Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals ...with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
The rapidly evolving COVID-19 pandemic required systemic change in how healthcare was delivered to minimize virus transmission whilst maintaining safe service delivery. Deemed at ‘moderate-high ...risk’, maternity patients are an important patient group that require consideration. Public Health England (PHE) issued national guidance on how to adjust these services.
To explore how maternity units in England implemented PHE guidance.
An online survey of 22 items was distributed to individuals that had worked on an England-based maternity unit during the COVID-19 pandemic. The questionnaire was designed and tested by the multidisciplinary research team. Data was collected from November 2020 to July 2021.
Forty-four participants across 33 maternity units responded. Ninety-three percent were able to test all women requiring an overnight stay for COVID-19. Only 27% reported birth partners were tested for COVID-19. Only 73% reported they were able to isolate all COVID-19-positive patients in single rooms. Eighty-four percent stated they were aware of current PHE guidance on personal protective equipment (PPE) and 82% felt ‘confident’ in donning/doffing of PPE. Priorities for the future include rapid testing and a focus on community service provision.
PHE COVID-19 guidance was implemented differently in maternity units across England due to the varying resources available at each trust leading to variable ability to test and isolate patients as recommended. More specific, tailored guidance for infection control measures against COVID-19 is needed for maternity settings due to their unique position.
Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing ...melanoma tumor-associated antigen (TAA)-dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.
The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutation-positive and mutation-negative subtypes, ...timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F- essential thrombocythemia do not commonly progress to become V617F+. Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F+. We also investigated the existence of a “pre-JAK2” phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F+ granulocytes. Our results demonstrate that inherent XCIP variability between granulocytes and T cells produces a systematically biased pattern of results that may be misinterpreted as evidence for an excess of clonally derived granulocytes, an observation that limits the utility of XCIP analysis in this context. Lastly, we studied 4 patients with V617F+ myeloproliferative disorders who subsequently developed acute myeloid leukemia. In 3 patients the leukemic cells were V617F-, suggesting that in these patients the leukemia arose in a V617F- cell.
We measure the correlation of galaxy lensing and cosmic microwave background lensing with a set of galaxies expected to trace the matter density field. The measurements are performed using pre-survey ...Dark Energy Survey (DES) Science Verification optical imaging data and millimetre-wave data from the 2500 sq. deg. South Pole Telescope Sunyaev–Zel'dovich (SPT-SZ) survey. The two lensing–galaxy correlations are jointly fit to extract constraints on cosmological parameters, constraints on the redshift distribution of the lens galaxies, and constraints on the absolute shear calibration of DES galaxy-lensing measurements. We show that an attractive feature of these fits is that they are fairly insensitive to the clustering bias of the galaxies used as matter tracers. The measurement presented in this work confirms that DES and SPT data are consistent with each other and with the currently favoured Λ cold dark matter cosmological model. It also demonstrates that joint lensing–galaxy correlation measurement considered here contains a wealth of information that can be extracted using current and future surveys.
CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature associated with ...killer lectin-like receptor (KLR) expression. Although KLR+ TEX (TKLR) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using single-cell RNA sequencing (scRNA-seq), flow cytometry, RNA velocity, and single-cell T cell receptor sequencing (scTCR-seq), we demonstrate that deleting the pseudokinase Trib1 shifts TEX toward CX3CR1+ intermediates with robust enrichment of TKLR via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8+ TKLR in Trib1-deficient cells is CD8 intrinsic, while CD4-depletion studies demonstrate CD4+ T cells are required for improved viral control in Trib1 conditional knockout mice. Further, Trib1 loss augments anti-programmed death-ligand 1 (PD-L1) blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.
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•Trib1 deficiency promotes effector gene expression during T cell exhaustion (TEX)•Trib1 deletion in TEX drives clonal expansion of effector-like CD8+ TINT and TKLR•Promotion of TKLR in Trib1 KO is CD8 intrinsic, but viral control requires CD4 cells•Trib1 deletion improves viral control during PD-L1 blockade
McClory et al. demonstrate that deletion of Trib1 in T cells promotes clonal expansion of exhausted CD8+ TINT and TKLR cells with an effector-like transcriptional program during chronic LCMV infection. Trib1 deletion improves viral control during PD-L1 blockade, suggesting that targeting Trib1 may improve outcomes during chronic infection and cancer.
We examined antibody and memory B cell responses longitudinally for ∼9–10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 ...and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%–50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit the added protection afforded by repeat short interval boosting. These data provide insight into the quantity and quality of mRNA-vaccine-induced immunity over time through 3 or more antigen exposures.
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•Neutralizing antibody titers stabilize ∼6 months after primary vaccination•Memory B cells are stable for >9 months postvaccination and >50% cross-bind Omicron•Omicron-reactive memory B cells are reactivated by a 3rd dose of wild-type vaccine•Low preboost antibody levels correlate with a greater fold increase after boosting
Immunization with 2 doses of mRNA vaccine encoding the ancestral SARS-CoV-2 spike protein induces a population of durable memory B cells with broad reactivity to viral variants including Omicron. Boosting with a 3rd dose of ancestral vaccine increases variant-neutralizing antibody levels, highlighting the significance of vaccine-induced B cell memory.
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