Author
Fahd Al-Mulla
Other affiliations: University of Glasgow, Tzu Chi University, Cancer Research UK ...read more
Bio: Fahd Al-Mulla is an academic researcher from Kuwait University. The author has contributed to research in topics: Medicine & Population. The author has an hindex of 41, co-authored 269 publications receiving 8033 citations. Previous affiliations of Fahd Al-Mulla include University of Glasgow & Tzu Chi University.
Topics: Medicine, Population, Internal medicine, Inflammation, Adipose tissue
Papers published on a yearly basis
Papers
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TL;DR: The COVID Human Genetic Effort established to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance finds an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001.
Abstract: Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
1,659 citations
Imperial College London1, The Royal Marsden NHS Foundation Trust2, University of Western Australia3, Queensland University of Technology4, St. Vincent's Health System5, University of New South Wales6, Charles University in Prague7, University of Paris8, French Institute of Health and Medical Research9, Max Planck Society10, Ludwig Maximilian University of Munich11, National and Kapodistrian University of Athens12, University of Massachusetts Boston13, University of Hong Kong14, Royal College of Surgeons in Ireland15, University of Palermo16, Kanazawa University17, University of Fukui18, Tokyo Medical and Dental University19, Dokkyo Medical University20, Maastricht University21, Rikshospitalet–Radiumhospitalet22, Tan Tock Seng Hospital23, Autonomous University of Barcelona24, Linköping University25, University of Lausanne26, National Cheng Kung University27, University of Leeds28, University of Edinburgh29, University of Birmingham30, AstraZeneca31, University of Glasgow32, University of Manchester33, Cancer Research UK34, Yale University35, Brown University36, University of Pittsburgh37, Vanderbilt University38, Yeshiva University39, Military Medical Academy40
TL;DR: In this paper, the effect of the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer was investigated using a multivariate analysis.
Abstract: Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.
753 citations
Washington University in St. Louis1, Baylor College of Medicine2, Xi'an Jiaotong University3, Ontario Institute for Cancer Research4, Institute for Systems Biology5, Broad Institute6, University of Texas MD Anderson Cancer Center7, Mayo Clinic8, Kuwait University9, University of Toronto10, Princeton University11, Wake Forest University12
TL;DR: The largest investigation of predisposition variants in cancer to date finds 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types, informing future guidelines of variant classification and germline genetic testing in cancer.
543 citations
University of Queensland1, QIMR Berghofer Medical Research Institute2, Royal Melbourne Hospital3, University of Vermont4, Kuwait University5, University of Toronto6, Aalborg University7, Leiden University8, French Institute of Health and Medical Research9, University of Edinburgh10, University Hospital of Wales11, University of Rouen12, University of Utah13, Huntsman Cancer Institute14, University of Connecticut Health Center15, Ludwig Maximilian University of Munich16, Garvan Institute of Medical Research17, University of Western Sydney18, University of New South Wales19, Karolinska University Hospital20, University of Hong Kong21, Oslo University Hospital22, University of Helsinki23, University of Rochester Medical Center24, Zhejiang University25, University of Cape Town26, University of Copenhagen27, University of Düsseldorf28, University of Newcastle29, John Hunter Hospital30, University Medical Center Groningen31, State University of New York System32, Memorial University of Newfoundland33, University of Florence34
TL;DR: This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.
Abstract: The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.
407 citations
William H. Goodson1, Leroy Lowe2, David O. Carpenter3, Michael Gilbertson +177 more•Institutions (105)
TL;DR: Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer.
Abstract: Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
238 citations
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Journal Article•
28,685 citations
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
17,834 citations
TL;DR: The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for Macrophage-centered diagnostic and therapeutic strategies.
Abstract: Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
4,721 citations