Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers

The human GT198 gene (gene symbol PSMC3IP) is located at chromosome 17q21, 470 kb proximal to BRCA1, a locus previously linked to breast and ovarian cancer predisposition. Its protein product (also known as TBPIP and Hop2) has been shown to regulate steroid hormone receptor–mediated gene activation and to stimulate homologous recombination in DNA repair. Here, we screened germline mutations in GT198 in familial and early-onset breast and ovarian cancer patients. We have identified 8 germline variants in a total of 212 index patients including reoccurring nonsense mutation c.310C>T (p.Q104X) and 5′ UTR mutation c.-37A>T, each found in 2 unrelated families. Most identified index patients from cancer families had early onsets with a median age of 35 years. c.310C>T was absent in a total of 564 control individuals analyzed. GT198 gene amplification with an imbalanced mutant copy gain was identified in the blood DNA of one of the patients carrying c.310C>T. When tested, this truncating mutation abolished DNA damage–induced Rad51 foci formation. In addition, we have identified 15 somatic mutations in 2 tumors from 1 patient carrying germline mutation c.-37A>T. The presence of a somatic mutation on the wild-type allele showed that GT198 was biallelically mutated in the tumor. The somatic mutations identified near a splicing junction site caused defective alternative splicing and truncated the open reading frame. Therefore, distinct mutations may cause a similar consequence by truncating the full-length protein and inducing a loss of the wild type. Our study provides the first evidence of the presence of inactivating mutations in GT198 in familial and early-onset breast and ovarian cancer patients. Mutations in GT198, a gene regulating DNA repair, potentially contribute to an increased risk in familial breast and ovarian cancers

Culturally appropriate communication in Malaysia:budi bahasa as warranty component in Malaysian discourse

This paper discusses the Malaysian cultural appropriateness (CA), budi bahasa in communication. CA is a root anchoring Malaysian life and, indeed, all things Malaysian.Society inculcates the norms and taboos with clear-cut identification of the dos and don'ts in relational communication among (and between) Malaysians.Although Malaysians may practice different religious rituals or hold different ideologies, they still pay attention to being appropriate and polite in communication to respect each other's differences, a vital concern for those living in this multicultural country.In no small measure, budi (virtue/politeness) helps govern the rules of communication, but the term is nuanced, carrying with it multiple meanings derived from the cultural context. Traditionally, respect, care for other people's emotion, politeness and language use are among the criteria measuring a budi bahasa (man of culture).But, there are other measures as well. Budi bahasa (man of culture) is incorporated in the principles articulated in the Rukunegara

Immunocompromised patients with acute respiratory distress syndrome : Secondary analysis of the LUNG SAFE database

The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Top 100 research questions for biodiversity conservation in Southeast Asia

Southeast (SE) Asia holds high regional biodiversity and endemism levels but is also one of the world's most threatened regions. Local, regional and global threats could have severe consequences for the future survival of many species and the provision of ecosystem services. In the face of myriad pressing environmental problems, we carried out a research prioritisation exercise involving 64 experts whose research relates to conservation biology and sustainability in SE Asia. Experts proposed the most pressing research questions which, if answered, would advance the goals of biodiversity conservation and sustainable development in SE Asia. We received a total of 333 questions through three rounds of elicitation, ranked them (by votes) following a workshop and grouped them into themes. The top 100 questions depict SE Asia as a region where strong pressures on biodiversity interact in complex and poorly understood ways. They point to a lack of information about multiple facets of the environment, while exposing the many threats to biodiversity and human wellbeing. The themes that emerged indicate the need to evaluate specific drivers of biodiversity loss (wildlife harvesting, agricultural expansion, climate change, infrastructure development, pollution) and even to identify which species and habitats are most at risk. They also suggest the need to study the effectiveness of practice-based solutions (protected areas, ecological restoration), the human dimension (social interventions, organisational systems and processes and, the impacts of biodiversity loss and conservation interventions on people). Finally, they highlight gaps in fundamental knowledge of ecosystem function. These 100 questions should help prioritise and coordinate research, conservation, education and outreach activities and the distribution of scarce conservation resources in SE Asia

Proteomic profiling and glycomic analysis of the yeast cell wall in strains with Aflatoxin B 1

The use of microorganisms for Aflatoxin B1 elimination has been studied as a new alternative tool and it is known that cell wall carried out a critical role. For that reason, cell wall and soluble intracellular fraction of eight yeasts with AFB1 detoxification capability were analysed. The quantitative and qualitative comparative label-free proteomic allowed the identification of diverse common constituent proteins, which revealed that putative cell wall proteins entailed less than 10% of the total proteome. It was possible to characterize different enzymes linked to cell wall polysaccharides biosynthesis as well as other proteins related with the cell wall organization and regulation. Additionally, the concentration of the principal polysaccharides was determined which permitted us to observe that β-glucans concentration was higher than mannans in most of the samples. In order to better understand the biosorption role of the cell wall against the AFB1, an antimycotic (Caspofungin) was used to damage the cell wall structure. This assay allowed the observation of an effect on the normal growth of those yeasts with damaged cell walls that were exposed to AFB1. This effect was not observed in yeast with intact cell walls, which may reveal a pro�tective role of this structure against mycotoxin