Mcfaddentucker0458
Predicting high healthcare resource users is important for informing prevention strategies and healthcare decision-making. We aimed to cross-provincially validate the High Resource User Population Risk Tool (HRUPoRT), a predictive model that uses population survey data to estimate 5 year risk of becoming a high healthcare resource user. The model, originally derived and validated in Ontario, Canada, was applied to an external validation cohort. HRUPoRT model predictors included chronic conditions, socio-demographics, and health behavioural risk factors. The cohort consisted of 10,504 adults (≥18 years old) from the Canadian Community Health Survey in Manitoba, Canada (cycles 2007/08 and 2009/10). A person-centred costing algorithm was applied to linked health administrative databases to determine respondents' healthcare utilization over 5 years. Model fit was assessed using the c-statistic for discrimination and calibration plots. In the external validation cohort, HRUPoRT demonstrated strong discrimination (c statistic = 0.83) and was well calibrated across the range of risk. HRUPoRT performed well in an external validation cohort, demonstrating transportability of the model in other jurisdictions. HRUPoRT's use of population survey data enables a health equity focus to assist with decision-making on prevention of high healthcare resource use.
The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain.
Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase.
The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%,
= 0.005), Twist (23.6% vs. 45.9%,
= 0.010) and ZEB1 (15.0% vs. 55.9%,
= 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4,
= 0.018) and H3K36me3 demethylase (UTX,
= 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase,
= 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (
linear = 1.204) and MLL4-Slug (
linear = 0.987) was increased in direct proportion, and EZH2-Twist (
linear = -2.723) decreased in reverse proportion.
The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.
The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.A total of 71 patients with Lyme disease were identified for analysis in whom treatment with disulfiram was initiated between 15 March 2017 and 15 March 2020. Four patients were lost to follow-up, leaving 67 evaluable patients. Our retrospective review found patients to fall into a "high-dose" group (≥4 mg/kg/day) and a "low-dose" group ( less then 4 mg/kg/day). In total, 62 of 67 (92.5%) patients treated with disulfiram were able to endorse a net benefit of the treatment with regard to their symptoms. Moreover, 12 of 33 (36.4%) patients who completed one or two courses of "high-dose" therapy enjoyed an "enduring remission", defined as remaining clinically well for ≥6 months without further anti-infective treatment. The most common adverse reactions from disulfiram treatment in the high-dose group were fatigue (66.7%), psychiatric symptoms (48.5%), peripheral neuropathy (27.3%), and mild to moderate elevation of liver enzymes (15.2%). We observed that although patients on high dose experienced a higher risk for adverse reactions than those on a low dose, high-dose patients were significantly more likely to achieve enduring remission.Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5'-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.Despite the promising anticancer effects of immune checkpoint inhibitors, their low objective response rate remains to be resolved; thus, combination therapies have been investigated. We investigated the combination of an anti-programmed cell death 1 (aPD-1) monoclonal antibody with the knockdown of vascular endothelial factor receptor 2 (VEGFR2) on tumor endothelial cells to overcome resistance to immune checkpoint inhibitors and improve the objective response rate. The successful delivery of small interfering RNA to tumor endothelial cells was achieved by RGD peptide-modified lipid nanoparticles composed of a novel, pH-sensitive, and biodegradable ssPalmO-Phe. DisodiumPhosphate RGD-modified lipid nanoparticles efficiently induced the knockdown of VEGFR2 in tumor endothelial cells (TECs), which induced vascular normalization. The combination of a PD-1 monoclonal antibody with Vegfr2 knockdown enhanced CD8+ T cell infiltration into tumors and successfully suppressed tumor growth and improved response rate compared with monotherapy.
