BackgroundGlioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients.MethodsWe used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro.ResultsPIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations.ConclusionPIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.
Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (−)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.
Generalized pustular psoriasis (GPP) is a rare heterogeneous cutaneous disease characterized by multiple flares of painful pustules with widespread inflammation. 1 Chronic systemic inflammation in GPP may result in anaemia by mechanisms such as iron sequestration in macrophages. 2 Lee et al. 3 demonstrated an increased risk of psoriasis in chronic kidney disease patients with low haemoglobin levels. Though some level of associations between anaemia and GPP has been previously considered, we sought to evaluate whether the presence of anaemia was associated with adverse inpatient outcomes in patients hospitalized with GPP.We reviewed the National Inpatient Sample, a publicly available, de-identified database of US hospital encounters produced by the Agency for Healthcare Research and Quality (AHRQ), from the years 2016 to 2020. GPP diagnosis was identified by searching for International Classifications of Disease, 10th Edition (ICD-10-CM) code L40.1 (generalized pustular psoriasis) as a primary diagnosis.We utilized the AHRQ Elixhauser Comorbidity Software Refined (CMR) to identify deficiency anaemia comorbidity. A full list of ICD-10-CM codes categorized under deficiency anaemia can be viewed in Table S1. The CMR was used to search for the presence of leukaemia, lymphoma, metastatic cancer, solid tumor without metastasis and in situ/malignant. Demographic characteristics including age, sex, race, income, insurance status and outcome measures of length of hospital stay and cost of inpatient visit were collected. Cost was standardized between hospitals using cost-to-charge ratio files.Patients under the age of 18 were excluded. The sample was separated into cohorts by the presence or absence of a deficiency anaemia comorbidity. Univariate analysis was conducted between groups
ObjectiveEvaluating the association between arterial hypertension and tinnitus while controlling for gender, race, diabetes, hearing loss, and depression as potential confounders.Study DesignThe present study employed a cross-sectional design.SettingHealth interviews were conducted in the respondents’ homes.PatientsRespondents represent a nationwide sample of the noninstitutionalized civilian population of the United States. A total of 5,735 adults were identified by the NHANES 2015 to 2016 questionnaires.InterventionsQuestionnaires were administered to each participant.Main Outcome MeasuresParticipants’ responses regarding tinnitus, hypertension, hearing loss, depression, diabetes, and demographics were used to evaluate potential associations. Multivariate logistic regression analyses were conducted on different age groups with the presence of hypertension as the response variable.ResultsParticipants aged 20 to 39 with tinnitus were significantly more likely to be diagnosed with hypertension (OR = 2.49; p = 0.024) after adjusting for potential confounding. No significant association between tinnitus and hypertension was found for older age groups. The diagnosis of diabetes was associated with hypertension in ages 20 to 39 (OR = 7.11; p = 0.001), 40 to 59 (OR = 3.45; p = 0.020), and 60 to 69 (OR = 3.89; p = 0.032).ConclusionsTinnitus is associated with hypertension in younger age groups of 20 to 39 years of age but not in age groups greater than 40 years. Diabetes is also associated with hypertension in individuals aged 20 to 69 years. This finding of tinnitus as a risk factor for hypertension in younger populations may inform better clinical practice and lead to earlier detection of hypertension in at-risk patients.
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