L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
Sintering is the process of forming materials and components from a powder under the action of thermal energy. It is a key materials science subject; most ceramic materials and many specialist metal ...powder products for use in key industries such as electronics, automotive and aerospace are formed this way. Written by one of the leading experts in the field, this book offers an unrivalled introduction to sintering and sintering processes for students of materials science and engineering, and practicing engineers in industry. The book is unique in providing a complete grounding in the principles of sintering and equal coverage of the three key sintering processes: densification, grain growth and microstructure. Students and professional engineers alike will be attracted by the emphasis on developing a detailed understanding of the theory and practical processes of sintering, the balanced coverage of ceramic and metal sintering, and the accompanying examination questions with selected solutions.
The overall skill of ENSO prediction in retrospective forecasts made with ten different coupled GCMs is investigated. The coupled GCM datasets of the APCC/CliPAS and DEMETER projects are used for ...four seasons in the common 22 years from 1980 to 2001. As a baseline, a dynamic-statistical SST forecast and persistence are compared. Our study focuses on the tropical Pacific SST, especially by analyzing the NINO34 index. In coupled models, the accuracy of the simulated variability is related to the accuracy of the simulated mean state. Almost all models have problems in simulating the mean and mean annual cycle of SST, in spite of the positive influence of realistic initial conditions. As a result, the simulation of the interannual SST variability is also far from perfect in most coupled models. With increasing lead time, this discrepancy gets worse. As one measure of forecast skill, the tier-1 multi-model ensemble (MME) forecasts of NINO3.4 SST have an anomaly correlation coefficient of 0.86 at the month 6. This is higher than that of any individual model as well as both forecasts based on persistence and those made with the dynamic-statistical model. The forecast skill of individual models and the MME depends strongly on season, ENSO phase, and ENSO intensity. A stronger El Niño is better predicted. The growth phases of both the warm and cold events are better predicted than the corresponding decaying phases. ENSO-neutral periods are far worse predicted than warm or cold events. The skill of forecasts that start in February or May drops faster than that of forecasts that start in August or November. This behavior, often termed the spring predictability barrier, is in part because predictions starting from February or May contain more events in the decaying phase of ENSO.
Abstract This study examined the hypothesis that apoptotic inhibition via mitochondrial pathway was involved in hyperbaric oxygen preconditioning (HBO-PC)–induced neuroprotection on ...ischemia–reperfusion injury in rat brain. Male Sprague–Dawley rats (250∼280 g, n =144) were divided into control, middle cerebral artery occlusion (MCAO) for 90 min, and HBO-PC plus MCAO groups. HBO-PC was conducted four times by giving 100% oxygen at 2.5 atm absolute (ATA), for 1 h at 12 h intervals for 2 days. At 24 h after the last HBO-PC, MCAO was performed and at 24 h after MCAO, neurological function, brain water content, infarct volume, and cell death were evaluated. Enzymatic activity of capase-3 and −9, and expression of cytochrome c , Bcl-2 and Bax proteins were performed in the samples from hippocampus, ischemic penumbra and core of the brain cortex, respectively. HBO-PC reduced brain edema, decreased infarction volume, and improved neurological recovery. HBO-PC reduced cytoplasm cytochrome c levels, decreased caspase enzyme activity, upregulated the ratio of Bcl-2 and Bax expression, and abated the apoptosis of ischemic tissue. HBO-PC protects brain tissues from ischemia–reperfusion injury by suppressing mitochondrial apoptotic pathways.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by ...phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.
Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig‐to‐nonhuman primate (NHP) model has not been ...demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen‐free (DPF) miniature pigs and infused intraportally into streptozotocin‐induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti‐thymocyte globulin (ATG) induction and maintenance with anti‐CD154 monoclonal antibody and low‐dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90–110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow‐up period showed excellent glucose disposal capacity and porcine C‐peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.
The authors report control of diabetes for longer than six months in four consecutive nonhuman primates by the transplantation of adult pig islets using a modest immunosuppressive regimen with an acceptable adverse effect profile.
Summary
Background
Nasal polyposis is a multi‐factorial disease associated with chronic inflammatory condition of the paranasal sinuses. Myofibroblast differentiation and extracellular matrix (ECM) ...accumulation are involved in the pathogenesis of nasal polyposis.
Objective
The aim of this study was to study the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on transforming growth factor (TGF)‐β1‐induced myofibroblast differentiation and ECM accumulation in nasal polyp‐derived fibroblasts (NPDFs).
Methods
Nasal polyp‐derived fibroblasts were isolated from nasal polyps of patients who have chronic rhinosinusitis with nasal polyp. TSA was treated in TGF‐β1‐induced NPDFs. Expression levels of HDAC2, α‐smooth muscle actin (SMA), TGF‐β1, collagen type I, acetylated Histone H3, acetylated Histone H4, phosphorylated Smad2/3 and Smad7 were determined by RT‐PCR, western blot and/or immunofluorescent staining. The total collagen amount production was analysed by Sircol soluble collagen assay and contractile activity was measured by collagen gel contraction assay. HDAC2 inhibition by TSA or HDAC2 silencing was established by RT‐PCR and western blot. The epigenetic effect on α‐SMA gene inactivation was examined by chromatin immunoprecipitation assay. Proliferation was determined by Ki67‐positive cell staining and cytotoxicity was assessed by 3‐(4,5‐ dimethylthiazol‐2yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay.
Results
The expression levels of HDAC2, α‐SMA and TGF‐β1 were increased in nasal polyp tissues compared to normal inferior turbinate tissues. TSA and HDAC2 silencing inhibited expression levels α‐SMA, collagen and HDAC2. TSA induced hyperacetylation of histone and suppressed opening of α‐SMA gene promoter in TGF‐β1‐induced NPDFs. TSA inhibited TGF‐β1‐induced Smad 2/3 and rescued TGF‐β1‐suppressed Smad7 signalling pathway. Finally, TSA blocked proliferation in TGF‐β1‐induced NPDFs and has no cytotoxic effect in NPDFs.
Conclusions and Clinical Relevance
These results suggest that HDAC inhibition is associated with myofibroblast differentiation and extracelluar matrix accumulation in nasal polyposis. TSA may be useful as an inhibitor of nasal polyp growth, and thus has potential to be used as a novel treatment option for nasal polyposis.
Given observed initial conditions, how well do coupled atmosphere-ocean models predict precipitation climatology with 1-month lead forecast? And how do the models' biases in climatology in turn ...affect prediction of seasonal anomalies? We address these questions based on analysis of 1-month lead retrospective predictions for 21 years of 1981-2001 made by 13 state-of-the-art coupled climate models and their multi-model ensemble (MME). The evaluation of the precipitation climatology is based on a newly designed metrics that consists of the annual mean, the solstitial mode and equinoctial asymmetric mode of the annual cycle, and the rainy season characteristics. We find that the 1-month lead seasonal prediction made by the 13-model ensemble has skills that are much higher than those in individual model ensemble predictions and approached to those in the ERA-40 and NCEP-2 reanalysis in terms of both the precipitation climatology and seasonal anomalies. We also demonstrate that the skill for individual coupled models in predicting seasonal precipitation anomalies is positively correlated with its performances on prediction of the annual mean and annual cycle of precipitation. In addition, the seasonal prediction skill for the tropical SST anomalies, which are the major predictability source of monsoon precipitation in the current coupled models, is closely link to the models' ability in simulating the SST mean state. Correction of the inherent bias in the mean state is critical for improving the long-lead seasonal prediction. Most individual coupled models reproduce realistically the long-term annual mean precipitation and the first annual cycle (solstitial mode), but they have difficulty in capturing the second annual (equinoctial asymmetric) mode faithfully, especially over the Indian Ocean (IO) and Western North Pacific (WNP) where the seasonal cycle in SST has significant biases. The coupled models replicate the monsoon rain domains very well except in the East Asian subtropical monsoon and the tropical WNP summer monsoon regions. The models also capture the gross features of the seasonal march of the rainy season including onset and withdraw of the Asian-Australian monsoon system over four major sub-domains, but striking deficiencies in the coupled model predictions are observed over the South China Sea and WNP region, where considerable biases exist in both the amplitude and phase of the annual cycle and the summer precipitation amount and its interannual variability are underestimated.
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