754 results found
Stebbing J, Sánchez Nievas G, Falcone M, et al., 2020, JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality., Sci Adv
Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials.
Zagorac S, de Giorgio A, Dabrowska A, et al., 2020, SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells., Cancer Res
In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet how transcriptional regulation of cell cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle and increase in self-renewal gene expression is coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long non-coding RNA (lncRNA) that we name SCIRT, which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing towards repression. These data suggest that the interaction of a lncRNA with EZH2 can alter the affinity of EZH2 for its protein binding partners to regulate cancer cell state transitions.
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, 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.
Ditsiou A, Cilibrasi C, Simigdala N, et al., 2020, The structure-function relationship of oncogenic LMTK3., Sci Adv, Vol: 6
Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.
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: 100029-100029, ISSN: 2666-5352
Williams J, Stebbing J, 2020, COVID-19 and the risk to cancer patients in China., International Journal of Cancer, ISSN: 0020-7136
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
Sims JT, Krishnan V, Chang C-Y, et al., 2020, Characterization of the Cytokine Storm Reflects Hyperinflammatory Endothelial Dysfunction in COVID-19, Journal of Allergy and Clinical Immunology, 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.
Cereser B, Tabassum N, Belluz LDB, et al., 2020, Mutational landscapes of normal breast during age and pregnancy determine cancer risk
<jats:title>ABSTRACT</jats:title><jats:p>The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood<jats:sup>1–10</jats:sup>. 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<jats:sup>11</jats:sup>. 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).</jats:p>
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:p>Purpose: To examine the risk factors for Intensive Care Unit (ICU) admission, mechanical ventilation and mortality in hospitalized patients with COVID-19.Methods: 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 1st to April 10th 2020. Primary outcomes included ICU admission, mechanical ventilation and death occurring while hospitalized or within 30 days. Results: 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 x 109/l), but lymphocyte counts were lower (0.6 vs 1.0 x 109/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 >39o 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, 1.04-2.30), ICU admission (4.92, 1.37-17.64) and mechanical ventilation (2.35, 1.14-4.82). Conclusion: Demographics, including age over 65 years, current smoker, diabetes, hypertension, and cerebrovascular disease, were associated with increased risk of mortality. Mortality was also associated with glucocorticoid use, mechanical ventilation and ICU admission.Take-Home Message: COVID-19 patients with risk factors were
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
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
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
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
Magbanua MJM, Hendrix LH, Hyslop T, et al., 2020, Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-line chemotherapy., J Natl Cancer Inst
BACKGROUND: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. METHODS: Serial CTC data from 469 patients (2,202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs (bCTC), combined CTC status at baseline to the end of cycle 1 (cCTC), and tCTC. Akaike Information Criterion (AIC) was used to select the model that best predicted PFS and OS. RESULTS: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (tCTCneg, 56.9% ), low (tCTClo, 23.7%), intermediate (tCTCmid, 14.5%), or high (tCTChi, 4.9%). Patients with tCTClo, tCTCmid and tCTChi patterns had statistically significant inferior PFS and OS compared to those with tCTCneg (P<.001). AIC indicated that the tCTC model best predicted PFS and OS when compared to bCTC and cCTC models. Validation studies in an independent cohort of 1,856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. CONCLUSIONS: We identified four novel prognostic groups in MBC based on similarities in CTC trajectory patterns during chemotherapy. Prognostic groups included patients with very poor outcome (tCTCmid+tCTChi, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be utilized for fine-tuning of CTC-based risk-stratification strategies to guide future prospective clinical trials in MBC.
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, 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
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests of varying specificity and sensitivity are now available. For informing individuals whether they have had coronavirus disease 2019 (COVID-19), they need to be very accurate. For measuring population prevalence of past infection, the numbers of false positives and negatives need to be roughly equal. With a series of worked examples for a notional population of 100,000 people, we show that even test systems with a high specificity can yield a large number of false positive results, especially where the population prevalence is low. For example, at a true population prevalence of 5%, using a test with 99% sensitivity and specificity, 16% of positive results will be false and thus 950 people will be incorrectly informed they have had the infection. Further confirmatory testing may be needed. Giving false reassurance on which personal or societal decisions might be based could be harmful for individuals, undermine public confidence and foster further outbreaks.
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.
Lenz H-J, Richardson P, Stebbing J, 2020, The Emergence of Baricitinib: A Story of Tortoises Versus Hares., Clin Infect Dis
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.
Peng L, Zagorac S, Stebbing J, 2020, Managing patients with cancer in the COVID-19 era, EUROPEAN JOURNAL OF CANCER, Vol: 132, Pages: 5-7, ISSN: 0959-8049
Smith K, Galazi M, Openshaw MR, et al., 2020, The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer, CLINICAL GENITOURINARY CANCER, Vol: 18, Pages: E217-E223, ISSN: 1558-7673
Magbanua MJM, Li W, Wolf DM, et al., 2020, Circulating tumor DNA (ctDNA) and magnetic resonance imaging (MRI) for monitoring and predicting response to neoadjuvant therapy (NAT) in high-risk early breast cancer patients in the I-SPY 2 TRIAL, AACR Special Conference on Advances in Liquid Biopsies, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 59-60, ISSN: 1078-0432
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
Pallett S, Denny S, Patel A, et al., 2020, Point-of-care serological assays for SARS-CoV-2 in a UK hospital population: potential for enhanced case finding
Abstract Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility.We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays ( n= 15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13. Specificity was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.