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.     

Preventing heart disease: is treating the high risk sufficient?

Monte Carlo simulation was used to assess the effects of several intervention strategies on coronary heart disease mortality rates in a Finnish and a North American cohort. Lowering total serum cholesterol by 4%, smoking by 15%, and diastolic blood pressure by 3% for the whole cohort would be expected to reduce the incidence of non-fatal myocardial infarction by at least 13% and coronary heart disease deaths by at least 18%. Lowering serum cholesterol by 34%, diastolic blood pressure to 90 mmHg, and reducing smoking by 20% in the subset of the population with all three risk factors in the highest quartile would result in a 6-8% reduction in non-fatal myocardial infarction and a 2-9% reduction in deaths from coronary heart disease in these cohorts. These data demonstrate that in populations with a relatively high incidence of heart disease, treating the entire population will produce larger effects than focusing only on high-risk populations.     

Radiation dose reduction during hysterosalpingography: an application of scanning-beam digital radiography

Hysterosalpingography was performed in 31 patients by means of a low-dose scanning-beam digital radiographic system. The technique permits adequate evaluation of gynecologic abnormalities while allowing significant reduction in radiation: 2.4-mR (6.1 X 10(-7) C/kg) exposure to the skin and 0.7-mrad (7 X 10(-6) Gy) mean dose to the ovaries per image obtained. Sixteen patients demonstrated readily recognizable and documented abnormalities, corroborated by laparoscopy, laparotomy, or other supportive evidence.     

Influence of complement on sperm motility

Isolated sperm from normo-, oligo- and astheno-spermic men were incubated for 20 h in medium supplemented with 8% heat-inactivated or untreated human serum, and in medium with heated or untreated serum deficient in complement factor C3. Before and after incubation, sperm motility was assessed by means of a computer-assisted semen analyser. The results did not show significant differences between the motility of sperm incubated in heated or untreated serum. It is concluded that heating of homologous serum is not necessary for preserving sperm motility and in some cases may even be disadvantageous.     

Using serum cholesterol to identify high risk and stimulate behavior change: will it work?

If the measurement of serum cholesterol is to be used to identify a sub-population at high risk of subsequent disease and to stimulate behavior change in this group to lower serum cholesterol, the test must be able to both discriminate and motivate the group. The ability of the test to motivate has been documented in a randomized trial. This paper therefore tests, in a cohort of United States men ages 40-59 at entry, the ability of serum cholesterol to discriminate between individuals who would and would not die from coronary heart disease. While risk of death increased with increasing serum cholesterol, the values for men who developed coronary heart disease overlapped the values of the men who did not develop the disease. Overall test accuracy declined from 92% correctly classified when 5% of the population was defined as "at high risk" to 55% when 50% of the population was defined as "at high risk". On a receiver operating curve, defining 5% of the men as "high risk" yielded a false positive rate of 5% and a true positive rate of 8%. Increasing the proportion of men defined as "at high risk" to 50% increased the true positive rate to 75% but also increased the false positive rate to over 50%. Monte Carlo simulation demonstrated that lowering mean serum cholesterol 0.78 mmol/l in the entire population would lower deaths from coronary heart disease by 28%. The same effect could be achieved by lowering the serum cholesterol of all people in the top 20% of the distribution to 4.66 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Image-directed percutaneous biopsies with a biopsy gun

Core tissue for histologic study is believed by many pathologists to be more diagnostic than material from needle aspiration. Recently, a biopsy "gun" has been introduced, which simplifies core biopsies. With this device, 182 biopsies of multiple anatomic sites were performed with ultrasonic, computed tomographic, and fluoroscopic guidance and 18-gauge needles. High-quality histopathologic specimens were obtained in 177 of the biopsies, and diagnostic target tissue was obtained in 167. Only three significant complications occurred: one bleeding complication that required transfusion and two cases of pneumothorax that necessitated placement of chest tubes. The biopsy gun eliminated the disjointed movements of conventional "skinny" needle biopsies, and none of the samples demonstrated significant "crush" artifact or obscuring blood, problems that are commonly associated with manual biopsy techniques. Patient discomfort was decreased with this system compared with that of manual biopsies, and the total procedure time was reduced. Because of these distinct advantages, the authors now use the biopsy gun exclusively for all percutaneous biopsies and recommend that other institutions consider the use of this biopsy method.     

Location and sequence of atherosclerotic plaque formation in white Carneau and show racer pigeons: reevaluation and redefinition.

Sudan staining of gross specimens with correlated histologic sections was used to localize the accumulation of fat in the aortas of genetically susceptible and resistant strains of pigeons. The birds were maintained on a cholesterol-free grain diet, and studies were done sequentially from ages 1 month to 4 years. Evidence suggests that the accumulation of lipids in musculoelastic cushions located at the origin of small branches is not necessarily a precursor of complicated lesions, but that it occurs concurrently in susceptible and resistant strains. In contrast, in the "lesion area," lipid accumulation is more striking and occurs earlier in the susceptible strain. It precedes proliferation by three to six months. Thus, in this model, two distinct types of fatty streaks can be identified and their biologic features can be defined and related to their propensity for atherogenesis.