A novel BRCA2 mutation in an Indonesian family found with a new, rapid, and sensitive mutation detection method based on pooled denaturing gradient gel electrophoresis and targeted sequencing

BACKGROUND: Breast cancer is increasing in Indonesia and other developing countries. Germline mutations in the BRCA1/2 genes are most strongly associated with a high risk for breast cancer development. There have been no reports on BRCA1/2 gene mutations in the Indonesian population. Genetic research yielding insight into mutations affecting the Indonesian population can help in risk assessment of individual patients. AIMS: To screen the BRCA1/2 genes for mutations in early onset Indonesian breast cancer patients and their families with a new, simple, and sensitive BRCA1/2 mutation screening strategy based on denaturing gradient gel electrophoresis (DGGE) and targeted sequencing. METHODS: DNA was isolated from the blood of four Indonesian breast cancer patients from high risk families and seven family members, and the polymerase chain reaction was performed with specially designed primers throughout the BRCA1/2 coding sequences to produce fragments suitable for pooled DGGE analysis. The aberrantly migrating samples were reamplified and sequenced. RESULTS: Two mutations were found in exons 13 and 16 of BRCA1 and two mutations in exons 2 and 14 of BRCA2, which turned out to be established polymorphisms according to the Breast Cancer Information Core. In addition, a novel 6 bp deletion in exon 11, leading to a premature stop, was found in BRCA2. CONCLUSION: Pooled DGGE and targeted sequencing revealed four BRCA1/2 polymorphisms and one novel BRCA2 mutation in a group of Indonesian patients at high risk of hereditary breast cancer. This illustrates that the proposed method is sensitive and particularly suited for screening unknown populations.     

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases.     

Encoded Exposure and Social Norms in Entertainment-Education

Entertainment-education is an effective health communication strategy that combines or embeds educational messages into entertainment programs to bring about social and behavior change. For years, scholars have considered how entertainment-education works. Some contemporary theories posit that entertainment-education does not engender behavior change directly but does so through mediating variables. This study adds to the literature on this topic by exploring the direct relationship between exposure and social norms instead of their relationship through behavior as a mediator. Novel to this study is the use of encoded exposure, a continuous and recognition-based measure of exposure that includes ever watching, recall, involvement, and dose in its operationalization. Using cross-sectional data from Kyunki … Jeena Issi Ka Naam Hai, an entertainment-education program in India, this exploratory analysis indicates a positive and significant relationship between encoded exposure and social norms. How can this finding be applied to future programs? Questions remain, and replication is needed, but if it is not essential to go through behavior in order to change social norms, then implications emerge for the theory and practice of entertainment-education.     

A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.     

Spatial and multidimensional visualization of Indonesia's village health statistics

Background  

A community health assessment (CHA) is used to identify and address health issues in a given population. Effective CHA requires timely and comprehensive information from a wide variety of sources, such as: socio-economic data, disease surveillance, healthcare utilization, environmental data, and health resource allocation.     

Allosteric peptide regulators of chemokine receptors CXCR4 and CXCR7

The chemokine CXCL12 and its shared seven-transmembrane receptors CXCR4 and CXCR7 regulate diseases including cancer, atherosclerosis, autoimmunity, and HIV infection, making these molecules promising drug targets. These molecules also control key processes in normal development and physiology, suggesting the need to selectively modulate CXCR4 and/or CXCR7 functions and signaling to reduce potential complications of long-term therapy. We previously identified two peptides that functioned as allosteric agonists driving CXCR4-dependent chemotaxis, providing key structural information to design a small number of additional peptides to investigate determinants of CXCL12 interactions and signaling through CXCR4 and CXCR7. In the current study, we show that the previously identified peptides only minimally activated CXCR4 signaling through the cytosolic adapter protein β-arrestin 2 and do not initiate signaling to ERK1/2. By comparison, peptides with diverse N-terminal amino acid sequences effectively activated CXCR7 signaling to β-arrestin 2. One peptide, designated as GSLW based on its N-terminal amino acids, activated CXCR7 signaling and potentiated CXCL12-CXCR7 signaling without blocking the scavenger function of CXCR7 to internalize CXCL12. These results advance our understanding of CXCR7 ligand recognition and signaling, and provide structural information to target allosteric binding sites on this receptor as chemical probes and potential therapeutic agents.