Fibrosis occurs when there is an imbalance in extracellular matrix (ECM) deposition and degradation. Excessive ECM deposition results in scarring and thickening of the affected tissue, and interferes ...with tissue and organ homeostasis - mimicking an exaggerated "wound healing" response. Many transforming growth factor-β (TGF-β) ligands are potent drivers of ECM deposition, and additionally, have a natural affinity for the ECM, creating a concentrated pool of pro-fibrotic factors at the site of injury. Consequently, TGF-β ligands are upregulated in many human fibrotic conditions and, as such, are attractive targets for fibrosis therapy. Here, we will discuss the contribution of TGF-β proteins in the pathogenesis of fibrosis, and promising anti-fibrotic approaches that target TGF-β ligands.
Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a ...carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×10
TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.
Purpose
Pediatric palliative care (PPC) improves quality of life for children and adolescents with cancer. Little is known about disparities between different racial and ethnic groups in the ...frequency and timing of PPC referrals. We evaluated the impact of race and ethnicity on the frequency and timing of PPC referral after initiation of an embedded PPO clinic where no formal consultation triggers exist.
Methods
Patients with cancer between 0 and 25 years at diagnosis who experienced a high-risk event between July 2015 and June 2018 were eligible. Demographic, disease, and PPC information were obtained. Descriptive statistics and logistic regression were used to assess likelihood of receiving PPC services by race/ethnicity.
Results
Of 426 patients who experienced a high-risk event, 48% were non-Hispanic White, 31% were non-Hispanic Black, 15% were Hispanic of any race, and 4% were non-Hispanic Asian. No significant differences were found between race/ethnicity and age at diagnosis/death, sex, and diagnosis. PPC consultation (
p
= 0.03) differed by race. Non-Hispanic Black patients were 1.7 times more likely than non-Hispanic White patients to receive PPC after adjustment (
p
= 0.01). White patients spent less days in the hospital in the last 90 days of life (3.0 days) compared with Black (8.0), Asian (12.5), or Hispanic patients (14.0,
p
= 0.009)
Conclusion
Disparities exist in patients receiving pediatric oncology and PPC services. Cultural tendencies as well as unconscious and cultural biases may affect PPC referral by race and ethnicity. Better understanding of cultural tendencies and biases may improve end-of-life outcomes for children and young adults with cancer.
Hunting is one of the greatest threats to nonhuman primates worldwide. Despite Madagascar’s status as a primate mega-diversity country, a critical lack of information on the hunting of lemurs at the ...national scale persists. Here, we synthesize the current state of knowledge of the annual rates of household-level lemur hunting near ten protected areas, representing most ecoregions in Madagascar. We examine geographic and taxonomic variation in lemur hunting, including an analysis of hunting relative to species density, extinction risk, and intrinsic ecological characteristics of species. We found that lemurs are commonly hunted across Madagascar; the rural households in our study ate, on average, more than one lemur each year, or a median of 4.1% of the lemur species’ population size where densities are known. However, this pressure varied significantly across sites and species, reaching its highest levels in the northeastern rainforest region. While hunting levels are concerning for numerous threatened species, hunting pressure was driven primarily by species availability, and among ecological traits, small body size was related to increased hunting; however, conservation status showed no such relationship. This first national-level assessment of hunting, including one-third of Madagascar’s lemur species and more than a tenth of the world’s primates, identifies regional variation and lemur taxa at acute risk from hunting—important steps toward developing targeted strategies to conserve one of the world’s most threatened groups of vertebrates.
Pediatric palliative care (PPC) can improve quality of life of children with life-threatening conditions and their families. However, PPC resources vary by state and within a state, and PPC resources ...and personnel are often inequitably distributed toward urban areas with major hospital systems. A community needs assessment (CNA) that evaluates the current status of PPC and pediatric hospice care can help identify gaps and opportunities to improve PPC access.
A CNA was performed in the state of Georgia to explore the scope and gaps of PPC and hospice services and plan for what is needed to grow PPC and hospice services.
The CNA used a mixed-methods approach, including a community profile, literature search, windshield survey, key informant interviews, and a quantitative online survey. The methodology is outlined in a companion article, entitled “A methodological approach to conducting a statewide community needs assessment of pediatric palliative care and hospice resources.”
Four key themes were identified from synthesis of primary and secondary data collection: defining and providing PPC, the environment for PPC in Georgia, coordination and collaboration, and the future of PPC in Georgia. Recommendations to improve PPC services in Georgia were categorized by feasibility and importance. High feasibility and high importance recommendations included expanding PPC education for both providers and patients and creating a formal network or coalition of PPC providers and allies who can work collaboratively at multiple care levels across Georgia in expanding PPC services.
In Georgia, this assessment provides the foundation for next steps in coordinated efforts between hospital-based clinicians, state hospice and palliative care organizations, and state policy makers to ultimately expand PPC care available to children and families.
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in ...cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
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