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Islands of CD123 high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123 + mononucleated cells that are lineage-negative, CD45 + , CD11c − , CD33 − , HLA-DR + , BDCA-2 + , BDCA-4 + in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34 + cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described “immune sanctuary” sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant–associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.

This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as STAT3-JAK2 fusion. In addition, novel clonal markers of disease, such as AXL and JAK3 somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with IRF4 translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e., CCND3-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.

Campylobacter jejuni is the leading cause of human gastroenteritis worldwide with over 500 million cases annually. Chemotaxis and motility have been identified as important virulence factors associated with C. jejuni colonisation. Group A transducer-like proteins (Tlps) are responsible for sensing the external environment for bacterial movement to or away from a chemical gradient or stimulus. In this study, we have demonstrated Cj1564 (Tlp3) to be a multi-ligand binding chemoreceptor and report direct evidence supporting the involvement of Cj1564 (Tlp3) in the chemotaxis signalling pathway via small molecule arrays, surface plasmon and nuclear magnetic resonance (SPR and NMR) as well as chemotaxis assays of wild type and isogenic mutant strains. A modified nutrient depleted chemotaxis assay was further used to determine positive or negative chemotaxis with specific ligands. Here we demonstrate the ability of Cj1564 to interact with the chemoattractants isoleucine, purine, malic acid and fumaric acid and chemorepellents lysine, glucosamine, succinic acid, arginine and thiamine. An isogenic mutant of cj1564 was shown to have altered phenotypic characteristics of C. jejuni, including loss of curvature in bacterial cell shape, reduced chemotactic motility and an increase in both autoagglutination and biofilm formation. We demonstrate Cj1564 to have a role in invasion as in in vitro assays the tlp3 isogenic mutant has a reduced ability to adhere and invade a cultured epithelial cell line; interestingly however, colonisation ability of avian caeca appears to be unaltered. Additionally, protein-protein interaction studies revealed signal transduction initiation through the scaffolding proteins CheV and CheW in the chemotaxis sensory pathway. This is the first report characterising Cj1564 as a multi-ligand receptor for C. jejuni, we therefore, propose to name this receptor CcmL, Campylobacter chemoreceptor for multiple ligands. In conclusion, this study identifies a novel multifunctional role for the C. jejuni CcmL chemoreceptor and illustrates its involvement in the chemotaxis pathway and subsequent survival of this organism in the host.

Male circumcision (MC) reduces men's risk of contracting HIV by approximately 60% and has the potential to significantly alter HIV epidemics. However, MC does not significantly reduce the risk of HIV transmission to women from a circumcised man. In Malawi, several researchers has examined the acceptability, accessibility and sexual behaviour change after circumcision in men but behaviour change in women following their partner's circumcision remains uncertain. In order to fully realise the protective benefits of MC against HIV, factors related to risky sexual behaviour is imperative as some studies have shown potentials of increased risky behaviour in men following voluntary medical male circumcision (VMMC). This study aimed to explore the perceptions and opinions of female school teachers and health workers on HIV-protective benefits of MC and its impact on risk compensatory behaviour among women in Malawi. We conducted a cross-sectional survey of women (N = 68) between May and June 2016 in three districts of southern Malawi. Risk compensatory behaviour was measured by number of sexual partners and use of protection during sex among female teachers and health care workers who are involved with educating people on benefits of VMMC. The bivariable analysis was conducted to test for association between HIV-protective benefits and risk compensatory behaviour. Purposive sampling was used to conduct eight qualitative in-depth interviews with women from the selected districts and the qualitative data was analysed thematically. The mean age of women who participated in the survey was 30 years. Most women (94.1%) correctly indicated that HIV-positive circumcised men can still infect their partner and approximately, 90% of were knowledgeable of risky sexual behaviour for HIV. However, 55.9% perceived MC can lead women to adopt risky sexual behaviour. On the contrary to this finding, qualitative data indicate women's misconceptions regarding their partners' circumcision and HIV-protective benefits. Most women expressed that risky sexual behaviour such as having multiple sexual partners and inconsistent or non-use of condoms can easily be observed among women if they learn of their partners' partial HIV-protective benefits circumcision. Exploring women's sexual behaviour change in the right of HIV-protective benefits of MC fills in a research knowledge important to public health. In-depth studies are therefore required to give more evidence that will guide the development of HIV risk-reduction interventions.

Cells from all domains of life express glycan structures attached to lipids and proteins on their surface, called glycoconjugates. Cell-to-cell contact mediated by glycan:glycan interactions have been considered to be low-affinity interactions that precede high-affinity protein–glycan or protein–protein interactions. In several pathogenic bacteria, truncation of surface glycans, lipooligosaccharide (LOS), or lipopolysaccharide (LPS) have been reported to significantly reduce bacterial adherence to host cells. Here, we show that the saccharide component of LOS/LPS have direct, high-affinity interactions with host glycans. Glycan microarrays reveal that LOS/LPS of four distinct bacterial pathogens bind to numerous host glycan structures. Surface plasmon resonance was used to determine the affinity of these interactions and revealed 66 high-affinity host–glycan:bacterial–glycan pairs with equilibrium dissociation constants (K D) ranging between 100 nM and 50 μM. These glycan:glycan affinity values are similar to those reported for lectins or antibodies with glycans. Cell assays demonstrated that glycan:glycan interaction-mediated bacterial adherence could be competitively inhibited by either host cell or bacterial glycans. This is the first report to our knowledge of high affinity glycan:glycan interactions between bacterial pathogens and the host. The discovery of large numbers of glycan:glycan interactions between a diverse range of structures suggests that these interactions may be important in all biological systems.

This study explores the perceived roles of children in antimicrobial resistance (AMR) in two sites across Nepal. AMR is a global challenge and underpinned by many complex behavioural drivers including how antimicrobial medicines are sourced and used. Because of this social dynamic, several research groups are using community engagement (CE) approaches to understand AMR at community level. However, most data negate the importance of children in behaviours linked to, and potentially driving AMR. In this study, authors apply secondary analysis methods to 10 transcripts representing the views of 23 adults engaged in an AMR-focused film-making project. By focusing on participants’ reference to children, we reveal that antimicrobial usage and adherence to health providers’ messages can be influenced by the age of the patient. Secondly that children are involved in some of the behaviours which are known to drive antimicrobial resistance such as purchasing over-the-counter antibiotic drugs. Finally, community members discuss that, with careful creation of resources, AMR could be meaningfully presented in educational settings with a view to children acting as agents of change around AMR-driving behaviours. Findings suggest that age-inclusive community engagement projects could be effective in tackling AMR at community level in Nepal and other low resource settings.

Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta (POLQ) transcription by binding its promoter loci, driving POLΘ-mediated MMEJ that is essential to withstand cyclin D1-induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced POLQ expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POLΘ in cyclin D1-overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POLΘ inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.

Abstract Primary leptomeningeal lymphoma is exceedingly rare. We describe 2 rare lymphoma cases with exclusive leptomeningeal disease: 1 ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) and 1 primary effusion lymphoma (PEL). Case 1: A 19-year-old man presented with symptoms concerning for leptomeningitis. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis. Spine MRI demonstrated pial enhancement from T10 through the conus medullaris and cauda equina enhancement/thickening. A biopsy showed leptomeningeal involvement by large lymphoma cells with hallmark cells and brisk mitotic activity. By immunohistochemistry, cells were CD7/CD30-positive with cytoplasmic ALK staining. No systemic disease was identified. The diagnosis of primary leptomeningeal ALK+ ALCL was made. Despite 2 CSF relapses requiring systemic therapy and autologous bone marrow transplant, the patient was in complete clinical remission 9 years after the diagnosis. Case 2: A 60-year-old, human immunodeficiency virus-positive man presented with symptoms suggestive of leptomeningitis. Brain MRIs revealed multifocal, supratentorial, and infratentorial leptomeningeal enhancement. A right frontal biopsy demonstrated leptomeningeal involvement by large lymphoma cells negative for B-cell immunostains, but CD138, MUM-1, and HHV8-positive, with aberrant CD3 expression. EBV-encoded RNA in situ hybridization was positive. In absence of solid lesions/extracranial involvement, the diagnosis of leptomeningeal PEL was rendered. Despite initial complete remission after chemotherapy, the patient died 9 months later.