Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Extent: 14 p.The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel Thomas, Jason A. Powell, Benjamin D. Green, Emma F. Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C.W. Zannettino, Stuart M. Pitson, Timothy P. Hughes, Angel F. Lopez, Peter R. Shepherd, Andrew H. Wei, Paul G. Ekert and Mark A. Guthridg

The utility of empirical mupirocin for eradication of methicillin-resistant Staphylococcus aureus colonisation in Far North Queensland, Australia

Methicillin-resistant Staphylococcus aureus (MRSA) infections are common in Far North Queensland (FNQ) and their incidence is increasing. Decolonisation regimens that include topical mupirocin are recommended in Australian guidelines to reduce recurrent infection. Mupirocin resistance was identified in 3,932/15,851 (24.8%) methicillin-sensitive Staphylococcus aureus (MSSA) isolates and in 533/5,134 (10.4%) MRSA isolates from FNQ between 1997 and 2016. Factors associated with mupirocin resistance in multivariate analysis were an MSSA isolate, age < 40 years, rural residence and female gender. These data support the use of mupirocin in MRSA decolonisation in FNQ, although addressing the underlying social determinants of health that drive the incidence of S. aureus infections remain a priority for local healthcare provision

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.National Institutes of Health grants: (UL1RR025741, K24AR002138, P602AR30692, P01AR49084, UL1TR000165, P01AI083194, RO1AR43814, P60AR053308, UL1TR000004, AR43727, R21AI070304, RO1AR057172, UL1RR025014, R01AR051545-03, UL1RR029882, P60AR062755, P30AR53483, U19AI082714, P30GM103510, U01AI101934, AI063274, AR056360, AI083194, R37AI024717, P01083194, P01AR049084, PR094002); Northwestern University Feinberg School of Medicine; University of Alabama Birmingham; National Institute of Arthritis and Musculoskeletal and Skin Diseases; University of California Los Angeles; University of California San Francisco; Hopkins University; University of Colorado School of Medicine; University of Southern California; Seattle Children's Research Institute Arthritis Foundation; Medical University of South Carolina; Oklahoma Medical Research Foundation; Cincinnati Children's Hospital Medical Center; US Departments of Defense grant: (PR094002); Veterans Affairs; Alliance for Lupus Research; Kirkland Scholar Award; Korea Healthcare technology R & D project: (A121983); Ministry for Health and Welfare; Republic of Korea; Swedish Research Council; Instituto de Salud Carlos III grant: (PS09/00129); European Union FEDER funds; Fundação para a Ciência e Tecnologia fellowships: (SFRH/BPD/29354/2006, SFRH/BPD/34648/2007)

Suicides in Aboriginal and non-Aboriginal people following hospital admission for suicidal ideation and self-harm: A retrospective cohort data linkage study from the Northern Territory

Purpose: This study aimed to explore risk factors for suicide in Aboriginal and non-Aboriginal people following hospital admission for suicidal ideation and self-harm in the Northern Territory, Australia to help clarify opportunities for improved care and intervention for these population groups. Methods: Individuals with at least one hospital admission involving suicidal ideation and/or self-harm between 1 July 2001 and 31 December 2013 were retrospectively recruited and followed up using linked mortality records to 31 December 2014. Survival analyses stratified by Indigenous status identified socio-demographic and clinical characteristics from index hospital admissions associated with suicide. Results: Just over half of the 4391 cohort members identified as Aboriginal (n = 2304; 52.4%). By 2014, 281 deaths were observed comprising 68 suicides, representing a 2.6% and 2.0% probability of suicide for Aboriginal and non-Aboriginal people, respectively. After adjusting for other characteristics, a higher risk of suicide was associated with male sex (Aboriginal adjusted hazard ratio: 4.14; 95% confidence interval: [1.76, 9.75]; non-Aboriginal adjusted hazard ratio: 5.96; 95% confidence interval: [1.98, 17.88]) and repeat hospital admissions involving self-harm (Aboriginal adjusted hazard ratio: 1.37; 95% confidence interval: [1.21, 1.55]; non-Aboriginal adjusted hazard ratio: 1.29; 95% confidence interval: [1.10, 1.51]). Severe mental disorders were associated with a four times higher risk of suicide (adjusted hazard ratio: 4.23; 95% confidence interval: [1.93, 9.27]) in Aboriginal people only. Conclusion: The findings highlight non-clinical risk factors for suicide that suggest the need for comprehensive psychosocial assessment tailored to Aboriginal and non-Aboriginal people hospitalised with suicidal ideation or self-harm. Implementing appropriate management and aftercare within a broader public health framework is needed to support recovery and reduce long-term suicide risk in the community, especially for Aboriginal people and males

Evaluation of an Australian indigenous housing programme: community level impact on crowding, infrastructure function and hygiene

Background and Aim: Housing programmes in indigenous Australian communities have focused largely on achieving good standards of infrastructure function. The impact of this approach was assessed on three potentially important housing-related influences on child health at the community level: (1) crowding, (2) the functional state of the house infrastructure and (3) the hygienic condition of the houses.\ud \ud Methods: A before-and-after study, including house infrastructure surveys and structured interviews with the main householder, was conducted in all homes of young children in 10 remote Australian indigenous communities.\ud \ud Results: Compared with baseline, follow-up surveys showed (1) a small non-significant decrease in the mean number of people per bedroom in the house on the night before the survey (3.4, 95% CI 3.1 to 3.6 at baseline vs 3.2, 95% CI 2.9 to 3.4 at follow-up; natural logarithm transformed t test, t=1.3, p=0.102); (2) a marginally significant overall improvement in infrastructure function scores (Kruskal–Wallis test, χ2=3.9, p=0.047); and (3) no clear overall improvement in hygiene (Kruskal–Wallis test, χ2=0.3, p=0.605).\ud \ud Conclusion: Housing programmes of this scale that focus on the provision of infrastructure alone appear unlikely to lead to more hygienic general living environments, at least in this study context. A broader ecological approach to housing programmes delivered in these communities is needed if potential health benefits are to be maximised. This ecological approach would require a balanced programme of improving access to health hardware, hygiene promotion and creating a broader enabling environment in communities.\u

Efficacy and safety of intravenous lincosamide therapy in methicillin-resistant staphylococcus aureus bacteremia

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia has a high case-fatality rate, but currently recommended antimicrobial therapies have many shortcomings. The efficacy and safety of lincosamide therapy for MRSA bacteremia is incompletely defined. A retrospective audit was done of the management of all adults with MRSA bacteremia at an Australian tertiary referral hospital between 1 January 2007 and 31 December 2020. A total of 176 patients were included. The case-fatality rate declined from 14/57 (25%) in the first half of the study to 12/119 (10%) in the second half (P = 0.01). Of the 172 patients receiving antibiotics, 62 (36%) received a lincosamide- predominant regimen (lincosamide monotherapy for >50% of the intravenous course). The patients receiving lincosamide-predominant intravenous therapy had lower in-hospital mortality (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.01 to 0.53; P= 0.01) and a lower incidence of renal complications (OR [95% CI], 0.34 [0.1520.75]; P = 0.008) than patients receiving an alternative regimen. In multivariate analysis that also considered age, disease severity, comorbidity, infectious diseases consultation, source control, and the year of admission, patients receiving a lincosamide-predominant regimen were still less likely to die in the hospital than those receiving an alternative regimen (OR [95% CI], 0.05 [0.00 to 0.65]; P = 0.02). Lincosamides appear to have utility, at least as stepdown therapy, in the treatment of MRSA bacteremia, particularly in young, clinically stable patients with few comorbidities in whom endocarditis has been excluded. Prospective studies will help define their optimal role

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.info:eu-repo/semantics/publishedVersio