Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

PP147 Olaratumab with Doxorubicin for advanced soft tissue sarcoma

Introduction: The National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaratumab (Lartruvo®), Eli Lilly & Company Limited, to submit evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the Institute's Single Technology Appraisal. The Peninsula Technology Assessment Group critically reviewed the submitted evidence. Methods: Clinical effectiveness was derived from an open-label, randomized controlled trial, JGDG. The economic analysis was based on a partitioned survival model with a time horizon of 25 years. The perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5 percent per year. The company's evidence was submitted in anticipation that olaratumab would be considered as an alternative to doxorubicin, which has been used as a first-line treatment for advanced STS. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement with the NHS England. Results: In the company's submission, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus doxorubicin alone were GBP 46,076 (USD 61,403) and GBP 47,127 (USD 62,804) per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of GBP 50,000 (USD 66,632) per QALY gained, applicable to end-of-life treatments, was 0.54. The respective estimates in our analysis were approximately GBP 60,000 (USD 79,959) per QALY gained, and the probability of cost-effectiveness was 0.21. The increase in the ICERs was primarily due to differences in extrapolation of overall survival, and drug administration costs. Conclusions: Based on the available evidence, olaratumab in combination with doxorubicin improves the survival of patients with advanced STS. However, this treatment is unlikely to be cost-effective. Olaratumab is now recommended for use within the Cancer Drugs Fund

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence▿

West Nile virus (WNV) infection causes neurological disease at all levels of the neural axis, accompanied by neuroinflammation and neuronal loss, although the underlying mechanisms remain uncertain. Given the substantial activation of neuroinflammatory pathways observed in WNV infection, we hypothesized that WNV-mediated neuroinflammation and cell death occurred through WNV infection of both glia and neurons, which was driven in part by WNV capsid protein expression. Analysis of autopsied neural tissues from humans with WNV encephalomyelitis (WNVE) revealed WNV infection of both neurons and glia. Upregulation of proinflammatory genes, CXCL10, interleukin-1β, and indolamine-2′,3′-deoxygenase with concurrent suppression of the protective astrocyte-specific endoplasmic reticulum stress sensor gene, OASIS (for old astrocyte specifically induced substance), was evident in WNVE patients compared to non-WNVE controls. These findings were supported by increased ex vivo expression of these proinflammatory genes in glia infected by WNV-NY99. WNV infection caused endoplasmic reticulum stress gene induction and apoptosis in neurons but did not affect glial viability. WNV-infected astrocytic cells secreted cytotoxic factors, which caused neuronal apoptosis. The expression of the WNV-NY99 capsid protein in neurons and glia by a Sindbis virus-derived vector (SINrep5-WNVc) caused neuronal death and the release of neurotoxic factors by infected astrocytes, coupled with proinflammatory gene induction and suppression of OASIS. Striatal implantation of SINrep5-WNVC induced neuroinflammation in rats, together with the induction of CXCL10 and diminished OASIS expression, compared to controls. Moreover, magnetic resonance neuroimaging showed edema and tissue injury in the vicinity of the SINrep5-WNVc implantation site compared to controls, which was complemented by neurobehavioral abnormalities in the SINrep5-WNVc-implanted animals. These studies underscore the important interactions between the WNV capsid protein and neuroinflammation in the pathogenesis of WNV-induced neurological disorders

Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Care Excellence Single Technology Appraisal.

The manufacturer of olaratumab (Lartruvo(®)), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were £46,076 and £47,127 per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of £50,000 per QALY gained, applicable to end-of-life treatments, was 0.54. The respective ICERs from the ERG's analysis were approximately £60,000/QALY gained, and the probability of the treatment being cost effective was 0.21. In August 2017, the NICE Appraisal Committee recommended olaratumab in combination with doxorubicin for this indication for use via the UK Cancer Drugs Fund under the agreed CAA until further evidence being collected in the ongoing phase III trial-ANNOUNCE-becomes available in December 2020