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Pultrusion is a high-volume manufacturing process for Fibre-Reinforced Polymer (FRP) composites. It requires careful tuning and optimisation of process parameters to obtain the maximum production rate. The present work focuses on the correlation between the set die temperatures of 80 °C, 100 °C, 120 °C, and 140 °C and the resin cure state at constant pull speeds. Lab-scale oven trials were conducted to understand the thermal behaviour of the resin system and to provide a temperature range for the pultrusion trials. Dielectric Analysis (DEA) was used during pultrusion trials to monitor the effect of die temperature on the cure progression. The DEA results showed that, by increasing die temperature, the exothermic peak shifts closer towards the die entry. Moreover, the degree of cure for samples processed at 140 °C was 97.7%, in comparison to 86.2% for those cured at 100 °C. The rate of conversion and the degree of cure correspond directly to the set die temperatures of the pultrusion trials, contributing to understanding the effect of die temperature on cure progression. Mechanical and thermal material properties were measured. Samples cured at 120 °C showed the highest mechanical performance, exceeding those cured at 140 °C, linked to the generation of higher internal stress due to the higher rate of conversion. This work can be used as a guide for pultruded composite sections, to understand the cure behaviour of resin systems under various applied temperatures and the impact of the die temperature conditions on thermal and mechanical properties.

Study Purpose: With increasing state legalization, marijuana use has become commonplace throughout much of the United States. Existing literature on unintentional exposure focuses primarily on children.We report on a cluster of adults with unwitting marijuana exposure., Methods: A cluster of cases were referred to the Medical Toxicology Service after ingesting marijuana-contaminated food at a family event. We conducted a retrospective analysis of twelve subject charts and a qualitative analysis with six of these subjects who willingly consented to be interviewed about their experiences. The study was approved by the Institutional Review Board., Results: Three of the subjects (25%) required prolonged observation due to persistent symptoms. Eleven (92%) were urine immunoassay positive for tetrahydrocannabinol (THC). Two subjects (17%) tested positive for ethanol in their blood. Common symptoms experienced by the subjects included confusion (50%), difficulty speaking (67%), nausea (25%), tremors (17%), and feelings of unreality (33%). All interviewed subjects reported sleepiness and three (50%) reported a negative impact on work. Subjects also reported multiple emotions, including anger, confusion, disbelief, and helplessness. None of the cases resulted in admission for critical care or death., Conclusions: Our series illuminates effects of unwitting and/or unintentional marijuana exposure in adults. Unintentional marijuana poisonings have increased, but legal and regulatory barriers have limited the study of marijuana outside highly controlled conditions. While the marijuana exposure in this study did not result in admission for critical care or death, it did result in psychological distress and adversely affected work in some cases.

Background: Tuberculosis (TB) remains a major global health concern. Previous research reveals that TB may have a seasonal peak during the spring and summer seasons in temperate climates; however, few studies have been conducted in tropical climates. This study evaluates the influence of seasonality on laboratory-confirmed TB diagnosis in Rwanda, a tropical country with two rainy and two dry seasons., Methods: A retrospective chart review was performed at the University Teaching Hospital-Kigali (CHUK). From January 2016 to December 2017, 2717 CHUK patients with TB laboratory data were included. Data abstracted included patient demographics, season, HIV status, and TB laboratory results (microscopy, GeneXpert, culture). Univariate and multivariable logistic regression (adjusted for age, gender, and HIV status) analyses were performed to assess the association between season and laboratory-confirmed TB diagnoses., Results: Patients presenting during rainy season periods had a lower odds of laboratory-confirmed TB diagnosis compared to the dry season (aOR=0.78, 95% CI 0.63-0.97, p=0.026) when controlling for age group, gender, and HIV status. Males, adults, and people living with HIV were more likely to have laboratory-confirmed TB diagnosis. On average, more people were tested for TB during the rainy season per month compared to the dry season (120.3 vs. 103.3), although this difference was not statistically significant., Conclusion: In Rwanda, laboratory-confirmed TB case detection shows a seasonal variation with patients having higher odds of TB diagnosis occurring in the dry season. Further research is required to further elucidate this relationship and to delineate the mechanism of season influence on TB diagnosis.

"Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A Streptococcus (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4 + germinal center T follicular helper (GC-T FH ) cells. RT children exhibited reduced antibody responses to an important GAS virulence factor, streptococcal pyrogenic exotoxin A (SpeA). Risk and protective human leukocyte antigen (HLA) class II alleles for RT were identified. Lastly, SpeA induced granzyme B production in GC-T FH cells from RT tonsils with the capacity to kill B cells and the potential to hobble the germinal center response. These observations suggest that RT is a multifactorial disease and that contributors to RT susceptibility include HLA class II differences, aberrant SpeA-activated GC-T FH cells, and lower SpeA antibody titers., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for identification of biomarkers that can more accurately stratify patients with primary PCa., Objective: To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa)., Design, Setting, and Participants: To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes. Multiple independent clinical cohorts including an intermediate-risk cohort were used to validate the biomarkers., Outcome Measurements and Statistical Analysis: The outcome measurement defining aggressive PCa was metastasis following radical prostatectomy. A generalized linear model with lasso regularization was used to build a 93-gene stroma-derived metastasis signature (SDMS). The SDMS association with metastasis was assessed using a Wilcoxon rank-sum test. Performance was evaluated using the area under the curve (AUC) for the receiver operating characteristic, and Kaplan-Meier curves. Univariable and multivariable regression models were used to compare the SDMS alongside clinicopathological variables and reported signatures. AUC was assessed to determine if SDMS is additive or synergistic to previously reported signatures., Results and Limitations: A close association between stromal gene expression and metastatic phenotype was observed. Accordingly, the SDMS was modeled and validated in multiple independent clinical cohorts. Patients with higher SDMS scores were found to have worse prognosis. Furthermore, SDMS was an independent prognostic factor, can stratify risk in intermediate-risk PCa, and can improve the performance of other previously reported signatures., Conclusions: Profiling of stromal gene expression led to development of an SDMS that was validated as independently prognostic for the metastatic potential of prostate tumors., Patient Summary: Our stroma-derived metastasis signature can predict the metastatic potential of early stage disease and will strengthen decisions regarding selection of active surveillance versus surgery and/or radiation therapy for prostate cancer patients. Furthermore, profiling of stroma cells should be more consistent than profiling of diverse cellular populations of heterogeneous tumors., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multihitting time," the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients' survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology., (© 2017 Shrestha et al.; Published by Cold Spring Harbor Laboratory Press.)

Composite lymphoma (CL) is an infrequently diagnosed entity in which two or more distinct types of lymphomas occur synchronously in the same organ or anatomical site. Most commonly, CLs are composed of two non-Hodgkin B-cell lymphomas. We present a case of a composite lymphoma with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) and classical Hodgkin lymphoma (CHL) components involving the terminal ileum, colon and pericolic lymph nodes. Immunohistochemical evaluation for determination of cell of origin of the DLBCL-NOS component indicated a germinal center B-cell subtype. Immunoglobulin heavy chain fragment length analysis revealed identical dominant monoclonal peaks on the DH1-6-JH reaction, and also a dominant monoclonal peak observed only in the framework II reaction done on the CHL component, indicating a partial clonal relationship between the two components. Additionally, a review of the available literature reveals a total of 20 previously reported cases of CL with DLBCL-NOS and CHL components, and most of the tested cases showed clonal relationship between the two components. The overall findings indicate that in most cases, the two components of CL with DLBCL-NOS and CHL components are clonally related, and suggest a shared origin from a common B-cell precursor., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

A range of current candidate AIDS vaccine regimens are focused on generating protective HIV-neutralizing Ab responses. Many of these efforts rely on the rhesus macaque animal model. Understanding how protective Ab responses develop and how to increase their efficacy are both major knowledge gaps. Germinal centers (GCs) are the engines of Ab affinity maturation. GC T follicular helper (Tfh) CD4 T cells are required for GCs. Studying vaccine-specific GC Tfh cells after protein immunizations has been challenging, as Ag-specific GC Tfh cells are difficult to identify by conventional intracellular cytokine staining. Cytokine production by GC Tfh cells may be intrinsically limited in comparison with other Th effector cells, as the biological role of a GC Tfh cell is to provide help to individual B cells within the GC, rather than secreting large amounts of cytokines bathing a tissue. To test this idea, we developed a cytokine-independent method to identify Ag-specific GC Tfh cells. RNA sequencing was performed using TCR-stimulated GC Tfh cells to identify candidate markers. Validation experiments determined CD25 (IL-2Rα) and OX40 to be highly upregulated activation-induced markers (AIM) on the surface of GC Tfh cells after stimulation. In comparison with intracellular cytokine staining, the AIM assay identified >10-fold more Ag-specific GC Tfh cells in HIV Env protein-immunized macaques (BG505 SOSIP). CD4 T cells in blood were also studied. In summary, AIM demonstrates that Ag-specific GC Tfh cells are intrinsically stingy producers of cytokines, which is likely an essential part of their biological function., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS(+) (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.

More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC.

Castleman disease is a rare lymphoproliferative disorder that may have a unicentric or multicentric clinical presentation. Herein we present the case of a 49-year-old female with a 3-year history of progressively worsening lymphadenopathy associated with fevers, chills and night sweats. Laboratory studies showed anemia and mildly elevated sedimentation rate. A computed tomogram scan of the chest, abdomen and pelvis showed multiple enlarged bilateral axillary, supraclavicular, subpectoral, submental, retroperitoneal, and para-aortic lymph nodes. A right axillary lymph node biopsy was performed and found to display histopathologic features compatible with the plasma cell type of Castleman disease. The patient was found to be human immunodeficiency virus (HIV)-positive, with a viral load of 104,000/mL and a CD4 cell count of 84 cells/mm(3). Molecular studies on the lymph node specimen revealed an incomplete monoclonal DH-JH rearrangement in the IgH gene. The patient was initially treated with antiretroviral therapy with a combination of elvitegravir, cobicistat, emtricitabine and tenofovir that improved her fatigue and malaise. As treatment for Castleman disease, she was administered a combination of rituximab and etoposide, which led to a reduction in lymphadenopathy. To the best of the authors' knowledge, this is the first reported case of multicentric Castleman disease with monoclonal incomplete IgH gene rearrangement in an HIV-positive patient.

Background: Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization., Results: Ten tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype., Conclusions: The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.

Understanding the heterogeneous drug response of cancer patients is essential to precision oncology. Pioneering genomic analyses of individual cancer subtypes have begun to identify key determinants of resistance, including up-regulation of multi-drug resistance (MDR) genes and mutational alterations of drug targets. However, these alterations are sufficient to explain only a minority of the population, and additional mechanisms of drug resistance or sensitivity are required to explain the remaining spectrum of patient responses to ultimately achieve the goal of precision oncology. We hypothesized that a pan-cancer analysis of in vitro drug sensitivities across numerous cancer lineages will improve the detection of statistical associations and yield more robust and, importantly, recurrent determinants of response. In this study, we developed a statistical framework based on the meta-analysis of expression profiles to identify pan-cancer markers and mechanisms of drug response. Using the Cancer Cell Line Encyclopaedia (CCLE), a large panel of several hundred cancer cell lines from numerous distinct lineages, we characterized both known and novel mechanisms of response to cytotoxic drugs including inhibitors of Topoisomerase 1 (TOP1; Topotecan, Irinotecan) and targeted therapies including inhibitors of histone deacetylases (HDAC; Panobinostat) and MAP/ERK kinases (MEK; PD-0325901, AZD6244). Notably, our analysis implicated reduced replication and transcriptional rates, as well as deficiency in DNA damage repair genes in resistance to TOP1 inhibitors. The constitutive activation of several signaling pathways including the interferon/STAT-1 pathway was implicated in resistance to the pan-HDAC inhibitor. Finally, a number of dysregulations upstream of MEK were identified as compensatory mechanisms of resistance to the MEK inhibitors. In comparison to alternative pan-cancer analysis strategies, our approach can better elucidate relevant drug response mechanisms. Moreover, the compendium of putative markers and mechanisms identified through our analysis can serve as a foundation for future studies into these drugs.

The current first-line treatment for advanced metastatic prostate cancer, i.e. docetaxel-based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti-prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase-I Clinical Trial. Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti-tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat., (Copyright © 2013 Federation of European Biochemical Societies. All rights reserved.)

Effective treatment for metastatic prostate cancer is critically needed. The present study was aimed at identifying metastasis-driving genes as potential targets for therapy (oncotargets). A differential gene expression profile of metastatic LTL-313H and non-metastatic LTL-313B prostate cancer tissue xenografts, derived from one patient's specimen, was subjected to integrative analysis using the Ingenuity Upstream Regulator Analysis tool. Six candidate master regulatory genes were identified, including GATA2, a gene encoding a pioneer factor, a special transcription factor facilitating the recruitment of additional transcription factors. Elevated GATA2 expression in metastatic prostate cancer tissues correlated with poor patient prognosis. Furthermore, GATA2 gene silencing in human prostate cancer LNCaP cells led to a marked reduction in cell migration, tissue invasion, focal adhesion disassembly and to a dramatic change in cell transcriptomes, indicating that GATA2 plays a critical role in prostate cancer metastasis. As such, GATA2 could represent a prostate cancer metastasis-driving gene and a potential target for therapy of metastatic prostate cancer.

Early massively-parallel sequencing studies have revealed the mutational landscape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of genomic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abundance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed 'chromoplexy', which may drive cancer evolution through the phenomena of punctuated equilibrium by concurrently dysregulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defining discovery undoubtedly offers an important glimpse into the evolutionary process of prostate cancer.

Motivation: Molecular profiles of tumour samples have been widely and successfully used for classification problems. A number of algorithms have been proposed to predict classes of tumor samples based on expression profiles with relatively high performance. However, prediction of response to cancer treatment has proved to be more challenging and novel approaches with improved generalizability are still highly needed. Recent studies have clearly demonstrated the advantages of integrating protein-protein interaction (PPI) data with gene expression profiles for the development of subnetwork markers in classification problems., Results: We describe a novel network-based classification algorithm (OptDis) using color coding technique to identify optimally discriminative subnetwork markers. Focusing on PPI networks, we apply our algorithm to drug response studies: we evaluate our algorithm using published cohorts of breast cancer patients treated with combination chemotherapy. We show that our OptDis method improves over previously published subnetwork methods and provides better and more stable performance compared with other subnetwork and single gene methods. We also show that our subnetwork method produces predictive markers that are more reproducible across independent cohorts and offer valuable insight into biological processes underlying response to therapy., Availability: The implementation is available at: http://www.cs.sfu.ca/~pdao/personal/OptDis.html, Contact: cenk@cs.sfu.ca; alapuk@prostatecentre.com; ccollins@prostatecentre.com.