Cell-based therapies for glioblastoma: Promising tools against tumor heterogeneity

Glioblastoma (GBM) is a highly aggressive tumor with a devastating impact on quality-of-life and abysmal survivorship. Patients have very limited effective treatment options. The successes of targeted small molecule drugs and immune checkpoint inhibitors seen in various solid tumors have not translated to GBM, despite significant advances in our understanding of its molecular, immune, and microenvironment landscapes. These discoveries, however, have unveiled GBM's incredible heterogeneity and its role in treatment failure and survival. Novel cellular therapy technologies are finding successes in oncology and harbor characteristics that make them uniquely suited to overcome challenges posed by GBM, such as increased resistance to tumor heterogeneity, modularity, localized delivery, and safety. Considering these advantages, we compiled this review article on cellular therapies for GBM, focusing on cellular immunotherapies and stem cell-based therapies, to evaluate their utility. We categorize them based on their specificity, review their preclinical and clinical data, and extract valuable insights to help guide future cellular therapy development

B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres

Background: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. Methods: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. Findings: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. Interpretation: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. Fund: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund

What proportion of riverine nutrients reaches the open ocean?

Globally, rivers deliver significant quantities of nitrogen (N) and phosphorus (P) to the coastal ocean each year. Currently, there are no viable estimates of how much of this N and P escapes biogeochemical processing on the shelf to be exported to the open ocean; most models of N and P cycling assume that either all or none of the riverine nutrients reach the open ocean. We address this problem by using a simple mechanistic model of how a low-salinity plume behaves outside an estuary mouth. The model results in a global map of riverine water residence times on the shelf, typically a few weeks at low latitudes and up to a year at higher latitudes, which agrees well with observations. We combine the map of plume residence times on the shelf with empirical relationships that link residence time to the proportions of dissolved inorganic N (DIN) and P (DIP) exported and use a database of riverine nutrient loads to estimate the global distribution of riverine DIN and DIP supplied to the open ocean. We estimate that 75% of DIN and 80% of DIP reaches the open ocean. Ignoring processing within estuaries yields annual totals of 17 Tg DIN and 1.2 Tg DIP reaching the open ocean. For DIN this supply is about 50% of that supplied via atmospheric deposition, with significant east-west contrasts across the main ocean basins. The main sources of uncertainty are exchange rates across the shelf break and the empirical relationships between nutrient processing and plume residence time

Childhood Obesity

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community

Making an IMPACT: The Story of a Medical Student-Designed, Peer-Led Healthy Eating and Physical Activity Curriculum

Despite the importance of healthful dietary choices in combating the childhood obesity epidemic, neither primary and secondary schools nor medical schools provide adequate nutrition education. In 2005, two medical students at the University of North Carolina started the Improving Meals and Physical Activity in Children and Teens (IMPACT) program, which utilized a peer-educator model to engage medical students and high school students in teaching 4th graders about healthy eating and physical activity. Over the years, medical student leaders of IMPACT continued the program, orienting the curriculum around the 5-2-1-0 Let’s Go campaign, aligning the IMPACT curriculum with North Carolina state curricular objectives for 4th graders and engaging and training teams of health professional students to deliver the program. The IMPACT project demonstrates how medical and other health professional students can successfully promote nutrition and physical activity education for themselves and for children through community-based initiatives. Ongoing efforts are aimed at increasing family participation in the curriculum to maximize changes in eating and physical activity of IMPACT participants and ensuring sustainability of the organization by engaging health professional student participants in continuing to improve the program

Cognitive function in adolescence and the risk for premature diabetes and cardiovascular mortality in adulthood

Abstract Background Epidemiological studies have demonstrated a relationship between cognitive function in youth and the future risk of death. Less is known regarding the relationship with diabetes related death. This study assessed the relationship between cognitive function in late adolescence and the risk for diabetes, cardiovascular- (CVD) and all-cause mortality in adulthood. Methods This retrospective study linked data from 2,277,188 16–19 year olds who had general intelligence tests (GIT) conducted during pre-military recruitment assessment with cause of death as coded by the Israel Central Bureau of Statistics. The associations between cognitive function and cause-specific mortality were assessed using Cox models. Results There were 31,268 deaths that were recorded during 41,916,603 person-years of follow-up, with a median follow-up of 19.2 (IQR 10.7, 29.5) years. 3068, 1443, 514 and 457 deaths were attributed to CVD, CHD, stroke, and diabetes, respectively. Individuals in the lowest GIT vs. highest GIT quintiles in unadjusted models had the highest risk for all-cause mortality (HR 1.84, 95% CI 1.78, 1.91), total CVD (HR 3.32, 95% CI 2.93, 3.75), CHD (HR 3.49 95% CI 2.92, 4.18), stroke (HR 3.96 95% CI 2.85, 5.5) and diabetes-related (HR 6.96 95% CI 4.68, 10.36) mortality. These HRs were attenuated following adjustment for age, sex, birth year, body-mass index, residential socioeconomic status, education and country of origin for all-cause (HR 1.23, 95% CI 1.17, 1.28), CVD (HR 1.76, 95% CI 1.52, 2.04), CHD (HR 1.7 95% CI 1.37, 2.11), stroke (HR 2.03, 95% CI 1.39, 2.98) and diabetes-related (HR 3.14 95% CI 2.00, 4.94) mortality. Results persisted in a sensitivity analyses limited to participants with unimpaired health at baseline and that accounted competing risk. Conclusions This analysis of over 2 million demonstrates a strong relationship between cognitive function at youth and the risk for diabetes, all-cause and CVD-related mortality independent of adolescent obesity