Adv Exp Med Biol
-
Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1). ⋯ It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells. Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.
-
Cancer immunotherapy is emerging as the most promising novel strategy for cancer treatment. Cancer immunotherapy is broadly categorized into three forms: immune checkpoint modulation, adoptive cell transfer, and cancer vaccine. Immune checkpoint blockade is demonstrated as the most clinically effective treatment with low immune-related adverse events (irAE). ⋯ Breast cancers such as triple negative breast cancer and HER-2 negative breast cancer respond to immune checkpoint blockade therapy due to their high immunogenicity. PD-1/PD-L1 blockade has just received FDA approval as a standard cancer therapy for solid tumors such as breast cancer. Development of immune checkpoint blockade focuses on two directions: one is to identify proper biomarkers of immune checkpoint blockade in breast cancer, and the other is to combine therapies with PD-1/PD-L1 blockade antibodies to achieve optimal clinical outcomes.
-
Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. ⋯ In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.
-
Interleukin-2 (IL-2) is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. ⋯ OS, our disease of interest, has a peak incidence in the adolescent and young adult years. Our goal is to complete this trial in the next 2 years. In this chapter, we summarize the different effects of IL-2 and cover the advantages of the aerosol delivery route for diseases of the lung with an emphasis on some of our most recent work using combination therapy aerosol IL-2 and NK cells for the treatment of OS lung metastases.
-
Hypertension remains the most important risk factor for cardiovascular disease. If antihypertensive drugs choice is well guided today, blood pressure (BP) target still a subject of controversies. Residual risk is matter of debate and the lower- the better dogma is come back again regarding to data reported from recent trials. ⋯ In diabetic patients, SBP target should be less than 140 mmHg according to ACCORD trial. However, for patients with protein-creatinine ratio >500 mg/g (albumin-creatinine ratio > 300 mg/g), with or without diabetes, lower SBP target should be proposed for renal protection aiming SBP < 130 mmHg as recommended by KDIGO guidelines. In patients at low or intermediate risk, without cardiovascular disease, SBP should start to be treated when SBP is above 140 mmHg, and when treated, target BP should be less than 140 mmHg as reported by HOPE-3 trial.