Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours.

Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours.

Catheter-related bloodstream infection by Microbacterium paraoxydans in a pediatric patient with B-cell precursor acute lymphocytic leukemia: A case report and review of literature on Microbacterium bacteremia.

Microbacterium species are coryneform gram-positive rods that are widely distributed in the environment and have been recently recognized as rare pathogens in humans. However, information about the epidemiologic and clinical characteristics of Microbacterium species is scarce. We herein reported an 11-year-old girl with acute leukemia who was found to have catheter-related bloodstream infection in her neutropenic phase. Gram-positive bacilli repeatedly grew on the blood cultures and were later confirmed by 16S rRNA analysis as Microbacterium paraoxydans. A literature review found available clinical courses in 21 cases (7 pediatric cases) of Microbacterium spp. bacteremia. Our case and those in literature suggested that Microbacterium spp. bacteremia often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases and that 16S rRNA sequence was useful in identifying in detail the species of Microbacterium.

Elucidating the Crystallite Size Dependence of the Thermochromic Properties of Nanocomposite VO2 Thin Films.

Fenestration elements that enable spectrally selective dynamic modulation of the near-infrared region of the electromagnetic spectrum are of great interest as a means of decreasing the energy consumption of buildings by adjusting solar heat gain in response to external temperature. The binary vanadium oxide VO2 exhibits a near-room-temperature insulator-metal electronic transition accompanied by a dramatic modulation of the near-infrared transmittance. The low-temperature insulating phase is infrared transparent but blocks infrared transmission upon metallization. There is considerable interest in harnessing the thermochromic modulation afforded by VO2 in nanocomposite thin films. However, to prepare a viable thermochromic film, the visible-light transmittance must be maintained as high as possible while maximizing thermochromic modulation in the near-infrared region of the electromagnetic spectrum, which necessitates the development of high-crystalline-quality VO2 nanocrystals of the optimal particle size embedded within the appropriate host matrix and refractive index matched to the host medium. Here, we demonstrate the preparation of acrylate-based nanocomposite thin films with varying sizes of embedded VO2 nanoparticles. The observed strong size dependence of visible-light transmittance and near-infrared modulation is explicable on the basis of optical simulations. In this article, we elucidate multiple scattering and absorption mechanisms, including Mie scattering, temperature-/phase-variant refractive-index mismatch between VO2 nanocrystals and the encapsulating matrix, and the appearance of a surface plasmon resonance using temperature-variant absorptance and diffuse transmittance spectroscopy measurements performed as a function of particle loading for the different sizes of VO2 nanocrystals. Nanocrystals with dimensions of 44 ± 30 nm show up to >32% near-infrared energy modulation across the near-infrared region of the electromagnetic spectrum while maintaining high visible-light transmission. The results presented here, providing mechanistic elucidation of the size dependence of the different scattering mechanisms, underscore the importance of nanocrystallite dimensions, refractive-index matching, and individualized dispersion of particles within the host matrix for the preparation of viable thermochromic thin films mitigating Mie scattering and differential refractive-index scattering.

Effects of SA237, a humanized anti-interleukin-6 receptor monoclonal antibody, on pre- and postnatal development in cynomolgus monkey.

BACKGROUND: SA237 is a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody in which the constant and variable regions have been engineered for a longer plasma half-life. According to literature, blocking of IL-6 related functions could have an influence on pregnancy sustainment, development of the immune system, and brain growth. METHODS: SA237 effects on dams, embryo-fetal development, parturition and postnatal development were investigated in an enhanced pre- and postnatal development study, in which SA237 was subcutaneously administered to pregnant cynomolgus monkeys at dose levels of 2 or 50 mg/kg once weekly from gestation day 20 until parturition. Infant development, including immune function and learning ability tests, was comprehensively assessed at multiple examinations until approximately 10 months after birth. RESULTS: SA237 plasma concentrations were almost equivalent between dams and their infants and dropped throughout the postnatal period, pharmacologically relevant exposure was maintained for 147 days after birth at 50 mg/kg. Because the binding of SA237 to IL-6R inhibited IL-6R-mediated clearance of IL-6, serum IL-6 increased in dams and infants. However, there were no SA237-related adverse effects on dams, embryos, fetuses, or infants. SA237 pharmacological effects contributed to the suppression of plasma cell differentiation and antibody production by inhibiting IL-6 signaling, and T cell-dependent antibody reaction was minimally suppressed in infants, but physiological immunoglobulin class switching and general antibody production against a T cell-dependent antigen were maintained. CONCLUSION: The exposure to SA237 did not adversely affect dams, embryo-fetal development, parturition, and postnatal development, including immune function and neuronal development. Birth Defects Research 109:843-856, 2017. © 2017 Wiley Periodicals, Inc.

Intracellular Dynamics and Fate of a Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody, Tocilizumab.

Tocilizumab (TCZ), a humanized anti-interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, abrogates signal transducer protein gp130-mediated IL-6 signaling by competitively inhibiting the binding of IL-6 to the receptor, and shows clinical efficacy in autoimmune and inflammatory diseases. Despite accumulating evidence for therapeutic efficacy, the behavior and fate of TCZ at the cellular level remain largely unknown. To address this, we evaluated the endocytosis and intracellular trafficking of IL-6R in HeLa cells. The results of our study provide evidence that IL-6R is constitutively internalized from the cell surface by ligand or TCZ binding and the expression of gp130 in an independent manner and is targeted via endosomes without being significantly directed to the recycling pathway to, and degraded in, lysosomes. Furthermore, the cytoplasmic tail of IL-6R is required for constitutive endocytosis of the receptor, which is mediated by the clathrin and AP-2 complex. We further demonstrate that FcRn, whose function is to regulate the serum persistence of IgG, is confined primarily to early/recycling endosomes and rapidly transits between these compartments and late endosomes/lysosomes without being degraded. Importantly, the expression of FcRn induces the segregation of TCZ from IL-6R, resulting in extensive colocalization of TCZ and FcRn in IL-6R-depleted endosomal compartments. Collectively, our results suggest that FcRn can accelerate the retrieval of the internalized TCZ, not only from endosomes but also from lysosomes. Our findings provide new insight into the mechanism by which the antibody internalized into cells is rescued from lysosomal degradation and into how its serum levels are maintained.

High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy.

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface glycoprotein overexpressed in hepatocellular carcinoma (HCC) cells and may serve as a potential molecular target for therapeutic intervention. This study evaluated the prognostic significance of serum GPC3 in HCC patients receiving curative surgery. A novel sandwich enzyme-linked immunosorbent assay for the quantitative and sensitive determination of serum GPC3 N-terminal subunit antigen (sGPC3N) was developed and used to measure sGPC3N levels in 25 healthy volunteers and 115 HCC patients who underwent curative partial hepatectomy. The relationships between sGPC3N and clinicopathologic features were analyzed and the prognostic impact on overall survival (OS) or disease-free survival (DFS) was also investigated. Mean and median levels of sGPC3N in healthy controls were 110.12 and 115.95 pg mL(-1) , respectively, with 185.52 pg mL(-1) (mean + 2 SD) being set as the upper limit of the normal range. In HCC patients, sGPC3N levels were significantly increased (mean/median, 405.16/236.19 pg mL(-1) ) compared to healthy controls (p < 0.0001), and 60% of HCC cases (69/115) showed sGPC3N levels that were higher than the upper normal limit. High sGPC3N levels were significantly associated with serum AFP level, high Child-Pugh score and positive HCV. Kaplan-Meier analysis indicated that elevated pre-operative sGPC3N was associated with shorter OS and DFS after hepatectomy (p ≤ 0.01). Multivariate analysis revealed elevated sGPC3N as an independent poor prognostic marker for OS (p < 0.05) and DFS (p < 0.01). The pre-operative sGPC3N level serves as an independent prognostic biomarker in HCC patients.

Characteristics of cardiac allograft vasculopathy induced by immunomodulation in the miniature Swine.

PURPOSE: We aimed to develop swine cardiac transplantation model for study of cardiac allograft vasculopathy (CAV) and to characterize the mechanisms of its formation. METHODS: Heterotropic cardiac transplantation was performed in swine leukocyte antigen mismatched miniature swine, and CAV was induced by immunomodulation by cyclosporine A (CyA). Histology and immunohistochemistry were performed to identify cellular components of CAV. Fluorescence in situ hybridization (FISH) was developed for detection of 1 and Y-chromosome for identification of cell origin in the female donor to the male recipient heart transplantation model. RESULTS: CAV was successfully developed by immunomodulation of CyA. Severity of CAV revealed more prominent in the distal epicardial coronary arteries than proximal coronary arteries. Phenotype of the SMCs proliferated in the intimal thickening of CAV were mostly embryonal/secretory type. Our new chromosome specific probes for FISH method were useful for discrimination of sex of each cell, and proliferated SMCs were revealed to be mainly donor origin. CONCLUSION: CAV mimicking human heart transplantation can be developed by appropriate immunomodulation in the swine. In swine CAV, proliferated SMCs seen in the intimal thickening were demonstrated to be from the donor origin.

[Left atrium thrombus after mitral valve replacement presented with syncope; report of a case].

Left atrial free ball thrombus (LABT) after mitral valve replacement (MVR) is very rare, and sudden death may occur by thrombus impaction to the mitral valve orifice. A 81-year-old woman who underwent MVR and tricuspid annuloplasty ten years ago presented with syncope. She was admitted to a hospital, and echocardiography revealed a LABT. When she took sitting position, she fainted. The free ball thrombus possibly impacted mitral valve orifice. She was transferred to our hospital and an emergent operation was performed. There was a LABT of 4 cm in diameter, which was removed. Postoperative course was uneventful. There are 12case reports which described LABT after MVR, and anticoagulant therapy was insufficient in most of those cases. Strict anticoagulant therapy is important to prevent left atrial thrombus after MVR.

Significant pericardial involvement of immunoglobulin G4-related disease.

A 60-year-old woman was hospitalized with cardiac tamponade due to effusive pericarditis presenting with significant thickening of the pericardium. Serum immunoglobulin G4 (IgG4) level was elevated to 1,800 mg/dL, and an open biopsy specimen from the pericardium revealed massive infiltration of lymphocytes and IgG4-positive plasma cells. She had experienced adenopathies in the lacrimal and parotid glands 6 months earlier, and was diagnosed as having IgG4-related Mikulicz's disease by similar cell infiltration in the salivary gland biopsy. The significant involvement of the pericardium as a manifestation of IgG4-related disease is described, as well as the successful treatment with oral corticosteroids.

Pericoronary pseudotumor caused by helicobacter cinaedi.

Cardiac tumors and tumor-like lesions are uncommon; most are true neoplasms. We here report a case of a pericoronary tumor-like lesion surrounding the right coronary artery in a 39-year-old man who presented with fever and chest pain. Although clarithromycin was administered for 1 week, his fever persisted. Helicobacter cinaedi (H. cinaedi) was isolated from blood cultures and found to be sensitive to ceftriaxone. A computed tomography scan showed a tumor-like lesion with no (18)F-fl uorodeoxyglucose uptake surrounding the right coronary artery. After administration of ceftriaxone, the tumor-like lesion diminished in size according to meticulous computed tomography examinations. We therefore concluded that it was caused by H. cinaedi infection. The patient has been followed up closely for 1 year and remains asymptomatic.

Delayed esophageal perforation secondary to thoracic aortic aneurysm rupture in a patient with human immunodeficiency virus infection.

A 65-year-old man infected with human immunodeficiency virus underwent emergency surgery for rupture of a mycotic descending thoracic aneurysm. The aneurysm was replaced with a prosthetic graft wrapped with omentum. Esophageal perforation occurred 3 weeks after surgery. The patient's condition remained stable, and we adopted a conservative treatment. The esophageal fistula had not healed completely and a biopsy of the scar revealed gastric cancer. We performed a distal gastrectomy, Roux-Y reconstruction, and enterostomy for enteral feeding. Follow-up endoscopy revealed healing of the fistula, and the patient was eventually discharged. We managed this potentially fatal complication with minimally invasive treatment.

Prosthesis-sparing aortic root replacement following aortic valve replacement.

Reoperation on the aortic root is considered to be challenging because of high hospital mortality. Prosthesis-sparing aortic root replacement, in which the aortic prosthesis is preserved during reoperation, and could avoid passing sutures through the weakened aortic annuls after the initial prosthesis has been removed. We report 3 cases of prosthesis-sparing aortic root replacement. Prior procedures were aortic valve replacement and the Bentall operation 14 to 35 years previously. Postoperative courses were uneventful, with no signs of pseudoaneurysm or valve malfunction observed during follow-up periods of 93 to 360 days.

Comprehensive and temporal analysis of secreted proteins in the medium from IL-6 exposed human hepatocyte.

We have previously identified intracellular secretory acute phase response (sAPR) proteins in human hepatocytes following interleukin-6 (IL-6) induction by fluorogenic derivatization (FD)-liquid chromatography (LC)-tandem mass spectrometry (MS/MS). In this report, we utilized this method, which uses 7-chloro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoxadiazole-4-sulfonamide (DAABD-Cl) as the FD reagent, to comprehensively and time-dependently analyze secreted proteins in the medium, including sAPR proteins. Since DAABD-Cl selectively reacts with thiol moieties of cysteinyl residues, direct derivatization, high-resolution LC separation and identification of the secreted proteins in the culture medium were successfully achieved without a pretreatment step. As a result, 14 sAPR proteins were identified simultaneously during a 72 h induction by IL-6. The secretion levels of 11 proteins increased, whereas the secretion levels of three important transport proteins decreased (albumin, retinol-binding protein 4 and transthyretin). In addition, the secretion level of a haptoglobin was found to increase significantly between 0 and 6 h by 1.88-fold compared with the control sample. The secretion levels of four cytoplasmic proteins increased: LDH, a known marker for cell damage, and GSTA1, FABP1 and ADH1B, which are marker proteins for hepatocellular damage. The secretion levels of the other two newly identified cytoplasmic proteins, profilin-1 and SOD2, were also found to increase, suggesting that these two proteins represent novel markers for cell damage. These results suggest that the FD-LC-MS/MS proteomics method can be used to analyze comprehensively and time-dependently the secreted proteins and thereby can offer information that aids our understanding of the dynamics of protein secretion affected by the exposure of cytokines such as IL-6.

Hybrid thoracic endovascular aortic repair of ascending aortic pseudoaneurysm.

We report the successful thoracic endovascular aortic repair of an ascending aortic pseudoaneurysm. Because the risk of resternotomy after conventional surgery was very high, endovascular repair with extra-anatomic reconstruction of the supra-aortic vessels was performed using the femoral artery as the donor artery. Complete exclusion of the pseudoaneurysm was achieved, with no postoperative complications or neurologic sequelae.

Infective endocarditis associated with mitral valve prolapse in a patient with Klinefelter syndrome.

We herein report a case of infective endocarditis associated with mitral valve prolapse (MVP) in a 34-year-old man with Klinefelter syndrome. The patient was admitted with a fever and headache that had persisted for three weeks. Repeated blood cultures showed growth of Streptococcus oralis. Echocardiography demonstrated severe mitral regurgitation with a large vegetation attached to the prolapsed anterior leaflet. Surgical plasty of the mitral valve was performed because the vegetation measured over 10 mm in diameter and there was a risk of recurrence of embolic complications. This case demonstrates the link between MVP and Klinefelter syndrome and highlights the importance of performing cardiovascular screening and preventing endocarditis.

Platelet function during cardiopulmonary bypass using multiple electrode aggregometry: comparison of centrifugal and roller pumps.

Blood trauma may be lower with centrifugal pumps (CPs) than with roller pumps (RPs) during cardiopulmonary bypass (CPB), because, unlike RPs, CPs do not compress the tubing, and shear stress is considered lower in CPs than in RPs. However, relative platelet function remains unclear. Using multiple electrode aggregometry (MEA), we compared platelet function with CP and RP. Ten swine underwent CPB for 3 h, with five weaned off using CP and five using RP. Platelet function was measured using MEA, as were hemoglobin concentration and platelet count, before sternotomy, after heparin infusion, 30 min and 3 h after starting CPB, after protamine infusion, and 60 min after stopping CPB. Platelet activation was initiated with adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor-activating protein 6 (TRAP). Fibrinogen, platelet factor 4 (PF4), and ß-thromboglobin (ß-TG) concentrations were measured before sternotomy and 60 min after stopping CPB. In the CP group and using ADP, aggregation was significantly reduced 30 min (P = 0.019) and 3 h (P = 0.027) after starting CPB, recovering to baseline 60 min after CPB was stopped. In the RP group, aggregation was significantly decreased 30 min (P = 0.007) and 3 h (P = 0.003) after starting CPB and after protamine administration (P = 0.028). With AA, aggregation significantly decreased 30 min after starting CPB in both the CP (P = 0.012) and RP (P = 0.016) groups, slightly increasing 3 h after starting CPB and after protamine infusion, and recovering to baseline 60 min after CPB cessation. With TRAP, aggregation in the CP and RP groups decreased 30 min after starting the pump, although changes were not significant; aggregation gradually recovered after 3 h and returned to baseline 60 min after the pumps were stopped. There were no significant differences at all sampling points of MEA. In both groups, fibrinogen, PF4, and ß-TG concentrations were similar 60 min after pump cessation and before sternotomy. Platelet function, evaluated with MEA, was lowest 30 min after CPB was started but did not decrease over time in either group. As assessed by MEA, platelet function using CP and RP did not differ significantly. Platelet dysfunction was caused mainly by initial contact with foreign materials and may not be dependent on type of pump.

Computed tomography attenuation predicts the growth of pure ground-glass nodules.

OBJECTIVES: Cases of lung cancer with pure ground-glass nodules (GGNs) have been detected with increasing frequency since the advent of computed tomography (CT), and growth is sometimes noted during follow-up. The objective of this study was to evaluate the potential predictive factors for pure GGN growth. MATERIALS AND METHODS: We retrospectively examined 124 cases involving pure GGNs. Patients were monitored for > 2 years using high-resolution CT. After a median follow-up period of 57.0 months, GGNs showed growth in 64 of the 124 cases. We compared the patient characteristics and tumor properties of cases with and without growth. The predictive value of the mean CT attenuation for GGN growth was evaluated using receiver operating characteristic curve analysis. RESULTS: Univariate analysis revealed significant differences between mean CT attenuation values in patients with and without growth (-602.9 ± 90.7 Hounsfield units [HU] vs -705.7 ± 77.7HU, P < 0.0001). The final incidence of growth was estimated to be significantly higher for lesions with a mean CT attenuation value of ≥ -670HU (n = 62; 93.2%) than for lesions with values of < -670HU (n = 62; 31.6%; P < 0.0001). The sensitivity and specificity for predicting tumor growth using this cutoff value were 78.1% and 80.0%, respectively (area under the curve, 0.81). CONCLUSION: The mean CT attenuation value could be useful in predicting the growth of GGNs.

Surgical outcomes of acute type A aortic dissection in elderly patients.

BACKGROUND: Age is still considered a risk factor in the repair of acute type A aortic dissection. Instead of total arch replacement, we performed hemiarch or partial arch replacement with intimal tear exclusion to reduce death in elderly patients and evaluated early-term and midterm outcomes. METHODS: From January 2004 to April 2012, 59 patients older than 70 years (mean age, 77.0±4.3 years) underwent emergency operations for acute type A aortic dissection at our institution. We performed hemiarch, partial arch, or total arch replacement, according to the location of the primary entry tear. The characteristics, surgical procedures, and early-term and midterm outcomes of these patients were reviewed. RESULTS: We performed hemiarch replacement in 47 patients, partial arch replacement in 4, and total arch replacement in 8. The primary entry site was excluded in 56 of 59 patients (94.9%). In-hospital mortality was 6.8%, and neurologic impairment occurred in 25.4%. We obtained midterm outcomes for 55 of 59 patients, with a mean follow-up period of 43.9±23.7 months. Fourteen patients died, two of these of aortic-related causes. One patient required repeat aortic operation for rupture of a pseudoaneurysm. Follow-up computed tomography imaging was done in 28 of 55 patients during the 12 months after the operation. No significant difference was noted in the increase in maximal aortic diameter between patients with and without residual dissection. CONCLUSIONS: In-hospital mortality was 6.8%; relatively low compared with previous reports. Hemiarch and partial arch replacement with entry tear exclusion may reduce deaths associated with acute type A aortic dissection repair in elderly patients, without increasing the risk of reoperation and aortic-related death.