IGHV sequencing reveals acquired N-glycosylation sites as a clonal and stable event during follicular lymphoma evolution.

Follicular lymphoma B cells undergo continuous somatic hypermutation (SHM) of their immunoglobulin variable region genes, generating a heterogeneous tumor population. SHM introduces DNA sequences encoding N-glycosylation sites asparagine-X-serine/threonine (N-gly sites) within the V-region that are rarely found in normal B-cell counterparts. Unique attached oligomannoses activate B-cell receptor signaling pathways after engagement with calcium-dependent lectins expressed by tissue macrophages. This novel interaction appears critical for tumor growth and survival. To elucidate the significance of N-gly site presence and loss during ongoing SHM, we tracked site behavior during tumor evolution and progression in a diverse group of patients through next-generation sequencing. A hierarchy of subclones was visualized through lineage trees based on SHM semblance between subclones and their discordance from the germline sequence. We observed conservation of N-gly sites in more than 96% of subclone populations within and across diagnostic, progression, and transformation events. Rare N-gly-negative subclones were lost or negligible from successive events, in contrast to N-gly-positive subclones, which could additionally migrate between anatomical sites. Ongoing SHM of the N-gly sites resulted in subclones with different amino acid compositions across disease events, yet the vast majority of resulting DNA sequences still encoded for an N-gly site. The selection and expansion of only N-gly-positive subclones is evidence of the tumor cells' dependence on sites, despite the changing genomic complexity as the disease progresses. N-gly sites were gained in the earliest identified lymphoma cells, indicating they are an early and stable event of pathogenesis. Targeting the inferred mannose-lectin interaction holds therapeutic promise

Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma

We are indebted to the patients for donating tumor specimens as part of this study. The authors thank the Centre de Ressources Biologiques (CRB)-Santé of Rennes (BB-0033-00056) for patient samples, Queen Mary University of London Genome Centre for Illumina Miseq sequencing, and the support by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London for Illumina Hiseq sequencing. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This work was supported by grants from the Kay Kendall Leukaemia Fund (KKL 757 awarded to J.O.), Cancer Research UK (22742 awarded to J.O., 15968 awarded to J.F., Clinical Research Fellowship awarded to S.A.), Bloodwise through funding of the Precision Medicine for Aggressive Lymphoma (PMAL) consortium, Centre for Genomic Health, Queen Mary University of London, Carte d’Identité des Tumeurs (CIT), Ligue National contre le Cancer, Pôle de biologie hospital universitaire de Rennes, CRB-Santé of Rennes (BB-0033-00056), and CeVi/Carnot program

Evaluasi Pelaksanaan RANHAM 2004-2009 dan Rencana Ratifikasi Optional Protocol To The Convention Against Torture (CAT) dalam RANHAM 2004-2009 dan Perencanaan RANHAM 2010-2014

Dalam rangka mengevaluasi kepatuhan (comply) Pemerintah Indonesia dalam menjalankan United Nations Convention Against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (UNCAT) yang telah dirati kasi dengan UU No 5 1998, Kemitraan merasa perlu mengadakan kajian ini karena alasan-alasan berikut: (i) Secara hukum Indonesia wajib menjalankan UNCAT karena telah mengikatkan diri pada Konvensi tersebut sejak tahun 1998, sehingga semua pasal-pasal UNCAT (kecuali pasal 20 karena Indonesia mengecualikan diri) bersifat wajib atau legally binding untuk melaksanakannya. (ii) Indonesia belum sepenuhnya mengintegrasikan UNCAT dalam sejumlah peraturan Perundang-undangan nasional sehingga perlu dicermati secara khusus. (iii) Rencana Aksi Nasional Hak Asasi Manusia (RANHAM) 1998-2003 dan RANHAM 2004-2009 dirasa masih memiliki kekosongan substansi dan pelaksanaannya belum konsisten dengan apa yang dituangkan dalam ke dua RANHAM tersebut. Berdasarkan alan-alasan di atas dan makin maraknya pelanggaran HAM yang terjadi di Indonesia, Kemitraan dengan bantuan dana dari Uni Eropa mencoba mengevaluasi secara komprehensive pelaksanaan RANHAM 2004-2009 dan melihat kemungkinan rencana rati kasi Optional Protocol UNCAT yang telah disepakati oleh Majelis Umum PBB pada tanggal 18 Desember 2002 dan telah enter into force pada tanggal 22 Juni 2006. Disamping itu, kajian ini juga memberikan masukan bagi Perencanaan RANHAM 2010-2014

Patient and public involvement in research evaluating integrated care for people experiencing homelessness: findings from the PHOENIx Community Pharmacy Pilot Randomised‐Controlled Trial

Introduction: There is a paucity of research on and a limited understanding of patient and public involvement (PPI) in the context of research in homelessness and, in particular, direct involvement of people with lived and living experience of homelessness (PEH) as expert advisors. We aim to report on outcomes and reflections from lived experience advisory panel (LEAP) meetings and PPI activities, held throughout the study lifecycle of a pilot randomised‐controlled trial (RCT) focused on evaluating integrated health and practical support for PEH. Methods: Community Pharmacy Homeless Outreach Engagement Non‐medical Independent prescribing Rx (PHOENIx Community Pharmacy RCT) is an integrated health and social care intervention for people experiencing homelessness who present to community pharmacy. Intervention includes weekly support from a pharmacist prescriber and a third sector support worker for up to 6 months. PPI activities undertaken throughout the study were documented, including outcomes of LEAP meetings. Outcome reporting followed Guidance for Reporting Involvement of Patients and the Public 2 Short Form (GRIPP2‐SF). Results: In total, 17 members were recruited into the LEAP; six meetings (three in two study sites) were held. PPI input was also received through representation from homelessness third sector organisation staff as study co‐applicants and core membership in the trial steering committee. Together, the PPI activities helped shape the study proposal, design of study materials, data analysis and dissemination materials. LEAP panel members offered valuable input via their experience and expertise into the delivery and refinement of interventions. Although longitudinal input was received from some LEAP members, ensuring repeat attendance in the pre‐planned meetings was challenging. Conclusion: People who face social exclusion and marginalisation can provide highly valuable input as equal partners in co‐design and delivery of interventions seeking to improve their health and well‐being. Fluid membership and flexible methods of seeking and incorporating advice can offer pragmatic approaches to minimising barriers to continued involvement in research. Patient or Public Contribution: This study reports findings and learning relevant to involvement of people with lived and living experience of homelessness as advisors in a research study. It is important for researchers to offer fluid memberships and use diverse methods to receive input from lived experience members, as traditional PPI methodology may be insufficient to ensure inclusivity. Staff and volunteers from third sector organisations were important PPI partners who bring their experience based on frontline service provision, often as the first port of call for people experiencing severe and multiple disadvantage

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year–old patients with superior PFS and OS treated with ibrutinib–R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection