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  1. Article ; Online: Paediatric, maternal, and congenital mpox: a systematic review and meta-analysis.

    Sanchez Clemente, Nuria / Coles, Charlotte / Paixao, Enny S / Brickley, Elizabeth B / Whittaker, Elizabeth / Alfven, Tobias / Rulisa, Stephen / Agudelo Higuita, Nelson / Torpiano, Paul / Agravat, Priyesh / Thorley, Emma V / Drysdale, Simon B / Le Doare, Kirsty / Muyembe Tamfum, Jean-Jacques

    The Lancet. Global health

    2024  Volume 12, Issue 4, Page(s) e572–e588

    Abstract: Background: Although mpox has been detected in paediatric populations in central and west Africa for decades, evidence synthesis on paediatric, maternal, and congenital mpox, and the use of vaccines and therapeutics in these groups, is lacking. A ... ...

    Abstract Background: Although mpox has been detected in paediatric populations in central and west Africa for decades, evidence synthesis on paediatric, maternal, and congenital mpox, and the use of vaccines and therapeutics in these groups, is lacking. A systematic review is therefore indicated to set the research agenda.
    Methods: We conducted a systematic review and meta-analysis, searching articles in Embase, Global Health, MEDLINE, CINAHL, Web of Science, Scopus, SciELO, and WHO databases from inception to April 17, 2023. We included studies reporting primary data on at least one case of confirmed, suspected, or probable paediatric, maternal, or congenital mpox in humans or the use of third-generation smallpox or mpox vaccines, targeted antivirals, or immune therapies in at least one case in our population of interest. We included clinical trials and observational studies in humans and excluded reviews, commentaries, and grey literature. A pooled estimate of the paediatric case fatality ratio was obtained using random-effects meta-analysis. This study is registered with PROSPERO (CRD420223336648).
    Findings: Of the 61 studies, 53 reported paediatric outcomes (n=2123 cases), seven reported maternal or congenital outcomes (n=32 cases), two reported vaccine safety (n=28 recipients), and three reported transmission during breastfeeding (n=4 cases). While a subset of seven observational studies (21 children and 12 pregnant individuals) reported uneventful treatment with tecovirimat, there were no randomised trials reporting safety or efficacy for any therapeutic agent. Among children, the commonest clinical features included rash (86 [100%] of 86), fever (63 [73%] of 86), and lymphadenopathy (40 [47%] of 86). Among pregnant individuals, rash was reported in 23 (100%) of 23; fever and lymphadenopathy were less common (six [26%] and three [13%] of 23, respectively). Most paediatric complications (12 [60%] of 20) arose from secondary bacterial infections. The pooled paediatric case fatality ratio was 11% (95% CI 4-20), I
    Interpretation: Our review highlights critical knowledge gaps in the epidemiology, prevention, and treatment of mpox in children and pregnant individuals, especially those residing in endemic countries. Increased funding, international collaboration, and equitable research is needed to inform mpox control strategies tailored for at-risk communities in endemic countries.
    Funding: None.
    Translations: For the French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.
    MeSH term(s) Female ; Pregnancy ; Child ; Humans ; Mpox (monkeypox) ; Family ; Exanthema ; Lymphadenopathy ; Vaccines
    Chemical Substances Vaccines
    Language English
    Publishing date 2024-02-21
    Publishing country England
    Document type Meta-Analysis ; Systematic Review ; Journal Article
    ZDB-ID 2723488-5
    ISSN 2214-109X ; 2214-109X
    ISSN (online) 2214-109X
    ISSN 2214-109X
    DOI 10.1016/S2214-109X(23)00607-1
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  2. Article ; Online: Community transmission of monkeypox in the United Kingdom, April to May 2022.

    Vivancos, Roberto / Anderson, Charlotte / Blomquist, Paula / Balasegaram, Sooria / Bell, Anita / Bishop, Louise / Brown, Colin S / Chow, Yimmy / Edeghere, Obaghe / Florence, Isaac / Logan, Sarah / Manley, Petra / Crowe, William / McAuley, Andrew / Shankar, Ananda Giri / Mora-Peris, Borja / Paranthaman, Karthik / Prochazka, Mateo / Ryan, Cian /
    Simons, David / Vipond, Richard / Byers, Chloe / Watkins, Nicholas A / Welfare, Will / Whittaker, Elizabeth / Dewsnap, Claire / Wilson, Allegra / Young, Yvonne / Chand, Meera / Riley, Steven / Hopkins, Susan

    Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin

    2022  Volume 27, Issue 22

    Abstract: Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, ... ...

    Abstract Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.
    MeSH term(s) Female ; Homosexuality, Male ; Humans ; Male ; Mpox (monkeypox)/diagnosis ; Mpox (monkeypox)/epidemiology ; Mpox (monkeypox)/transmission ; Monkeypox virus/genetics ; Sexual and Gender Minorities ; United Kingdom/epidemiology
    Language English
    Publishing date 2022-05-27
    Publishing country Sweden
    Document type Journal Article
    ZDB-ID 1338803-4
    ISSN 1560-7917 ; 1025-496X
    ISSN (online) 1560-7917
    ISSN 1025-496X
    DOI 10.2807/1560-7917.ES.2022.27.22.2200422
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  3. Article ; Online: Frequent and Persistent PLCG1 Mutations in Sézary Cells Directly Enhance PLCγ1 Activity and Stimulate NFκB, AP-1, and NFAT Signaling.

    Patel, Varsha M / Flanagan, Charlotte E / Martins, Marta / Jones, Christine L / Butler, Rosie M / Woollard, Wesley J / Bakr, Farrah S / Yoxall, Antoinette / Begum, Nelema / Katan, Matilda / Whittaker, Sean J / Mitchell, Tracey J

    The Journal of investigative dermatology

    2019  Volume 140, Issue 2, Page(s) 380–389.e4

    Abstract: Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel ...

    Abstract Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1.
    MeSH term(s) Animals ; COS Cells ; Chlorocebus aethiops ; Gain of Function Mutation ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; INDEL Mutation ; Jurkat Cells ; Models, Molecular ; Mutagenesis, Site-Directed ; NF-kappa B/metabolism ; NFATC Transcription Factors/metabolism ; Phospholipase C gamma/genetics ; Phosphorylation/genetics ; Protein Domains/genetics ; Sezary Syndrome/genetics ; Sezary Syndrome/pathology ; Signal Transduction/genetics ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Transcription Factor AP-1/metabolism
    Chemical Substances NF-kappa B ; NFATC Transcription Factors ; Transcription Factor AP-1 ; PLCG1 protein, human (EC 3.1.4.11) ; Phospholipase C gamma (EC 3.1.4.3)
    Language English
    Publishing date 2019-07-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2019.07.693
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  4. Article ; Online: Genomic investigations of unexplained acute hepatitis in children.

    Morfopoulou, Sofia / Buddle, Sarah / Torres Montaguth, Oscar Enrique / Atkinson, Laura / Guerra-Assunção, José Afonso / Moradi Marjaneh, Mahdi / Zennezini Chiozzi, Riccardo / Storey, Nathaniel / Campos, Luis / Hutchinson, J Ciaran / Counsell, John R / Pollara, Gabriele / Roy, Sunando / Venturini, Cristina / Antinao Diaz, Juan F / Siam, Ala'a / Tappouni, Luke J / Asgarian, Zeinab / Ng, Joanne /
    Hanlon, Killian S / Lennon, Alexander / McArdle, Andrew / Czap, Agata / Rosenheim, Joshua / Andrade, Catarina / Anderson, Glenn / Lee, Jack C D / Williams, Rachel / Williams, Charlotte A / Tutill, Helena / Bayzid, Nadua / Martin Bernal, Luz Marina / Macpherson, Hannah / Montgomery, Kylie-Ann / Moore, Catherine / Templeton, Kate / Neill, Claire / Holden, Matt / Gunson, Rory / Shepherd, Samantha J / Shah, Priyen / Cooray, Samantha / Voice, Marie / Steele, Michael / Fink, Colin / Whittaker, Thomas E / Santilli, Giorgia / Gissen, Paul / Kaufer, Benedikt B / Reich, Jana / Andreani, Julien / Simmonds, Peter / Alrabiah, Dimah K / Castellano, Sergi / Chikowore, Primrose / Odam, Miranda / Rampling, Tommy / Houlihan, Catherine / Hoschler, Katja / Talts, Tiina / Celma, Cristina / Gonzalez, Suam / Gallagher, Eileen / Simmons, Ruth / Watson, Conall / Mandal, Sema / Zambon, Maria / Chand, Meera / Hatcher, James / De, Surjo / Baillie, Kenneth / Semple, Malcolm Gracie / Martin, Joanne / Ushiro-Lumb, Ines / Noursadeghi, Mahdad / Deheragoda, Maesha / Hadzic, Nedim / Grammatikopoulos, Tassos / Brown, Rachel / Kelgeri, Chayarani / Thalassinos, Konstantinos / Waddington, Simon N / Jacques, Thomas S / Thomson, Emma / Levin, Michael / Brown, Julianne R / Breuer, Judith

    Nature

    2023  Volume 617, Issue 7961, Page(s) 564–573

    Abstract: Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the ... ...

    Abstract Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK
    MeSH term(s) Child ; Humans ; Acute Disease/epidemiology ; Adenovirus Infections, Human/epidemiology ; Adenovirus Infections, Human/immunology ; Adenovirus Infections, Human/virology ; B-Lymphocytes/immunology ; Gene Expression Profiling ; Genomics ; Hepatitis/epidemiology ; Hepatitis/immunology ; Hepatitis/virology ; Immunohistochemistry ; Liver/immunology ; Liver/virology ; Proteomics ; T-Lymphocytes/immunology
    Language English
    Publishing date 2023-03-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06003-w
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  5. Article ; Online: Forecasting stroke-like episodes and outcomes in mitochondrial disease.

    Ng, Yi Shiau / Lax, Nichola Z / Blain, Alasdair P / Erskine, Daniel / Baker, Mark R / Polvikoski, Tuomo / Thomas, Rhys H / Morris, Christopher M / Lai, Ming / Whittaker, Roger G / Gebbels, Alasdair / Winder, Amy / Hall, Julie / Feeney, Catherine / Farrugia, Maria Elena / Hirst, Claire / Roberts, Mark / Lawthom, Charlotte / Chrysostomou, Alexia /
    Murphy, Kevin / Baird, Tracey / Maddison, Paul / Duncan, Callum / Poulton, Joanna / Nesbitt, Victoria / Hanna, Michael G / Pitceathly, Robert D S / Taylor, Robert W / Blakely, Emma L / Schaefer, Andrew M / Turnbull, Doug M / McFarland, Robert / Gorman, Gráinne S

    Brain : a journal of neurology

    2021  Volume 145, Issue 2, Page(s) 542–554

    Abstract: In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. ... ...

    Abstract In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.
    MeSH term(s) Adult ; DNA, Mitochondrial/genetics ; Humans ; MELAS Syndrome/genetics ; Mitochondrial Diseases/complications ; Mitochondrial Diseases/genetics ; Mutation ; Retrospective Studies ; Stroke/diagnostic imaging ; Stroke/genetics
    Chemical Substances DNA, Mitochondrial
    Language English
    Publishing date 2021-12-17
    Publishing country England
    Document type Journal Article ; Multicenter Study ; Observational Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab353
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  6. Article ; Online: Diffusion-weighted MR imaging of female pelvic tumors: a pictorial review.

    Whittaker, Charlotte S / Coady, Andy / Culver, Linda / Rustin, Gordon / Padwick, Malcolm / Padhani, Anwar R

    Radiographics : a review publication of the Radiological Society of North America, Inc

    2009  Volume 29, Issue 3, Page(s) 759–74; discussion 774–8

    Abstract: Functional imaging is becoming increasingly important in the evaluation of cancer patients because of the limitations of morphologic imaging, particularly in the assessment of response to therapy. Diffusion-weighted magnetic resonance (MR) imaging has ... ...

    Abstract Functional imaging is becoming increasingly important in the evaluation of cancer patients because of the limitations of morphologic imaging, particularly in the assessment of response to therapy. Diffusion-weighted magnetic resonance (MR) imaging has been established as a useful functional imaging tool in neurologic applications for a number of years, but recent technical advances now allow its use in abdominal and pelvic applications. Diffusion-weighted MR imaging studies of female pelvic tumors have shown reduced apparent diffusion coefficient (ADC) values within cervical and endometrial tumors. In addition, this unique noninvasive modality has demonstrated the capacity to help discriminate between benign and malignant uterine lesions and to help assess the extent of peritoneal spread from gynecologic malignancies. Potential pitfalls can be avoided by reviewing diffusion-weighted MR imaging findings in conjunction with anatomic imaging findings. Increasing familiarity with ADC calculation and manipulation software will allow radiologists to provide new information for the care of patients with known or suspected gynecologic malignancies.
    MeSH term(s) Aged ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Endometrial Neoplasms/pathology ; Female ; Genital Neoplasms, Female/pathology ; Humans ; Leiomyoma/pathology ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; Pelvic Neoplasms/pathology
    Language English
    Publishing date 2009-05
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 603172-9
    ISSN 1527-1323 ; 0271-5333
    ISSN (online) 1527-1323
    ISSN 0271-5333
    DOI 10.1148/rg.293085130
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  7. Article ; Online: Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance.

    Butler, Rosie M / McKenzie, Robert C / Jones, Christine L / Flanagan, Charlotte E / Woollard, Wesley J / Demontis, Maria / Ferreira, Silvia / Tosi, Isabella / John, Susan / Whittaker, Sean J / Mitchell, Tracey J

    The Journal of investigative dermatology

    2019  Volume 139, Issue 9, Page(s) 1975–1984.e2

    Abstract: FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sézary syndrome. This ... ...

    Abstract FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sézary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Sézary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P ≤ 0.01) of SS patients, associated with reduced mRNA expression (P = 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Sézary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 co-expression in primary Sézary cells was detected. Critically, Sézary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P ≤ 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients.
    MeSH term(s) Apoptosis/drug effects ; Apoptosis/genetics ; CD4-Positive T-Lymphocytes ; DNA Copy Number Variations ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Depsipeptides/pharmacology ; Depsipeptides/therapeutic use ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Neoplastic Cells, Circulating ; Phosphorylation/drug effects ; Polymorphism, Single Nucleotide ; Primary Cell Culture ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Sezary Syndrome/blood ; Sezary Syndrome/drug therapy ; Sezary Syndrome/genetics ; Sezary Syndrome/pathology ; Skin/cytology ; Skin/pathology ; Skin Neoplasms/blood ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Tumor Cells, Cultured ; Tyrosine/metabolism
    Chemical Substances DNA-Binding Proteins ; Depsipeptides ; Histone Deacetylase Inhibitors ; RAD23B protein, human ; STAT3 Transcription Factor ; STAT3 protein, human ; Tyrosine (42HK56048U) ; romidepsin (CX3T89XQBK) ; DNA Repair Enzymes (EC 6.5.1.-)
    Language English
    Publishing date 2019-03-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2019.03.1130
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  8. Article: Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus.

    Houldcroft, Charlotte J / Bryant, Josephine M / Depledge, Daniel P / Margetts, Ben K / Simmonds, Jacob / Nicolaou, Stephanos / Tutill, Helena J / Williams, Rachel / Worth, Austen J J / Marks, Stephen D / Veys, Paul / Whittaker, Elizabeth / Breuer, Judith

    Frontiers in microbiology

    2016  Volume 7, Page(s) 1317

    Abstract: Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV ...

    Abstract Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.
    Language English
    Publishing date 2016-09-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2016.01317
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  9. Article ; Online: Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome.

    Woollard, Wesley J / Pullabhatla, Venu / Lorenc, Anna / Patel, Varsha M / Butler, Rosie M / Bayega, Anthony / Begum, Nelema / Bakr, Farrah / Dedhia, Kiran / Fisher, Joshua / Aguilar-Duran, Silvia / Flanagan, Charlotte / Ghasemi, Aria A / Hoffmann, Ricarda M / Castillo-Mosquera, Nubia / Nuttall, Elisabeth A / Paul, Arisa / Roberts, Ceri A / Solomonidis, Emmanouil G /
    Tarrant, Rebecca / Yoxall, Antoinette / Beyers, Carl Z / Ferreira, Silvia / Tosi, Isabella / Simpson, Michael A / de Rinaldis, Emanuele / Mitchell, Tracey J / Whittaker, Sean J

    Blood

    2016  Volume 127, Issue 26, Page(s) 3387–3397

    Abstract: Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor ... ...

    Abstract Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.
    MeSH term(s) Cell Survival/genetics ; DNA Repair ; Epigenesis, Genetic ; Female ; Gene Expression Regulation, Neoplastic ; Genome, Human ; Genomic Instability ; Humans ; Male ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Sezary Syndrome/genetics ; Sezary Syndrome/metabolism ; Signal Transduction/genetics
    Chemical Substances Neoplasm Proteins
    Language English
    Publishing date 2016-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2016-02-699843
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  10. Article ; Online: SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

    Dejnirattisai, Wanwisa / Huo, Jiandong / Zhou, Daming / Zahradník, Jiří / Supasa, Piyada / Liu, Chang / Duyvesteyn, Helen M.E. / Ginn, Helen M. / Mentzer, Alexander J. / Tuekprakhon, Aekkachai / Nutalai, Rungtiwa / Wang, Beibei / Dijokaite, Aiste / Khan, Suman / Avinoam, Ori / Bahar, Mohammad / Skelly, Donal / Adele, Sandra / Johnson, Sile Ann /
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    Cell. 2022 Feb. 03, v. 185, no. 3 p.467-484.e15

    2022  

    Abstract: ... announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization ... of potent monoclonal antibodies and antibodies under commercial development. Omicron S has ...

    Institution OPTIC Consortium
    ISARIC4C Consortium
    Abstract On 24ᵗʰ November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.
    Keywords Severe acute respiratory syndrome coronavirus 2 ; evolution ; neutralization ; pandemic ; vaccines ; SARS-CoV-2 ; Omicron ; variants ; immune evasion ; receptor interaction ; Spike ; RBD
    Language English
    Dates of publication 2022-0203
    Size p. 467-484.e15.
    Publishing place Elsevier Inc.
    Document type Article ; Online
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2021.12.046
    Database NAL-Catalogue (AGRICOLA)

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