Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania

<p>Abstract</p> <p>Background</p> <p>Chronic inflammation activated by macrophage innate pathogen recognition receptors such as TLR4 can lead to a range of inflammatory diseases, including atherosclerosis, Crohn's disease, arthritis and cancer. Unlike many microbes, the kinetoplastid protozoan pathogen <it>Leishmania </it>has been shown to avoid and even actively suppress host inflammatory cytokine responses, such as LPS-induced IL-12 production. The nature and scope of <it>Leishmania</it>-mediated inflammatory cytokine suppression, however, is not well characterized. Advancing our knowledge of such microbe-mediated cytokine suppression may provide new avenues for therapeutic intervention in inflammatory disease.</p> <p>Methods</p> <p>We explored the kinetics of a range of cytokine and chemokine responses in primary murine macrophages stimulated with LPS in the presence versus absence of two clinically distinct species of <it>Leishmania </it>using sensitive multiplex cytokine analyses. To confirm that these effects were parasite-specific, we compared the effects of <it>Leishmania </it>uptake on LPS-induced cytokine expression with uptake of inert latex beads.</p> <p>Results</p> <p>Whilst <it>Leishmania </it>uptake alone did not induce significant levels of any cytokine analysed in this study, <it>Leishmania </it>uptake in the presence of LPS caused parasite-specific suppression of certain LPS-induced pro-inflammatory cytokines, including IL-12, IL-17 and IL-6. Interestingly, <it>L. amazonensis </it>was generally more suppressive than <it>L. major</it>. We also found that other LPS-induced proinflammatory cytokines, such as IL-1α, TNF-α and the chemokines MIP-1α and MCP-1 and also the anti-inflammatory cytokine IL-10, were augmented during <it>Leishmania </it>uptake, in a parasite-specific manner.</p> <p>Conclusions</p> <p>During uptake by macrophages, <it>Leishmania </it>evades the activation of a broad range of cytokines and chemokines. Further, in the presence of a strong inflammatory stimulus, <it>Leishmania </it>suppresses certain proinflammatory cytokine responses in a parasite-specific manner, however it augments the production of other proinflammatory cytokines. Our findings highlight the complexity of inflammatory cytokine signalling regulation in the context of the macrophage and <it>Leishmania </it>interaction and confirm the utility of the <it>Leishmania</it>/macrophage infection model as an experimental system for further studies of inflammatory regulation. Such studies may advance the development of therapies against inflammatory disease.</p

Chronic Nicotine Modifies Skeletal Muscle Na,K-ATPase Activity through Its Interaction with the Nicotinic Acetylcholine Receptor and Phospholemman

Our previous finding that the muscle nicotinic acetylcholine receptor (nAChR) and the Na,K-ATPase interact as a regulatory complex to modulate Na,K-ATPase activity suggested that chronic, circulating nicotine may alter this interaction, with long-term changes in the membrane potential. To test this hypothesis, we chronically exposed rats to nicotine delivered orally for 21–31 days. Chronic nicotine produced a steady membrane depolarization of ∼3 mV in the diaphragm muscle, which resulted from a net change in electrogenic transport by the Na,K-ATPase α2 and α1 isoforms. Electrogenic transport by the α2 isoform increased (+1.8 mV) while the activity of the α1 isoform decreased (−4.4 mV). Protein expression of Na,K-ATPase α1 or α2 isoforms and the nAChR did not change; however, the content of α2 subunit in the plasma membrane decreased by 25%, indicating that its stimulated electrogenic transport is due to an increase in specific activity. The physical association between the nAChR, the Na,K-ATPase α1 or α2 subunits, and the regulatory subunit of the Na,K-ATPase, phospholemman (PLM), measured by co-immuno precipitation, was stable and unchanged. Chronic nicotine treatment activated PKCα/β2 and PKCδ and was accompanied by parallel increases in PLM phosphorylation at Ser63 and Ser68. Collectively, these results demonstrate that nicotine at chronic doses, acting through the nAChR-Na,K-ATPase complex, is able to modulate Na,K-ATPase activity in an isoform-specific manner and that the regulatory range includes both stimulation and inhibition of enzyme activity. Cholinergic modulation of Na,K-ATPase activity is achieved, in part, through activation of PKC and phosphorylation of PLM

Insights from computational modeling in inflammation and acute rejection in limb transplantation

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection. © 2014 Wolfram et al

Drug Resistance in Eukaryotic Microorganisms

Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies

EFEKTIVITAS PENGAWASAN UNIT KERJA ANTI FRAUD PADA BANK MUAMALAT INDONESIA

Perkembangan perbankan syari‟ah di Indonesia demikian pesat yang ditandai dengan berdirinya Bank Muamalat Indonesia. Perkembangan ini berimplikasi pada besarnya tantangan perbankan syari‟ah di Indonesia terutama dalam mempertahankan identitasnya sebagai perusahaan yang bergerak berlandaskan prinsip-prinsip syari‟ah. Sejak berdirinya perbankan syariah,berbagai kontroversi muncul dari masyarakat, masalah yang paling banyak disorot adalah pelekatan label syariah pada institusi keuangan Islam yang masih dianggap belum layak. Keraguan masyarakat tersebut seolah terjawab dengan munculnya kasus yang cukup menggemparkan yakni kasus fraud (tindak kecurangan) yang terjadi di lembaga syariah. Bank Muamalat Indonesia merupakan bank syari‟ah pertama yang muncul dengan gagasan bank murni syari‟ah. Akan tetapi, bank Muamalat Indonesia juga tak luput dari kasus fraud yang dilakukan oleh karyawan bank tersebut. Berdasarkan Laporan Tahunan BMI menyebutkan bahwa telah terjadi peningkatan kasus fraud dari tahun sebelumnya yang berjumlah 18 kasus menjadi 82 kasus pada tahun 2016. Padahal perusahaan yang menggunakan identitas syariah seharusnya dapat lebih meminimalisir bahkan meniadakan resiko terjadinya kasus fraud dengan adanya internal control perusahaan. Dari latar belakang tersebut, peneliti berusaha mendalami peran pengawasan Unit Kerja Anti Fraud dalam fraud preventive pada Bank Muamalat Indonesia. Penelitian ini merupakan penelitin pustaka yang bersifat deskriptif analisis dengan pendekatan kualitatif. Adapun sumber bahan hukum primer yang dipakai yaitu berdasarkan Laporan Tahunan Bank Muamalat Indonesia Tahun 2016. Sedangkan sumber bahan hukum sekunder berupa buku-buku, jurnal,karya ilmiah, artikel, terkait dengan strategi anti fraud perbankan syariah. Dari hasil penelitian dikemukakan bahwa peningkatan kasus fraud yang terjadi pada Bank Muamalat Indonesia disebabkan kurang efektifnya pengawasan Unit Kerja Anti Fraud. Hal ini dikarenakan kegiatan yang dilakukan selama tahun 2016 belum menujukkan adanya usaha preventif terhadap kasus fraud. Sedangkan pencegahan merupakan pilar penting dalam keefektivan sebuah pengawasan. Tujuan perusahaan dalam mencegah fraud dapat tercapai, jika fungsi pengawasan dilakukan sebelum terjadinya penyimpangan-penyimpangan sehingga lebih bersifat mencegah (prefentive control). Oleh karena itu, keefektivan pengawasan Unit Kerja Anti Fraud diharapkan dapat meminimalisir tindak kecurangan demi mewujudkan perusahaan yang patuh terhadap ketentuan syariah sesuai dengan identitas perusahaan. vii Usaha pencegahan terjadinya kasus pada Bank Muamalat Indonesia diharapkan dapat menjadi bukti terlaksananya tatakelola perusahaan (Good Corporate Governance) pada Bank Syari‟ah dengan baik. Hal ini berdasarkan dalam dalam perbankan syariah dikenal adanya prinsip-prinsip syariah yang mendukung bagi terlaksananya prinsip GCG yakni keharusan bagi subjek hukum termasuk bank untuk menerapkan prinsip kejujuran (shiddiq), edukasi kepada masyarakat (tabligh), kepercayaan (amanah), dan pengelolaan secara profesional (fathanah)