ToyBox Study Malaysia: Improving healthy energy balance and obesity‐related behaviours among pre‐schoolers in Malaysia

The prevalence of childhood overweight and obesity is increasing in Malaysia and currently nearly 10% of children aged between 6 months and 12 years are overweight and almost 12% are obese. Early interventions to prevent excess weight gain are needed. ToyBox Study Malaysia is a feasibility project, funded by the Medical Research Council Newton‐Ungku Omar Fund, to assess the practicalities of adapting the existing European ToyBox Study intervention programme to the Malaysian kindergarten setting. The main aims of all ToyBox programmes are related to improving four key energy balance‐related behaviours, namely drinking water, eating healthy snacks and meals, reducing sedentary behaviour and increasing physical activity. Using stratified sampling, the ToyBox Study Malaysia intervention will be delivered and compared to usual practice by assessing behaviour, physical activity and health‐related outcomes as measured by questionnaires, accelerometry and anthropometry. It is hoped that the evidence‐based ToyBox Study Malaysia will help to achieve healthier energy balance‐related behaviours in the children and their families and provide lifelong benefits to health. This article provides information on the dietary patterns, physical activity levels and prevalence of overweight and obesity in Malaysian children, and the approach of the ToyBox Study Malaysia.     

Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells

The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.     

Safety of 5-Aminosalicylic Acid Derivatives in Patients with Sensitivity to Acetylsalicylic Acid and Nonsteroidal Anti-inflammatory Drugs

Background:

One of the cornerstones of the management of inflammatory bowel disease is the use of 5-aminosalicylic acid (5-ASA) compounds for treatment of flares and as maintenance therapy during remission. There are concerns about using 5-ASA in patients with a history of hypersensitivity to acetylsalicylic acid (ASA).

Objective:

To assess the literature with respect to the safety of 5-ASA compounds in patients with documented sensitivity to ASA or nonsteroidal anti-inflammatory drugs (NSAIDs).

Data Sources:

A literature search was conducted in the MEDLINE and Embase databases, using various search terms, including “aminosalicylic acids”, “non-steroidal anti-inflammatory agents,” “hypersensitivity”, and “allergy”. The search was limited to articles (of any study design) published in English. Abstracts, full articles, and reference lists from retrieved articles were assessed to identify further relevant literature.

Study Selection and Data Extraction:

Of 485 citations identified in the initial search, 4 case reports were relevant to the study objective and were analyzed in detail.

Data Synthesis:

Three of the case reports described the successful use of 5-ASA compounds in patients with prior sensitivity to ASA or an NSAID. The fourth report described a reaction to 5-ASA in a patient who had previously tolerated ASA. All of the reports were limited by lack of investigation into the validity of the reported sensitivity to ASA or 5-ASA.

Conclusions:

There is a dearth of evidence demonstrating cross-reactivity between ASA or NSAID and 5-ASA. This lack of information may relate to the mechanism of action of 5-ASA. This agent controls inflammation by inhibiting prostaglandin E2 and leukotrienes. In contrast, ASA-induced or NSAID-induced reactions are due to inhibition of the cycloxygenase-1 enzyme and subsequent release of histamine and synthesis of leukotrienes. Further reports describing the safety of 5-ASA use in patients with sensitivity to ASA or NSAIDs are needed before safety in this situation can be definitively determined. In patients with sensitivity to ASA or NSAID who require 5-ASA, a test dose of 5-ASA (to rule out potential cross-reactivity) or further investigation of the ASA or NSAID sensitivity is recommended.     

Toxic fibrillar oligomers of amyloid-β have cross-β structure

Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-β(1-42) (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-β structure, in which adjacent β-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical β-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.     

Unique FISH patterns associated with cancer progression of oral dysplasia

Subgroups of patients with oral pre-malignant lesions (OPLs) are at extremely high risk for developing invasive cancer in spite of surgical excision. The objective of this study was to evaluate the utility of specific genes and their associated centromeres as markers to stratify OPLs for their cancer risk. Samples used in this study included 35 oral dysplasia with known outcome and 20 normal oral mucosa. Of the dysplasias, 20 were from an ongoing longitudinal study showing progression. The remaining 15 cases (2 of which progressed) were chosen from the population-based, provincial BC Oral Biopsy Service (OBS). Copy number alterations at EGFR, CEP7, CCND1, and CEP11 were evaluated by fluorescent in situ hybridization (FISH). There was no significant difference in demographics between progressors and non-progressors. Specific FISH profiles at these genes and their corresponding centromeres were associated with progression. High gene gain of CCND1 was associated with an 8-fold elevated risk of progression compared with those with no gain in time-to-progression analysis. Numerical alterations of EGFR and CCND1 and their centromeres might be an effective means for identifying OPLs at risk. Future studies will expand on this analysis and set the stage for application of this approach in routine clinical practice.     

Submandibular gland mucocele associated with a mixed ranula

Mucoceles of the submandibular gland are extremely rare pathologic occurrences that present an investigative and management dilemma owing to their clinical indistinguishability from plunging ranulas. Of the few that have been documented, these mucous extravasation cysts involved the submandibular gland alone. We describe perhaps the first case of an extensive submandibular gland mucocele occurring in conjunction with a mixed ranula from the ipsilateral sublingual gland, and discuss the various considerations in the management of such lesions.