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Purpose:Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.Experimental Design:We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell–restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.Results:Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.Conclusions:The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.

Supplemental Table 4: Abundance information of top 20 CDR3 sequences and top 10 heavy chains and top 10 light chains (see supplemental Excel file) Supplemental Table 5: DESeq2 normalized counts, log2-fold change, and p-values and adjusted p-values for selected oncogenes, Myc and TCL1A (see supplemental Excel file)

Supplemental Figure 1: Commonly used murine cell surface markers of B-cell development Supplemental Figure 2: Multicolor flow cytometry gating strategy and representative flow plots from a WT spleen sample Supplemental Figure 3: Histopathological assessment of bone marrow aspirates Supplemental Figure 4: Relative changes of mature B-cell subsets in marrow and blood Supplemental Figure 5: Myc and TCL1 expression in CD21-IgM-, CD21-IgM+ and CD19+CD5+ populations Supplemental Figure 6: Characterization of BCR and V gene usage Supplemental Figure 7: B220low/+CD19+CD5+ CLL-like population in recipients of flow-sorted dTG malignancy components Supplemental Figure 8: Immunophenotype of B220+ non-CLL cells in recipients of flow-sorted dTG malignancy components Supplemental Table 1: Fluorophores, concentrations and suppliers of antibodies used to stain murine cells Supplemental Table 2: Low-input RNA-seq post-alignment quality control metrics Supplemental Table 3: Alignment statistics of heavy- and light chain- (lambda and kappa) B-cell receptor (BCR) reads Supplemental Table 6: Characteristics of recipient mice and engrafted diseases after injection of flow-sorted CLL, CD21-IgM- and CD21-IgM+ cells obtained from pooled diseased dTG donor mice (n=3)

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL).Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water.Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle.Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831–41. ©2016 AACR.

Supplementary Table S1. Kinase selectivity of acalabrutinib as assessed by DiscoveRX KinomeScan screening.

Supplementary Figure S5: Acalabrutinib demonstrates similar changes in proliferation and tumor burden in the CLL xenograft mouse model as ibrutinib.

Supplementary Figure S1: Acalabrutinib is a more potent BCR-inhibitor than ibrutinib in vivo at 1mg/kg and 3mg/kg. Supplementary Figure S2: In vivo gating strategy for murine cells. Supplementary Figure S3: In vivo acalabrutinib treatment inhibits BCR signal transduction similarly to ibrutinib. Supplementary Figure S4: In vitro gating strategy for patient MNCs.

ObjectivesThis study examined patterns of sexual violence against adults and children in Kenya during the COVID-19 pandemic to inform sexual violence prevention, protection, and response efforts.DesignA prospective cross-sectional research design was used with data collected from March to August 2020.SettingKenya.Participants317 adults, 224 children.Main measuresPerpetrator and survivor demographic data, characteristics of the assault.ResultsBivariate analyses found that children were more likely than adults to be attacked during daytime (59% vs 44%, p2(5, n=541)=53.3, pConclusionsPatterns of sexual violence against adult and child survivors during the COVID-19 pandemic are different, suggesting age-related measures are needed in national emergency plans to adequately address sexual violence during the pandemic and for future humanitarian crises.

Dietary patterns associated with risk for colorectal cancer (CRC) may contribute to continuing health disparities in Latinx populations. Latinx from low-income communities, aged 25-65, were randomized to a 12-week storytelling-based intervention (ST) (n = 300) or didactic learning (DL)(n = 285) classes on cancer screening and dietary changes related to CRC risk facilitated by Latinx lay health workers (promotora/es de salud). Dietary intake was assessed pre-and post-intervention (24-hour dietary recall) with no significant differences found between ST and DL groups. Specific dietary changes in both groups included increases (plt;.05) in dietary fiber (ST from 17.0 to 18.2; DL from 16.38 to 17.8 gms), calcium (ST from 715.7 to 781.9; DL 666.4 to 748.7 mgs), and vegetables (ST 2.5 to 2.8; DL 2.4 to 2.6 servings/day). Although between-intervention group effects were not significant, both culturally-adapted interventions were found to change a selection of key CRC-preventive dietary behaviors.

We examined how encoding view influences the information that is stored in and retrieved from memory during an eyewitness identification task. Participants watched a mock crime and we varied the angle from which they viewed the perpetrator. In Experiment 1, participants (N = 2904) were tested with a static photo lineup; the viewing angle of the lineup members was the same or different from the perpetrator at encoding. In Experiment 2, participants (N = 1430) were tested with a novel interactive lineup in which they could rotate the lineup faces into any angle. In both experiments, discrimination accuracy was greater when the viewing angle at encoding and test matched. Participants reinstated the angle of the interactive faces to match their encoding angle. Our results highlight the importance of encoding specificity for eyewitness identification, and show that people actively seek out information in the testing environment that matches the study environment to aid memory retrieval.

Purpose:Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.Experimental Design:We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell–restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.Results:Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.Conclusions:The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.

Sexual and gender based violence (SGBV) is notoriously difficult to investigate and prosecute. SGBV occurs in varied contexts and requires flexibility in the investigative approach in order to develop a strong evidence base to enable successful prosecutions. In this paper we focus on the need for innovation and development of training protocols for gathering testimonial and forensic evidence in SGBV cases, particularly in low resource environments, such as developing countries, displaced communities, and conflict and post-conflict societies. We discuss existing international guidelines that have been developed for improving the documentation and investigation of SGBV in these contexts, and argue there are significant gaps in the knowledge base that impede the effective implementation of such guidelines. In particular, collaborative research between academics, practitioners and NGOs is needed to address several priority areas. These include the development of programmes geared towards training non-specialist practitioners who work in low resource environments, as well as research programmes that evaluate the implementation of the programmes. This research will improve access to justice for victims and accountability for perpetrators of sexual violence. Keywords: Sexual violence, Forensic, Interviews, DNA, Investigation

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which novel therapeutics with improved efficacy are greatly needed. To provide support for clinical immune checkpoint blockade, we comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on primary MCL cells. MCL cells showed constitutive expression of Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1), variable CD200, absent PD-L2, Lymphocyte Activation Gene 3 (LAG-3), and Cytotoxic T-cell Associated Protein 4 (CTLA-4). Effector cells from MCL patients expressed PD-1. Co-culture of MCL cells with T-cells induced PD-L1 surface expression, a phenomenon regulated by IFNγ and CD40:CD40L interaction. Induction of PD-L1 was attenuated by concurrent treatment with ibrutinib or duvelisib, suggesting BTK and PI3K are important mediators of PD-L1 expression. Overall, our data provide further insight into the expression of checkpoint molecules in MCL and support the use of PD-L1 blocking antibodies in MCL patients.

Kenya is a diverse and populous nation that employs DNA evidence in its criminal justice system, and therefore requires reliable information on autosomal STR allele frequency variation across the country and in its many ethnic groups. In order to provide reference data and to assess population structure, we analysed the 21 autosomal STRs in the GlobalFiler multiplex in a sample of 510 indigenous Kenyans representing the country’s eight former provinces, 43 of its 47 counties, three main linguistic families and all 29 ethnic groups that each comprise >0.5% of the 2019 census population. The indigenous population originated from successive migrations of Cushitic, Nilotic and Bantu speaking groups who settled in regions that suited their distinctive sustenance lifestyles. Consequently, they now largely reside in a patchwork of communities with strong associations with particular counties and provinces and limited degrees of inter-group marriage, as shown by DNA donors’ ancestry details. We found significant genetic differentiation between the three Nilotic language sub-families, with Western Nilotes (the Luo ethnic group) showing greater similarity to the Bantu than the Southern and Eastern Nilotes which themselves showed closer affinity to the Cushitic speakers. This concurs with previous genetic, linguistic and social studies. Comparisons with other African populations also showed that linguistic affiliation is a stronger factor than geography. This study revealed several rare off-ladder alleles whose structure was determined by Sanger sequencing. Among the unusual features that could affect profile interpretation were a deletion of Amelogenin Y but no other forensic marker (autosomal or Y-chromosomal), a triallelic pattern at TPOX and an extremely short SE33 allele falling within the expected size range of D7S820. Compared with the currently implemented Identifiler multiplex, Random Match Probabilities decreased from 6.4 × 10–19 to 3.9 × 10–27. The appreciation of local population structure provided by the geographically and ethnically representative sample in this study highlights the structured genetic landscape of Kenya.

Summary Recent studies have shown the potential of SP to identify and quantify groundwater flow in fractured rocks, including hydraulically active fractures, fracture connectivity, and preferential flow directions. The presented work reports combined laboratory and field SP experiments applied to a fractured gneissic aquifer system in NW Scotland characterised by the occurrence of several fracture sets and a major regional-scale fault zone. Field surveys involved both SP transects and azimuthal SP surveys and revealed clear anomalies including anisotropy that matched the dominant fracture set directions, for both local scale fracture sets and the regional fault zone, which were previously mapped from outcrop observations and electrical resistivity tomography. Collected fractured gneiss samples were analysed in the laboratory and provided values for the electrokinetic coupling coefficient and zeta potential which were further used to quantitatively interpret field SP data in terms of groundwater pressure gradients. Results showed that groundwater pressure gradients were notably higher along one of the dominant fracture set than along the other near-orthogonal one, which coincides with the fault zone. These results confirm the hydrogeological conceptual model in which the fault zone would act as a high permeability/high flow rate drain for the surrounding, less fractured rock mass.

We compare patterns of sexual violence against adults (n = 317) and children (n = 224) in Kenya during the COVID-19 pandemic in order to inform sexual violence prevention and protection efforts. The data we analyse were coded from interviews conducted by human rights defenders who were assisting survivors in obtaining vital services. We found that children were more likely than adults to be attacked during the daytime, by a single perpetrator rather than multiple perpetrators, and in a private as opposed to a public location. Children were violated most often by neighbors and family members, whereas adults were equally likely to be attacked by strangers and persons known to them. On average, the children in the sample were four years younger compared to the average age reported in national samples pre-pandemic (age 12 versus 16). Survivors were more likely to be female than male. Policy recommendations are offered based on our findings.

In developed countries, DNA profiling routinely forms part of the forensic strategy in the investigation of sexual violence. Medical examinations provide opportunities for recovering DNA evidence from intimate swabs, which can be particularly probative in cases where the identity of the perpetrator is unknown and proof of intercourse between two people is required. In low-resource environments, such as developing countries, remote geographic locations, conflict (and post-conflict) affected regions and displaced communities where access to medical examinations is lacking, DNA evidence is not available to support prosecutions and perpetrators are rarely identified and held accountable for crimes of sexual violence. This paper reports the results of a proof-of-concept study testing the efficacy of a novel self-examination intimate swab designed for recovering DNA following unprotected sexual intercourse. The results of this study corroborate previous research which has demonstrated that male DNA profiles can be successfully recovered by post-coital, self-examination methods, and discusses how this novel approach could enable the integration of DNA evidence into victim-centred approaches to investigating and prosecuting sexual violence in low-resource environments. The results and discussion challenge the prevailing assumption that intimate DNA swabs must be collected by trained medical professionals in order to be of evidential value.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

Objectives The purpose of this study was to evaluate the cardiorespiratory response and energy expenditure during the practice of Tai Chi Easy (TCE). TCE has been proposed as a low-intensity alternative to traditional physical activity. Design Oxygen cost data were collected from 10 healthy adult women (mean age of 47.9±12.8 years) at rest and during a 30-min session of TCE using an automated metabolic cart and heart rate (HR) telemetry. The Borg rating of perceived exertion (RPE) scale was utilized to measure subjective intensity of the TCE movements. Results The mean oxygen consumption (VO 2 ) for the movements ranged from 4.3mlkg –1 min −1 to 5.5mlkg –1 min −1 with an overall mean of 5.0mlkg –1 min −1 . The mean HR for all activity was 67.0 beats per minute and the mean energy expenditure (EE) was 1.6Kcalmin −1 . Conclusions Cardiorespiratory and EE responses to TCE indicate that this a low intensity exercise appropriate for individuals requiring activity prescriptions of approximately 2 metabolic equivalents (METs).

Meditative movement (MM) practices are increasingly being studied, including examination of the potential for these modalities to contribute to weight management. A search was conducted for randomized controlled trials testing one or both of two forms of MM, Tai Chi and Qigong, reporting effects on changes in body composition. Data from these studies were extracted and tabled, and a meta-analysis of studies with inactive control conditions was conducted. Risk of bias was assessed, and seven RCTs had a low risk of bias. Sources of bias include publication bias and selection of English only. Publications meeting inclusion criteria yielded 24 studies (N = 1621 participants). Significant improvements in body composition, primarily body mass index, were noted for 41.7% of studies. A synthesis table describes the distribution of design factors, including type of comparison condition (inactive vs. active) and baseline body composition status (whether or not overweight/obese). A meta-analysis was conducted on 12 studies with inactive controls (using a random effects model) finding a small-to-medium treatment effect (SMD = − 0.388, CI = [− 0.732, − 0.044], t = 2.48, p

Volume crime offences such as domestic burglary are commonly assessed for forensic opportunities by the first attending officer present at the scene. Conversely, less serious volume crime offences such as thefts from motor vehicles are very frequent and are routinely assessed for forensic opportunities by the victim talking to the police over the telephone. It is not clear whether this difference in attendance policy leads to differences in the types and quantity of forensic material recovered. The current study explored whether there was a benefit to evidence recovery for attended as opposed to non-attended assessments. Five hundred thefts from motor vehicles offences recorded by Northamptonshire Police (UK) between 14 January 2010 and 28 February 2011 were analysed; 250 were attended forensic assessments and 250 were non-attended assessments. Significant differences were found between the two scenarios, with attended assessments more likely to yield DNA, property and trace substance material. Conversely, fingerprints were more likely to be recovered at non-attended assessments. Despite the fruitful findings of the current study, future research would benefit from establishing the methods used by the first attending officer and forensic investigator when assessing and gathering evidence. Similarly, it is unclear whether these differences in forensic material are reflected in the identification of an offender and subsequently in the solving of the crime.

Successful interventions are needed to help improve obesity rates in the United States. Roughly two-thirds of adults in the United States are overweight, and almost one-third are obese. In 1991, the National Institutes of Health released a consensus statement endorsing bariatric surgery as the only means for sustainable weight loss for severely obese patients. However, approximately one-third of bariatric patients will experience significant post surgical weight gain. Purpose of study This study is designed to determine if meditative movement (MM) would be a feasible physical activity (PA) modality to initiate weight loss in bariatric surgery patients who have re-gained weight. Methods used A feasibility study was recently completed in 39 bariatric patients at Scottsdale Bariatric Center (SBC) during regularly scheduled bariatric support groups at SBC. A short demonstration of MM was presented after which a short focus group was conducted to gauge interest level, acceptability and the potential demand for MM programs in this population. Attitudes and intentions surrounding MM were also collected. Findings Approximately 75% of participants indicated they would consider practicing MM as part of their post surgical PA routine. Conclusions MM may be a feasible PA modality in bariatric patients to improve bariatric surgery weight outcomes.

Background Adherence to recommendations for physical activity (PA) among adults in the United States is reported as poor, particularly among low-income Latinos. In particular, Latina women are at increased risk for inactivity and chronic illness, but national health survey reports aggregate data across demographic strata, limiting descriptive information that could guide targeted PA promotion. The purpose of the study was to determine PA patterns among a low-income group of Latina women in the southwestern United States. Methods As part of a large community intervention trial to increase cancer prevention behaviors, PA data were collected from 1,006 Latina women using a modified version of the Arizona Activity Frequency Questionnaire. Findings The weekly PA mean across all exercise types was calculated to be 9.3 ± 16.4 hours, which is substantially higher than the daily PA recommendation of 30 minutes most days of the week. The highest daily PA means were associated with occupational activities: Cleaning, 2.7 hours; walking, 2.5 hours; lifting, 1.9 hours; and light yard work, 1.0 hours. Conclusions In this sample of low-income Latina women, the average PA hours per week exceed the current PA recommendations. Data collection instruments used in this population could more accurately assess PA if they included a wider range of activities and specific questions about work-related activity.

A flow cytometric method (RAPID-B™) with detection sensitivity of one viable cell of Escherichia coli serotype O157:H7 in fresh spinach (Spinacia oleracea) was developed and evaluated. The major impediment to achieving this performance was mistaking autofluorescing spinach particles for tagged target cells. Following a 5 h non-selective enrichment, artificially inoculated samples were photobleached, using phloxine B as a photosensitizer. Samples were centrifuged at high speed to concentrate target cells, then gradient centrifuged to separate them from matrix debris. In external laboratory experiments, RAPID-B and the reference method both correctly detected E. coli O157:H7 at inoculations of ca. 15 cells. In a follow-up study, after 4 cell inoculations of positives and 6 h enrichment, RAPID-B correctly identified 92% of 25 samples. The RAPID-B method limit of detection (LOD) was one cell in 25 g. It proved superior to the reference method (which incorporated real time-PCR, selective enrichment, and culture plating elements) in accuracy and speed.

Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.

Despite many years of empirical research focusing on investigative interviewing and detecting deception, very little research attention has been paid to the various types of evidence which feature in police interviews with suspects. In particular, the use of forensic evidence in the context of police interviews has not been previously considered, although in recent years the availability of various types of forensic analyses has dramatically increased. In the current study 398 experienced police interviewers from various countries completed a questionnaire about their experience of using various types of forensic evidence in interviews with suspects, as well as their perceptions regarding the strength of various sources of forensic information and how this may affect their interviewing strategy. The results indicated that although the participants have forensic evidence available in a large proportion of their interviews with suspects, the vast majority of police interviewers have received no training about how to interpret or use such forensic information. However, the perceived strength of forensic evidence was reported by some participants to affect their interview strategy and specifically the timing of the disclosure of such evidence during an interview. These findings are discussed with reference to police training and interview techniques, and suggestions for further research are offered.

In order to investigate the role of pre-trial attitudes about forensic science in juror decision-making, a previous study demonstrated the predictive validity of the Forensic Evidence Evaluation Bias Scale (FEEBS), using a murder trial scenario, which featured ambiguous prosecution DNA evidence. The current study validates the FEEBS using two new crime types and the conditions include a manipulation of the presence of DNA evidence in the trial scenario. The FEEBS successfully predicted mock jurors' perceptions of the probative value of DNA evidence for both robbery and sexual assault trials. The two subscales of the FEEBS were demonstrated to have different predictive ability depending on the presence or absence of DNA evidence. A confirmatory factor analytic technique was used to validate the underlying two-factor structure of the FEEBS, as previously proposed. These results are discussed with reference to the CSI Effect literature, and the potential for improvement to less empirically supported voir dir...

Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling.

Breast cancer survivors (BCSs) experience symptoms affecting overall quality of life (QOL), often for a prolonged period post-treatment. Meditative Movement (MM), including Qigong and Tai Chi Easy (QG/TCE), has demonstrated benefit for improving QOL issues such as fatigue and sleep, but there is limited evidence of its impact on cognitive function, overall physical activity, and body weight for BCSs.This double-blind, randomized controlled pilot study with 87 female BCSs explored effects of QG/TCE on mental and physical QOL (Medical Outcomes Survey, Short Form), cognitive function (Functional Assessment of Cancer Therapy-Cognitive Function and two cognitive performance tests from the WAIS III), overall levels of physical activity (PA)(Brief Physical Activity Questionnaire) and body mass index (BMI).Twelve weekly sessions of QG/TCE were compared to sham Qigong (SQG), a gentle movement control intervention similar to QG/TCE but without the focus on breathing and meditative state.Both groups demonstrated pre-to-post-intervention improvements in physical and mental health, level of PA, self-reported cognitive function, and cognitive performance tests, though without significant differences between QG/TCE and SQG. For a subset of women enrolled later in the study, a significant reduction in BMI [-0.66 (p=0.048)] was found for QG/TCE compared to SQG.Practices that include gentle movement (such as QG/TCE or our sham protocol) among women with a history of breast cancer may improve many facets of the cancer experience, including QOL, cognitive function, and PA patterns. Practicing QG/TCE may show some advantage for BMI reduction compared to non-meditative gentle exercise.

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water. Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle. Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831–41. ©2016 AACR.

Previous research has provided support for the impact of juror pre-trial bias on judicial decision making, particularly in cases where the evidence presented at trial is of weak or ambiguous probative value. In an effort to identify whether a pre-trial bias for forensic evidence exists, the Forensic Evidence Evaluation Bias Scale (FEEBS) was developed and tested. The results of a principal components analysis suggested that two distinct constructs were being measured, corresponding to a pro-prosecution and pro-defence bias toward forensic evidence. In a second validation study, scores on these two subscales were compared with other existing juror bias measures (Juror Bias Scale and Belief in a Just World) and in a mock juror decision making task only the pro-prosecution subscale of the FEEBS predicted the perceived strength of forensic evidence. A partial mediation model is presented which explains the relationship between this bias and verdict preferences. The implications of this potential juro...

Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.

This study aims to identify quantitatively the level of increased stress in civilian crime scene investigators (CSIs) whilst they were performing a variety of tasks as part of their normal duties. Mean above-average resting heart rate was used as the quantitative measure of physiological changes, recorded once a second for 12 CSIs during a working shift of 8 hours over a period of 7 days. Each CSI maintained an activity log of their work which enabled the physiological readings to be aligned to tasks undertaken. As well as physical stress, results show that CSIs undergo psychosocial stress during the examination of routine crime scenes such as domestic burglary and vehicle examination. Increased levels of stress diminished between scene visits. Reasons for increased stress reactivity at routine crime scenes are considered and opportunities for further work discussed. This study demonstrates quantitatively the stress undergone by civilian CSIs and questions the effect this might have on the effective recovery of forensic material from the crime scene as well as the welfare of the CSI.

The cyclin dependent kinase (CDK) inhibitor flavopiridol has demonstrated promising clinical results in relapsed CLL patients leading to efforts to develop improved CDK inhibitors. Dinaciclib (SCH727965) is a pan-CDK inhibitor, derived from a detailed screen in ovarian xenograft mouse models for therapeutic index, whose toxicity in solid tumor phase I studies appears favorable. Dinaciclib in CLL cells demonstrates concentration dependent apoptosis that is superior to flavopiridol following a clinically relevant 2-hour exposure. Dinaciclib potently down-regulates expression of Mcl-1 in CLL cells and antagonizes protection mediated by multiple soluble proteins important in the microenvironment of CLL including TNF-α IL-4, BAFF, and CD40-ligand. In contrast, contact with stromal cells or fibronectin abrogates the cytotoxicity of dinaciclib that is antagonized by a pan inhibitor and p110 alpha isoform specific inhibitor of the phosphatidylinositol 3-kinase pathway suggesting potential for combination strategies. These data justify clinical development of dinaciclib in CLL.

Car key burglary has recently become the focus of empirical investigation as offenders, no longer able to steal vehicles without first obtaining their keys, resort to “burgling” target properties. Research surrounding the modus operandi of these offenses is beginning to emerge; however, little attention has been paid to investigating the characteristics of car key burglary offenders. Challenging the assumption that car key burglary offenses are perpetrated by regular burglars, this study aims to differentiate between offenders. Logistic regression analysis of 110 car key and 110 regular burglary offenders revealed that car key burglars are more likely to have previous vehicle theft convictions and are also more likely to be detected on information supplied to the police than regular burglars. Regular burglars are more likely to have previous shoplifting convictions. It was concluded that car key burglars are a distinct sample of offenders and the implications of these findings are discussed.

As a result of the mandatory introduction in 1998 of electronic immobilisers in all new vehicles, car crime has evolved so that criminals resort to stealing vehicle keys during domestic burglaries in order to steal the vehicle subsequently. This new offence is referred to as ‘car key burglary’. Building upon previous research (Shaw, Smith, & Bond, 2010), car key burglary data provided by Northamptonshire Police from 1 January 2008 to 31 December 2009 was analysed to identify the crime-scene characteristics that can differentiate a car key burglary from a regular domestic burglary. Significant differences were found between car key burglaries and regular domestic burglaries pertaining to the security of the property and the types of items stolen, with secure premises and items likely to be left in a vehicle overnight (such as satellite navigation systems, in-car DVD players and mobile telephones) being more indicative of car key burglary. The implications of these findings are considered and the limitations discussed in terms of the current methods of recording police data. Suggestions as to how police data recording might be amended to facilitate a better understanding of car key burglary are considered.

Keywords:forensic science;forensic psychology;jury decision making;evidence;probative value Abstract: The most widely accepted model of juror decision making acknowledges the importance of both the case-specific information presented in the courtroom, as well as the prior general knowledge and beliefs held by each juror. The studies presented in this paper investigated whether mock jurors could differentiate between evidence of varying strengths in the absence of case information and then followed on to determine the influence that case context (and therefore the story model) has on judgments made about the strength of forensic DNA evidence. The results illustrated that mock jurors correctly identified various strengths of evidence when it was not presented with case information; however, the perceived strength of evidence was significantly inflated when presented in the context of a criminal case, particularly when the evidence was of a weak or ambiguous standard. These findings are discussed in relation to the story model, and the potential implications for real juries.

Keywords:forensic science;DNA;fingerprints;deprivation;crime scene;criminalistics;socioeconomic status Abstract: Previous research has shown that as crime scene location deprivation increases (lower socioeconomic status), the recovery of forensic material, principally DNA and fingerprints, also increases. However, this increase does not result in more crimes being solved by forensic means. In this study, we analyze stolen vehicle data and find a statistically significant positive association between deprivation and the amount of forensic material that matched either the victim or an associate of the victim on a criminal database. The nature of this association was investigated further by inspecting recovered stolen vehicles to establish whether the condition of a stolen vehicle and the tidiness of its interior influenced the recovery of forensic material that was attributed to the victim or an associate. Contradictory results suggest that other factors may contribute to understanding the association between the recovery of victim- or associate-attributable forensic material and crime scene location deprivation.