Reduction of Oxidative Stress and Excitotoxicity by Mesenchymal Stem Cell Biomimetic Co-Delivery System for Cerebral Ischemia-Reperfusion Injury Treatment.

A cerebral ischemia-reperfusion injury is ensued by an intricate interplay between various pathological processes including excitotoxicity, oxidative stress, inflammation, and apoptosis. For a long time, drug intervention policies targeting a single signaling pathway have failed to achieve the anticipated clinical efficacy in the intricate and dynamic inflammatory environment of the brain. Moreover, inadequate targeted drug delivery remains a significant challenge in cerebral ischemia-reperfusion injury therapy. In this study, a multifunctional nanoplatform (designated as PB-006@MSC) is developed using ZL006-loaded Prussian blue nanoparticles (PBNPs) camouflaged by a mesenchymal stem cell (MSC) membrane (MSCm). ZL006 is a neuroprotectant. It can be loaded efficiently into the free radical scavenger PBNP through mesoporous adsorption. This can simultaneously modulate multiple targets and pathways. MSCm biomimetics can reduce the nanoparticle immunogenicity, efficiently enhance their homing capability to the cerebral ischemic penumbra, and realize active-targeting therapy for ischemic stroke. In animal experiments, PB-006@MSC integrated reactive oxygen species (ROS) scavenging and neuroprotection. Thereby, it selectively targeted the cerebral ischemic penumbra (about fourfold higher accumulation at 24 h than in the non-targeted group), demonstrated a remarkable therapeutic efficacy in reducing the volume of cerebral infarction (from 37.1% to 2.3%), protected the neurogenic functions, and ameliorated the mortality.

Quantitative Analysis of Primary Compressive Trabeculae Distribution in the Proximal Femur of the Elderly.

OBJECTIVE: As osteoporosis progresses, the primary compressive trabeculae (PCT) in the proximal femur remains preserved and is deemed the principal load-bearing structure that links the femoral head with the femoral neck. This study aims to elucidate the distribution patterns of PCT within the proximal femur in the elderly population, and to assess its implications for the development and optimization of internal fixation devices used in hip fracture surgeries. METHODS: This is a retrospective cohort study conducted from March 2022 to April 2023. A total of 125 patients who underwent bilateral hip joint CT scans in our hospital were enrolled. CT data of the unaffected side of the hip were analyzed. Key parameters regarding the PCT distribution in the proximal femur were measured, including the femoral head's radius (R), the neck-shaft angle (NSA), the angle between the PCT-axis and the head-neck axis (α), the distance from the femoral head center to the PCT-axis (δ), and the lengths of the PCT's bottom and top boundaries (L-bottom and L-top respectively). The impact of gender differences on PCT distribution patterns was also investigated. Student's t-test or Mann-Whitney U test were used to compare continuous variables between genders. The relationship between various variables was investigated through Pearson's correlation analysis. RESULTS: PCT was the most prominent bone structure within the femoral head. The average NSA, α, and δ were 126.85 ± 5.85°, 37.33 ± 4.23°, and 0.39 ± 1.22 mm, respectively, showing no significant gender differences (p > 0.05). Pearson's correlation analysis revealed strong correlations between α and NSA (r = -0.689, p < 0.001), and R and L-top (r = 0.623, p < 0.001), with mild correlations observed between δ and NSA (r = -0.487, p < 0.001), and R and L-bottom (r = 0.427, p < 0.001). Importantly, our study establishes a method to accurately localize PCT distribution in true anteroposterior (AP) radiographs of the hip joint, facilitating precise screw placement in proximal femur fixation procedures. CONCLUSION: Our study provided unprecedented insights into the distribution patterns of PCT in the proximal femur of the elderly population. The distribution of PCT in the proximal femur is predominantly influenced by anatomical and geometric factors, such as NSA and femoral head size, rather than demographic factors like gender. These insights have crucial implications for the design of internal fixation devices and surgical planning, offering objective guidance for the placement of screws in hip fracture treatments.

Pediatric femoral shaft fractures: the American Academy of Orthopaedic Surgeons clinical practice guidelines versus actual management in a teaching hospital.

Background: In 2009, the clinical practice guidelines (CPG) were released by the American Academy of Orthopaedic Surgeons (AAOS), which outline an age-based approach for treating pediatric femoral shaft fractures (PFSF), both nonoperatively and operatively. The aim of the current study was to investigate potential disparities between the recommended treatments for PFSF based on the AAOS-CPG and the actual treatments administered in The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University. Methods: A retrospective review was conducted on the medical charts and radiographs of all PFSF treated at The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from January 2014 to January 2022. We identified 445 children who met our inclusion criteria and evaluated their treatments according to the AAOS-CPG. Actual treatments were then compared with the treatments recommended by the AAOS-CPG. Binomial and multivariate logistic regression was used to examine whether different factors could predict the choice between operative and nonoperative management. Results: Operative treatments were undertaken in 102 of 215 (47.4%) fractures in children younger than 6 years, in 102 of 122 (83.6%) fractures in those between 6 and 12 years of age, and in 107 of 108 (99.1%) fractures in those older than 12 years. Nonoperative management was conducted in 113 of 215 (52.6%) fractures in children younger than 6 years, in 20 of 122 (16.4%) fractures in those between 6 and 12 years of age, and in 1 of 108 (0.9%) fractures in those older than 12 years of age. Surgeon decisions for non-surgery were in agreement with the CPG 52.6% of the time, whereas agreement reached 90.9% for surgical choices. Predictors of actual operative management were age (P=0.01), patient weight (P<0.001), fracture pattern (P<0.001), presence of other orthopedic injuries requiring surgery (P=0.002), and polytrauma (P=0.02). Conclusions: There was limited concordance between actual treatments and CPG recommendations, particularly for the nonoperative management of fractures in children under 6 years old. Age, patient weight, fracture pattern, presence of other orthopedic injuries requiring surgery, and polytrauma were the main predictors of our operative decision-making process.

Expressions of glycemic parameters, lipid profile, and thyroid hormone in patients with type 2 diabetes mellitus and their correlation.

OBJECTIVE: This study aimed to investigate the expressions of glycemic parameters, lipid profile, and thyroid hormone in type 2 diabetes mellitus (T2DM) patients and their correlation. METHODS: Eighty-four patients with T2DM in our hospital were included as the observation group. The T2DM patients were divided into mild group, moderate group, and severe group according to the fasting plasma glucose (FPG) level. Another 84 healthy subjects in the same period of health examination in our hospital were included as the control group. The levels of glycemic parameters, (HbA1c and FPG), lipid profile (TC, TG, LDL-C, and HDL-C) and thyroid hormone (FT3, TSH, and FT4) were measured by automatic biochemical analyzer. The correlation between glycemic parameters, lipid profile, and thyroid hormone was analyzed by Pearson correlation analysis. RESULTS: The FPG, TC, TG, LDL-C, HbA1c, and TSH levels were significantly elevated, while the HDL-C and FT3 levels were significantly declined in the observation group versus to control group (p < .05). The levels of HbA1c, FPG, TC, LDL-C, and TSH were significantly increased, while the levels of HDL-C and FT3 were decreased in moderate and severe groups, when compared to mild group (p < .05). The levels of HbA1c, FPG, TC, LDL-C and TSH were higher, while the level of FT3 was lower in severe group than those in moderate group (p < .05). Pearson Correlation analysis showed that FT3 level in T2DM patients was positively correlated with FPG, HbAlc, TC, TG, and LDL-C levels (p < .05), but negatively correlated with HDL-C level (p < .05). TSH level was negatively correlated with FPG, HbAlc, TC, TG, and LDL-C levels (p < .05), while positively correlated with HDL-C level. CONCLUSION: The thyroid hormone levels were of clinical significance in evaluating glycolipid metabolism and severity of T2DM. Clinical detection of glycolipid metabolism and thyroid hormone levels in T2DM patients is of great significance for diagnosis, evaluation, and targeted treatment of the disease.

Impact of non-emergency surgical timing on postoperative recovery quality in mild or asymptomatic SARS-CoV-2 infected patients: a grouped cohort study.

OBJECTIVE: To explore the relationship between the timing of non-emergency surgery in mild or asymptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infected individuals and the quality of postoperative recovery from the time of confirmed infection to the day of surgery. METHODS: We retrospectively reviewed the medical records of 300 cases of mild or asymptomatic SARS-CoV-2 infected patients undergoing elective general anaesthesia surgery at Yijishan Hospital between January 9, 2023, and February 17, 2023. Based on the time from confirmed SARS-CoV-2 infection to the day of surgery, patients were divided into four groups: ≤2 weeks (Group A), 2-4 weeks (Group B), 4-6 weeks (Group C), and 6-8 weeks (Group D). The primary outcome measures included the Quality of Recovery-15 (QoR-15) scale scores at 3 days, 3 months, and 6 months postoperatively. Secondary outcome measures included postoperative mortality, ICU admission, pulmonary complications, postoperative length of hospital stay, extubation time, and time to leave the PACU. RESULTS: Concerning the primary outcome measures, the QoR-15 scores at 3 days postoperatively in Group A were significantly lower compared to the other three groups (P < 0.05), while there were no statistically significant differences among the other three groups (P > 0.05). The QoR-15 scores at 3 and 6 months postoperatively showed no statistically significant differences among the four groups (P > 0.05). In terms of secondary outcome measures, Group A had a significantly prolonged hospital stay compared to the other three groups (P < 0.05), while other outcome measures showed no statistically significant differences (P > 0.05). CONCLUSION: The timing of surgery in mild or asymptomatic SARS-CoV-2 infected patients does not affect long-term recovery quality but does impact short-term recovery quality, especially for elective general anaesthesia surgeries within 2 weeks of confirmed infection. Therefore, it is recommended to wait for a surgical timing of at least greater than 2 weeks to improve short-term recovery quality and enhance patient prognosis.

Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

Association between blood urea nitrogen to serum albumin ratio and in-hospital mortality in critical patients with diabetic ketoacidosis: a retrospective analysis of the eICU database.

Background: This study aimed to investigate the association between blood urea nitrogen to serum albumin ratio (BAR) and the risk of in-hospital mortality in patients with diabetic ketoacidosis. Methods: A total of 3,962 diabetic ketoacidosis patients from the eICU Collaborative Research Database were included in this analysis. The primary outcome was in-hospital death. Results: Over a median length of hospital stay of 3.1 days, 86 in-hospital deaths were identified. One unit increase in LnBAR was positively associated with the risk of in-hospital death (hazard ratio [HR], 1.82 [95% CI, 1.42-2.34]). Furthermore, a nonlinear, consistently increasing correlation between elevated BAR and in-hospital mortality was observed (P for trend =0.005 after multiple-adjusted). When BAR was categorized into quartiles, the higher risk of in-hospital death (multiple-adjusted HR, 1.99 [95% CI, (1.1-3.6)]) was found in participants in quartiles 3 to 4 (BAR≥6.28) compared with those in quartiles 1 to 2 (BAR<6.28). In the subgroup analysis, the LnBAR-hospital death association was significantly stronger in participants without kidney insufficiency (yes versus no, P-interaction=0.023). Conclusion: There was a significant and positive association between BAR and the risk of in-hospital death in patients with diabetic ketoacidosis. Notably, the strength of this association was intensified among those without kidney insufficiency.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Serum Mac-2 binding protein glycosylation isomer dynamics in patients achieving sustained virologic response for hepatitis C virus.

BACKGROUND AND AIM: Understanding the dynamics of serum Mac-2 binding protein glycosylation isomer (M2BPGi) remains pivotal for hepatitis C virus (HCV) patients' post-sustained virologic response (SVR12) through direct-acting antivirals (DAAs). METHODS: We compared areas under receiver operating characteristic curves (AUROCs) of M2BPGi, FIB-4, and APRI and assess M2BPGi cutoff levels in predicting fibrosis stages of ≥F3 and F4 utilizing transient elastography in 638 patients. Variations in M2BPGi levels from pretreatment to SVR12 and their association with pretreatment alanine transaminase (ALT) levels and fibrosis stage were investigated. RESULTS: The AUROCs of M2BPGi were comparable to FIB-4 in predicting ≥F3 (0.914 vs 0.902, P = 0.48) and F4 (0.947 vs 0.915, P = 0.05) but were superior to APRI in predicting ≥F3 (0.914 vs 0.851, P = 0.001) and F4 (0.947 vs 0.857, P < 0.001). Using M2BPGi cutoff values of 2.83 and 3.98, fibrosis stages of ≥F3 and F4 were confirmed with a positive likelihood ratio ≥10. The median M2BPGi change was -0.55. Patients with ALT levels ≥5 times ULN or ≥F3 demonstrated more pronounced median decreases in M2BPGi level compared to those with ALT levels 2-5 times ULN and <2 times ULN (-0.97 vs -0.68 and -0.44; P < 0.001) or with < F3 (-1.52 vs -0.44; P < 0.001). CONCLUSIONS: Serum M2BPGi is a reliable marker for advanced hepatic fibrosis. Following viral clearance, there is a notable M2BPGi decrease, with the extent of reduction influenced by ALT levels and fibrosis stage.

Observation of stacking engineered magnetic phase transitions within moiré supercells of twisted van der Waals magnets.

Recent demonstrations of moiré magnetism, featuring exotic phases with noncollinear spin order in the twisted van der Waals (vdW) magnet chromium triiodide CrI3, have highlighted the potential of twist engineering of magnetic (vdW) materials. However, the local magnetic interactions, spin dynamics, and magnetic phase transitions within and across individual moiré supercells remain elusive. Taking advantage of a scanning single-spin magnetometry platform, here we report observation of two distinct magnetic phase transitions with separate critical temperatures within a moiré supercell of small-angle twisted double trilayer CrI3. By measuring temperature-dependent spin fluctuations at the coexisting ferromagnetic and antiferromagnetic regions in twisted CrI3, we explicitly show that the Curie temperature of the ferromagnetic state is higher than the Néel temperature of the antiferromagnetic one by ~10 K. Our mean-field calculations attribute such a spatial and thermodynamic phase separation to the stacking order modulated interlayer exchange coupling at the twisted interface of moiré superlattices.

Dissecting the vascular-cognitive nexus: energetic vs. conventional hemodynamic parameters.

Blood pressure or flow measurements have been associated with vascular health and cognitive function. We proposed that energetic hemodynamic parameters may provide a more nuanced understanding and stronger correlation with cognitive function, in comparisons with conventional aortic and carotid pressure and flow parameters. The study comprised 1858 participants, in whom we assessed cognitive function via MoCA method, and measured central aortic and carotid pressure and flow waveforms. In addition to various pressure and flow parameters, we calculated energetic hemodynamic parameters through integration of pressure multiplying flow with respect to time. Energetic hemodynamic parameters, particularly aortic and carotid mean and pulsatile energy and pulsatility index (PI), were significantly associated with MoCA score more than any aortic and carotid pressure and flow parameters, after adjusting for age, sex, education, depression score, heart rate, BMI, HDL-cholesterol, and glucose levels. MoCA exhibited a strong positive relationship with carotid mean energy (standardized beta = 0.053, P = 0.0253) and a negative relationship with carotid energy PI (standardized beta = -0.093, P = 0.0002), exceeding the association with all traditional pressure- or flow-based parameters. Aortic pressure reflection coefficient at the aorto-carotid junction was positively correlated with mean carotid energy and negatively correlated with PI. Aortic characteristic impedance positively correlated with carotid energy PI but not mean energy. Our research indicates that energetic hemodynamic parameters, particularly carotid mean energy and carotid energy PI, have a stronger association with MoCA scores than traditional pressure- or flow-based metrics. This correlation with cognitive function is notably influenced by the properties of the aorto-carotid interface.

MicroRNA-223-3p Targeting SGK1 Regulates Apoptosis and Inflammation in Sepsis-Associated Acute Kidney Injury.

INTRODUCTION: Sepsis and septic shock are significant contributors to the development of acute kidney injury (AKI) in critically ill patients. This study aims to elucidate the role and mechanism of microRNA-223-3p in sepsis-associated AKI (SA-AKI). METHODS: Bioinformatics methods were used to analyze the expression of microRNA-223-3p in sepsis patients, its correlation with inflammatory cytokines and to predict the binding site of microRNA-223-3p with SGK1. The binding relationship between microRNA-223-3p and SGK1 was validated using a dual-luciferase reporter gene assay. The expression of microRNA-223-3p was assayed using qPCR in patient serum or lipopolysaccharide (LPS)-treated HK-2 cells. Cell apoptosis, expression of Bax, Bcl-2, cleaved caspase-3, and levels of TNF-α, IL-1ß, and IL-6 were measured using TUNEL assay, western blot (WB), and ELISA, respectively. SGK1 expression of HK-2 cells with different treatments was detected using qPCR and WB. RESULTS: The expression of microRNA-223-3p was found to be upregulated in sepsis patients and HK-2 cells treated with LPS. Furthermore, microRNA-223-3p promoted apoptosis and inflammation in LPS-induced HK-2 cells. This promotion was mediated by the negative regulation of SGK1 by microRNA-223-3p. CONCLUSION: The microRNA-223-3p was found to regulate SGK1 and promote apoptosis and inflammation in LPS-induced HK-2 cells. Our study has elucidated the mechanism of microRNA-223-3p in SA-AKI, providing a potential target for sepsis treatment.

Radical meta-C-H Halogenation of Azines via N-Benzyl Activation Strategy.

Regioselective halogenation of six-membered N-heteroarenes is crucial for precise functional derivatization. We present a meta-selective halogenation method for pyridines, quinolines, and isoquinolines via electrophilic halogen radical addition utilizing an N-benzyl activation strategy. This method achieves C3- and C5-dihalogenation in pyridines, C3- and C6-dihalogenation in quinolines, and C3-monohalogenation in isoquinolines. The feasibility and potential applications of this method were validated through scale-up reactions and the bromination of quinoline derivatives with biomolecular fragments.

Fibrosis-4 index stratifies risks of hepatocellular carcinoma in patients with chronic hepatitis C.

BACKGROUND AND AIMS: Risk stratification for patients with a higher risk of hepatocellular carcinoma (HCC) is crucial. We aimed to investigate the role of the Fibrosis-4 (FIB-4) index in predicting chronic hepatitis C (CHC)-related HCC. METHODS: A retrospective cohort study consecutively included treatment-naive CHC patients receiving longitudinal follow-up at the National Taiwan University Hospital from 1986 to 2014. The clinical data were collected and traced for HCC development. Multivariable Cox proportional hazard regression analysis was used to investigate the predictors for HCC. RESULTS: A total of 1285 patients in the ERADICATE-C cohort were included. The median age was 54, 56% were females, and 933 had HCV viremia. There were 33%, 38%, and 29% of patients having FIB-4 index <1.45, 1.45-3.25, and ≥3.25, respectively. After a median of 9-year follow-up, 186 patients developed HCC. Multivariable analysis revealed that older age, AFP≥20 ng/mL, cirrhosis, and a higher FIB-4 index were independent predictors for HCC. Compared with patients with FIB-4 index <1.45, those with FIB-4 1.45-3.25 had a 5.51-fold risk (95% confidence interval [CI]: 2.65-11.46), and those with FIB-4 ≥ 3.25 had 7.45-fold risk (95% CI: 3.46-16.05) of HCC. In CHC patients without viremia, FIB-4 index 1.45-3.25 and FIB-4 ≥ 3.25 increased 6.78-fold and 16.77-fold risk of HCC, respectively, compared with those with FIB-4 < 1.45. CONCLUSION: The baseline FIB-4 index can stratify the risks of HCC in untreated CHC patients, even those without viremia. The FIB-4 index should thus be included in the management of CHC.

[A clinical study of HoloSight Orthopaedic Trauma Surgery Robot-assisted infra-acetabular screw placement for acetabular fractures].

Objective: To investigate the effectiveness of HoloSight Orthopaedic Trauma Surgery Robot-assisted infra-acetabular screw placement for treatment of acetabular fractures. Methods: The clinical data of 23 patients with acetabular fractures treated with open reduction and internal fixation and infra-acetabular screw placement in two medical centers between June 2022 and October 2023 were retrospectively analyzed. According to the the method of infra-acetabular screw placement, the patients were divided into navigation group (10 cases, using HoloSight Orthopaedic Trauma Surgery Robot-assisted screw placement) and freehand group (13 cases, using traditional X-ray fluoroscopy to guide screw placement). There was no significant difference in gender, age, body mass index, cause of injury, time from injury to operation, and Judet-Letournel classification between the two groups ( P>0.05). The time of infra-acetabular screw placement, the fluoroscopy frequency, the guide pin adjustment times, the quality of screw placement, the quality of fracture reduction, and the function of hip joint were compared between the two groups. Results: All patients completed the operation successfully. The time of screw placement, the fluoroscopy frequency, and guide pin adjustment times in the navigation group were significantly less than those in the freehand group ( P<0.05). The quality of screw placement in the navigation group was significantly better than that in the freehand group ( P<0.05). Patients in both groups were followed up 6-11 months, with an average of 7.7 months. There were 9 and 9 cases in the navigation group and the freehand group who achieved excellent and good fracture reduction quality at 1 week after operation, and 12 and 12 cases with excellent and good hip joint function at last follow-up, respectively, and there was no significant difference between the two groups ( P>0.05). The fractures in both groups healed well, and there was no significant difference in healing time ( P>0.05). During the follow-up, there was no complication related to screw placement, such as failure of internal fixation, vascular and nerve injury, incisional hernia. Conclusion: In the treatment of acetabular fractures, compared with the traditional freehand screw placement, the HoloSight Orthopaedic Trauma Surgery Robot-assisted screw placement can reduce the time of screw placement, improve the accuracy of screw placement, and reduce the amount of radiation, which is an efficient, accurate, and safe surgical method.

Social Determinants of Health and Other Predictors in Initiation of Treatment with CDK4/6 Inhibitors for HR+/HER2- Metastatic Breast Cancer.

In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) have replaced endocrine therapy alone as the standard of care; however, several barriers to treatment initiation still exist. We assessed social determinants of health (SDOH) and other factors associated with the initiation of CDK4/6i for HR+/HER2- MBC in the Medicare population. Using a retrospective cohort design, patients aged ≥65 years and diagnosed during 2015-2017 were selected from the SEER-Medicare database. Time from MBC diagnosis to first CDK4/6i initiation was the study outcome. The effect of SDOH measures and other predictors on the outcome was assessed using the multivariable Fine and Gray hazard modeling. Of 752 eligible women, 352 (46.8%) initiated CDK4/6i after MBC diagnosis (median time to initiation: 27.9 months). In adjusted analysis, SDOH factors significantly associated with CDK4/6i initiation included high versus low median household income (HHI) (hazard ratio [HR] = 1.70; 95% CI = 1.03-2.81) and the percentage of population with high versus low Medicare-only coverage (HR = 1.54; 95% CI = 1.04-2.27). In summary, older Medicare patients with HR+/HER2- MBC residing in areas with high median HHI and a high proportion of Medicare-only coverage had higher rates of initiating CDK4/6i, suggesting inequitable access to these novel, effective treatments and a need for policy intervention.

Pre-Existing and New-Onset Metabolic Dysfunctions Increase Cirrhosis and Its Complication Risks in Chronic Hepatitis B.

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB. METHODS: Patients with CHB were consecutively recruited between 2006 and 2021. The presence of MD was based on the 5 cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria. RESULTS: Eleven thousand five hundred two treatment-naive noncirrhotic patients with CHB were included with a median follow-up of 5.3 years. Patients in the MD group (n = 7,314) were older and had lower hepatitis B virus DNA levels than non-MD patients (n = 4,188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, P < 0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI: 1.03-1.63, P = 0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, P = 0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within 5 years, 95% CI: 0.44-0.74, P < 0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, P = 0.020). Among individuals with hepatic steatosis, patients with MASLD exhibited a higher cirrhosis risk than non-MD patients. DISCUSSION: Concurrent and new-onset MDs increase the risks of cirrhosis and cirrhotic complications in patients with CHB, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression.

Identification of a signature of histone modifiers in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a cancer that is closely associated with epigenetic alterations, and histone modifiers (HMs) are closely related to epigenetic regulation. Therefore, this study aimed to comprehensively explore the function and prognostic value of HMs-based signature in KIRC. HMs were first obtained from top journal. Then, the mRNA expression profiles and clinical information in KIRC samples were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Cox regression analysis and least absolute shrinkage and selection operator (Lasso) analysis were implemented to find prognosis-related HMs and construct a risk model related to the prognosis in KIRC. Kaplan-Meier analysis was used to determine prognostic differences between high- and low-risk groups. Immune infiltration and drug sensitivity analysis were also performed between high- and low-risk groups. Eventually, 8 HMs were successfully identified for the construction of a risk model in KIRC. The results of the correlation analysis between risk signature and the prognosis showed HMs-based signature has good prognostic value in KIRC. Results of immune analysis of risk models showed there were significant differences in the level of immune cell infiltration and expression of immune checkpoints between high- and low-risk groups. The results of the drug sensitivity analysis showed that the high-risk group was more sensitive to several chemotherapeutic agents such as Sunitinib, Tipifarnib, Nilotinib and Bosutinib than the low-risk group. In conclusion, we successfully constructed HMs-based prognostic signature that can predict the prognosis of KIRC.

Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.