Role of Kindlin-1 in pulmonary breast cancer metastasis

Kindlin-1 is a focal adhesion (FA) protein and the founding member of the Kindlin family of proteins (Kindlins 1-3), which all have an important role in integrin signalling. Loss of functional Kindlin-1 has been associated with a congenital disease called Kindler syndrome that is characterised by a number of skin abnormalities including atrophy and blistering. Increased or decreased expression of the Kindlin family of proteins has been linked to a number of tumour types and Kindlin-1 is specifically associated with pulmonary metastasis in basal-like breast cancer. The mechanisms by which Kindlin-1 mediates metastasis to the lungs in breast cancer remain relatively unknown and this study aimed to investigate the role of Kindlin-1 in breast cancer. In line with previous reports, we have shown that Kindlin-1 regulates primary breast tumour formation. Our data suggest that the interaction of Kindlin-1 with integrins is specifically important for tumour initiation. The Kindlins have also been shown to have roles independent of integrin and have been found outside of focal adhesions; Kindlin-2 has been shown to have a nuclear localisation signal (NLS) and initial studies have identified a nuclear role for Kindlin-2 in the promotion of breast cancer, however, nuclear roles of the Kindlins remain mostly unexplored. We explored a potential nuclear role for Kindlin-1 and revealed a novel cellular location for Kindlin-1 in cancer cells. We show that Kindlin-1 is present in the nucleus of breast cancer and squamous cell carcinoma cells and that Kindlin-1 has an NLS that can be altered to prevent protein localisation to the nucleus. Furthermore, we show that presence of Kindlin-1 in the nucleus is important for primary tumour growth and mice inoculated with cells that express mutant Kindlin-1 that cannot localise to the nucleus, have significantly lower tumour growth compared to mice inoculated with cells expressing wild-type Kindlin-1. We also provide evidence that the immune system impacts on the Kindlins ability to regulate tumour growth. Specifically, Kindlin-1 was shown to inhibit IL-6 production, which promotes differentiation of naïve CD4+ T cells into Tregs and results in tumour development due to suppression of the anti-tumour response of the immune system. Our findings are particularly interesting as the FA protein FAK has previously been reported to have an immune-modulatory role in the nucleus of squamous cell carcinoma cells through regulation of the transcription of inflammatory cytokines and chemokines. Our data suggest that Kindlin-1 may also have similar important roles in the nucleus that warrants further investigation. As Kindlin-1 does not have catalytic activity, further studies are warranted to investigate the nuclear roles of Kindlin-1 and the interaction of Kindlin-1 with the immune system, as understanding these roles may offer new avenues for therapeutic intervention. Very few binding partners have been identified for the Kindlin family and known binding partners include phosphoinositides and some focal adhesions proteins such as integrin-linked kinase (ILK) and migfilin. We carried out proteomic analyses and identified a number of novel binding partners of Kindlin-1 in different breast cancer cell models. Our findings suggest that Kindlin-1 is an adaptor protein in the cell that regulates a number of key signalling hubs, which control several cellular processes including metabolism, cell proliferation, cell migration, apoptosis and signal transduction

‘You’re on the waiting list’: An interpretive phenomenological analysis of young adults’ experiences of waiting lists within mental health services in the UK

Waiting lists in mental health services are currently considered too long. Lengthy waits of up to 18 weeks are commonly reported in the UK. Waiting lists have long been associated with a variety of negative psychological responses, however there is little understanding behind young adults’ personal experiences of such delays within mental health services. The current study aimed to explore young adults’ experiences of waiting lists in mental healthcare in the UK. Seven young adults were interviewed in the current study (aged 19–22). Interpretive phenomenological analysis was utilised to explore participant accounts. Three super-ordinate themes were generated: Reliance on Alternative Methods of Support; Inability to Function Sufficiently; and Emergence of Negative Beliefs, Emotions and Thoughts. Participants primarily reported a variety of negative psychological and behavioural consequences associated with waiting lists in mental health services, as well as exacerbated existing physical and psychological health issues. In accordance with the limited number of previous studies, waiting lists are considered by patients to be barriers to mental health support and intervention. Future direction is advised

Kindlin-1 promotes pulmonary breast cancer metastasis

Abstract In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here, we show that in a mouse model of polyomavirus middle T antigen–induced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate β integrin heterodimers. Kindlin-1 loss reduced α4 integrin–mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti–VCAM-1 blocking antibody prevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer. Significance: These findings provide a mechanistic proof in mice that Kindin-1, an integrin-binding adaptor protein, is a critical mediator of early lung metastasis of breast cancer. Cancer Res; 78(6); 1484–96. ©2018 AACR.</jats:p

Impaired Sprouting and Axonal Atrophy in Cerebellar Climbing Fibres following In Vivo Silencing of the Growth-Associated Protein GAP-43

The adult mammalian central nervous system has a limited ability to establish new connections and to recover from traumatic or degenerative events. The olivo-cerebellar network represents an excellent model to investigate neuroprotection and repair in the brain during adulthood, due to its high plasticity and ordered synaptic organization. To shed light on the molecular mechanisms involved in these events, we focused on the growth-associated protein GAP-43 (also known as B-50 or neuromodulin). During development, this protein plays a crucial role in growth and in branch formation of neurites, while in the adult it is only expressed in a few brain regions, including the inferior olive (IO) where climbing fibres (CFs) originate. Following axotomy GAP-43 is usually up-regulated in association with regeneration. Here we describe an in vivo lentiviral-mediated gene silencing approach, used for the first time in the olivo-cerebellar system, to efficiently and specifically downregulate GAP-43 in rodents CFs. We show that lack of GAP-43 causes an atrophy of the CF in non-traumatic conditions, consisting in a decrease of its length, branching and number of synaptic boutons. We also investigated CF regenerative ability by inducing a subtotal lesion of the IO. Noteworthy, surviving CFs lacking GAP-43 were largely unable to sprout on surrounding Purkinje cells. Collectively, our results demonstrate that GAP-43 is essential both to maintain CFs structure in non-traumatic condition and to promote sprouting after partial lesion of the IO

Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study

Objective Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. Methods This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis and bacterial vaginosis at enrolment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. Results 1,435 pregnant women had fetal/birth weight assessed 3,950 times. Compared to women without malaria or STIs/RTIs (n=399), malaria-only (n=267), STIs/RTIs-only (n=410) or both (n=353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% CI]: malaria=-0.18 [-0.31,-0.04], p=0.01]; STIs/RTIs=-0.14 [-0.26,-0.03], p=0.01]; both=-0.20 [-0.33,-0.07], p=0.003). Paucigravidae experienced the greatest impact. Conclusion Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe