Advances in the treatment of acute graft‐versus‐host disease

Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologic malignant and non‐malignant hematologic diseases and other diseases. However, acute graft‐versus‐host disease (GVHD) is a life‐threatening complication of allogeneic transplantation. Acute GVHD may occur in 30% of transplant recipients, which is a syndrome of erythematous skin eruption, cholestatic liver disease and intestinal dysfunction, resulting from the activation of donor T lymphocytes by host antigen‐presenting cells, resulting in an immune‐mediated inflammatory response. Recent scientific advances in the understanding of the pathogenesis involved in the development of acute GVHD and clinical investigation have provided more effective therapeutic strategies for acute GVHD. This review focuses on major scientific and clinical advances in the treatment of acute GVHD.     

Inverse‐probability‐of‐treatment weighted estimation of causal parameters in the presence of error‐contaminated and time‐dependent confounders

Inverse‐probability‐of‐treatment weighted (IPTW) estimation has been widely used to consistently estimate the causal parameters in marginal structural models, with time‐dependent confounding effects adjusted for. Just like other causal inference methods, the validity of IPTW estimation typically requires the crucial condition that all variables are precisely measured. However, this condition, is often violated in practice due to various reasons. It has been well documented that ignoring measurement error often leads to biased inference results. In this paper, we consider the IPTW estimation of the causal parameters in marginal structural models in the presence of error‐contaminated and time‐dependent confounders. We explore several methods to correct for the effects of measurement error on the estimation of causal parameters. Numerical studies are reported to assess the finite sample performance of the proposed methods.     

A cure‐rate model for Q‐learning: Estimating an adaptive immunosuppressant treatment strategy for allogeneic hematopoietic cell transplant patients

Cancers treated by transplantation are often curative, but immunosuppressive drugs are required to prevent and (if needed) to treat graft‐versus‐host disease. Estimation of an optimal adaptive treatment strategy when treatment at either one of two stages of treatment may lead to a cure has not yet been considered. Using a sample of 9563 patients treated for blood and bone cancers by allogeneic hematopoietic cell transplantation drawn from the Center for Blood and Marrow Transplant Research database, we provide a case study of a novel approach to Q‐learning for survival data in the presence of a potentially curative treatment, and demonstrate the results differ substantially from an implementation of Q‐learning that fails to account for the cure‐rate.     

Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges

Post‐traumatic stress disorder (PTSD) is arguably the most common psychiatric disorder to arise after exposure to a traumatic event. Since its formal introduction in the DSM‐III in 1980, knowledge has grown significantly regarding its causes, maintaining mechanisms and treatments. Despite this increased understanding, however, the actual definition of the disorder remains controversial. The DSM‐5 and ICD‐11 define the disorder differently, reflecting disagreements in the field about whether the construct of PTSD should encompass a broad array of psychological manifestations that arise after trauma or should be focused more specifically on trauma memory phenomena. This controversy over clarifying the phenotype of PTSD has limited the capacity to identify biomarkers and specific mechanisms of traumatic stress. This review provides an up‐to‐date outline of the current definitions of PTSD, its known prevalence and risk factors, the main models to explain the disorder, and evidence‐supported treatments. A major conclusion is that, although trauma‐focused cognitive behavior therapy is the best‐validated treatment for PTSD, it has stagnated over recent decades, and only two‐thirds of PTSD patients respond adequately to this intervention. Moreover, most people with PTSD do not access evidence‐based treatment, and this situation is much worse in low‐ and middle‐income countries. Identifying processes that can overcome these major barriers to better management of people with PTSD remains an outstanding challenge.     

Model selection for G‐estimation of dynamic treatment regimes

Dynamic treatment regimes (DTRs) aim to formalize personalized medicine by tailoring treatment decisions to individual patient characteristics. G‐estimation for DTR identification targets the parameters of a structural nested mean model, known as the blip function, from which the optimal DTR is derived. Despite its potential, G‐estimation has not seen widespread use in the literature, owing in part to its often complex presentation and implementation, but also due to the necessity for correct specification of the blip. Using a quadratic approximation approach inspired by iteratively reweighted least squares, we derive a quasi‐likelihood function for G‐estimation within the DTR framework, and show how it can be used to form an information criterion for blip model selection. We outline the theoretical properties of this model selection criterion and demonstrate its application in a variety of simulation studies as well as in data from the Sequenced Treatment Alternatives to Relieve Depression study.     

Auxin‐treatment induces recovery of phytoplasma‐infected periwinkle

Aims: To test the effect of auxin‐treatment on plant pathogenic phytoplasmas and phytoplasma‐infected host. Methods and Results: In vitro grown periwinkle shoots infected with different ‘Candidatus Phytoplasma’ species were treated with indole‐3‐acetic acid (IAA) or indole‐3‐butyric acid (IBA). Both auxins induced recovery of phytoplasma‐infected periwinkle shoots, but IBA was more effective. The time period and concentration of the auxin needed to induce recovery was dependent on the ‘Candidatus Phytoplasma’ species and the type of auxin. Two ‘Candidatus Phytoplasma’ species, ‘Ca. P. pruni’ (strain KVI, clover phyllody from Italy) and ‘Ca. P. asteris’ (strain HYDB, hydrangea phyllody), were susceptible to auxin‐treatment and undetected by nested PCR or detected only in the second nested PCR in the host tissue. ‘Ca. P. solani’ (strain SA‐I, grapevine yellows) persisted in the host tissue despite the obvious recovery of the host plant and was always detected in the direct PCR. Conclusions: Both auxins induced recovery of phytoplasma‐infected plants and affected tested ‘Candidatus Phytoplasma’ species in the same manner, implying that the mechanism involved in phytoplasma elimination/survival is common to both, IAA and IBA. Significance and Impact of the Study: The results imply that in the case of some ‘Candidatus Phytoplasma’ species, IBA‐treatment could be used to eliminate phytoplasmas from in vitro grown Catharanthus roseus shoots.     

Tendinopathy diagnosis and treatment monitoring using attenuated total reflectance‐Fourier transform infrared spectroscopy

Tendinopathy, an important sports injury afflicting athletes and general public, is associated with huge economic losses. The currently used diagnostic tests are subjective, show moderate sensitivity and specificity; while treatment failures persist despite advances in therapy. This highlights the need for tendinopathy diagnostic and treatment monitoring tools. This study investigates tendon injury, natural healing and effect of treatment using ATR‐FTIR complemented with histopathology. Control (C), injured (I) and treated (T) rat tendons were extracted 3, 7, 14 and 28 days post‐injury/treatment, representing phases of healing; and subjected to hematoxylin & eosin staining as well as spectroscopy. While C showed no change, I‐ and T‐related histological changes could be clearly observed in stained sections. ATR‐FTIR spectra highlighted the biochemical changes within groups. Multivariate analysis could classify C, I and T with 75%; different days between groups with 84%; and different days within group with 65% efficiency. Results suggest that such analysis can not only identify C, I or T but also different phases of healing. Difference between I and T at different time points also suggest change in rate of healing. Further studies may help develop this technique for clinical diagnosis and treatment monitoring in future.      

High‐throughput microarray profiling of cell wall polymers during hydrothermal pre‐treatment of wheat straw

Lignocellulosic plant material is potentially a sustainable source of fermentable sugars for bioethanol production. However, a barrier to this is the high resistance or recalcitrance of plant cell walls to be hydrolyzed. Therefore, a detailed knowledge of the structural features of plant cell walls that contribute to recalcitrance is important for improving the efficiency of bioethanol production. In this work we have used a technique known as Comprehensive Microarray Polymer Profiling (CoMPP) to analyze wheat straw before and after being subjected to hydrothermal pre‐treatments at four different temperatures. The CoMPP technique combines the specificity of monoclonal antibodies with the high‐throughput capacity of microarrays. Changes in the relative abundance of cell wall polysaccharides could be tracked during processing, and a reduction in xylan, arabinoxylans, xyloglucan, and mixed‐linked glucan epitopes was detected at the two highest temperatures of pre‐treatment used. This work demonstrates the potential of CoMPP as a complementally technique to conventional methods for analyzing biomass composition. Biotechnol. Bioeng. 2010; 105: 509–514. © 2009 Wiley Periodicals, Inc.     

Targeting miR‐193a‐AML1‐ETO‐β‐catenin axis by melatonin suppresses the self‐renewal of leukaemia stem cells in leukaemia with t (8;21) translocation

AML1‐ETO, the most common fusion oncoprotein by t (8;21) in acute myeloid leukaemia (AML), enhances hematopoietic self‐renewal and leukemogenesis. However, currently no specific therapies have been reported for t (8;21) AML patients as AML1‐ETO is still intractable as a pharmacological target. For this purpose, leukaemia cells and AML1‐ETO‐induced murine leukaemia model were used to investigate the degradation of AML1‐ETO by melatonin (MLT), synthesized and secreted by the pineal gland. MLT remarkedly decreased AML1‐ETO protein in leukemic cells. Meanwhile, MLT induced apoptosis, decreased proliferation and reduced colony formation. Furthermore, MLT reduced the expansion of human leukemic cells and extended the overall survival in U937T‐AML1‐ETO‐xenografted NSG mice. Most importantly, MLT reduced the infiltration of leukaemia blasts, decreased the frequency of leukaemia stem cells (LSCs) and prolonged the overall survival in AML1‐ETO‐induced murine leukaemia. Mechanistically, MLT increased the expression of miR‐193a, which inhibited AML1‐ETO expression via targeting its putative binding sites. Furthermore, MLT decreased the expression of β‐catenin, which is required for the self‐renewal of LSC and is the downstream of AML1‐ETO. Thus, MLT presents anti‐self‐renewal of LSC through miR‐193a‐AML1‐ETO‐β‐catenin axis. In conclusion, MLT might be a potential treatment for t (8;21) leukaemia by targeting AML1‐ETO oncoprotein.     

Occurrence and reduction of human viruses,F‐specific RNA coliphage genogroups and microbial indicators at a full‐scale wastewater treatment plant in Japan

Aims

To evaluate and compare the reductions of human viruses and F‐specific coliphages in a full‐scale wastewater treatment plant based on the quantitative PCR (qPCR) and plate count assays.

Methods and Results

A total of 24 water samples were collected from four locations at the plant, and the relative abundance of human viruses and F‐RNA phage genogroups were determined by qPCR. Of the 10 types of viruses tested, enteric adenoviruses were the most prevalent in both influent and effluent wastewater samples. Of the different treatment steps, the activated sludge process was most effective in reducing the microbial loads. Viruses and F‐RNA phages showed variable reduction; among them, GI and GIII F‐RNA phages showed the lowest and the highest reduction, respectively.

Conclusions

Ten types of viruses were present in wastewater that is discharged into public water bodies after treatment. The variability in reduction for the different virus types demonstrates that selection of adequate viral indicators is important for evaluating the efficacy of wastewater treatment and ensuring the water safety.

Significance and Impact of the Study

Our comprehensive analyses of the occurrence and reduction of viruses and indicators can contribute to the future establishment of appropriate viral indicators to evaluate the efficacy of wastewater treatment.     

The Use of Two‐Way Linear Mixed Models in Multitreatment Meta‐Analysis

Summary Meta‐analysis summarizes the results of a series of trials. When more than two treatments are included in the trials and when the set of treatments tested differs between trials, the combination of results across trials requires some care. Several methods have been proposed for this purpose, which feature under different labels, such as network meta‐analysis or mixed treatment comparisons. Two types of linear mixed model can be used for meta‐analysis. The one expresses the expected outcome of treatments as a contrast to a baseline treatment. The other uses a classical two‐way linear predictor with main effects for treatment and trial. In this article, we compare both types of model and explore under which conditions they give equivalent results. We illustrate practical advantages of the two‐way model using two published datasets. In particular, it is shown that between‐trial heterogeneity as well as inconsistency between different types of trial is straightforward to account for.     

Meta‐analysis of rare events under the assumption of a homogeneous treatment effect

We studied the performance of several meta‐analysis methods in rare event settings, when the treatment effect is assumed to be homogeneous and baseline prevalences are either homogeneous or heterogeneous. We conducted extensive simulations that included the three most common effect sizes with count data: the odds ratio, the relative risk, and the risk difference. We investigated several important scenarios by varying the level of rareness, the value of the trials’ arms unbalance, and the size of the treatment effect. We found that the Mantel–Haenszel method and the Binomial regression model provided the best results across all the scenarios investigated. The Peto method performed satisfactorily only when the true effect size was not too large and the degree of unbalance moderate. Inverse variance was the least reliable method. The use of a continuity correction factor slightly improved the performance of the inverse variance method but deteriorated that of the Peto and Mantel–Haenszel methods. A method based on median unbiased estimators of the probabilities provided similar results to those obtained when using the inverse variance method with a continuity correction. Therefore, when the treatment effect can be assumed to be homogeneous and for either homogeneous or heterogeneous baseline prevalences, we highly recommend using the Mantel‐Haenszel method without continuity correction (for all the effect sizes) or the Binomial regression model (for the odds ratio only) to meta‐analyze the data.     

Therapeutic effects of hydrogen on chronic graft‐versus‐host disease

The incidence of chronic graft‐versus‐host disease (cGVHD) is rising recent years, which has been the leading cause of non‐transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti‐inflammatory, antioxidant, anti‐fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC‐incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen‐rich saline increased survival rate of cGVHD mice. Administration of hydrogen‐rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values.