Clinical Effectiveness and Safety of Transarterial Chemoembolization: Hepatic Artery Infusion Chemotherapy Plus Tyrosine Kinase Inhibitors With or Without Programmed Cell Death Protein-1 Inhibitors for Unresectable Hepatocellular Carcinoma-A Retrospective Study.

BACKGROUND: Locoregional treatment with transarterial chemoembolization (TACE) or hepatic artery infusion chemotherapy (HAIC) and systemic targeted immunotherapy with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC) have achieved promising efficacy. The retrospective study aimed to evaluate the efficacy and safety of TACE and HAIC plus TKI with or without PD-1 for uHCC. PATIENTS AND METHODS: From November 2020 to February 2024, the data of 44 patients who received TACE-HAIC + TKI + PD-1 (THKP group) and 34 patients who received TACE-HAIC + TKI (THK group) were retrospectively analyzed. Primary outcomes were overall survival (OS) and progress-free survival (PFS), and secondary outcomes were objective response rate (ORR), disease control rate (DCR), conversion rates, and adverse events (AEs). RESULTS: A total of 78 patients were recruited in our single-center study. The patients in THKP group had prolonged median OS [25 months, 95% confidence interval (CI) 24.0-26.0 vs 18 months, 95% CI 16.1-19.9; p = 0.000278], median PFS [16 months, 95% CI 14.1-17.9 vs 12 months 95% CI 9.6-14.4; p = 0.004] and higher ORR (38.6% vs 23.5%, p = 0. 156) and DCR (88.6% vs 64.7%, p = 0.011) compared with those in THK group. Multivariate analysis showed that treatment option and alpha-fetoprotein (AFP) level were independent prognostic factors of OS and PFS. The frequency of AEs were similar between the two groups. CONCLUSIONS: The THKP group had better efficacy for uHCC than the THK group, with acceptable safety.

Structures reveal how SGLT inhibitors work.

Sodium glucose cotransporters (SGLTs) transport glucose against its concentration gradient by harnessing the electrochemical potential gradient of sodium ions. SGLT inhibitors are widely prescribed to treat diabetes and other conditions. Recent structural studies have uncovered how chemically diverse SGLT inhibitors bind and inhibit the transporter at the atomic level.

H2-Promoted Benign Coke Strategy for Dimethyl Ether Carbonylation with Long-Term Stability and High Activity.

Zeolite-catalyzed dimethyl ether (DME) carbonylation provides a novel route to producing methyl acetate (MeOAc). Mordenite (MOR) has drawn significant interest because of its remarkable MeOAc selectivity in DME carbonylation, albeit with limited catalytic stability. Herein, novel MOR-based DME carbonylation catalysts, distinguished by long-term stability and high activity were successfully developed, based on an H2-promoted benign coke strategy. Both the H2 cofeeds and the presence of metal species with hydrogenation capability are demonstrated to be crucial for the regulation of coke depositions. The coke deposits can potentially cover the acid sites in the 12-MR main channels, thereby mitigating the occurrence of undesirable methanol-to-hydrocarbon side reactions. Meanwhile, the elimination of ultralarge coke species under the assistance of H2 and Cu species could ensure smooth mass transfer within the catalyst, contributing to its remarkable catalytic performance. The most highlighted DME carbonylation performance was achieved on coke-mediated CuZn-HMOR with a high MeOAc yield of 0.4-0.5 g·gcat-1·h-1 for over 520 h (over 50× enhancement versus HMOR), exhibiting promising industrial application potential. The current strategy is expected to inspire further research into zeolite-catalyzed reactions, which could be potentially improved by the presence of benign coke.

Protective effect of empagliflozin against palmitate-induced lipotoxicity through AMPK in H9c2 cells.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as novel cardioprotective agents. However, their direct impact on cardiomyocyte injury is yet to be studied. In this work, we investigate the underlying molecular mechanisms of empagliflozin (EMPA), an SGLT2 inhibitor, in mitigating palmitate (PA)-induced cardiomyocyte injury in H9c2 cells. We found that EMPA significantly attenuated PA-induced impairments in insulin sensitivity, ER stress, inflammatory cytokine gene expression, and cellular apoptosis. Additionally, EMPA elevated AMP levels, activated the AMPK pathway, and increased carnitine palmitoyl transferase1 (CPT1) gene expression, which collectively enhanced fatty acid oxidation and reduced stress signals. This study reveals a novel mechanism of EMPA's protective effects against PA-induced cardiomyocyte injury, providing new therapeutic insights into EMPA as a cardioprotective agent.

Causal association of epigenetic aging and osteoporosis: a bidirectional Mendelian randomization study.

BACKGROUND: The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study. METHODS: We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis. RESULT: There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538-0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge. CONCLUSION: There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis.

Study on creep characteristics and component model of saline soil in hexi corridor.

Accurate mastery of the creep characteristics of unsaturated saline soil is extremely important for the long-term stability and safe operation of all types of buildings. In this paper, the research object focused on the saline soil of the Zhangye area, Hexi corridor. The indoor triaxial CU creep test was carried out by means of graded loading to study the creep characteristics of saline soil under different salt content and loading stress. The Merchant and Burgers models were used to predict the creep behavior of the saline soils, and the predicted results were compared with the experimental values. The results showed that the triaxial creep curve of saline soil developed in stage III. Namely, transient creep stage, deceleration creep stage and steady-state creep stage. The creep deformation increases with the increase of salt content and loading stress. The stress-strain isochronous curve has non-linear growth, and the cluster of curves develops from dense to sparse after increasing to long-term strength (100∼150 kPa). The parameters of the Merchant and Burgers model vary with salt content and loading stress, and the creep curve predicted by the Burgers model is closer to the test value.

Apocynin exerts cytoprotective effects on dexamethasone-induced osteoblasts by inhibiting oxidative stress through the Nrf2 signalling pathway.

Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.

Design and Synthesis of Bistetrazole-Based Energetic Salts Bearing the Nitrogen-Rich Fused Ring.

A series of bistetrazole-based energetic salts bearing a nitrogen-rich fused ring were designed and synthesized. Among them, compounds 4-10 showed good detonation properties and excellent thermostability. By treating nitrogen-rich fused ring 3 with concentrated hydrochloric acid, a new type of Dimroth rearrangement was observed that afforded compound 12 efficiently. This new transformation herein constitutes a valuable addition to the Dimroth rearrangement.

Causal relationships between COVID-19 and osteoporosis: a two-sample Mendelian randomization study in European population.

Introduction: The causal relationship between Coronavirus disease 2019 (COVID-19) and osteoporosis (OP) remains uncertain. We aimed to assess the effect of COVID-19 severity (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, and severe COVID-19) on OP by a two-sample Mendelian randomization (MR) study. Methods: We conducted a two-sample MR analysis using publicly available genome-wide association study (GWAS) data. Inverse variance weighting (IVW) was used as the main analysis method. Four complementary methods were used for our MR analysis, which included the MR-Egger regression method, the weighted median method, the simple mode method, and the weighted mode method. We utilized the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) global test to identify the presence of horizontal pleiotropy. Cochran's Q statistics were employed to assess the existence of instrument heterogeneity. We conducted a sensitivity analysis using the leave-one-out method. Results: The primary results of IVW showed that COVID-19 severity was not statistically related to OP (SARS-CoV-2 infection: OR (95% CI) = 0.998 (0.995 ~ 1.001), p = 0.201403; COVID-19 hospitalization: OR (95% CI) =1.001 (0.999 ~ 1.003), p = 0.504735; severe COVID-19: OR (95% CI) = 1.000 (0.998 ~ 1.001), p = 0.965383). In addition, the MR-Egger regression, weighted median, simple mode and weighted mode methods showed consistent results. The results were robust under all sensitivity analyses. Conclusion: The results of the MR analysis provide preliminary evidence that a genetic causal link between the severity of COVID-19 and OP may be absent.

A numerical study of the hemodynamic behavior and gas transport in cardiovascular systems with severe cardiac or cardiopulmonary failure supported by venoarterial extracorporeal membrane oxygenation.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been extensively demonstrated as an effective means of bridge-to-destination in the treatment of patients with severe ventricular failure or cardiopulmonary failure. However, appropriate selection of candidates and management of patients during Extracorporeal membrane oxygenation (ECMO) support remain challenging in clinical practice, due partly to insufficient understanding of the complex influences of extracorporeal membrane oxygenation support on the native cardiovascular system. In addition, questions remain as to how central and peripheral venoarterial extracorporeal membrane oxygenation modalities differ with respect to their hemodynamic impact and effectiveness of compensatory oxygen supply to end-organs. In this work, we developed a computational model to quantitatively address the hemodynamic interaction between the extracorporeal membrane oxygenation and cardiovascular systems and associated gas transport. Model-based numerical simulations were performed for cardiovascular systems with severe cardiac or cardiopulmonary failure and supported by central or peripheral venoarterial extracorporeal membrane oxygenation. Obtained results revealed that: 1) central and peripheral venoarterial extracorporeal membrane oxygenation modalities had a comparable capacity for elevating arterial blood pressure and delivering oxygenated blood to important organs/tissues, but induced differential changes of blood flow waveforms in some arteries; 2) increasing the rotation speed of extracorporeal membrane oxygenation pump (ω) could effectively improve arterial blood oxygenation, with the efficiency being especially high when ω was low and cardiopulmonary failure was severe; 3) blood oxygen indices (i.e., oxygen saturation and partial pressure) monitored at the right radial artery could be taken as surrogates for diagnosing potential hypoxemia in other arteries irrespective of the modality of extracorporeal membrane oxygenation; and 4) Left ventricular (LV) overloading could occur when ω was high, but the threshold of ω for inducing clinically significant left ventricular overloading depended strongly on the residual cardiac function. In summary, the study demonstrated the differential hemodynamic influences while comparable oxygen delivery performance of the central and peripheral venoarterial extracorporeal membrane oxygenation modalities in the management of patients with severe cardiac or cardiopulmonary failure and elucidated how the status of arterial blood oxygenation and severity of left ventricular overloading change in response to variations in ω. These model-based findings may serve as theoretical references for guiding the application of venoarterial extracorporeal membrane oxygenation or interpreting in vivo measurements in clinical practice.

Structures of human SGLT in the occluded state reveal conformational changes during sugar transport.

Sodium-Glucose Cotransporters (SGLT) mediate the uphill uptake of extracellular sugars and play fundamental roles in sugar metabolism. Although their structures in inward-open and outward-open conformations are emerging from structural studies, the trajectory of how SGLTs transit from the outward-facing to the inward-facing conformation remains unknown. Here, we present the cryo-EM structures of human SGLT1 and SGLT2 in the substrate-bound state. Both structures show an occluded conformation, with not only the extracellular gate but also the intracellular gate tightly sealed. The sugar substrate are caged inside a cavity surrounded by TM1, TM2, TM3, TM6, TM7, and TM10. Further structural analysis reveals the conformational changes associated with the binding and release of substrates. These structures fill a gap in our understanding of the structural mechanisms of SGLT transporters.

Efficient hydrodeoxygenation of methyl levulinate into pentanoic biofuels over Ru/USY catalysts.

Catalytic hydrodeoxygenation of neat methyl levulinate into pentanoic biofuels is one of the pivotal reactions in biomass valorization. A combined pentanoic acid/methyl pentanoate yield of 92% can be achieved for Ru/USY with a Si/Al ratio of 15 at 220 °C and 40 bar H2. The superior performance of Ru/USY-15 for the efficient production of pentanoic biofuels is attributed to the optimal site balance between the Ru species and strong acid sites (ca. 1 : 5).

Design and Analysis of a Fluid-Filled RF MEMS Switch.

In the present study, a fluid-filled RF MEMS (Radio Frequency Micro-Electro-Mechanical Systems) switch is proposed and designed. In the analysis of the operating principle of the proposed switch, air, water, glycerol and silicone oil were adopted as filling dielectric to simulate and research the influence of the insulating liquid on the drive voltage, impact velocity, response time, and switching capacity of the RF MEMS switch. The results show that by filling the switch with insulating liquid, the driving voltage can be effectively reduced, while the impact velocity of the upper plate to the lower plate is also reduced. The high dielectric constant of the filling medium leads to a lower switching capacitance ratio, which affects the performance of the switch to some extent. By comparing the threshold voltage, impact velocity, capacitance ratio, and insertion loss of the switch filled with different media with the filling media of air, water, glycerol, and silicone oil, silicone oil was finally selected as the liquid filling medium for the switch. The results show that the threshold voltage is 26.55 V after filling with silicone oil, which is 43% lower under the same air-encapsulated switching conditions. When the trigger voltage is 30.02 V, the response time is 10.12 µs and the impact speed is only 0.35 m/s. The frequency 0-20 GHz switch works well, and the insertion loss is 0.84 dB. To a certain extent, it provides a reference value for the fabrication of RF MEMS switches.

Identification and Validation of Hub Genes in the Stenosis of Arteriovenous Fistula.

Arteriovenous fistula (AVF) is the most widely used hemodialysis vascular access in China. However, stenosis of the AVF limits its use. The mechanism of AVF stenosis is currently unknown. Therefore, the purpose of our study was to explore the mechanisms of AVF stenosis. In this study, we identified the differentially expressed genes (DEGs) based on the Gene Expression Omnibus (GEO) dataset (GSE39488) between venous segments of AVF and normal veins. A protein-protein interaction (PPI) network was constructed to identify hub genes of AVF stenosis. Finally, six hub genes (FOS, NR4A2, EGR2, CXCR4, ATF3, and SERPINE1) were found. Combined with the results of the PPI network analysis and literature search, FOS and NR4A2 were selected as the target genes for further investigation. We validated the bioinformatic results via reverse transcription PCR (RT-PCR) and Western blot analyses on human and rat samples. The expression levels of the mRNA and protein of FOS and NR4A2 were upregulated in both human and rat samples. In summary, we found that FOS may play an important role in AVF stenosis, which could be a potential therapeutic target of AVF stenosis.

The Protein Fusion Strategy Facilitates the Structure Determination of Small Membrane Proteins by Cryo-EM.

Despite the resolution revolution of cryo-EM, structures of small membrane proteins (<80 kDa) are still understudied. These proteins are notoriously reluctant to structure determination by single-particle cryo-EM. Protein fusion might represent a plausible strategy to overcome such difficulties. This Perspective enumerates recent exemplary progress and discusses the future potential of the protein fusion strategy.

Stepwise Asymmetric Allylic Substitution-Isomerization Enabled Mimetic Synthesis of Axially Chiral B,N-Heterocycles.

Axially chiral molecules bearing multiple stereogenic axes are of great importance in the field of organic chemistry. However, the efficient construction of atropisomers featuring two different types of stereogenic axes has rarely been explored. Herein, we report the novel atroposelective synthesis of configurationally stable axially chiral B,N-heterocycles. By using stepwise asymmetric allylic substitution-isomerization (AASI) strategy, diaxially chiral B,N-heterocycles bearing B-C and C-N axes that are related to the moieties of axially chiral enamines and arylborons were also obtained. In this case, all four stereoisomers of diaxially chiral B,N-heterocycles were stereodivergently afforded in high enantioselectivities. Density functional theory (DFT) studies demonstrated that the NH⋅⋅⋅π interactions played a unique role in the promotion of stereospecific isomerization, thereby leading to the highly efficient central-to-axial chirality transfer.

Structural mechanism of SGLT1 inhibitors.

Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.

Urinary metals as influencing factors of coronary heart disease among a population in Guangzhou, China.

The cardiovascular system is highly sensitive to toxic metal exposure and trace element dysregulation. However, previous findings relating to metal exposure and coronary heart disease (CHD) have partially been conflicting and difficult to exhibit the combined effect of metal mixtures. This case-control study investigated urinary concentrations of ten metal/metalloids among clinically-diagnosed CHD patients and healthy adults during May to December 2021 in Guangzhou, China. We found that cadmium (Cd) status in urine from CHD patients was remarkably higher than its reference, while chromium (Cr), nickel (Ni), copper (Cu) and selenium (Se) concentrations were lower (p < 0.05). Spearman correlation analysis showed that urinary arsenic (As) and Se were highly correlated (rs=0.830, p < 0.001), indicating their similar sources. Principal component analysis (PCA) exhibited denser distribution of Cd-Sn in cases than in controls. Logistic regression analysis exhibited significant associations between urinary Cd (adjusted OR: 1.965, 95% CI: 1.222-3.162), Se (0.787, 95% CI: 0.695-0.893), Ni (0.493, 95% CI: 0.265-0.916) and CHD risk. Quantile g-computation showed negative joint effect of metal mixtures on CHD (adjusted OR: 0.383, 95% CI: 0.159-0.932) (p < 0.05), suggesting the need for supplementing essential trace elements. The negative partial effect was primarily attributed to Se and Ni, while positive partial effect was mainly due to tin (Sn) and Cd. Nevertheless, we also found a quantile increase of Cd-Sn level was negatively correlated with 8.26% (95% CI: 3.44-13.08%) decrease of high-density lipoprotein cholesterol (p < 0.001), and 71.2% of the joint effect attributed to Cd. Based on random forest, Se, Cd and Ni were found to be the dominant influencing factors of CHD. The role of Ni in CHD is yet to be uncovered, while excessive Cd exposure and low Se status among CHD patients need to be mitigated.

Comparative efficacy of five balloons for treating autogenous arteriovenous fistula stenosis: a Bayesian network meta-analysis.

BACKGROUND: Arteriovenous fistula (AVF) was the lifeline of patients with maintenance hemodialysis (MHD). However, stenosis of AVF may limit its use. Currently, AVF stenosis is commonly treated with balloon angioplasty. Meanwhile, several balloons were available. Therefore, this study aimed to explore the effectiveness of angioplasty with five different balloons in patients with AVF stenosis. METHODS: A network meta-analysis (NMA) was performed to synthesize direct and indirect evidence. We carried out a comprehensive literature search in PubMed, Embase, the Cochrane Central Register of Controlled Trials, Scopus, and ClinicalTrials.gov databases from database inception to January 31, 2021. The main outcomes were primary patency rates of AVF after 3, 6, 9, and 12 months. The NMA was performed using Stata 15 (network and mvmeta commands) and GeMTC software. RESULTS: Twenty randomized controlled trials (RCTs) involving 2,607 participants were included. Direct meta-analyses revealed no significant difference in primary patency rates between different balloons after 3, 6 and 9 months. However, NMA demonstrated that the effectiveness of plain balloon angioplasty (PBA) was inferior to that of the drug-coated balloon (DCB) after 3 and 9 months. Moreover, the results suggested that the high-pressure balloon (HPB) was inferior to DCB after 9 months. Thereafter, the analysis of the surface under the cumulative ranking curve (SUCRA) revealed that DCB was ranked as the first effective treatment after 3 months. The drug-eluting balloon (DEB) was the most effective treatment after 6, 9, and 12 months. The analyses revealed no significant publication bias. DISCUSSION: DEB may be the most effective treatment of AVF stenosis, followed by DCB. However, prospective studies involving large sample sizes of clinical trials and a direct comparison between DEB and DCB are required to clarify the individual value of different treatment options.

Realizing Fast Synthesis of High-Silica Zeolite Y with Remarkable Catalytic Performance.

High-silica zeolite Y (FAU) plays a vital role in (petro)chemical industries. However, the slow nucleation and growth kinetics of the high-silica FAU framework limit its direct synthesis and the improvement of framework SiO2 /Al2 O3 ratio (SAR). Here, a facile strategy is developed to realize the fast crystallization of high-silica zeolite Y, which involves the combination of high crystallization temperature, ultra-stable Y (USY) seeds and efficient organic-structure directing agent (OSDA). The synthesis can be finished in 5-16 h at 160 °C and with tunable SAR up to 18.2, and the key factors affecting crystallization kinetics and phase purity are elucidated. Moreover, the crystallization process was monitored to reveal the fast crystal growth mechanism. The high-silica products possess high (hydro)thermal stability and abundant strong acid sites, which endow them excellent catalytic cracking performance, obviously superior to commercial USY.