Support vector machines for prediction of peptidyl prolyl cis/trans isomerization

Abstract: A new method for peptidyl prolyl cis/trans isomerization prediction based on the theory of support vector machines (SVM) was introduced. The SVM represents a new approach to supervised pattern classification and has been successfully applied to a wide range of pattern recognition problems. In this study, six training datasets consisting of different length local sequence respectively were used. The polynomial kernel functions with different parameter d were chosen. The test for the independent testing dataset and the jackknife test were both carried out. When the local sequence length was 20‐residue and the parameter d = 8, the SVM method archived the best performance with the correct rate for the cis and trans forms reaching 70.4 and 69.7% for the independent testing dataset, 76.7 and 76.6% for the jackknife test, respectively. Matthew's correlation coefficients for the jackknife test could reach about 0.5. The results obtained through this study indicated that the SVM method would become a powerful tool for predicting peptidyl prolyl cis/trans isomerization.     

Therapeutic targets: progress of their exploration and investigation of their characteristics

Modern drug discovery is primarily based on the search and subsequent testing of drug candidates acting on a preselected therapeutic target. Progress in genomics, protein structure, proteomics, and disease mechanisms has led to a growing interest in and effort for finding new targets and more effective exploration of existing targets. The number of reported targets of marketed and investigational drugs has significantly increased in the past 8 years. There are 1535 targets collected in the therapeutic target database compared with approximately 500 targets reported in a 1996 review. Knowledge of these targets is helpful for molecular dissection of the mechanism of action of drugs and for predicting features that guide new drug design and the search for new targets. This article summarizes the progress of target exploration and investigates the characteristics of the currently explored targets to analyze their sequence, structure, family representation, pathway association, tissue distribution, and genome location features for finding clues useful for searching for new targets. Possible "rules" to guide the search for druggable proteins and the feasibility of using a statistical learning method for predicting druggable proteins directly from their sequences are discussed.     

Giardiasis: recent progress in chemotherapy and drug development

Giardiasis is a protozoal disease infecting 200 million people throughout the world. Giardiasis is widespread primarily in developing countries. Infections are correlated with poor hygienic conditions, poor water quality control, and overcrowding. There are very few therapeutics currently available, and drug development to treat giardiasis is hampered mainly by socioeconomic obstacles. This article presents the history of antigiardial chemotherapy and current state of therapeutic availability along with the future prospectus of development of antigiardial agents. In addition to accumulated knowledge about the previous and current antigiardial drugs, advanced technologies including computer-aided drug design and combinatorial synthetic chemistry, as well as high throughput screening techniques, accelerate understanding of the disease and further research toward a suitable antigiardial agent.     

Vaccination strategies in lymphomas and leukaemias: recent progress

The successful identification of a range of leukaemia-specific and lymphoma-specific antigens in recent years has stimulated efforts to develop therapeutic vaccination strategies. A number of clinical trials have established the safety and immunogenicity of vaccination against tumour antigens, although there are limited data on the clinical efficacy of this approach in haematological malignancies. After encouraging results of phase I/II trials using idiotype vaccines in lymphoma, the outcome of the three phase III trials has been somewhat disappointing. Several other promising strategies are currently being developed to improve these results, including optimization of antigen delivery. In myeloid leukaemias, clinical trials of vaccination with peptides derived from a number of leukaemia antigens, including WT1, PR1, RHAMM and BCR-ABL, have shown evidence of immunogenicity, but limited data are available on the clinical efficacy of this approach. In this review, we focus on the results of clinical trials of vaccination in leukaemia and lymphoma, and discuss potential strategies to enhance the efficacy of immunotherapy in the future.     

Histamine in the retina: recent progress and perspectives

This article presents some new findings, and shortly surveys recently published data, on histamine (HA) in the retina of several vertebrates (carp, hen, rabbit, rat, guinea pig, cow, man). Analysis of various parameters (HA level, activity of histidine decarboxylase and HA-methyltransferase, release and uptake of HA, 3H-mepyramine binding, effect of HA on cAMP accumulation, diurnal variations) in vertebrate retina and brain shows that histaminergic systems in these sites are comparable, although some species-dependent differences have been observed. Interestingly, exposure of dark-adapted rabbits to light affects several histaminergic parameters selectively, i.e. in the retina and not in the brain. The reviewed data suggest that in retinas of at least some vertebrates HA may be a physiologically important amine.     

Inactivated influenza vaccines: recent progress and implications for the elderly

The current public health strategy for the containment of influenza is annual vaccination, which is recommended for the elderly and for those in risk factor categories that present the highest morbidity and mortality. However, because the immune response in the elderly is known to be less vigorous than in younger adults, research in the last decade has focused on improving the immune response to vaccination and increasing the protection of aged populations. The decreased efficacy of vaccines in the elderly is due to several factors, such as a decrease in the number of Langerhans cells, the limited capacity of dendritic cells to present antigen, defects in the expression of Toll-like receptors and the reduced expression of MHC class I and II molecules. Also, production of mature naive T cells by the thymus decreases with age. Among several approaches proposed to address the need for more immunogenic vaccines compared with conventional agents, the most well proven is the use of adjuvants. The first licensed adjuvant, aluminium-based mineral salts (alum), introduced in the 1920s, remains the standard worldwide adjuvant for human use and it has been widely used for almost a century. However, the addition of alum adjuvant to a split or subunit influenza vaccine has induced only marginal improvements. Other adjuvants have been developed and approved for human use since 1997; in particular, MF59, an oil-in-water adjuvant emulsion of squalene, which is able to increase immunogenicity of seasonal, pre-pandemic and pandemic subunit vaccines while maintaining acceptable safety and tolerability profiles. More recently, another oil-in-water emulsion, AS03, has been approved as a component of pre-pandemic H5N1 and pandemic H1N1 2009 vaccines. Besides adjuvants, several other strategies have been assessed to enhance antibody response in the elderly and other less responsive subjects, such as high-dose antigen vaccines, carrier systems (liposomes/virosomes) and the intradermal route of immunization. In particular, the potential of intradermal vaccination is well documented and the recent availability of an appropriate injection system, which combines simplicity, safety and ease of use, has allowed evaluation of the tolerability, safety and immunogenicity of the intradermal influenza vaccine in large numbers of subjects. Data that emerged from large clinical trials showed an improved immunogenicity compared with that of standard vaccine. Observational studies or comparisons between adjuvanted, intradermal or high-dose versus conventional vaccines are needed to evaluate whether the greater immunogenicity observed in a number of recent studies is correlated with greater protection against influenza and influenza-related complications and death.     

Gene therapy for primary immunodeficiency diseases: recent progress and misgivings

The progress of clinical gene therapy trials during the last two decades has been remarkable, and its application has also expanded into various fields of human diseases. Among them, hereditary diseases such as the primary immunodeficiency diseases (PID) were considered suitable candidates for gene therapy because the therapeutic strategy was very simple, therefore, effective gene therapy may be obtained without significant difficulty compared to other more complex diseases such as cancer. Indeed, the first clinical gene therapy trial was safely performed and was in part, effective for adenosine deaminase (ADA) deficiency patients, a type of severe combined immunodeficiency diseases (SCID). However, because of certain unforeseen obstacles, it took approximately 10 years until the first curative effects were obtained for gene therapy in patients with X-linked SCID (X-SCID). Here, I review and discuss the background and historical events leading up to PID gene therapy, the safety issues, which unexpectedly arose after the successful report, and finally I will attempt to predict the future trends in this form of gene therapy.     

Rod-shaped mesoporous silica nanoparticles for nanomedicine: recent progress and perspectives

Introduction: Interest in mesoporous silica nanoparticles for drug delivery has resulted in a good understanding of the impact of size and surface chemistry of these nanoparticles on their performance as drug carriers. Shape has emerged as an additional factor that can have a significant effect on delivery efficacy. Rod-shaped mesoporous silica nanoparticles show improvements in drug delivery relative to spherical mesoporous silica nanoparticles.

Areas covered: This review summarises the synthesis methods for producing rod-shaped mesoporous silica nanoparticles for use in nanomedicine. The second part covers recent progress of mesoporous silica nanorods by comparing the impact of sphere and rod-shape on drug delivery efficiency.

Expert opinion: As hollow mesoporous silica nanorods are capable of higher drug loads than most other drug delivery vehicles, such particles will reduce the amount of mesoporous silica in the body for efficient therapy. However, the importance of nanoparticle shape on drug delivery efficiency is not well understood for mesoporous silica. Studies that visualize and quantify the uptake pathway of mesoporous silica nanorods in specific cell types and compare the cellular uptake to the well-studied nanospheres should be the focus of research to better understand the role of shape in uptake.     

Proteomics approach on microcystin binding proteins in mouse liver for investigation of microcystin toxicity.

Microcystins (MC) produced by freshwater cyanobacteria are potent hepatotoxins. MC inhibit protein phosphatases (PP) 1 and 2A. MC and okadaic acid (OA), which is a similar PP inhibitor whereas it has a less affinity to PP1 than PP2A, behave similarly to primary culture hepatocytes, with inducements of phosphorylations of cytoskeleton, morphological changes and apoptosis. Although the distribution of OA in mouse liver was observed immunohistochemically, no OA injury was found. The purpose of this study was therefore to determine why only MC has specific toxicities on the liver. A systematic process of MC affinity chromatography and proteomics, using two-dimensional gel electrophoresis and MALDI-TOFMS, indicated the existence of some MC-binding proteins including the complexes of PP1, PP2A, and PP4 with their own regulatory subunits in mouse liver extracts. The competitive inhibition experiments using affinity chromatography with OA showed that two of the three protein complexes strongly interacted with OA, whereas only the complex of PP1 with the inhibitory subunit NIPP1 did not strongly interacted with OA. These results suggest that the PP1 complex is not related to the common behavior of MC and OA of primary culture hepatocytes, and is related to the specific hepatotoxicities of MC.     

Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier

Purpose

The purpose of this study was to evaluate how risk estimates generated from cumulative meta-analysis performs over time for drugs having their benefit/risk ratio re-evaluated due to safety issues and, additionally, assess whether results are consistent with regulatory authorities’ conclusions.

Methods

Four major regulatory authorities were searched for their issued safety alerts supported by longitudinal, comparative studies (experimentals and/or observationals). The random-effects model was used to pooled odds ratios (OR) over time by including studies according to the year they first became available.

Results

Seventeen safety alerts were included in this study. In 2008, proton-pump inhibitors (PPIs) were associated with an increased risk for bone fractures [OR 1.25, 95 % confidence interval (CI) 1.00–1.55, P?=?0.049); the US Food and Drug Association (FDA) issued a safety alert in 2010 and added warnings to the label. An increased risk for Clostridium-difficile-associated diarrhea was pooled for PPIs in 2004 (OR 1.89, 1.19–3.02, P?=?0.007); US FDA issued a safety alert in 2012, adding warnings to the label. PPIs were associated with pneumonia in 2009 (OR 1.40, 1.06–1.85, P?=?0.017); US FDA issued an alert in 2012 but concluded that the benefit/risk (B/R) ratio remains positive. Statins were associated with an increased risk for diabetes (OR 1.07, 1.01–1.15, P?=?0.033) in 2008. The European Medicines Agency (EMA) issued an alert in 2012, including warnings to the label. The remaining cumulative meta-analyses did not estimate increased risks in advance of regulatory decisions.

Conclusion

This study demonstrates that meta-analysis may help predict iatrogenic risks. However, between-study heterogeneity can considerably affect the estimated results, and therefore, this technique should not replace further assessments during BR ratio re-evaluations.     

Strategies for preventing porcine xenograft rejection: recent progress and future developments

Interest in xenotransplantation (the use of animal organs for transplantation) has been revived because of the severe shortage of human donor organs, and pigs are currently thought to be the species most suitable for widespread use. Recent insights into the mechanisms underlying vascular rejection, endothelial cell activation and cellular responses to xenogeneic tissue have led to the development of novel methods designed to inhibit immune-mediated xenograft rejection. The first clinical trials of porcine organs are expected within the next few years, once outstanding questions about the safety of transplanted pig tissues have been addressed. They will herald a new era in medical practice, characterised by the practical application of modern molecular and genetic techniques to solve clinical problems. In the future, it is hoped that these same techniques may resolve some of the problems currently associated with long-term systemic immunosuppression and serve to inhibit the progress of chronic rejection, the process that currently limits the lifespan of transplanted allografts. This article reviews the pathophysiology of xenograft rejection and highlights the novel strategies to prevent hyperacute xenograft rejection that are likely to be useful in clinical practice. Other strategies designed to inhibit later stages of xenograft rejection are also presented, with emphasis on the need for graft-specific or ‘tailored’ immunosuppression. Areas where future development is likely are also discussed.     

BRPF蛋白的生物学功能及其抑制剂研究进展

BRPF（Bromodomain and PHD finger containing）蛋白作为表观遗传“reader”结构域，能特异性地识别组蛋白“尾部”乙酰化的赖氨酸残基以促进靶基因的转录。本文综述了BPRF 蛋白如何识别和结合乙酰赖氨酸标记，讨论了乙酰化组蛋白识别对其生物学功能的重要性，以及总结了BRPF bromodomain抑制剂的研究进展。     

Porphyrin-based sensitizers in the detection and treatment of cancer: recent progress

It has been known for some time that porphyrins and related compounds have the ability to selectively accumulate in tumor tissues, and to persist there for long periods of time. This property, along with the well-described photophysical and photosensitizing properties of porphyrin-type molecules, has led to their potential use as adjuvants and sensitizers in a variety of medical applications, such as in photodynamic therapy (PDT), boron neutron capture therapy (BNCT), radiation therapy (RT) and in magnetic resonance imaging (MRI). Both PDT and BNCT are binary cancer therapies that involve activation of tissue-localized sensitizers with either light (in PDT) or low-energy neutrons (in BNCT). In both of these therapeutic methodologies, local tumor control with minimal side effects relative to other forms of cancer treatment (surgery, radiotherapy, chemotherapy) can be achieved. Porphyrins constitute a major class of pharmacological agents currently under investigation. Photofrin, a porphyrin derivative, has been approved in the USA as a PDT drug by the U.S. Food and Drug Administration (FDA), and also in Japan, Canada and in eleven European countries. Recently, the FDA approved Visudyne, another porphyrin derivative for the PDT treatment of the 'wet-form' of age-related macular degeneration. In addition to cancer treatment porphyrins are also under investigation for application in the treatment of a variety of other diseases.     

Oral delivery of proteins: progress and prognostication

The delivery of proteins has gained momentum with the development of biotechnology sector that provided large-scale availability of therapeutic proteins. The availability is mostly due to the advances in recombinant DNA technology. The low oral bioavailability, however, continues to be a problem for several proteins because of their large molecular size, low permeation through biological membranes, and susceptibility to molecular changes in both biological and physical environments. The demand for effective delivery of proteins by the oral route has brought a tremendous thrust in recent years both in the scope and complexity of drug delivery technology. The important therapeutic proteins and peptides being explored for oral delivery include insulin, calcitonin, interferons, human growth hormone, glucagons, gonadotropin-releasing hormones, enkephalins, vaccines, enzymes, hormone analogs, and enzyme inhibitors. This article reviews the progress in oral delivery of these proteins, provides comments on the strategies to improve their oral bioavailability, and highlights their current market trends.     

腹腔镜胆囊切除术中转开腹及近期再次手术原因分析和中转开腹时机探索

目的分析腹腔镜胆囊切除术（LC） 中转开腹及近期再手术原因并探讨中转开腹时机。方法回顾性分析我院850例LC中49例中转开腹及10例术后近期再手术临床资料。结果 LC 中转开腹手术原因： 胆囊三角解剖欠清、胆囊粘连32例,腹腔内出血6例,胆管损伤4例,发现胃癌1例,意外胆囊癌2例,胆总管结石3例,腹腔镜器械原因1例。近期再次手术原因： 肝总管横断损伤及胆囊管根部损伤各1例,迷走胆管漏2例,胆总管结石残留 3 例,腹腔出血 3例。结论选择合适病例,严格掌握中转开腹时机,就可以减少LC并发症的发生。     

Support for non-prescribed anabolic androgenic steroids users: a qualitative exploration of their needs

Abstract

Anabolic Androgenic Steroids (AAS) are used by the general population (particularly male gym users) for their anabolic effects (increased muscle mass). Few studies have sought AAS users’ views on what information and support they need. This study focuses on ideal support wanted by people who use AAS. Interviews were conducted with 23 self-declared adult AAS users. Using thematic analysis, six themes were identified aligned to support and information wanted by AAS users: (1) specific types of information wanted: managing risks, (2) mechanisms for communication of advice, (3) specific types of support wanted: medical and emotional, (4) stigmatisation of people who use AAS, (5) paying for support services, (6) legality of AAS use.

Integral to the support was that it should be considered within the context of use and identity. Support needs to be specific, targeted towards AAS users ensuring that balanced and evidenced-based advice is given. Sensitivity to AAS users’ perceptions of their drug-use and the stigma of being classified in the same sub-set as other illicit drug users is relevant to facilitating successful engagement. Furthermore, there is a need to consider the emotional issues surrounding AAS use and how to meet these needs.