Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Verruciform xanthoma: report of three patients with comparative dermoscopic study.

We report three cases of verruciform xanthoma (VX) in male patients aged 82, 88 and 39 years, respectively. The clinical appearance was of a mulberry-like area consisting of small papillae, which is typical of and specific to VX, and the diagnosis were histologically confirmed in all cases. Dermoscopy revealed that each surface papilla contained linear or hairpin vessels, which were surrounded by a marginal whitish rim. These structures are thought to correspond to dilated vessels in dermal papillae and papillated acanthotic epidermis, respectively. Furthermore, observation under compression (similar to diascopy) revealed yellow dots and debris, reflecting lipid-laden foam cells. In order to compare these findings with those of other disorders with similar findings, two patients with xanthogranuloma, six with sebaceous naevus, and three with senile sebaceous hyperplasia were examined. The dermoscopic findings in these patients were not similar to those of VX. Therefore, we believe that the above dermoscopic findings are specific to VX and could be helpful in diagnosis.

Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti-muscle-specific receptor tyrosine kinase (MuSK)-antibody (Ab)-positive myasthenia gravis (MG) patients, and anti-acetylcholine receptor (AChR)-Ab-positive MG patients are not clearly defined. METHODS: The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 MuSK-Ab-positive patients nationwide were investigated and were compared with those in AChR-Ab-positive patients followed at our institute (n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. RESULTS: Thymoma was not present in any of the MuSK-Ab-positive patients but presented in 21 patients (25.3%) amongst the AChR-Ab-positive patients. Titin Abs were absent in MuSK-Ab-positive patients but positive in 25 (30.1%) of the AChR-Ab-positive patients. Concomitant autoimmune diseases were present in eight MuSK-Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 AChR-Ab-positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. CONCLUSIONS: Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between MuSK-Ab-positive and AChR-Ab-positive MG were indicated, suggesting that, in contrast with AChR-Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of MuSK-Ab-positive MG.

Foetal exposure to phthalate esters and anogenital distance in male newborns.

Phthalate esters, commonly used as plasticizers, show anti-androgenic activity and cause male reproductive malformation in experimental animals. However, the effects of prenatal exposure to phthalate esters in humans have not been extensively studied. The purpose of this study was to examine the relationship between prenatal exposure to phthalate esters and the anogenital distance (AGD) as a reproductive endpoint in human male newborns. Spot urine samples were collected from 111 Japanese pregnant women after obtaining their informed consent. Seven urinary phthalate ester metabolites were determined by high performance liquid chromatography-tandem mass spectrometry. Urinary isoflavones concentrations were measured as possible covariates because their oestrogenicities and high exposure levels among Japanese have the potential to affect male genital development. Birth outcomes and AGD, the distance from the centre of the anus to external genitalia, were measured for their male newborns. In a multiple regression model, the log-transformed mono-2-ethylhexyl phthalate concentration (specific gravity-corrected) was negatively significant, and maternal smoking status was positively significant, in explaining anogenital index (AGI) when potential covariates were controlled for. Urinary isoflavones did not significantly contribute to AGI in any models. Our results suggest that prenatal exposure to di(2-ethylhexyl) phthalate affects reproductive development in human males.

Consideration of reactivity to acute fish toxicity of α,ß-unsaturated carbonyl ketones and aldehydes.

To understand the key factor for fish toxicity of 11 α,ß-unsaturated carbonyl aldehydes and ketones, we used quantum chemical calculations to investigate their Michael reactions with methanethiol or glutathione. We used two reaction schemes, with and without an explicit water molecule (Scheme-1wat and Scheme-0wat, respectively), to account for the effects of a catalytic water molecule on the reaction pathway. We determined the energies of the reactants, transition states (TS), and products, as well as the activation energies of the reactions. The acute fish toxicities of nine of the carbonyl compounds were evaluated to correlate with their hydrophobicities; no correlation was observed for acrolein and crotonaldehyde. The most toxic compound, acrolein, had the lowest activation energy. The activation energy of the reaction could be estimated with Scheme-1wat but not with Scheme-0wat. The complexity of the reaction pathways of the compounds was reflected in the difficulty of the TS structure searches when Scheme-1wat was used with the polarizable continuum model. The theoretical estimations of activation energies of α,ß-unsaturated carbonyl compounds with catalytic molecules or groups including hydrogen-bond networks may complement traditional tools for predicting the acute aquatic toxicities of compounds that cannot be easily obtained experimentally.

Limbic encephalitis associated with systemic lupus erythematosus.

A 34-year-old woman with systemic lupus erythematosus (SLE) presented with general fatigue, seizures and memory loss. Magnetic resonance imaging of the brain showed a high signal area in the mesial temporal lobe bilaterally. Computed tomography scan of the chest and abdomen and ultrasound of pelvis detected no malignancy and tumour marker, antibodies to antineuronal antibodies (anti-Hu, anti-Ta and anti-Ma) and antibodies to voltage-gated potassium channels were all negative. The present case is limbic encephalitis (LE) associated with SLE and the pathogenesis may include autoimmunity shared. Our experience indicates that the immunologic spectrum of LE will expand to include additional immune mechanisms.

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family.

The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ov-serpin)/clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity.

TAK1 represses transcription of the human telomerase reverse transcriptase gene.

In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor beta (TGF-beta) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-beta-activated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Luminescent yeast cells entrapped in hydrogels for estrogenic endocrine disrupting chemical biodetection.

In the construction of luminescent yeast cell based fibre-optic biosensors, we demonstrate a novel approach for estrogenic endocrine disrupting chemical (EDC) biodetection by entrapping genetically modified Saccharomyces cerevisiae cells, containing the estrogen receptor alpha-mediated expression of the luc reporter gene, in hydrogel matrices based on calcium alginate or PVA. In order to insure a significant signal, an optimal immobilization ratio of 1:2 alginate 3% (w/v): 5 x 10(6) [cells/ml], respectively, was used with the highest 17-beta-estradiol (beta-E2) induction factor after 2.5 h of incubation with 10[nM] beta-E2. It was shown that biocompatible alginate beads, 4.27-4.55 x 10(5) [CFU/bead], which were characterized by a detection limit of 0.08[microg l(-1)] and an EC50 of 0.64[microg l(-1)] for beta-E2, retained their viability for luminescence measurements after 1 month of storage at -80 degrees C slow freeze condition, and thus repeated cell cultivations were not required. The assay reproducibility for each tested EDC, represented by the coefficients of variation (CV), ranged from 4.35 to 18.47%. An alternative immobilization method, based on a room temperature partial drying of polyvinyl alcohol (PVA) solution (LentiKat Liquid) and cell suspension mix, was investigated with only a slightly lower detection limit for beta-E2 than that reported with alginate beads. Alginate yeast based hydrogels may also be applicable to the analysis of environmental water samples since the trend of detected estrogenic activities with alginate beads roughly correlated with LC-MS-MS analytical results.

Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production.

Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT-PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-beta1 levels in the non-HCC region. To define the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liver-specific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA- and chemical-induced liver fibrosis. The expression of TGF-beta1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-beta1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-beta1 expression, and SOCS3 prevents this process.

3T phased array MRI improves the presurgical evaluation in focal epilepsies: a prospective study.

BACKGROUND: Although detection of concordant lesions on MRI significantly improves postsurgical outcomes in focal epilepsy (FE), many conventional MR studies remain negative. The authors evaluated the role of phased array surface coil studies performed at 3 Tesla (3T PA MRI). METHODS: Forty patients with medically intractable focal epilepsies were prospectively imaged with 3T PA-MRI including high matrix TSE T2, fluid attenuated inversion recovery, and magnetization prepared rapid gradient echo. All patients were considered candidates for epilepsy surgery. 3T PA-MRIs were reviewed by a neuroradiologist experienced in epilepsy imaging with access to clinical information. Findings were compared to reports of prior standard 1.5T MRI epilepsy studies performed at tertiary care centers. RESULTS: Experienced, unblinded review of 3T PA-MRI studies yielded additional diagnostic information in 48% (19/40) compared to routine clinical reads at 1.5T. In 37.5% (15/40), this additional information motivated a change in clinical management. In the subgroup of patients with prior 1.5T MRIs interpreted as normal, 3T PA-MRI resulted in the detection of a new lesion in 65% (15/23). In the subgroup of 15 patients with known lesions, 3T PA-MRI better defined the lesion in 33% (5/15). CONCLUSION: Phased array surface coil studies performed at 3 Tesla read by an experienced unblinded neuroradiologist can improve the presurgical evaluation of patients with focal epilepsy when compared to routine clinical 1.5T studies read at tertiary care centers.

Effusive--constrictive epicarditis that developed more than 5 years after ventricular septal defect closure: two cases relieved by epicardiectomy.

We describe two children diagnosed with effusive-constrictive epicarditis that developed more than 5 years after ventricular septal defect (VSD) closure. Constrictive epicarditis is extremely rare in children and there are few reports of infants with effusive-constrictive epicarditis associated with congenital heart disease surgery. This is the first pediatric case report of effusive-constrictive epicarditis occurring after VSD closure that was relieved by epicardiectomy.

Ventricular tachycardia in a neonate with prenatally diagnosed cardiac tumors: a case with tuberous sclerosis.

We report a patient with prenatally diagnosed tuberous sclerosis. Fetal ultrasonography demonstrated multiple cardiac tumors and arrhythmia. After birth, because of frequent supraventricular extrasystoles, the infant was admitted to the neonatal intensive care unit. Findings on 24-hour ambulatory electrocardiogram (ECG) showed frequent supraventricular tachycardia and ventricular tachycardia with four beats as the longest run. At the age of 12 days, he developed cardiopulmonary arrest after crying out. A monitored ECG showed ventricular tachycardia. Twenty minutes after onset, a 12-lead ECG showed ventricular fibrillation, which returned to normal sinus rhythm with repeated DC cardioversion. Oral antiarrhythmic therapy with carteolol hydrochloride was effective. The patient showed no further symptoms after oral medication was initiated and the tumors regressed spontaneously.

Juxtacortical chondroma of the hand: treatment by resection of the tumour and the adjacent bone cortex.

A recurrence of a juxtacortical chondroma of the finger after marginal excision prompted us to review the treatment of this condition. Although the recommended treatment is simple curettage or marginal excision, the reported recurrence rate is significantly higher for lesions in the hand than those in other locations and recurrences only occurred in patients who had local treatments which did not include excision of the adjacent bone cortex. We report five patients with juxtacortical chondroma of the fingers. The first patient underwent marginal excision without resection of the underlying bone cortex. The other four patients underwent intralesional, marginal or wide excisions of tumour with resection of the bone cortex underlying the lesion. Recurrence was only seen in the patient who did not undergo resection of the bone cortex. Resection of the underlying bone cortex after excision of this tumour may be advisable for the treatment of this tumour in the hand to reduce the rate of recurrence.

High microvascular density is correlated with high VEGF, iNOS and COX-2 expression in penetrating growth-type early gastric carcinomas.

AIMS: Early gastric carcinomas have two characteristic growth types, superficial spreading (SUP) and penetrating (PEN). Higher mucosal apoptotic activity and lower p21(WAF1/CIP1) expression and submucosal low proliferative activity have been shown in the former, compared with the latter. In order to cast light on whether angiogenesis contributes to these growth patterns, the present immunohistochemical study was performed with cancer tissues. METHODS AND RESULTS: Of a total of 807 early gastric carcinomas, 30 PEN and 33 SUP type submucosal invasive carcinoma cases were immunohistochemically compared. CD34 positivity, microvascular density (MVD), and expression of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS), but not cyclooxygenase 2 (COX-2) were higher in cancer cells in both mucosal and submucosal layers in PEN than in SUP (P < 0.05). Submucosal MVD in PEN type was greater (P < 0.01) in cases with high than with low Ki67 labelling. Significant correlations were shown between MVD and VEGF, iNOS and COX-2, and VEGF and iNOS expression in the PEN type, but only a weak correlation between iNOS and COX-2 expression was evident with the SUP type. CONCLUSIONS: Increased MVD in PEN type has an intimate causal relationship to angiogenic factors, high VEGF and iNOS expression. The SUP type, in contrast, has characteristics of low angiogenesis.

Estrogenic and thyroid hormone activity of a series of hydroxy-polychlorinated biphenyls.

A series of novel synthetic monohydroxy polychlorinated biphenyls (OH-PCBs) (5 trichloro-, 5 tetrachloro- and 5 pentachloro-compounds) have been characterized (1H and 13C NMR and high resolution MS) and their estrogenic and thyroid hormone activities assessed using a yeast two-hybrid assay, both with and without possible metabolic activation by rat liver S9 preparation. Moderate estrogenic activity was found for 2,3,4(')-trichlorobiphenyl-4-ol (compound 5) but this was eliminated when exposed to the S9 mix. 2,2('),3('),4,6-Pentachlorobiphenyl-3-ol (13) and 2('),3,3('),6-tetrachlorobiphenyl-4-ol (10) both showed weak estrogenicity in the absence of the S9 mix. The estrogenicity of compound (10) was enhanced 10-fold by exposure to S9 metabolic activation but that of compound (13) remained unchanged. 2('),4,5('),6-Tetrachlorobiphenyl-2-ol (6) showed strong thyroid hormonal activity (5% of that of T4) whereas 3('),4,6-trichlorobiphenyl-3-ol (4), compound (10) and 2,3('),4,5('),6-pentachlorobiphenyl-3-ol (14) showed moderate activity, and 2('),3,3('),5-tetrachlorobiphenyl-2-ol (8) and 3,3('),5,5('),6-pentachlorobiphenyl-2-ol (11) showed weak activity. The activity of (4) was eliminated by S9 metabolic activation whereas those of (6) and (14) were weakened and that of (10) remained unchanged.