Familial Hemophagocytic Lymphohistiocytosis in a Premature Low Birth Weight Infant: a Rare Case Report.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) onset in the fetal and neonatal periods is sporadic, and infants are susceptible to intrauterine death. Early and accurate diagnosis and treatment are the keys to preventing complications and death in FHL patients due to the complex and diverse clinical manifestations of the disease. METHODS: We report a rare case of a preterm infant with a low birth weight of 2,010 g and a gestational age of 32 + 4 weeks who presented with a leaky syndrome similar to sepsis after birth. Anti-infective, other support, and symptomatic treatments were not effective. Bone marrow examination results on day 13 suggested hemophago-cytosis. RESULTS: Various compound heterozygous UNC13D genes were found by exome sequencing, which confirmed the diagnosis of FHL type 3. Genetic variants of this locus have never been reported in the literature. CONCLUSIONS: Neonatal onset FHL is challenging to diagnose, especially in premature infants. It is necessary to complete exome sequencing if the patient has no apparent pathogen infection or effective treatment.

Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo.

Nucleic acid therapeutics offer tremendous promise for addressing a wide range of common public health conditions. However, the in vivo nucleic acids delivery faces significant biological challenges. Lipid nanoparticles (LNPs) possess several advantages, such as simple preparation, high stability, efficient cellular uptake, endosome escape capabilities, etc., making them suitable for delivery vectors. However, the extensive hepatic accumulation of LNPs poses a challenge for successful development of LNPs-based nucleic acid therapeutics for extrahepatic diseases. To overcome this hurdle, researchers have been focusing on modifying the surface properties of LNPs to achieve precise delivery. The review aims to provide current insights into strategies for LNPs-based organ-selective nucleic acid delivery. In addition, it delves into the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs. In conclusion, this review provides a comprehensive overview to provide guidance and valuable insights for further research and development of organ-selective nucleic acid delivery systems.

Spatiotemporal-Controlled NIR-II Immune Agonist Sensitizes Cancer Immunotherapy.

The integration of nanomedicine and immunotherapy has presented a promising opportunity for the treatment of cancer and diverse diseases. However, achieving spatiotemporal controllable immunotherapy with excellent efficacy and safety performances remains a significant challenge. This study develops a biodegradable near-infrared II (NIR-II) photothermal response polymer nanoparticle (PTEQ) system. This platform exhibits intrinsic immunostimulatory properties while concurrently delivering siRNA for Programmed Death-Ligand 1 (siPD-L1), leveraging enhanced immune responses and immune checkpoint blockade for safe and effective cancer therapy. In the CT26 tumor-bearing mouse model, PTEQ, as an immune stimulant, significantly boosts the infiltration of CD4+ and CD8+ T cells within the tumor microenvironment (TME). The PTEQ/siPD-L1+laser group not only initiates NIR-II photothermal therapy but also promotes the activation and infiltration of T cells, M1 macrophage polarization, and maturation of dendritic cells in the TME, resulting in the complete elimination of tumors in 7/10 cases, achieving a 100% survival rate. In another in vivo vaccine experiment, all tumors on the right side are completely eliminated in the PTEQ/siPD-L1+laser group, reaching a 100% tumor eradication rate. These findings underscore the potential of this strategy to overcome the current immunotherapeutic limitations and achieve immune therapy normalization.

Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity.

Emerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (-229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

mRNA-based modalities for infectious disease management.

The novel coronavirus disease 2019 (COVID-19) is still rampant all over the world, causing incalculable losses to the world. Major pharmaceutical organizations around the globe are focusing on vaccine research and drug development to prevent further damage caused by the pandemic. The messenger RNA (mRNA) technology has got ample of attention after the success of the two very effective mRNA vaccines during the recent pandemic of COVID-19. mRNA vaccine has been promoted to the core stage of pharmaceutical industry, and the rapid development of mRNA technology has exceeded expectations. Beyond COVID-19, the mRNA vaccine has been tested for various infectious diseases and undergoing clinical trials. Due to the ability of constant mutation, the viral infections demand abrupt responses and immediate production, and therefore mRNA-based technology offers best answers to sudden outbreaks. The need for mRNA-based vaccine became more obvious due to the recent emergence of new Omicron variant. In this review, we summarized the unique properties of mRNA-based vaccines for infectious diseases, delivery technologies, discussed current challenges, and highlighted the prospects of this promising technology in the future. We also discussed various clinical studies as well preclinical studies conducted on mRNA therapeutics for diverse infectious diseases.

mRNA vaccines for COVID-19 and diverse diseases.

Since its outbreak in late 2019, the novel coronavirus disease 2019 (COVID-19) has spread to every continent on the planet. The global pandemic has affected human health and socioeconomic status around the world. At first, the global response to the pandemic was to isolate afflicted individuals to prevent the virus from spreading, while vaccine development was ongoing. The genome sequence was first presented in early January 2020, and the phase I clinical trial of the vaccine started in March 2020 in the United States using novel lipid-based nanoparticle (LNP), encapsulated with mRNA termed as mRNA-1273. Till now, various mRNA-based vaccines are in development, while one mRNA-based vaccine got market approval from US-FDA for the prevention of COVID-19. Previously, mRNA-based vaccines were thought to be difficult to develop, but the current development is a significant accomplishment. However, widespread production and global availability of mRNA-based vaccinations to combat the COVID-19 pandemic remains a major challenge, especially when the mutations continually occur on the virus (e.g., the recent outbreaks of Omicron variant). This review elaborately discusses the COVID-19 pandemic, the biology of SARS-CoV-2 and the progress of mRNA-based vaccines. Moreover, the review also highlighted a detailed description of mRNA delivery technologies and the application potential in controlling other life-threatening diseases. Therefore, it provides a comprehensive view and multidisciplinary insights into mRNA therapy for broader audiences.

Clinical metagenomic sequencing for rapid diagnosis of neonatal meningitis caused by Ureaplasma parvum: A case report.

INTRODUCTION: It is challenging to obtain favorable results through conventional diagnostic testing for Ureaplasma parvum (UP), a conditional pathogen, because of the atypical clinical phenotype of UP meningitis. PATIENT CONCERNS AND DIAGNOSIS: Herein, we report a pediatric case of neonatal meningitis caused by UP in a spontaneously delivered full-term baby. The infant's temperature peak was 38.3°C at the age of 9 days. The patient was diagnosed with neonatal suppurative meningitis. INTERVENTIONS AND OUTCOMES: The pathogen was diagnosed in a timely and accurate manner by metagenome sequencing, and the patient was eventually discharged with azithromycin. CONCLUSIONS: Neonatal Ureaplasma meningitis may be more common than previously suspected. The clinical manifestations were not obvious and were similar to those of neonatal meningitis caused by other bacteria. When conventional treatments and conventional pathogenic tests are negative, mNGS is a better choice for timely and accurate pathogen identification.

Feasibility and Efficacy of Pulsed-Dose Oxygen Delivery During Noninvasive Ventilation.

BACKGROUND: It is difficult to apply noninvasive ventilation (NIV) simultaneously with pulsed-dose oxygen delivery. We evaluated the feasibility and efficacy of pulsed-dose oxygen delivery during NIV. METHODS: A bench study was conducted using a simulated lung during NIV, with a breathing frequency of 10 or 20 breaths/min and 3 oxygen injection sites (site A on face mask, site B proximal to face mask, and site C at the ventilator outlet) with continuous flow oxygen delivery of 1, 3, or 5 L/min) or pulsed-dose oxygen delivery (numerical settings of 1, 3, or 5 representing the oxygen pulse characteristics). [Formula: see text] under different experimental conditions and the influence of mode of oxygen delivery on NIV (compared to baseline and continuous flow oxygen delivery vs pulsed-dose oxygen delivery) were compared. In the clinical study, we enrolled 10 subjects with COPD exacerbation who received NIV with either continuous flow oxygen delivery or pulsed-dose oxygen delivery. Under the same targeted pulse oxygen saturation (88-92%), the numerical settings of different modes of oxygen delivery were titrated, and the clinical parameters during the different modes of oxygen delivery were compared. RESULTS: In the bench study, the ratio of the [Formula: see text] with pulsed-dose oxygen delivery to the [Formula: see text] with continuous flow oxygen delivery at the same numerical setting was 0.94 ± 0.15. The oxygen injection site had a significant influence on [Formula: see text] in pulsed-dose oxygen delivery or continuous flow oxygen delivery mode (P < .05). Pulsed-dose oxygen delivery worked effectively with the ventilator, as demonstrated by the fine synchronization in the breathing cycle of the ventilator, the simulated lung, and the pulsed-dose oxygen delivery. When compared with each other or compared to the baseline individually, pulsed-dose oxygen delivery and continuous flow oxygen delivery showed no clinically important effects on NIV (all P > .05 or changes < 10%). In the clinical study, the mean numerical settings for pulsed-dose oxygen delivery and continuous flow oxygen delivery modes after titration were 2.68 ± 0.32 and 2.31 ± 0.56 L/min, respectively. There was no significant difference between continuous flow oxygen delivery and pulsed-dose oxygen delivery (P > .05). CONCLUSIONS: Integration of pulsed-dose oxygen delivery into NIV could achieve efficacy similar to that achieved with continuous flow oxygen delivery.

Evaluation of in vitro toxicity of silica nanoparticles (NPs) to lung cells: Influence of cell types and pulmonary surfactant component DPPC.

Cultured human lung epithelial cells, particularly A549 cells, are commonly used as the in vitro model to evaluate the inhalational toxicity of nanoparticles (NPs). However, A549 cells are cancer cells that might not reflect the response of normal tissues to NP exposure. In addition, the possible influence of pulmonary surfactant also should be considered. This study used silica NPs as model NPs, and evaluated the toxicity of silica NPs to both 16HBE human bronchial epithelial cells and A549 adenocarcinomic cells, with or without the presence of pulmonary surfactant component dipalmitoyl phosphatidylcholine (DPPC). We found that silica NPs induced cytotoxicity at the concentration of 128 µg/mL in 16HBE cells but not A5490 cells, and the cytotoxicity of silica NPs to 16HBE cells was inhibited by DPPC. Intracellular reactive oxygen species (ROS) was only induced in 16HBE cells, accompanying with decreased thiol levels. Moreover, 16HBE cells internalized more silica NPs compared with A549 cells, and the internalization was reduced with the presence of DPPC in both types of cells. The retention of ABC transporter substrate Calcein was only significantly induced by silica NPs at high concentrations in 16HBE cells, and was partially reduced due to the presence of DPPC. In addition, ABC transporter inhibitor MK571 increased the toxicity of silica NPs to both types of cells, with 16HBE cells being more sensitive. Our data revealed that the cell types and pulmonary surfactant components could influence the toxicological consequences of silica NPs to human lung cells. Therefore, it is recommended that in vitro studies should carefully select suitable models to evaluate the inhalational toxicity of NPs.

Multi-walled carbon nanotubes promoted lipid accumulation in human aortic smooth muscle cells.

It has been shown before that exposure to nanomaterials (NMs) might promote the formation of foam cells, the key cells involved in all stages of atherosclerosis. However, to our best knowledge, previous studies, particularly in vitro studies, only investigated the transformation of macrophages into foam cells, whereas the importance of smooth muscle cells (SMCs) was overlooked. The present study investigated the toxicity of pristine multi-walled carbon nanotubes (MWCNTs; Code XFM19) and carboxylated MWCNTs (Code XFM21) to human aortic smooth muscle cells (HASMCs). The results showed that exposure to both types of MWCNTs significantly reduced mitochondrial activity but might not damage lysosomes. MWCNT exposure had minimal impact on cytokine release but significantly promoted lipid accumulation, which was significantly inhibited when the cells were pre-incubated with ER stress inhibitors or antioxidants. The mRNA levels of ER stress markers DDIT3 and XBP-1 s and protein levels of chop and p-chop were induced particularly by XFM21, accompanying with increased SREBF1 and SREBF2 mRNA as well as FASN protein, the key regulators involved in de novo lipogenesis. In addition, the mRNA levels of KLF4 and KLF5 and protein levels of KLF were induced after exposure to both types of MWCNTs, associated with an increase of CD68 protein levels. We concluded that MWCNTs might promote lipid accumulation in HASMCs through the induction of ER stress leading to de novo lipogenesis, as well as the activation of KLF pathway resulting in SMC transformation.

Isoflavanones from Desmodium oxyphyllum and their cytotoxicity.

Two new isoflavanones, (3R)-7-hydroxy-4'-methoxy-5-methoxycarbonyl-isoflavanone (1) and (3R)-8-hydroxy-4'-methoxy-7-methoxycarbonyl-isoflavanone (2), together with seven known isoflavanones (3-9) were isolated from Desmodium oxyphyllum of the Leguminosae family. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compound 1 showed good cytotoxicity against NB4 and SHSY5Y cell lines with IC50 values of 3.1 and 2.5 µM; compound 2 exhibited cytotoxicity against PC3 cell lines with a IC50 value of 3.6 µM; compound 4 showed cytotoxicity against A549 and SHSY5Y cell lines with IC50 values of 3.6 and 2.8 µM; and compound 5 displayed cytotoxicity against NB4, SHSY5Y, and MCF7 cell lines with IC50 values of 2.6, 3.8, and 2.8 µM, respectively. Other compounds also showed moderate cytotoxicity for some tested cell lines with IC50 values between 5.4 and 8.8 µM.