Diffusion-rate sieving of propylene and propane mixtures in a cooperatively dynamic porous crystal.

Selective molecular recognition is an important alternative to the energy-intensive industrial separation process. Porous coordination polymers (PCPs) offer designing platforms for gas separation because they possess precise controllability over structures at the molecular level. However, PCPs-based gas separations are dominantly achieved using strong adsorptive sites for thermodynamic recognition or pore-aperture control for size sieving, which suffer from insufficient selectivity or sluggish kinetics. Developing PCPs that work at high temperatures and feature both high uptake capacity and selectivity is urgently required but remains challenging. Herein, we report diffusion-rate sieving of propylene/propane (C3H6/C3H8) at 300 K by constructing a PCP material whose global and local dynamics cooperatively govern the adsorption process via the mechanisms of the gate opening for C3H6 and the diffusion regulation for C3H8, respectively, yielding substantial differences in both uptake capacity and adsorption kinetics. Dynamic separation of an equimolar C3H6/C3H8 mixture reveals outstanding sieving performance with a C3H6 purity of 99.7% and a separation factor of 318.

Iridium(III)-Based PD-L1 Agonist Regulates p62 and ATF3 for Enhanced Cancer Immunotherapy.

Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4+ and CD8+ T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression.

Associations Between Self-Reported Visual Difficulty, Age of Onset, and Cognitive Function Trajectories Among Chinese Older Adults.

Objectives: This study examined the association between self-reported visual difficulty and age-related cognitive declines among older Chinese adults and how the timing of visual difficulty onset plays a role in cognitive trajectories. Methods: Data were drawn from the 2011-2018 wave of the China Health and Retirement Longitudinal Study, involving 9974 respondents aged 60 years or older (mean age 65.44 years, range 60-101 years). Results: At baseline, 14.16% respondents had self-reported visual difficulty. Growth curve models showed that Chinese older adults with visual difficulty experienced a faster decline in cognitive function compared to those without visual difficulty (ß = -0.02, p < .01). Older adults who began experiencing visual difficulty between 61 and 75 years of age had steeper cognitive declines compared to those with earlier or later onset (ß = -0.05, p < .01). Discussion: Older adults with self-reported visual difficulty experience faster rates of cognitive decline. Future research should explore potential factors that underlie the association between onset timing of visual difficulty and cognitive function.

Combined Transcranial Doppler and Melatonin Levels to Predict Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

OBJECTIVE: To investigate the early prediction value of transcranial Doppler ultrasound (TCD) combined with serum melatonin level for delayed cerebral ischemia (DCI) caused by subarachnoid hemorrhage (SAH). METHODS: This paper is a prospective study. A total of 120 patients with SAH treated were included. The patients were divided into the DCI group (40 cases) and non-DCI group (80 cases) according to whether DCI occurred 14 days after SAH (DCI usually occurs 4 to 14 d after bleeding). Baseline data, serum melatonin level, and TCD test results within 24 hours after admission were compared between the 2 groups. Multivariate logistic analysis was used to analyze the factors affecting the occurrence of DCI after SAH. The value of serum melatonin level, middle cerebral artery mean blood flow velocity (MBFV) and their combination in predicting DCI in SAH patients was evaluated. RESULTS: Univariate analysis showed that there were statistically significant differences in the proportion of Fisher grade, Hunt-Hess grade, serum melatonin level, middle cerebral artery systolic blood flow velocity (Vs), MBFV and pulse index (PI) between the 2 groups (P<0.05). Serum melatonin levels, middle cerebral artery Vs, MBFV, and PI in the DCI group were higher than those in non-DCI group. Logistic regression (LR) analysis showed that serum melatonin level (OR=1.796, 95% CI: 1.575-4.123) and middle cerebral artery MBFV (OR=3.279, 95% CI: 2.112-4.720] were the influencing factors for DCI in SAH patients (P<0.05). CONCLUSION: Middle cerebral artery MBFV and serum melatonin levels were higher in patients with SAH complicated with DCI, and the combination of the 2 could provide a reference for early clinical prediction of DCI in patients with aneurysmal subarachnoid hemorrhage (aSAH).

Promoting CO2 Electroreduction to Ethane by Iodide-Derived Copper with the Hydrophobic Surface.

Electrochemical reduction of CO2 to value-added products provides a feasible pathway for mitigating net carbon emissions and storing renewable energy. However, the low dimerization efficiency of the absorbed CO intermediate (*CO) and the competitive hydrogen evolution reaction hinder the selective electroreduction of CO2 to ethane (C2H6) with a high energy density. Here, we designed hydrophobic iodide-derived copper electrodes (I-Cu/Nafion) for reducing CO2 to C2H6. The Faradaic efficiency of C2H6 reached 23.37% at -0.7 V vs RHE over the I-Cu/Nafion electrode in an H-type cell, which was about 1.7 times higher than that of the I-Cu electrode. The hydrophobic properties of the I-Cu/Nafion electrodes led to an increase in the local CO2 concentration and stabilized the Cu+ species. In situ Raman characterizations and density functional theory calculations indicate that the enhanced performances could be ascribed to the strong *CO adsorption and decreased the formation energy of *COOH and *COCOH intermediates. This study highlights the effect of the hydrophobic surface on Cu-based catalysts in the electroreduction of CO2 and provides a promising way to adjust the selectivity of C2 products.

Graphene Quantum Dots Eradicate Resistant and Metastatic Cancer Cells by Enhanced Interfacial Inhibition.

Drug-resistant and metastatic cancer cells such as a small population of cancer stem cells (CSCs) play a crucial role in metastasis and relapse. Conventional small-molecule chemotherapeutics, however, are unable to eradicate drug-resistant CSCs owing to limited interface inhibitory effects. Herein, it is reported that enhanced interfacial inhibition leading to eradication of drug-resistant CSCs can be dramatically induced by self-insertion of bioactive graphene quantum dots (GQDs) into DNA major groove (MAG) sites in cancer cells. Since transcription factors regulate gene expression at the MAG site, MAG-targeted GQDs exert greatly enhanced interfacial inhibition, downregulating the expression of a collection of cancer stem genes such as ALDH1, Notch1, and Bmi1. Moreover, the nanoscale interface inhibition mechanism reverses cancer multidrug resistance (MDR) by inhibiting MDR1 gene expression when GQDs are used at a nontoxic concentration (1/4 × half-maximal inhibitory concentration (IC50)) as the MDR reverser. Given their high efficacy in interfacial inhibition, CSC-mediated migration, invasion, and metastasis of cancer cells can be substantially blocked by MAG-targeted GQDs, which can also be harnessed to sensitize clinical cytotoxic agents for improved efficacy in combination chemotherapy. These findings elucidate the inhibitory effects of the enhanced nano-bio interface at the MAG site on eradicating CSCs, thus preventing cancer metastasis and recurrence.

Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

BACKGROUND AND OBJECTIVES: Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. METHODS: Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. RESULTS: Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). DISCUSSION: OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.

Impact of sarcopenia in elderly patients undergoing elective total hip arthroplasty on postoperative outcomes: a propensity score-matched study.

OBJECTIVE: Frailty poses a crucial risk for postoperative complications in the elderly, with sarcopenia being a key component. The impact of sarcopenia on postoperative outcomes after total hip arthroplasty (THA) is still unclear. This study investigated the potential link between sarcopenia and postoperative outcomes among elderly THA patients. METHODS: Totally 198 older patients were enrolled in this study. Sarcopenia in this group was determined by assessing the skeletal muscle index, which was measured using computed tomography at the 12th thoracic vertebra and analyzed semi-automatically with MATLAB R2020a. Propensity score matching (PSM) was employed to evaluate postoperative complications of grade II and above (POCIIs). RESULTS: The variables balanced using PSM contained age, sex and comorbidities including hypertension, diabetes, hyperlipidemia and COPD. Before PSM, sarcopenic patients with reduced BMI (24.02 ± 0.24 vs. 27.11 ± 0.66, P < 0.001) showed higher POCIIs rates (48.31% vs. 15%, P = 0.009) and more walking-assisted discharge instances (85.96% vs. 60%, P = 0.017) compared with non-sarcopenia patients. After PSM, this group maintained reduced BMI (23.47 ± 0.85 vs. 27.11 ± 0.66, P = 0.002), with increased POCIIs rates (54.41% vs. 15%, P = 0.002) and heightened reliance on walking assistance at discharge (86.96% vs. 60%, P = 0.008). CONCLUSION: Sarcopenia patients exhibited a higher incidence of POCIIs and poorer physical function at discharge. Sarcopenia could serve as a valuable prognostic indicator for elderly patients undergoing elective THA.

Deciphering the importance of culture pH on CD22 CAR T-cells characteristics.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells have demonstrated significant efficacy in targeting hematological malignancies, and their use continues to expand. Despite substantial efforts spent on the optimization of protocols for CAR T-cell manufacturing, critical parameters of cell culture such as pH or oxygenation are rarely actively monitored during cGMP CAR T-cell generation. A comprehensive understanding of the role that these factors play in manufacturing may help in optimizing patient-specific CAR T-cell therapy with maximum benefits and minimal toxicity. METHODS: This retrospective study examined cell culture supernatants from the manufacture of CAR T-cells for 20 patients with B-cell malignancies enrolled in a phase 1/2 clinical trial of anti-CD22 CAR T-cells. MetaFLEX was used to measure supernatant pH, oxygenation, and metabolites, and a Bio-Plex assay was used to assess protein levels. Correlations were assessed between the pH of cell culture media throughout manufacturing and cell proliferation as well as clinical outcomes. Next-generation sequencing was conducted to examine gene expression profiles of the final CAR T-cell products. RESULTS: A pH level at the lower range of normal at the beginning of the manufacturing process significantly correlated with measures of T-cell expansion and metabolism. Stable or rising pH during the manufacturing process was associated with clinical response, whereas a drop in pH was associated with non-response. CONCLUSIONS: pH has potential to serve as an informative factor in predicting CAR T-cell quality and clinical outcomes. Thus, its active monitoring during manufacturing may ensure a more effective CAR T-cell product.

Impact of the COVID-19 pandemic on the demographic and disease burden of pediatric malignant solid tumors in China: a single-center, cross-sectional study.

Background: With the development of the novel coronavirus disease 2019 (COVID-19), China implemented measures in an attempt to control the infection rate. We conducted a single-center, cross-sectional study to ascertain the impact of the COVID-19 pandemic on the equitable availability of medical resources for children diagnosed with malignant solid tumors in China. Methods: Data on the demographics, clinical characteristics, and medical expenses of 876 patients diagnosed with neuroblastoma, rhabdomyosarcoma (RMS), Wilms tumor, hepatoblastoma (HB), Ewing sarcoma (ES), and central nervous system (CNS) tumors from 2019 to 2021, during the COVID-19 pandemic, were retrospectively collected from the National Center for Children's Health. The Pearson χ2 test and Mann-Whitney test were performed to analyze the differences among variables. Results: Except for the regional origin of children with tumors during the epidemic, no significant differences were found in the demographic or clinical characteristics of patients at initial diagnosis. The number of patients from northern China and northeastern China who attended Beijing Children's Hospital (BCH) increased after the outbreak of COVID-19 (P=0.001). There was no significant alteration observed in the frequency of hospitalizations per individual per annum (P=0.641) or the mean expense incurred per individual per hospitalization (P=0.361). In addition, the medical insurance coverage rate of real-time settlement increased year by year. Conclusions: After the COVID-19 outbreak, the origin of patients with solid tumor who visited BCH was concentrated in the northern region of China. COVID-19 had no impact on the other demographic factors, clinical characteristics, or economic burden of patients with pediatric malignant solid tumors.

Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

A nomogram prediction model of pseudomyxoma peritonei established based on new prognostic factors of HE stained pathological images analysis.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical malignant syndrome, and its rarity causes a lack of pathology research. This study aims to quantitatively analyze HE-stained pathological images (PIs), and develop a new predictive model integrating digital pathological parameters with clinical information. METHODS: Ninety-two PMP patients with complete clinic-pathological information, were included. QuPath was used for PIs quantitative feature analysis at tissue-, cell-, and nucleus-level. The correlations between overall survival (OS) and general clinicopathological characteristics, and PIs features were analyzed. A nomogram was established based on independent prognostic factors and evaluated. RESULTS: Among the 92 PMP patients, there were 34 (37.0%) females and 58 (63.0%) males, with a median age of 57 (range: 31-76). A total of 449 HE stained images were obtained for QuPath analysis, which extracted 40 pathological parameters at three levels. Kaplan-Meier survival analysis revealed eight clinicopathological characteristics and 20 PIs features significantly associated with OS (p < 0.05). Partial least squares regression was used to screen the multicollinearity features and synthesize four new features. Multivariate survival analysis identified the following five independent prognostic factors: preoperative CA199, completeness of cytoreduction, histopathological type, component one at tissue-level, and tumor nuclei circularity variance. A nomogram was established with internal validation C-index 0.795 and calibration plots indicating improved prediction performance. CONCLUSIONS: The quantitative analysis of HE-stained PIs could extract the new prognostic information on PMP. A nomogram established by five independent prognosticators is the first model integrating digital pathological information with clinical data for improved clinical outcome prediction.

Structures and bonding characteristics of KCl(H2O)n clusters with n = 1-10 based on density functional theory.

Aqueous inorganic salt solutions play a prominent role in both physiological and chemical experiments, and significant attention has been directed toward understanding the mechanisms underlying salt dissolution. In our effort to elucidate the hydration process of potassium chloride, we employed a comprehensive genetic algorithm to explore the structures of KCl(H2O)n (n = 1-10). A series of stable structures were identified by high-level ab initio optimization and single-point energy calculations with a zero-point energy correction. An analysis of the probability distribution of KCl(H2O)1-10 revealed that clusters with high probability at low temperatures exhibit reduced probabilities at higher temperatures, while others become more prevalent. When n = 1-9, the contact ion pair configurations or partially dissociated structures dominate in the system, and the probability distribution plot shows that the proportion of the solvent-separated ion pair (SSIP) structures of KCl(H2O)n is very small, while the SSIP configuration in KCl(H2O)10 becomes a stable structure with increasing temperature. The results from natural bond orbital analysis reveal a stronger interaction between chloride ions and water molecules. These findings provide valuable insights for a more comprehensive understanding of the intricacies of potassium chloride dissolution in water.

Clinical features, treatment strategies, and prognosis of epithelioid inflammatory myofibroblastic sarcoma in children: a multicenter experience.

Background: Inflammatory myofibroblastic tumors (IMTs) are a spectrum of tumors that range in morphology and biological behavior from benign, intermediate, to apparently malignant and epithelioid inflammatory myofibroblastic sarcoma (EIMS) is one of the malignant subtypes. This study tried to provide experience and new ideas for treating this rare disease. Methods: This study retrospectively analyzed and followed up 12 children with EIMS admitted to Beijing Children's Hospital, Baoding Children's Hospital, and Children's Hospital of Chongqing Medical University from August 2016 to May 2022. Results: Of the 12 children, 7 were male and 5 were female, with a median age of 74.50 [interquartile range (IQR), 61.50-90.00] months. Of these patients, eight had a single lesion and four had multiple lesions. The maximum diameter of the single tumor foci was 19.30 cm, the full meridian of the multiple tumor foci target lesions was 32.67 cm, and the median maximum tumor size was 11.99 (IQR, 7.80-15.70) cm. The site of disease was the abdominopelvic cavity in eight cases, the thoracic cavity in two cases, the maxillofacial region in one case, and the larynx in one case. The clinical manifestations were predominantly elevated body temperature (n=8). There was one case of ROS1 fusion mutation and nine cases of ALK fusion mutation. Of the 12 children, 6 were biopsied at the initial diagnosis and 6 were surgically treated. Follow-up treatment included preoperative neoadjuvant chemotherapy (n=4), peritoneal thermal perfusion therapy (n=2), targeted therapy (n=3), postoperative chemotherapy (n=5), and radiotherapy (n=3). The follow-up time was 14.50 (IQR, 10.50-31.50) months, with eight cases of tumor-free survival, two cases of death, and two cases of loss of follow-up. Conclusions: EIMS in children is extremely rare and clinically aggressive. The clinical presentation is nonspecific, and the initial diagnosis of the tumor is often large. Mutations in the ALK gene are common in EIMS. Surgery is the mainstay of EIMS treatment, and patients benefit from a multidisciplinary combination that includes targeted therapies, with long-term prognosis remaining subject to ongoing follow-up.

Two-dimensional fullerene-based monolayer materials assembled by C80 and Sc3N@C80.

Construction of two-dimensional (2D) materials using fullerenes as building blocks has attracted particular attention, primarily due to their ability to integrate desired functionalities into devices. However, realization of stable 2D phases of polymerized fullerenes remains a big challenge. Here, we propose two stable 2D monolayer phases with covalently bridged C80 cages, namely α-C80-2D and ß-C80-2D, which are semiconductors with strong absorption in the long wave range and appreciable carrier mobility, respectively. The high stability originates from the bond energy released by the [2+2] cycloaddition polymerization of C80 is greater than the deformation energy of a cage. Starting from α-C80-2D, endohedral incorporation of the Sc3N molecule into each C80 cage leads to 2D semiconductors of α-Sc3N@C80-2D and α'-Sc3N@C80-2D, which possess exceptional stability and diverse physical properties, including unique electronic band structures, strong optical absorption in the visible (VIS) to near-infrared (NIR) regime, and anisotropic optical characteristics. Remarkably, a temperature-induced order-disorder transition in the α-Sc3N@C80-2D phase has been observed at elevated temperatures above 600 K. These findings expand the family of 2D carbon materials and provide useful clue for the potential applications of fullerene-assembled monolayer networks.

Intratumoral CXCR4hi neutrophils display ferroptotic and immunosuppressive signatures in hepatoblastoma.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.

BACKGROUND & AIMS: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. METHODS: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. RESULTS: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss. CONCLUSIONS: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. CLINICALTRIALS: gov, Number: NCT05039450.

Unraveling the mechanism of norfloxacin removal and fate of antibiotics resistance genes (ARGs) in the sulfur-mediated autotrophic denitrification via metagenomic and metatranscriptomic analyses.

The co-contamination of antibiotics and nitrogen has attracted widespread concerns due to its potential harm to ecological safety and human health. Sulfur-driven autotrophic denitrification (SAD) with low sludge production rate was adopted to treat antibiotics laden-organic deficient wastewater. Herein, a lab-scale sequencing batch reactor (SBR) was established to explore the simultaneous removal of nitrate and antibiotics, i.e. Norfloxacin (NOR), as well as microbial response mechanism of SAD sludge system towards NOR exposure. About 80.78 % of NOR was removed by SAD sludge when the influent NOR level was 0.5 mg/L, in which biodegradation was dominant removal route. The nitrate removal efficiency decreased slightly from 98.37 ± 0.58 % to 96.58 ± 1.03 % in the presence of NOR. Thiobacillus and Sulfurimonas were the most abundant sulfur-oxidizing bacteria (SOB) in SAD system, but Thiobacillus was more sensitive to NOR. The up-regulated genes related to Xenobiotics biodegradation and metabolism and CYP450 indicated the occurrence of NOR biotransformation in SAD system. The resistance of SAD sludge to the exposure of NOR was mainly ascribed to antibiotic efflux. And the effect of antibiotic inactivation was enhanced after long-term fed with NOR. The NOR exposure resulted in the increased level of antibiotics resistance genes (ARGs) and mobile genetic elements (MGEs). Besides, the enhanced ARG-MGE co-existence patterns further reveals the higher horizontal mobility potential of ARGs under NOR exposure pressures. The most enriched sulfur oxidizing bacterium Thiobacillus was a potential host for most of ARGs. This study provides a new insight for the treatment of NOR-laden wastewater with low C/N ratio based on the sulfur-mediated biological process.

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition.

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

BACKGROUND: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. METHODS AND RESULTS: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. CONCLUSIONS: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.