scholarly journals Cardiovascular Disease (CVD) Risk Assessment of HIV Medication Regimens using hematopoietic CD34+ progenitor cells

2022 ◽  
Author(s):  
Adrian Farid Elzarki ◽  
Seshagiri Rao Nandula ◽  
Hassan Awal ◽  
Gary L Simon ◽  
Sabyasachi Sen
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Risk Assessment ◽  
Arterial Stiffness ◽  
Progenitor Cells ◽  
Outcome Measures ◽  
Progenitor Cell ◽  
Cell Function ◽  
Hematopoietic Progenitor Cell ◽  
Cvd Risk

Abstract Background To determine the effects of integrase inhibitor (INSTI) in comparison to non INSTI based regimens such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens on cardiovascular disease (CVD) risk in HIV+ patients without overt history of CVD or diabetes, with normal CD4:CD8 count. For CVD risk assessment we primarily used hematopoietic CD34+ progenitor cells, as a biomarker.Methods19 male subjects ages 32-61 years with BMI 21.0- 36.0, were enrolled. This was a single time point, cross-sectional, observational study. Subjects were enrolled under 2 groups (either on INSTI based regimen with 13 subjects or NNRTI (non-INSTI) based regimens with 6 subjects) who were taking stable doses of HAART. The medication regimens were a combination of one NRTI (typically tenofovir-emtricitabine) plus one INSTI or NNRTI. Our outcome measures were focused on cardiovascular and endothelial cell function and systemic inflammation. Our primary outcome measures were peripheral blood derived hematopoietic progenitor cell number (CD34 and CD133 positive), CD34+ cell function and gene expression studies. Our secondary outcomes were arterial stiffness measures and serum-based markers of inflammation. ResultsA significant increase in percentage number of progenitor cells, CD133+ cells (P=0.004) was noted along with an increase of double progenitor mark positive CD133+/CD34+ progenitor cell population was observed in INSTI group as compared to NNRTI group, by flow-cytometry. mRNA gene expression for antioxidant gene catalase was noted along with a trend towards a decrease in gene expression of inflammatory marker IL6 (p=0.06) was observed in CD34+ from INSTI group vs NNRTI group. The plasma IL-6 and CRP levels did not change significantly between the groups. Neutrophil-Lymphocyte ratio (NLR), an important marker of inflammation, was noted to be lower in INSTI group. A mean fasting glucose level was also lower in the INSTI group compared to NNRTI group (p=0.03). Interestingly, Urine- Microalbumin levels were higher in the INSTI group compared to NNRTI group (p=0.08), while eGFR levels were lower in the INSTI group (p=0.002). The arterial stiffness measures did not show statistically significant differences between the two groups. ConclusionWe conclude that the INSTI regimen may provide a better CVD risk profile compared to NNRTI based HAART regimen; however the increased albuminuria along with lower eGFR, noted in INSTI group is of concern. Because of the small size, these results would need replication in additional studies before changing clinical practice.Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT03782142?cond=Hiv&spons=Sabyasachi+sen&cntry=US&state=US%3ADC&city=Washington&draw=2&rank=1ClinicalTrials.gov Identifier: NCT03782142

scholarly journals Targeted gene transfer to human hematopoietic progenitor cell lines through the c-kit receptor

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 472-478 ◽  
Author(s):  
P Schwarzenberger ◽  
SE Spence ◽  
JM Gooya ◽  
D Michiel ◽  
DT Curiel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Progenitor Cell ◽  
Gene Transfection ◽  
Luciferase Reporter ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Covalently Linked

In this report, we describe a novel gene therapy approach for hematopoietic stem/progenitor cells using a specific receptor-mediated gene transfection procedure to target c-kit+ cell lines. The vector consists of plasmid DNA containing a luciferase reporter gene that is condensed by electrostatic forces with polylysine (PL) covalently linked to streptavidin (binds biotinylated ligand) and PL covalently linked to adenovirus (AD; to achieve endosomal lysis) with the final addition of biotinylated steel factor (SLF-biotin). Targeted transfection of growth factor-dependent hematopoietic progenitor cell lines that express c-kit showed specific luciferase gene expression over cell lines that did not express c-kit. This effect was dependent on the dose of SLF-biotin and was competed by excess SLF or with monoclonal antibodies that recognize c-kit and block the binding of SLF to its receptor. Maximum transfection efficiency (> 90%) requires a 2- hour incubation period of the vector with the cells, and maximum gene expression occurred 30 hours later. Removal of the endosomalytic agent, AD, from the vector resulted in the loss of gene expression. Vector targeting was versatile and could be changed by the addition of other biotinylated ligands. In principle, this vector should be broadly applicable to deliver genes to hematopoietic stem/progenitor cells in vitro and in vivo.

scholarly journals SUN-578 Role of Linagliptin on CD34+ Endothelial Progenitor Cells and Arterial Stiffness in Renal Function Impaired Type 2 Diabetes Subjects

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hassan Awal ◽  
Cleyton Domingues ◽  
Fiona Dore ◽  
Nabanita Kundu ◽  
Neeki Ahmadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Renal Function ◽  
Treatment Group ◽  
Arterial Stiffness ◽  
Progenitor Cells ◽  
Cell Number ◽  
Cvd Risk ◽  
Cd34 Cells

Abstract Introduction: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both Type 2 Diabetes and Chronic Kidney Disease (CKD) leading to poor regeneration of endothelium and renal tubules. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. DPP4 inhibitor increase endogenous SDF1a which has been shown to increase CD34+ cells migration and thereby improve CVD risk. However, cellular mechanisms of DPP4i mediated improvement of CVD in patients with Type 2 Diabetes with established CKD is not established. Hypothesis: Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may recover endothelial function in a diabetic kidney disease (DKD) population. Methods: 31 subjects taking 1–2 grams of metformin and/or Insulin were enrolled in this 12 weeks, double blind, two-arm, randomized placebo matched trial, with 5 mg Linagliptin compared to placebo. Type 2 diabetes subjects (30–70 years old), HbA1c of 6.5–10%, and all stages of CKD were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as Arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. During trial HbA1C was maintained between 7–8% for all subjects. Every subject was used as their own control. A mixed model regression analysis was done with p value <0.05 considered significant. Results: A double positive CD34/CD184 cell count had a statistically significant increase (p<0.02) as determined by flow cytometry in treatment group though there was no statistically significant increase in CD34+ cell number, or colony formation units. Gene expression analysis on CD34+ cells showed reduced expression of TP53 (p<0.04). Arterial stiffness measures such as augmentation Index (p<0.04) along with augmentation pressure (p<0.02) were significantly reduced in the treatment group. A reduction in LDL: HDL ratio was noted in treatment group (p <0.04). No change in renal function was noted during the 12 week period.. We are currently analyzing urinary exosome based data to enquire further into renal function Conclusions: In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34+ progenitor cells with a concomitant improvement in arterial stiffness and LDL parameters within 12 weeks of intervention.

scholarly journals Application of Cardiovascular disease (CVD) risk assessment equations to the Thai population

2019 ◽  
Vol 2 (1) ◽  
pp. 4-11
Author(s):  
Rungkarn Inthawong ◽  
Khaled Khatab ◽  
Malcolm Whitfield ◽  
Karen Collins ◽  
Maruf A. Raheem ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Assessment ◽  
Cvd Risk ◽  
Thai Population

scholarly journals Cardiovascular disease risk prediction in older people: a qualitative study

2021 ◽  
pp. BJGP.2020.1038
Author(s):  
Denise Ann Taylor ◽  
Katharine Wallis ◽  
Sione Feki ◽  
Sione Segili Moala ◽  
Manusiu He-Naua Esther Latu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Assessment ◽  
Qualitative Study ◽  
Older People ◽  
Focus Groups ◽  
Risk Prediction ◽  
Heart Attack ◽  
Clinical Decision Making ◽  
Community Dwelling ◽  
Cvd Risk

Background: Despite cardiovascular disease (CVD) risk prediction equations becoming more widely available for people aged 75 years and over, views of older people on CVD risk assessment are unknown. Aim: To explore older people’s views on CVD risk prediction and its assessment. Design and Setting: Qualitative study of community dwelling older New Zealanders. Methods: We purposively recruited a diverse group of older people. Semi-structured interviews and focus groups were conducted, transcribed verbatim and thematically analysed. Results: Thirty-nine participants (mean age 74 years) of Māori, Pacific, South Asian and European ethnicities participated in one of 26 interviews or three focus groups. Three key themes emerged, (1) Poor knowledge and understanding of cardiovascular disease and its risk assessment, (2) Acceptability and perceived benefit of knowing and receiving advice on managing personal cardiovascular risk; and (3) Distinguishing between CVD outcomes; stroke and heart attack are not the same. Most participants did not understand CVD terms but were familiar with ‘heart attack,’ ‘stroke’ and understood lifestyle risk factors for these events. Participants valued CVD outcomes differently, fearing stroke and disability which might adversely affect independence and quality of life, but being less concerned about a heart attack, perceived as causing less disability and swifter death. These findings and preferences were similar across ethnic groups. Conclusion: Older people want to know their CVD risk and how to manage it, but distinguish between CVD outcomes. To inform clinical decision making for older people, risk prediction tools should provide separate event types rather than just composite outcomes.

scholarly journals Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1014-1019 ◽  
Author(s):  
C Carlo-Stella ◽  
M Cazzola ◽  
A Gasner ◽  
G Barosi ◽  
L Dezza ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitor Cells ◽  
Definitive Treatment ◽  
Hematopoietic Progenitor Cell ◽  
In Vitro Growth ◽  
Hematopoietic Progenitor ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder due to clonal expansion of a pluripotent hematopoietic progenitor cell with secondary marrow fibrosis. No definitive treatment has as yet been devised for this condition, which shows a marked variability in clinical course. To evaluate whether excessive hematopoietic progenitor cell proliferation could be controlled by recombinant human interferon alpha (rIFN-alpha) and gamma (rIFN-gamma), we studied the effects of these agents on the in vitro growth of pluripotent and lineage-restricted circulating hematopoietic progenitor cells in 18 patients with MMM. A significant increase in the growth (mean +/- 1 SEM) per milliliter of peripheral blood of CFU-GEMM (594 +/- 253), CFU-Mk (1,033 +/- 410), BFU-E (4,799 +/- 2,020) and CFU- GM (5,438 +/- 2,505) was found in patients as compared with normal controls. Both rIFN-alpha and rIFN-gamma (10 to 10(4) U/mL) produced a significant dose-dependent suppression of CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM growth. Concentrations of rIFN-alpha and rIFN-gamma causing 50% inhibition of colony formation were 37 and 163 U/mL for CFU-GEMM, 16 and 69 U/mL for CFU-Mk, 53 and 146 U/mL for BFU-E, and 36 and 187 U/mL for CFU-GM, respectively. A marked synergistic effect was found between rIFN-alpha and rIFN-gamma: combination of the two agents produced inhibitory effects greater than or equivalent to those of 10- to 100- fold higher concentrations of single agents. These studies (a) confirm that circulating hematopoietic progenitors are markedly increased in MMM, (b) indicate that these presumably abnormal progenitors are normally responsive to rIFNs in vitro, and (c) show that IFNs act in a synergistic manner when used in combination. Because rIFN-gamma can downregulate collagen synthesis in vivo, this lymphokine could be particularly useful in the treatment of patients with MMM.

scholarly journals The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function

Haematologica ◽  
2019 ◽  
Vol 105 (2) ◽  
pp. 317-324 ◽  
Author(s):  
Andreas Brown ◽  
Desiree Schuetz ◽  
Yang Han ◽  
Deidre Daria ◽  
Kalpana J. Nattamai ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Progenitor Cell ◽  
Cell Function ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Trait Locus

Functional Correction of Fanconi Anemia Group A Hematopoietic Cells by Retroviral Gene Transfer

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3296-3303 ◽  
Author(s):  
Kai-Ling Fu ◽  
Jerome R. Lo Ten Foe ◽  
Hans Joenje ◽  
Kathleen W. Rao ◽  
Johnson M. Liu ◽  
...  
Keyword(s):  
Cell Growth ◽  
Progenitor Cells ◽  
Fanconi Anemia ◽  
Progenitor Cell ◽  
Hematopoietic Cells ◽  
Retroviral Vectors ◽  
Retroviral Vector ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Increased Risk

Abstract Fanconi anemia (FA) is an autosomal recessive genetic disorder characterized by a variety of physical anomalies, bone marrow failure, and an increased risk for malignancy. FA cells exhibit chromosomal instability and are hypersensitive to DNA cross-linking agents such as mitomycin C (MMC). FA is a clinically heterogeneous disorder and can be functionally divided into at least five different complementation groups (A-E). We previously described the use of a retroviral vector expressing the FAC cDNA in the complementation of mutant hematopoietic cells from FA-C patients. This vector is currently being tested in a clinical trial of ex vivo hematopoietic progenitor cell transduction. The FA-A group accounts for over 65% of all FA cases, and the FAA cDNA was recently identified by both expression and positional cloning techniques. We report here the transduction and phenotypic correction of lymphoblastoid cell lines from four unrelated FA-A patients, using two amphotropic FAA retroviral vectors. Expression of the FAA transgene was adequate to normalize cell growth, cell-cycle kinetics, and chromosomal breakage in the presence of MMC. We then analyzed the effect of retroviral vector transduction on hematopoietic progenitor cell growth. After FAA transduction of mutant progenitor cells, either colony number or colony size increased in the presence of MMC. In addition, FAA but not FAC retroviral transduction markedly improved colony growth of progenitor cells derived from an unclassified FA patient. FAA retroviral vectors should be useful for both complementation studies and clinical trials of gene transduction.

scholarly journals Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 10-19 ◽  
Author(s):  
S Rafii ◽  
F Shapiro ◽  
J Rimarachin ◽  
RL Nachman ◽  
B Ferris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Divalent Cations ◽  
Hematopoietic Cells ◽  
Hematopoietic Progenitor Cell ◽  
Microvascular Endothelial Cells ◽  
Microvascular Endothelial

Abstract To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells within the bone marrow (BM) microenvironment, we have devised a technique for the in vitro study of the interaction of human BM microvascular endothelial cells (BMEC) with hematopoietic cells. Microvessels isolated by collagenase digestion of spicules obtained from filtered BM aspirate were plated on gelatin-coated plastic dishes, and colonies of endothelial cells grown from microvessel explants were further purified by Ulex europaeus lectin affinity separation. BMEC monolayers isolated by this technique grew in typical cobblestone fashion, stained positively with antibody to factor VIII/von Willebrand factor, and incorporated acetylated LDL. Immunohistochemical studies showed that BM microvessels and BMEC monolayers express CD34, PECAM, and thrombospondin. Incubation of resting BMEC with BM mononuclear hematopoietic cells resulted in the selective adhesion of relatively large numbers of CD34+ progenitor cells and megakaryocytes. The binding of purified BM-derived CD34+ progenitor cells to BMEC was dependent on divalent cations and was partially blocked by antibodies to CD34. IL-1 beta treatment of BMEC monolayers resulted in an increase of CD34+ progenitor cell adhesion by mechanisms independent of CD34 or divalent cations. BMEC exhibit specific affinity for CD34+ progenitor cells and megakaryocytes, suggesting that the BM microvasculature may play a role in regulating the trafficking, proliferation, and differentiation of lineage specific hematopoietic elements, and possibly of pluripotent stem cells within the CD34+ population.

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