490 BioTech (United States)

<sec><title>OBJECTIVE</title>Poor sustained sputum culture conversion with guidelines-based therapy for Mycobacterium avium complex lung disease highlights the need for new and improved multidrug combinations.</sec><sec><title>DESIGN</title>We tested eight drugs by performing minimum inhibitory concentration (MIC) experiments with the ATCC#700898 strain and 49 clinical isolates, followed by single and multidrug combination studies.</sec><sec><title>RESULTS</title>MIC90 of rifabutin, rifampin, azithromycin, and ethambutol were 4, 16, 256, and 128 mg/L, respectively. Among other drugs, MIC90 (mg/L) in lowest to highest rank order were for bedaquiline (0.25), tedizolid (16), tebipenem (64), and minocycline (128). As monotherapy, none of the drugs had better MAC kill compared to rifampin. While minocycline alone killed 1.76 ± 0.33 log10 CFU/mL MAC, replacement of rifabutin in the standard therapy resulted in 6.27 ± 0.28 log10 CFU/mL MAC kill, showing minocycline's synergistic effect with azithromycin and ethambutol. An example of a macrolide-rifamycin-ethambutol-free oral regimen, the azithromycin-minocycline-tedizolid combination killed 4.35 ± 0.42 log10 CFU/mL MAC. The tebipenem-tedizolid-minocycline combination killed 4.82 ± 0.42 log10 CFU/mL; however, addition of bedaquiline resulted in a lower kill of 2.71 ± 0.22 log10 CFU/mL, suggesting a likely antagonism.</sec><sec><title>CONCLUSION</title>We tested eight different drugs to identify several rifamycin-, macrolide-, and ethambutol-free oral multidrug combinations. The minocycline-based regimens warrant further preclinical and clinical testing.</sec>.

Background/Objectives: Ciltacabtagene autoleucel (cilta-cel) for relapsed/refractory multiple myeloma is typically administered inpatient (IP) to monitor for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Because cilta-cel toxicities are typically delayed, outpatient (OP) administration (infusion and early monitoring) is being explored. We synthesized available evidence on OP and IP administration. Methods: MEDLINE, Embase, and Cochrane Library were searched from inception to 5 August 2025, supplemented by conference and gray literature searches. Eligible studies of adults with multiple myeloma receiving cilta-cel reported efficacy, safety, resource use, costs, and/or quality-of-life outcomes; findings were synthesized descriptively due to heterogeneity. Results: Seventy-four records (56 studies) were included; 90 patients received OP cilta-cel. OP clinical evidence (primarily three real-world studies) showed high response rates (ORR: 95%; median follow-up 4.6 months) and reported 1-year PFS and OS of 86% and 96%. In IP studies, median ORR was 91%, with median 1-year PFS 76% and median 1-year OS 85%. Any-grade CRS and ICANS occurred in 79-84% and 17-22% of OP patients (largely low grade); IP cohorts reported a median ICANS incidence of 17% (range 5-23%). Most OP patients were later hospitalized (86-93%), but stays were shorter (median 4-6.5 days) than in an IP cohort (median 19 days). Comparisons were unadjusted and may reflect selection differences. One modeling-based economic analysis estimated savings of ~$19,000 per OP-treated patient. Conclusions: OP cilta-cel appears feasible for selected patients and may reduce costs without compromising outcomes. Findings are descriptive and hypothesis-generating and prospective multicenter studies are needed to define long-term safety, durability, quality of life, and cost-effectiveness.

Abstract Pathogens such as Porphyromonas gingivalis ( P. gingivalis ) may lead to Alzheimer’s disease (AD), but how they get into the brain and cause AD remains unclear, especially their level in blood is usually low. AD involves early breakdown of the blood-brain barrier (BBB). BBB disruption may allow blood-derived neurotoxic components to penetrate the BBB and enter the brain. We investigated whether BBB disruption permits P. gingivalis to enter the brain and accelerate disease-related changes. Using animal models, human BBB organoids and bEnd.3 cells, we found that a leaky BBB, especially through increased caveolin-1-dependent transcytosis, allowed P. gingivalis to cross into the brain. The bacteria triggered the hyperphosphorylation of Tau protein, increased Aβ levels, and sustained neuroinflammation via activated glial cells. These findings indicate that BBB dysfunction facilitates P. gingivalis invasion, creating a vicious cycle of infection and neurodegeneration that may drive AD progression.

Настоящее исследование посвящено изучению роли независимого технического заказчика в реализации крупных строительных проектов на примере российского опыта. Актуальность исследования обусловлена возрастающей сложностью и капиталоёмкостью современных строительных проектов, требующих привлечения проектного финансирования. Методологической базой исследования являются методы кейс-стади, сравнительного и функционального анализа. В результате обобщения научных источников по исследовательской проблематике показано, что независимый технический заказчик выступает ключевым элементом системы управления проектом, обеспечивая целостное планирование, координацию участников, контроль соответствия проектным решениям и нормативным требованиям, а также интеграцию технических, организационных и финансовых процессов. Доказано, что независимый технический заказчик позволяет своевременно выявлять отклонения, предотвращать перерасход средств, минимизировать технологические ошибки и снижать вероятность срывов графика проведения строительных работ. Именно присутствие независимого технического заказчика обеспечивает системный контроль жизненного цикла проекта и способствует успешной реализации крупных инвестиционно-строительных проектов. В исследовании обоснована необходимость институционального закрепления роли технического заказчика в моделях управления строительством на российском рынке. Полученные результаты обладают практической ценностью и представляют интерес для государственных и частных заказчиков, формирующих организационные модели реализации крупных инфраструктурных программ. Выводы исследования позволяют обоснованно внедрять институт независимого технического заказчика как инструмент повышения прозрачности, управляемости и ответственности участников проектов строительства. This study is devoted to the study of the role of an independent technical customer in the implementation of large construction projects using the example of the Russian experience. The relevance of the research is due to the increasing complexity and capital intensity of modern construction projects that require project financing. The methodological basis of the research is the methods of case study, comparative and functional analysis. As a result of the generalization of scientific sources on research issues, it is shown that an independent technical customer acts as a key element of the project management system, ensuring holistic planning, coordination of participants, control of compliance with design decisions and regulatory requirements, as well as the integration of technical, organizational and financial processes. It has been proven that an independent technical customer can detect deviations in a timely manner, prevent cost overruns, minimize technological errors and reduce the likelihood of disruptions to the construction schedule. It is the presence of an independent technical customer that ensures the systematic monitoring of the project life cycle and contributes to the successful implementation of large investment and construction projects. The study substantiates the need for institutional consolidation of the role of the technical customer in construction management models in the Russian market. The results obtained have practical value and are of interest to public and private customers who form organizational models for the implementation of large infrastructure programs. The findings of the study make it possible to reasonably implement the institution of an independent technical customer as a tool to increase transparency, manageability and responsibility of construction project participants.

BackgroundMicroglia‐mediated neuroinflammation plays a pivotal role in the initiation and propagation of pathological markers of neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD). CSF1‐R signaling mediates microglial activation, proliferation, and survival; both CSF1‐R upregulation and increased proliferation of microglia have been observed in AD patients. Imaging technologies that effectively profile reactive microgliosis in vivo have the potential to be diagnostic tools, facilitate patient stratification in clinical trials, and monitor treatment. There is currently no clinically approved tool to profile reactive microgliosis in vivo. We present a novel molecular imaging technique for neuroinflammation by targeting CSF1‐R with MRI sensitive liposomes.MethodLiposomes with DSPE‐PEG‐Caflanone as the targeting moiety, and Gd(III) DSPE‐DOTA as the MRI contrast source were formulated using standard protocols. Caflanone is a potent CSF1‐R ligand. In vitro nanoparticle cell uptake studies and blocking experiments with free Caflanone employing both human and mouse microglia cell lines were used to establish receptor‐mediated internalization of the agent. Two AD mouse models (APP/PSEN1 and P301S) and one PD mouse model (A53TαS Tg) were used in in vivo MRI studies. Controls included wild type (WT) litter mates injected with the same agent. Mice were pre‐scanned to establish a baseline followed by injection of the agent. Post‐contrast scans were obtained at 4 days post‐injection, followed by euthanasia, and brain removal for ex vivo immunohistochemical analysis.ResultAs shown in figure 1, in vitro cell assays showed internalization of the Caflanone labeled nanoparticles within 1.5 hours of exposure. Coincubation with increasing concentrations of free Caflanone resulted in diminished particle uptake at high concentrations of the free ligand. In vivo MRI demonstrated increased brain retention of the nanoparticles in transgenic mice compared to controls. Ex‐vivo immunohistochemical analysis showed the nanoparticles in the cytosolic compartment of IBA1 reactive cells surrounding amyloid‐β (Aβ) plaques in the APP/PSEN1 mouse model.ConclusionResults demonstrate precision delivery of Caflanone labeled liposomes bearing an MRI diagnostic payload to activated microglia in three different mouse models of neurodegenerative disorders. These nanoparticles can also deliver a therapeutic payload with similar precision, opening a new frontier for the development of both diagnostics and therapeutics for neuroinflammation.

BackgroundMicroglia‐mediated neuroinflammation plays a pivotal role in the initiation and propagation of pathological markers of neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). CSF1‐R signaling mediates microglial activation, proliferation, and survival; both CSF1‐R upregulation and increased proliferation of microglia have been observed in AD patients. Imaging technologies that effectively profile reactive microgliosis in vivo have the potential to be diagnostic tools, facilitate patient stratification in clinical trials, and monitor treatment. There is currently no clinically approved tool to profile reactive microgliosis in vivo. We present a novel molecular imaging technique for neuroinflammation by targeting CSF1‐R with MRI sensitive liposomes.MethodLiposomes with DSPE‐PEG‐Caflanone as the targeting moiety, and Gd(III) DSPE‐DOTA as the MRI contrast source were formulated using standard protocols. Caflanone is a potent CSF1‐R ligand. In vitro nanoparticle cell uptake studies and blocking experiments with free Caflanone employing both human and mouse microglia cell lines were used to establish receptor‐mediated internalization of the agent. Two AD mouse models (APP/PSEN1 and P301S) and one PD mouse model (A53TαS Tg) were used in in vivo MRI studies. Controls included wild type (WT) litter mates injected with the same agent. Mice were pre‐scanned to establish a baseline followed by injection of the agent. Post‐contrast scans were obtained at 4 days post‐injection, followed by euthanasia, and brain removal for ex vivo immunohistochemical analysis.ResultAs shown in Figure 1, in vitro cell assays showed internalization of the Caflanone labeled nanoparticles within 1.5 hours of exposure. Coincubation with increasing concentrations of free Caflanone resulted in diminished particle uptake at high concentrations of the free ligand. In vivo MRI demonstrated increased brain retention of the nanoparticles in transgenic mice compared to controls. Ex‐vivo immunohistochemical analysis showed the nanoparticles in the cytosolic compartment of IBA1 reactive cells surrounding amyloid‐β (Aβ) plaques in the APP/PSEN1 mouse model.ConclusionResults demonstrate precision delivery of Caflanone labeled liposomes bearing an MRI diagnostic payload to activated microglia in three different mouse models of neurodegenerative disorders. These nanoparticles can also deliver a therapeutic payload with similar precision, opening a new frontier for the development of both diagnostics and therapeutics for neuroinflammation.

Clinical experience with cranial nerve palsy in

Abstract Lead (Pb) toxicity is a global health concern that primarily affects the liver. This study explored the protective effects of lactobacilli against Pb(II)-induced hepatotoxicity in mice. Three strains of lactobacilli— Lacticaseibacillus paracasei GMNL-32, Limosilactobacillus fermentum GMNL-93, and Lacticaseibacillus casei GMNL-277—were evaluated for Pb adsorption and cytoprotective properties. The results indicated that probiotic treatment reduced the liver-to-body weight ratio, aspartate transaminase and alanine transaminase levels, and liver damage without increasing Pb excretion. It also upregulated the expression of gut tight junction proteins, reduced the levels of inflammatory cytokines (tumor necrosis factor-α and interleukin-6), and modulated the diversity and composition of the gut microbiota. Strong correlations were observed between probiotics, microbial abundance, metabolic pathways, and reduced liver inflammation. Overall, this study suggests that GMNL-32, GMNL-93, and GMNL-277 can mitigate Pb-induced hepatotoxicity by modulating the gut microbiota and regulating metabolism. Thus, these probiotics hold promise as protective agents against Pb-induced hepatotoxicity.

Medical IoT devices for health monitoring require constant power and connectivity, yet they face challenges in complex indoor environments like hospitals due to signal blockages and energy constraints. This paper proposes a deep learning-based approach for determining the optimal position and phase shift of a Reconfigurable Intelligent Surface (RIS) to enhance both energy harvesting and communication throughput. Simulations using OpenEMS and Octave model signal behavior in a hospital-like scenario. A regression-based neural network is trained using TensorFlow to predict the optimal RIS configuration. Results demonstrate a nonlinear, positively correlated relationship between RIS parameters and performance metrics, enabling intelligent optimization of RIS for real-time health IoT applications.