Pig kidney graft survival in a baboon for 136 days: longest life‐supporting organ graft survival to date

The longest survival of a non‐human primate with a life‐supporting kidney graft to date has been 90 days, although graft survival > 30 days has been unusual. A baboon received a kidney graft from an α‐1,3‐galactosyltransferase gene‐knockout pig transgenic for two human complement‐regulatory proteins and three human coagulation‐regulatory proteins (although only one was expressed in the kidney). Immunosuppressive therapy was with ATG+anti‐CD20mAb (induction) and anti‐CD40mAb+rapamycin+corticosteroids (maintenance). Anti‐TNF‐α and anti‐IL‐6R were administered. The baboon survived 136 days with a generally stable serum creatinine (0.6 to 1.6 mg/dl) until termination. No features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein‐losing nephropathy were observed. There was no evidence of an elicited anti‐pig antibody response. Death was from septic shock (Myroides spp). Histology of a biopsy on day 103 was normal, but by day 136, the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion. The combination of (i) a graft from a specific genetically engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti‐inflammatory agents prevented immune injury and a protein‐losing nephropathy, and delayed coagulation dysfunction. This outcome encourages us that clinical renal xenotransplantation may become a reality.     

Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.     

Immunosuppressive and metabolic agents that influence allo- and xenograft survival by in vivo expansion of T regulatory cells

The transplanted organs or cells survive if the recipient receives adequate long-term immunosuppressive therapy. Immunosuppressive therapy combined with cell-based strategies (eg, regulatory T cell [Treg]-based therapy) promotes graft survival. A combination of Treg-based therapy and minimal or no immunosuppressive drug therapy would have the potential to minimize the risks of the complications and side effects of these drugs. Fortunately, some immunosuppressive and other agents not only impede the effector T cell response, but also help generate new CD4⁺ Tregs from conventional effector T cells. These agents include IL-2, TGF-β, agents that block the CD40/CD40L costimulation pathway, mTOR inhibitors, and histone deacetylase inhibitors. Consequently, a state of relative unresponsiveness to the transplanted organ may be induced through the expansion of Tregs. We here review the effect of these various agents on expansion of CD4⁺ Tregs in allo- and xenotransplantation. The expansion of Tregs might allow a dose reduction of the standard immunosuppressive drugs.     

The tumour shape of lung adenocarcinoma is related to the postoperative prognosis

We evaluated the tumour shape as a potential prognostic indicator in lung adenocarcinoma patients. Among 994 patients who underwent curative surgery, 78 cases of adenocarcinoma (N0M0) with tumours ≥ 31 mm in diameter were reviewed. The patients were divided into two groups based on the ratio between the longest and the smallest axis length. The patients who had tumours whose ratios were > 0.5 were defined as the globular shape group (GL) and the others, whose ratio was 0.5 or less, were defined as the ellipse shape group (EL). The 78 patients were divided into two subgroups (57 in the GL and 21 in the EL). The tumour shape was related to the prognosis, and the 5-year overall survival (OS) rate in the GL was 51.5%, and that in the EL was 85.5% (P = 0.018). The 5-year disease-free survival rate of the GL was 46.6% and that of the EL patients was 85.0% (P = 0.04). The multivariate analysis showed that the shape of the tumour and the presence of pleural invasion were the independent and significant factors predicting the OS (P = 0.04 and P < 0.01, respectively). In adenocarcinoma patients, the shape of the tumour is related to the postoperative survival.     

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin

Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The K_m value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the K_m and V_max values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd.     

Tidal volume and diaphragm muscle activity in rats with cervical spinal cord injury

[Purpose] The purpose of this study was to make an experimental model of cervical spinal cord injury (CSCI) using Wistar rats, in order to analyze the influence of CSCI on the respiratory function. [Subjects] Thirty-two male 12-week-old Wistar rats were used. [Methods] The CSCI was made at the levels from C3 to C7, and we performed pneumotachography and electromyography (EMG) on the diaphragm. Computed tomography was used to determine the level of spinal cord damage. [Results] After the operation, the tidal volume of the rats with a C3 level injury decreased to approximately 22.3% of its pre-injury value. In addition, in the same rats, the diaphragmatic electromyogram activity decreased remarkably. Compared with before CSCI, the tidal volume decreased to 78.6% of its pre-injury value in CSCI at the C5 level, and it decreased to 94.1% of its pre-injury value in CSCI at the C7 level. [Conclusion] In the rats that sustained a CSCI in this study, the group of respiratory muscles that receive innervation from the thoracic spinal cord was paralyzed. Therefore, the EMG signal of the diaphragm increased. These results demonstrate that there is a relationship between respiratory function and the level of CSCI.Key words: Cervical spinal cord injury, Respiratory function, Electromyography of diaphragm muscle     

Easy Diagnosis of Aortic Invasion in Patients with Lung Cancer Using Cine Magnetic Resonance Imaging

Selecting the proper treatment strategy for locally advanced lung cancer, such as T4 tumors, is difficult. Therefore, obtaining an accurate diagnosis of T4 tumors is required. It can be difficult to determine whether the tumor invades adjacent structures. We describe the case of a patient easily diagnosed to be without aortic invasion using cine magnetic resonance imaging (MRI). We herein report the case of an 80-year-old male who presented a lung tumor. The transbronchial lung washing cytology findings were consistent with those of adenocarcinoma. In addition, the computed tomography findings indicated suspected aortic invasion of the lung tumor, as the mass girdled the descending aorta beyond 120° adjoining at a length of 10 cm. However, cine MRI display clearly demonstrated a clear area of isolation between the aorta and lung tissue based on differences in the heart rhythm from the patient''s respiratory movements. Therefore, the lesion was clinically diagnosed as a stage IIB (T3N0M0) tumor. Radiation was administered due to the patient''s advanced age and comorbidities such as chronic obstructive pulmonary disease. He remains alive without disease progression 6 months after the therapy. Our findings, therefore, indicate the usefulness of easily diagnosing the absence of aortic invasion in patients with lung cancer using cine MRI without the need for a special software program.Key Words: Cine magnetic resonance imaging, Diagnosis, Aorta, Invasion, Lung cancer