Immune factors preceding diagnosis of glioma: a Prostate Lung Colorectal Ovarian Cancer Screening Trial nested case-control study.

BackgroundEpidemiological studies of adult glioma have identified genetic and environmental risk factors, but much remains unclear. The aim of the current study was to evaluate anthropometric, disease-related, and prediagnostic immune-related factors for relationship with glioma risk.MethodsWe conducted a nested case-control study among the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. One hundred and twenty-four glioma cases were identified and each matched to four controls. Baseline characteristics were collected at enrollment and were evaluated for association with glioma status. Serum specimens were collected at yearly intervals and were analyzed for immune-related factors including TGF-β1, TNF-α, total IgE, and allergen-specific IgE. Immune factors were evaluated at baseline in a multivariate conditional logistic regression model, along with one additional model that incorporated the latest available measurement.ResultsA family history of glioma among first-degree relatives was associated with increased glioma risk (OR = 4.41, P = .002). In multivariate modeling of immune factors at baseline, increased respiratory allergen-specific IgE was inversely associated with glioma risk (OR for allergen-specific IgE > 0.35 PAU/L: 0.59, P = .03). A logistic regression model that incorporated the latest available measurements found a similar association for allergen-specific IgE (P = .005) and showed that elevated TGF-β1 was associated with increased glioma risk (P-value for trend <.0001).ConclusionThe results from this prospective prediagnostic study suggest that several immune-related factors are associated with glioma risk. The association observed for TGF-β1 when sampling closer to the time of diagnosis may reflect the nascent brain tumor's feedback on immune function

Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics.

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case-control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10(-9) to 0.004) and NHWs (p values of 2.2 × 10(-6) to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53-1.99 and 1.37-1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (>50 chromosomes; ORs of 2.21-3.22 and 1.67-2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p < 1 × 10(-5)), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches

The Iowa Homemaker vol.11, no.8

House Not for Sale… By Joanne M. Hansen, page 1 Home Management Mothers… By Helen Bishop, page 2 “Tell Me a Poem”… By Lorraine Sandstrom, page 3 When the Box Was Opened… By Cora B. Miller, page 4 Just Serve Yourself… By Ida M. Shilling, page 4 Modernizing Marriage… By Ethel Cessna Morgan, page 5 Girls 4-H Clubs By Clara Austin, page 6 Alumnae Echoes… By Anafred Stephenson, page 8 Editorial, page 9 Inside Information By Helen Jewell and Betty Martin, page 1

Using mixed methods evaluation to assess the feasibility of online clinical training in evidence based interventions : a case study of cognitive behavioural treatment for low back pain

Background: Cognitive behavioural (CB) approaches are effective in the management of non-specific low back pain (LBP). We developed the CB Back Skills Training programme (BeST) and previously provided evidence of clinical and cost effectiveness in a large pragmatic trial. However, practice change is challenged by a lack of treatment guidance and training for clinicians. We aimed to explore the feasibility and acceptability of an online programme (iBeST) for providing training in a CB approach. Methods: This mixed methods study comprised an individually randomised controlled trial of 35 physiotherapists and an interview study of 8 physiotherapists. Participants were recruited from 8 National Health Service departments in England and allocated by a computer generated randomisation list to receive iBeST (n = 16) or a face-to-face workshop (n = 19). Knowledge (of a CB approach), clinical skills (unblinded assessment of CB skills in practice), self-efficacy (reported confidence in using new skills), attitudes (towards LBP management), and satisfaction were assessed after training. Engagement with iBeST was assessed with user analytics. Interviews explored acceptability and experiences with iBeST. Data sets were analysed independently and jointly interpreted. Results: Fifteen (94 %) participants in the iBeST group and 16 (84 %) participants in the workshop group provided data immediately after training. We observed similar scores on knowledge (MD (95 % CI): 0.97 (−1.33, 3.26)), and self-efficacy to deliver the majority of the programme (MD (95 % CI) 0.25 (−1.7; 0.7)). However, the workshop group showed greater reduction in biomedical attitudes to LBP management (MD (95 % CI): −7.43 (−10.97, −3.89)). Clinical skills were assessed in 5 (33 %) iBeST participants and 7 (38 %) workshop participants within 6 months of training and were similar between groups (MD (95 % CI): 0.17(−0.2; 0.54)). Interviews highlighted that while initially sceptical, participants found iBeST acceptable. A number of strategies were identified to enhance future versions of iBeST such as including more skills practice. Conclusions: Combined quantitative and qualitative data indicated that online training was an acceptable and promising method for providing training in an evidence based complex intervention. With future enhancement, the potential reach of this training method may facilitate evidence-based practice through large scale upskilling of the workforce

TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion

Structure, spin correlations and magnetism of the S=1/2S = 1/2 square-lattice antiferromagnet Sr2_2CuTe1−x_{1-x}Wx_xO6_6 (0≤x≤10 \leq x \leq 1)

Quantum spin liquids are highly entangled magnetic states with exotic properties. The $S = 1/2$ square-lattice Heisenberg model is one of the foundational models in frustrated magnetism with a predicted, but never observed, quantum spin liquid state. Isostructural double perovskites Sr$_2$CuTeO$_6$ and Sr$_2$CuWO$_6$ are physical realizations of this model, but have distinctly different types magnetic order and interactions due to a $d^{10}/d^0$ effect. Long-range magnetic order is suppressed in the solid solution Sr$_2$CuTe$_{1-x}$W$_x$O$_6$ in a wide region of $x = 0.05-0.6$, where the ground state has been proposed to be a disorder-induced spin liquid. Here we show that the spin-liquid-like $x = 0.2$ and $x = 0.5$ samples have distinctly different local spin correlations, which suggests they have different ground states. Furthermore, the previously ignored interlayer coupling between the square-planes is likely to play a role in the suppression of magnetic order on the W-rich side at $x \approx 0.6$. These results highlight the complex magnetism of Sr$_2$CuTe$_{1-x}$W$_x$O$_6$ and hint at a new quantum critical point at $x \approx 0.3$.Comment: 19+8 pages, 6+8 figure