using liposome-mediated transfection technology. CCK-8 method was used to determine the activity of transfected HL-60 cells after treatment with cytarabine. The apoptosis rate of HL-60 transfected cells was determined by TUNEL method. The expression of TLK2 mRNA in HL-60 cells transfected with inhibitor-miR-21 was determined by RT-qPCR. RESULTS: The relative expression levels of miR-21 and TLK2 mRNA in BMMNCs of AML patients were significantly higher than those of controls (both P < 0.05). After HL-60 cells were treated with cytarabine, both the cell activity of inhibitor-miR-21 group and mimics-miR-21 group decreased significantly with the increase of cytarabine concentration (both P < 0.05). However, at each concentration point of cytarabine, the cell activity of inhibitor-miR-21 group was lower than that of control group (P < 0.05), while mimics-miR-21 group was higher than control group (P < 0.05). After HL-60 cells were treated with cytarabine, the apoptosis rate of inhibitor-miR-21 group was significantly increased (P < 0.05), while that of mimics-miR-21 group was significantly decreased (P < 0.05). After HL-60 cells were treated with inhibitor-miR-21, the relative expression of TLK2 mRNA decreased significantly (P < 0.05). CONCLUSION: miR-21 is highly expressed in AML patients, which may promote the apoptosis of AML cells by inhibiting the expression of TLK2.

Incidence and prognosis of olfactory and gustatory dysfunctions related to SARS-CoV-2 Omicron strain infection in China: A national multicenter survey of 35,566 individuals.

Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China. Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.

Mac-2 binding protein glycosylation isomer at 5 years of antiviral therapy predict hepatocellular carcinoma and mortality beyond year 5 in chronic hepatitis B patients with cirrhosis.

Whether serum Mac-2 binding protein glycosylation isomer (M2BPGi) level at year 5 of treatment could predict hepatocellular carcinoma (HCC) development and mortality beyond year 5 of entecavir or tenofovir disoproxil fumarate (TDF) treatment in chronic hepatitis B (CHB) patients with cirrhosis remain unclear. This retrospective study investigated the role of M2BPGi level at year 5 of treatment in predicting HCC and mortality beyond year 5 in CHB patients with cirrhosis. This study analyzed 1385 cirrhotic patients receiving entecavir or TDF treatment. Of them, 899 patients who did not develop HCC within the first 5 years of treatment were enrolled. In the entire cohort, there was no significant difference in the annual incidence of HCC before and after year 5 of entecavir or TDF treatment (P = 0.455). Multivariable Cox analysis identified old age, higher AFP and M2BPGi levels at 5 years of treatment as independent predictors of HCC occurrence beyond year 5. We developed the HCC risk prediction model, AMA, based on age, M2BPGi and AFP levels at 5 years of treatment, with the total score ranging from 0 to 8. The AMA model accurately categorized patients into low (≤2), medium (2-5), and high (≥5) risk groups in the development and validation groups (P<0.001) and exhibited good discriminant function in predicting HCC beyond year 5 in cirrhotic patients (AUROC: 0.743 at 5 years). The M2BPGi of 1.0 COI at 5 years of treatment stratified the risk of all-cause and liver-related mortality beyond year 5 (P<0.001). In conclusions, M2BPGi level at 5 years of treatment is a useful marker for predicting HCC development and mortality beyond year 5 of entecavir or TDF therapy in CHB patients with cirrhosis.

Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Value of soluble fms-like tyrosine kinase 1 for predicting acute pancreatitis severity: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to explore the relationship between serum soluble fms-like tyrosine kinase 1 and the severity of acute pancreatitis and its diagnostic utility. METHODS: This study was carried out by searching Chinese and English literature from the establishment of the database to July 9, 2023, systematically, and assessing the quality and heterogeneity of the articles included. RESULTS: Thirteen studies with a total of 986 patients were included. Patients with severe acute pancreatitis showed higher levels of soluble fms-like tyrosine kinase 1 compared with mild acute pancreatitis [weighted mean difference=76.64 pg/mL, 95% confidence interval (95%CI 50.39-102.89, p<0.001)]. Soluble fms-like tyrosine kinase 1 predicted pooled sensitivity, specificity, and area under the curve were 79%, 74%, and 0.85 for severe acute pancreatitis, with some heterogeneity (I2>50% or p<0.05). In the subgroup analysis, cutoff >150 pg/mL was found to be a heterogeneous factor. CONCLUSION: Soluble fms-like tyrosine kinase 1 is a reliable tool for identifying acute pancreatitis severity, but only as a screening tool.

Role of reimbursement and Physicians' awareness in the survival of sorafenib-eligible advanced hepatocellular carcinoma patients.

In 2008, sorafenib became the first approved systemic therapeutic agent for advanced HCC. Although its pharmacological efficacy has been established, reimbursement for such a new, high-cost drug, as well as physicians' awareness and prescription practice, likewise contribute to its clinical effectiveness. We therefore conducted a retrospective study using 38 sorafenib-eligible, advanced HCC patients when sorafenib was approved but not yet reimbursed as a control and 216 patients during the reimbursed era. Study group showed longer survival at 8.2 months versus the control's 4.9 months (p = 0.0063 hazard ratio: 0.612 [0.431 ~ 0.868], p = 0.0059). Among the 42 (19.4%) patients who survived more than 2 years, 50% had tumor rupture, and all 32 patients with portal vein tumor thrombus and/or extrahepatic metastasis received sorafenib (p = 0.003). Furthermore, during their first 2 years of HCC management, sorafenib had been given in 29.1% of the treatment courses among survivors between 2 and 5 years while it was prescribed in 55.8% among the more than 5 years survivor group (p < 0.001). In conclusion, survival of sorafenib-eligible HCC patients significantly improved after reimbursement. Patients who underwent longer sorafenib treatment had a survival advantage, except for those with tumor rupture. Reimbursement and awareness of prescriptions for a newly introduced medication therefore improve clinical effectiveness.

Combined effects of cadmium and sulfamethoxazole on Eisenia fetida: Insights into accumulation, subcellular partitioning, biomarkers and toxicological responses.

Cadmium (Cd) and sulfamethoxazole (SMX) frequently coexist in farmlands, yet their synergistic toxicological impacts on terrestrial invertebrates remain unexplored. In this study, earthworms were exposed to artificial soils percolated with Cd (5 mg/kg), SMX (5 mg/kg) or combination of them for 7 days, followed by a 12-day elimination phase in uncontaminated soil. The uptake of Cd and SMX by the earthworms, along with their subcellular distribution, was meticulously analyzed. Additionally, a suite of biomarkers-including superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and weight loss-were evaluated to assess the health status of the earthworms and the toxicological effects of the Cd and SMX mixture. Notably, the cotreatment with Cd and SMX resulted in a significantly higher weight loss in Eisenia fetida (41.25 %) compared to exposure to Cd alone (26.84 %). Moreover, the cotreatment group exhibited substantially higher concentrations of Cd in the total internal body, fraction C (cytosol), and fraction E (tissue fragments and cell membranes) in Eisenia fetida compared to Cd alone counterparts. The combined exposure also significantly elevated the SMX levels in the total body and fraction C compared with the SMX-only treated earthworms. Additionally, Eisenia fetida subjected to the combined treatment showed markedly increased activities of SOD, CAT, and MDA compared to those treated with Cd alone. The effect addition indices (EAIs), ranging from 1.00 to 2.23, unequivocally demonstrated a synergistic effect of the combined treatments. Interestingly, relocating the earthworms to clean soil did not mitigate the observed adverse effects. These findings underscore the increased risk posed by the Cd-SMX complex to terrestrial invertebrates in agricultural areas.

Nationwide distribution of perfluoroalkyl ether carboxylic acids in Chinese diets: An emerging concern.

With the phase-out of perfluorooctanoic acid (PFOA) and its replacement by perfluoroalkyl ether carboxylic acids (PFECAs), there is a potential for increased exposure to various new PFECAs among the general population in China. While there are existing studies on dietary exposure to legacy perfluoroalkyl and polyfluoroalkyl substances (PFASs), research on dietary exposure to PFECAs, especially among the general Chinese populace, remains scarce. In the present study, we investigated the distribution of PFECAs in dietary sources from 33 cities across five major regions in China, along with the associated dietary intake. Analysis indicated that aquatic animal samples contained higher concentrations of legacy PFASs compared to those from terrestrial animals and plants. In contrast, PFECAs were found in higher concentrations in plant and terrestrial animal samples. Notably, hexafluoropropylene oxide dimer (HFPO-DA) was identified as the dominant compound in vegetables, cereals, pork, and mutton across the five regions, suggesting widespread dietary exposure. PFECAs constituted the majority of PFAS intake (57 %), with the estimated daily intake (EDI) of HFPO-DA ranging from 2.33 to 3.96 ng/kg bw/day, which corresponds to 0.78-1.32 times the reference dose (RfD) (3.0 ng/kg bw/day) set by the United States Environmental Protection Agency. Given the ubiquity of HFPO-DA and many other PFECAs in the nationwide diet of China, there is an urgent need for further research into these chemicals to establish relevant safety benchmarks or consumption advisory values for the diet.

MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Cardiovascular mortality risk in patients with ovarian cancer: a population-based study.

OBJECTIVES: Ovarian cancer (OC) can occur at different ages and is affected by a variety of factors. In order to evaluate the risk of cardiovascular mortality in patients with ovarian cancer, we included influencing factors including age, histological type, surgical method, chemotherapy, whether distant metastasis, race and developed a nomogram to evaluate the ability to predict occurrence. At present, we have not found any correlation studies on cardiovascular death events in patients with ovarian cancer. This study was designed to provide targeted measures for effective prevention of cardiovascular death in patients with ovarian cancer. METHODS: Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of cardiovascular diseases on overall survival (OS) and ovarian cancer-specific survival (OCSS). We compared multiple groups including clinical, demographic, therapeutic characteristics and histological types. Cox risk regression analysis, Kaplan-Meier survival curves, and propensity score matching were employed for analyzing the data. RESULTS: A total of 88,653 ovarian cancer patients were collected, of which 2,282 (2.57%) patients died due to cardiovascular-related diseases. Age, chemotherapy and whether satisfactory cytoreduction surgery is still the most important factors affecting the prognosis of ovarian cancer patients, while different histological types, diagnosis time, and race also have a certain impact on the prognosis. The newly developed nomogram model showed excellent predictive performance, with a C-index of 0.759 (95%CI: 0.757-0.761) for the group. Elderly patients with ovarian cancer are still a high-risk group for cardiovascular death [HR: 21.07 (95%CI: 5.21-85.30), p < 0.001]. The calibration curve showed good agreement from predicted survival probabilities to actual observations. CONCLUSION: This study found that age, histology, surgery, race, chemotherapy, and tumor metastasis are independent prognostic factors for cardiovascular death in patients with ovarian cancer. The nomogram-based model can accurately predict the OS of ovarian cancer patients. It is expected to inform clinical decision-making and help develop targeted treatment strategies for this population.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

Ultrasound-based radiomics-clinical nomogram for noninvasive prediction of residual cancer burden grading in breast cancer.

PURPOSE: To assess the predictive value of an ultrasound-based radiomics-clinical nomogram for grading residual cancer burden (RCB) in breast cancer patients. METHODS: This retrospective study of breast cancer patients who underwent neoadjuvant therapy (NAC) and ultrasound scanning between November 2020 and July 2023. First, a radiomics model was established based on ultrasound images. Subsequently, multivariate LR (logistic regression) analysis incorporating both radiomic scores and clinical factors was performed to construct a nomogram. Finally, Receiver operating characteristics (ROC) curve analysis and decision curve analysis (DCA) were employed to evaluate and validate the diagnostic accuracy and effectiveness of the nomogram. RESULTS: A total of 1122 patients were included in this study. Among them, 427 patients exhibited a favorable response to NAC chemotherapy, while 695 patients demonstrated a poor response to NAC therapy. The radiomics model achieved an AUC value of 0.84 in the training cohort and 0.83 in the validation cohort. The ultrasound-based radiomics-clinical nomogram achieved an AUC value of 0.90 in the training cohort and 0.91 in the validation cohort. CONCLUSIONS: Ultrasound-based radiomics-clinical nomogram can accurately predict the effectiveness of NAC therapy by predicting RCB grading in breast cancer patients.

Long-term Risks of Cirrhosis and Hepatocellular Carcinoma Across Steatotic Liver Disease Subtypes.

INTRODUCTION: The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD). METHODS: We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC. RESULTS: After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference. DISCUSSION: This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Investigating the influence of XAV-939, a tankyrase inhibitor, on the density and gating of erg-mediated K+ currents in mouse MA-10 Leydig tumor cells.

XAV-939(XAV) is a chemical compound that inhibits the activity of tankyrase. However, the precise way in which XAV alters membrane ionic currents is not well understood. In this study,our goal was to examine the impact of XAV on the ionic currents in mouse MA-10 Leydig cells, specifically focusing on the magnitude, gating properties,and voltage-dependent hysteresis of erg-mediated K+currents(IK(erg)). In our whole-cell current recordings we observed that the addition of XAV inhibited the density of IK(erg) in a concentration-dependent manner with an IC50 of 3.1 µM. Furthermore we found that continued exposure to XAV, further addition of neither liraglutide nor insulin-like growth factor-1 counteracted XAV-mediated inhibition of IK(erg). Additionally the presence of XAV suppressed the mean current versus voltage relationship of IK(erg) across the entire voltage-clamp step analyzed. This compound shifted the steady-state activation curve of IK(erg) to a less negative potential by approximately 12 mV. The presence of XAV increased the time constant of deactivating IK(erg) in MA-10 cells. The voltage-dependent clockwise hysteresis of IK(erg) responding to prolonged upright isosceles-triangular ramp voltage became diminished by adding XAV; moreover subsequent addition of NS3623 effectively reversed XAV-induced decrease of hysteretic area of IK(erg). XAV also inhibited the proliferation of this cell line and the IC50 value of XAV-induced inhibition of cell proliferation was 2.8M. Overall the suppression of IK(erg) by XAV may serve as a significant ionic mechanism that contribute to the functional properties of MA-10 cells. However, it is important to note that this effect cannot be attributed solely to the inhibition of tankyrase.

Multiparametric MRI-based intratumoral and peritumoral radiomics for predicting the pathological differentiation of hepatocellular carcinoma.

PURPOSE: To explore the predictive potential of intratumoral and multiregion peritumoral radiomics features extracted from multiparametric MRI for predicting pathological differentiation in hepatocellular carcinoma (HCC) patients. METHODS: A total of 265 patients with 277 HCCs (training cohort n = 193, validation cohort n = 84) who underwent preoperative MRI were retrospectively analyzed. The risk factors identified through stepwise regression analysis were utilized to construct a clinical model. Radiomics models based on MRI (arterial phase, portal venous phase, delayed phase) across various regions (entire tumor, Peri_5mm, Peri_10mm, Peri_20mm) were developed using the LASSO approach. The features obtained from the intratumoral region and the optimal peritumoral region were combined to design the IntraPeri fusion model. Model performance was assessed using the area under the curve (AUC). RESULTS: Larger size, non-smooth margins, and mosaic architecture were risk factors for poorly differentiated HCC (pHCC). The clinical model achieved AUCs of 0.77 and 0.73 in the training and validation cohorts, respectively, while the intratumoral model achieved corresponding AUC values of 0.92 and 0.82. The Peri_10mm model demonstrated superior performance to the Peri_5mm and Peri_20mm models, with AUC values of 0.87 vs. 0.84 vs. 0.73 in the training cohort and 0.80 vs. 0.77 vs. 0.68 in the validation cohort, respectively. The IntraPeri model exhibited remarkable AUC values of 0.95 and 0.86 in predicting pHCC in the training and validation cohorts, respectively. CONCLUSIONS: Our study highlights the potential of a multiparametric MRI-based radiomic model that integrates intratumoral and peritumoral features as a tool for predicting HCC differentiation. CRITICAL RELEVANCE STATEMENT: Both clinical and multiparametric MRI-based radiomic models, particularly the intratumoral radiomic model, are non-invasive tools for predicting HCC differentiation. Importantly, the IntraPeri fusion model exhibited remarkable predictiveness for individualized HCC differentiation. KEY POINTS: • Both the intratumoral radiomics model and clinical features were useful for predicting HCC differentiation. • The Peri_10mm radiomics model demonstrated better diagnostic ability than other peritumoral region-based models. • The IntraPeri radiomics fusion model outperformed the other models for predicting HCC differentiation.

Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC.

BACKGROUND & AIMS: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the development of cirrhosis and hepatocellular carcinoma (HCC) by chronic hepatitis B (CHB) or C infection and antiviral treatment statuses is not well-known. METHODS: A total of 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997-2013. MASLD was identified by abdominal ultrasonography and cardiometabolic profiles. Data linkage was performed using 3 nationwide databases-National Health Insurance, Cancer Registry, and Death Certification System-to obtain information on antiviral treatment, vital status, and newly diagnosed cirrhosis and HCC. Follow-up was conducted until December 31, 2019. RESULTS: In the total population, 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed. Although MASLD significantly increased the cumulative risks of cirrhosis or HCC (P < .0001), the associated risk was more pronounced when comparing CHB or C infection with the presence of MASLD. Stratifying the participants based on their MASLD and CHB or C statuses, hazard ratios (HRadj) with 95% confidence intervals for HCC were 8.81 (7.83-9.92) for non-steatotic liver disease (SLD) with CHB or C, 1.52 (1.32-1.74) for MASLD without CHB or C, and 8.86 (7.76-10.12) for MASLD with CHB or C, compared with non-SLD without CHB or C (all P < .0001). Among CHB or C patients who received antivirals during follow-up, MASLD was associated with increased risks of cirrhosis and HCC, with HRadj of 1.23 (1.01-1.49) and 1.32 (1.05-1.65), respectively. CONCLUSIONS: These findings underscore the need to prioritize treatment of chronic viral hepatitis before addressing MASLD.

Differences in pulmonary nodular consolidation and pulmonary cavity among drug-sensitive, rifampicin-resistant and multi-drug resistant tuberculosis patients: the Guangzhou computerized tomography study.

Background: Pulmonary nodular consolidation (PN) and pulmonary cavity (PC) may represent the two most promising imaging signs in differentiating multidrug-resistant (MDR)-pulmonary tuberculosis (PTB) from drug-sensitive (DS)-PTB. However, there have been concerns that literature described radiological feature differences between DS-PTB and MDR-PTB were confounded by that MDR-PTB cases tend to have a longer history. This study seeks to further clarify this point. Methods: All cases were from the Guangzhou Chest Hospital, Guangzhou, China. We retrieved data of consecutive new MDR cases [n=46, inclusive of rifampicin-resistant (RR) cases] treated during the period of July 2020 and December 2021, and according to the electronic case archiving system records, the main PTB-related symptoms/signs history was ≤3 months till the first computed tomography (CT) scan in Guangzhou Chest Hospital was taken. To pair the MDR-PTB cases with assumed equal disease history length, we additionally retrieved data of 46 cases of DS-PTB patients. Twenty-two of the DS patients and 30 of the MDR patients were from rural communities. The first CT in Guangzhou Chest Hospital was analysed in this study. When the CT was taken, most cases had anti-TB drug treatment for less than 2 weeks, and none had been treated for more than 3 weeks. Results: Apparent CT signs associated with chronicity were noted in 10 cases in the DS group (10/46) and 9 cases in the MDR group (10/46). Thus, the overall disease history would have been longer than the assumed <3 months. Still, the history length difference between DS patients and MDR patients in the current study might not be substantial. The lung volume involvement was 11.3%±8.3% for DS cases and 8.4%±6.6% for MDR cases (P=0.022). There was no statistical difference between DS cases and MDR cases both in PN prevalence and in PC prevalence. For positive cases, MDR cases had more PN number (mean of positive cases: 2.63 vs. 2.28, P=0.38) and PC number (mean of positive cases: 2.14 vs. 1.38, P=0.001) than DS cases. Receiver operating characteristic curve analysis shows, PN ≥4 and PC ≥3 had a specificity of 86% (sensitivity 25%) and 93% (sensitivity 36%), respectively, in suggesting the patient being a MDR cases. Conclusions: A combination of PN and PC features allows statistical separation of DS and MDR cases.

CircXRN2 accelerates colorectal cancer progression through regulating miR-149-5p/MACC1 axis and EMT.

In China, there has been a persistent upward trend in the incidence and mortality rates of colorectal cancer (CRC), with CRC ranking second in incidence and fifth in mortality among all malignant tumors. Although circular RNAs (circRNAs) have been implicated in the progression of various cancers, their specific role in CRC progression remains largely unexplored. The objective of this study was to elucidate the role and underlying mechanisms of circXRN2 in CRC. Differential expression of circXRN2 was identified through whole transcriptome sequencing. The expression levels of circXRN2 and miR-149-5p were quantified in CRC tissues, corresponding adjacent normal tissues, and CRC cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The stability of circXRN2 was confirmed through RNase R and actinomycin D experiments. The binding interaction between circXRN2 and miR-149-5p was validated through RNA pull-down, RNA immunoprecipitation, and dual-luciferase assays. The biological functions of circXRN2 were assessed through a battery of in vitro experiments, including the CCK-8 assay, EdU assay, scratch assay, Transwell assay, and flow cytometry assay. Additionally, in vivo experiments involving a tumor transplantation model and a liver-lung metastasis model were conducted. The influence of circXRN2 on the expression of epithelial-mesenchymal transition (EMT)-related genes was determined via Western blotting analysis. In CRC tissues and cells, there was an upregulation in the expression levels of both circXRN2 and ENC1, while miR-149-5p exhibited a downregulation in its expression. The overexpression of circXRN2 was found to enhance tumor proliferation and metastasis, as evidenced by results from both in vitro and in vivo experiments. Functionally, circXRN2 exerted its antitumor effect by suppressing cell proliferation, migration, and invasion while also promoting apoptosis. Mechanistically, the dysregulated expression of circXRN2 had an impact on the expression of proteins within the EMT signaling pathway. Our results demonstrated that circXRN2 promoted the proliferation and metastasis of CRC cells through the miR-149-5p/ENC1/EMT axis, suggesting that circXRN2 might serve as a potential therapeutic target and novel biomarker in the progression of CRC.