CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Metabolomics of head and neck cancer in biofluids: an integrative systematic review.

INTRODUCTION: Head and neck cancer (HNC) is the fifth most common cancer globally. Diagnosis at early stages are critical to reduce mortality and improve functional and esthetic outcomes associated with HNC. Metabolomics is a promising approach for discovery of biomarkers and metabolic pathways for risk assessment and early detection of HNC. OBJECTIVES: To summarize and consolidate the available evidence on metabolomics and HNC in plasma/serum, saliva, and urine. METHODS: A systematic search of experimental research was executed using PubMed and Web of Science. Available data on areas under the curve was extracted. Metabolic pathway enrichment analysis were performed to identify metabolic pathways altered in HNC. Fifty-four studies were eligible for data extraction (33 performed in plasma/serum, 15 in saliva and 6 in urine). RESULTS: Metabolites with high discriminatory performance for detection of HNC included single metabolites and combination panels of several lysoPCs, pyroglutamate, glutamic acid, glucose, tartronic acid, arachidonic acid, norvaline, linoleic acid, propionate, acetone, acetate, choline, glutamate and others. The glucose-alanine cycle and the urea cycle were the most altered pathways in HNC, among other pathways (i.e. gluconeogenesis, glycine and serine metabolism, alanine metabolism, etc.). Specific metabolites that can potentially serve as complementary less- or non-invasive biomarkers, as well as metabolic pathways integrating the data from the available studies, are presented. CONCLUSION: The present work highlights utility of metabolite-based biomarkers for risk assessment, early detection, and prognostication of HNC, as well as facilitates incorporation of available metabolomics studies into multi-omics data integration and big data analytics for personalized health.

Comparison of two treatments for atlantoaxial instability injury: C1-C2 transarticular screw fixation versus C1 lateral mass-C2 pedicle screw fixation.

Objective: This study evaluated the effectiveness and safety of C1-C2 transarticular screw fixation (transarticular screw fixation com-bined with bone grafting) and C1 lateral mass-C2 pedicle screw fixation (modified Harms technique) in patients with C1-C2 instability. Materials and methods: This prospective, self-controlled, single-center study evaluated two fixation techniques for the treatment of atlantoaxial instability injury. From June 2006 to February 2017, 118 patients were admitted to our hospital because of atlantoaxial instability injury. These patients were divided into two groups: group 1, including 52 patients who underwent C1-C2 transarticular screw fixation (C1C2-TAS group), and group 2, including 66 patients who underwent C1 lateral mass-C2 pedicle screw fixation (C1LM-C2PS group). Results: There were significant differences in the operation time, blood loss amount, and hospital stay length between the groups (p<0.001). The mean operation time (78.94 vs. 110.91 min; p=0.0003) and hospital stay length (5.31 vs. 8.34 days; p=0.0003) were shorter, and the mean blood loss amount during surgery (122.31 vs. 258.33 mL; p<0.0001) was smaller in the C1C2-TAS group than in the C1LM-C2PS group. The surgical complication rate was low and no vertebral artery injury was observed. After surgery, the clinical presentations were significantly reduced in both groups. The patients showed sati-sfactory internal fixation on postoperative radiography and computed tomography. Conclusion: Both C1-C2 transarticular screw fixation and C1 lateral mass-C2 pedicle screw fixation are effective and safe in treat-ing atlantoaxial instability injury. Notably, C1-C2 transarticular screw fixation yields a shorter operation time and hospital stay length and a smaller intraoperative blood loss amount than does C1 lateral mass-C2 pedicle screw fixation.

Spontaneous pregnancies post-microsurgical varicocelectomy in infertile men with severe oligozoospermia: a preliminary vietnamese report.

Background: This study evaluated whether microsurgical varico-celectomy performed in infertile men with severe oligozoospermia (SO) resulted in improved semen parameters or increased rates of spontaneous pregnancy (SP) and performed a cost-effectiveness analysis comparing intrauterine insemination (IUI), in vitro fertilization (IVF), and varicocelectomy. Methods: This study included 25 patients with SO who underwent microsurgical varicocelectomy between September 2019 and May 2022, which resulted in post-surgical SP in all cases. Men with azoospermia, abnormal karyotype, or Y-chromosome microdeletion were excluded from the study. Serum luteinizing, follicle-stimulating, and testosterone hormones were measured preoperatively. Semen was analyzed every 3 months postoperation. The incidence of SP was recorded at each visit. Cost-effectiveness for assisted reproductive technologies was calculated based on reported costs. Several parameters were evaluated as potential predictors of the response to microsurgical varicocelectomy using univariate and multivariate analyses. Results: After a mean postoperative observation period of 7 months, 25 couples with SP after microsurgical varicocelectomy were recruited. The mean sperm concentration increased from 3 million/mL (interquartile range [IQR]: 2-5 million/mL) to 12 million/mL (IQR: 5-17 million/mL; p<0.05), and mean sperm motility improved from 4% (IQR: 3%-6%) to 7.6% (p<0.05). Total motile sperm count (TMSC) increased to 3.08 million (IQR: 1.02-5.83 million) from a preoperative value of 0.34 million (IQR: 0.16-0.83 million). A cost-effectiveness analysis comparing IVF with varicocelectomy indicates that varicocelectomy may represent a better first-line option for infertile men with very low preoperative TMSC. However, further research remains necessary to confirm this result. Conclusion: Varicocelectomy should be discussed as a treatment option for men with SO and may improve sperm quality and fertility potential, resulting in SP.

A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models.

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

Tumour microbiomes and Fusobacterium genomics in Vietnamese colorectal cancer patients.

Perturbations in the gut microbiome have been associated with colorectal cancer (CRC), with the colonic overabundance of Fusobacterium nucleatum shown as the most consistent marker. Despite its significance in the promotion of CRC, genomic studies of Fusobacterium is limited. We enrolled 43 Vietnamese CRC patients and 25 participants with non-cancerous colorectal polyps to study the colonic microbiomes and genomic diversity of Fusobacterium in this population, using a combination of 16S rRNA gene profiling, anaerobic microbiology, and whole genome analysis. Oral bacteria, including F. nucleatum and Leptotrichia, were significantly more abundant in the tumour microbiomes. We obtained 53 Fusobacterium genomes, representing 26 strains, from the saliva, tumour and non-tumour tissues of six CRC patients. Isolates from the gut belonged to diverse F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and a potential new subspecies of Fusobacterium periodonticum. The Fusobacterium population within each individual was distinct and in some cases diverse, with minimal intra-clonal variation. Phylogenetic analyses showed that within four individuals, tumour-associated Fusobacterium were clonal to those isolated from non-tumour tissues. Genes encoding major virulence factors (Fap2 and RadD) showed evidence of horizontal gene transfer. Our work provides a framework to understand the genomic diversity of Fusobacterium within the CRC patients, which can be exploited for the development of CRC diagnostic and therapeutic options targeting this oncobacterium.

Panels of circulating microRNAs as potential diagnostic biomarkers for breast cancer: a systematic review and meta-analysis.

PURPOSE: Circulating microRNAs (miRNAs) are potential diagnostic biomarkers for breast cancer (BC). The application of miRNA panels could improve the performance of screening tests. Here, we integrated bioinformatic tools and meta-analyses to select circulating miRNAs with high diagnostic accuracy and combined these markers to develop diagnostic panels for BC. METHODS: Analyses across databases were performed to identify potential BC-related circulating miRNAs. Next, a comprehensive meta-analysis was conducted for each miRNA following the PRISMA guidelines. An electronic and manual search for relevant literature was carried out by two reviewers through PubMed, ScienceDirect, Biomed Central, and Google Scholar. The quality of the included studies was assessed using the QUADAS-2, and the statistical analyses were performed using R software 4.1.1. Finally, the accurate biomarkers confirmed through meta-analyses were combined into diagnostic models for BC. RESULTS: Twenty-seven circulating miRNAs were identified as BC-related by bioinformatic tools. After screening, only 10 miRNAs presented in 45 studies were eligible for meta-analyses. By assessing pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, 8 miRNAs (miR-21, miR-30b, miR-125b, miR-145, miR221 miR-222, and miR-335) were revealed as promising BC diagnostic biomarkers. Two panels constructed from these miRNAs showed excellent diagnostic accuracy for BC, with areas under the SROC curve of 0.917 and 0.944. CONCLUSION: We identified 8 potential circulating miRNAs and 2 diagnostic models that are useful for diagnosing BC. However, the established miRNA panels have not been tested in any experimental studies and thus should be validated in large case-control studies for clinical use.

Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme.

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.

[miRNA-16 AS an Internal Control in Breast Cancer Studies: A Systematic Review and Meta-analysis].

Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) is a method of choice for quantifying micro RNAs (miRNAs). Typically, RT-qPCR data are normalized to reference genes. While miRNAs are used for diagnosing and subtyping breast cancer, various studies show their deregulation in this condition, thus, undermining miRNAs' utility as a reference. This review examines the expression pattern of miR-16 and suggests normalization approaches for breast cancer. We analyzed the data from selected peer-reviewed studies to calculate the standardized mean difference (SMD) with subsequent Chi-square testing and identified the difference in miR-16 expression between breast cancer patients and healthy controls. With a negative SMD value of-0.56 and Chi-square of 62.62 (p-value = 0.05), the deregulation of miR-16 in breast cancer was confirmed. High variance in the stability value (SV) of miR-16 expression levels confirmed its inappropriateness as a control gene in breast cancer. The combination of miR-16 and miR-425 was confirmed as an accurate endogenous control.

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.

Patients requiring pediatric palliative care for advanced heart disease in France: A descriptive study.

INTRODUCTION: Pediatric palliative care (PPC) teams address unmet needs and improve the quality of life of patients with life-limiting conditions across pediatric subspecialties. However, little is known about the timing, reasons, and nature of PPC team interventions in advanced heart diseases (AHD). OBJECTIVES: Here we describe how, when, and why PPC teams interact with referred teams of children suffering from AHD. METHODS: We conducted a retrospective nationwide survey among PPC teams in France. All patients referred to participating PPC teams for a cardiologic disease in 2019 were studied. RESULTS: Among six PPC teams, 18 patients with AHD had a PPC consultation in 2019. Six of these patients had cardiomyopathy and 12 had congenital heart disease (CHD). The median age at referral was 0.9 months for CHD and 72 months for cardiomyopathy. An antenatal diagnosis had been made for six families with CHD, and two of them were referred to PPC before birth allowing for a prenatal palliative care plan. The main reason for referral was ethical considerations (50%) followed by organization for home-based palliative care (28%). PPC teams participated in ethical discussions when asked to but also provided family support (12/18), home-based PPC (9/18), coordination of care (5/18), support of the referred team (4/18), and symptoms management (3/18) CONCLUSION: The main reason for referral to PPC was ethical considerations, but PPC interventions followed a holistic model of care. Prospective outcomes measurement and partnerships should be further developed.

Efficacy of Topical Herbal Anti-inflammatory Treatment (HAT1) for Treating Psoriasis: An Investigator-Initiated Open Label Study.

Atopical botanical complex from a novel combination of phytochemicals, denoted as herbal anti-inflammatory treatment 1 (HAT1), was developed for topical treatment of psoriasis.

Admission screening and cohort care decrease carbapenem resistant enterobacteriaceae in Vietnamese pediatric ICU's.

OBJECTIVES: To assess if admission screening for Carbapenem Resistant Enterobacteriaceae (CRE) and cohort care can reduce CRE acquisition (CRE colonization during hospital stay), Hospital Acquired Infections (HAI), hospital-stay, mortality, and costs in three Intensive Care Units (ICU's) at the Vietnamese National Children's Hospital. METHOD: CRE screening using rectal swabs and ChromIDCarbas elective culture at admission and if CRE negative, once weekly. Patients were treated in cohorts based on CRE colonization status. RESULTS: CRE colonization at baseline point-prevalence screening was 76.9% (103/134). Of 941 CRE screened at admission, 337 (35.8%) were CREpos. 694 patients met inclusion criteria. The 244 patients CRE negative at admission and screened > 2 times were stratified in 8 similar size groups (periods), based on time of admission. CRE acquisition decreased significant (OR - 3.2, p < 0.005) from 90% in period 2 (highest) to 48% in period 8 (last period). Patients with CRE acquisition compared to no CRE acquisition had a significantly higher rate of culture confirmed HAI, n = 20 (14%) vs. n = 2 (2%), longer hospital stays, 3.26 vs. 2.37 weeks, and higher total treatment costs, 2852 vs. 2295 USD. CONCLUSION: Admission CRE screening and cohort care in pediatric ICU's significantly decreased CRE acquisition, cases of HAI and duration of hospital-stay.

Antibacterial activity of Hibiscus rosa-sinensis L. red flower against antibiotic-resistant strains of Helicobacter pylori and identification of the flower constituents.

Utilization of plant resources for treatment of Helicobacter pylori infections is one of the appealing approaches as rapid emergence of antibiotic-resistant strains is occurring throughout the world. Ethanol extract and its fractions from Hibiscus rosa-sinensis red flower were assessed for antibacterial and urease inhibitory activities towards forty-three clinical strains and two reference strains of H. pylori. The ethyl acetate fraction exhibited the most potent bacteriostatic activity with minimum inhibitory concentrations (MICs) of 0.2-0.25 mg/mL and minimum bactericidal concentrations (MBCs) of 1.25-1.5 mg/mL against all test strains, including forty-three strains resistant to one to four antibiotics, azithromycin (MICs, 8-256 µg/mL), erythromycin (MICs, 8-128 µg/mL), levofloxacin (MICs, 8-256 µg/mL), and/or metronidazole (MICs, 8-256 µg/mL). The fraction had similar antibacterial activities toward these test strains suggesting the preparation and the antibiotics do not have a common mechanism of anti-H. pylori activity. The fraction also had stronger effects on biofilm formation, morphological conversion, and urease activity of H. pylori than the other fractions and the ethanol extract. These flower preparations were non-toxic to three human cell lines, and nine compounds were also isolated and identified from the ethyl acetate fraction. In vivo research needs to be conducted to confirm the potential usefulness of H. rosa-sinensis flower and its constituents for effective prevention and treatment of H. pylori disease.

Antibacterial activity of Hibiscus rosa-sinensis L. red flower against antibiotic-resistant strains of Helicobacter pylori and identification of the flower constituents

Utilization of plant resources for treatment of Helicobacter pylori infections is one of the appealing approaches as rapid emergence of antibiotic-resistant strains is occurring throughout the world. Ethanol extract and its fractions from Hibiscus rosa-sinensis red flower were assessed for antibacterial and urease inhibitory activities towards forty-three clinical strains and two reference strains of H. pylori. The ethyl acetate fraction exhibited the most potent bacteriostatic activity with minimum inhibitory concentrations (MICs) of 0.2-0.25 mg/mL and minimum bactericidal concentrations (MBCs) of 1.25-1.5 mg/mL against all test strains, including forty-three strains resistant to one to four antibiotics, azithromycin (MICs, 8-256 µg/mL), erythromycin (MICs, 8-128 µg/mL), levofloxacin (MICs, 8-256 µg/mL), and/or metronidazole (MICs, 8-256 µg/mL). The fraction had similar antibacterial activities toward these test strains suggesting the preparation and the antibiotics do not have a common mechanism of anti-H. pylori activity. The fraction also had stronger effects on biofilm formation, morphological conversion, and urease activity of H. pylori than the other fractions and the ethanol extract. These flower preparations were non-toxic to three human cell lines, and nine compounds were also isolated and identified from the ethyl acetate fraction. In vivo research needs to be conducted to confirm the potential usefulness of H. rosa-sinensis flower and its constituents for effective prevention and treatment of H. pylori disease.

Variations in Antimicrobial Activities of Human Monocyte-Derived Macrophage and Their Associations With Tuberculosis Clinical Manifestations.

Macrophages play a significant role in preventing infection through antimicrobial activities, particularly acidification, and proteolysis. Mycobacterium tuberculosis (Mtb) infection can lead to diverse outcomes, from latent asymptomatic infection to active disease involving multiple organs. Monocyte-derived macrophage is one of the main cell types accumulating in lungs following Mtb infection. The variation of intracellular activities of monocyte-derived macrophages in humans and the influence of these activities on the tuberculosis (TB) spectrum are not well understood. By exploiting ligand-specific bead-based assays, we investigated macrophage antimicrobial activities real-time in healthy volunteers (n = 53) with 35 cases of latent TB (LTB), and those with active TB (ATB), and either pulmonary TB (PTB, n = 70) or TB meningitis (TBM, n = 77). We found wide person-to-person variations in acidification and proteolytic activities in response to both non-immunogenic IgG and pathogenic ligands comprising trehalose 6,6'-dimycolate (TDM) from Mtb or ß-glucan from Saccharamyces cerevisiase. The variation in the macrophage activities remained similar regardless of stimuli; however, IgG induced stronger acidification activity than immunogenic ligands TDM (P = 10-5, 3 × 10-5 and 0.01 at 30, 60, and 90 min) and ß-glucan (P = 10-4, 3 × 10-4 and 0.04 at 30, 60, and 90 min). Variation in proteolysis activity was slightly higher in LTB than in ATB (CV = 40% in LTB vs. 29% in ATB, P = 0.03). There was no difference in measured antimicrobial activities in response to TDM and bacterial killing in macrophages from LTB and ATB, or from PTB and TBM. Our results indicate that antimicrobial activities of monocyte-derived macrophages vary among individuals and show immunological dependence, but suggest these activities cannot be solely responsible for the control of bacterial replication or dissemination in TB.