Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

BackgroundDiffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.MethodsSyngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.ResultsExpression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.ConclusionsVirus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.     

Treatment of Tobacco Use in Preconception Care

Maternal and Child Health Journal -     

SODIUM EFFECTS ON THE FIBRILLATORYPROPENSITY OF NON-IONIC CONTRAST MEDIA

Removing sodium from standard ionic contrastmedia markedly increases the incidence of ventricu-lar fibrillation in patients undergoing coronary arvgiography. Newer nonionic contrast media, Iopa-midol (IOP), Iohexol (IOH) and Ioversol (IOV),contain only trace amounts of sodium. To determinewhether sodium influences the fibrillatory propen-sity of nonionic contrast media, we measured theprolongation in QT interval and performed program-med electrical stimulation with l,2 and 3 ventricularextra stimuli in 40 dogs during 4 ml intracoronaryinjections of IOP, IOH and IOV. Solutions of eachcontrast media with added NaCI at concentrations of0.225To, 0.45% and 0.970 were compared to stockcontrast media. The addition of NaCI markedlyincreased the amount of QT interval prolongationproduced by each contrast media. With IOP, theamount of QT interval prolongation was 40+11msec with standard IOP but was 58+11 msec with0.225'70 NaCI/IOP, 84+17 msec with 0.45'To NaCI/IOP, and 132+42 msec with 0.970 NaCl/IOP(P相似文献   

The influence of stigma on the sexual risk behavior of rural men who have sex with men.

Research investigating predictors of risky sexual behavior of rural MSM is sparse, even though the prevalence of HIV in rural areas has increased. This study explored two sets of predictors of 93 rural MSM's levels of risky sexual behavior: mental health variables and stigma emanating from men's family members, health care professionals, and people in the rural communities in which they live. Over 47% of the men were found to be at modified high to high risk. Logistic regression using a continuation logit model was used to test the relationship of the predictor variables and the four levels of risk. Findings indicate that self-esteem was predictive of the highest sexual risk behavior but not lower levels of risk. Stigma was predictive of modified high sexual risk when compared to low and no risk categories. No variables differentiated men at low risk from men at no risk.