Profile of time-dependent VEGF upregulation in human pulmonary endothelial cells, HPMEC-ST1.6R infected with DENV-1, -2, -3, and -4 viruses

In this study, the upregulated expression level of vascular endothelial growth factor (VEGF) in a pulmonary endothelial cell line (HPMEC-ST1.6R) infected with dengue virus serotypes 1, 2, 3, and 4 (DENV-1, -2, -3 and -4), was investigated. This cell line exhibits the major constitutive and inducible endothelial cell characteristics, as well as angiogenic response. Infection by all four DENV serotypes was confirmed by an observed cytopathic effect (CPE), as well as RT-PCR (reverse-transcription polymerase chain reaction) assays. As we had previously reported, the DENV-infected HPMEC-ST1.6R cells exhibited an elongated cytoplasmic morphology, possibly representing a response to VEGF and activation of angiogenesis. In this study, increase in VEGF expression level at designated time points of 0, 8, 24, 96 and 192 hours post-infection was investigated, using a microbead-based Bio-Plex immunoassay. Increased level of VEGF expression in infected-HPMEC-ST1.6R was detected at 8 hours post-infection. Interestingly, VEGF expression level began to decrease up to 96 hours post-infection, after which an upsurge of increased VEGF expression was detected at 192 hours post-infection. This profile of VEGF upregulated expression pattern associated with DENV infection appeared to be consistent among all four DENV-serotypes, and was not observed in mock-infected cells. In this study, the expression level of VEGF, a well-established vascular permeabilizing agent was shown to be elevated in a time-dependent manner, and exhibited a unique dual-response profile, in a DENV-infected endothelial cell. The experimental observation described here provided additional insights into potential mechanism for VEGF-mediated vascular leakage associated with DENV, and support the idea that there are potential applications of anti-VEGF therapeutic interventions for prevention of severe DENV infections

Uptake of home-based voluntary HIV testing in sub-Saharan Africa: a systematic review and meta-analysis

Improving access to HIV testing is a key priority in scaling up HIV treatment and prevention services. Home-based voluntary counselling and testing (HBT) as an approach to delivering wide-scale HIV testing is explored here

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08)

"Men are always scared to test with their partners … it is like taking them to the Police": Motivations for and barriers to couples' HIV counselling and testing in Rakai, Uganda: a qualitative study.

INTRODUCTION: Uptake of couples' HIV counselling and testing (couples' HCT) can positively influence sexual risk behaviours and improve linkage to HIV care among HIV-positive couples. However, less than 30% of married couples have ever tested for HIV together with their partners. We explored the motivations for and barriers to couples' HCT among married couples in Rakai, Uganda. METHODS: This was a qualitative study conducted among married individuals and selected key informants between August and October 2013. Married individuals were categorized by prior HCT status as: 1) both partners never tested; 2) only one or both partners ever tested separately; and 3) both partners ever tested together. Data were collected on the motivations for and barriers to couples' HCT, decision-making processes from tested couples and suggestions for improving couples' HCT uptake. Eighteen focus group discussions with married individuals, nine key informant interviews with selected key informants and six in-depth interviews with married individuals that had ever tested together were conducted. All interviews were audio-recorded, translated and transcribed verbatim and analyzed using Nvivo (version 9), following a thematic framework approach. RESULTS: Motivations for couples' HCT included the need to know each other's HIV status, to get a treatment companion or seek HIV treatment together - if one or both partners were HIV-positive - and to reduce mistrust between partners. Barriers to couples' HCT included fears of the negative consequences associated with couples' HCT (e.g. fear of marital dissolution), mistrust between partners and conflicting work schedules. Couples' HCT was negotiated through a process that started off with one of the partners testing alone initially and then convincing the other partner to test together. Suggestions for improving couples' HCT uptake included the need for couple- and male-partner-specific sensitization, and the use of testimonies from tested couples. CONCLUSIONS: Couples' HCT is largely driven by individual and relationship-based factors while fear of the negative consequences associated with couples' HCT appears to be the main barrier to couples' HCT uptake in this setting. Interventions to increase the uptake of couples' HCT should build on the motivations for couples' HCT while dealing with the negative consequences associated with couples' HCT

Loss of susceptibility as a novel breeding strategy for durable and broad-spectrum resistance

Recent studies on plant immunity have suggested that a pathogen should suppress induced plant defense in order to infect a plant species, which otherwise would have been a nonhost to the pathogen. For this purpose, pathogens exploit effector molecules to interfere with different layers of plant defense responses. In this review, we summarize the latest findings on plant factors that are activated by pathogen effectors to suppress plant immunity. By looking from a different point of view into host and nonhost resistance, we propose a novel breeding strategy: disabling plant disease susceptibility genes (S-genes) to achieve durable and broad-spectrum resistance

Vascular islands during microvascular regression and regrowth in adult networks

Objective: Angiogenesis is the growth of new vessels from pre-existing vessels and commonly associated with two modes: capillary sprouting and capillary splitting. Our previous work suggests vascular island incorporation might be another endothelial cell dynamic involved in microvascular remodeling. Vascular islands are defined as endothelial cell segments disconnected from nearby networks, and their origin remains unclear. The objective of this study was to determine whether vascular islands associated with microvascular regression are involved in network regrowth.Methods: Mesenteric tissues were harvested from adult male Wistar rats according to the experimental groups: unstimulated, post stimulation (10 and 70 days), and 70 days post stimulation + restimulation (3 and 10 days). Stimulation was induced by mast cell degranulation via intraperitoneal injections of compound 48/80. Tissues were immunolabeled for PECAM (endothelial cells), NG2 (pericytes), collagen IV (basement membrane), and BrdU (proliferation).Results: Vascular area per tissue area and length density increased by day 10 post stimulation compared to the unstimulated group. At day 70, vascular area and length density were then decreased, indicating vascular regression compared to day 10. The number of vascular islands at day 10 post stimulation was dramatically reduced compared to the unstimulated group. During regression at day 70, the number of islands increased. The disconnected endothelial cells were commonly bridged to surrounding networks by collagen IV labeling. NG2-positive pericytes were observed along both the islands and the collagen IV tracks. At 3 days post restimulation, vascular islands contained BrdU-positive cells. By day 10 post restimulation, the number of vascular islands was dramatically reduced.Conclusion: The results suggest that vascular islands originating during microvascular regression are capable of proliferation and incorporation into nearby networks during regrowth

1858-12-15 Annual Report of the Trustees of the Maine Insane Hospital

https://digitalmaine.com/amhi_reports/1031/thumbnail.jp

1858-12-15 Annual Report of the Trustees of the Maine Insane Hospital

https://digitalmaine.com/amhi_reports/1031/thumbnail.jp