Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy.

This was a single-arm, multicenter, open-label phase I trial. Lentiviral vectors (LV) carrying the ABCD1 gene (LV-ABCD1) was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy (CCALD), and multi-site injection was performed. The injection dose increased from 200 to 1600 µL (vector titer: 1×109 TU/mL), and the average dose per kilogram body weight ranges from 8 to 63.6 µL/kg. The primary endpoint was safety, dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein. A total of 7 patients participated in this phase I study and were followed for 1 year. No injection-related serious adverse event or death occurred. Common adverse events associated with the injection were irritability (71%, 5/7) and fever (37.2 â„ƒ-38.5 â„ƒ, 57%, 4/7). Adverse events were mild and self-limited, or resolved within 3 d of symptomatic treatment. The maximal tolerable dose is 1600 µL. In 5 cases (83.3%, 5/6), no lentivirus associated antibodies were detected. The overall survival at 1-year was 100%. The ABCD1 protein expression was detected in neutrophils, monocytes and lymphocytes. This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo; even the maximal dose did not increase the risk of adverse events. Furthermore, the direct LV-ABCD1 injection displayed low immunogenicity. In addition, the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed. This study has been registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, registration number: ChiCTR1900026649).

Analysis of the pharmacokinetics and efficacy of RBD1016 - A GalNAc-siRNA targeting Hepatitis B Virus X gene using semi-mechanistic PK/PD model.

Small interference RNA (siRNA) is a class of short double-stranded RNA molecules that cause mRNA degradation through an RNA interference mechanism and is a promising therapeutic modality. RBD1016 is a siRNA drug in clinical development for the treatment of chronic Hepatitis B Virus (HBV) infection, which contains a conjugated with N-acetylglucosamine moiety that can facilitate its hepatic delivery. We aimed to construct a semi-mechanistic model of RBD1016 in pre-clinical animals, to elucidate the pharmacokinetic/pharmacodynamic (PK/PD) profiles in mice and PK profiles in monkeys, which can lay the foundation for potential future translation of RBD1016 PK and PD from the pre-clinical stage to the clinic stage. The proposed semi-mechanistic PK/PD model fitted PK and PD data in HBV transgenic mice well and described plasma and liver concentrations in the monkeys well. The simulation results showed that our model has a reasonable predictive ability for Hepatitis B surface antigen (HBsAg) levels after multiple dosing in mice. Further PK and PD data for RBD1016, including clinical data, will assist in refining the model presented here. Our current effort focused on model building for RBD1016, we anticipate that the model could apply to other GalNAc-siRNA drugs.

Plexiform fibrohistiocytic tumor: A series of 10 case studies.

OBJECTIVES: We sought to investigate the clinicopathologic features and differential diagnosis of plexiform fibrohistiocytic tumor (PFHT) and its pathogenesis. METHODS: Ten cases of PFHT were collected from Xi Jing Hospital, Fourth Military Medical University, from September 2008 to December 2022 for clinical data as well as microscopic and immunohistochemical observation. CCND1 gene amplification and break were assayed by fluorescence in situ hybridization (FISH). RESULTS: We report 10 cases of PFHT according to histologic classification. Seven cases were of histiocytoid type, and 3 had mucous degeneration in the nodules. One case was of fibroblastic type, which was mainly composed of fibroblast-like cells. Two cases were of mixed type. Immunohistochemically, the osteoclast-like multinucleated giant cells, histiocyte-like cells, and occasional spindle cells in the adjacent fascicles were reactive for CD68 (10/10), CD163 (5/8), CD10 (8/8), cyclin D1 (8/8), CDK4 (5/8), ß-catenin (4/6), MITF (2/6), and PGP9.5 (4/5). Vimentin (9/9) was strongly positive in tumor cells and peripheral fibroblast-like cells. The positive index of Ki-67 was 5% to 40%, with an average of 20%. The FISH analysis showed neither amplification nor break of the CCND1 gene. All cases underwent surgical resection, and patients were followed up for 9 months to 11 years. Only 2 cases recurred. CONCLUSIONS: Plexiform fibrohistiocytic tumor is a low-grade malignant soft tissue neoplasm. The diagnosis mainly depends on histopathologic and immunohistochemical markers. Cyclin D1 and CD10 expression has diagnostic value for the diagnosis and differential diagnosis of PFHT combined with its plexiform morphology. The overexpression of cyclin D1 suggests an involvement of cell cycle regulatory genes in the pathogenesis of PFHT.

Ultrasound manifestations of primary intestinal non-Hodgkin lymphoma with liver metastasis in a child.

Non-Hodgkin lymphoma (NHL) is a highly aggressive malignant tumor arising in lymph nodes or extra-nodal lymphoid tissues, with an incidence of 8.3 per million. It accounts for approximately 7% of childhood and adolescent malignancies, second only to leukemia and brain tumors. Despite the gastrointestinal tract being the most common extra-nodal site involved by lymphoma, primary intestinal lymphoma (PIL) is rare and typically affects middle-aged men without specific clinical symptoms. Here, we present the case of a 2-year-old child indicative of PIL with the informed consent of the parents.

Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study.

BACKGROUND: Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. METHODS: Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. RESULTS: From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1-77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6-14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3-83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3-4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5-1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. CONCLUSIONS: Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03781219.

Gender-Driven English Speech Emotion Recognition with Genetic Algorithm.

Speech emotion recognition based on gender holds great importance for achieving more accurate, personalized, and empathetic interactions in technology, healthcare, psychology, and social sciences. In this paper, we present a novel gender-emotion model. First, gender and emotion features were extracted from voice signals to lay the foundation for our recognition model. Second, a genetic algorithm (GA) processed high-dimensional features, and the Fisher score was used for evaluation. Third, features were ranked by their importance, and the GA was improved through novel crossover and mutation methods based on feature importance, to improve the recognition accuracy. Finally, the proposed algorithm was compared with state-of-the-art algorithms on four common English datasets using support vector machines (SVM), and it demonstrated superior performance in accuracy, precision, recall, F1-score, the number of selected features, and running time. The proposed algorithm faced challenges in distinguishing between neutral, sad, and fearful emotions, due to subtle vocal differences, overlapping pitch and tone variability, and similar prosodic features. Notably, the primary features for gender-based differentiation mainly involved mel frequency cepstral coefficients (MFCC) and log MFCC.

Solid-State Synthesis of Na4Fe3(PO4)2P2O7/C by Ti-Doping with Promoted Structural Reversibility for Long-Cycling Sodium-Ion Batteries.

The cathode material Na4Fe3(PO4)2P2O7 (NFPP) has shown great potential for sodium-ion batteries (SIBs) due to its cost-effectiveness, prolonged cycle life, and high theoretical capacity. However, the practical large-scale production of NFPP is hindered by its poor intrinsic electron conductivity and the presence of a NaFePO4 impurity. In this study, we propose a mutually reinforcing approach involving Ti doping, mechanical nano treatment, and in situ carbon coating to produce Ti-NFPP via the solid-state methods of synthesis. Ti doping strengthens the covalent Fe-O interaction, hence accelerating the electron transfer and the redox reactions Fe2+/Fe3+. In situ carbon coating improves electrical conductivity and allows for accommodating the volumetric variation. Nanosized treatment promotes the uniform progression of solid-state reactions. The synthesized Na4Fe2.98Ti0.01(PO4)2P2O7 material (Ti-NFPP) exhibits promising electrochemical properties with an initial discharge specific capacity of 112.5 mA h g-1 at 0.1 C. A volumetric change of only 2.98% was observed during the de/sodiation process, indicating an enhanced reversibility of the crystal lattice. Moreover, it demonstrates exceptional cycling stability with a capacity retention rate of 97.2 mA h g-1 at 10 C over 5000 cycles. These findings offer a promising pathway for the large-scale production of Ti-NFPP in SIBs.

Cerium oxide /Co-Co Prussian blue analogue composite catalyst for enhanced peroxymonosulfate activation for effective removal of tetracycline hydrochloride from water.

In this paper, a novel CeO2/Co3[Co(CN)6]2 (CeO2/PBACo-Co) composite was prepared with co-precipitation and utilized to activate peroxymonosulfate (PMS) to eliminate tetracycline hydrochloride (TCH). Catalyst screening showed that the composite with a CeO2:PBACo-Co mass ratio of 1:5 (namely, 0.2-CeO2/PBACo-Co) had the best performance. The degradation efficiency of TCH in 0.2-CeO2/PBACo-Co/Oxone system was investigated. The experimental results illustrated that 98% of 50 mg/L TCH and 48.5% of TOC were degraded by 50 mg/L 0.2-CeO2/PBACo-Co and 400 mg/L Oxone within 120 min at 25 °C and initial pH 5.3. Recycling studies showed that the elimination rate of TCH can still achieve 85.8% after five cycles, suggesting that 0.2-CeO2/PBACo-Co composite processes good reusability. Trapping experiments and EPR tests revealed that the reaction system produced multiple active species (1O2, O2•-, SO4•-, and •OH). We proposed the catalytic mechanism of 0.2-CeO2/PBACo-Co for PMS activation, which mainly involves the promoted Co3+/Co2+ cycle by Ce3+ donated electrons. These results indicate that CeO2/PBACo-Co composite is an effective catalyst for wastewater remediation.

Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Ordered porous Mn - Co spinel oxide (CoMn2O4) with vacancies modulation as efficient electrocatalyst for Li - O2 battery.

Nonaqueous Li - O2 battery (LOB) is considered one of the most promising energy storage system due to its ultrahigh theoretical specific capacity (3500 Wh kg-1). Introducing vacancies in CoMn2O4 catalysts is regarded as an effective strategy to enhance the electrochemical performances of LOB. However, the relation between vacancy types in CoMn2O4 and catalytic performances in the LOB remains ambiguous. Herein, ordered porous CoMn2O4 with oxygen and metal vacancies is obtained via solvothermal reaction followed by temperature-controlled calcination using polystyrene spheres as templates. The increase in treatment temperature reduces the content of oxygen vacancies while increasing that of the metal vacancies. Notably, experimental results and theoretical calculations show that oxygen vacancies in CoMn2O4 have a greater influence than metal vacancies in modulating the LiO2 adsorption during the reaction processes and reducing the overpotential. CoMn2O4 synthesized at 500 ℃ (CoMnO-500) with higher oxygen vacancies exhibits stronger adsorption onto the LiO2, facilitating the formation of film-like Li2O2. Therefore, an LOB with the CoMnO-500 catalyst presents the lowest overpotential of 1.2 V and longest cycle lifespan of 286 cycles at a current density of 200 mA g-1. This study offers insights into the effect of CoMn2O4 vacancies on the formation pathway of Li2O2 discharge products.

Synthesis and Neuroprotective Evaluation of Substituted Indanone/Benzofuranone and Piperidine Hybrids.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

An Outbreak of Serogroup Y Meningococcal Meningitis in a Private Secondary Vocational School - Guangzhou City, Guangdong Province, China, 2023.

What is already known about this topic?: The inclusion of meningococcal vaccines in the National Immunization Program (NIP) over several years has significantly reduced the incidence of meningococcal meningitis in China to historic lows. Worldwide, there has been a diversification of meningococcal serogroups, leading to a shift in dominant serogroups in China from serogroup A to serogroups C and B, accompanied by a rise in reports of serogroups Y and W. What is added by this report?: An outbreak of serogroup Y Neisseria meningitidis (Nm) in a secondary vocational school involved a single confirmed severe case and 24 individuals with laboratory-confirmed Nm carriage. Epidemiological investigation revealed that the outbreak was localized to the classroom of the confirmed case. Prolonged close contact within a confined space was identified as a significant risk factor for Nm transmission. The genotype sequence identified was type 1655 (ST-1655), which is categorized under clonal complex 23 (CC-23) and bears resemblance to 8 previously confirmed cases of serogroup Y meningococcal meningitis within Guangdong Province. This suggests that serogroup Y infections continue to sporadically emerge and have become prevalent strains. What are the implications for public health practice?: This outbreak underscores the critical need to enhance surveillance of meningococcal serogroups and population carrier, and advocate for vaccination with MenY-containing vaccines.

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

Characterizing Infections in Two Epidemic Waves of SARS-CoV-2 Omicron Variants: A Cohort Study in Guangzhou, China.

BACKGROUND: After the adjustment of COVID-19 epidemic policy, mainland China experienced two consecutive waves of Omicron variants within a seven-month period. In Guangzhou city, as one of the most populous regions, the viral infection characteristics, molecular epidemiology, and the dynamic of population immunity are still elusive. METHODS: We launched a prospective cohort study in the Guangdong Provincial CDC from December 2022 to July 2023. Fifty participants who received the same vaccination regimen and had no previous infection were recruited. RESULTS: 90% of individuals were infected with Omicron BA.5* variants within three weeks in the first wave. Thirteen cases (28.26%) experienced infection with XBB.1* variants, occurring from 14 weeks to 21 weeks after the first wave. BA.5* infections exhibited higher viral loads in nasopharyngeal sites compared to oropharyngeal sites. Compared to BA.5* infections, the XBB.1* infections had significantly milder clinical symptoms, lower viral loads, and shorter durations of virus positivity. The infection with the BA.5* variant elicited varying levels of neutralizing antibodies against XBB.1* among different individuals, even with similar levels of BA.5* antibodies. The level of neutralizing antibodies specific to XBB.1* determined the risk of reinfection. CONCLUSIONS: The rapid large-scale infections of the Omicron variants have quickly established herd immunity among the population in mainland China. In the future of the COVID-19 epidemic, a lower infection rate but a longer duration can be expected. Given the large population size and ongoing diversified herd immunity, it remains crucial to closely monitor the molecular epidemiology of SARS-CoV-2 for the emergence of new variants of concern in this region. Additionally, the timely evaluation of the immune status across different age groups is essential for informing future vaccination strategies and intervention policies.

Gel polymer electrolytes for rechargeable batteries toward wide-temperature applications.

Rechargeable batteries, typically represented by lithium-ion batteries, have taken a huge leap in energy density over the last two decades. However, they still face material/chemical challenges in ensuring safety and long service life at temperatures beyond the optimum range, primarily due to the chemical/electrochemical instabilities of conventional liquid electrolytes against aggressive electrode reactions and temperature variation. In this regard, a gel polymer electrolyte (GPE) with its liquid components immobilized and stabilized by a solid matrix, capable of retaining almost all the advantageous natures of the liquid electrolytes and circumventing the interfacial issues that exist in the all-solid-state electrolytes, is of great significance to realize rechargeable batteries with extended working temperature range. We begin this review with the main challenges faced in the development of GPEs, based on extensive literature research and our practical experience. Then, a significant section is dedicated to the requirements and design principles of GPEs for wide-temperature applications, with special attention paid to the feasibility, cost, and environmental impact. Next, the research progress of GPEs is thoroughly reviewed according to the strategies applied. In the end, we outline some prospects of GPEs related to innovations in material sciences, advanced characterizations, artificial intelligence, and environmental impact analysis, hoping to spark new research activities that ultimately bring us a step closer to realizing wide-temperature rechargeable batteries.

Pulmonary artery dissection secondary to ventricular septal defect and pulmonary valve stenosis.

The aortic short axis view demonstrated the widening of the pulmonary artery and the membrane-like echo in the pulmonary artery divided it into true lumen and false lumen. And the flow of the ruptured openings on the band-like echo was clearly revealed by Color Doppler.

Myxoma with rich blood supply in the left atrium.

Cardiac myxoma is the most common primary benign cardiac tumors, mostly found in the left atrium. It was previously reported that the main component of myxoma was myxoid stroma riched in acid-mucopolysaccharide, the blood vessels in which were sparsely distributed, being characterized as hypovascular tumor by contrast echocardiography (CE) and computed tomography angiography (CTA). There are few reports of myxoma with rich blood supply and we report one in the left atrium.

Contribution of Matrix Metalloproteinase-2 Genotypes to Taiwan Pterygium Risk.

BACKGROUND/AIM: In the literature, the studies about the role of matrix metalloproteinase-2 (MMP-2) in pterygium diagnosis are mainly based on its protein expression. The role of MMP-2 variants has never been examined. The aim of this study was to examine the association of MMP-2 genotypes with pterygium risk. MATERIALS AND METHODS: MMP-2 rs243865 and rs2285053 were genotyped in 140 pterygium cases and 280 non-pterygium controls by typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping technology. RESULTS: The genotypic frequency of MMP-2 rs243865 CC, CT and TT were 86.4%, 12.9% and 0.7% in the pterygium group and 81.1%, 17.1% and 1.8% in the non-pterygium group (p for trend=0.3389). The variant CT and TT carriers had a 0.70- and 0.38-fold pterygium risk (95%CI=0.39-1.26 and 0.04-3.25, p=0.2982 and 0.6686, respectively). As for MMP-2 rs2285053, the genotypic frequency of CC, CT and TT were 67.1%, 28.6% and 4.3% in the pterygium group, non-significantly different from those in non-pterygium group (p for trend=0.7081). The CT and TT carriers had a 0.88- and 0.71-fold pterygium risk (95%CI=0.56-1.38 and 0.27-1.88, p=0.6612 and 0.6456, respectively). The allelic analysis results showed that MMP-2 rs243865 variant T allele was not associated with pterygium risk (7.1% versus 10.4%, OR=0.67, 95%CI=0.39-1.13, p=0.1649). As for MMP-2 rs2285053, the T allele was not associated with pterygium risk either (18.6% versus 21.1%, OR=0.85, 95%CI=0.59-1.23, p=0.4136). CONCLUSION: The genotypes at MMP-2 rs243865 or rs2285053 played minor role in determining individual susceptibility for pterygium among Taiwanese.