👤 Anne-Marie Feeney

Alterations in lipids and apolipoproteins contribute to cardiovascular disease (CVD) and are common in people with HIV. The aim of our study was to compare lipid profiles and body composition between people with and without HIV and to explore whether any associations with HIV could be explained by socio-demographic, clinical characteristics and body composition. Cross-sectional analysis of a cohort study enrolling people with HIV and HIV-negative controls. Apolipoproteins [ApoB-100, ApoA1, Lp(a)] were analysed by immunoturbidimetry. Lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL]), clinical/demographic data and dual-energy X-ray absorptiometry (DXA)-measured body composition parameters were collected. Between-group differences were assessed with Student's T-test. Linear regression models assessed associations of lipids and apolipoproteins with HIV status and associations with socio-demographic, clinical characteristics and body composition. We included 108 people with HIV on treatment (93.5% with viral suppression) and 96 controls. People with HIV were younger, more likely to be male, with obesity, of African ethnicity, smokers and with a higher representation of CVD, hypertension, diabetes and statin use. ApoB-100, TC, HDL and LDL were significantly lower in people with HIV, with no between-group difference in ApoA, Lp(a) and body composition. HIV infection remained independently associated with lower TC and LDL after adjustment for possible confounders. People with HIV from a contemporary cohort had lower pro-atherogenic lipid parameters compared to controls, and no differences in body composition between people with HIV and controls were observed. Traditional risk factors for CVD and chronic inflammation might have a greater impact than dyslipidaemia itself on the increased CVD risk in people with HIV. Show less

Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less

Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of Show less

Transplantation of xenogeneic organs is an attractive solution to the existing organ shortage dilemma, thus, securing a clinically acceptable prolongation of xenograft survival is an important goal. In preclinical transplantation models, recipients of liver, kidney, heart, or lung xenotransplants demonstrate significant graft damages through the release of pro-inflammatory molecules, including the C-reactive protein, cytokines, and histone-DNA complexes that all foster graft rejection. Recent studies have demonstrated that mitigation of ischemia reperfusion injury (IRI) greatly improves xenograft survival. Organ IRI develops primarily on a complex network of cytokines and chemokines responding to molecular cues from the graft milieu. Among these, interleukin 27 (IL-27) plays an immunomodulatory role in IRI onset due to graft environment-dependent pro- and anti- inflammatory activities. This review focuses on the impact of IL-27 on IRI of liver xenotransplants and provides insights on the function of IL-27 that could potentially guide genetic engineering strategies of donor pigs and/or conditioning of organs prior to transplantation. Show less

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role. Show less