User’s Guide to ADMB2R: A Set of AD Model Builder Output Routines Compatible with the R Statistics Language

ADMB2R is a collection of AD Model Builder routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 ADMB2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the ADMB2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer ADMB2R to others in the hope that they will find it useful. (PDF contains 30 pages)

User’s Guide to C2R: A Set of C Language Output Routines Compatible with the R Statistics Language

C2R is a collection of C routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 C2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the C2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer C2R to others in the hope that they will find it useful. (PDF contains 27 pages)

User’s Guide to For2R: A Module of Fortran 95 Output Routines Compatible with the R Statistics Language

For2R is a collection of Fortran routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 For2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the For2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer For2R to others in the hope that they will find it useful. (PDF contains 31 pages)

Single cell proteomics microchip to profile immune function, with applications in stem cell biology, translational disease mechanism study and clinical therapeutics monitoring

In response to infection or tissue dysfunction, immune cells develop into highly heterogeneous repertoires with diverse functions. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. However, currently only 3-5 functional proteins can be measured from single cells. We developed a single cell functional proteomics approach that integrates a microchip platform with multiplex cell purification. This approach can quantitate 20 proteins from >5,000 phenotypically pure single cells simultaneously. With a 1-million fold miniaturization, the system can detect down to ~100 molecules and requires only ~104 cells. Single cell functional proteomic analysis finds broad applications in basic, translational and clinical studies. In the three studies conducted, it yielded critical insights for understanding clinical cancer immunotherapy, inflammatory bowel disease (IBD) mechanism and hematopoietic stem cell (HSC) biology.

To study phenotypically defined cell populations, single cell barcode microchips were coupled with upstream multiplex cell purification based on up to 11 parameters. Statistical algorithms were developed to process and model the high dimensional readouts. This analysis evaluates rare cells and is versatile for various cells and proteins. (1) We conducted an immune monitoring study of a phase 2 cancer cellular immunotherapy clinical trial that used T-cell receptor (TCR) transgenic T cells as major therapeutics to treat metastatic melanoma. We evaluated the functional proteome of 4 antigen-specific, phenotypically defined T cell populations from peripheral blood of 3 patients across 8 time points. (2) Natural killer (NK) cells can play a protective role in chronic inflammation and their surface receptor – killer immunoglobulin-like receptor (KIR) – has been identified as a risk factor of IBD. We compared the functional behavior of NK cells that had differential KIR expressions. These NK cells were retrieved from the blood of 12 patients with different genetic backgrounds. (3) HSCs are the progenitors of immune cells and are thought to have no immediate functional capacity against pathogen. However, recent studies identified expression of Toll-like receptors (TLRs) on HSCs. We studied the functional capacity of HSCs upon TLR activation. The comparison of HSCs from wild-type mice against those from genetics knock-out mouse models elucidates the responding signaling pathway.

In all three cases, we observed profound functional heterogeneity within phenotypically defined cells. Polyfunctional cells that conduct multiple functions also produce those proteins in large amounts. They dominate the immune response. In the cancer immunotherapy, the strong cytotoxic and antitumor functions from transgenic TCR T cells contributed to a ~30% tumor reduction immediately after the therapy. However, this infused immune response disappeared within 2-3 weeks. Later on, some patients gained a second antitumor response, consisted of the emergence of endogenous antitumor cytotoxic T cells and their production of multiple antitumor functions. These patients showed more effective long-term tumor control. In the IBD mechanism study, we noticed that, compared with others, NK cells expressing KIR2DL3 receptor secreted a large array of effector proteins, such as TNF-α, CCLs and CXCLs. The functions from these cells regulated disease-contributing cells and protected host tissues. Their existence correlated with IBD disease susceptibility. In the HSC study, the HSCs exhibited functional capacity by producing TNF-α, IL-6 and GM-CSF. TLR stimulation activated the NF-κB signaling in HSCs. Single cell functional proteome contains rich information that is independent from the genome and transcriptome. In all three cases, functional proteomic evaluation uncovered critical biological insights that would not be resolved otherwise. The integrated single cell functional proteomic analysis constructed a detail kinetic picture of the immune response that took place during the clinical cancer immunotherapy. It revealed concrete functional evidence that connected genetics to IBD disease susceptibility. Further, it provided predictors that correlated with clinical responses and pathogenic outcomes.

Tratamento da Neofobia Alimentar em pacientes com obesidade associada ou não à compulsão alimentar

Tendo como base a visão evolucionista e a abordagem terapêutica cognitivo-comportamental, o objetivo deste trabalho foi propor um protocolomodificado de tratamento para pessoas obesas com compulsão alimentar periódica.A idéia norteadora é que estratégias que foram úteis para a sobrevivência daespécie poderiam estar influenciando no ganho de peso. Entre estas estratégias,destacam-se: a tendência a consumir uma grande quantidade de alimentos, facilitando o consumo de alimentos hipercalóricos; e a neofobia alimentar, dificultando o consumo de frutas, legumes e verduras. Obedecendo à lógicaancestral herdada pela espécie, a primeira proporciona reservas para momentos deescassez de alimentos e a segunda implica em uma recusa em consumir alimentosdesconhecidos evitando que substâncias tóxicas sejam ingeridas. Ambos os fatores poderiam contribuir para a obesidade. Os tratamentos convencionais buscam controlar a ingestão calórica. O que aqui se propõe, além desse controle, é tentardiminuir o nível de neofobia alimentar. Com essa hipótese de trabalho espera-se aumentar o consumo de alimentos, principalmente os mais saudáveis e hipocalóricos, contribuindo para reduzir a ingestão de alimentos hipercalóricos. Otratamento incluiu técnicas de exposição, modelação e imitação adicionadas a umtratamento já utilizado para obesos com compulsão alimentar periódica. Foram criados dois grupos, o primeiro com 4 participantes funcionando como grupo decontrole, que recebeu um tratamento convencional de TCC; o outro, com 6 participantes aqui denominado grupo de intervenção, que recebeu o tratamento deTCC modificado. A pesquisa foi qualificada como quase-experimental. O resultadoobtido foi uma redução do índice de neofobia alimentar, do Índice de massa corporal, um aumento no consumo de alimentos saudáveis e a redução de gordurase açúcares no chamado grupo de intervenção. Embora tenha alcançado estes resultados, o tratamento ainda precisa ser reformulado e ampliado.

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-beta 3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Who has the Right to Govern Online Activity? A Criminal and Civil Point of View

Kohl, U. (2004). Who has the right to govern online activity? A criminal and civil point of view. International Review of Law, Computers & Technology 18 (3), 387-410 RAE2008

Konstrukcje tożsamości i bogactwo kulturowe w autobiografiach Güntera Grassa i Marcela Reicha-Ranickiego jako wyzwanie translatorskie

Wydział Neofilologii: Instytut Filologii Germańskiej

Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS: Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. RESULTS: Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. CONCLUSIONS: Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

Hypertension - a contemporary approach to nursing care

The incidence of hypertension is increasing as the number of patients with obesity and diabetes mellitus increases. Hypertension results when the peripheral vascular resistance is increased, the blood viscosity is elevated and/or the flow of blood through the main arteries is impeded. Chronic hypertension results in enlarged heart, myocardial damage and lung and renal abnormalities. While some causative factors such as obesity can be controlled, others for example genetics are more difficult to treat because often there is more than one factor involved. This paper explores how essential and secondary factors contribute to the incidence of hypertension and the physiological changes resulting from raised blood pressure. It proposes that although traditional treatment has some success, nurse-led clinics are having better success not only in controlling raised blood pressure but also in reducing cardiac, pulmonary and renal morbidity. It is more cost-effective, staff is more productive and clients are more compliant with treatment.

Breaking New Ground: The First Generation of Women to Work as Professional Authors in English Canada (1880-1920)

In the later decades of the nineteenth century and the early decades of the twentieth, large numbers of Canadian women were stepping out of the shadows of private life and into the public world of work and political action. Among them, both a cause and an effect of these sweeping social changes, was the first generation of Canadian women to work as professional authors. Although these women were not unified by ideology, genre, or date of birth, they are studied here as a generation defined by their time and place in history, by their material circumstances, and by their collective accomplishment. Chapters which focus on E. Pauline Johnson (Tekahionwake), the Eaton sisters (Sui Sin Far and Onoto Watanna), Joanna E. Wood, and Sara Jeannette Duncan explore some of the many commonalities and interrelationships among the members of this generation as a whole. This project combines archival research with analytical bibliography in order to clarify and extend our knowledge of Johnson’s and Duncan’s professional lives and publishing histories, and to recover some of Wood’s “lost” stories. This research offers a preliminary sketch of the long tradition of the platform performance (both Native and non-Native) with which Johnson and others engaged. It explores the uniquely innovative ethnographic writings of Johnson, Duncan, and the Eaton sisters, among others, and it explores thematic concerns which relate directly to the experiences of working women. Whether or not I convince other scholars to treat these authors as a generation, with more in common than has previously been supposed, the strong parallels revealed in these pages will help to clarify and contextualize some of their most interesting work.

Resistance mechanisms to cancer chemotherapy

Resistance to chemotherapy ('drug resistance') is a fundamental problem that limits the effectiveness of many chemotherapies currently used to treat cancer. Drug resistance can occur due to a variety of mechanisms, such as increased drug inactivation, drug efflux from cancer cells, enhanced repair of chemotherapy-induced damage, activation of pro-survival pathways and inactivation of cell death pathways. In this article, we review some of the major mechanisms of drug resistance and discuss how new molecularly-targeted therapies are being increasingly used to overcome these resistance mechanisms.

Response of vulval lichen sclerosus and squamous hyperplasia to photodynamic treatment using sustained topical delivery of aminolevulinic acid from a novel bioadhesive patch system

This study evaluated the clinical and histopathological responses of vulval lichen sclerosus (LS) and squamous hyperplasia (SH) to photodynamic therapy (PDT). A novel bioadhesive patch containing aminolevulinic acid (ALA) at a dose of (38 mg/cm(2)) was used to treat 10 patients before irradiation with light of 630 nm. Clinical, histopathological and pathological responses to treatment were assessed at 6 weeks post-treatment. After 17 cycles of PDT, six patients reported significant symptomatic relief and no cutaneous photosensitivity. Histopathological differences were not demonstrated, but statistically significant induction of apoptosis was seen. It can be concluded that ALA-PDT patch-based formulation is pragmatic and primarily offers symptomatic management of vulval LS and SH.

Binding of serum albumin to the anthelmintic drugs albendazole, triclabendazole and their sulphoxides

The binding of drugs to plasma proteins – especially serum albumin – is an important factor in controlling the availability and distribution of these drugs. In this study we have investigated the binding of two drugs commonly used to treat liver fluke infections, albendazole (ABZ) and triclabendazole (TCBZ), and their sulphoxide metabolites to bovine serum albumin (BSA). Both ABZ and TCBZ caused shifts in the mobility of BSA in native gel electrophoresis. No such changes were observed with the sulphoxides under identical conditions. The drugs, and their sulphoxides, caused quenching of the intrinsic tryptophan fluorescence of BSA, indicating association between the drugs and this protein. Quantification of this quenching suggested a 5–10-fold reduction in affinity of the sulphoxides compared to the parent compounds. These results are discussed in respect to previous work on the pharmacodynamics of these fasciolicides and will inform the design of novel anthelmintics.

The addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for advanced colorectal cancer: results of the MRC COIN trial.

Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3—29·2] in the control group vs 17·0 months [9·4—30·1] in the cetuximab group; HR 1·04, 95% CI 0·87—1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0—12·5] in the control group vs 8·6 months [5·1—13·8] in the cetuximab group; HR 0·96, 0·82—1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5—27·4); KRAS mutant, 14·4 months (8·5—24·0); all wild-type, 20·1 months (11·5—31·7).
Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.