The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation.

INTRODUCTION: Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. METHODS: The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database (NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow-up), bleed site, severity, pain-score and outcome. RESULTS: Haemtrack was used by 90% of haemophilia treatment centres (HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported ≥75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. CONCLUSION: The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice.

A review of percutaneous transhepatic biliary drainage at a tertiary referral centre.

AIM: To review percutaneous biliary drainage (PBD) procedures performed in Beaumont Hospital, Dublin, Ireland, over a 6-year period, to determine the 30-day morbidity and mortality. MATERIALS AND METHODS: A total of 119 patients undergoing 193 PBD procedures were identified over a 6 year period. Of the patients, 6.7% (eight patients) had stone disease, 63% (75 patients) had a malignancy, and the remainder were diagnosed with other conditions. Standard techniques of PBD and biliary stent insertion were applied, with 73 patients (61%) having same-day procedures and all undergoing gelfoam embolisation of percutaneous tracts. All patients received intravenous prophylactic antibiotics and intravenous hydration prior to PBD. RESULTS: The technical success rate was 97%, with a mean drop of 105 mmol/l between pre- and post-procedure bilirubin. Thirty-day mortality was 10.9% (13 deaths), with major and minor morbidities of 5% (six patients) and 7.6% (nine patients), respectively. Major complications included sepsis in two patients, major haemorrhage in two patients, and renal failure in two patients. Minor complications included infection in seven patients, bile leak causing self-limiting pain in one patient, and minor haemorrhage in one patient. CONCLUSION: The study confirms that PBD and stent insertion is a safe and effective technique in Beaumont Hospital, associated with an overall acceptable morbidity and mortality comparable with other studies.

Spiral plasmonic nanoantennas as circular polarization transmission filters.

We present simulation and experimental results for easily fabricated spiral plasmonic antenna analogues providing circular polarization selectivity. One circular polarization state is concentrated and transmitted through a subwavelength aperture, while the opposite circular state is blocked. The spectral bandwidth, efficiency, and extinction ratios are tunable through geometric parameters. Integration of such structures onto a focal plane array in conjunction with linear micropolarizers enables complete Stokes vector imaging, that, until now, has been difficult to achieve. An array of these structures forms a plasmonic metamaterial that exhibits high circular dichroism.

Ultra-high extinction ratio micropolarizers using plasmonic lenses.

The design of a new type of plasmonic ultra-high extinction ratio micropolarizing transmission filter is presented along with an experimental demonstration. A pair of dielectric coated metal gratings couple incident TM polarized light into surface plasmons, which are fed into a central metal-insulator-metal (MIM) waveguide, followed by transmission through a sub-wavelength aperture. Extinction ratios exceeding 10¹¹ are predicted by finite element simulation. Good absolute agreement for both the spectral and polarization response is obtained between measurement and simulations using measured geometric parameters. The filters can be easily fabricated and sized to match the pixel pitch of current focal plane arrays.

Integration of cell cycle control with transcriptional regulation by the retinoblastoma protein.

Rapid progress in several areas of molecular biology has led to the realization that the retinoblastoma protein may play a pivotal role in the coordination between cell cycle control and regulation of gene expression. This role is a subtle one, and is important in only certain mammalian cell types. Exploring the details of these connections, and why only some cells rely on them, is already beginning to shed light on the regulation of cell multiplication.

Hybrid plasmon/dielectric waveguide for integrated silicon-on-insulator optical elements.

VLSI compatible optical waveguides on silicon are currently of particular interest in order to integrate optical elements onto silicon chips, and for possible replacements of electrical cross-chip/inter-core interconnects. Here we present simulation and experimental verification of a hybrid plasmon/dielectric, single-mode, single-polarization waveguide for silicon-on-insulator wafers. Its fabrication is compatible with VLSI processing techniques, and it possesses desirable properties such as the absence of birefringence and low sensitivity to surface roughness and metallic losses. The waveguide structure naturally forms an MOS capacitor, possibly useful for active device integration. Simulations predict very long propagation lengths of millimeter scale with micron scale confinement, or sub-micron scale confinement with propagation lengths still in excess of 100 microns. The waveguide may be tuned continuously between these states using standard VLSI processing. Extremely long propagation lengths have been simulated: one configuration presented here has a simulated propagation length of 34 cm.

Wounding and its role in RSV-mediated tumor formation.

Tumors induced in chickens by Rous sarcoma virus remain localized at the site of injection even though the animals become viremic. Tumors have now been shown to be inducible at other sites if a wound is inflicted or if the tissue is injured by administration of tumor promoters. These findings indicate that local wounding plays a role in the spread of tumorigenicity of Rous sarcoma virus.

Retinoblastoma protein and the cell cycle.

Deregulation of the cell cycle may contribute one of the primary mechanisms through which cancer arises. Eukaryotic cell division has been found to be a strictly controlled process, involving response to both positive and negative external signals and assessment of the cell's internal state. Several recent discoveries have strengthened and refined the theory that the retinoblastoma protein is involved in the decision between cell division and differentiation, and have begun to provide an outline of the nature of this involvement.

Use of intravenous immunoglobulin for the treatment of autoimmune encephalitis: audit of the NHS experience.

OBJECTIVES: The treatments of limbic and other autoimmune encephalitis include immunosuppression, symptomatic treatment, and in the case of paraneoplastic syndromes, appropriate therapy for underlying neoplasms. When immunotherapy is considered, intravenous immunoglobulin is one option for treatment, either alone or in combination with corticosteroids. To date, however, evidence for the use of intravenous immunoglobulin in this context comes from case series/expert reviews as no controlled trials have been performed. We aimed to analyse the NHS England Database of intravenous immunoglobulin usage, which was designed to log use and guide procurement, to explore usage and therapeutic effect of intravenous immunoglobulin in autoimmune encephalitis in England. DESIGN: We conducted a retrospective audit and review of the NHS England Database on intravenous immunoglobulin use. SETTING: NHS England Database of intravenous immunoglobulin use which covers secondary and tertiary care prescribing and use of intravenous immunoglobulin for all patients in hospitals in England. PARTICIPANTS: Hospital in-patients with confirmed or suspected autoimmune/limbic encephalitis between September 2010 and January 2017. RESULTS: A total of 625 patients who were 18 years of age or older were treated with intravenous immunoglobulin for autoimmune encephalitis, of whom 398 were determined as having 'highly likely' or 'definite' autoimmune/limbic encephalitis. Ninety-six percent were treated with a single course of intravenous immunoglobulin. The availability and accuracy of reporting of outcomes was very poor, with complete data only available in 27% of all cases. CONCLUSIONS: This is the first review of data from this unique national database. Whilst there was evidence for clinical improvement in many cases of patients treated with intravenous immunoglobulin, the quality of outcome data was generally inadequate. Methods to improve quality, accuracy and completeness of reporting are crucial to maximise the potential value of this resource as an auditing tool.

Interference and resonant cavity effects explain enhanced transmission through subwavelength apertures in thin metal films.

Transmission through an opaque Au film with a single subwavelength aperture centered in a smooth cavity between linear grating structures is studied experimentally and with a finite element model. The model is in good agreement with measured results and is used to investigate local field behavior. It shows that a surface plasmon polariton (SPP) is launched along the metal surface, while interference of the SPP with the incident light along with resonant cavity effects give rise to suppression and enhancement in transmission. Based on experimental and modeling results, peak location and structure of the enhancement/suppression bands are explained analytically, confirming the primary role of SPPs in enhanced transmission through small apertures in opaque metal films.

Mammalian growth-associated H1 histone kinase: a homolog of cdc2+/CDC28 protein kinases controlling mitotic entry in yeast and frog cells.

Mammalian growth-associated H1 histone kinase, an enzyme whose activity is sharply elevated at mitosis, is similar to cdc2+ protein kinase from Schizosaccharomyces pombe and CDC28 protein kinase from Saccharomyces cerevisiae with respect to immunoreactivity, molecular size, and specificity for phosphorylation sites in H1 histone. Phosphorylation of specific growth-associated sites in H1 histone is catalyzed by yeast cdc2+/CDC28 kinase, as shown by the in vitro thermal lability of this activity in extracts prepared from temperature-sensitive mutants. In addition, highly purified Xenopus maturation-promoting factor catalyzes phosphorylation of the same sites in H1 as do the mammalian and yeast kinases. The data indicate that growth-associated H1 kinase is encoded by a mammalian homolog of cdc2+/CDC28 protein kinase, which controls entry into mitosis in yeast and frog cells. Since H1 histone is known to be an in vivo substrate of the mammalian kinase, this suggests that phosphorylation of H1 histone or an H1 histone counterpart is an important component of the mechanism for entry of cells into mitosis.

Survey of distribution of seasonal influenza vaccine doses in 201 countries (2004-2015): The 2003 World Health Assembly resolution on seasonal influenza vaccination coverage and the 2009 influenza pandemic have had very little impact on improving influenza control and pandemic preparedness.

There is no global monitoring system for influenza vaccination coverage, making it difficult to assess progress towards the 2003 World Health Assembly (WHA) vaccination coverage target. In 2008, the IFPMA Influenza Vaccine Supply International Task Force (IVS) developed a survey method to assess the global distribution of influenza vaccine doses as a proxy for vaccination coverage rates. The latest dose distribution data for 2014 and 2015 was used to update previous analyses. Data were confidentially collected and aggregated by the IFPMA Secretariat, and combined with previous IFPMA IVS survey data (2004-2013). Data were available from 201 countries over the 2004-2015 period. A "hurdle" rate was defined as the number of doses required to reach 15.9% of the population in 2008. Overall, the number of distributed doses progressively increased between 2004 and 2011, driven by a 150% increase in AMRO, then plateaued. One percent fewer doses were distributed in 2015 than in 2011. Twenty-three countries were above the hurdle rate in 2015, compared to 15 in 2004, but distribution was highly uneven in and across all WHO regions. Three WHO regions (AMRO, EURO and WPRO) accounted for about 95% of doses distributed. But in EURO and WPRO, distribution rates in 2015 were only marginally higher than in 2004, and in EURO there was an overall downward trend in dose distribution. The vast majority of countries cannot meet the 2003WHA coverage targets and are inadequately prepared for a global influenza pandemic. With only 5% of influenza vaccine doses being distributed to 50% of the world's population, there is urgency to redress the gross inequities in disease prevention and in pandemic preparedness. The 2003WHA resolution must be reviewed and revised and a call issued for the renewed commitment of Member States to influenza vaccination coverage targets.

Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies.

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.

Tumor suppressor genes: new prospects for cancer research.

Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. Until recently, the only tumorigenic mutations that have been studied in detail are those that activate oncogenes. The discovery of tumor suppressor genes, for which inactivating mutations elicit tumorigenesis, has added a new dimension to our understanding of neoplasia. The retinoblastoma susceptibility gene RB is the prototype tumor suppressor gene and has been shown to suppress the transformed phenotype for several different cancers. Additional studies have revealed other tumor suppressor genes that may operate in a variety of tissues through a variety of mechanisms. These mechanisms may regulate the choice between cellular proliferation and differentiation and appear to involve such processes as the initiation of DNA replication, regulation of expression of certain genes, intercellular communication and adhesion, and the transduction of external signals to intracellular effectors. The elucidation of these mechanisms will enhance our understanding of both oncogenesis and the fundamental operations of the cell.

PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas.

By a combination of cDNA library screening, rapid amplification of cDNA ends analysis, and BAC sequencing, a novel human patched-like gene (PTCH2) has been cloned and sequenced. The genomic organization is similar to PTCH1 with 22 exons and, by radiation hybrid mapping, PTCH2 has been localized to chromosome 1p33-34, a region often lost in a variety of tumors. Several alternatively spliced mRNA forms of PTCH2 were identified, including transcripts lacking segments thought to be involved in sonic hedgehog binding and mRNAs with differentially defined 3' terminal exons. In situ hybridization revealed high expression of PTCH2 transcripts in both familial and sporadic basal cell carcinomas in similarity to what has been observed for PTCH1, suggesting a negative regulation of PTCH2 by PTCH1. This finding tightly links PTCH2 with the sonic hedgehog/PTCH signaling pathway, implying that PTCH2 has related, but yet distinct, functions than PTCH1.

HER2 drives Mucin-like 1 to control proliferation in breast cancer cells.

Mucin-like 1 (MUCL1) was first identified as a breast-specific gene over a decade ago. Based on its highly restricted mRNA expression in breast tissue and continued expression during breast tumorigenesis and progression, MUCL1 is an attractive tumor-associated antigen and a potential therapeutic target. However, very little is known about the cellular location, biological functions and regulation of the MUCL1 protein, which will have a major impact on its druggability. Here we describe our efforts to fully characterize the cellular localization of MUCL1, investigate its regulation by key breast cancer oncogenes such as human epidermal growth factor receptor 2 (HER2) and discover its functional roles in breast cancer. Although some mucins are membrane bound, our data indicate that MUCL1 is secreted by some breast cancer cells, whereas others only express high levels of intracellular MUCL1. MUCL1 expression is highest in HER2-amplified breast tumors and inhibiting HER2 activity in tumor cells resulted in a decreased MUCL1 expression. In-depth investigation demonstrated that phosphoinositide3-kinase/Akt pathway, but not Ras/MEK pathway, controls MUCL1 expression downstream of HER2. Phenotypic assays revealed a strong dependence of HER2-positive cells on MUCL1 for cell proliferation. We further identified the mechanism by which MUCL1 regulates cell growth. Knockdown of MUCL1 induced a G1/S phase arrest concomitant with decreased cyclin D and increased p21 and p27 levels. Finally, we investigated the impact of MUCL1 loss on kinase signaling pathways in breast cancer cells through phospho-kinase array profiling. MUCL1 silencing abrogated phospho-focal adhesion kinase (FAK), Jun NH2-terminal kinase (JNK) and c-Jun signals, but not extracellular signal-regulated kinase or Akt pathway activities, thereby pointing to FAK/JNK pathway as the downstream effector of MUCL1 signaling. We are the first to identify an important role for MUCL1 in the proliferation of breast cancer cells, probably mediated via the FAK/JNK signaling pathway. Taken together, these data suggest a potential utility for therapeutic targeting of this protein in breast cancer.

Engineered mutants of pRB with improved growth suppression potential.

We have constructed a panel of substitution mutants which affect one or more of the putative cdk target sites of the RB protein. We have examined the activity of these mutants relative to wild-type RB by both a transcriptional repression assay and by measuring growth suppression in vitro. We find that some phosphorylation site mutants of pRB can repress E2 transcription more strongly than wild-type RB. These mutants are partially resistant to phosphorylation by cdks and can arrest tumor cells in G1 in vitro. Our results indicate a functional correlation between the ability to repress E2F-dependent transcription and the ability to suppress tumor cell growth in vitro. In addition, we describe two classes of RB mutants: N-terminal truncated p56RB and a novel mutant of RB containing multiple substitutions near its nuclear localization signal. Both classes of RB mutants have greater activity than the wild-type protein. Because RB is a key regulator of cell cycle progression, expression of a more potent, phosphorylation resistant RB may have utility in both RB(-/-) and RB(+/+) tumors as well as in hyperproliferative disorders.

Molecular genetic studies of the Cdc7 protein kinase and induced mutagenesis in yeast.

The Saccharomyces cerevisiae CDC7 gene encodes a protein kinase that functions in DNA replication, repair, and meiotic recombination. The sequence of several temperature-sensitive (ts) cdc7 mutations was determined and correlated with protein kinase consensus domain structure. The positions of these ts alleles suggests some general principles for predicting ts protein kinase mutations. Pedigree segregation lag analysis demonstrated that all of the mutant proteins are less active or less stable than wild-type Cdc7p. Two new mutations were constructed, one by site-directed and the other by insertional mutagenesis. All of the cdc7 mutants were assayed for induced mutagenesis in response to mutagenic agents at the permissive temperature. Some cdc7 mutants were found to be hypomutable, while others are hypermutable. The differences in mutability are observed most clearly when log phase cells are used. Both hypo- and hypermutability are recessive to wild type. Cdc7p may participate in DNA repair by phosphorylating repair enzymes or by altering chromatin structure to allow accessibility to DNA lesions.