Integrative analysis reveals different feature of intrahepatic cholangiocarcinoma subtypes.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment. METHODS: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated. RESULTS: We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway. CONCLUSIONS: Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.

Laparoscopic versus open surgery for hilar cholangiocarcinoma: a retrospective cohort study on short-term and long-term outcomes.

BACKGROUND: Laparoscopic surgery (LS) for hilar cholangiocarcinoma (HCCa) remains under development, and its feasibility and safety remain controversial. This study therefore evaluated the outcomes of this technique and compared them to those of open surgery (OS). METHODS: In total, 149 patients underwent surgical resection for HCCa at our center between February 2017 and September 2020. After screening and propensity score matching, 47 OS group patients and 20 LS group patients remained, and their baseline characteristics, pathologic findings, surgical outcomes, and long-term outcomes were compared. RESULT: The baseline characteristics and pathologic findings were comparable between the two groups. The mean incision length was longer in the OS group than in the LS group (21.0 cm vs. 13.2 cm, P < 0.001). No significant differences were observed in the other surgical outcomes between the two groups. Regarding long-term outcomes, the overall survival rate and disease-free survival rate of the OS group were significantly higher than those of the LS group (P = 0.0057, P = 0.043). However, the two groups had significantly different follow-up times (19.2 months vs. 14.7 months, P = 0.041). CONCLUSION: LS for HCCa is technically achievable, and our study revealed that it is equivalent to OS in terms of short-term outcomes but was poorer in terms of long-term outcomes.

Laparoscopic versus open hepatectomy for intrahepatic cholangiocarcinoma in patients aged 60 and older: a retrospective cohort study.

Objective laparoscopic surgical excision is the recommended treatment for liver cancers, yet its benefits in patients aged 60 and older remain poorly understood. Thus, this study evaluated the feasibility, safety, and clinical outcomes of laparoscopic hepatectomy for patients aged 60 and older with intrahepatic cholangiocarcinoma (ICC).MethodsAfter screening, 107 patients who underwent hepatectomy for ICC were enrolled and grouped into either laparoscopic (LH) or open hepatectomy (OH) groups. Baseline characteristics, pathological findings, and long-term outcomes were compared between the two groups. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using univariate and multivariate analyses.ResultsAmong baseline characteristics and pathological findings, only pre-operative albumin was higher in the LH group. The LH group had more favorable short-term outcomes such as incision length, level of postoperative total bilirubin, and length of postoperative stays than the OH group. The postoperative complication, lymph node dissection and R0 resection rate, and long-term outcomes including OS and DFS were not significantly different between the two groups. Cancer Antigen-19-9(CA-19-9) and pathological differentiation were independent prognostic factors for OS, whereas CA-19-9 and neutrophil count were independent prognostic factors for DFS.ConclusionLH is safe, reliable, and feasible for treatment of ICC patients aged 60 and older as it had better short-term clinical outcomes than OH and achieved long-term prognoses that were comparable to those of OH.

A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer's disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study.

BACKGROUND: ANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study. METHODS: We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting. RESULTS: There were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up (718.42 ± 378.17 vs. 522.04 ± 283.07 pg/mL, p < 0.001). Compared with the first quartile, multivariable-adjusted hazard ratio (95% confidence intervals [CIs]) for kidney function decline was 2.59 (95% CI, 1.41-4.77) for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD (relative risk: 1.33; 95% CI, 1.01-1.74). The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline (p for nonlinear trend = 0.66, p for linear trend < 0.001). CONCLUSIONS: Participants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.

Nuclear receptor TLX regulates islet beta cell proliferation via E2F6.

Both type 1 and type 2 diabetes are associated with loss of functional beta cell mass, and strategies to restore beta cells are urgently needed. We reported previously that overexpression of the nuclear receptor TLX induces beta cell proliferation, but the underlying molecular mechanism has not been defined. Here, we identified direct targets of TLX in beta cells at the genome-wide level by ChIP-Seq. These targets include a cadre of regulators that are known to be critical for proliferation. Among these ChIP targets, E2F6 was tightly associated with the cell cycle modules, and thus, we further analyzed E2F6 expression and function in beta cells. We showed that E2F6 is strongly downregulated by TLX, and its expression inhibits beta cell proliferation. Moreover, coexpression of E2F6 with TLX partially abrogated the proliferative effects of TLX. These results strongly suggest that TLX acts through E2F6 to regulate beta cell proliferation. Together, the results of this study reveal a direct interaction between TLX and E2F6 and suggest new targets for the expansion of functional beta cell mass.

Efficacy of low-intensity extracorporeal shock wave therapy for the treatment of chronic prostatitis/chronic pelvic pain syndrome: A systematic review and meta-analysis.

AIMS: Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been applied in urolithiasis and some chronic diseases. We performed a systematic review and meta-analysis to assess the efficacy of Li-ESWT for the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: A comprehensive search of MEDLINE, Web of Science, EMBASE, and the Cochrane Library to January 6, 2019 was performed for randomized controlled trials (RCTs) reporting on patients with CP/CPPS treated with Li-ESWT compared with the sham group. Outcomes were evaluated based on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). The quality assessment of included studies was performed by the Cochrane System. RESULTS: Six publications involving five RCTs with 280 patients were assessed in this review. NIH-CPSI total score, pain domain and quality of life (QOL) were significantly better in the Li-ESWT group than those in the control group at the endpoint (P < 0.00001, P = 0.003, and P < 0.00001), 4 weeks (P < 0.00001, P = 0.0002 and P < 0.00001) and 12 weeks (P < 0.00001, P < 0.00001, and P = 0.0002) after the treatment. For urinary score, significant difference existed at 12 weeks after the treatment (P = 0.006). At 24 weeks after treatment, there was no significant difference between the two groups in NIH-CPSI total score (P = 0.26), pain domain (P = 0.32), urinary score (P = 0.07), and QOL (P = 0.29). CONCLUSIONS: Li-ESWT showed great efficacy for the treatment of CP/CPPS at the endpoint and during the follow-up of 4 and 12 weeks, though the efficacy of 24-week follow-up was not significantly different due to insufficient data. Generally, Li-ESWT is a promising minimal invasive method for the treatment of CP/CPPS.

Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level.

Type 2 diabetes (T2D) is a high risk factor for Alzheimer's disease (AD). Our previous study identified that hyperphosphorylation of tau protein, which is one of the pathophysiologic hallmarks of AD, also occurred in T2D rats' brain; while glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, could decrease the phosphorylation of tau, probably via augmenting insulin signaling pathway. The purpose of this study was to further explore the mechanisms that underlie the effect of exendin-4 (ex-4, a GLP-1 receptor agonist) in reducing tau phosphorylation. We found that peripheral ex-4 injection in T2D rats reduced hyperphosphorylation of tau protein in rat hippocampus, probably via increasing hippocampal insulin which activated insulin signaling. Furthermore, we found that ex-4 could neither activate insulin signaling, nor reduce tau phosphorylation in HT22 neuronal cells in the absence of insulin. These results suggested that insulin is required in reduction of tau hyperphosphorylation by ex-4 in brain rats with T2D.

Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice.

Increasing evidence has shown that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease. Neurofibrillary tangles, which consist of hyperphosphorylated tau and misfolded microtubules, is one of the neuropathological hallmarks of Alzheimer's disease. Db/db mice, a rodent model of T2D, also exhibited age-dependent tau hyperphosphorylation. Glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, has been found to have neuroprotective effects. The aim of this study was to explore the potential effects of liraglutide (a GLP-1 analog), or insulin, on tau phosphorylation in T2D animals. Male db/db mice (3-3.5 weeks) were daily injected subcutaneously with liraglutide (n = 27), insulin (n = 27), or saline (n = 26), and five to seven mice were killed every 2 weeks for analysis of plasma and cerebrospinal (CSF) insulin levels by ELISA, and protein levels in the hippocampal formation by western blot. We found that db/db mice treated with saline exhibited an age-dependent decrease in CSF insulin and an increase in hippocampal tau phosphorylation. Liraglutide injection reversed the CSF insulin to ~1 mIU/L by the end of 8 weeks treatment, and prevented the hyperphosphorylation of tau protein in the hippocampal formation. By contrast, insulin injection had no effects on CSF insulin or phosphorylation of tau protein. In summary, this study indicates that early GLP-1 analog intervention prevented the age-dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta.

The changes of leukocyte telomere length and telomerase activity after sitagliptin intervention in newly diagnosed type 2 diabetes.

BACKGROUND: In recent years, increasing evidence suggests a potential importance of telomere biology in type 2 diabetes. The aim of this study was to determine whether sitagliptin, a medicine generally used in diabetes, can influence the telomere and telomerase in newly diagnosed type 2 diabetic patients. METHODS: Type 2 diabetic patients (T2D, n = 38) and non-diabetic subjects (control, n = 31) were randomly selected from the outpatient of Tongji Hospital, Tongji Medical College, Huazhong university of Science and Technology. Leukocyte telomere length ratio was measured using a quantitative polymerase chain reaction and was analysed. Telomerase activity was measured by polymerase chain reaction enzyme-linked immunosorbent assay method. Peripheral insulin resistance (homeostasis model assessment) was calculated from fasting plasma glucose and fasting plasma insulin. RESULTS: Telomere length of the type 2 diabetic patients (1.58 ± 0.57) was significantly shorter than those of control subjects (3.98 ± 0.90) and was significantly elongated after intervention by sitagliptin. There was no significant difference between the T2D and control group in telomerase activity, and the treatment of sitagliptin in T2D group showed no significant effect on the telomerase activity. CONCLUSIONS: In type 2 diabetes patients, leukocyte telomere length is significantly reduced, whereas the telomerase activity seems less influenced. Sitagliptin might protect ß-cells in the pancreas by elongating the telomere length.

Hyperactivity in the Gunn rat model of neonatal jaundice: age-related attenuation and emergence of gait deficits.

BACKGROUND: Neonatal jaundice resulting from elevated unconjugated bilirubin occurs in 60-80% of newborn infants. Although mild jaundice is generally considered harmless, little is known about its long-term consequences. Recent studies have linked mild bilirubin-induced neurological dysfunction (BIND) with a range of neurological syndromes, including attention-deficit hyperactivity disorder. The goal of this study was to measure BIND across the lifespan in the Gunn rat model of BIND. METHODS: Using a sensitive force plate actometer, we measured locomotor activity and gait in jaundiced (jj) Gunn rats versus their nonjaundiced (Nj) littermates. Data were analyzed for young adult (3-4 mo), early middle-aged (9-10 mo), and late middle-aged (17-20 mo) male rats. RESULTS: jj rats exhibited lower body weights at all ages and a hyperactivity that resolved at 17-20 mo of age. Increased propulsive force and gait velocity accompanied hyperactivity during locomotor bouts at 9-10 mo in jj rats. Stride length did not differ between the two groups at this age. Hyperactivity normalized, and gait deficits, including decreased stride length, propulsive force, and gait velocity, emerged in the 17-20-mo-old jj rats. CONCLUSION: These results demonstrate that, in aging, hyperactivity decreases with the onset of gait deficits in the Gunn rat model of BIND.

A meta-analysis of salicylates for type 2 diabetes mellitus.

The aim of this study was to assess the effects and safety of salicylates on type 2 diabetes mellitus (T2DM). We searched six databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CBM, CNKI and VIP) for all randomized controlled trials (RCTs) and self-control studies which investigated the effects of salicylates on T2DM. We included 34 RCTs and 17 self-control studies involving 13 464 patients with T2DM. It was demonstrated that salicylates had obvious effects on several parameters for patients with T2DM. (1) Any dose of salicylates could significantly reduce HbA1c level [mean difference (MD) -0.39%; 95% CI -0.47 to -0.32] in RCTs, but only high doses of salicylates (≥3000 mg/day) could effectively reduce fasting plasma glucose (FPG) level [standardized mean difference (SMD) -1.05; 95% CI -1.47 to -0.62] for patients with T2DM in both RCTs and self-control studies. Furthermore, high doses of salicylates could also increase plasma fasting insulin level (MD 12.20 mU/L; 95% CI 3.33 to 21.07); (2) In both RCTs and self-control studies, high doses of salicylates could significantly reduce plasma triglycerides concentration. The results for RCTs were MD -0.44 mmol/L, 95% CI -0.71 to -0.18, and those for self-control studies were 227±29 mg/dL (pre-treatment) and 117±8 mg/dL (post-treatment) (P=0.009); (3) All trials which reported cardiovascular events were RCTs using low doses (<1000 mg/day) of salicylates, and it was revealed that aspirin could significantly reduce the risk of myocardial infarction (OR 0.73; 95% CI 0.57 to 0.92); (4) Two RCTs and two self-control studies with ≥3000 mg/day salicylates reported adverse effects, and the overall effects were mild, and tinnitus occurred most frequently. No evidence of gastrointestinal bleeding was found in all these studies. In conclusion, from our systematic review, the anti-diabetic effect of salicylates is in a dose-dependent manner. High doses of salicylates may have beneficial effects on reducing FPG, HbA1c level and increasing fasting insulin concentration, and may also have some positive effects on lipidemia and inflammation-associated parameters for patients with T2DM, without serious adverse effects.

Sphenoid sinus is a rare site for tumor-induced osteomalacia: A case report and literature review.

Background: In this paper, we present a rare case of tumor-induced osteomalacia (TIO) and a literature review of this rare disease. Methods: A case of TIO of the isolated sphenoid sinus was reported. Furthermore, the clinical features of TIO in the sphenoid sinus and other sinonasal sinuses were also reviewed and summarized. Results: A 35-year-old man with muscle weakness and lower back pain came to the Department of Neurology. No obvious neurological disease was found; however, magnetic resonance imaging of the extremities accidentally showed a tumor in the axilla. Bone scintigraphy showed suspicious bone metastasis. Hypophosphatemia was neglected. Interestingly, 2-deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) detected a tumor in the axilla and another in the sphenoid sinus, but only the tumor in the sphenoid sinus had somatostatin receptor (SSTR) expression in 68-gallium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid octreotate (Ga-68 DOTATATE) PET/CT. The sphenoid sinus tumor was proven to be a phosphaturic mesenchymal tumor (PMT), and the phosphate levels returned to normal after surgery. The literature review showed only 17 cases of TIOs that occurred in the sphenoid sinus, with an average age of 43.3 ± 13.7 years. Only three cases of TIOs in the sphenoid sinus did not invade the nasal cavity or other paranasal sinuses, which could be identified as isolated sphenoid sinus diseases. We compared the clinical features of sphenoid TIOs with those of non-sphenoid sinonasal TIOs, and it was found that the concentration of 1,25-dihydroxy vitamin D in the group with sphenoid TIOs was much higher than that in the group with non-sphenoid sinonasal TIOs. A total of 153 cases of TIOs in the sinonasal sinus were reviewed. The ethmoid sinus was found to be the major site (64.7%), followed by the nasal cavity (50.3%), maxillary sinus (19.0%), frontal sinus (16.4%), and sphenoid sinus (11.8%). There were 66 patients (43.1%) who showed tumors invading more than one sinus. Most of the tumors (69.3%) were diagnosed as PMTs by pathology, followed by hemangiopericytoma (14.3%). Immunostaining was beneficial in the differential diagnosis of these tumors; however, larger sample sizes are needed for better accuracy. Conclusion: TIO in the sinonasal sinus, especially in the sphenoid sinus, is rare. Moreover, isolated sphenoid sinus disease can be easily misdiagnosed. When the clinical manifestation of osteomalacia is atypical, associating it with sphenoid sinus disease is even more difficult. Thus, TIO in the sphenoid sinus needs further exploration.

Development and validation of prognostic risk prediction models for hepatocellular carcinoma patients treated with immune checkpoint inhibitors based on a systematic review and meta-analysis of 47 cohorts.

Objective: To identify the risk factors associated with prognosis in patients with hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICI) via meta-analysis. And to construct prediction models to aid in the prediction and improvement of prognosis. Methods: We searched PubMed, Embase, Web of Science and Cochrane Library for relevant studies from inception to March 29, 2023. After completing literature screening and data extraction, we performed meta-analysis, sensitivity analysis, and subgroup analysis to identify risk factors associated with OS and PFS. Using the pooled hazard ratio value for each risk factor, we constructed prediction models, which were then validated using datasets from 19 centers in Japan and two centers in China, comprising a total of 204 patients. Results: A total of 47 studies, involving a total of 7649 ICI-treated HCC patients, were included in the meta-analysis. After analyzing 18 risk factors, we identified AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number, vascular invasion and combination therapy as predictors for OS prediction model, while AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number and vascular invasion were selected as predictors for PFS model. To validate the models, we scored two independent cohorts of patients using both prediction models. Our models demonstrated good performance in these cohorts. In addition, in the pooled cohort of 204 patients, Our models also showed good performance with area under the curve (AUC) values of 0.712, 0.753, and 0.822 for the OS prediction model at 1-year, 2-year, and 3-year follow-up points, respectively, and AUC values of 0.575, 0.749 and 0.691 for the PFS prediction model Additionally, the calibration curve, decision curve analysis, and Kaplan-Meier curves in the pooled cohort all supported the validity of both models. Conclusion: Based on the meta-analysis, we successfully constructed the OS and PFS prediction models for ICI-treated HCC patients. We also validated the models externally and observed good discrimination and calibration. The model's selected indicators are easily obtainable, making them suitable for further application in clinical practice.

Fucosyltransferase 5 Promotes the Proliferative and Migratory Properties of Intrahepatic Cholangiocarcinoma Cells via Regulating Protein Glycosylation Profiles.

Background: The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing globally, and its prognosis has not improved substantially in recent years. Understanding the pathogenesis of ICC may provide a theoretical basis for its treatment. In this study, we investigated the effects and underlying mechanisms of fucosyltransferase 5 (FUT5) on the malignant progression of ICC. Methods: FUT5 expression in ICC samples and adjacent nontumor tissues was compared using quantitative real-time polymerase chain reaction and immunohistochemical assays. We performed cell counting kit-8, colony formation, and migration assays to determine whether FUT5 influenced the proliferation and mobility of ICC cells. Finally, mass spectrometry was performed to identify the glycoproteins regulated by FUT5. Results: FUT5 mRNA was significantly upregulated in most ICC samples compared with corresponding adjacent nontumor tissues. The ectopic expression of FUT5 promoted the proliferation and migration of ICC cells, whereas FUT5 knockdown significantly suppressed these cellular properties. Mechanistically, we demonstrated that FUT5 is essential for the synthesis and glycosylation of several proteins, including versican, ß3 integrin, and cystatin 7, which may serve key roles in the precancer effects of FUT5. Conclusions: FUT5 is upregulated in ICC and promotes ICC development by promoting glycosylation of several proteins. Therefore, FUT5 may serve as a therapeutic target for the treatment of ICC.

Botanical drugs for treating erectile dysfunction: clinical evidence.

Phosphodiesterase-5 inhibitors (PDE5-i) have been widely used in clinical practice for the treatment of erectile dysfunction (ED). However, due to its suboptimal therapeutic effects and side effects, it is necessary to develop new medicines for ED treatment. Botanical drugs have been widely investigated as potential ED treatment drugs and have shown promising therapeutic effects. This review summarized 34 studies, including five botanical drugs with PDE5 inhibitory activity, seven botanical drugs without PDE5 inhibitory activity, and six mixed botanical drugs. The results of clinical studies regarding the aforementioned botanical drugs and relevant mechanisms are summarized in this study. It is necessary to conduct high-quality clinical trials to verify the dosage, targeted patients and therapeutic effects, and further pharmacology experiments are also needed to identify the active compounds.

Application of a Radiomics Machine Learning Model for Differentiating Aldosterone-Producing Adenoma from Non-Functioning Adrenal Adenoma.

To evaluate the secretory function of adrenal incidentaloma, this study explored the usefulness of a contrast-enhanced computed tomography (CECT)-based radiomics model for distinguishing aldosterone-producing adenoma (APA) from non-functioning adrenal adenoma (NAA). Overall, 68 APA and 60 NAA patients were randomly assigned (8:2 ratio) to either a training or a test cohort. In the training cohort, univariate and least absolute shrinkage and selection operator regression analyses were conducted to select the significant features. A logistic regression machine learning (ML) model was then constructed based on the radiomics score and clinical features. Model effectiveness was evaluated according to the receiver operating characteristic, accuracy, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis. In the test cohort, the area under the curve (AUC) of the Radscore model was 0.869 [95% confidence interval (CI), 0.734-1.000], and the accuracy, sensitivity, specificity, and F1 score were 0.731, 1.000, 0.583, and 0.900, respectively. The Clinic-Radscore model had an AUC of 0.994 [95% CI, 0.978-1.000], and the accuracy, sensitivity, specificity, and F1 score values were 0.962, 0.929, 1.000, and 0.931, respectively. In conclusion, the CECT-based radiomics and clinical radiomics ML model exhibited good diagnostic efficacy in differentiating APAs from NAAs; this non-invasive, cost-effective, and efficient method is important for the management of adrenal incidentaloma.

Degradation behavior of ZE21C magnesium alloy suture anchors and their effect on ligament-bone junction repair.

Current materials comprising suture anchors used to reconstruct ligament-bone junctions still have limitation in biocompatibility, degradability or mechanical properties. Magnesium alloys are potential bone implant materials, and Mg2+ has been shown to promote ligament-bone healing. Here, we used Mg-2 wt.% Zn-0.5 wt.% Y-1 wt.% Nd-0.5 wt.% Zr (ZE21C) alloy and Ti6Al4V (TC4) alloy to prepare suture anchors to reconstruct the patellar ligament-tibia in SD rats. We studied the degradation behavior of the ZE21C suture anchor via in vitro and in vivo experiments and assessed its reparative effect on the ligament-bone junction. In vitro, the ZE21C suture anchor degraded gradually, and calcium and phosphorus products accumulated on its surface during degradation. In vivo, the ZE21C suture anchor could maintain its mechanical integrity within 12 weeks of implantation in rats. The tail of the ZE21C suture anchor in high stress concentration degraded rapidly during the early implantation stage (0-4weeks), while bone healing accelerated the degradation of the anchor head in the late implantation stage (4-12weeks). Radiological, histological, and biomechanical assays indicated that the ZE21C suture anchor promoted bone healing above the suture anchor and fibrocartilaginous interface regeneration in the ligament-bone junction, leading to better biomechanical strength than the TC4 group. Hence, this study provides a basis for further research on the clinical application of degradable magnesium alloy suture anchors.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance.

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.