Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy.

Population pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer.

WHAT IS KNOWN AND OBJECTIVE: This study aimed to elucidate the pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer (NSCLC) and to investigate the relationship between erlotinib exposure and the occurrence of interstitial lung disease (ILD)-like events. METHODS: Population pharmacokinetics analysis was performed using nonlinear mixed-effects modelling software (NONMEM) based on 348 plasma samples from 97 patients obtained in two phase II clinical studies. Individual empirical Bayesian estimates (EBEs) of apparent oral clearance (CL/F) and Cmax were compared between the patients who developed and did not develop ILD-like events. RESULTS: A 1-compartment model with first-order absorption and first-order elimination was used to describe the plasma concentrations of erlotinib. The estimated population pharmacokinetics parameters were as follows: 4·71 L/h for CL/F, 163 L for apparent volume of distribution (Vc /F) and 1·97 h(-1) for absorption rate constant (Ka ). Total bilirubin (TBIL) and alpha 1-acid glycoprotein (AGP) were identified as statistically significant covariates for CL/F. No differences in CL/F and Cmax were observed between the patients with ILD-like events and those without ILD-like events. WHAT IS NEW AND CONCLUSIONS: A population pharmacokinetics model of erlotinib was developed and validated in Japanese patients. There was no relationship between exposure of erlotinib before the occurrence of ILD-like events and the occurrence of ILD-like events when erlotinib was administered at the same dosage. The high plasma concentration of erlotinib reported in patients after the onset of ILD-like events may be explained by CL/F decrease which occurs along with increasing levels of AGP which was identified as a covariate for CL/F.

Endogenous memory CD8 T cells directly mediate cardiac allograft rejection.

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance-inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pretransplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen or adoptive transfer of donor antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here, we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming.

Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts.

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2−/− versus WT allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1ß and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.

Eye movements during emotion recognition in faces.

When distinguishing whether a face displays a certain emotion, some regions of the face may contain more useful information than others. Here we ask whether people differentially attend to distinct regions of a face when judging different emotions. Experiment 1 measured eye movements while participants discriminated between emotional (joy, anger, fear, sadness, shame, and disgust) and neutral facial expressions. Participant eye movements primarily fell in five distinct regions (eyes, upper nose, lower nose, upper lip, nasion). Distinct fixation patterns emerged for each emotion, such as a focus on the lips for joyful faces and a focus on the eyes for sad faces. These patterns were strongest for emotional faces but were still present when viewers sought evidence of emotion within neutral faces, indicating a goal-driven influence on eye-gaze patterns. Experiment 2 verified that these fixation patterns tended to reflect attention to the most diagnostic regions of the face for each emotion. Eye movements appear to follow both stimulus-driven and goal-driven perceptual strategies when decoding emotional information from a face.

Effect of occlusal rehabilitation on spatial memory and hippocampal neurons after long-term loss of molars in rats.

Experimental loss of occlusal support caused by the extraction or grinding of molar teeth has been reported to foment the impairment of learning and memory in laboratory animals. The purpose of this study was to examine the effect of occlusal reconstruction after long-term loss of molars on spatial memory by using 8-arm radial maze and by assessing histopathological changes of neuron density in the hippocampus. Experimental dentures were inserted into the oral cavities of molarless rats to recover the occlusal support. Age-matched groups of control, molarless and denture-wearing rats were trained to perform the maze tasks. The difference of the error incidence in the maze task was evaluated between three groups. The difference of neuron density between three groups was also evaluated at the end of the maze task. Serum corticosterone levels were also measured to estimate the chronic stress, which could be caused by extraction, insertion of the experimental denture or any experimental procedure. The error incidence in the denture-wearing group was significantly higher than that of the control group, but significantly lower than that of the molarless group. Significant differences of neuron density were observed between three groups in each of the hippocampal CA1, CA3 and DG subfields. No significant difference of the serum corticosterone levels between three groups could be observed. From the results of this study, it was suggested that the recovery of occlusal support would bring amelioration of cognitive impairment concomitant with long period loss of molars in rats.

Pth1r in Neural Crest Cells Regulates Nasal Cartilage Differentiation.

Neural crest cells (NCC) arise from the dorsal margin of the neural plate border and comprise a unique cell population that migrates to and creates the craniofacial region. Although factors including Shh, Fgf8, and bone morphogenetic proteins have been shown to regulate these biological events, the role of parathyroid hormone 1 receptor (Pth1r) has been less studied. We generated an NCC-specific mouse model for Pth1r and researched gene expression, function, and interaction focusing on nasal cartilage framework and midfacial development. Wnt1-Cre;Pth1rfl/fl;Tomatofl/+ mice had perinatal lethality, but we observed short snout and jaws, tongue protrusion, reduced NCC-derived cranial length, increased mineralization in nasal septum and hyoid bones, and less bone mineralization at interfrontal suture in mutants at E18.5. Importantly, the mutant nasal septum and turbinate cartilage histologically revealed gradual, premature accelerated hypertrophic differentiation. We then studied the underlying molecular mechanisms by performing RNA seq analysis and unexpectedly found that expression of Ihh and related signaling molecules was enhanced in mutant nasomaxillary tissues. To see if Pth1r and Ihh signaling are associated, we generated a Wnt1-Cre; Ihhfl/fl;Pth1rfl/fl;Tomatofl/+ (DKO) mouse and compared the phenotypes to those of each single knockout mouse: Wnt1-Cre; Ihhfl/fl;Pth1rfl/+;Tomatofl/+ (Ihh-CKO) and Wnt1-Cre;Ihhfl/+;Pth1rfl/fl;Tomatofl/+ (Pth1r-CKO). Ihh-CKO mice displayed a milder effect. Of note, the excessive hypertrophic conversion of the nasal cartilage framework observed in Pth1r-CKO was somewhat rescued DKO embryos. Further, a half cAMP responsive element and the 4 similar sequences containing 2 mismatches were identified from the promoter to the first intron in Ihh gene. Gli1-CreERT2;Pth1rfl/fl;Tomatofl/+, a Pth1r-deficient model targeted in hedgehog responsive cells, demonstrated the enlarged hypertrophic layer and significantly more Tomato-positive chondrocytes accumulated in the nasal septum and ethmoidal endochondral ossification. Collectively, the data suggest a relevant Pth1r/Ihh interaction. Our findings obtained from novel mouse models for Pth1r signaling illuminate previously unknown aspects in craniofacial biology and development.

Steroid sulphatase and oestrogen sulphotransferase in human non-small-cell lung carcinoma.

BACKGROUND: Steroid sulphatase (STS) is one of the steroid-metabolising enzymes involved in desulphating inactive steroid sulphates and oestrogen sulphotransferase (EST) sulphates active oestrogen. The roles of both STS and EST have not been examined in oestrogen-dependent non-small-cell lung cancer (NSCLC). METHODS: We evaluated the immunoreactivity of STS and EST in NSCLC cases using immunohistochemistry. The function of STS and EST was further demonstrated using NSCLC cell lines. RESULTS: The immunoreactivity of STS and EST was detected in 49.5% and 27.8% of NSCLC cases, respectively. The immunoreactivity of STS was significantly higher in female adenocarcinoma cases. The STS-positive NSCLCs were also significantly correlated in an inversed manner with tumour size and cell proliferation and tended to be associated with better clinical outcome. However, the immunoreactivity of EST was significantly correlated with intracellular oestradiol concentration. Results of in vitro analysis demonstrated that oestrone sulphate (E1-S) induced and pregnenolone sulphate (Preg-S) inhibited the proliferation in STS-expressing cell lines. The inhibition by Preg-S was reversed by a specific progesterone receptor blocker. Simultaneous addition of E1-S and Preg-S significantly suppressed the proliferation. CONCLUSION: In NSCLC patients, STS is considered a good prognostic factor. Results of our present study also indicated the benefits of potential progesterone therapy for NSCLC patients.

Endogenous memory CD8 T cells are activated within cardiac allografts without mediating rejection.

Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 12-24 h posttransplant in mice and are activated to proliferate and produce IFN-γ. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti-LFA-1 mAb given to allograft recipients on days 3 and 4 posttransplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG-treated recipients on day 7 posttransplant, allografts from anti-LFA-1 mAb-treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor-reactive CD8 T cells producing IFN-γ. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti-LFA-1 mAb continued to proliferate up to day 7 posttransplant and did not upregulate expression of the exhaustion marker LAG-3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection.

Transient lymphopenia breaks costimulatory blockade-based peripheral tolerance and initiates cardiac allograft rejection.

Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long-term graft acceptance. After vascularized MHC-mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti-CD4 plus anti-CD8 mAb. Long-term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44(high) effector/memory T cells in lymphatic organs and strong recovery of donor-reactive T cell responses, indicating lymphopenia-induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4(+) Foxp(3+)) cell and B cell numbers as well as donor-specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor-reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.

Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma.

The pathogenesis of multiple myeloma (MM), an incurable tumour causing the deregulated proliferation of terminally differentiated B cells, is unknown. Chromosomal translocations (14q1) affecting band 14q32 and unidentified partner chromosomes are common in this tumour, suggesting that they may cause the activation of novel oncogenes. By cloning the chromosomal breakpoints in an MM cell line, we show that the 14q+ translocation represents a t(6;14)x(p25;q32) and that this aberration is recurrent in MM, as it was found in two of eleven MM cell lines. The translocation juxtaposes the immunoglobulin heavy-chain (IgH) locus to MUM1 (multiple myeloma oncogene 1)/IRF4 gene, a member of the interferon regulatory factor (IRF) family known to be active in the control of B-cell proliferation and differentiation. As a result, the MUM1/IRF4 gene is overexpressed--an event that may contribute to tumorigenesis, a MUM1/IRF4 has oncogenic activity in vitro. These findings identify a novel genetic alteration associated with MM, with implications for the pathogenesis and diagnostics of this tumour.

Pth1r Signal in Gli1+ Cells Maintains Postnatal Cranial Base Synchondrosis.

Cranial base synchondroses are the endochondral ossification centers for cranial base growth and thus indispensable for proper skull, brain, and midfacial development. The synchondroses are composed of mirror-image growth plates that are continuously maintained from the embryonic to postnatal stage through chondrocyte differentiation. Several factors, including Pth1r signaling, are known to control fetal synchondrosis development. However, there are currently no reports regarding any role for Pth1r signaling in postnatal cranial base and synchondrosis development. Also, the mesenchymal cells that source Pth1r signaling for synchondroses are not known. Here, we employed an inducible mouse model, a hedgehog-responsive Gli1-CreERT2 driver, focusing on the postnatal study. We performed 2 inducible protocols using Gli1-CreERT2;Tomatofl/+ mice that uncovered distinct patterning of Gli1-positive and Gli1-negative chondrocytes in the synchondrosis cartilage. Moreover, we generated Gli1-CreERT2;Pth1rfl/fl;Tomatofl/+ mice to assess their functions in postnatal synchondrosis and found that the mutants had survived postnatally. The mutant skulls morphologically presented unambiguous phenotypes where we noticed the shortened cranial base and premature synchondrosis closure. Histologically, gradual disorganization in mutant synchondroses caused an uncommon remaining central zone between hypertrophic zones on both sides while the successive differentiation of round, flat, and hypertrophic chondrocytes was observed in control sections. These mutant synchondroses disappeared and were finally replaced by bone. Of note, the mutant fusing synchondroses lost their characteristic patterning of Gli1-positive and Gli1-negative chondrocytes, suggesting that loss of Pth1r signaling alters the distribution of hedgehog-responsive chondrocytes. Moreover, we performed laser microdissection and RNA sequencing to characterize the flat proliferative and round resting chondrocytes where we found flat chondrocytes have a characteristic feature of both chondrocyte proliferation and maturation. Taken together, these data demonstrate that Pth1r signaling in Gli1-positive cells is essential for postnatal development and maintenance in cranial base synchondroses. Our findings will elucidate previously unknown aspects of Pth1r functions in cranial biology and development.

New image analysis of large food particles can discriminate experimentally suppressed mastication.

Objective parameters that could provide a basis for food texture selection for elderly or dysphagic patients have not been established. We, therefore, aimed to develop a precise method of measuring large particles (>2 mm in diameter) in a bolus and an analytical method to provide a scientific rationale for food selection under masticatory dysfunction conditions. We developed a new illumination system to evaluate the ability of twenty female participants (mean age, 23·4 ± 4·3 years) to masticate carrots, peanuts and beef with full, half and one quarter of the number of masticatory strokes. We also evaluated mastication under suppressed force, regulated by 20% electromyographic of the masseter muscle. The intercept and inclination of the regression line for the distribution of large particles were adopted as coefficients for the discrimination of masticatory efficiency. Single set of coefficient thresholds of 0·10 for the intercept and 1·62 for the inclination showed excellent discrimination of masticatory conditions for all three test foods with high specificity and sensitivity. These results suggested that our method of analysing the distribution of particles >2 mm in diameter might provide the basis for the appropriate selection of food texture for masticatory dysfunction patients from the standpoint of comminution.

Preliminary study evaluating the accuracy of MRI images on CBCT images in the field of orthodontics.

OBJECTIVE: The purpose of this study was to explore the 3-dimensional (3D) accuracy of magnetic resonance imaging (MRI) on cone-beam computed tomography (CBCT) images after the registration of MRI images on CBCT images. MATERIALS AND METHODS: Three Japanese adult females volunteered for this study. To transform digital imaging and communication in medicine (DICOM) data derived from MRI and CBCT images into polygon data, five software programs were used. CBCT and MRI images were obtained within one week, and both were registered by the iterative closest point (ICP) method. To assess the accuracy of the composite MRI-CBCT, the measurement errors of the MRI-CBCT were verified Measurement values were compared using frontal and cephalometric soft-tissue landmarks. Differences were analyzed using the non-parametric Mann-Whitney U test. RESULTS: There were no significant linear measurement errors (P > 0.05) when the images were measured from the superimposed MRI-CBCT images. CONCLUSION: The MRI images attained from MRI - CBCT registration showed accurate 3D linear measurements.

A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

Spontaneous repair of asymptomatic osteonecrosis associated with corticosteroid therapy in systemic lupus erythematosus: 10-year minimum follow-up with MRI.

Systemic lupus erythematosus (SLE) patients are at high risk of developing osteonecrosis. This study utilized MRI to document the long-term natural history of asymptomatic osteonecrosis associated with corticosteroid therapy in SLE patients. Two hundred and one SLE patients treated with high-dose corticosteroids were prospectively observed from 1986 to 1997. The inclusion criterion was that patients had received periodic MRI examinations of all their hip and knee joints for ≥10 years. Joints that were already collapsed and symptomatic at the first examination were excluded. Five hundred and thirty-seven joints (251 hips and 286 knees) were identified in 144 patients, with a mean follow-up period of 13.6 years (range, 10-20 years) and a follow-up rate of 73%. Mean age of SLE onset was 26 years, and the mean highest oral corticosteroid dosage was 57 mg/day. Osteonecrosis developed in 238 (44%) of 537 joints. At final follow-up, 117 (49%) of these 238 joints demonstrated spontaneous repair in the necrotic area. Osteonecrosis completely disappeared in 21 joints. Enlargement of osteonecrosis was noted in 35 joints (15%) following increased steroid dosage because of SLE recurrence. Finally, 52 joints (22%) were collapsed. Spontaneous repair of asymptomatic osteonecrosis was observed, whereas enlargement occurred only after corticosteroid dosage increases.

[Immunohistochemical evaluation of somatostatin receptor subtypes in surgical pathology specimens of neuroendocrine tumors]. / Immunhistochemische Beurteilung von Somatostatinrezeptorsubtypen im Entnahmematerial neuroendokriner Tumoren.

The clinical development of specific/selective or more potent analogues of somatostatin has made the evaluation of somatostatin receptor subtypes in archival specimens or 10% formalin-fixed and paraffin-embedded specimens of neuroendocrine tumor (NET) critical to conferring the maximum clinical benefits on NET patients. Immunohistochemistry of somatostatin receptor subtypes could contribute to profiling their expression patterns in these patients. Therefore, surgical pathologists are expected to be asked to immunostain and evaluate somatostatin receptor subtypes in NET specimens in the near future by clinicians. However, there are problems associated with immunohistochemistry of somatostatin receptor subtypes, in particular with their evaluation and interpretation. Therefore, both pathologists and clinicians involved in the care or management of NET patients should be aware of the advantages and limitations of immunohistochemical evaluation of somatostatin receptor subtypes in order to achieve the most efficient treatment outcome for patients.

Positronium formation at 4H SiC(0001) surfaces.

Positronium formation at 4H SiC(0001) surfaces were investigated upon the removal of natural oxide layers by hydrofluoric acid etching and heat treatment at 1000 K in ultra-high vacuum. Two types of positronium were observed in the positronium time-of-flight (PsTOF) measurements irrespective of conduction type and surface polarity. One type formed the major part of the PsTOF spectrum with a maximum energy of 4.7 ± 0.3 eV. This energy exceeded the theoretical value calculated with valence electrons. The PsTOF spectrum shape was different from those of metal surfaces, suggesting that the surface state electrons or conduction electrons need to be considered as the positronium source. Another positronium appeared at 1000 K in the tail of the PsTOF spectrum with a maximum energy of 0.2-0.5 eV. This thermally-assisted athermal positronium may be formed via the surface state positrons and electrons.

Acute antibody-mediated rejection in living ABO-incompatible kidney transplantation: long-term impact and risk factors.

The impact of acute antibody-mediated rejection (AAMR) on the long-term outcome on ABO-incompatible (ABOI) kidney transplantation is not well understood. We retrospectively analyzed the long-term impact of AAMR and risk factors for AAMR in 57 consecutive recipients performed between 1999 and 2004. Nineteen patients (33%) who developed AAMR within 3 months posttransplantation constituted of the AMR group. The graft survival rate was significantly lower in the AMR group (AMR vs. non-AMR, respectively; 5 years: 84% vs. 95%; 8 years: 45% vs. 95%; p = 0.009). The prevalence of transplant glomerulopathy at 1 year posttransplantation was significantly higher in the AMR group (AMR 64% vs. non-AMR 3%, p < 0.001). Multivariate analysis demonstrated that anti-blood group IgG antibody titers of 1:32 at the time of transplantation (OR, 9.52; p = 0.041) and donor-specific anti-HLA antibodies (DSHA) detected by Luminex single bead method (OR, 5.68; p = 0.015) were independent risk factors for AAMR regardless of baseline anti-blood group IgG antibody titers. Our results indicate that AAMR has a heavy impact on the long-term outcome and preoperative DSHA appears to have a more significant association with poor graft outcomes than anti-blood group antibodies, even in ABOI kidney transplantation.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.