Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection.

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1

Complejidad de las lesiones coronarias en pacientes diabéticos

Introduction and Objectives: Coronary artery disease in diabetic patients is presented in a very aggressive form with excessive progression of atherosclerosis and increased risk of stent restenosis or thrombosis in percutaneous coronary intervention. The objective of this research was to determine the relationship between diabetes mellitus and certain characteristics of coronary lesions and their relation with restenosis, thrombosis and development of new lesions after percutaneous procedure. Method: A retrospective-descriptive study was performed. Out of the 1,464 patients revascularized at the Medical and Surgical Research Center in Havana, Cuba, between August 1997 and February 2009, 270 diabetic patients were selected. Results: Diabetes mellitus was a risk factor for the following lesions: circumflex (OR*=1.48); ostium aorto-coronary (OR=3.58), left anterior descending (OR=2.41) and circumflex (OR=4.89), and trunk lesions extending into the left anterior descending artery (OR=9.79). Diabetics were more likely to develop complex lesions type B2 and C (OR=1.36), for curves higher than 90º (OR=3.03), with previous curves higher of 90 °(OR=6.13), injuries of more than 20 mm (OR=2.0), in branches (OR=1.69) and injuries due to absence of coronary flow (OR=4.15). They were also characterized by having smaller arteries of 3 mm (OR=1.32) and increased risk of developing new lesions (OR=2.11), restenosis (OR=2.11) and throm-bosis (OR=3.06) of stent. Conclusions: Diabetes mellitus was a risk factor for the development of complex coronary lesions with a high risk of further lesions, restenosis and stent thrombosis.Introducción y objetivos: La enfermedad coronaria en los pacientes diabéticos se presenta de forma muy agresiva con una excesiva progresión de la ateroscle-rosis y con mayor riesgo de reestenosis o trombosis de stent, en el intervencionismo coronario percutáneo. El objetivo de esta investigación fue determinar la rela-ción entre la diabetes mellitus y determinadas caracte-rísticas de las lesiones coronarias, así como su rela-ción con la reestenosis, la trombosis y el desarrollo de nuevas lesiones después del procedimiento percutá-neo. Método: Se realizó un estudio descriptivo-retros-pectivo. De los 1.464 pacientes revascularizados en el Centro de Investigaciones Médico-Quirúrgicas de La Habana, Cuba, entre agosto de 1997 y febrero de 2009, se seleccionaron 270 pacientes diabéticos. Re-sultados: La diabetes mellitus fue un factor de riesgo para las lesiones de circunfleja (OR*=1,48); de los ostium aorto-coronario (OR=3,58), de descendente an-terior (OR=2,41) y de circunfleja (OR=4,89); y para las lesiones de tronco con extensión a descendente anterior (OR=9,79). Los diabéticos tuvieron más riesgo de desarrollar lesiones complejas tipo B2 y C (OR=1,36), en curvaturas mayores de 90º (OR=3,03), con curvaturas previas superiores de 90º (OR = 6,13), lesiones de más de 20 mm (OR=2,0), en ramificacio-nes (OR=1,69) y lesiones por ausencia de flujo corona-rio (OR=4,15). Se caracterizaron también por tener arterias menores de 3 mm (OR=1,32) y mayor riesgo de desarrollar nuevas lesiones (OR=2,11), reestenosis (OR=2,11) y trombosis (OR=3,06) del stent. Conclu-siones: La diabetes mellitus se comportó como un factor de riesgo para el desarrollo de lesiones coro-narias complejas y con un elevado riesgo de desa-rrollar nuevas lesiones, reestenosis y trombosis de los stents

Factores clínicos y del procedimiento relacionados con la trombosis de stent

Introduction and Objectives: Stent thrombosis is a complication after percutaneous coronary intervention associated with high mortality and morbidity. Despite the use of dual antiplatelet therapy (aspirin and clopi-dogrel) and optimization of the technique, its incidence has not disappeared. The objective of this research was to determine the risk factors for thrombosis of the conventional metal stents. Method: A retrospective descriptive study was performed. Out of the 2,014 revascularized arteries at the Medical and Surgical Research Center in Havana, Cuba, between August 1997 and February 2009, the 289 redo ones were selected. Results: Thrombosis of the bare metal stents was present in 20 arteries, of which 11 corresponded to the anterior descending artery, and the highest inci-dence occurred in the first 24 hours and after 30 days. Diabetes mellitus was a risk factor for thrombosis (OR=3.06) and the release pressure of less than 10 atmospheres (OR=3.70) and complex lesions of types B2 and C (OR=8.80), all with statistical significance (p<0.05). Conclusions: The highest incidence of bare metal stent thrombosis was on the first day of revas-cularization after the termination of dual antiplatelet therapy and located in the anterior descending artery. Diabetes mellitus, complex lesions and low pressures of stent release, behaved as risk factors for thrombosis with statistically significant results.Introducción y objetivos: La trombosis del stent es una de las complicaciones posterior al intervencionis-mo coronario percutáneo, asociada a una elevada mortalidad y morbilidad. A pesar del uso de la doble terapia antiplaquetaria (aspirina y clopidogrel) y la opti-mización de la técnica, su incidencia no ha desapare-cido. El objetivo de esta investigación fue determinar los factores de riesgo de trombosis de los stent metá- licos convencionales. Método: Se realizó un estudio descriptivo-retrospectivo. De las 2.014 arterias revas-cularizadas en el Centro de Investigaciones Médico-Quirúrgicas de La Habana, Cuba; entre agosto de 1997 y febrero de 2009, se seleccionaron las 289 reestudiadas. Resultados: La trombosis de los stent metálicos convencionales estuvo presente en 20 arte-rias, de las cuales 11 resultaron ser la descendente anterior, y su mayor incidencia se presentó en las primeras 24 horas y después de los 30 días. La dia-betes mellitus se comportó como un factor de riesgo de trombosis (OR*=3,06), así como la presión de libera-ción de menos de 10 atmósferas (OR=3,70) y las lesio-nes complejas de los tipos B2 y C (OR=8,80), todos con significación estadística (p < 0,05). Conclusiones: La mayor incidencia de trombosis de los stent metá-licos convencionales fue en el primer día de la revas-cularización, después de la terminación de la doble terapia de antiagregación plaquetaria y en la arteria descendente anterior. La diabetes mellitus, las lesiones complejas y las bajas presiones de liberación del stent, se comportaron como factores de riesgo de trombosis con resultados estadísticamente significativos

Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1

Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1

Results of TDF + FTC combination (Round 3) dose ranging infection study.

<p>Results of TDF + FTC combination (Round 3) dose ranging infection study.</p

Prevention of vaginal and rectal HIV transmission by antiretroviral combinations in humanized mice

<div><p>With more than 7,000 new HIV infections daily worldwide, there is an urgent need for non-vaccine biomedical prevention (nBP) strategies that are safe, effective, and acceptable. Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) can be effective at preventing HIV infection. In contrast, other trials using the same ARVs failed to show consistent efficacy. Topical (vaginal and rectal) dosing is a promising regimen for HIV PrEP as it leads to low systematic drug exposure. A series of titration studies were carried out in bone marrow/liver/thymus (BLT) mice aimed at determining the adequate drug concentrations applied vaginally or rectally that offer protection against rectal or vaginal HIV challenge. The dose-response relationship of these agents was measured and showed that topical tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can offer 100% protection against rectal or vaginal HIV challenges. From the challenge data, EC₅₀ values of 4.6 μM for TDF and 0.6 μM for FTC for HIV vaginal administration and 6.1 μM TDF and 0.18 μM for FTC for rectal administration were obtained. These findings suggest that the BLT mouse model is highly suitable for studying the dose-response relationship in single and combination ARV studies of vaginal or rectal HIV exposure. Application of this sensitive HIV infection model to more complex binary and ternary ARV combinations, particularly where agents have different mechanisms of action, should allow selection of optimal ARV combinations to be advanced into pre-clinical and clinical development as nBP products.</p></div

Results of broad-range (Round 1) dose ranging infection study.

<p>Results of broad-range (Round 1) dose ranging infection study.</p

Results of narrow-range (Round 2) dose ranging infection study for EC₅₀ determination.

<p>Results of narrow-range (Round 2) dose ranging infection study for EC₅₀ determination.</p

TFV and TFV-DP tissue concentration-time profiles following either vaginal or rectal dosing using 32 μM TDF.

<p>Median effect plots for (A) vaginal and (B) rectal drug dosing. <i>F</i>_<i>a</i>, fraction affected; <i>F</i>_<i>u</i>, fraction unaffected; <i>D</i>, dose (nM); blue circles, TDF; red circles, FTC; green circles, TDF-FTC combination. Dose response index (DRI) plots for (C) vaginal and (D) rectal dosing of both drugs in the TDF-FTC combination. <i>F</i>_<i>a</i>, fraction affected; blue circles, TDF; red circles, FTC. The DRI of 1 shown in as a broken line represents no dose reduction relative to the drugs evaluated individually. Predicted EC₅₀-EC₉₇ values for the TDF-FTC combination for (E) vaginal and (F) rectal drug dosing.</p