58 results found
Guerrero A, Innes AJ, Roux P-F, et al., 2022, 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice, Nature Aging
Mullish BH, 2022, National clinical expert consensus statement: Coronavirus monoclonal antibodies as a prophylactic therapy against COVID-19 for immunocompromised groups
- Novel long-acting coronavirus prophylactic monoclonal antibodytherapies have been shown to be effective in preventing COVID19 in immunocompromised individuals who are at increased riskfrom SARS-CoV-2.- Prophylactic antibody therapies should be made available in atimely manner to give an antibody immunity boost to vulnerablepatients.- Real world evaluations should be co-implemented to provideconfidence of ongoing effectiveness.- Successful delivery of a coronavirus prophylactic antibodytherapy programme would deliver significant benefits tohealthcare systems, communities and immunocompromisedindividuals.
Innes A, McVinnie K, Nadal-Melsio E, et al., 2022, A case of chronic neutrophilic leukaemia and multiple myeloma showing the benefits of lenalidomide and cyclophosphamide therapy in treating both conditions, American Journal of Hematology, ISSN: 0361-8609
Claudiani S, Parker EL, Milojkovic D, et al., 2022, Long-term persistence of natural anti-SARS-CoV-2 antibodies and mild impact of SARS-CoV-2 infection in CML patients: results from a seroprevalence study, LEUKEMIA & LYMPHOMA, Vol: 63, Pages: 1504-1507, ISSN: 1042-8194
Claudiani S, Apperley JF, Parker EL, et al., 2021, Durable humoral responses after the second anti-SARS-CoV-2 vaccine dose in chronic myeloid leukaemia patients on tyrosine kinase inhibitors, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 197, Pages: E1-E4, ISSN: 0007-1048
Booth S, Curley HM, Varnai C, et al., 2021, Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy, British Journal of Haematology, Vol: 196, Pages: 892-901, ISSN: 0007-1048
Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.
Innes AJ, Mullish BH, Ghani R, et al., 2021, Fecal microbiota transplant mitigates adverse outcomes in patients colonized with multidrug-resistant organisms undergoing allogeneic hematopoietic cell transplantation, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-8, ISSN: 2235-2988
The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT).This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. Weperformed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy forMDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDROgroup), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival wassignificantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensivecare (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant difference and statistically comparablepatient/transplant characteristics, as the sample size was small, a matched-pair analysis to non-MDRO colonized control cohorts(2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4%versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than theirpaired non-colonized cohort. There was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2%respectively, p=0.24) between the FMT-MDRO group and their paired cohort. Negative outcomes, including mortality associatedwith MDRO colonization, may be ameliorated by pre-HCT FMT, despite lack of intestinal decolonization. Further work is needed toexplore the observed benefit.
Mullish BH, Innes AJ, Ghani R, et al., 2021, FECAL MICROBIOTA TRANSPLANT PRIOR TO ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN PATIENTS COLONIZED WITH MULTI-DRUG RESISTANT ORGANISMS IS ASSOCIATED WITH IMPROVED SURVIVAL, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S168-S169, ISSN: 0016-5085
Ghani R, Mullish BH, McDonald JAK, et al., 2021, Disease prevention not decolonization – a model for fecal microbiota transplantation in patients colonized with multidrug-resistant organisms, Clinical Infectious Diseases, Vol: 72, Pages: 1444-1447, ISSN: 1058-4838
Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia and length of stay in 20 patients colonized/ infected with MDRO receiving FMT (compared to pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.
Vergis N, Phillips R, Cornelius V, et al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215
OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C
Maynard S, Ros-Soto J, Chaidos A, et al., 2021, The role of ibrutinib in COVID-19 hyperinflammation: a case report, International Journal of Infectious Diseases, Vol: 105, Pages: 274-276, ISSN: 1201-9712
Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.
Ghani R, Mullish B, Innes A, et al., 2021, Faecal microbiota transplant (FMT) prior to allogeneic haematopoietic cell transplantation (HCT) in patients colonised with multidrug-resistant organisms (MDRO) results in improved survival, ECCMID
Innes A, Sun B, Wagner V, et al., 2021, XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence, Genes and Development, Vol: 35, Pages: 379-391, ISSN: 0890-9369
Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.
Salisbury RA, Curto-Garcia N, OSullivan J, et al., 2021, Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm, Leukemia, Vol: 35, Pages: 2424-2430, ISSN: 0887-6924
Claudiani S, Apperley JF, Szydlo R, et al., 2020, TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 193, Pages: 346-355, ISSN: 0007-1048
Innes AJ, Ghani R, Mullish BH, et al., 2020, O105. Faecal microbiota transplant (FMT) can reduce the high NRM associated with multi-drug resistant organism (MDRO) colonisation prior to allogeneic HCT., The 46th Annual Meeting of the European Society for Blood and Marrow Transplantation, Publisher: Springer Nature [academic journals on nature.com], Pages: 122-122, ISSN: 0268-3369
Ellington MJ, Davies F, Jauneikaite E, et al., 2020, A multi-species cluster of GES-5 carbapenemase producing Enterobacterales linked by a geographically disseminated plasmid, Clinical Infectious Diseases, Vol: 71, Pages: 2553-2560, ISSN: 1058-4838
BACKGROUND: Early and accurate treatment of infections due to carbapenem-resistant organisms is facilitated by rapid diagnostics but rare resistance mechanisms can compromise detection. One year after a GES-5 carbapenemase-positive Klebsiella oxytoca infection was identified by whole genome sequencing (WGS) (later found to be part of a cluster of three cases), a cluster of 11 patients with GES-5-positive K. oxytoca was identified over 18 weeks in the same hospital.METHODS: Bacteria were identified by MALDI-TOF, antimicrobial susceptibility testing followed EUCAST guidelines. Ertapenem-resistant isolates were referred to Public Health England for characterization using PCR detection of GES, pulse-field gel electrophoresis (PFGE) and WGS for the second cluster.RESULTS: The identification of the first GES-5 K. oxytoca isolate was delayed, being identified on WGS. A GES-gene PCR informed the occurrence of the second cluster in real-time. In contrast to PFGE, WGS phylogenetic analysis refuted an epidemiological link between the two clusters; it also suggested a cascade of patient-to-patient transmission in the later cluster. A novel GES-5-encoding plasmid was present in K. oxytoca,E. coli and E. cloacae isolates from unlinked patients within the same hospital group and in human and wastewater isolates from three hospitals elsewhere in the UK.CONCLUSIONS: Genomic sequencing revolutionized the epidemiological understanding of the clusters, it also underlined the risk of covert plasmid propagation in healthcare settings and revealed the national distribution of the resistance-encoding plasmid. Sequencing results also informed and led to the ongoing use of enhanced diagnostic tests for detecting carbapenemases locally and nationally.
Claudiani S, Rosadas C, McClure M, et al., 2020, Prevalence of Sars-Cov-2 Infection in Patients with Chronic Myeloid Leukemia, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Innes AJ, Cook LB, Marks S, et al., 2020, Ruxolitinib for tocilizumab-refractory severe COVID-19 infection., British Journal of Haematology, Vol: 190, Pages: e198-e200, ISSN: 0007-1048
Whilst the majority of patients with COVID-19 infection have mild self-limiting symptoms, for some the SARS-CoV2 virus can trigger a severe hyperinflammatory syndrome which is life threatening. Anti-IL6 therapy has shown promise in restraining the hyperinflammatory syndrome and while IL-6 is a pleiotropic mediatory of the inflammatory response, redundancy within inflammatory pathways means that the use of such targeted monoclonal therapy may have too restricted a repertoire in some patients. We present the case of a 53-year-old haematopoetic stem cell transplant recipient who developed a severe COVID-19 that was refractory to anti-IL6 therapy, but responded to Jak-Stat inhibition with ruxolitinib, demonstrating its safety and efficacy in this setting.
Nesr G, Laffan M, Claudiani S, et al., 2020, Platelet function in patients with chronic myeloid leukemia treated with asciminib, Leukemia & Lymphoma, Vol: 61, Pages: 3021-3023, ISSN: 1042-8194
Gupta RK, Peppa D, Hill AL, et al., 2020, Evidence for HIV-1 cure after CCR5 Delta 32/Delta 32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report, LANCET HIV, Vol: 7, Pages: E340-E347, ISSN: 2352-3018
Ghani R, Mullish BH, McDonald JA, et al., 2020, 1144 FECAL MICROBIOTA TRANSPLANT FOR MULTI-DRUG RESISTANT ORGANISMS: IMPROVED CLINICAL OUTCOMES BEYOND INTESTINAL DECOLONISATION, Publisher: Elsevier BV, ISSN: 0016-5085
Ghani R, Mullish BH, McDonald J, et al., 2020, Disease prevention not decolonisation: a cohort study for faecal microbiota transplantation for patients colonised with multidrug-resistant organisms, ECCMID 2020
Senescence is a cellular stress response that results in the stable arrest of old, damaged or pre-neoplastic cells. Oncogene-induced senescence is tumour suppressive but can also exacerbate tumorigenesis through the secretion of proinflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed ‘senolytics’, have proved beneficial in animal models of many age-associated diseases. In the present study, we show that the cardiac glycoside ouabain is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the proapoptotic Bcl-2 family protein NOXA. We demonstrate that cardiac glycosides synergize with anti-cancer drugs to kill tumour cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent pre-neoplastic cells. The findings of the present study suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanisms. Given the broad range of senescent cells targeted by cardiac glycosides, their use against age-related diseases warrants further exploration.
Cuartero S, Innes AJ, Merkenschlager M, 2019, Towards a better understanding of cohesin mutations in AML, Frontiers in Oncology, Vol: 9, ISSN: 2234-943X
Classical driver mutations in acute myeloid leukemia (AML) typically affect regulatorsof cell proliferation, differentiation, and survival. The selective advantage of increasedproliferation, improved survival, and reduced differentiation on leukemia progression isimmediately obvious. Recent large-scale sequencing efforts have uncovered numerousnovel AML-associated mutations. Interestingly, a substantial fraction of the mostfrequently mutated genes encode general regulators of transcription and chromatinstate. Understanding the selective advantage conferred by these mutations remains amajor challenge. A striking example are mutations in genes of the cohesin complex,a major regulator of three-dimensional genome organization. Several landmark studieshave shown that cohesin mutations perturb the balance between self-renewal anddifferentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data nowbegin to uncover the molecular mechanisms that underpin this phenotype. Amongthese mechanisms is a role for cohesin in the control of inflammatory responses inHSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and driveHSPC differentiation. Consistent with this, cohesin mutations promote resistance toinflammatory signals, and may provide a selective advantage for AML progression.In this review, we discuss recent progress in understanding cohesin mutations inAML, and speculate whether vulnerabilities associated with these mutations could beexploited therapeutically
Innes A, Wooley P, Szydlo R, et al., 2019, Complete remission with incomplete count recovery (CRi) prior to allogeneic HCT for acute myeloid leukaemia is associated with a high non-relapse mortality., Leukemia, Vol: 34, Pages: 667-670, ISSN: 1476-5551
Beckerson J, Szydlo RM, Hickson M, et al., 2019, Impact of route and adequacy of nutritional intake on outcomes of allogeneic haematopoietic cell transplantation for haematologic malignancies, Clinical Nutrition, Vol: 38, Pages: 738-744, ISSN: 0261-5614
BACKGROUND: Allogeneic haematopoietic cell transplantation (HCT) is often associated with poor oral intake due to painful mucositis and gastrointestinal sequalae that occur following a preparative regimen of intensive chemotherapy and/or total body radiation. Although attractive to assume that optimal nutrition improves HCT outcomes, there are limited data to support this. It is also unclear whether artificial nutrition support should be provided as enteral tube feeding or parenteral nutrition (PN). METHODS: We analysed day-100 non-relapse mortality (NRM), incidence of acute graft-versus-host disease (GvHD), acute gastrointestinal GvHD, 5-year survival and GvHD-free/relapse-free survival (GRFS) according to both route and adequacy of nutritional intake prior to neutrophil engraftment, together with other known prognostic factors, in a retrospective cohort of 484 patients who underwent allogeneic HCT for haematologic malignancy between 2000 and 2014. RESULTS: Multivariate analyses showed increased NRM with inadequate nutrition (hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.2-7.2) and adequate PN (HR 2.9; 95% CI 1.6-5.4) compared to adequate enteral nutrition (EN) both P < .001. There were increased incidences of gastrointestinal GvHD of any stage and all GvHD ≥ grade 2 in patients who received PN (odds ratio (OR) 2.0; 95% CI 1.2-3.3; P = .006, and OR 1.8; 95% CI 1.1-3.0; P = .018, respectively), compared to adequate EN. Patients who received adequate PN and inadequate nutrition also had reduced probabilities of survival and GRFS at 5 years. CONCLUSION: Adequate EN during the early transplantation course is associated with reduced NRM, improved survival and GRFS at 5 years. Furthermore, adequate EN is associated with lower incidence of overall and gut acute GvHD than PN, perhaps because of its ability to maintain mucosal integrity, modulate the immune response to intensive chemo/radiotherapy and support the gastroi
Gupta RK, Abdul-Jawad S, McCoy LE, et al., 2019, HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation, Nature, Vol: 568, Pages: 244-248, ISSN: 0028-0836
A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may b
Innes AJ, Gil J, 2019, IMR90 ER:RAS: A cell model of oncogene-induced senescence, Methods in Molecular Biology, Vol: 1896, Pages: 83-92, ISSN: 1940-6029
Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence-associated secretory phenotype (SASP).
Innes AJ, Woolley P, Szydlo R, et al., 2018, Complete remission with incomplete count recovery (CRi) prior to allogeneic hematopoietic cell transplantation for acute myeloid leukemia is associated with a high non-relapse mortality without increased relapse risk, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology, ISSN: 1528-0020
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