Visible light primarily induces biosynthesis of proanthocyanidins and increases the level of B-ring hydroxylation in proanthocyanidin subunits, whereas UV light specifically induces biosynthesis of ...flavonol in young berry skins of wine grape. Display omitted
► Visible light induces biosynthesis of proanthocyanidins in young grape skins. ► Visible light increases the level of B-ring hydroxylation of proanthocyanidins. ► UV light specifically induces biosynthesis of flavonol. ► The decrease in proanthocyanidin biosynthesis by light exclusion is limited. ► Members of a MYB transcription factor family are regulated differently by light.
Biosynthesis of phenolic compounds is known to be sensitive to light environments, which reflects the possible role of these compounds for photoprotection in plants. Herein, the effects of UV and visible light on biosynthesis of flavonoids was investigated, i.e., proanthocyanidins (PAs) and flavonols, in young berry skins of a red-wine grape, Vitis vinifera cv. Cabernet Sauvignon. Shading with light-proof boxes from the flowering stage until 49days after treatment (DAT) partially decreased PA concentrations, and completely decreased flavonol concentrations in the berry skins. Shading decreased the transcript abundance of a flavonol-related gene more remarkably than those of PA-related genes. In addition, light exclusion influenced the composition of PAs, such as the decrease in the proportion of trihydroxylated subunits and the mean degree of polymerization (mDP) within PAs. However, solar UV exclusion did not affect the concentration and composition of PAs, whereas this exclusion remarkably decreased the flavonol concentration. Consistently, UV exclusion did not influence the transcript levels of PA-related genes, whereas it dramatically decreased that of flavonol-related genes. These findings indicated a different light regulation of the biosynthesis of these flavonoids in young berry skins of wine grape. Visible light primarily induces biosynthesis of PAs and affects their composition, whereas UV light specifically induces biosynthesis of flavonols. Distinct roles of members of a MYB transcription factor family for light regulation of flavonoid biosynthesis were proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•The role of l-lactate in fear memory in STZ-induced diabetic mice was studied.•Brain l-lactate levels were increased in STZ-induced diabetic mice.•l-lactate enhanced fear memory, which was inhibited ...by AMPA receptor antagonist.•AMPA receptor antagonist also inhibited fear memory in STZ-induced diabetic mice.•Increase in l-lactate enhances fear memory through glutamate functions in diabetes.
Previous reports suggest that diabetes mellitus is associated with psychiatric disorders, including depression and anxiety, but the mechanisms involved are unknown. We have reported that streptozotocin (STZ)-induced diabetic mice show enhancement of conditioned fear memory. To clarify the mechanisms through which diabetes affects conditioned fear memory, the present study investigated the role of l-lactate and glutamatergic function in enhancement of conditioned fear memory in diabetes. l-lactate levels in the amygdala and hippocampus, which are known to play important roles in fear memory, were significantly increased in STZ-induced diabetic mice. The glucose transporter (GLUT) 1 was significantly increased both in the amygdala and in the hippocampus. In contrast, GLUT3, the monocarboxylic acid transporter (MCT) 1 and MCT2 in the amygdala and hippocampus were not altered in STZ-induced diabetic mice. I.c.v. injection of l-lactate to non-diabetic mice significantly increased duration of freezing, whereas the MCT inhibitor 4-CIN significantly inhibited duration of freezing in STZ-induced diabetic mice. Injection of l-lactate significantly increased glutamate levels in the amygdala and hippocampus. Duration of freezing induced by l-lactate was significantly inhibited by the AMPA receptor antagonist NBQX. In addition, injection of NBQX into the amygdala and hippocampus significantly inhibited duration of freezing in STZ-induced diabetic mice. These results suggest that l-lactate levels are increased in the amygdala and hippocampus in diabetic mice, which may enhance fear memory though activation of glutamatergic function in the amygdala and hippocampus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and ...safety of two trough exposure concentrations of everolimus, 3–7 ng/mL (low exposure) and 9–15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. Methods In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2–65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov , number NCT01713946. Findings Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2–22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3–37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5–49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1–21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8–41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0–48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. Interpretation Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. Funding Novartis Pharmaceuticals Corporation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in ...patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients.
Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms.
Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus −6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores.
Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study evaluated the diagnostic accuracy of clinical, radiological, and histopathological examinations for differential diagnosis between atypical lipomatous tumor (ALT)/well-differentiated ...liposarcoma (WDLS) and lipoma, and aimed to develop a new combined scoring system for the preoperative diagnosis of ALT/WDLS. Eighty-nine lipomas and 56 ALT/WDLS were included and their clinical characteristics, magnetic resonance imaging (MRI) findings, histological findings by hematoxylin and eosin (HE) staining were investigated. Then, univariate and multivariate logistic regression analyses were performed for the findings, and a combined scoring system consisted of predictive factors of ALT/WDLS was developed. The univariate and multivariate logistic regression analyses revealed that tumor location (lower extremity), deep site, size (> 11 cm), thick septa (> 2 mm), enhancement of septa or nodular lesions, and lipoblasts were significantly different for the diagnosis of ALT/WDLS. We developed a combined scoring system based on the six predictive factors (total 0-16 points, the cutoff was 9 points). The area under the curve was 0.945, and sensitivity was 87.6% and specificity was 91.1% by the receiver operating characteristics curve. This combined scoring system does not require special equipment and reagents such as fluorescence in situ hybridization (FISH), and anyone can use it easily in many medical institutions with high diagnostic accuracy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic ...function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the β2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Adrenocortical carcinoma (ACC) is an uncommon cause of adrenal incidentaloma (AI). ACCs generally occur in large sizes, >4 cm in diameter, at initial presentation and grow rapidly. Therefore, there ...have been few reports of cases with long-term follow-up with imaging before ACC was diagnosed. Herein, we present a case of an adrenal mass that had remained small and unchanged for 5 years but later grew rapidly and was finally diagnosed as ACC. A 77-year-old hypertensive woman was referred to our hospital for the examination of a 5.4-cm left adrenal mass. Upon reviewing her previous unenhanced computed tomography (CT) scan, a 1.6-cm and 30 Hounsfield units (HU), homogeneous, round, left adrenal mass was incidentally detected 9 years ago. This mass remained unchanged until 4 years ago. One year ago, the mass enlarged to 3.0-cm and changed into an irregular form with heterogeneous density. The hormonal evaluation during the 9 years from the discovery of the AI was inadequate. The present examination diagnosed this case as ACC with subclinical Cushing’s syndrome. The patient underwent laparoscopic left adrenalectomy, and a histological diagnosis of high-grade ACC was made. The resected tumor had the CTNNB1 gene mutation. High unenhanced CT attenuation values (>10 HU) are one of the findings that raise suspicion of malignancy. This case suggests that patients with findings atypical of adenomas on an initial unenhanced CT might be carefully followed up given the possibility of development of ACCs, even if the initial tumor size is small.
Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, ...including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
We successfully established 10 PDX. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had EGFR mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent evidence suggests that hepatocellular carcinoma (HCC) is organized by a subset of cells with stem cell features (cancer stem cells; CSCs). CSCs are considered a pivotal target for the ...eradication of cancer, and liver CSCs have been identified by the use of various stem cell markers. However, little information is known about the expression patterns and characteristics of marker‐positive CSCs, hampering the development of personalized CSC‐targeted therapy. Here, we show that CSC markers EpCAM and CD90 are independently expressed in liver cancer. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene‐expression analysis of sorted cells suggested that EpCAM+ cells had features of epithelial cells, whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that the presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum alpha‐fetoprotein (AFP), whereas the presence of CD90+ cells was associated with a high incidence of distant organ metastasis. Serial xenotransplantation of EpCAM+/CD90+ cells from primary HCCs in immune‐deficient mice revealed rapid growth of EpCAM+ cells in the subcutaneous lesion and a highly metastatic capacity of CD90+ cells in the lung. In cell lines, CD90+ cells showed abundant expression of c‐Kit and in vitro chemosensitivity to imatinib mesylate. Furthermore, CD90+ cells enhanced the motility of EpCAM+ cells when cocultured in vitro through the activation of transforming growth factor beta (TGF‐β) signaling, whereas imatinib mesylate suppressed TGFB1 expression in CD90+ cells as well as CD90+ cell‐induced motility of EpCAM+ cells. Conclusion: Our data suggest the discrete nature and potential interaction of EpCAM+ and CD90+ CSCs with specific gene‐expression patterns and chemosensitivity to molecular targeted therapy. The presence of distinct CSCs may determine the clinical outcome of HCC. (HEPATOLOGY 2013)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Breast tissue has a branching structure that contains double‐layered cells, consisting primarily of luminal epithelial cells inside and myoepithelial cells outside. Ductal carcinoma in situ (DCIS) ...still has myoepithelial cells surrounding the cancer cells. However, myoepithelial cells disappear in invasive ductal carcinoma. In this study, we detected expression of neural EGFL like (NELL) 2 and one of its receptors, roundabout guidance receptor (ROBO) 3, in myoepithelial and luminal epithelial cells (respectively) in normal breast tissue. NELL2 also was expressed in myoepithelial cells surrounding the non‐cancerous intraductal proliferative lesions and DCIS. However, the expression level and proportion of NELL2‐positive cells in DCIS were lower than those in normal and non‐cancerous intraductal proliferative lesions. ROBO3 expression was decreased in invasive ductal carcinoma compared to that in normal and non‐cancerous intraductal proliferative lesions. An evaluation of NELL2's function in breast cancer cell lines demonstrated that full‐length NELL2 suppressed cell adhesion and migration in vitro. In contrast, the N‐terminal domain of NELL2 increased cell adhesion in the early phase and migration in vitro in some breast cancer cells. These results suggested that full‐length NELL2 protein, when expressed in myoepithelial cells, might serve as an inhibitor of breast cancer cell migration.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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