The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity

The diterpene ester ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus. Crude euphorbia extract causes local toxicity and transient inflammation when applied topically and has been used in the treatment of warts, skin keratoses and skin cancer. PEP005 is a broad range activator of the classical (α, β, γ) and novel (δ, ε, η, θ) protein kinase C isoenzymes. Direct pro-apoptotic effects of this drug have been demonstrated in several malignant cells, including melanoma cell lines and primary human acute myelogenous leukemia cells. At micromolar concentrations required to kill melanoma cells this agent causes PKC-independent secondary necrosis. In contrast, the killing of leukemic cells occurs in the nanomolar range, requires activation of protein kinase C δ (PKCδ) and is specifically associated with translocation of PKCδ from the cytoplasm to the nuclear membrane. However, in addition to this pro-apoptotic effect the agent seems to have immunostimulatory effects, including: (i) increased chemokine release by malignant cells; (ii) a general increase in proliferation and cytokine release by activated T cells, including T cells derived from patients with chemotherapy-induced lymphopenia; (iii) local infiltration of neutrophils after topical application with increased antibody-dependent cytotoxicity; and (iv) development of specific anti-cancer immune responses by CD8+ T cells in animal models. Published studies mainly describe effects from in vitro investigations or after topical application of the agent, and careful evaluation of the toxicity after systemic administration is required before the possible use of this agent in the treatment of malignancies other than skin cancers

Genome Sequencing and Analysis of a Type A Clostridium perfringens Isolate from a Case of Bovine Clostridial Abomasitis

Clostridium perfringens is a common inhabitant of the avian and mammalian gastrointestinal tracts and can behave commensally or pathogenically. Some enteric diseases caused by type A C. perfringens, including bovine clostridial abomasitis, remain poorly understood. To investigate the potential basis of virulence in strains causing this disease, we sequenced the genome of a type A C. perfringens isolate (strain F262) from a case of bovine clostridial abomasitis. The ∼3.34 Mbp chromosome of C. perfringens F262 is predicted to contain 3163 protein-coding genes, 76 tRNA genes, and an integrated plasmid sequence, Cfrag (∼18 kb). In addition, sequences of two complete circular plasmids, pF262C (4.8 kb) and pF262D (9.1 kb), and two incomplete plasmid fragments, pF262A (48.5 kb) and pF262B (50.0 kb), were identified. Comparison of the chromosome sequence of C. perfringens F262 to complete C. perfringens chromosomes, plasmids and phages revealed 261 unique genes. No novel toxin genes related to previously described clostridial toxins were identified: 60% of the 261 unique genes were hypothetical proteins. There was a two base pair deletion in virS, a gene reported to encode the main sensor kinase involved in virulence gene activation. Despite this frameshift mutation, C. perfringens F262 expressed perfringolysin O, alpha-toxin and the beta2-toxin, suggesting that another regulation system might contribute to the pathogenicity of this strain. Two complete plasmids, pF262C (4.8 kb) and pF262D (9.1 kb), unique to this strain of C. perfringens were identified

Disclosure to HIV-seropositive children in rural Zambia

Abstract Background Care of children living with HIV comprises various issues, some considered challenging. One of the challenging areas is the serostatus disclosure to HIV-positive children. This study describes the current situation of HIV disclosure among rural children in Zambia and examines the socio-demographic factors promoting disclosure. Methods We used a mixed method approach applying both quantitative and qualitative methods to obtain comprehensive picture of HIV serostatus disclosure for children. Data were collected in Mumbwa district, Zambia (2010–2012), included 57 clinical records of children older than 5 years old. We examined children’s age, gender, and cohabitation status with their parents, caregivers’ level of education and income, and the relation between children and caregivers. Logistic regression model was applied to examine associations between disclosure and socio-demographic characteristics. Semi-structured interviews with 50 caregivers and 22 HIV-positive children were conducted to qualitatively investigate attitude towards disclosure and support needed. Results Full disclosure was completed in 17 out of 57 (29.8%) patients. Median ages of patients in disclosed group and non-disclosed group were 10 and 9, respectively (IQR 8.0–13.0, 7.0–11.25). In univariate analyses, older age and male gender has positive relation to the completion of serostatus disclosure. In logistic regression models, cohabitation status with patients’ mothers showed positive correlation to the completion of serostatus disclosure. In the interviews with caregivers, all caregivers said that disclosure of serostatus is a necessary process and good for their children, while actual serostatus disclosure rate was low. Conclusion Serostatus disclosure to HIV-seropositive children is not prevalent in Rural Zambia. Although further researches would be desirable, increased support to caregivers would be beneficial

Longitudinal analysis of physical function in older adults: The effects of physical inactivity and exercise training.

Lack of exercise contributes to systemic inflammation and is a major cause of chronic disease. The long-term impact of initiating and sustaining exercise in late life, as opposed to sustaining a sedentary lifestyle, on whole-body health measures such as physical performance is not well known. This is an exploratory study to compare changes in physical performance among older adults initiating exercise late in life versus inactive older adults. Data from two observational cohorts were included in this analysis, representing two activity groups. The Active group cohort comprises older adults (n = 318; age 72.5 ± 7.2 years) enrolled in a supervised exercise program, Gerofit. The inactive group comprises older adults (n = 146; age 74.5 ± 5.5 years) from the Italian study Act on Ageing (AOA) who self-reported being inactive. Participants in both groups completed physical performance battery at baseline and 1-year including: 6-min walk test, 30-s chair stand, and timed up-and-go. Two-sample t-tests measured differences between Gerofit and AOA at baseline and 1-year across all measures. Significant between-group effects were seen for all performance measures (ps = 0.001). The AOA group declined across all measures from baseline to 1 year (range -18% to -24% change). The Gerofit group experienced significant gains in function for all measures (range +10% to +31% change). Older adults who initiated routine, sustained exercise were protected from age-related declines in physical performance, while those who remained sedentary suffered cumulative deficits across strength, aerobic endurance, and mobility. Interventions to reduce sedentary behaviors and increase physical activity are both important to promote multi-system, whole-body health