Human Genome Sciences Research Articles

Machine Learning of Three-Dimensional Protein Structures to Predict the Functional Impacts of Genome Variation.

Research in the human genome sciences generates a substantial amount of genetic data for hundreds of thousands of individuals, which concomitantly increases the number of variants of unknown significance (VUS). Bioinformatic analyses can successfully reveal rare variants and variants with clear associations with disease-related phenotypes. These studies have had a significant impact on how clinical genetic screens are interpreted and how patients are stratified for treatment. There are few, if any, computational methods for variants comparable to biological activity predictions. To address this gap, we developed a machine learning method that uses protein three-dimensional structures from AlphaFold to predict how a variant will influence changes to a gene's downstream biological pathways. We trained state-of-the-art machine learning classifiers to predict which protein regions will most likely impact transcriptional activities of two proto-oncogenes, nuclear factor erythroid 2 (NFE2L2)-related factor 2 (NRF2) and c-Myc. We have identified classifiers that attain accuracies higher than 80%, which have allowed us to identify a set of key protein regions that lead to significant perturbations in c-Myc or NRF2 transcriptional pathway activities.

P171 Efficacy and safety of upadacitinib in patients with active PsA and inadequate response to biologic DMARDs (SELECT-PsA-2): a double-blind, randomised controlled Phase III trial

P171 Efficacy and safety of upadacitinib in patients with active PsA and inadequate response to biologic DMARDs (SELECT-PsA-2): a double-blind, randomised controlled Phase III trial

Precisely, with William Haseltine, Ph.D.: COVID Control American Style

Clinical OMICsVol. 8, No. 1 Precisely, with William Haseltine, Ph.D.Precisely, with William Haseltine, Ph.D.: COVID Control American StyleWilliam HaseltineWilliam HaseltineWilliam A. Haseltine, Ph.D., is known for his pioneering work on cancer, HIV/AIDS, and genomics. He was a professor at Harvard Medical School, the Harvard School of Public Health and founder of its Division of Biochemical Pharmacology and Division of Human Retrovirology. He has founded twelve biotechnology companies, including Human Genome Sciences, and is the author of several books, including his recently released autobiography My Lifelong Fight Against Disease: From Polio and AIDS to COVID-19.Search for more papers by this authorPublished Online:11 Feb 2021https://doi.org/10.1089/clinomi.08.01.31AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 8Issue 1Jan 2021 InformationCopyright © GEN PublishingTo cite this article:William Haseltine.Precisely, with William Haseltine, Ph.D.: COVID Control American Style.Clinical OMICs.Jan 2021.46-48.http://doi.org/10.1089/clinomi.08.01.31Published in Volume: 8 Issue 1: February 11, 2021PDF download

Big data market analysis of e-health in medical neuroscience

Depression is associated with more than 100,000 patent applications for its diagnosis and prognosis, the highest number among mental disorders. This is followed by schizophrenia with 47,000, bipolar disorder with 32,110 and hypomania with 11,377. Among diagnostic tools, magnetic resonance imaging is associated with more than 31,000 patent applications. Among recent technologies, biomarkers are associated with more than 12,000 epigenetics with about 970 metabolomics with 515 genome-wide association study (GWAS) with 486 and bionics with 497 patent applications. The patent applications related to diagnosis and prognosis of psychiatric diseases peaked in 2008 and was overall decreasing until 2016, with a local peak in 2013. This trend has been observed despite the value addition of recent technologies like machine learning, big data and internet of things. However, more conservative diagnostic tools from the last decade like magnetic resonance imaging, epigenetics, bionics and neuro-psychological testing are improved by the recent technologies. For example, bionics is improved by sensors of internet of things to collect the data from patients around the world and use the big data analytics to efficiently diagnose the psychiatric diseases. The Regents of the University of California and Human Genome Sciences Incorporation are the respective academic and non-academic institutions leading the innovations related to diagnosis and prognosis of psychiatric diseases.Disclosure of interestThe authors declare that they have no competing interest.

Abstract functional combinations after Actavis: what future?

In a series of decisions concerning the complex issues arising in relation to supplementary protection certificates, the Court of Justice of the European Union (CJEU) recently behaved like Dr. Jekyll and Mr. Hyde, providing a well reasoned and impressively lucid decision in Neurim Pharmaceuticals (1991) Ltd v Comptroller-General of Patents,1 followed by three confusing decisions in Actavis Group PTC EHF e Actavis UK Ltd v Sanofi2 (Actavis), Georgetown University v Octrooicentrum Nederlandand3 (Georgetown II), and Eli Lilly and Company Ltd v Human Genome Sciences Inc.4 This article examines the Actavis decision and its practical consequences.

Sarilumab for the treatment of rheumatoid arthritis.

Simon Cooper has >18 years of global experience in the pharmaceutical industry. He joined Sanofi in July 2014 as the Vice President, Global Project Head. In his current position at Sanofi, Dr Cooper is responsible for the clinical development of sarilumab and the worldwide submission in rheumatoid arthritis. He joined Sanofi after serving as the Global Program Medical Director at Novartis since 2012. In this role, Dr Cooper acted as the clinical lead for secukinumab psoriasis submission. Prior to Novartis, Dr Cooper held various posts at Human Genome Sciences, USA, including Executive Director of Clinical Research, Senior Director of Clinical Research and Director of Clinical Research. During his tenure at Human Genome Sciences, USA, Dr Cooper was involved in the submission of belimumab leading to its approval for SLE, and was responsible for its subsequent clinical development program. Dr Cooper has also previously held positions at MedImmune Ltd, UK, Roche, Napp Pharmaceutical Research Ltd, Wyeth Research and Medeval Ltd. In these roles, his responsibilities ranged from medical oversight of clinical trials to medical support for commercial, medical affairs and business development. He received a Bachelor of Medicine and Bachelor of Surgery from University of Newcastle upon Tyne Medical School.

Abstract LB-113: A novel role of Withaferin A as an effective pro-apoptotic receptor agonist (PARA) and insights into the underlying molecular mechanisms

Abstract Introduction: Despite significant progress towards screening efforts and targeted therapies, breast cancer is still a leading cause of cancer-related mortality among women. Novel therapeutic strategies are clearly needed for effective targeting of breast cancer. Natural products continue to generate interest for identification of potential chemopreventive and therapeutic agents. Withaferin A (WFA) is a bioactive small molecule that has been proposed as a new-generation molecule capable of eliciting growth inhibitory effect on cancer cells. The molecular mechanisms by which WFA mediates inhibition of breast cancer remain elusive. The present study was designed to systematically elucidate the underlying mechanisms by which WFA inhibits growth and metastatic potential of breast cancer cells. Results: Because many cellular signaling events involve induced-phosphorylation of key targets, in the present study we utilized phosphokinase arrays to gain insight into the intricacies of WFA-mediated signaling networks and discovered that WFA induces RSK phosphorylation in breast cancer cells. Further analysis revealed an integral role of ERK in WFA-mediated RSK activation and WFA-induced ERK/RSK signaling resulted in concomitant upregulation and activation of Elk1(ETS-like transcription factor-1) and CHOP (C-EBP homology protein) leading to transcriptional upregulation of Death Receptor protein-5 (DR5). It is interesting to note that in recent years, many phase 1 and 2 single agent and combination clinical trials have been conducted to examine the efficacy and safety of recombinant human TRAIL (dulanermin, (Amgen/Genentech)), and the agonistic monoclonal antibodies to DR5 (lexatumumab (Human Genome Sciences), conatumumab (Amgen), drozitumab (Genentech), tigatuzumab (Daiichi-Sankyo) and LBY135 (Novartis)). Studies with these pro-apoptotic receptor agonists (PARAs) have been encouraging but no full phase 3 studies have been performed suggesting the need for novel PARAs with improved properties. Here, we show that WFA is more effective than three other known DR5 activators, TRAIL, etoposide and celecoxib, in activation of DR5 in breast cancer cells hence, appears to be a good candidate for further development as an effective DR5 inducer. WFA treatment effectively inhibited breast tumorigenesis in vivo and analysis of WFA-treated xenografts and MMTV-neu mice tumors showed increased activation of ERK/RSK axis and DR5 along with elevated nuclear accumulation of Elk1 and CHOP. Conclusion: These data provided first in vitro and in vivo evidence of the integral role of a previously unrecognized crosstalk between WFA and ERK/RSK and CHOP/Elk1 axes in breast tumor growth inhibition. Also, our findings may potentially open new avenues of research on the role of withaferin A as a novel pro-apoptotic receptor agonist (PARA). Citation Format: Arumugam Nagalingam, Panjamurthy Kuppusamy, Neeraj Saxena, Dipali Sharma. A novel role of Withaferin A as an effective pro-apoptotic receptor agonist (PARA) and insights into the underlying molecular mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-113. doi:10.1158/1538-7445.AM2014-LB-113

SAT0195 Impact of mycophenolate mofetil and/or corticosteroid treatment on outcomes of belimumab treatment in SLE

BackgroundCorticosteroids, antimalarials, and immunossuppressants, including mycophenolate mofetil (MMF), were permitted as background standard therapy in patients participating in the belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) SLE phase 3 trials. Belimumab...

SAT0204 Predictors for SLE flares: Baseline disease activity and demographic characteristics from the bliss trials’ combined placebo groups

BackgroundPredicting which SLE patients are at increased risk for clinically meaningful flares may be useful in making management decisions.ObjectivesTo identify demographic and disease-related predictors for flares.MethodsBaseline demographic and SLE-related disease...

SAT0197 Baseline laboratory characteristics from the combined placebo groups in the bliss trials are predictive of severe flare at 24 weeks

BackgroundIdentification and validation of potential serologic biomarkers of clinically meaningful SLE flare are major unmet medical needs in clinical practice and trials.ObjectivesTo examine biomarker predictors of SLE flares at baseline...

SAT0188 Early clinical improvement in SLE patients treated with belimumab

BackgroundThe belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) SLE trials utilized the SLE Responder Index (SRI) as the primary efficacy endpoint at wk 52. Increases in corticosteroid doses were allowed through...

FRI0132 Insulin resistance is improved by tocilizumab therapy in rheumatoid arthritis: results from the toward study

BackgroundInsulin resistance is increased in rheumatoid arthritis (RA). Reductions in inflammation, glucocorticoid therapy and disease-modifying anti-rheumatic drugs (DMARDs) have been associated with improvement in insulin resistance in patients with RA.ObjectivesTo...

SAT0458 Vasculitis care in the UK: How do patients perceive the care provided and what should the future hold?

BackgroundPrimary Systemic Vasculitis (PSV) is a group of life-threatening auto-immune multi-system disorders. The British Society for Rheumatology recommends that these patients are referred to a consultant with a special interest...

SAT0448 Clinical outcomes and healthcare utilization following early versus late diagnosis of systemic lupus

BackgroundSystemic lupus erythematosus (SLE) has a broad spectrum of clinical manifestations and laboratory abnormalities, posing formidable diagnostic challenges.ObjectivesTo compare clinical outcomes and healthcare resource utilization between patients (pts) with SLE...

Developing an appropriately supported CME-accredited programme in Europe

Objectives: The Lupus Academy was established as an independent, consortium-led continuing medical education (CME) initiative for physicians interested in the pathogenesis, diagnosis and management of patients with systemic lupus erythematosus (SLE) and related conditions, based on identification of an unmet clinical need. The Lupus Academy is intended to be a long-term enterprise that is committed to sharing best practice in the field of lupus. Challenge: European CME remains in its infancy and many regulatory aspects are yet to be finalised. Pharmaceutical company supporters must be willing to adopt an ‘arms length’ approach to funding to ensure that educational programmes are truly independent, whilst funding must be spent in an appropriate and ethical manner by education providers. This review manuscript describes the innovative approach of the Lupus Academy within the global CME environment; illustrates the interactions between pharmaceutical supporters, clinicians, education providers and support organisations, in adherence to international guidance; and shows how a pharmaceutical company can support a CME activity whilst satisfying the external regulatory environment. Project structure: The Lupus Academy was created by a Steering Committee of six international experts with funding from GlaxoSmithKline and Human Genome Sciences and support from three organisations to facilitate the delivery of logistics, medical education materials, and CME compliance and financial management. Together, these groups formed a Consortium in which all parties took equal and collective responsibility for the success of the programme, from content development to regulatory compliance, CME adherence and financial management. How and where the meeting took place: The Inaugural Meeting of the Lupus Academy took place in Barcelona, Catalonia, Spain in 2012. Programme content and learning objectives for the 1.5-day meeting were developed by a Steering Committee based on clinical training needs and advances in lupus, and the 17-strong expert faculty was selected by the Steering Committee. The Consortium worked with national and international lupus organisations to identify appropriate clinicians to attend the meeting; a broad range of delegates were attracted to the meeting from across a wide range of disciplines, including rheumatology, nephrology, dermatology, clinical immunology and internal medicine. Outcomes and results: The Inaugural Meeting included plenary sessions and interactive workshops with keypad voting to promote interactivity and delegate participation. The meeting was attended by 296 delegates from 30 countries across Europe, the Americas and the Asia Pacific region. Most delegates rated the educational content, meeting objectives and logistics of the meeting highly. Almost all delegates stated a preference for independent educational initiatives compared with pharmaceutical-controlled events and most delegates considered the absence of commercial bias to be important. Many of the delegates indicated that they would change their clinical practice based on what they learnt from the meeting. Conclusions and future objectives: The Inaugural Meeting of the Lupus Academy was considered a success by the Consortium members and financial supporters. The overall approach to the initiative, including the structure of the Consortium, the independence of the high-quality educational programme, the financial management and CME accreditation, was considered the key to its success. This long-term enterprise will continue as an annual event, with interactive workshops forming a greater part of future programmes to allow delegates to share clinical experiences. The second Annual Meeting of the Academy took place in Buenos Aires, Argentina in April 2013, the third is being planned for Berlin, Germany in March 2014. Keywords: Continuing medical education; CME; Lupus; Outcomes; Pharmaceutical; Sponsor (Published: 19 August 2013) DOI: 10.3109/21614083.2013.831242

Breaking the ice in systemic lupus erythematosus: belimumab, a promising new therapy

B lymphocyte stimulator (BLyS), a protein discovered in the 1990s that induces B cell proliferation and differentiation, promotes B cell survival, and is important in immunoglobulin class switching, was the target of a drug development program launched by Human Genome Sciences in the early part of the last decade. Belimumab, a human monoclonal antibody specific for soluble BLyS, was ultimately approved by the United States Food and Drug Administration (FDA) in March 2011 for active autoantibody patients with systemic lupus erythematosus (SLE) despite standard therapy. This program, whose studies spanned approximately 10 years from phase I through phase III, was founded on sound biology and advanced on logic and perseverance. Pre-clinical experimentation in murine models of SLE as well as observational studies in human SLE provided sufficient evidence to support the use of an inhibitor of BLyS as a novel therapy to reduce SLE disease activity. Progressing from phase I through a robust phase III program was no easy task given the complexities of SLE trial design. These challenges were overcome with the implementation of strict study entry requirements, the development of a novel responder index, and rigorous rules regarding background therapies. The success of two phase III studies and the approval of belimumab by the US Food and Drug Administration represent an unprecedented milestone in the history of SLE drug development. Belimumab was the first drug approved in SLE in over 50 years and was the first drug ever approved in SLE through the conventional route of randomized controlled trials. This article reviews the biology of BLyS, clinical trial results, and some of the emerging data from the robust phase II and III datasets.

Developing an appropriately supported CME-accredited programme in Europe

Objectives: The Lupus Academy was established as an independent, consortium-led continuing medical education (CME) initiative for physicians interested in the pathogenesis, diagnosis and management of patients with systemic lupus erythematosus (SLE) and related conditions, based on identification of an unmet clinical need. The Lupus Academy is intended to be a long-term enterprise that is committed to sharing best practice in the field of lupus. Challenge: European CME remains in its infancy and many regulatory aspects are yet to be finalised. Pharmaceutical company supporters must be willing to adopt an ‘arms length’ approach to funding to ensure that educational programmes are truly independent, whilst funding must be spent in an appropriate and ethical manner by education providers. This review manuscript describes the innovative approach of the Lupus Academy within the global CME environment; illustrates the interactions between pharmaceutical supporters, clinicians, education providers and support organisations, in adherence to international guidance; and shows how a pharmaceutical company can support a CME activity whilst satisfying the external regulatory environment. Project structure: The Lupus Academy was created by a Steering Committee of six international experts with funding from GlaxoSmithKline and Human Genome Sciences and support from three organisations to facilitate the delivery of logistics, medical education materials, and CME compliance and financial management. Together, these groups formed a Consortium in which all parties took equal and collective responsibility for the success of the programme, from content development to regulatory compliance, CME adherence and financial management. How and where the meeting took place: The Inaugural Meeting of the Lupus Academy took place in Barcelona, Catalonia, Spain in 2012. Programme content and learning objectives for the 1.5-day meeting were developed by a Steering Committee based on clinical training needs and advances in lupus, and the 17-strong expert faculty was selected by the Steering Committee. The Consortium worked with national and international lupus organisations to identify appropriate clinicians to attend the meeting; a broad range of delegates were attracted to the meeting from across a wide range of disciplines, including rheumatology, nephrology, dermatology, clinical immunology and internal medicine. Outcomes and results: The Inaugural Meeting included plenary sessions and interactive workshops with keypad voting to promote interactivity and delegate participation. The meeting was attended by 296 delegates from 30 countries across Europe, the Americas and the Asia Pacific region. Most delegates rated the educational content, meeting objectives and logistics of the meeting highly. Almost all delegates stated a preference for independent educational initiatives compared with pharmaceutical-controlled events and most delegates considered the absence of commercial bias to be important. Many of the delegates indicated that they would change their clinical practice based on what they learnt from the meeting. Conclusions and future objectives: The Inaugural Meeting of the Lupus Academy was considered a success by the Consortium members and financial supporters. The overall approach to the initiative, including the structure of the Consortium, the independence of the high-quality educational programme, the financial management and CME accreditation, was considered the key to its success. This long-term enterprise will continue as an annual event, with interactive workshops forming a greater part of future programmes to allow delegates to share clinical experiences. The second Annual Meeting of the Academy took place in Buenos Aires, Argentina in April 2013, the third is being planned for Berlin, Germany in March 2014.

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells while leaving normal cells unharmed, making it a desirable anticancer target. In the present study, metastatic melanoma cell lines were treated with lexatumumab (Human Genome Sciences, Inc.) a high-affinity monoclonal antibody agonistic to TRAIL receptor 2 (DR5). Binding of the antibody to the receptor led to activation of the extrinsic apoptosis pathway in approximately 20% of the treated cells. However, by combining subtoxic concentrations of the protein translation inhibitor anisomycin with lexatumumab, we obtained synergistic effects on cell viability compared with single agent treatment. Even the low doses of anisomycin could inhibit protein synthesis in melanoma cells with up to 30%, which might result in the shift in the levels of the proteins involved in apoptosis. Co-treatment with anisomycin increased activation of caspases and cleavage of the anti-apoptotic protein Livin, leading to formation of truncated p30-Livin α and p28-Livin β proteins with potential pro-apoptotic functions. Furthermore, ansiomcycin treatment decreased levels of antiapototic XIAP. In summary our results suggest that combinational treatment with anicomycin and lexatumumab represents a novel therapeutic strategy in the treatment of melanoma.

Industry Update: the Latest Developments in Therapeutic Delivery

This month’s article covers the period 16 July–15 August 2012. During those 30 days, Human Genome Sciences finally agreed to accept GlaxoSmithKline plc.’s improved offer and be taken over by its long-term partner. The deal was worth approximately US$3.6 billion and represented an improvement of approximately 10% over the initial offer made by GlaxoSmithKline in April 2012. There was also the US approval of Lucentis for the treatment of Diabetic Macular Edema, the first product for this condition to be approved by the US FDA. As ever, the information was largely sourced from company press releases and websites.

Industry Update: the Latest Developments in Therapeutic Delivery

The time period 16 May–15 June 2012 included the reports of successful fundraising from Flowonix, PhaseBio and Sangart, with almost US$100 million raised. Antibody–drug conjugates (ADCs) were the subject of several announcements. Merck entered into a collaborative effort with Ambrx to develop novel ADC technology, a deal that could be worth over $300 million, should all milestones be achieved. CellDex provided preliminary results from its Phase II study of ADC CDX-011 in metastatic breast cancer. In a presentation that won top billing at the American Society for Clinical Oncology meeting, Genentech shared Phase III results from the ADC T-DM1, also in breast cancer patients. An improved median time to progression-free survival, evidence of an overall survival benefit and an improved safety profile were reported. Weekly Bydureon™, from Alkermes and Amylin, was reported to show benefits over insulin detemir in Type 2 diabetics, while its would-be competitor albiglutide, from Human Genome Sciences and GlaxoSmithKline, met a non-inferiority endpoint in comparison with insulin lispro in the same patient population. Among opioids, Nektar’s NKTR-181 was granted fast-track status by the US FDA, while Alkermes’ ALKS 37 failed to meet criteria for advancement to Phase III and was dropped.