An updated investigation of the multidimensional structure of language lateralization in left- and right-handed adults: a test-retest functional transcranial Doppler sonography study with six language tasks.

A previous study we reported in this journal suggested that left and right-handers may differ in their patterns of lateralization for different language tasks (Woodhead et al. 2019 R. Soc. Open Sci. 6, 181801. (doi:10.1098/rsos.181801)). However, it had too few left-handers (N = 7) to reach firm conclusions. For this update paper, further participants were added to the sample to create separate groups of left- (N = 31) and right-handers (N = 43). Two hypotheses were tested: (1) that lateralization would be weaker at the group level in left-than right-handers; and (2) that left-handers would show weaker covariance in lateralization between tasks, supporting a two-factor model. All participants performed the same protocol as in our previous paper: lateralization was measured using functional transcranial Doppler sonography during six different language tasks, on two separate testing sessions. The results supported hypothesis 1, with significant differences in laterality between groups for four out of six tasks. For hypothesis 2, structural equation modelling showed that there was stronger evidence for a two-factor model in left than right-handers; furthermore, examination of the factor loadings suggested that the pattern of laterality across tasks may also differ between handedness groups. These results expand on what is known about the differences in laterality between left- and right-handers.

Investigating the effects of handedness on the consistency of lateralization for speech production and semantic processing tasks using functional transcranial Doppler sonography.

The left hemisphere is dominant for language in most people, but lateralization strength varies between different tasks and individuals. A large body of literature has shown that handedness is associated with lateralization: left handers have weaker language lateralization on average, and a greater incidence of atypical (right hemisphere) lateralization; but typically, these studies have relied on a single measure of language lateralization. Here we consider the relationships between lateralization for two different language tasks. We investigated the influence of handedness on lateralization using functional transcranial Doppler sonography (fTCD), using an existing dataset (N = 151 adults, 21 left handed). We compared a speech production task (word generation) and a semantic association task. We demonstrated stronger left-lateralization for word generation than semantic association; and a moderate correlation between laterality indices for the two tasks (r = 0.59). Laterality indices were stronger for right than left handers, and left handers were more likely than right handers to have atypical (right hemisphere) lateralization or inconsistent lateralization between the two tasks. These results add to our knowledge of individual differences in lateralization and support the view that language lateralization is multifactorial rather than unitary.

Testing the unitary theory of language lateralization using functional transcranial Doppler sonography in adults.

Hemispheric dominance for language can vary from task to task, but it is unclear if this reflects error of measurement or independent lateralization of different language systems. We used functional transcranial Doppler sonography to assess language lateralization within the middle cerebral artery territory in 37 adults (seven left-handers) on six tasks, each given on two occasions. Tasks taxed different aspects of language function. A pre-registered structural equation analysis was used to compare models of means and covariances. For most people, a single lateralized factor explained most of the covariance between tasks. A minority, however, showed dissociation of asymmetry, giving a second factor. This was mostly derived from a receptive task, which was highly reliable but not lateralized. The results suggest that variation in the strength of language lateralization reflects true individual differences and not just error of measurement. The inclusion of several tasks in a laterality battery makes it easier to detect cases of atypical asymmetry.

Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway.

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.

Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL).

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. PATIENTS AND METHODS: We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. RESULTS: One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin < 9.3 g/dl, lactate dehydrogenase (LDH) ≥ 1668 IU/l, white blood cell ≥ 208 K/l and ß2M ≥ 8 mg/l had significantly inferior OS and patients with hemoglobin < 9.3 g/dl had inferior progression-free survival (PFS). In multivariate analysis, we identified that presence of pleural effusion [hazard ratio (HR) 2.08 (95% CI 1.11-3.9); P = 0.02], high LDH (≥ 1668 IU/l) [HR 2.5 (95% CI 1.20-4.24); P < 0.001)], and low hemoglobin (< 9.3 g/dl) [HR 0.33 (95% CI 0.14-0.75); P = 0.008] were associated with shorter OS. Fifty-five previously untreated patients received treatment with an alemtuzumab-based regimen (42 monotherapy and 13 combination with pentostatin). Overall response rate, complete remission rate (CR) for single-agent alemtuzumab and alemtuzumab combined with pentostatin were 83%, 66% and 82%, 73% respectively. In patients who achieved initial CR, stem cell transplantation was not associated with longer PFS and OS. CONCLUSION: Outcomes in T-PLL remain poor. Multicenter collaborative effort is required to conduct prospective studies.

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

Decadal-Scale Forecasting of Climate Drivers for Marine Applications.

Climate influences marine ecosystems on a range of time scales, from weather-scale (days) through to climate-scale (hundreds of years). Understanding of interannual to decadal climate variability and impacts on marine industries has received less attention. Predictability up to 10 years ahead may come from large-scale climate modes in the ocean that can persist over these time scales. In Australia the key drivers of climate variability affecting the marine environment are the Southern Annular Mode, the Indian Ocean Dipole, the El Niño/Southern Oscillation, and the Interdecadal Pacific Oscillation, each has phases that are associated with different ocean circulation patterns and regional environmental variables. The roles of these drivers are illustrated with three case studies of extreme events-a marine heatwave in Western Australia, a coral bleaching of the Great Barrier Reef, and flooding in Queensland. Statistical and dynamical approaches are described to generate forecasts of climate drivers that can subsequently be translated to useful information for marine end users making decisions at these time scales. Considerable investment is still needed to support decadal forecasting including improvement of ocean-atmosphere models, enhancement of observing systems on all scales to support initiation of forecasting models, collection of important biological data, and integration of forecasts into decision support tools. Collaboration between forecast developers and marine resource sectors-fisheries, aquaculture, tourism, biodiversity management, infrastructure-is needed to support forecast-based tactical and strategic decisions that reduce environmental risk over annual to decadal time scales.

EFFECT OF SELENIUM SUPPLEMENTATION ON PROTEOMIC SERUM BIOMARKERS IN ELDERLY MEN.

OBJECTIVES: To determine the effect of selenium supplementation on the human proteomic profile. DESIGN: Serum samples were collected in this pilot study from a randomized placebo controlled Phase 2 clinical trial (Watchful Waiting (WW)). SETTING: Subjects were followed every three months for up to five years at the University of Arizona Prostate Cancer Prevention Program. PARTICIPANTS: One hundred and forty men (age < 85 years) had biopsy-proven prostate cancer, a Gleason sum score less than eight, no metastatic cancer, and no prior treatment for prostate cancer. INTERVENTION: As part of the WW trial, men were randomized to placebo, selenium 200 µg/day or selenium 800 µg/day. For the purpose of the current study, 40 subjects enrolled in the WW study (20 from the placebo group and 20 from Se 800 µg/day group) were selected. MEASUREMENTS: Baseline serum samples were collected at each follow-up visit and stored at -80 degrees Celsius. A multiplexed proteomic panel investigated changes in 120 proteins markers simultaneously. RESULTS: Thirteen proteins (Apolipoprotein J, IL-10, IL-1 alpha, MMP-3, IL-12p70, IL-2 receptor alpha, cathepsin B, eotaxin, EGFR, FGF-basic, myeloperoxidase, RANTES, TGF-beta) were determined to be either statistically (p-value < 0.05) or marginally significantly (0.05 < p-value <0.1) changed in the selenium supplemented group as compared to placebo. CONCLUSION: Although independent validation of these results is needed, this study is the first of its kind to utilize high throughput fluorescence based protein multiplex panel in analyzing changes in the proteomic profile due to selenium supplementation. Results from this study provide insight into the ability of selenium to modulate numerous protein markers and thus impact various biological processes in humans.

Umbilical cord blood graft engineering: challenges and opportunities.

We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specific T-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

Levels of tritium in soils and vegetation near Canadian nuclear facilities releasing tritium to the atmosphere: implications for environmental models.

Concentrations of organically bound tritium (OBT) and tritiated water (HTO) were measured over two growing seasons in vegetation and soil samples obtained in the vicinity of four nuclear facilities and two background locations in Canada. At the background locations, with few exceptions, OBT concentrations were higher than HTO concentrations: OBT/HTO ratios in vegetation varied between 0.3 and 20 and values in soil varied between 2.7 and 15. In the vicinity of the four nuclear facilities OBT/HTO ratios in vegetation and soils deviated from the expected mean value of 0.7, which is used as a default value in environmental transfer models. Ratios of the OBT activity concentration in plants ([OBT]plant) to the OBT activity concentration in soils ([OBT]soil) appear to be a good indicator of the long-term behaviour of tritium in soil and vegetation. In general, OBT activity concentrations in soils were nearly equal to OBT activity concentrations in plants in the vicinity of the two nuclear power plants. [OBT]plant/[OBT]soil ratios considerably below unity observed at one nuclear processing facility represents historically higher levels of tritium in the environment. The results of our study reflect the dynamic nature of HTO retention and OBT formation in vegetation and soil during the growing season. Our data support the mounting evidence suggesting that some parameters used in environmental transfer models approved for regulatory assessments should be revisited to better account for the behavior of HTO and OBT in the environment and to ensure that modelled estimates (e.g., plant OBT) are appropriately conservative.

A comparison of the direct cost of care in an open-bay and single-family room NICU.

OBJECTIVE: This research examined the proposition that the direct costs of care were no different in an open-bay (OPBY) as compared with a single-family room (SFR) neonatal intensive care (NICU) environment. STUDY DESIGN: This was a sequential cohort study. RESULT: General linear models were implemented using clinical and cost data for all neonates admitted to the two cohorts studied. Costs were adjusted to year 2007 U.S. dollars. Models were constructed for the unadjusted regression and subsequently by adding demographic variables, treatment variables, length of respiratory support and length of stay. With the exception of the last, none were found to achieve significance. The full model had R(2)=0.799 with P=0.0095 and predicted direct costs of care less in the SFR NICU. CONCLUSION: For the time, location and administrative practices in place, this study demonstrates that care can be provided in the SFR NICU at no additional cost as compared with OPBY NICU.

A reanalysis of cancer mortality in Canadian nuclear workers (1956-1994) based on revised exposure and cohort data.

BACKGROUND: A 15-country study of nuclear workers reported significantly increased radiation-related risks of all cancers excluding leukaemia, with Canadian data a major factor behind the pooled results. We analysed mortality (1956-1994) in the updated Canadian cohort and provided revised risk estimates. METHODS: Employment records were searched to verify and revise exposure data and to restore missing socioeconomic status. Excess relative risks per sievert (ERR/Sv) of recorded radiation dose and 95% confidence intervals (CIs) were estimated using Poisson regression. RESULTS: A significant heterogeneity of the dose-response for solid cancer was identified (P=0.02), with 3088 early (1956-1964) Atomic Energy of Canada Limited (AECL) workers having a significant increase (ERR/Sv=7.87, 95% CI: 1.88, 19.5), and no evidence of radiation risk for 42,228 workers employed by three nuclear power plant companies and post-1964 AECL (ERR/Sv=-1.20, 95% CI: <-1.47, 2.39). Radiation risks of leukaemia were negative in early AECL workers and non-significantly increased in other workers. In analyses with separate terms for tritium and gamma doses, there was no evidence of increased risk from tritium exposure. All workers had mortality lower than the general population. CONCLUSION: Significantly increased risks for early AECL workers are most likely due to incomplete transfer of AECL dose records to the National Dose Registry. Analyses of the remainder of the Canadian nuclear workers (93.2%) provided no evidence of increased risk, but the risk estimate was compatible with estimates that form the basis of radiation protection standards. Study findings suggest that the revised Canadian cohort, with the exclusion of early AECL workers, would likely have an important effect on the 15-country pooled risk estimate of radiation-related risks of all cancer excluding leukaemia by substantially reducing the size of the point estimate and its significance.

Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review.

BACKGROUND: The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate. METHODS: We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol. RESULTS: We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure. CONCLUSIONS: The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.

Differences in characteristics of men with localised prostate cancer who demonstrate low, intermediate or high prostate-specific antigen velocity.

BACKGROUND: Current diagnostic tools are inadequate for reliable prediction of prostate cancer (PCa) aggressiveness in patients with localised disease. This results in many patients being exposed to potentially unnecessary invasive treatment and its associated morbidities. In order to develop appropriate treatment strategies, it is essential to understand the differences between patients who will develop aggressive disease and those who will not. METHODS: A longitudinal study was conducted in men with localised PCa on active surveillance for their disease in which 140 subjects were followed every 3 months for up to 5 years. Change in prostate-specific antigen (PSA) over time (PSA velocity) was used as a marker for PCa progression. Subjects were categorised as slow, intermediate and fast progressors based on tertiles of PSA velocity. Differences in baseline markers were investigated using logistic regressions. Two approaches were used, slow progressors were compared with fast progressors (model 1) and slow progressors were compared with combination of intermediate and fast progressors (model 2). RESULTS: Aspirin was negatively associated with high PSA velocity in model 1 (odds ratio (95% confidence interval): 0.24 (0.06, 0.94), P-value = 0.04) and model 2 (odds ratio = 0.22 (0.08, 0.59), P-value = 0.003), whereas smoking was positively associated with high PSA velocity in model 1 (1.03 (0.92, 1.13), P-value = 0.01). CONCLUSIONS: These findings highlight the role of aspirin and smoking in PCa progression. They have potential towards risk stratification as well as PCa prevention and hence need to be investigated further.

Design and validation of a multiplex specific primer-directed polymerase chain reaction assay for killer-cell immunoglobulin-like receptor genetic profiling.

Current methodologies for the analysis of the killer-cell immunoglobulin-like receptor (KIR) locus utilize specific primer-directed polymerase chain reaction (SSP-PCR), which require a wide range of DNA input, multiple reaction conditions, and up to 16 individual reactions. We have developed and validated a multiplex SSP-PCR method for the genetic analysis of the KIR locus. Design and optimization of four multiplex groups targeting 14 genes and their alleles on the KIR locus has been completed. Each multiplex group contains PCR products that differ in size by a minimum of 15 bp to allow sufficient fragment length resolution for size discrimination by gel electrophoresis. This assay allows for efficient genotyping of the KIR locus while requiring a minimum amount of DNA input, utilizing the simplicity of SSP-PCR.

Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates.

PURPOSE: MP470 is a multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret that is being evaluated as an anticancer agent. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of MP470 were studied in a non-human primate model that is highly predictive of CSF penetration in humans. METHODS: Oral MP470, 300 mg, was administered to four non-human primates. Serial samples of blood were collected from four animals and CSF samples from three animals for pharmacokinetic studies. Plasma and CSF concentrations were measured using an LC-MS/MS assay. Both model-independent and model-dependent methods were used to analyze the pharmacokinetic data. RESULTS: Following a one-time oral dose of 300 mg, the MP470 plasma area under the curve (AUC) was 1,690 ± 821 nM h (mean ± SD). The half-life of MP470 in the plasma was 11.0 ± 3.4 h. There was no measurable MP470 in the CSF. CONCLUSIONS: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

Green tea improves metabolic biomarkers, not weight or body composition: a pilot study in overweight breast cancer survivors.

BACKGROUND: Overweight status after breast cancer treatment may increase a woman's risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters and lipid profiles in overweight breast cancer survivors. METHODS: The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, homeostasis model assessment--insulin resistance (HOMA-IR) and lipids was evaluated in overweight breast cancer survivors. Participants had a mean weight of 80.2 kg; body mass index (BMI) 30.1 kg m⁻²; and body fat 46.4%. Participants (n = 54) were randomised to 960 mL of decaffeinated green or placebo tea daily for 6 months. RESULTS: Mean (SD) tea intake among study completers (n = 39) was 5952 (1176) mL week⁻¹ and was associated with a significant reduction in energy intake (P = 0.02). Change in body weight of -1.2 kg (green tea) versus +0.2 kg (placebo) suggests a weight change effect, although this was not statistically significant. Decaffeinated green tea intake was associated with elevated high-density lipoprotein (HDL) levels (P = 0.003) and nonsignificant improvements in the HDL/LDL ratio and HOMA-IR (-1.1 ± 5.9: green tea; +3.2 ± 7.2: herbal). CONCLUSIONS: Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.

Association between polymorphic variation in VDR and RXRA and circulating levels of vitamin D metabolites.

The vitamin D metabolite 1,25(OH)2D is the bioactive ligand of the vitamin D receptor (VDR). VDR forms a heterodimer with the retinoid X receptors (RXRs) that when bound to ligand influences the transcriptional control of genes that regulate circulating levels of vitamin D metabolites. Whether genetic variation in VDR or RXRA affects circulating levels of 1,25(OH)2D or 25(OH)D has not been established. We used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between SNPs in VDR and RXRA and serum levels of 1,25(OH)2D and 25(OH)D. A total of 42 tagSNPs in VDR and 32 in RXRA were analyzed in a sample of 415 participants. Principal components analyses revealed a gene-level association between RXRA and serum 1,25(OH)2D concentrations (P=0.01), but not 25(OH)D. No gene-level association was found for VDR with either serum biomarker. At the single-SNP level, a significant positive trend was observed for increasing 1,25(OH)2D levels with each additional copy of the A allele for RXRA SNP rs9409929 (P-trend=0.003). After a multiple comparisons adjustment, no individual SNP in VDR or RXRA was significantly associated with either outcome. These results demonstrate an association between genetic variation in RXRA and 1,25(OH)2D serum concentrations.