MMP1, IL-1ß, sTNFR-1, and IL-6 are prognostic factors for patients with unresectable or metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC. METHODS: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan-Meier method, and the COX proportional hazards model. RESULTS: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1ß (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648-17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426-166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039). CONCLUSION: MMP1 may be associated with severe irAE, and MMP1, IL-1ß, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs.

Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated. METHODS: Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed to evaluate their clinical significance. RESULTS: Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95% CI 1.10-86.7, P = 0.009) and overall survival (OS; HR 11.4, 95% CI 1.19-52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122) but not in those treated with ICIs combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95% CI 0.06-0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95% CI 1.42-21.0, P = 0.008) and OS (HR 42.6, 95% CI 6.83-226, P < 0.001). The levels of sPD-L1 at baseline closely correlated with those of other soluble factors, such as sCD30, IL-2Ra, sTNF-R1, and sTNF-R2, which are known to be released from the cell surface by zinc-binding proteases ADAM10/17. CONCLUSIONS: These findings suggest the clinical significance of pretreatment sPD-L1 as well as posttreatment sPD-1 and sPD-L1 in NSCLC patients treated with ICI monotherapy.

Clinical significance of peripheral TCR and BCR repertoire diversity in EGFR/ALK wild-type NSCLC treated with anti-PD-1 antibody.

INTRODUCTION: TCR and BCR repertoire diversity plays a critical role in tumor immunity. Thus, analysis of TCR and BCR repertoires might help predict the clinical efficacy of anti-PD-1 treatment. METHODS: Blood samples from 30 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibody were collected before and six weeks after treatment initiation. The clinical significance of TCR and BCR repertoire diversity in peripheral blood was evaluated in all the enrolled patients (n = 30) or in the subset with (n = 10) or without (n = 20) EGFR/ALK mutation. RESULTS: TCR and BCR diversity was significantly correlated at baseline (R = 0.65; P = 1.6 × 10-4) and on treatment (R = 0.72; P = 1.2 × 10-5). Compared to non-responders (SD or PD), responders (PR) showed significantly decreased TCR and BCR diversity after treatment in the EGFR/ALK wild-type subset (P = 0.0014 and P = 0.034, respectively), but not in all the enrolled patients. The post-treatment reduction in TCR and BCR repertoire diversity was also significantly associated with the occurrence of adverse events in the EGFR/ALK wild-type subset (P = 0.022 and P = 0.014, respectively). Patients with more reduced TCR diversity showed better progression-free survival (PFS) in the EGFR/ALK wild-type subset (P = 0.011) but not in the mutant subset. CONCLUSIONS: These findings suggest the clinical significance of changes in peripheral TCR and BCR repertoire diversity after anti-PD-1 treatment in patients with NSCLC without EGFR/ALK mutation. Monitoring of the peripheral TCR and BCR repertoires may serve as a surrogate marker for the early detection of EGFR/ALK wild-type NSCLC patients who would benefit from anti-PD-1 treatment.

Illusory visual-depth reversal can modulate sensations of contact surface.

To perceive the external world stably, humans must integrate and manage continuous streams of information from various sensory modalities, in addition to drawing on past experiences and knowledge. In this study, we introduce a novel visuo-tactile illusion elicited by a visual-depth-reversal stimulus. The stimulus (a model of a building) was constructed so as to produce the same retinal image as an opaque cuboid, although it actually consisted of only three PVC boards forming a three-dimensional corner with the hollow inside facing the observer. Participants holding the model in their palm, therefore, observed, with both eyes or one eye, a building model that could be interpreted as either a concave or a convex cuboid. That is, tactile information from the contact surface contradicted the visual interpretation of a convex cuboid. Questionnaire and experimental results, however, showed that the building model was stably viewed as a standing cuboid, particularly under monocular observation. Participants also reported feeling a stable touch of the shrinking base of the apparently standing building model, thus ignoring the veridical contact surface. Given that the visual-tactile information was unchanged with or without the illusion and that the experimental task was tactile estimation, it is remarkable that participants failed to perceive actual touch based on the object's appearance. Results indicate the complexity and flexibility of visual-tactile integration processes. We also discuss the possibility that object knowledge influences visual-tactile integration.

Blockade of invariant TCR-CD1d interaction specifically inhibits antibody production against blood group A carbohydrates.

Previously, we detected B cells expressing receptors for blood group A carbohydrates in the CD11b(+)CD5(+) B-1a subpopulation in mice, similar to that in blood group O or B in humans. In the present study, we demonstrate that CD1d-restricted natural killer T (NKT) cells are required to produce anti-A antibodies (Abs), probably through collaboration with B-1a cells. After immunization of wild-type (WT) mice with human blood group A red blood cells (A-RBCs), interleukin (IL)-5 exclusively and transiently increased and the anti-A Abs were elevated in sera. However, these reactions were not observed in CD1d(-/-) mice, which lack NKT cells. Administration of anti-mouse CD1d blocking monoclonal Abs (mAb) prior to immunization abolished IL-5 production by NKT cells and anti-A Ab production in WT mice. Administration of anti-IL-5 neutralizing mAb also diminished anti-A Ab production in WT mice, suggesting that IL-5 secreted from NKT cells critically regulates anti-A Ab production by B-1a cells. In nonobese diabetic/severe combined immunodeficient (NOD/SCID/γc(null)) mice, into which peripheral blood mononuclear cells from type O human volunteers were engrafted, administration of anti-human CD1d mAb prior to A-RBC immunization completely inhibited anti-A Ab production. Thus, anti-CD1d treatment might constitute a novel approach that could help in evading Ab-mediated rejection in ABO-incompatible transplant recipients.

[Collaborative study on regulatory science for facilitating clinical development of gene therapy products for genetic diseases].

Gene therapy products are expected as innovative medicinal products for intractable diseases such as life-threatening genetic diseases and cancer. Recently, clinical developments by pharmaceutical companies are accelerated in Europe and the United States, and the first gene therapy product in advanced countries was approved for marketing authorization by the European Commission in 2012. On the other hand, more than 40 clinical studies for gene therapy have been completed or ongoing in Japan, most of them are conducted as clinical researches by academic institutes, and few clinical trials have been conducted for approval of gene therapy products. In order to promote the development of gene therapy products, revision of the current guideline and/or preparation of concept paper to address the evaluation of the quality and safety of gene therapy products are necessary and desired to clearly show what data should be submitted before First-in-Human clinical trials of novel gene therapy products. We started collaborative study with academia and regulatory agency to promote regulatory science toward clinical development of gene therapy products for genetic diseases based on lentivirus and adeno-associated virus vectors; National Center for Child Health and Development (NCCHD), Nippon Medical School and PMDA have been joined in the task force. At first, we are preparing pre-draft of the revision of the current gene therapy guidelines in this project.

Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma.

Introduction: This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). Methods: We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6 weeks after initiating pembrolizumab therapy. The association of estimated soluble immune mediators with clinical outcomes, including overall survival (OS), progression-free survival (PFS), anti-tumor responses, and irAEs, were statistically evaluated. Results: In the multivariate analysis, levels of 18 factors at baseline and 12 factors during treatment were significantly associated with OS. Regarding PFS, baseline levels of 17 factors were significantly associated with PFS. Higher levels of interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNF-R1), and IL-12 (p40), both at baseline and post-treatment, were significantly associated with worse OS. Conversely, low IL-6 and high TWEAK levels at baseline were associated with irAEs. Among identified factors, interferon (IFN) γ and IL-12 (p40) were repeatedly identified; high baseline levels of these factors were risk factors for worse OS and PFS, as well as progressive disease. Notably, using correlation and principal component analysis, factors significantly associated with clinical outcomes were broadly classified into three groups exhibiting similar expression patterns. Discussion: Measuring plasma levels of soluble immune mediators, such as IL-6, IL-8, sTNF-R1, IFNγ, and IL-12 (p40), could be recommended for predicting prognosis and irAEs in ICI-treated patients with aUC.

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has substantially improved the overall survival (OS) in patients with non-small-cell lung cancer (NSCLC); however, its response rate is still modest. In this study, we developed a machine learning-based platform, namely the Cytokine-based ICI Response Index (CIRI), to predict the ICI response of patients with NSCLC based on the peripheral blood cytokine profiles. METHODS: We enrolled 123 and 99 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy or combined chemotherapy in the training and validation cohorts, respectively. The plasma concentrations of 93 cytokines were examined in the peripheral blood obtained from patients at baseline (pre) and 6 weeks after treatment (early during treatment: edt). Ensemble learning random survival forest classifiers were developed to select feature cytokines and predict the OS of patients undergoing ICI therapy. RESULTS: Fourteen and 19 cytokines at baseline and on treatment, respectively, were selected to generate CIRI models (namely preCIRI14 and edtCIRI19), both of which successfully identified patients with worse OS in two completely independent cohorts. At the population level, the prediction accuracies of preCIRI14 and edtCIRI19, as indicated by the concordance indices (C-indices), were 0.700 and 0.751 in the validation cohort, respectively. At the individual level, patients with higher CIRI scores demonstrated worse OS [hazard ratio (HR): 0.274 and 0.163, and p<0.0001 and p=0.0044 in preCIRI14 and edtCIRI19, respectively]. By including other circulating and clinical features, improved prediction efficacy was observed in advanced models (preCIRI21 and edtCIRI27). The C-indices in the validation cohort were 0.764 and 0.757, respectively, whereas the HRs of preCIRI21 and edtCIRI27 were 0.141 (p<0.0001) and 0.158 (p=0.038), respectively. CONCLUSIONS: The CIRI model is highly accurate and reproducible in determining the patients with NSCLC who would benefit from anti-PD-1/PD-L1 therapy with prolonged OS and may aid in clinical decision-making before and/or at the early stage of treatment.

Rho inhibitor prevents ischemia-reperfusion injury in rat steatotic liver.

BACKGROUND & AIMS: Hepatic stellate cells are thought to play a role in modulating intrahepatic vascular resistance based on their capacity to contract via Rho signaling. We investigated the effect of a Rho-kinase inhibitor on ischemia-reperfusion injury in the steatotic liver. METHODS: Steatotic livers, induced by a choline-deficient diet in rats, were subjected to ischemia-reperfusion injury. Hepatic stellate cells isolated from steatotic livers were analyzed for contractility and Rho signaling activity. The portal pressure of the perfused rat liver and the survival rate after ischemia-reperfusion were also investigated. RESULTS: Hepatic stellate cells from steatotic livers showed increased contractility and upregulation of Rho-kinase 2 compared with those from normal livers. Furthermore, endothelin-1 significantly enhanced the contractility and phosphorylation level of myosin light chain and cofilin in hepatic stellate cells isolated from steatotic livers. A specific Rho-kinase inhibitor, fasudil, significantly suppressed the contractility and decreased the phosphorylation levels of myosin light chain and cofilin. Serum levels of endothelin-1 were markedly increased after IR in rats with steatotic livers, whereas fasudil significantly decreased endothelin-1 serum levels. Rats with steatotic livers showed a significant increase in portal perfusion pressure after ischemia-reperfusion and a significant decrease in survival rate; fasudil treatment significantly reduced these effects. CONCLUSIONS: Activation of Rho/Rho-kinase signaling in hepatic stellate cells isolated from steatotic livers is associated with an increased susceptibility to ischemia-reperfusion injury. A Rho-kinase inhibitor attenuated the activation of hepatic stellate cells isolated from steatotic livers and improved ischemia-reperfusion injury in steatotic rats.

Influence of the body on crossmodal interference effects between tactile and two-dimensional visual stimuli.

We investigated how tactile discrimination performance was interfered with by irrelevant two-dimensional visual stimuli using the crossmodal interference task. Participants made speeded discrimination responses to the location of vibrotactile targets presented to either tip or base of their forefinger, while trying to ignore simultaneously presented visual distractors presented to either side of the central fixation on a front display. The array of visual distractors was presented at four different angles, and the participants rested their stimulated hand on a desk in either a forward-pointing or inward-pointing posture. Although there was apparently no specific spatial relationship between the tactile and two-dimensional visual stimuli arrays and the spatial response requirement was controlled, visuotactile interference effects occurred between them. Moreover, we found that the spatial relationships between the arrays depended on the potential range of movement and the current posture of the vibrotactile-stimulated hand and possibly the stored orientation of our hand representation, even without any explicit cue referring to hands. Our results suggest that the visuotactile spatial interactions involve multiple mechanisms regarding our bodily perception and our internal body representation.

Cancer Vaccines: Toward the Next Breakthrough in Cancer Immunotherapy.

Until now, three types of well-recognized cancer treatments have been developed, i.e., surgery, chemotherapy, and radiotherapy; these either remove or directly attack the cancer cells. These treatments can cure cancer at earlier stages but are frequently ineffective for treating cancer in the advanced or recurrent stages. Basic and clinical research on the tumor microenvironment, which consists of cancerous, stromal, and immune cells, demonstrates the critical role of antitumor immunity in cancer development and progression. Cancer immunotherapies have been proposed as the fourth cancer treatment. In particular, clinical application of immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, in various cancer types represents a major breakthrough in cancer therapy. Nevertheless, accumulating data regarding immune checkpoint inhibitors demonstrate that these are not always effective but are instead only effective in limited cancer populations. Indeed, several issues remain to be solved to improve their clinical efficacy; these include low cancer cell antigenicity and poor infiltration and/or accumulation of immune cells in the cancer microenvironment. Therefore, to accelerate the further development of cancer immunotherapies, more studies are necessary. In this review, we will summarize the current status of cancer immunotherapies, especially cancer vaccines, and discuss the potential problems and solutions for the next breakthrough in cancer immunotherapy.

C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma.

PURPOSE: Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1 month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. METHODS: After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1 month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. RESULTS: The median follow-up was 8.3 months (range 0.2-29.8 months). The median PFS period was 4.5 months and the median immune-PFS (iPFS) period was 5.3 months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (≥ 2) at start of treatment and CRP level at 1 month after treatment (≥ 1.5 mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1 month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (≥ 1.5 mg/dL) obtained good iPFS if CRP was decreased (< 1.5 mg/dL) 1 month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1 month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. CONCLUSION: Our results indicated that the CRP level at 1 month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.

Characterization of hepatic sexual dimorphism in Alb-DsRed2 transgenic rats.

We previously created the Alb-DsRed2 transgenic (Tg) rat that specifically expresses the red fluorescent protein, DsRed2, in the liver. Herein, we demonstrate that the DsRed2 expression is sexually dimorphic and exhibits a male-specific pattern. The profiling of sexual dimorphism in DsRed2 expression during pre-pubertal development was investigated using an in vivo fluorescent imaging analysis. The DsRed2 expression decreased gradually in both sexes until 28days after birth. While DsRed2 expression was not persistent in the female liver, the male hepatic expression increased again at 35days. Sexual dimorphic DsRed2 expression did not change in gonadectomized male and female Tg-rats. However, female hepatic DsRed2 was induced 72h after the hypophysectomy. Hepatocytes isolated from the female Tg-rats also revealed DsRed2 induction by 96h in culture. These results suggest that the pituitary hormone suppresses the female hepatic DsRed2 expression causing the sexual dimorphism of DsRed2 expression.

Prospects for a personalized peptide vaccine against lung cancer.

Introduction: The tumor characteristics and immunological status of the host should be carefully considered for the successful development of cancer peptide vaccines. Recently, personalized peptide vaccines (PPV) that individually select antigens for each patient are being developed for lung cancer. Areas covered: Novel PPV, in which appropriate vaccine antigens are selected in each patient by assessing preexisting immunity to a panel of vaccine peptide candidates, have been attempted with promising results in early-phase clinical trials for lung cancer. Additionally, PPV targeting neo-antigens derived from genetic mutations have been currently attempted with high anticipation of success in various cancers, because they can be recognized as foreign by the host immune system. In this review, we present an overview of the current progress and future directions of such PPV for patients with lung cancer. Expert opinion: Both genetic characterization of tumor cells and assessment of the immune responses to potential tumor antigens might be a key component for facilitating successful cancer vaccine development. In addition, not only selection of immunogenic epitopes, but also appropriate modulation of the host immunological status should be considered; clinical trials combining neo-antigen vaccines and anti-PD-1 antibodies for lung cancer are currently ongoing and their results are awaited.

Depth inversion with a 3D structure influences brightness perception.

Whether or not depth perception influences brightness and/or lightness perception has been repeatedly discussed, and some studies have emphasized its importance. In addition, a small number of studies have empirically tested and shown the effect of depth inversion, such as seen in the Mach card illusion, on perceived lightness, and they interpreted such results in terms of lightness constancy. However, how perceived brightness changes contingent on depth inversion remains unexplained. Therefore, this study used the matching method to examine changes in brightness perception when depth inversion is observed. We created and used a three-dimensional (3D) concave object, composed of three sides made of card stock, which could be perceived as having two different shapes in 3D; it could be perceived as a horizontal concave object, corresponding to its actual physical structure, and as a convex standing object, similar in shape to a building. Participants observed this object as both a concave object and as a convex object, and judged the brightness of its surfaces during each observation. Our results show that the perception of the brightness of the object's surfaces clearly changed depending on the perception of depth. When the object was seen as convex, one part of the surface was perceived as darker than when the object was seen as concave, but the other part of the surface remained unchanged. Here we discuss the relationship between depth perception and brightness perception in terms of perceptual organization.

Role of invariant natural killer T cells in liver sinusoidal endothelial cell-induced immunosuppression among T cells with indirect allospecificity.

We have previously demonstrated that liver sinusoidal endothelial cells (LSECs) that endocytose portally injected allogeneic cells exert immunosuppressive effects on T cells with indirect allospecificity. In this study, we have demonstrated that invariant natural killer T cells plays a significant role in such immunosuppressive effects induced by LSECs. The endocytic activity of LSECs toward intraportally injected splenocytes from B6 major histocompatibility complex class II-deficient C2ta (C2D) mice was markedly impaired in BALB/c CD1d-deficient mice. The intraportal adoptive transfer of LSECs isolated from BALB/c wild-type mice treated with a portal injection of B6 C2D splenocytes into BALB/c mice significantly prolonged the survival of subsequently transplanted heart allografts; however, the transfer of LSECs isolated from similarly treated BALB/c CD1d-deficient mice did not produce such a survival prolonging effect. These findings indicate that natural killer T cells are required for the LSEC-induced immune modulation of T cells with indirect allospecificity.

Engraftment of human hepatocytes in the livers of rats bearing bone marrow reconstructed with immunodeficient mouse bone marrow cells.

BACKGROUND: Previously, we created, a chimeric mouse (humanized mouse), a severe combined immunodeficiency (SCID) mouse whose liver was >90% repopulated with human (h)-hepatocytes, which are useful for the testing of drug metabolism and toxicity, as well as a hepatitis B virus and hepatitis C virus-susceptible animal model. However, their small body size and small total blood volume limited the utilization for analytical purposes, which led us to develop a method to create a chimeric rat bearing h-hepatocyte-repopulated liver. METHODS: F344 nude rats devoid of T cells were irradiated with X-rays and injected with bone marrow cells (BMCs) from SCID mice (m(SCID)). The rate of replacement with m(SCID)-BMCs was evaluated by two-color flow cytometry analysis of peripheral blood mononuclear cells (PBMCs). After m(SCID)-BMCs repopulated the host bone marrow (BM), the rats were treated with retrorsine, partially hepatectomized (PHx), and transplanted with 5 x 10(6) h-hepatocytes isolated from the chimeric mice. h-Albumin (h-Alb) concentrations in the host blood and the expression levels of protein and mRNA of hepatocyte differentiation markers in the h-hepatocytes were evaluated by ELISA, immunostaining, and reverse transcription-PCR, respectively. RESULTS: The m(SCID)-BMCs successfully repopulated the rats, the percentage of mouse cells reaching 94% among host (r(nudeF344)) PBMCs at 4 weeks after m-BMC transplantation. h-Hepatocytes isolated from the chimeric mice were transplanted to the liver of the m(SCID)-BMC-repopulated rats. The engrafted h-hepatocytes expressed h-Alb and h-cytochrome P450 (CYP) subtypes and survived showing normal phenotypes until at least 3 weeks post-h-hepatocytes transplantation (h-HPCT). However, the blood concentrations of h-Alb declined at 4 weeks post-HPCT, concomitant with the emergence of both r(nudeF344)- and m(SCID)-macrophages, suggesting the rejection of h-hepatocytes due to the activation of macrophages. CONCLUSION: We developed a novel method to create a rat that bears the liver engrafted with h-hepatocytes, utilizing a rat with the BM composed of m(SCID)-BMCs as a host. This h-hepatocyte-bearing rat will be a valuable model for studying the immunologic mechanisms involved in xenogeneic transplantation and for generating rats with higher rates of repopulation with h-hepatocytes.

The selective effect of the image of a hand on visuotactile interactions as assessed by performance on the crossmodal congruency task.

Seeing one's own body (either directly or indirectly) can influence visuotactile crossmodal interactions. Previously, it has been shown that even viewing a simple line drawing of a hand can also modulate such crossmodal interactions, as if viewing the picture of a hand somehow primes the representation of one's own hand. However, factors other than the sight of a symbolic picture of a hand may have modulated the crossmodal interactions reported in previous research. In the present study, we examined the crossmodal modulatory effects of viewing five different visual images (photograph of a hand, line drawing of a hand, line drawing of a car, an U-shape, and an ellipse) on tactile performance. Participants made speeded discrimination responses regarding the location of brief vibrotactile targets presented to either the tip or base of their left index finger, while trying to ignore visual distractors presented to either the left or right of central fixation. We compared the visuotactile congruency effects elicited when the five different visual images were presented superimposed over the visual distractors. Participants' tactile discrimination performance was modulated to a significantly greater extent by viewing the photograph of a hand than when viewing the outline drawing of a hand. No such crossmodal congruency effects were reported in any of the other conditions. These results therefore suggest that visuotactile interactions are specifically modulated by the image of the hand rather than just by any simple orientation cues that may be provided by the image of a hand.