Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.

APOE4 is a major genetic risk factor for Alzheimer's disease and high amyloid-β (Aβ) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific APOE-modulated Aβ-dependent and Aβ-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of APOE in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate. We have previously demonstrated that systemic epidermal growth factor (EGF) treatment, which is important for vascular function, at early stages of pathology (treatment from 6 to 8 months) is beneficial for recognition and spatial memory and cerebrovascular function in female mice that express APOE4. These data raise the important question of whether EGF can improve APOE4-associated cerebrovascular and behavioral dysfunction when treatment is initiated at an age of advanced pathology. Positive findings would support the development of therapies that target cerebrovascular dysfunction associated with APOE4 in aging and AD in individuals with advanced cognitive impairment. Therefore, in this study female mice that express APOE4 in the absence (E4FAD-mice) or presence (E4FADþ mice) of Aβ overproduction were treated from 8 to 10 months of age systemically with EGF. EGF treatment mitigated behavioral dysfunction in recognition memory and spatial learning and improved hippocampal neuronal function in both E4FADþ and E4FAD-mice, suggesting that EGF treatment improves Aβ-independent APOE4-associated deficits. The beneficial effects of EGF treatment on behavior occurred in tandem with improved markers of cerebrovascular function, including lower levels of fibrinogen, lower permeability when assessed by MRI and higher percent area coverage of laminin and CD31 in the hippocampus. These data suggest a mechanistic link among EGF signaling, cerebrovascular function and APOE4-associated behavioral deficits in mice with advanced AD-relevant pathology.

No abstract

Sepsis is a clinical syndrome with physiologic and biochemical derangements caused by dysregulated inflammatory response to an infection. A recent retrospective study showed that vitamin C, hydrocortisone and thiamine in intensive care unit (ICU) patients with septic shock when added to standard care improved mortality and outcomes. We undertook a prospective single-blinded study to evaluate effects of addition of this triple therapy to standard ICU care on 28-day mortality in patients with septic shock. METHODS: Patients at LAC+USC Medical Center with septic shock defined as sepsis-induced hypotension requiring vasopressors with serum lactate level >2 mmol/L were enrolled within 24 hours of identification. Exclusion criteria included inability to obtain consent, incarceration, active malignancy, dementia, pregnancy or lactation, active ischemic or hemorrhagic stroke, active cardiogenic or other causes of shock, history of renal stones and current use of steroids. Patients were blinded as to treatment group and randomized by a blinded operator in block randomization in a 1:1 fashion in groups of 8. Patients received either standard ICU care (control) or standard care plus intravenous (IV) Vitamin C 1.5 gram every 6 hours for 4 days or until ICU discharge, IV hydrocortisone 50 mg every 6 hours for 7 days or until ICU discharge, and IV thiamine 200 mg every 12 hours for 4 days or until ICU discharge. Data were analyzed using SPSS with a chi squared test. P-value <0.05 was considered statistically significant.

No abstract