Characterization of a Full-Length TTP Family Member Association with RNA Sequence Elements

Post-transcriptional regulation of cytoplasmic mRNAs is an efficient mechanism of regulating the amounts of active protein within a eukaryotic cell. RNA sequence elements located in the untranslated regions of mRNAs can influence transcript degradation or translation through associations with RNA-binding proteins. Tristetraprolin (TTP) is the best known member of a family of CCCH zinc finger proteins that targets adenosine-uridine rich element (ARE) binding sites in the 3’ untranslated regions (UTRs) of mRNAs, promoting transcript deadenylation through the recruitment of deadenylases. More specifically, TTP has been shown to bind AREs located in the 3’-UTRs of transcripts with known roles in the inflammatory response. The mRNA-binding region of the protein is the highly conserved CCCH tandem zinc finger (TZF) domain. The synthetic TTP TZF domain has been shown to bind with high affinity to the 13-mer sequence of UUUUAUUUAUUUU. However, the binding affinities of full-length TTP family members to the same sequence and its variants are unknown. Furthermore, the distance needed between two overlapping or neighboring UUAUUUAUU 9-mers for tandem binding events of a full-length TTP family member to a target transcript has not been explored. To address these questions, we recombinantly expressed and purified the full-length C. albicans TTP family member Zfs1. Using full-length Zfs1, tagged at the N-terminus with maltose binding protein (MBP), we determined the binding affinities of the protein to the optimal TTP binding sequence, UUAUUUAUU. Fluorescence anisotropy experiments determined that the binding affinities of MBP-Zfs1 to non-canonical AREs were influenced by ionic buffer strength, suggesting that transcript selectivity may be affected by intracellular conditions. Furthermore, electrophoretic mobility shift assays (EMSAs) revealed that separation of two core AUUUA sequences by two uridines is sufficient for tandem binding of MBP-Zfs1. Finally, we found evidence for tandem binding of MBP-Zfs1 to a 27-base RNA oligonucleotide containing only a single ARE-binding site, and showed that this was concentration and RNA length dependent; this phenomenon had not been seen previously. These data suggest that the association of the TTP TZF domain and the TZF domains of other species, to ARE-binding sites is highly conserved. Domains outside of the TZF domain may mediate transcript selectivity in changing cellular conditions, and promote protein-RNA interactions not associated with the ARE-binding TZF domain.

In summary, the evidence presented here suggests that Zfs1-mediated decay of mRNA targets may require additional interactions, in addition to ARE-TZF domain associations, to promote transcript destabilization and degradation. These studies further our understanding of post-transcriptional steps in gene regulation.

Ecuadorian migration and family strategies of social mobility: dialectic relation between emotional and financial capital

This text deals with transnational strategies of social mobility in Ecuadorian migrant households in Spain. We apply the capital accumulation model (Moser, 2009) for this purpose. The main target of this article is, beyond thinking in terms of capital stock and accumulation, the analysis in depth of the dynamics of the different types of capital, that is to say, how they interact with each other in the framework of the social mobility strategies of the migrants and their families. We are bringing into light the way some households adopt investing decisions in capitals that don't translate into any addition or earnings in all cases, on the contrary, concentrating all their efforts on the accumulation of a certain asset they may, in some cases, lead to a loss of another. We will concentrate our analysis primarily on the dynamics between the physical and financial capital and the social and emotional capital, showing the tensions produced between these two types of assets. At the same time, we will highlight how migrants negotiate their family strategies of social mobility in the transnational area. Our study is based in empirical material obtained from qualitative fieldwork (in-depth interviews) with families of migrants in the urban district of Turubamba Bajo -(south of Quito) and in Madrid. A series of households were selected where interviews were carried out in the country of origin as well as in the context of immigration, with different family members, analysing the transnational social and economic strategies of families of migrant members. Family members of migrants established in Spain were interviewed in Quito, as well as key informants in the district (school teachers, nursery members of the staff, etc.). The research was framed within the projects "Impact of migration on the development: gender and transnationalism", Ministry of Science and Innovation (SEJ2007/63179) (Laura Oso, dir. 2007-2010),"Gender, transnationalism and intergenerational strategies of social mobility", Ministry of Economy and Competitiveness (FEM2011/26210) (Laura Oso, dir. 201-1-2015) and “Gender, Crossed Mobilities and Transnational Dynamics”, Ministry of Economy and Competitiveness (FEM2015-67164).

Worker, workplace or families: What influences family focused practices in adult mental health?

Introduction: Family focused practice is thought to lead to positive outcomes for all family members. However, there are multiple barriers and enablers in adult mental health services to practitioners undertaking these actions.
Aim: The aim of this study was to examine the relative importance of worker, workforce and family factors to predict family focused practices (FFPs) in adult mental health services.
Method: Three hundred and seven adult mental health workers completed a 45 items family focused practice measure of 16 family focused practices.
Thesis: It was found that worker skill and knowledge about family work and an ability to assess the degree of parental insight into the child’s connections to other family members and the community were important predictors of FFP, along with the closely related-worker confidence. While aspects of the worker, workplace and family each contribute to FFPs, this study highlighted the importance of worker skill, knowledge and confidence as central issues for adult mental health workers.
Implications for practice: Study implications include the need for training in specific FFPs, the provision of time to engage with clients on parenting issues and the need 5 to ensure that there are adequate services for workers to refer family members to

Providing a ‘whole-of-family’ approach to care: family-focused practices in mental health services

Introduction: Family members including children are all impacted by a family member’s mental illness. Although mental health services are increasingly encouraged to engage in family-focused practice, this is not a well-understood concept or practice in mental health care. Methods: An integrative review using systematic methods was conducted with international literature, with the aim of identifying concepts and practices of family-focused practice in child and youth and adult mental health services. Results: Findings from 40 peer-reviewed literature identified a range of understandings and applications of family-focused practice, including who comprises the ‘family’, whether the focus is family of origin or family of procreation or choice, and whether the context of practice is child and youth or adult. ‘Family’ as defined by its members forms the foundation for practice that aims to provide a whole-of-family approach to care. Six core practices comprise a family focus to care: assessment; psychoeducation; family care planning and goal-setting; liaison between families and services; instrumental, emotional and social support; and a coordinated system of care between families and services. Conclusion: By incorporating key principles and the core family-focused practices into their care delivery, clinicians can facilitate a whole-of-family approach to care and strengthen family members’ wellbeing and resilience, and their individual and collective health outcomes.

Heritage Language Maintenance and Biliteracy Development for Immigrants' Children: A Study of Chinese Immigrants' Family Language Policy and Biliteracy Practices

This study reports on research that examines the family language policy (FLP) and biliteracy practices of middle-class Chinese immigrant families in a metropolitan area in the southwest of the U.S. by exploring language practices pattern among family members, language and literacy environment at home, parents’ language management, parents’ language attitudes and ideologies, and biliteracy practices. In this study, I employed mixed methods, including survey and interviews, to investigate Chinese immigrant parents’ FLP, biliteracy practices, their life stories, and their experience of raising and nurturing children in an English-dominant society. Survey questionnaires were distributed to 55 Chinese immigrant parents and interviews were conducted with five families, including mothers and children. One finding from this study is that the language practices pattern at home shows the trend of language shift among the Chinese immigrants’ children. Children prefer speaking English with parents, siblings, and peers, and home literacy environment for children manifests an English-dominant trend. Chinese immigrant parents’ language attitudes and ideologies are largely influenced by English-only ideology. The priority for learning English surpasses the importance of Chinese learning, which is demonstrated by the English-dominant home literacy practices and an English-dominant language policy. Parents invest more in English literacy activities and materials for children, and very few parents implement Chinese-only policy for their children. A second finding from this study is that a multitude of factors from different sources shape and influence Chinese immigrants’ FLP and biliteracy practices. The factors consist of family-related factors, social factors, linguistic factors, and individual factors. A third finding from this study is that a wide variety of strategies are adopted by Chinese immigrant families, which have raised quite balanced bilingual children, to help children maintain Chinese heritage language (HL) and develop both English and Chinese literacy. The close examination and comparison of different families with English monolingual children, with children who have limited knowledge of HL, and with quite balanced bilingual children, this study discovers that immigrant parents, especially mothers, play a fundamental and irreplaceable role in their children’s HL maintenance and biliteracy development and it recommends to immigrant parents in how to implement the findings of this study to nurture their children to become bilingual and biliterate. Due to the limited number and restricted area and group of participant sampling, the results of this study may not be generalized to other groups in different contexts.

CAREGIVING FOR A FAMILY MEMBER WITH HEAD AND NECK CANCER

Objective: To know the perception of informal caregivers regarding the care for a family member with head and neck cancer. Methods: Qualitative study conducted between March and May 2014 in the radiotherapy outpatient center of the Centro de Alta Complexidade em Oncologia – CACON (Oncology High Complexity Center) of the Hospital Universitário de Brasília – HUB (University Hospital of Brasília) using semi-structured interviews with nine caregivers about the experience of caring for family members. Data underwent Content Analysis and four units of meaning were identified: “Representation of cancer in the Family”, “The care as debt, individual reward or reconstruction of family ties”, “Repercussions of cancer on the caregiver’s personal life” and “Social support and network used by caregivers”. Results: Feelings of sadness and surprise at the moment of diagnosis were attributed to cancer, as well as the idea of punishment. The care was seen as personal satisfaction, accomplishment and opportunity for family rapprochement. Work overload and change in routine were altered functions. Religiosity, exchange of experience in the waiting room and institutional support appeared as coping strategies. Conclusion: The experience of caring for family members with head and neck cancer directly interferes in the lives of caregivers. Pointing out the institutional embracement as a strategy within the social network reinforces the importance of integrating the caregivers as a significant part of the health care plan developed by the health team.

Studying the role of the strawberry Fra protein family in the flavonoid metabolism during fruit ripening

Strawberry fruits are highly appreciated worldwide due to their pleasant flavor and aroma and to the health benefits associated to their consumption. An important part of these properties is due to their content in secondary metabolites, especially phenolic compounds, of which flavonoids are the most abundant in the strawberry fruit. Although the flavonoid biosynthesis pathway is uncovered, little is known about its regulation. The strawberry Fra a (Fra) genes constitute a large family of homologs of the major birch pollen allergen Bet v 1 and for which no equivalents exist in Arabidopsis. Our group has shown that Fra proteins are involved in the formation of colored compounds in strawberries (Muñoz et al., 2010), which mainly depends on the production of certain flavonoids; that they are structurally homologs to the PYR/PYL/RCAR Arabidopsis ABA receptor, and that they are able to bind flavonoids (Casañal et al., 2013). With these previous results, our working hypothesis is that the Fra proteins are involved in the regulation of the flavonoids pathway. They would mechanistically act as the ABA receptor, binding a protein interactor and a ligand to regulate a signaling cascade and/or act as molecular carriers. The main objective of this research is to characterize the Fra family in strawberry and gain insight into their role in the flavonoid metabolism. By RNAseq expression analysis in ripening fruits we have identified transcripts for 10 members of the Fra family. Although expressed in all tissues analyzed, each family member presents a unique pattern of expression, which suggests functional specialization for each Fra protein. Then, our next approach was to identify the proteins that interact with Fras and their ligands to gain knowledge on the role that these proteins play in the flavonoids pathway. To identify the interacting partners of Fras we have performed a yeast two hybrid (Y2H) screening against cDNA libraries of strawberry fruits at the green and red stages. A protein that shares a 95% homology to the Heat stress transcription factor A-4-C like of Fragaria vesca (HSA4C) interacts specifically with Fra1 and not with other family members, which suggests functional diversification of Fra proteins in specific signaling pathways. The Y2H screening is not yet saturated, so characterization of other interacting proteins with other members of the Fra family will shed light on the functional diversity within this gene family. This research will contribute to gain knowledge on how the flavonoid pathway, and hence, the fruit ripening, is regulated in strawberry; an economically important crop but for which basic research is still very limited. References: Muñoz, C, et al. (2010). The Strawberry Fruit Fra a Allergen Functions in Flavonoid Biosynthesis. Molecular Plant, 3(1): 113–124. Casañal, A, et al (2013). The Strawberry Pathogenesis-related 10 (PR-10) Fra a Proteins Control Flavonoid Biosynthesis by Binding Metabolic Intermediates. Journal of Biological Chemistry, 288(49): 35322–35332.

Composite Indicators for the Family Change: ‘Familism' vs ‘Individualism' in the International Context

The aim of this paper is to propose a composite indicator to measure ‘familism’, conformed by two main dimensions: values on one hand (duty to take care of the family, importance of the family, sacrifices for the family...) and behaviours, on the other (predominance of married couples instead of cohabitant couples, high frequency of contact among members, family support…). In contrast to this idea of ‘familism’ we find that of individualism, that defends the independence of family members, tolerance to new family models, cohabitation instead of marriage,… , that implies less frequency of interaction among relatives and more governmental intervention towards children and elderly care. We observe that a higher degree of ‘familism’ does not always match with a lower degree of individualism when both dimensions, attitudes and behaviours, are considered. For instance, we find countries which are individualist in values but not in behaviours (such as Spain), whilst others, such as Japan, are ‘familist’ both in values and behaviours and finally, others, such as Sweden, are individualist with regards to both perspectives. We propose two different methodological approaches to the question. First, we use microdata from the Family, Work and Gender Roles module of the International Social Survey Programme-ISSP (years 1994, 2002 and 2012), in which 45 countries have participated. Information for the three rounds is collected for 17 countries with very different family values and welfare systems (for instance, Sweden, Japan, Russia, Spain, United Kingdom or the United States). From this data source, we create a first index on familism that can be related to individual sociodemographic characteristics. Second, we complete it through the inclusion of macro data (such as the divorce rate per country), in order to refine comparison at a country level by adding new variables to the previous index.

Composite Indicators for the Family Change: ‘Familism' vs ‘Individualism' in the International Context

The aim of this paper is to propose a composite indicator to measure ‘familism’, conformed by two main dimensions: values on one hand (duty to take care of the family, importance of the family, sacrifices for the family...) and behaviours, on the other (predominance of married couples instead of cohabitant couples, high frequency of contact among members, family support…). In contrast to this idea of ‘familism’ we find that of individualism, that defends the independence of family members, tolerance to new family models, cohabitation instead of marriage,… , that implies less frequency of interaction among relatives and more governmental intervention towards children and elderly care. We observe that a higher degree of ‘familism’ does not always match with a lower degree of individualism when both dimensions, attitudes and behaviours, are considered. For instance, we find countries which are individualist in values but not in behaviours (such as Spain), whilst others, such as Japan, are ‘familist’ both in values and behaviours and finally, others, such as Sweden, are individualist with regards to both perspectives. We propose two different methodological approaches to the question. First, we use microdata from the Family, Work and Gender Roles module of the International Social Survey Programme-ISSP (years 1994, 2002 and 2012), in which 45 countries have participated. Information for the three rounds is collected for 17 countries with very different family values and welfare systems (for instance, Sweden, Japan, Russia, Spain, United Kingdom or the United States). From this data source, we create a first index on familism that can be related to individual sociodemographic characteristics. Second, we complete it through the inclusion of macro data (such as the divorce rate per country), in order to refine comparison at a country level by adding new variables to the previous index.

Financial Characteristics of Family Businesses and Financial Aspects of Succession

Family businesses are special in many respects. By examining their financial characteristics one can come to unique conclusions/results. This paper explores the general characteristics of the financial behaviour of family businesses, presents the main findings of the INSIST project’s company case studies concerning financing issues and strategies, and intends to identify the financial characteristics of company succession. The whole existence of family businesses is characterized by a duality of the family and business dimensions and this remains the case in their financial affairs. The financial decisions in family businesses (especially SMEs) are affected by aspects involving a duality of goals rather than exclusively profitability, the simultaneous presence of family and business financial needs, and the preferential handling of family needs at the expense of business needs (although it has to be said that there is evidence of family investments being postponed for the sake of business, too. Family businesses, beyond their actual effectiveness, are guided by individual goals like securing living standards, ensuring workplaces for family members, stability of operation, preservation of the company’s good reputation, and keeping the company’s size at a level that the immediate family can control and manage. The INSIST project’s company case studies revealed some interesting traits of family business finances like the importance of financial support from the founder’s family during the establishment of the company, the use of bootstrapping techniques, the financial characteristics of succession, and the role of family members in financial management.

Critical pedagogy theory and the family business

In contemporary times family business research has been dominated by three theoretical perspectives; principal-agent theory, stewardship theory, and resource-based view theory (Siebels 2012) but at the same time scholars argue that what still needs further attention is how underlying processes and phenomena can be explained (Melin, Nordqvist & Sharma  2014). In order to understand themes such as repression or relations of asymmetry the suggestion in this chapter is to move towards a critical stance of thinking which involves problematizing the obvious issues in family firms (Alvesson & Deetz 2000) and moreover allowing the critical perspective to destabilize assumptions made within earlier research (Freire, 1974). By discussing critical theory in general but foremost the Freirean  (1970, 1974) critical pedagogy specifically, the arguments in the chapter revolves around how critical pedagogy can open up for a more novel view on family business. The purpose is via critical pedagogy discuss family business from a limited situation perspective, and to argue for a Freirean (1970) dialogue as means of developing a critical consciousness for family members in the family business context. The chapter concludes with some recommendations on platforms or common grounds in which dialogue and raising of consciousness can occur in which the concept can open up possibilities for interesting learning transfer and bring multidimensional knowledge into the family firm.

The role of cancer related inflammation, Src family kinases and matrix metalloproteinase 9 in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the UK with 41,000 new cases diagnosed in 2011. Despite undergoing potentially curative resection, a significant amount of patients develop recurrence. Biomarkers that aid prognostication or identify patients who are suitable for adjuvant treatments are needed. The TNM staging system does a reasonably good job at offering prognostic information to the treating clinician, but it could be better and identifying methods of improving its accuracy are needed. Tumour progression is based on a complex relationship between tumour behaviour and the hosts’ inflammatory responses. Sustained tumour cell proliferation, evading growth suppressors, resisting apoptosis, replicative immortality, sustained angiogenesis, invasion & metastasis, avoiding immune destruction, deregulated cellular energetics, tumour promoting inflammation and genomic instability & mutation have been identified as hallmarks. These hallmarks are malignant behaviors are what makes the cell cancerous and the more extreme the behaviour the more aggressive the cancer the more likely the risk of a poor outcome. There are two primary genomic instability pathways: Microsatellite Instability (MSI) and Chromosomal Instability (CI) also referred to as Microsatellite Stability (MSS). Tumours arising by these pathways have a predilection for specific anatomical, histological and molecular biological features. It is possible that aberrant molecular expression of genes/proteins that promote malignant behaviors may also act as prognostic and predictive biomarkers, which may offer superior prognostic information to classical prognostic features. Cancer related inflammation has been described as a 7th hallmark of cancer. Despite the systemic inflammatory response (SIR) being associated with more aggressive malignant disease, infiltration by immune cells, particularly CD8+ lymphocytes, at the advancing edge of the tumour have been associated with improved outcome and tumour MSI. It remains unknown if the SIR is associated with tumour MSI and this requires further study. The mechanisms by which colorectal cancer cells locally invade through the bowel remain uncertain, but connective tissue degradation by matrix metalloproteinases (MMPs) such as MMP-9 have been implicated. MMP-9 has been found in the cancer cells, stromal cells and patient circulation. Although tumoural MMP-9 has been associated with poor survival, reports are conflicting and contain relatively small sample sizes. Furthermore, the influence of high serum MMP-9 on survival remains unknown. Src family kinases (SFKs) have been implicated in many adverse cancer cell behaviors. SFKs comprise 9 family members BLK, C-SRC, FGR, FYN, HCK, LCK, LYN, YES, YRK. C-SRC has been the most investigated of all SFKs, but the role of other SFKs in cellular behaviors and their prognostic value remains largely unknown. The development of Src inhibitors, such as Dasatinib, has identified SFKs as a potential therapeutic target for patients at higher risk of poor survival. Unfortunately, clinical trials so far have not been promising but this may reflect inadequate patient selection and SFKs may act as useful prognostic and predictive biomarkers. In chapter 3, the association between cancer related inflammation, tumour MSI, clinicopathological factors and survival was tested in two independent cohorts. A training cohort consisting of n=182 patients and a validation cohort of n=677 patients. MSI tumours were associated with a raised CRP (p=0.003). Hypoalbuminaemia was independently associated with poor overall survival in TNM stage II cancer (HR 3.04 (95% CI 1.44 – 6.43);p=0.004), poor recurrence free survival in TNM stage III cancer (HR 1.86 (95% 1.03 – 3.36);p=0.040) and poor overall survival in CI colorectal cancer (HR 1.49 (95% CI 1.06 – 2.10);p=0.022). Interestingly, MSI tumours were associated with poor overall survival in TNM stage III cancer (HR 2.20 (95% CI 1.10 – 4.37);p=0.025). In chapter 4, the role of MMP-9 in colorectal cancer progression and survival was examined. MMP-9 in the tissue was assessed using IHC and serum expression quantified using ELISA. Serum MMP-9 was associated with cancer cell expression (Spearman’s Correlation Coefficient (SCC) 0.393, p<0.001)) and stromal expression (SCC 0.319, p=0.002). Serum MMP-9 was associated with poor recurrence-free (HR 3.37 (95% CI 1.20 – 9.48);p=0.021) and overall survival (HR 3.16 (95% CI 1.22 – 8.15);p=0.018), but tumour MMP-9 was not survival or MSI status. In chapter 5, the role of SFK expression and activation in colorectal cancer progression and survival was studied. On PCR analysis, although LYN, C-SRC and YES were the most highly expressed, FGR and HCK had higher expression profiles as tumours progressed. Using IHC, raised cytoplasmic FAK (tyr 861) was independently associated with poor recurrence free survival in all cancers (HR 1.48 (95% CI 1.02 – 2.16);p=0.040) and CI cancers (HR 1.50 (95% CI 1.02 – 2.21);p=0.040). However, raised cytoplasmic HCK (HR 2.04 (95% CI 1.11 – 3.76);p=0.022) was independently associated with poor recurrence-free survival in TNM stage II cancers. T84 and HT29 cell lines were used to examine the cellular effects of Dasatinib. Cell viability was assessed using WST-1 assay and apoptosis assessed using an ELISA cell death detection assay. Dasatinib increased T84 tumour cell apoptosis in a dose dependent manner and resulted in reduced expression of nuclear (p=0.008) and cytoplasmic (p=0.016) FAK (tyr 861) expression and increased nuclear FGR expression (p=0.004). The results of this thesis confirm that colorectal cancer is a complex disease that represents several subtypes of cancer based on molecular biological behaviors. This thesis concentrated on features of the disease related to inflammation in terms of genetic and molecular characterisation. MSI cancers are closely associated with systemic inflammation but despite this observation, they retain their relatively improved survival. MMP-9 is a feature of tissue remodeling during inflammation and is also associated with degradation of connective tissue, advanced T-stage and poor outcome when measured in the serum. The lack of stromal quantification due to TMA use rather than full sections makes the value of tumoural MMP-9 immunoreactivity in the prognostication and its association with MSI unknown and requires further study. Finally, SFK activation was also associated with SIR, however, only cytoplasmic HCK was independently associated with poor survival in patients with TNM stage II disease, the group of patients where identifying a novel biomarker is most needed. There is still some way to go before these biomarkers are translated into clinical practice and future work needs to focus on obtaining a reliable and robust scientific technique with validation in an adequately powered independent cohort.

ABSTINENCE AND ALCOHOL CONSUMPTION AMONG STUDENTS: THE INFLUENCE OF PERSONAL, FAMILY AND SOCIO-CULTURAL SPHERES

Introduction: Among young people, regular or alcohol abuse seems to ally with individual factors, which congregate to other generators behaviors health risk, in social environment, including family and school. The consumption of alcoholic beverages in the younger age groups, according to the World Development Report goes beyond 60%. In the Portuguese case, the Alentejo is the region that recorded higher consumption among schoolchildren. Objectives: This study aims to know the personal inluences of family, of belonging to the group and the school environment, on the withdrawal and consumption habits among young people. Methods: A qualitative nature of research, using comprehensive semi-structured interviews. The study was developed in a school district of Evora, Portugal. The sample consists of ten students from the 8th school grade, ive non-consumers-ive consumers aged between 13 and 15 years old. Results: The trial takes place between 12 and 14 years old as a result of curiosity, explicit or tacit motivation, “give style”, the environment, entertainment and observing behavior. Among the effects of intake indicated as motivators consumption highlight the joy of reaching states and willingness. Family members tend to encourage moderate drinking on festive occasions. family models exaggerated consumption repudiate ingestion. The elements of the group of belonging tend to motivate explicitly, the intake among consumers students. The school promotes initiatives on the theme, punctually. Conclusions: The consumption of alcohol among young people suffer the personal, family and belonging group inluences. The initiatives in school tend to have no effect.

Familial Systemic Mastocytosis With Germline Kit K509i Mutation Is Sensitive To Treatment With Imatinib, Dasatinib And Pkc412.

Mastocytosis are myeloproliferative neoplasms commonly related to gain-of-function mutations involving the tyrosine kinase domain of KIT. We herein report a case of familial systemic mastocytosis with the rare KIT K509I germ line mutation affecting two family members: mother and daughter. In vitro treatment with imatinib, dasatinib and PKC412 reduced cell viability of primary mast cells harboring KIT K509I mutation. However, imatinib was more effective in inducing apoptosis of neoplastic mast cells. Both patients with familial systemic mastocytosis had remarkable hematological and skin improvement after three months of imatinib treatment, suggesting that it may be an effective front line therapy for patients harboring KIT K509I mutation.

Risk Of Leukemia In First Degree Relatives Of Patients With Nonsyndromic Cleft Lip And Palate.

The aim of this study was to determine the frequency of leukemia in parents of patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P). This case-control study evaluated first-degree family members of 358 patients with NSCL/P and 1,432 subjects without craniofacial alterations or syndromes. Statistical analysis was carried out using Fisher's test. From the 358 subjects with NSCL/P, 3 first-degree parents had history of leukemia, while 2 out of 1,432 subjects from the unaffected group had a family history of leukemia. The frequency of positive family history of leukemia was not significantly increased in first-degree relatives of patients with NSCL/P.