Antineoplastic activity of azacarbazoles. II. Effect of alpha-carboline and its derivatives on transplantable animal neoplasms

The antineoplastic properties of alpha-carboline, alpha-carboline hydrochloride, alpha-carboline N-1 methyl iodide and c-6 substituted fluoro-, chloro, nitro- and phenyl-alpha-carboline were studied. None of the compounds proved to be active when tested against i.p. transplanted B16 melanoma or i.m. implanted Lewis lung carcinoma. In addition, alpha-carboline was assessed against i.p. inoculated plasmacytoma MP26 and colon carcinoma 26, and solid tumors of mammary carcinoma 16/C and Walker carcinosarcoma 256. Under conditions tested these neoplasms did not respond to alpha-carboline.     

Evidence for selective expression of the p53 codon 72 polymorphs: implications in cancer development.

Polymorphism at codon 72 of p53 results in either the arginine or proline form of p53, whose functional significance in carcinogenesis is controversial. We have investigated if the expression of these p53 polymorphs is selectively regulated, using mRNA from peripheral blood of healthy Asian (Chinese) and the Caucasian (Polish) arginine/proline (arg/pro) heterozygote subjects. Asians were found to preferentially express the pro allele whereas the Caucasians preferentially express the arg allele. On the contrary, about 75% of the heterozygote Chinese breast cancer patients preferentially expressed the arg allele, which rarely contained any somatic mutations. Moreover, histologically normal tissues from Chinese heterozygote breast cancer patients showed selective expression of the arg allele, in contrast to the preferential expression of the pro allele in heterozygote healthy normal breast tissues. Together, the data suggest that the expression of the different p53 polymorphs is selectively regulated in different ethnic populations, and that the arg allele is activated during cancer development in Asians. Thus, the expression status of the p53 polymorphs, rather than the genotypic status, might be a useful indicator for cancer susceptibility.     

Comparison of the effects of valproic acid and levetiracetam on apoptosis in the human ovarian cancer cell line OVCAR-3

BackgroundWe have previously shown that due to its cytotoxic and cytostatic activities, valproic acid (VPA), but not levetiracetam (LEV), may have potential as a drug for treating human ovarian cancer. In the present study, we compare apoptotic mechanisms including gene and protein expression in the human ovarian cancer cell line, OVCAR-3, following exposure to VPA and LEV.MethodsCells were cultured with VPA or LEV at concentrations between 0.1 mM and 10 mM. Apoptosis was assessed by DNA fragmentation assay and expression of apoptosis-regulatory genes determined by real-time PCR and confirmed by western blotting. Time-dependent effects of VPA and LEV on activity of caspases (-3, -8 and -9) activity were evaluated by fluorescent assay and western blotting.ResultsExposure to VPA at concentrations above 5 mM resulted in an increase in DNA fragmentation, modulated expression of genes and proteins associated with apoptosis and activated caspase ca scade. Exposure to LEV, however, did not affect DNA fragmentation and modulation of the mechanisms of apoptosis was not observed in LEV-treated cells at all doses used.ConclusionsExposure to high concentrations of VPA significantly stimulated apoptosis, by modulating the expression of genes and proteins responsible for cell death and also by activation of caspases cascade. Such effects were not observed with LEV. These data suggest that VPA should be seriously evaluated as an anti-cancer drug for ovarian cancer.     

p53 tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma

Germline p53 mutations are associated with Li–Fraumeni syndrome (LFS) and other familial cancer phenotypes not fulfilling the definition for LFS. The majority of germline p53 mutations cluster in exons 5–8, corresponding to a DNA binding domain. We report the identification of two germline mutations and a somatic mutation in a tetramerization domain (TD), a rare site for mutations. The germline mutation, R342X (16915C>T), and the novel mutation, R342P (16916G>C), were found in a child with adrenocortical carcinoma and in a LFS pediatric patient with multiple primaries. The novel somatic mutation, R337G (16900C>G), was discovered in myelodysplastic syndrome with transformation to acute myeloblastic leukemia, developing as the third primary in the LFS child. These findings add further information on p53 TD mutations and TD contribution to tumorigenesis.     

Is there a time and place for health education in chain pharmacies? Perspectives of Polish community pharmacists

Pharmaceutical practice has evolved significantly from the provision of drugs to a more patient-centred model. However, the ownership structure of pharmacies may impact the level of cognitive services provided by them. The discrepancy may be observed between pharmacists’ opinions on how involved they should get and their actual involvement in health promotion and disease prevention. Given the growing market share of pharmacy chains in Europe, this study aimed to investigate the attitudes of pharmacists employed in them towards their role as health educators. It applies Ajzen's theory of planned behaviour to examine pharmacists’ perspectives with the use of semi-structured in-depth interviews. A total of 10 semi-structured face-to-face interviews were conducted in May 2017 among Polish pharmacists employed in chains. Obtained results showed that respondents welcomed the possibility of providing health education, but simultaneously they seek physicians’ and patients’ acceptance for undertaking this task. Competency gaps and unfavourable working conditions may also decrease pharmacists’ intention to serve as health educators. Including the role of a health educator to the scope of the pharmacists’ practice requires a precise definition of their competencies and responsibilities together with additional training aimed to fill potential gaps in their qualifications. The pharmacists’ image as a health educator should also be widely communicated to patients and other healthcare professionals.     

A Minimal Intervention to Promote Smoke-Free Homes Among 2-1-1 Callers: A Randomized Controlled Trial

Objectives. We tested the efficacy of a minimal intervention to create smoke-free homes in low-income households recruited through the United Way of Greater Atlanta 2-1-1, an information and referral system that connects callers to local social services.Methods. We conducted a randomized controlled trial (n = 498) from June 2012 through June 2013, with follow-up at 3 and 6 months. The intervention consisted of 3 mailings and 1 coaching call.Results. Participants were mostly smokers (79.7%), women (82.7%), African American (83.3%), and not employed (76.5%), with an annual household income of $10 000 or less (55.6%). At 6-months postbaseline, significantly more intervention participants reported a full ban on smoking in the home than did control participants (40.0% vs 25.4%; P = .002). The intervention worked for smokers and nonsmokers, as well as those with or without children.Conclusions. Minimal intervention was effective in promoting smoke-free homes in low income households and offers a potentially scalable model for protecting children and adult nonsmokers from secondhand smoke exposure in their homes.Despite declines in exposure to secondhand smoke (SHS) over the last 2 decades, children and nonsmoking adults who live with a person who smokes still experience significant exposure to SHS.1–3 SHS exposure causes lung cancer, coronary heart disease, and stroke in nonsmoking adults, aexacerbates asthma, and causes impaired lung function, middle ear disease, respiratory illness, and sudden infant death syndrome in children.3–5Exposure differs markedly between those who live with someone who smokes in the home and those who do not. In 2007 and 2008, 93.4% of nonsmoking adults who lived with someone who smoked inside the home had elevated serum cotinine levels compared with 33.4% of those who did not live with someone who smoked inside the home.6 This pattern was similar, but more striking, for children and youths.6 Certain subgroups of the US population are less likely to have household smoking restrictions and are disproportionately affected by SHS exposure in the home. For instance, African American nonsmokers have an increased prevalence of detectable serum cotinine compared with other major racial/ethnic groups and are less likely to report home smoking bans.6–8 Low income families and those with less education are less likely to have full smoking bans.6,8–11 Other predictors of household smoking bans include the presence of children, the presence of a nonsmoking adult in the home, and fewer friends and family members who smoke.9,10,12–17Home smoking bans can lead to lower levels of SHS exposure, less smoking, and increased attempts to quit.7,13,18–22 The prevalence of smoke-free homes has increased as states and communities have legislated smoke-free public places.23,24 Intervention studies have typically examined the effects of counseling parents of children with asthma, infants, or medically compromised children on exposure levels.25–29 Effective interventions involve multiple counseling sessions and often combine smoking cessation and smoke-free home messages.30–32 Much of the existing intervention research has taken place or recruited participants through clinical settings.30–33 Minimal interventions to create smoke-free homes in community-based settings have not been adequately studied.31,33,34Minimal interventions have the potential for greater reach than more intensive interventions, and thus, have the potential for a greater impact at the population level.35–38 Similarly, interventions that target general populations, including households with no young children, can help to achieve population-level reductions in SHS exposure. We tested the efficacy of a minimal intervention with callers to the United Way of Greater Atlanta, Georgia, 2-1-1 number. The 2-1-1 information and referral system consists of more than 200 nonprofit state and local call centers operating in all 50 states and connects more than 16 million callers per year to local health and social services.39 Callers to 2-1-1 are disproportionately low-income, unemployed, uninsured, and have fewer years of education relative to the general population.40 2-1-1 callers have a higher rate of smoking and lower likelihood of a home smoking ban than the general population.41,42 Because 2-1-1 provides extensive reach to vulnerable populations, they are strategic partners for testing, delivering, and ultimately sustaining interventions to reduce risk and improve the lives of low-income persons in the United States.40We tested the efficacy of a minimal intervention to create smoke-free homes among 2-1-1 callers. Our study builds on formative research on family dynamics related to establishing household smoking bans,43,44 a pilot study to test a brief intervention,45 and a cross-site survey of 2-1-1 callers that showed a relatively low prevalence of smoke-free homes.41 This randomized controlled trial is the first in a series of studies that will move from testing efficacy to effectiveness to dissemination of the intervention through 2-1-1 centers nationally.     

A high proportion of founder BRCA1 mutations in Polish breast cancer families

Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention.     

The influence of chokeberry juice supplementation on the reduction of oxidative stress resulting from an incremental rowing ergometer exercise

The aim of the study was to investigate the influence of an increased intake of anthocyanins, contained in chokeberry juice, on the redox parameters in rowers performing a physical exercise during a 1-month training camp. The athletes were randomly assigned to receive 150 mL of chokeberry juice daily, containing 23 mg/100 mL of anthocyanins (supplemented group), or placebo (control group). Before and after the supplementation period, the subjects performed an incremental rowing exercise test. Blood samples were taken from the antecubital vein before each exercise test, 1 min after the test, and following a 24-h recovery period. After the supplementation period, TBARS concentrations in the samples collected 1 min after the exercise test and following a 24-h recovery period were significantly lower in the subjects receiving chokeberry juice than in the control group. In the supplemented group, glutathione peroxidase activity was lower in the samples collected 1 min after the exercise test, and superoxide dismutase activity was lower in the samples taken following a 24-h recovery, as compared to the subjects receiving placebo. These findings indicate that an increased intake of anthocyanins limits the exercise-induced oxidative damage to red blood cells, most probably by enhancing the endogenous antioxidant defense system.