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Voltage-gated calcium channels (CaV) regulate numerous vital functions in nerve and muscle cells. To fulfill their diverse functions, the multiple members of the CaV channel family are activated over a wide range of voltages. Voltage sensing in potassium and sodium channels involves the sequential transition of positively charged amino acids across a ring of residues comprising the charge transfer center. In CaV channels, the precise molecular mechanism underlying voltage sensing remains elusive. Here we combined Rosetta structural modeling with site-directed mutagenesis to identify the molecular mechanism responsible for the specific gating properties of two CaV1.1 splice variants. Our data reveal previously unnoticed interactions of S4 arginines with an aspartate (D1196) outside the charge transfer center of the fourth voltage-sensing domain that are regulated by alternative splicing of the S3-S4 linker. These interactions facilitate the final transition into the activated state and critically determine the voltage sensitivity and current amplitude of these CaV channels.

Background: Recently, histologic grade was removed from salivary tumor nomenclature by the WHO to include disease of higher grade. One such entity, cribriform adenocarcinoma (CAC), is an aggressive group of polymorphous adenocarcinoma (PAC), with frequent nodal metastasis and locoregional recurrence. We aim to examine the biologic behavior of this disease as compared with the PAC general cohort inclusive of all subtypes.Methods: A systematic review of the literature on polymorphous adenocarcinoma and cribriform adenocarcinoma was completed. A descriptive analysis was performed for the following predictor variables: nodal and distant metastasis, in addition to recurrence. The outcome variables, disease free recurrence, and disease specific survival, where plotted using Kaplan-Meier curves.Results: PAC and CAC both show median age of diagnosis in the sixth decade of life and a female predominance. CAC occurs most frequently in the tongue and PAC in the palate. The 2 groups show a similar biologic behavior in regards to incidence of distant metastasis (4.1 vs 5.5%), recurrence (12.5 vs 17.8%), and death from disease (3 vs 2.7%). However, there was an increased incidence of nodal metastasis in CAC (53%) as compared with that in PAC of all subtypes (14%).Conclusions: CAC exhibits more aggressive biologic behavior as compared with the PAC cohort. Although CAC is not an officially recognized entity, these tumors likely comprise a significant portion of the cases of PAC with poor outcomes and are deserving of attention and consideration for escalation in oncologic treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to review the clinical presentation, systemic work-up, and outcomes of all previously reported ocular adnexal (OA) metastases from renal cell carcinoma (RCC). METHODS: This was a literature review. PubMed and Google Scholar databases were searched for all well-documented cases of OA metastases from RCC. RESULTS: Final analysis identified 44 patients with either biopsy-confirmed (41/44, 93%) or treatment response-documented (3/44, 6%) OA metastases from RCC. Thirty-four (77%) patients were male. The median age was 60 years (mean: 60, range: 22-87 years). The most common presenting signs were proptosis (19/44, 43%) and OA mass (14/44, 32%). Metastases most frequently involved the orbital bones (10/44, 23%) and adjacent extraconal fat, extending from the sinonasal tract in 7/10 (70%) of these cases. OA metastases were initial manifestation of RCC in 18/44 (41%) patients. At the time of primary tumor diagnosis, 22 of 30 (73%) patients had American Joint Committee on Cancer Stage IV disease with metastases to 2 or more sites in 13 (57%) patients. Seventeen of42 (40%) patients underwent local therapy only, which most commonly included excision/ exenteration with margin control (10/17, 59%). Twenty-five of 42 (60%) patients had systemic therapy, which included biologic agents and chemotherapy. The absolute 5-year survival rate was 66% with significantly improved survival in patients reported after 2006 (92% vs. 42%, P = 0.04) and in those with isolated OA metastases (100% vs. 27%, P = 0.02) at 30 months. CONCLUSION: Although RCC metastases to OA occur in a setting of advanced disease, the recent advances in diagnostic modalities and targeted therapies resulted in improved survival. [ABSTRACT FROM AUTHOR]

We investigated the effect of combination antiretroviral therapy (cART) on immune recovery, particularly on the percentages of PD-1-positive cells within the major leukocyte subsets. Cryopreserved peripheral blood mononuclear cells and plasma samples collected longitudinally from a subset of 13 children and adolescents (between 9.7 and 18.2 years old) who were enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1066 were used for this study. Immunophenotyping by flow cytometry was performed to determine the effect of raltegravir-containing cART regimen on the distribution of leukocyte populations, on the expression of PD-1 on T cell subpopulations, and on the expression of well-established markers of T cell activation (CD38 and HLA-DR) on CD8 T cells. C reactive protein (CRP), lipopolysaccharide (LPS), IL-6, and soluble CD163 were assayed in plasma samples by an enzyme-linked immunosorbent assay. Plasma viral loads were decreased in all subjects (by an average of 2.9 log units). The cART regimen, including raltegravir, induced changes in CD8 T cell subsets, consistent with an effective antiretroviral outcome and improved immunologic status, including increased percentages of CD8 stem cell memory T cells (Tscm). The percentages of CD8 PD-1-positive cells decreased significantly as compared with baseline levels. Among the proinflammatory markers measured in plasma, sCD163 showed a decline that was associated with cART. cART therapy, including raltegravir, over 48 weeks in children is associated with immune restoration, consistent with effective antiretroviral therapy, namely decreased percentages of PD-1+ CD8+ T cells, an increase in CD8 Tscm cells, and decreased levels of sCD163. [ABSTRACT FROM AUTHOR]