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Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence. Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.

IntroductionSudden unexpected infant death (SUID) remains a leading cause of infant mortality in the USA, disproportionately affecting Black/African American infants. In Cook County, Illinois, Black/African American infants had SUID rates 14 times higher than non-Hispanic white infants between 2020 and 2021. Despite widespread safe sleep education, racial disparities persist. Our Specific, Measurable, Acheivable, Relevant, and Time-Bound (SMART) aim was to increase safe sleep compliance among mothers of Black/African American infants discharged from our neonatal intensive care unit (NICU) by 5% over 12 months by providing targeted, equitable and culturally sensitive education, measured using an adapted validated safe sleep survey.MethodsThis project, conducted in a level III NICU at the University of Illinois Hospital in Chicago began planning in May 2023. Baseline data were collected (November 2023–February 2024) via caregiver surveys and chart reviews. Plan-Do-Study-Act (PDSA) cycles (March–November 2024) introduced interventions like the ‘Alone-Back-Crib’ (ABC) Safe Sleep handouts on SUID disparities, staff education, and short videos. Compliance was assessed postdischarge through surveys and clinic questionnaires, with preintervention and postintervention data analysed using χ² and t-tests. A control chart (p-chart) tracked process changes.ResultsAmong 248 infants (70 baseline, 178 intervention), mean safe sleep compliance increased from 96% to 97% (p=0.26). Reports of infants ‘never’ sleeping alone in a crib declined from 11.4% to 3.9% (p=0.01). Caregivers valued enhanced messaging on SUID disparities.ConclusionsDespite high baseline compliance, culturally tailored education reinforced safe sleep practices. While overall adherence changed minimally, increased awareness and behavioural shifts highlight the need for sustained interventions, community engagement, implicit bias training and systemic strategies to reduce racial disparities in SUID.

The complex encompasses a group of gram-negative opportunistic pathogens that cause chronic lung infections in people with cystic fibrosis. Distinct from other respiratory pathogens, causes a unique clinical disease in a subset of patients known as 'cepacia syndrome', fulminant pneumonia accompanied by bacteraemia and sepsis with a mortality rate of up to 75%. Due to the bacteraemia associated with this disease, the mechanisms that allow to resist the bactericidal effects of serum complement-depending killing are vital. Antibodies usually promote serum killing; however, we have described 'cloaking antibodies', specific for lipopolysaccharides that paradoxically protect serum-sensitive bacteria from complement-mediated lysis. Cloaking antibodies that protect have been found in 24%-41% of patients with chronic lung diseases. The presence of these antibodies is also associated with worse clinical outcomes. Here, we sought to determine the relevance of cloaking antibodies in patients with infection. Twelve spp. were isolated from nine pwCF and characterised for susceptibility to healthy control serum. Patient serum was analysed for the titre of the cloaking antibody. The ability of the patient serum to prevent healthy control serum (HCS) killing of its cognate isolates was determined. We found that several of the strains were shared between patients. Ten of the 12 isolates were highly susceptible to HCS killing. Four of nine (44%) patients had cloaking antibodies that protected their cognate strain from serum killing. Depleting cloaking antibodies from patient serum restored HCS killing of isolates. Cloaking antibodies are prevalent in patients with pulmonary infection and protect these strains from serum killing. Removal of cloaking antibodies via plasmapheresis, as previously described for individuals with life-threatening infection, may be a useful new strategy for those with serious and life-threatening infection.

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N -dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.

Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

Despite available medications for dyslipidemia, many treated patients still have suboptimal lipid levels. The aim of this study was to examine the extent of residual dyslipidemia in United States adults. Of 2509 United States adults aged ≥18 years from the National Health and Nutrition Examination Survey (NHANES) 2009-2010, 1,129 (41.8% weighted) had hyperlipidemia on the basis of modified treatment guidelines for low-density lipoprotein (LDL) cholesterol according to risk category or pharmacologic treatment. Of these, 484 (42.4%) were treated with lipid-modifying therapy, and the proportions of subjects who still had LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or non-HDL cholesterol not at recommended levels were examined. In this cohort treated for hyperlipidemia, the mean age was 60.1 ± 14.9 years, and 52% were men. Only 36.5% of subjects receiving treatment for hyperlipidemia were at goal or normal levels for all 3 lipids (LDL cholesterol, HDL cholesterol, and triglycerides). LDL cholesterol remained higher than goal for 37.5% of subjects, 28.9% had low HDL cholesterol, and 36.3% had elevated triglycerides. One, 2, and 3 lipid parameters were at abnormal levels in 32.4%, 23.0%, and 8.2% of subjects, respectively; 36.5% had no lipid disorder. In addition, 38.6% of treated subjects were above non-HDL cholesterol goal, and even in those at LDL cholesterol goal, 12.9% were not at non-HDL cholesterol goal. Those with cardiovascular disease conditions had poorer goal attainment of LDL cholesterol, HDL cholesterol, and composite all lipids than those without cardiovascular disease. In conclusion, despite widely available treatments for dyslipidemia, many patients remain at suboptimal lipid levels, indicating need for greater adherence to lifestyle and medical therapies to address these gaps in the management of dyslipidemia.

The current outbreak of severe acute respiratory distress syndrome (SARS) or nCOVID-19 pandemic, caused by the coronavirus-2 (CoV-2), continues to wreak havoc globally. As novel vaccines are being discovered and developed, small molecule drugs still constitute a viable treatment option for SARS-CoV-2 infections due to their advantages such as superior patient compliance for oral therapies, reduced manufacturing costs and ease of large scale distribution due to better stability and storage profiles. Discovering new drugs for SARS-CoV-2 infections is a time consuming and expensive proposition. In this regard, drug repurposing is an appealing approach which can provide rapid access to therapeutics with proven record of safety and efficacy. We investigated the drug repurposing potential of a library of dipeptidyl peptidase 4 (DPP4) inhibitors which are currently marketed for type-2 diabetes as treatment option for SARS-CoV-2 infections. These computational studies led to the identification of three marketed DPP4 inhibitors; gemigliptin, linagliptin and evogliptin as potential inhibitors of SARS-CoV-2 Mpro viral cysteine protease. In addition, our computational modeling shows that these drugs have the potential to inhibit other viral cysteine proteases from the beta coronavirus family, including the SAR-CoV Mpro and MERS-CoV CLpro suggesting their potential to be repurposed as broad-spectrum antiviral agents.

Purpose The availability of take home naloxone (THN) was increased for Canadians in 2016, including access to kits via pharmacies. Unlike typical over-the-counter (OTC) and prescription drugs, THN kits may be stored in non-standard conditions, including in vehicles, backpacks, and out of doors. To evaluate whether these non-standard storage conditions affect stability, we investigated the impact of heat and freeze-thaw cycling on naloxone hydrochloride stability. Methods To assess the effect of heat, naloxone hydrochloride ampoules were exposed to 80 °C in a temperature-controlled oven for 8 h followed by 16 h at room temperature. To assess the effect of freeze-thaw cycles, naloxone hydrochloride ampoules were exposed to − 20 °C for 16 h followed by 8 h at 4 °C. The impact of these conditions on naloxone hydrochloride stability was evaluated each day for 1 week and after 2 and 4 weeks. The concentration of remaining naloxone hydrochloride was quantified using high-performance liquid chromatography (HPLC). Naloxone hydrochloride ampoules stored at room temperature served as the experimental control. Results Naloxone hydrochloride ampoules exhibit no changes in drug concentration following exposure to heat or freeze-thaw cycles for up to 28 days compared to ampoules maintained at room temperature (as indicated in the product monograph). Conclusions Naloxone hydrochloride remains chemically stable following exposure to heat or freeze-thaw cycles after 28 days. If THN kits are stored in non-standard conditions (for up to 28 days) the active naloxone is likely to remain stable. Despite this, pharmacists should continue to emphasize the importance of appropriate storage of THN kits to ensure optimal efficacy should naloxone administration be required in an emergency situation.