Hypersensitivity reactions associated with platinum-containing antineoplastic agents for thoracic malignancies

Recently, the use of platinum-containing antineoplastic agents for extended periods has increased. In this study, we determined the relationship between the hypersensitivity reactions to cisplatin or carboplatin and the frequency of administration among patients with thoracic malignancies. The study included 255 patients with thoracic malignancies who were treated with chemotherapy containing cisplatin or carboplatin in our institution between April 2007 and October 2008. A total of 89 patients received a median of 3 courses of cisplatin and 140 patients a median of 4 courses of carboplatin. A median of 6 courses of cisplatin plus carboplatin was administered to a further 26 patients. The total incidence of hypersensitivity reactions was 1.96%. Patients who were treated with <6 courses of platinum-containing antineoplastic agent did not experience any hypersensitivity reaction, but one patient, who was administered with 6 courses of platinum-containing antineoplastic agent experienced a hypersensitivity reaction (0.44%), as did four patients who were administered ≥7 courses (13.8%). Univariate and multivariate analyses indicated that the number of courses of platinum-containing antineoplastic agents was significantly correlated to the incidence of hypersensitivity reactions to these agents.     

The influence of light intensities irradiated directly and indirectly through resin composite to self-etch adhesives on dentin bonding

This study was designed to evaluate effects of light-irradiated intensities directly and indirectly through resin composites to one- and two-step self-etch adhesives on dentin bonding. One-step (Clearfil S(3) Bond; TS, Bond Force; BF) or two-step (Clearfil SE Bond; SE) self-etch adhesives was applied to dentin surface. The adhesive agent was light-cured with light-intensity of 350 or 600 mW/cm(2), and then resin composite with different colors (translucent or opaque shade) was filled and light-cured with the same light-intensity as the bonding procedure. After 24 h water storage, bond strengths to dentin were determined using μTBS test. For the 600 and 350 mW/cm(2) groups, translucent shade resin obtained higher μTBS than opaque shade resin. Using SE and BF, the 350 mW/cm(2) group in translucent shade resin was higher μTBS than the 600 mW/cm(2) group in opaque shade resin, while TS showed no different μTBS between them.     

Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice

In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.     

Morphological Development and Expression of Neurotrophin Receptors in the Laryngeal Sensory Corpuscles

Morphological development of sensory structures in the laryngeal mucosa of postnatal rats was observed by use of immunohistochemistry for protein gene‐product 9.5 (PGP9.5). Moreover, expression changes of high affinity neurotrophin receptors, TrkA, TrkB and TrkC, and low affinity neurotrophin receptor p75^NTR were examined to elucidate the relationship to morphogenesis. Intraepithelial nerve endings and parent axons of the laminar endings with immunoreactivity for PGP9.5 have already appeared in the rat on embryonic day 18 (E18) as well as solitary chemoreceptor cells in the glottic cleft. According to neurotrophin receptors, TrkA immunoreactivity were observed on and after postnatal week 3 (3W) in the nervous sensory structures, that is, free nerve endings, laminar endings and sub‐ and intragemmal plexuses of the taste buds. In the laminar endings, TrkC immunoreactivity was also observed on and after 3W. According to the laryngeal sensory cells, the solitary chemoreceptor cells were immunoreactive to TrkA, TrkB, and TrkC on and after postnatal day 3 (P3). In the taste buds in arytenoid region, taste cells were immunoreactive for TrkA, TrkB, and TrkC on and after 3W, P14, and 3W, respectively. Immunoreactivity for p75^NTR was observed on the surface of taste cells on and after P9. The results of the present study suggest that sensory structures in the laryngeal mucosa were developed on perinatal days to involve respiratory reflex, and that neurotrophin receptors may take part in the regulation and maintenance of sensory structures. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction,and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients

Background Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers. Methods Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID. Results Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand–foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for ≥3 months. Abnormal TSH correlated with exposure to axitinib (r = 0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r = –0.94). Axitinib showed antitumor activity across multiple tumor types. Conclusions Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure.     

Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2

Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.     

Kinetics of cytokine and chemokine responses in patients with primary human herpesvirus 6 infection

BackgroundCytokines and chemokines induced by human herpesvirus 6 (HHV-6) infection may play an important role in the observed HHV-6-associated clinical complications. However, basic data for cytokine and chemokine synthesis in primary HHV-6 infected patient without complication is lacking.ObjectiveAim of this study was to elucidate basic kinetic data for expressions of cytokines and chemokines in patients with primary HHV-6 infection without complication.Study designTwenty-six patients suffering from fever were enrolled in this study. Fourteen biomarkers were measured in 74 serially collected sera samples from 26 patients. Additionally, serum samples obtained from 14 healthy children were used for control.ResultsTwenty of the 26 patients were diagnosed with primary HHV-6 infection based on viral isolation and serological analysis. The mean age (P = 0.1289) and proportion of males to females (P = 0.9999) between the patients with and without primary HHV-6 infection were not statistically different. At the acute phase of the disease, three cytokines (IFN-γ; P = 0.0046, IL-2; P = 0.0366, and IL-4; P = 0.0255) and one chemokine (MCP-1; P = 0.0019) were significantly higher in patients with primary HHV-6 infection compared to those without infection. Interleukin-5 levels during the convalescent period were significantly higher in patients with HHV-6 infection (P = 0.0205). By 1 month post-infection, cytokine and chemokine expression had returned to almost basal levels.ConclusionAs suggested by the previous in vitro studies, present in vivo analysis also suggests that HHV-6 has potency for induction of cytokines and chemokines.     

RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.     

Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study assists the view that a fasting plasma glucose level ≥100 mg/dL increases cardiovascular risk

Aims/Introduction: To evaluate the relationship between fasting plasma glucose (FPG) level and cardiovascular disease in patients with hypercholesterolemia, and to evaluate the effect of pravastatin on risk reduction in a post‐hoc analysis of the large‐scale Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study. Materials and Methods: A total of 7832 patients were randomized to diet alone or diet plus low‐dose pravastatin (10–20 mg/day, average 8.3 mg during follow‐up periods) and followed for >5 years. In this analysis, the relationship between FPG and risk of cardiovascular disease events over 5 years were studied in 6673 patients with recorded baseline FPG levels by using the multivariable Cox proportional hazards model with the restricted quadratic spline based on three knots for FPG quartiles. Results: The spline curve showed an obvious sharp increased risk from a FPG of ≥100 mg/dL. The spline curve in the diet plus pravastatin group was consistently lower than in the diet group, regardless of the FPG level. Conclusions: The risk of cardiovascular disease appears to increase when FPG is ≥100 mg/dL, with a sharp increased risk found above this level in patients with hypercholesterolemia. Statin treatment seems to be beneficial to reduce cardiovascular disease risk in this population. This trial was registered with ClinicalTrials.gov (no. NCT00211705). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00121.x, 2011)