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Global perspectives on cancer : incidence, care, and experience
\"Two leading oncologists, along with experts spanning several medical disciplines, shed light on the global pandemic of cancer, particularly the difference in diagnosis, treatment, and care between global communities\"--Provided by publisher.
Book
Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)
PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s).
Journal Article
استعادة التوازن : استراتيجية للشرق الأوسط برسم الرئيس الجديد
لا شك في أن الرئيس الرابع والأربعين للولايات المتحدة الأميركية سيجد في انتظاره سلسلة من التحديات الحاسمة، المعقدة والمتشابكة في الشرق الأوسط، التي تتطلب إيلاءها اهتماما عاجلا. ذلك أن النموذج الذي اعتمده جورج بدليو بوش القائم على تغيير أنظمة الحكم ونشر الديمقراطية بالقوة لم يعد يتلاءم والظروف المتغيرة التي ستواجه الإدارة الجديدة على الأرجح الحاجة ماسة إذن لأفكار جديدة، وتحليلات غير حزبية، وتوصيات حصيفة. والكتاب الذي بين أيديكم يفي بتلك الحاجة على أفضل وجه. في اتسعادة التوازن، تتضافر جهود الخبراء والمختصين بشؤون الشرق الأوسط من مجلس العلاقات الخارجية ومركز صبان لسياسة الشرق الأوسط بمعهد بروكنغز، لتطرح استراتيجية أميركية جديدة لمنظمة حيوية لكن متفجرة كالشرق الأوسط فبناء على أبحاث ميدانية معنقة، قام هؤلاء الخبراء ببلورة مجموعة من التوصيات السياسية برسم الرئيس الأميركي الجديد وقد قامت بفحصها وتمحيصها ونقدها هيئة من المختصين من كلا الحزبين يتمتعون بخبرة سياسية واسعة ومعرفة غنية بالمنطقة، هذا التمرين في تخطيط السياسات الذي استغرق سنة كاملة هو الأول من نوعه على الإطلاق، الذي يوحد جهود وقدرات العاملين في هاتين المؤسستين المحترمتين بالسياسة الخارجية لتنصب على درس وتحليل واحدة من أخطر وأهم مناطق العالم. وكل فصل من هذا الكتاب يستضيف اثنين أو أكثر من الباحثين في مجلس العلاقات الخارجية ومعهد بروكنغز لمعاينة واستعراض التحديات التي ستواجه الرئيس المقبل.
Book
Sequencing and Analysis of JC Virus DNA From Natalizumab-Treated PML Patients
Background. Progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumabtreated PML patients. Methods. Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. Results. Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VPl mutations, but VP1 mutations were not observed without NCCR rearrangement. Conclusions. These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development.
Journal Article
Progressive Multifocal Leukoencephalopathy (PML) Development Is Associated With Mutations in JC Virus Capsid Protein VP1 That Change Its Receptor Specificity
Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset. Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase. JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.
Journal Article
My week with Marilyn
In the summer of 1956, 23-year-old Colin Clark, determined to make his way in the film business, worked as a lowly assistant on the set of The Prince and the Showgirl, the film that famously united Sir Laurence Olivier and Marilyn Monroe. When his diary account was published, one week was missing. This is the story of that week: an idyll in which he escorted a Monroe desperate to get away from Hollywood hangers-on and the pressures of work.
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