Publications
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Majra D, Benson J, Pitts J, et al., 2021, SARS-CoV-2 (COVID-19) superspreader events, JOURNAL OF INFECTION, Vol: 82, Pages: 36-40, ISSN: 0163-4453
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- Citations: 72
Boiardi F, Stebbing J, 2021, Reducing transmission of SARS-CoV-2 with intranasal prophylaxis, EBIOMEDICINE, Vol: 63, ISSN: 2352-3964
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- Citations: 2
Sims JT, Krishnan V, Chang C-Y, et al., 2021, Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 107-111, ISSN: 0091-6749
BackgroundPhysicians treating COVID-19 patients increasingly believe that the hyperinflammatory acute stage of COVID-19 results in a cytokine storm. The circulating biomarkers seen across the spectrum of COVID-19 have not been characterized compared to healthy controls, but such analyses are likely to yield insights into the pursuit of interventions that adequately reduce the burden of these cytokine storms.ObjectiveTo identify and characterize the host inflammatory response to SARS-CoV-2 infection, we assessed levels of proteins related to immune responses and cardiovascular disease, in patients stratified as mild, moderate, and severe, versus matched healthy controls.MethodsBlood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with age- and sex-matched healthy controls to provide insights into differential regulation of 185 markers.ResultsResults indicate a dominant hyperinflammatory milieu in the circulation and vascular endothelial damage markers within COVID-19 patients, and strong biomarker association with patient response as measured by Ordinal scale. As patients progress, we observe statistically significant dysregulation of IFNγ, IL-1RA, IL-6, IL-10, IL-19, MCP-1, -2, -3, CXCL9, CXCL10, CXCL5, ENRAGE and PARP-1. Furthermore, in a limited series of patients who were sampled frequently confirming reliability and reproducibility of our assays, we demonstrate that intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine storm.ConclusionThese wide-ranging circulating biomarkers show an association with increased disease severity and may help stratify patients and selection of therapeutic options. They also provide insights into mechanisms of SARS-CoV-2 pathogenesis and the host response.
Glasbey JC, Omar O, Nepogodiev D, et al., 2021, Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 88-96, ISSN: 0007-1323
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- Citations: 43
Xia Y, Jin R, Peng L, et al., 2021, EGFR-mutated squamous cell lung cancer and its association with outcomes, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S966-S967, ISSN: 0923-7534
Peng L, Xiao K, Cui J, et al., 2021, Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC, ONCOTARGETS AND THERAPY, Vol: 14, Pages: 3409-3415, ISSN: 1178-6930
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- Citations: 2
Ottaviani S, Stebbing J, 2020, What is the best drug to treat COVID-19? The need for randomized controlled trials, Medicine, Vol: 1, Pages: 9-10, ISSN: 1357-3039
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the biggest public health challenge to the biomedical community of the last century. Despite multiple public health measures,1, 2, 3 there remains an urgent need for pharmacologic therapies to treat infected patients, minimize mortality, and decrease pressures on intensive care units and health systems and optimally, they should also decrease subsequent transmission.
Lythgoe M, Stebbing J, Pickford E, et al., 2020, 805 Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumours, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: A481-A482, ISSN: 2051-1426
Background The gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).Methods Treatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.Results In part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression pan
Kalil AC, Stebbing J, 2020, Baricitinib: the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial, LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 1349-1351, ISSN: 2213-2600
Tabassum N, Zhang H, Stebbing J, 2020, Repurposing fostamatinib to combat SARS-CoV-2-induced acute lung injury., Cell Reports Medicine, Vol: 1, Pages: 1-2, ISSN: 2666-3791
A screen by Kost-Alimova et al.1 suggests that the FDA-approved SYK inhibitor fostamatinib inhibits MUC1 in the respiratory tract and has the potential to treat serious outcomes of coronavirus COVID-19, including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).
Peng L, Mao Q-Q, Jiang B, et al., 2020, Bilateral Posterior Uveitis and Retinal Detachment During Immunotherapy: A Case Report and Literature Review, FRONTIERS IN ONCOLOGY, Vol: 10, ISSN: 2234-943X
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- Citations: 4
Zhang H, Han H, He T, et al., 2020, Clinical characteristics and outcomes of COVID-19-infected cancer patients: a systematic review and meta-analysis, Journal of the National Cancer Institute, Vol: 113, Pages: 371-380, ISSN: 0027-8874
BACKGROUND: Previous studies have indicated Coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate. METHODS: We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariate logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes. RESULTS: We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the UK and Europe, followed by the USA and Canada (35.7%) and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (odds ratio [OR] = 3.57; 95% CI = 1.80 to 7.06), male (OR = 2.10; 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00; 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariate analysis, only age greater than 65 years (OR = 3.16; 95% CI = 1.45 to 6.88) and being male (OR = 2.29; 95% CI = 1.07 to 4.87) were associated with increased risk of severe events. CONCLUSION: Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate when compared with that of COVID-19 patients without cancer. Age and gender appear to be risk factors associated with a poorer prognosis.
Pelisser M, Thompson J, Majra D, et al., 2020, Sports balls as potential SARS-CoV-2 transmission vectors., Public Health in Practice, Vol: 1, Pages: 1-5, ISSN: 2666-5352
Objects passed from one player to another have not been assessed for their ability to transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found that the surface of sport balls, notably a football, tennis ball, golf ball, and cricket ball could not harbour inactivated virus when it was swabbed onto the surface, even for 30 s. However, when high concentrations of 5000 dC/mL and 10,000 dC/mL are directly pipetted onto the balls, it could be detected after for short time periods. Sports objects can only harbour inactivated SARS-CoV-2 under specific, directly transferred conditions, but wiping with a dry tissue or moist 'baby wipe' or dropping and rolling the balls removes all detectable viral traces. This has helpful implications to sporting events.
Ditsiou A, Cilibrasi C, Simigdala N, et al., 2020, The structure-function relationship of oncogenic LMTK3, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548
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- Citations: 13
Glasbey JC, Bhangu A, 2020, Elective cancer surgery in COVID-19–free surgical pathways during the SARS-CoV-2 pandemic: an international, multicenter, comparative cohort study, Journal of Clinical Oncology, Vol: 39, Pages: 66-78, ISSN: 0732-183X
PURPOSEAs cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway.PATIENTS AND METHODSThis international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation).RESULTSOf 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76).CONCLUSIONWithin available resources, dedicated COVID-19–free
Williams J, Stebbing J, 2020, COVID‐19 and the risk to cancer patients in China, International journal of cancer, ISSN: 0020-7136
Peng L, Stebbing J, Wang Y-J, 2020, Reply to letter to the editor: baricitinib and toxicity is a rare occurrence., Expert Opin Drug Saf, Vol: 19, Pages: 1371-1372
COVIDSurg Collaborative, 2020, Delaying surgery for patients with a previous SARS-CoV-2 infection, British Journal of Surgery, ISSN: 0007-1323
Tabassum N, Cereser B, Stebbing J, 2020, A cell-cycle signature classifier for pan-cancer analysis, ONCOGENE, Vol: 39, Pages: 6041-6042, ISSN: 0950-9232
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- Citations: 8
Cereser B, Tabassum N, Belluz LDB, et al., 2020, Mutational landscapes of normal breast during age and pregnancy determine cancer risk, Biorxiv
<h4>ABSTRACT</h4> The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood 1–10 . Similarly, the mutational landscape of both epithelial and stromal components of the mammary gland has not been investigated. Both are relevant for breast cancer (BC), as the interplay between age, pregnancy, and cancer risk has not been fully characterized 11 . We describe whole genome sequencing analysis of epithelial and stromal compartments from the normal breast. We show that, in a similar way to other normal organs, the mutational burden of the mammary nulliparous epithelium significantly increases with age. In a nulliparous status, mutated clones are maintained at a consistently small size throughout the life of the individual; however, at parity, pre-existent clones significantly increase in size with age. Both epithelial and stromal compartments of the healthy breast contain pre-existing known cancer mutations, albeit at low rate, indicative of subsequent positive selection for mutations in tissue-specific driver genes. In line with this, both compartments also present gene enrichment in preferentially mutated cancer pathways. Our results show that mutational landscapes differ between the parous and nulliparous epithelium and suggest an explanation for both differential breast cancer risk and development of pregnancy-associated BC (PABC).
Ren HG, Guo X, Blighe K, et al., 2020, Risk Factors for ICU Admission, Mechanical Ventilation and Mortality in Hospitalized Patients with COVID-19 in Hubei, China
<jats:sec><jats:title>Purpose</jats:title><jats:p>To examine the risk factors for Intensive Care Unit (ICU) admission, mechanical ventilation and mortality in hospitalized patients with COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This was a retrospective cohort study including 432 patients with laboratory-confirmed COVID-19 who were admitted to three medical centers in Hubei province from January 1<jats:sup>st</jats:sup> to April 10<jats:sup>th</jats:sup> 2020. Primary outcomes included ICU admission, mechanical ventilation and death occurring while hospitalized or within 30 days.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Of the 432 confirmed patients, 9.5% were admitted to the ICU, 27.3% required mechanical ventilation, and 33.1% died. Total leukocyte count was higher in survivors compared with those who died (8.9 vs 4.8 × 10<jats:sup>9</jats:sup>/l), but lymphocyte counts were lower (0.6 vs 1.0 × 10<jats:sup>9</jats:sup>/l). D-dimer was significantly higher in patients who died compared to survivors (6.0ug/l vs 1.0ug/l, p<0.0001. This was also seen when comparing mechanically versus non-mechanically-ventilated patients. Other significant differences were seen in AST, ALT, LDH, total bilirubin and creating kinase. The following were associated with increased odds of death: age > 65 years (adjusted hazard ratio (HR 2.09, 95% CI 1.02-4.05), severe disease at baseline (5.02, 2.05-12.29), current smoker (1.67, 1.37-2.02), temperature >39<jats:sup>°</jats:sup> C at baseline (2.68, 1.88-4.23), more than one comorbidity (2.12, 1.62-3.09), bilateral patchy shadowing on chest CT or X-ray (3.74, 1.78-9.62) and organ failure (6.47, 1.97-26.23). The following interventions were associated with higher CFR: glucocorticoids (1.60
Pallett SJC, Rayment M, Patel A, et al., 2020, Point-of-care serological assays for delayed SARS-CoV-2 case identification among health-care workers in the UK: a prospective multicentre cohort study, LANCET RESPIRATORY MEDICINE, Vol: 8, Pages: 885-894, ISSN: 2213-2600
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- Citations: 75
Richardson PJ, Corbellino M, Stebbing J, 2020, Baricitinib for COVID-19: a suitable treatment? Reply, LANCET INFECTIOUS DISEASES, Vol: 20, Pages: 1013-1014, ISSN: 1473-3099
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- Citations: 45
Carli G, Cecchi L, Stebbing J, et al., 2020, Asthma phenotypes, comorbidities, and disease activity in COVID-19: The need of risk stratification. Reply to Morais-Almeida, ALLERGY, ISSN: 0105-4538
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- Citations: 3
Stebbing J, Krishnan V, de Bono S, et al., 2020, Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients, EMBO Molecular Medicine, Vol: 12, Pages: 1-15, ISSN: 1757-4676
Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI)-algorithms, to be useful for COVID-19 infection via a proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and supports its assessment in randomized trials in hospitalized COVID-19 patients.
Kumleben N, Bhopal R, Czypionka T, et al., 2020, Test, test, test for COVID-19 antibodies: the importance of sensitivity, specificity and predictive powers, PUBLIC HEALTH, Vol: 185, Pages: 88-90, ISSN: 0033-3506
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- Citations: 30
Peng L, Xiao K, Ottaviani S, et al., 2020, A real-world disproportionality analysis of FDA Adverse Event Reporting System (FAERS) events for baricitinib., Expert Opinion on Drug Safety, Vol: 19, Pages: 1505-1511, ISSN: 1474-0338
BACKGROUND: Baricitinib is approved for the treatment of rheumatoid arthritis (RA). The authors retrospectively investigated adverse events (AEs) by data-mining a self-reporting database to better understand toxicities, especially since it has been used during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A reporting odds ratio (ROR) was used to detect the risk signals from the data in the US Food and Drug Administration (FDA) adverse event reporting system database (FAERS). The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). RESULTS: The search retrieved 1,598 baricitinib-associated cases within the reporting period: 86 PTs with significant disproportionality were retained. Infections including 'herpes zoster,' 'oral herpes,' and 'herpes virus infection' were found at a similar rate to those reported in trials, and such events were rare. Reports emerged for several thrombotic adverse events, while these events were also rare. Unexpected safety signals as opportunistic infections were detected. Serious outcomes as death and life-threatening outcomes accounted for 9.76% of the reported cases. CONCLUSIONS: The incidence of these AEs does not appear above the background expected. These data are consistent with routine clinical observations and suggest the importance of pharmacovigilance.
Peng L, Yang J-S, Stebbing J, 2020, Lessons to Europe from China for cancer treatment during the COVID-19 pandemic, BRITISH JOURNAL OF CANCER, Vol: 123, Pages: 7-8, ISSN: 0007-0920
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- Citations: 2
Richardson P, Griffin I, Tucker C, et al., 2020, Baricitinib as potential treatment for 2019-nCoV acute respiratory disease (vol 395, pg e30, 2020), LANCET, Vol: 395, Pages: 1906-1906, ISSN: 0140-6736
Gagliano T, Shah K, Gargani S, et al., 2020, PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression, Journal of Clinical Investigation, Vol: 130, Pages: 3188-3204, ISSN: 0021-9738
As there is growing evidence for the tumor microenvironment's (TME) role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was undetectable in breast cancer cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.
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