The introduction of targeted agents has resulted in a breakthrough in advanced cancer treatment. We propose a new classification for these agents to evaluate them in appropriate clinical trials according to agent class. Class I agents that inhibit driver oncogene activities result in massive and rapid tumor shrinkage, with response rates as high as 70% when administered to patients with appropriate targets. These agents can be evaluated in single-arm phase II trials with response rate as the primary endpoint. Class II agents inhibit one oncogene that is partially responsible for accelerating tumor cell proliferation. Their clinical features include synergism with cytotoxic agents and moderate single-agent activity, as shown by response rates of between 10% and 30%. Randomized phase II trials in patients with over-expressed targets are appropriate for the evaluation of these agents. Class III agents inhibit proliferation regulators that are not always oncogenic. Their clinical activity is unique, as they confer a survival benefit on patients with a minimum tumor shrinkage effect. Class IV agents target environmental molecules that act on normal cells surrounding tumor cells, such as the endothelial cells that form vessels. Placebo-controlled randomized phase II trials are required to identify the clinical activities of both class III and IV agents. Class V agents act by enhancing anti-tumor immunity. Immune-related response criteria should aid the evaluation of these agents. We believe that this classification for targeted agents should facilitate their further clinical development.
Pulmonary arterial hypertension (PAH) is a progressive disease, with a poor prognosis. The pathophysiologic mechanism of PAH is unknown, but may involve both tissue remodeling and inflammatory processes. Hyaluronan (HA) is a large glycosaminoglycan polymer and a major component of the extracellular matrix. In the present study, we measured plasma HA levels in PAH associated with systolic congestive heart failure (CHF, n = 16) or chronic obstructive pulmonary disease (COPD, n = 18). The control group was consisted of 14 healthy individuals without pulmonary or cardiovascular disease. Plasma HA levels (ng/mL) were determined in all patients by an enzyme linked HA binding assay. Pulmonary arterial pressure (PAP) was calculated in echocardiography (mmHg). Pulmonary arterial pressures were significantly higher in CHF and COPD (CHF: 55.0 ± 11 mmHg and COPD: 62.5 ± 21 mmHg, p < 0.001 for each), compared to the control group (25.4 ± 5.9 mmHg). Plasma HA levels were significantly higher in CHF (73.0 ± 37.5 ng/ml, p = 0.007) and COPD (87.3 ± 53.2 ng/ml, p = 0.001) compared to control patients (26.2 ± 8.4 ng/ml). There was no significant difference in plasma HA levels between the CFH and COPD groups (p = 0.690). In COPD, plasma HA levels were significantly correlated with PAP, left atrium diameter. There was no significant correlation between plasma HA levels and age or with echocardiography parameters in CHF. Both CHF and COPD are associated with increased plasma HA levels. Elevated plasma HA may contribute to the development of PAH.
N-methyl-D-aspartate receptors (NMDARs) are one type of ionotropic glutamate receptors (GluRs) and are heterotetrametric cation channels composed of NMDAR1 (NR1), NMDAR2 (NR2A, 2B, 2C or 2D) and NMDAR3 (NR3A or NR3B) subunits. The main subunits are NR1 and NR2 and their combinations are classified into several diverse forms including NR1/NR1/NR2A/NR2A, NR1/NR1/NR2B/NR2B and NR1/NR1/NR2A/NR2B. NMDARs are physiologically related to synapse development and synaptic plasticity in the central nervous system. Anti-NMDAR encephalitis is a form of autoimmune limbic encephalitis mainly affecting young women, with various manifestations including initial psychiatric symptoms, subsequent unresponsiveness, intractable generalized seizure, dysautonomia and orofacial dyskinesia. This disorder is often accompanied by ovarian teratoma that is originated from oocytes. Anti-neural antibody for the NR1/NR2 heteromer of NMDAR has been identified as a disease-specific hallmark. It has been emphasized that neural components in ovarian teratoma act as a trigger to produce anti-NMDAR antibodies, although about half of the patients with anti-NMDAR encephalitis are not associated with ovarian teratoma. To identify NMDAR-related epitopes located outside of the brain, we performed immunohistochemical examinations of normal human ovary and testis using specific antibodies against NR1, NR2A and NR2B, respectively, and found expression of the NR2B epitope in the cytoplasm of oocytes. In contrast, the testis showed no immunohistochemical reactivity. Therefore, oocytes contain NMDAR-related epitopes including NR2B. The NMDAR-related epitopes in normal oocytes may cause an antigen-antibody reaction in certain pathological conditions. The presence of NR2B immunoreactivity in oocytes may account for the fact that anti-NMDAR encephalitis predominantly affects young females.
Polycystic ovary syndrome (PCOS) is one of major causes of irregular menstruation. It is defined as a condition involving the combination of hyperandrogenism and chronic oligomenorrhea or anovulation, and is thought to have a variety of etiologies. Insulin resistance (impaired insulin sensitivity) has been suggested to be one of the etiologies of PCOS. PCOS patients often need to take medication to treat anovulation and infertility. Therefore, it would be beneficial to patients if simple non-pharmacological treatments can be developed. Recently the efficacy of vinegar to improve insulin resistance has been reported. To study the effect of vinegar on metabolic and hormonal indices and ovulatory function in PCOS, seven patients seeking a non-pharmacological treatment for PCOS took a beverage containing 15 g of apple vinegar daily for 90 to 110 days. Ovulation, the menstrual interval, fasting serum glucose level, fasting serum insulin level, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were compared before and after intake of the vinegar beverage. Intake of the vinegar beverage resulted in a decrease of the homeostasis model assessment insulin resistance index (HOMA-R) in six patients, as well as a decrease of the LH/FSH ratio in five of seven patients. Ovulatory menstruation was observed within 40 day in four of seven patients. These findings suggest the possibility of vinegar to restore ovulatory function through improving insulin sensitivity in PCOS patients, thus, avoiding pharmacological treatment. Intake of vinegar might reduce medical cost and treatment time for insulin resistance, anovulation, and infertility in patients with PCOS.
Heart disease is one of the most important causes of death in developed countries. Nε-carboxymethyllysine (CML) is a major advanced glycation end product formed by combined reactions of non-enzymatic glycation and oxidation (glycoxidation), and it represents a general marker of oxidative stress. CML has been suggested to be involved in the pathogenesis of heart disease. Plasma CML is elevated in aging, atherosclerosis and/or diabetes. In this study, we measured cardiac CML levels to elucidate its role in the pathogenesis of heart disease. Cardiac tissues were collected from 105 patients (55.6 ± 17.0 years old: age range, 1-78 years) undergoing cardiac surgery. The diseases comprised coronary heart disease (CHD), CHD associated with diabetes mellitus (DM), valvular heart disease and congenital heart disease. The concentration of CML in cardiac tissues of each group was 4.31 ± 0.66, 5.29 ± 0.59, 2.74 ± 1.05 and 1.75 ± 1.16 μg/g, respectively. ELISA was used for measuring cardiac and plasma CML concentrations. Multiple linear regression analysis showed a significant positive correlation of CML concentrations with age (r = 0.803, p < 0.001), DM (r = 0.567, p < 0.001) and CHD (r = 0.523 p < 0.001). R2 was 0.872 (p < 0.001); the three independent variables could explain 87.2% variation of CML concentrations. Cardiac CML concentrations exhibited a significant positive correlation with plasma CML (r = 0.983, p < 0.001). Our data indicate that cardiac CML concentrations increase with age, DM and/or CHD, and exhibit a positive correlation with plasma CML concentrations.
Nursing students must develop their abilities to provide appropriate nursing services. They need to acquire the level of nursing knowledge to pass the national examination according to Japanese law. Moreover, even if the awareness of the rights of people who receive nursing services increases, students must not have a sense of resistance toward those rights. Therefore, we investigated the factors associated with students’ motivation to pass their examination and such a sense of resistance. We produced items related to reasons students wanted to become registered nurses with reference to job satisfaction and their learning environment (e.g., teachers’ manners and school events unrelated to the examination). There were 3,417 female nursing students analyzed in 29 vocational schools that allow graduation after a 3-year study period (average age, 21.93 years [standard deviation, 5.44]). Older and third-year students had a stronger motivation to pass the examination and a weaker sense of resistance to people’s rights compared with younger and first- to second-year students. Students who answered a “Lack of enthusiasm for becoming a registered nurse” had a weakened motivation and a strengthened sense of resistance. Factors enhancing students’ motivation to pass their examination were “Professional commitment,” “Desire for companionship,” and “School events unrelated to the national examination.” Factors strengthening students’ sense of resistance to people’s rights were “Living stability” and “Social appraisal.” Teachers must develop methods to teach ethics so that their students respect the rights of people who receive nursing services and to ensure that they acquire the necessary nursing knowledge.
Laryngomalacia is the most common cause of stridor in neonates and infants, where the soft cartilages and tissues surrounding the upper larynx collapse inward during respiration. On the other hand, acquired idiopathic laryngomalacia in adults is quite rare, but should be borne in mind for differential diagnosis of upper airway distress. Allergic factors may cause airway distress, but have not been highlighted previously as the background of laryngomalacia. In this report, we describe two patients with acquired idiopathic laryngomalacia with reference to allergic rhinitis and high serum levels of immunoglobulin E. The first patient was a 16-year-old female who presented with inspiratory stridor and dyspnea due to attachment between the epiglottis and bilateral arytenoids, and the second patient was an 18-year-old male who also presented with inspiratory stridor due to attachment between the epiglottis and posterior pharyngeal wall. The respiratory function of both patients was within the normal range but the inspiratory stridor interfered with daily life. Laryngomicrosurgery was performed in both patients using a CO2 laser to remove the arytenoid mucosa in the first patient, and to remove the tip of the epiglottis in the second. Both patients were followed up while receiving oral anti-allergic agents. Laser supraglottic laryngoplasty to remove the vibrating excess tissue was effective for resolving the symptoms. However, recurrence occurred three times in the first patient, and inferior turbinotomy to improve nasal respiration was useful for diminishing the symptoms.
Occlusal disharmony sometimes causes not only stiffness of neck but also psychiatric depression, suggesting that the condition of oral cavity may affect the central nervous system. Dynorphin A is an endogenous opioid peptide that specifically binds the κ-opioid receptor and has a protective role against stress. Dynorphinergic nervous system is intensely distributed in the amygdala and hippocampus that are coping areas with stress. As a model of malocclusion, we placed dental resin on the molars to increase the occlusal vertical dimension (bite-raise). After various survival times, we analyzed the amygdala and hippocampus by immunohistochemistry and immunosorbent assay (ELISA). Furthermore, the effects on learning and memory were assessed by Morris water maze test. In the amygdala, the levels of dynorphin A were increased on the 1st day after increasing the vertical dimension as indicated by immunohistochemical and ELISA assessments. The levels of dynorphin A returned to control levels on the 5th day. In the hippocampus, there were no noticeable changes in dynorphin A levels. The water maze test indicated that increasing the vertical dimension caused longer escape latency times on the 3rd day compared to those of sham-operated group. However, the bite-raised mice treated with a dynorphin antagonist, nor-binaltorphimine, showed similar escape latency times to the times of sham-operated group, even on the 3rd day. These results suggest that occlusal disharmony causes stress resulting in a transient increase of dynorphin A levels at least in the amygdala and that the increased dynorphin A levels transiently impair learning and memory.
Cardiovascular disease is common in the patients with end-stage renal disease, who often suffer from secondary hyperparathyroidism (SHP). Vitamin D is considered for the first-line therapy managing SHP in hemodialysis (HD) patients and has a beneficial effect in the chronic inflammation and development of cardiovascular disease. The soluble receptor for advanced glycation end products (sRAGE) may be protective by binding AGE in the pathogenesis of atherosclerotic vascular complications, whereas extracellular RAGE-binding protein (EN-RAGE) represents pro-inflammatory ligands for RAGE. We have hypothesized that vitamin D treatment may alter the levels of sRAGE and EN-RAGE in HD patients. Therefore, this prospective observational study was performed in 51 HD patients with SHP who had low serum 1,25 dihydroxyvitamin D3 (1,25D) levels and elevated intact parathyroid hormone (PTH) levels. We evaluated the changes in the values of sRAGE, EN-RAGE, and other inflammatory marker, interleukin-6 (IL-6), before and at the end of the 8-week calcitriol treatment. After calcitriol treatment, the serum levels of 1,25D were increased, whereas the serum intact PTH levels were decreased. In addition, the sRAGE levels were increased, whereas those of IL-6 were decreased after calcitriol treatment. A positive correlation between 1,25D and sRAGE levels (r = 0.609, P < 0.001) and a negative correlation between sRAGE and EN-RAGE levels (r = −0.368, P = 0.020) were detected after calcitriol treatment. This study suggests that calcitriol treatment could play an anti-inflammatory role through the increasing sRAGE in HD patients with SHP.