Thermodynamic analysis of interactions between N-linked sugar chains and F-box protein Fbs1

Fbs1 is a recently discovered F-box protein that was proposed to recognize high-mannose-type asparagine-linked glycoprotein sugar chains. To reveal the specificity of Fbs1, Manalpha1-->6Manbeta1-->4GlcNAc(2), Manalpha1-->3Manbeta1-->4GlcNAc(2), and Manalpha1-->3(Manalpha1--> 6)Manbeta1-->4GlcNAc(2) were synthesized and their affinities for Fbs1 were evaluated in comparison with previously synthesized Man(9)GlcNAc(2) and Man(8)GlcNAc(2). These analyses revealed that Man(3)GlcNAc(2) had the strongest affinity and the chitobiose and alpha1-->6 linked Man residue are necessary for Fbs1 to recognize a sugar.     

Cell culture and in vivo analyses of cytopathic hepatitis C virus mutants

HCV-JFH1 yields subclones that develop cytopathic plaques (Sekine-Osajima Y, et al., Virology 2008; 371:71). Here, we investigated viral amino acid substitutions in cytopathic mutant HCV-JFH1 clones and their characteristics in vitro and in vivo. The mutant viruses with individual C2441S, P2938S or R2985P signature substitutions, and with all three substitutions, showed significantly higher intracellular replication efficiencies and greater cytopathic effects than the parental JFH1 in vitro. The mutant HCV-inoculated mice showed significantly higher serum HCV RNA and higher level of expression of ER stress-related proteins in early period of infection. At 8 weeks post inoculation, these signature mutations had reverted to the wild type sequences. HCV-induced cytopathogenicity is associated with the level of intracellular viral replication and is determined by certain amino acid substitutions in HCV-NS5A and NS5B regions. The cytopathic HCV clones exhibit high replication competence in vivo but may be eliminated during the early stages of infection.     

Combination of hemoglobin,alkaline phosphatase,and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer

Background

We aimed to find the prognostic factors predicting overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) who had docetaxel (DTX) chemotherapy, and to construct a model predicting the optimum number of cycles of DTX.

Methods

A total of 279 CRPC patients who received DTX (≥50 mg/m²) every 3–4 weeks were studied retrospectively. Prognostic factors predicting treatment cycles as well as OS were analyzed, and a risk table for predicting treatment cycles was constructed.

Results

The longer treatment group (>10 cycles) had a significantly longer OS than the standard treatment group (p < 0.0001). Multivariate analysis demonstrated that a decrease of ≥50 % in prostate-specific antigen (PSA), serum markers at the start of DTX therapy [PSA, alkaline phosphatase (ALP), and C-reactive protein (CRP)], and the number of DTX courses were independent predictors of OS. The risk table employing the combination of three factors [ALP (cut-off 189 IU/L), hemoglobin (11.3 g/dL), and age (65 years) at the start of DTX therapy], and scoring based on the hazard ratio of each risk factor (ALP 4, hemoglobin 2, age 3) could effectively predict the probability of the length of DTX therapy, with lower score (0–6) predicting >10 cycles, and higher score (7–9) predicting ≤5 cycles (p < 0.0001). No significant difference was found regarding grade 3/4 adverse events between the two groups.

Conclusion

A model using three factors prior to chemotherapy may be beneficial for deciding the duration of DTX therapy in patients with CRPC.     

Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis

Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4(+) cells. However, it remains unknown whether colitogenic CD4(+) cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4(+) cells, we performed sequential transfers of LP CD4(+) cells from colitic CD4(+)CD45RB(high) cell-transferred SCID mice into new SCID mice. Although SCID mice transferred with colitic LP CD4(+) cells stably developed colitis until at least the sixth transfer, the interval to the development of colitis gradually lengthened as the number of transfers increased. The incidence of colitis gradually decreased after the seventh transfer. Furthermore, non-colitic LP CD4(+) cells from mice transferred over seven times expressed significantly higher levels of PD-1 and produced significantly lower amounts of IFN-gamma, TNF-alpha, and IL-17 than colitic LP CD4(+) cells recovered after the first transfer. Most notably, we found that re-transfer of non-colitic LP CD4(+) cells recovered after multiple transfers prevented the development of colitis in SCID mice co-transferred with CD4(+)CD45RB(high) cells. Thus, colitogenic LP CD4(+) cells may be exhausted over time, become non-functional, convert to regulatory cells, and finally suppress colitis in the process of immunosenescence.     

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia

Aim: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non‐schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). Methods: The data for the 251 schizophrenia subjects used in the previous discriminant‐analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. Results: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. Conclusion: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.     

Head region of unconventional myosin I family members is responsible for the organ‐specificity of their roles in left–right polarity in Drosophila

In Drosophila, Myosin31DF (Myo31DF), encoding a Myosin ID protein, has crucial roles in left–right (LR) asymmetric development. Loss of Myo31DF function leads to laterality inversion for many organs, including the embryonic gut. Here, we found that Myo31DF was required before LR asymmetric morphogenesis in the hindgut, suggesting it functions in LR patterning instead of directly in hindgut morphological changes. Myosin61F (Myo61F) encodes another Myosin I, and Myo31DF or Myo61F overexpression reverses the laterality of different organs. Myo31DF and Myo61F have domains conserved in Myosin proteins, particularly in the proteins' head regions. We studied the roles of these domains in LR patterning using overexpression analysis. The Actin‐binding and ATP‐binding domains were essential for both proteins, but the IQ domains, binding sites for Myosin light chains, were required only by Myo31DF. Our results also suggest that the organ specificities of the Myo31DF and Myo61F activities depended on their head regions. Developmental Dynamics 237:3528–3537, 2008. © 2008 Wiley‐Liss, Inc.     

Desmoid‐type fibromatosis in a boy with Down syndrome

Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age‐matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid‐type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β‐catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β‐catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.     

Correcting Estimation Bias in Randomized Clinical Trials With a Test of Treatment-by-Biomarker Interaction

The key elements in recent drug development aiming toward personalized medicine involve the development of baseline predictive biomarkers to predict the responsiveness to new treatments. When biological evidence to support the biomarker hypothesis is not strong, it is particularly important to evaluate the clinical validity of a predictive biomarker based on data from clinical trials. All-comers randomized clinical trials stratified with biomarker measurements can provide the opportunity to evaluate the predictive value of the biomarker, and a test of treatment-by-biomarker interaction is applied for this purpose. If the interaction is significant, it is natural to proceed to a subgroup analysis that evaluates treatment efficacy within biomarker-based subgroups. However, estimation bias can arise when using the standard estimation method without regard to the significant interaction because of the correlation between the interaction test and subgroup analysis. In this paper, after evaluating the bias function for the standard estimators, we provide bias-corrected point and interval estimation methods, including polynomial approximations of the bias function previously developed for a fallback analysis plan. The magnitude of bias reduction and precision of the proposed estimators are assessed via simulations. Applications to biomarker-stratified, randomized phase III trials in oncology are provided. Supplementary materials for this article are available online.