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Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Abstract The digital revolution in healthcare, amplified by the COVID-19 pandemic and artificial intelligence (AI) advances, has led to a surge in the development of digital technologies. However, integrating digital health solutions, especially AI-based ones, in rare diseases like Waldenström macroglobulinemia (WM) remains challenging due to limited data, among other factors. CURATE.AI, a clinical decision support system, offers an alternative to big data approaches by calibrating individual treatment profiles based on that individual’s data alone. We present a case study from the PRECISE CURATE.AI trial with a WM patient, where, over two years, CURATE.AI provided dynamic Ibrutinib dose recommendations to clinicians (users) aimed at achieving optimal IgM levels. An 80-year-old male with newly diagnosed WM requiring treatment due to anemia was recruited to the trial for CURATE.AI-based dosing of the Bruton tyrosine kinase inhibitor Ibrutinib. The primary and secondary outcome measures were focused on scientific and logistical feasibility. Preliminary results underscore the platform’s potential in enhancing user and patient engagement, in addition to clinical efficacy. Based on a two-year-long patient enrollment into the CURATE.AI-augmented treatment, this study showcases how AI-enabled tools can support the management of rare diseases, emphasizing the integration of AI to enhance personalized therapy.

Abstract Many Asian elephant populations inhabit fragmented human‐dominated landscapes. Human–elephant conflict (HEC) has intensified in such regions, resulting in the deaths of hundreds of people and elephants each year. Controversy between stakeholders then arises as people debate the merits of HEC mitigation approaches, stifling progress. We conducted a survey to evaluate the opinions of experts, farmers and others who have and have not experienced HEC (n = 611), on the causes of HEC, the importance of, conservation of and co‐existence with elephants, and on the acceptability and effectiveness of potential HEC mitigation methods. Analysis of variance and the Potential for Conflict Index showed that all groups agreed with nine of the 10 causes of HEC assessed, on average. All respondent groups had mostly positive attitudes towards the importance and conservation of elephants. However, farmers exposed to HEC disagreed that people should co‐exist with elephants and supported the view that elephants should be removed from human habitats. All groups agreed on the acceptability and effectiveness of electric fencing, early warning systems with infrasonic call detectors, Global Positioning System collars and geophones. However, there was disparity in views between the experts and other stakeholder groups on the acceptability and effectiveness of restricting elephants to protected areas, and translocation of problem elephants to protected areas away from their capture site or to wild elephant holding grounds. While similar views between stakeholders on many subjects are encouraging for elephant conservation, the disparities identified should be given greater attention when planning HEC management programs to minimize conflict between stakeholders.

Abstract Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Os insetos parasitoides possuem grande importância ecológica e econômica, pois atuam como reguladores de populações de insetos fitófagos, controlando pragas florestais e agrícolas. No entanto, apesar da sua relevância, os parasitoides ainda podem ser considerados como pouco estudados na região Norte do Brasil. Nesse sentido, o objetivo desse trabalho é registrar pela primeira vez a espécie Ceyxia pseudovillosa Andrade & Tavares, 2009 (Hymenoptera: Chalcididae) no estado do Acre, oriunda de coleta por armadilha Malaise na terra indígena Puyanawa, Mâncio Lima, Acre. Este registro aumenta tanto o conhecimento acerca das espécies de Chalcididae ocorrentes no estado do Acre, bem como o conhecimento acerca da distribuição geográfica dessa espécie no Brasil.

Abstract Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.

Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. There are nearly 100 million new dengue cases yearly in more than 120 countries, with a five-fold increase in incidence over the past four decades. While many patients experience a mild illness, a subset suffer from severe disease, which can be fatal. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. While thrombocytopaenia and coagulopathy are major causes of bleeding in severe dengue, leucocyte abnormalities are emerging as important markers of prognosis. In this review, we provide our perspective on the clinical aspects and pathophysiology of haematologic manifestations in dengue. We also discuss the key gaps in our current practice and areas to be addressed by future research.

Brain-computer interface (BCI) technology is a topic of study with assistive robot systems that are expanding significantly nowadays. Several advancements have been made in the BCI sector to aid disabled people. However, most studies have used more electrodes, and most design structures are different from the anatomy of the human hand. To control robot fingers like real human hands with fewer electrodes is yet to be developed. This research aims to investigate the controllability of robot fingers using motor imagery. The proposed electroencephalogram (EEG) acquisition system comprises eight EEG electrodes attached to the primary motor cortex region of the human brain. The real human hand's anatomical behavior aided in the robot's development. Initially, the performance of the robot finger model was evaluated on the computer simulation. Finally, a robot model was developed, and flexion and extension movements were examined. According to the experiment's findings, finger flexion and extension control with eight EEG electrodes showed promising results with an accuracy of 90.0±1.43% and a precision of 0.89. Furthermore, we observed that as people age, the accuracy of robot control decreases.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Background: There is a need to rethink evaluator competencies given the harsh and paralyzing realities of COVID. The pandemic was a time where there was a need to balance diverse perspectives given the limited scientific evidence that existed when faced with a genuinely unprecedented time. In the Fall of 2021 (September to October), the Evaluation Centre for Complex Health Interventions in partnership with the Asia Pacific Evaluation Association organized a three-part webinar series in response to the multiple issues that surfaced during COVID-19, and specifically, the implications of the pandemic for rethinking evaluator competencies and evaluator training. The presenters were from multiple countries including India, Canada, USA, UK, and South Africa. Purpose: The presenters pushed for more responsive evaluation approaches to address inequities and sustainability and for a decolonized approach to knowledge building. The webinar raised a number of themes that have potential implications for future discussions on evaluator competencies including: enhancing evaluation contributions to the Sustainable Development Goals (SDGs), the need to rethink evaluation criteria, the need to embrace and address varieties of uncertainties, focus on diversity and heterogeneity; understanding the role of contexts in complex programs and policies; the need to reconceptualize sustainability; being more explicit about inequities and vulnerabilities; and the need to pay attention to systems and system dynamics. Setting: The webinars were organized by the Evaluation Centre and the Asia Pacific Evaluation Association on a Zoom platform. Intervention: Not applicable. Research Design: Not applicable. Data Collection and Analysis: Not applicable. Findings: Not applicable.

A transição da assistência alimentar para a estruturação de programas nacionais de alimentação escolar autônomos tem sido objeto de discussões sobre sustentabilidade e desenvolvimento rural em todo o mundo. Nesse contexto, projetos de cooperação Sul-Sul, triangular e em rede destacam-se na tentativa de indução da formação de políticas e estruturas institucionais destinadas à garantia do Direito Humano à Alimentação Adequada. Insere-se nessa agenda a construção de mercados institucionais para a compra de alimentos da agricultura familiar e iniciativas com esse objetivo têm sido fomentadas em diversos países africanos, dentre eles, Moçambique e São Tomé e Príncipe. Este trabalho aborda o desenvolvimento de programas de alimentação escolar em Moçambique e São Tomé e Príncipe com foco na cooperação brasileira para o desenvolvimento da agenda dos mercados institucionais. Para tanto, foi realizado process tracing de projetos de cooperação executados com o apoio do Brasil, Programa Mundial de Alimentos e Organização para Alimentação e Agricultura analisados a partir da perspectiva da transferência de políticas. Assim, foram identificados avanços reconhecidos como marcas da cooperação, bem como desafios para a estruturação de mercados institucionais como uma política social.

There is a growing urgency to discover better materials that capture CO2 from air and improve battery performance. An important step is to search large databases of materials properties to find examples that resemble known carbon capture agents or electrolytes and then test them for effectiveness. This paper describes novel computational tools for accelerated discovery of solvents, nano-porous materials, and electrolytes. These tools have produced interesting results so far, such as the identification of a relatively isolated location in amine configuration space for the solvents with known carbon capture use, and the demonstration of an end-to-end simulation and process model for carbon capture in MOFs.

Abstract In spite of recent moves to wean the world of fossil fuels, coal remains the main source of power in many countries. Coal yards are prone to spontaneous ignition, a problem faced in every country that stores or transports coal. Depending on the environment-temperature, ventilation, and the rank of the coal-heating and self-ignition can be a longer or shorter process, but the possibility can never be entirely dismissed. A plethora of studies have modelled this oxidation behavior and proposed countermeasures. Most often, human intervention is necessary, which is both slow and dangerous for the firefighters involved. In this study, we propose to build a complete firefighting solution which is mounted on a number of towers sufficient to cover the area of an open coal yard, complete with redundancy. Each tower includes an inexpensive infrared detector, a water dispenser and a controller programmed to identify areas of elevated temperature, and actuate the dispenser. The heat direction algorithm calculates the parameters to position the water dispenser so that it covers the area. A prototype has been built from inexpensive components to demonstrate the effectiveness at detecting and extinguishing arising fires, and a solution has been costed for the coal yard in the case study. This work has been conducted in collaboration with the managers of the coal yard of a power plant.

Deamidation, a common post-translational modification, may impact multiple physiochemical properties of a therapeutic protein. MEDI7247, a pyrrolobenzodiazepine (PBD) antibody–drug conjugate (ADC), contains a unique deamidation site, N102, located within the complementarity-determining region (CDR), impacting the affinity of MEDI7247 to its target. Therefore, it was necessary to monitor MEDI7247 deamidation status in vivo. Due to the low dose, a sensitive absolute quantification method using immunocapture coupled with liquid chromatography–tandem mass spectrometry (LBA-LC-MS/MS) was developed and qualified. We characterized the isomerization via Electron-Activated Dissociation (EAD), revealing that deamidation resulted in iso-aspartic acid. The absolute quantification of deamidation requires careful assay optimization in order not to perturb the balance of the deamidated and nondeamidated forms. Moreover, the selection of capture reagents essential for the correct quantitative assessment of deamidation was evaluated. The final assay was qualified with 50 ng/mL LLOQ for ADC for total and nondeamidated antibody quantification, with qualitative monitoring of the deamidated antibody. The impact of deamidation on the pharmacokinetic characteristics of MEDI7247 from clinical trial NCT03106428 was analyzed, revealing a gradual reduction in the nondeamidated form of MEDI7247 in vivo. Careful quantitative biotransformation analyses of complex biotherapeutic conjugates help us understand changes in product PTMs after administration, thus providing a more complete view of in vivo pharmacology.

Asparagine deamidation is a post-translational modification (PTM) that converts asparagine residues into iso-aspartate and/or aspartate. Non-enzymatic asparagine deamidation is observed frequently during the manufacturing, processing, and/or storage of biotherapeutic proteins. Depending on the site of deamidation, this PTM can significantly impact the therapeutic’s potency, stability, and/or immunogenicity. Thus, deamidation is routinely monitored as a potential critical quality attribute. The initial evaluation of an asparagine’s potential to deamidate begins with identifying sequence liabilities, in which the n + 1 amino acid is of particular interest. NW is one motif that occurs frequently within the complementarity-determining region (CDR) of therapeutic antibodies, but according to the published literature, has a very low risk of deamidating. Here we report an unusual case of this NW motif readily deamidating within the CDR of an antibody drug conjugate (ADC), which greatly impacts the ADC’s biological activities. Furthermore, this NW motif solely deamidates into iso-aspartate, rather than the typical mixture of iso-aspartate and aspartate. Interestingly, biological activities are more severely impacted by the conversion of asparagine into iso-aspartate via deamidation than by conversion into aspartate via mutagenesis. Here, we detail the discovery of this unusual NW deamidation occurrence, characterize its impact on biological activities, and utilize structural data and modeling to explain why conversion to iso-aspartate is favored and impacts biological activities more severely.

Electronic nicotine delivery systems (ENDS) (also known as ‘e-cigarettes’) can support smoking cessation, although the long-term health impacts are not yet known. In 2019, a cluster of lung injury cases in the USA emerged that were ostensibly associated with ENDS use. Subsequent investigations revealed a link with vitamin E acetate, an additive used in some ENDS liquid products containing tetrahydrocannabinol (THC). This became known as the EVALI (E-cigarette or Vaping product use Associated Lung Injury) outbreak. While few cases were reported in the UK, the EVALI outbreak intensified attention on ENDS in general worldwide. We aimed to describe and explore public commentary and discussion on Twitter immediately before, during and following the peak of the EVALI outbreak using text mining techniques. Specifically, topic modelling, operationalised using Latent Dirichlet Allocation (LDA) models, was used to discern discussion topics in 189,658 tweets about ENDS (collected April–December 2019). Individual tweets and Twitter users were assigned to their dominant topics and countries respectively to enable international comparisons. A 10-topic LDA model fit the data best. We organised the ten topics into three broad themes for the purposes of reporting: informal vaping discussion; vaping policy discussion and EVALI news; and vaping commerce. Following EVALI, there were signs that informal vaping discussion topics decreased while discussion topics about vaping policy and the relative health risks and benefits of ENDS increased, not limited to THC products. Though subsequently attributed to THC products, the EVALI outbreak disrupted online public discourses about ENDS generally, amplifying health and policy commentary. There was a relatively stronger presence of commercially oriented tweets among UK Twitter users compared to USA users.

Increasing deployment of renewable energy resources for power generation has been playing a pivotal role in reducing carbon emissions associated with electrical power systems. Distributed Energy Systems (DES) enable the integration of small-scale renewable energy resources and storage technologies within low-voltage (LV) distribution networks, which supply power to residential and commercial consumers. Care must be taken when designing these systems, as they could potentially impair the operation and infrastructure of existing power networks. While nonlinear balanced optimal power flow formulations have historically been incorporated into oversimplified Mixed-Integer Linear Programming (MILP) DES design models, these do not accurately model the distribution networks to which most DES are connected. Low-voltage radial distribution networks are most closely represented by nonconvex multi-phase formulations, which are computationally complex and difficult to solve. The exclusion of these constraints within DES design models could, however, lead to infeasible designs, i.e., designs which are incompatible with the existing network and its operations. This study proposes a novel optimisation algorithm, capable of solving the large-scale and combined problem of designing DES with multiphase optimal power flow. A large-scale Nonlinear Programming (NLP) model with full power flow constraints and reformulated complementarity constraints for DES operation is used to find a feasible upper bound, if the lower bound proposed by the MILP for DES design is infeasible. The algorithm is tested using a residential case study based on a section of the IEEE EU LV network. Results for this case study show that the proposed algorithm finds a feasible DES design and operational schedule by installing three times the battery capacity initially recommended by the MILP. The MILP design remains infeasible with respect to the multiphase power flow constraints. This framework could be used to support the increase of local renewable energy generation and consumption, and the subsequent reduction of carbon intensity in existing power networks.

Aversive geofencing devices (AGDs) or animal-borne satellite-linked shock collars might become a useful tool to mitigate human-elephant conflict (HEC). AGDs have the potential to condition problem elephants to avoid human-dominated landscapes by associating mild electric shocks with preceding audio warnings given as they approach virtual boundaries. We assessed the opinions of different stakeholders (experts, farmers, and others who have and have not experienced HEC; n = 611) on the potential use of AGDs on Asian elephants. Most respondents expressed positive opinions on the potential effectiveness of AGDs in managing elephant movement (62.2%). About 62.8% respondents also provided positive responses for the acceptability of AGDs if pilot studies with captive elephants have been successful in managing their movements. Some respondents perceived AGDs to be unacceptable because they are unethical or harmful and would be unsuccessful given wild elephants may respond differently to AGDs than captive elephants. Respondents identified acceptability, support and awareness of stakeholders, safety and wellbeing of elephants, logistical difficulties, durability and reliable functionality of AGDs, and uncertainties in elephants’ responses to AGDs as potential challenges for implementing AGDs. These issues need attention when developing AGDs to increase support from stakeholders and to effectively reduce HEC incidents in the future.

Abstract The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004–0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m2 by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.

PurposePrevious studies have associated low pH in intervertebral discs (IVDs) with discogenic back pain. The purpose of this study was to determine whether quantitative CEST (qCEST) MRI can be used to detect pH changes in IVDs in vivo.MethodsThe exchange rate ksw between glycosaminoglycan (GAG) protons and water protons was determined from qCEST analysis. Its dependence on pH value was investigated in GAG phantoms with varying pH and concentrations. The relationship between ksw and pH was studied further in vivo in a porcine model on a 3T MR scanner and validated using a pH meter. Sodium lactate was injected into the IVDs to induce various pH values within the discs ranging from 5 to 7.ResultsPhantom and animal results revealed that ksw measured using qCEST MRI is highly correlated with pH level. In the animal studies, the relationship can be described as ksw  =9.2 × 106 × 10-pH + 196.9, R2  = 0.7883.ConclusionThe exchange rate between GAG and water protons determined from qCEST MRI is closely correlated with pH value. This technique has the potential to noninvasively measure pH in the IVDs of patients with discogenic pain. Magn Reson Med 76:1677-1683, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler’s syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Asian elephants are a principal cause of human-wildlife conflict. This results in the death/injury of elephants and humans and large-scale crop and property damage. Most current human-elephant conflict (HEC) mitigation tools lack the flexibility to accommodate the ecological needs of elephants and are ineffective at reducing HEC in the long-term. Here we review common HEC mitigation tools used in Asia and the potential of Aversive Geofencing Devices (AGDs) to manage problem elephants. AGDs can be configured to monitor animal movements in real-time and deliver auditory warnings followed by electric stimuli whenever animals attempt to move across user-specified virtual boundaries. Thus, AGDs are expected to condition elephants to avoid receiving shocks and keep them away from virtually fenced areas, while providing alternative routes that can be modified if required. Studies conducted using AGDs with other species provide an overview of their potential in conditioning wild animals. We recommend that the efficacy and welfare impact of AGDs be evaluated using captive elephants along with public perception of using AGDs on elephants as a means of addressing the inherent deficiencies of common HEC mitigation tools. If elephants could be successfully conditioned to avoid virtual fences, then AGDs could resolve many HEC incidents throughout Asia.

Abstract Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.

Some of the major factors that help the decision-making process of an insurance company include Time of the first claim (TFC), claim Size and the frequency of claims. However, in most situations researchers focus mainly on the second and third factors mentioned above. We hypothesize the importance of the TFC of an insurance contract in the decision-making process. Empirical evidence of motor vehicle insurance data in Sri Lanka suggests that nine covariates are responsible for the claim sizes. In the current study, our main objective is to find the key factors of those nine that are responsible for the TFC of the insurance contract. This study is based on the claim data in the whole year of 2016 of non-life insurance policies of a particular insurance company in Sri Lanka. Considering the TFC as right-censored data, selected nonparametric methods, i.e., Kaplan-Meier, Nelson-Aalen estimators, and Cox Proportional Hazard Model are used to analyze the data. We identified the five most influential covariates namely, vehicle type, log of Premium Value and that of Assured Sum, the lease type and the age range via fitting the Cox Model to TFC data. After a thorough residual analysis, the Logistic regression model has been used to identify the important covariates to classify future customers as risky or not.

Rural Tea Development Societies (RTS) have been established by the Tea Small Holdings Development Authority (TSHDA) to address the critical issues faced by the tea smallholders. This study attempted to assess the present status and the capacity of the RTS and also identify the attributes that affect their capacity. The perception of Tea Inspectors (TIs), the key entities responsible for extension support for the smallholders, were collected from twelve Focus Group Discussions. The opinions of 65 TIs with over five years of work experiences (who interact with about 575 RTS in seven major tea smallholding area) were analysed by qualitatively. Results revealed, that the majority of RTS are not performing well due to internal factors such as poor leadership, lack of enthusiasm of members, lack of trustworthiness, status of the members, attitudes of members and also due to external factors such as ruralurban context, government benefits, the role of the extension agent, changes in the external environment, the effect of other organisation and politics. Contribution of the Main Officers, Management Committee and the membership is greater in RTS that are highly active than that of the poorly active RTS. The self-reliance capacity was low in the majority of the RTS and was highly dependent on TIs and the government’s assistance. Inbuilt weaknesses in the organisational culture were identified, mainly with respect to attitudes. The majority of RTSs are not goal-oriented. The majority of RTS are not dynamic in organisational performances. Finally, their key extension agents feel that critical intervention is required to overcome the above weaknesses.

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

B-cell receptor (BCR) signalling is critical for the survival of B-cell lymphomas and is a therapeutic target of drugs such as Ibrutinib. However, the role of T-cell receptor (TCR) signalling in the survival of T/Natural Killer (NK) lymphomas is not clear. ZAP-70 (zeta associated protein-70) is a cytoplasmic tyrosine kinase with a critical role in T-cell receptor (TCR) signalling. It has also been shown to play a role in normal NK cell signalling and activation. High ZAP-70 expression has been detected by immunohistochemistry in peripheral T cell lymphoma (PTCL) and NK cell lymphomas (NKTCL). We therefore, studied the role of TCR pathways in mediating the proliferation and survival of these malignancies through ZAP-70 signalling. ZAP-70 protein was highly expressed in T cell lymphoma cell lines (JURKAT and KARPAS-299) and NKTCL cell lines (KHYG-1, HANK-1, NK-YS, SNK-1 and SNK-6), but not in multiple B-cell lymphoma cell lines. siRNA depletion of ZAP-70 suppressed the phosphorylation of ZAP-70 substrates, SLP76, LAT and p38MAPK, but did not affect cell viability or induce apoptosis in these cell lines. Similarly, while stable overexpression of ZAP-70 mediates increased phosphorylation of target substrates in the TCR pathway, it does not promote increased survival or growth of NKTCL cell lines. The epidermal growth factor receptor (EGFR) inhibitor Gefitinib, which has off-target activity against ZAP-70, also did not show any differential cell kill between ZAP-70 overexpressing (OE) or knockdown (KD) cell lines. Whole transcriptome RNA sequencing highlighted that there was very minimal differential gene expression in three different T/NK cell lines induced by ZAP-70 KD. Importantly, ZAP-70 KD did not significantly enrich for any downstream TCR related genes and pathways. Altogether, this suggests that high expression and constitutive signalling of ZAP-70 in T/NK lymphoma is not critical for cell survival or downstream TCR-mediated signalling and gene expression. ZAP-70 therefore may not be a suitable therapeutic target in T/NK cell malignancies.

Policies that address post-war displacement often reflect temporal linearity as transitional periods during which they are developed imply a shift from one situation to another. These policies obscure complexities experienced by local communities for whom displacement is ongoing and interminable. This essay applies Sri Lanka’s National Policy on Durable Solutions for Conflict-Affected Displacement (NPDSCAD) to the case of Northern Muslims who were expelled from the Northern Province of Sri Lanka in 1990 and have lived in prolonged displacement for over 25 years. For these Muslims, return-remain is an oscillation and not an either/or option. Using “frames of recognition” to analyze policy documents and data from fieldwork, the paper critically unpacks the category of Internally Displaced Persons (IDPs) – the displacement-related frame applied to the Northern Muslims – to reveal the multiple subject positions respondents navigate in presenting their own stance to this category. Calling for recognition of the circumstances of their displacement, the respondents’ footing to the IDP frame holds in it both needs-based and justice-based discourses and demands that Northern Muslims be recognized as political subjects. Return-remain is complicated by issues respondents face as they travel between their current home in Puttalam and origins in the North. The paper concludes that while the Northern Muslims are denied full recognition by the NPDSCAD, their complex experiences continue to contest the frames deployed by the policy.