Παρασκευή, 1 Απριλίου 2016

Metachronous T-Lymphoblastic Lymphoma and Burkitt Lymphoma in a Child With Constitutional Mismatch Repair Deficiency Syndrome

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Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with a high risk of developing early-onset malignancies of the blood, brain, and intestinal tract. We present the case of a patient with T-lymphoblastic lymphoma at the age of 3 years, followed by Burkitt lymphoma 10 years later. This patient also exhibited numerous nonmalignant findings including café au lait spots, lipomas, bilateral renal nodules, a nonossifying fibroma, multiple colonic adenomas, and a rapidly enlarging pilomatrixoma. The spectrum of malignant and nonmalignant neoplasms in this patient highlights the remarkable diversity, and early onset, of lesions seen in children with CMMRD.



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Relapsed or Refractory Lymphoblastic Lymphoma in Children: Results and Analysis of 23 Patients in the EORTC 58951 and the LMT96 Protocols

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Background

The treatment of children with T-cell lymphoblastic lymphoma (T-LBL) and precursor B-cell lymphoblastic lymphoma (pB-LBL) has improved during the last decades. However, patients with relapsed or refractory lymphomas still have a poor prognosis.

Methods

We report the characteristics and evolution of T-LBL and pB-LBL relapses in two multicenter prospective studies (LMT 96, European Organization for Research and Treatment of Cancer 58951).

Results

From 1997 to 2008, 194 patients were included in these studies (157 T-LBL; 37 pB-LBL); among them, 23 patients underwent relapse or progression (18 T-LBL and 5 pB-LBL). The median age was 7.7 years (range 1.4–16.3). The survival rate at 8 years was 8.7% (21 deaths). The median time from diagnosis to relapse was 9 months [1–69] and 11 months [1–45] for T-LBL and pB-LBL, respectively. Twenty-two patients received a second-line treatment but remission was achieved in only seven patients. In 10 patients, intensification with hematopoietic stem cell transplantation (HSCT) was performed and four of them had a second relapse. Two patients still alive had T-LBL, experienced relapses 15 and 69 months after diagnosis, and received HSCT. Relapse during the intensive phase and second-line treatment without HSCT were identified as risk factors for bad prognosis (P = 0.01).

Conclusions

The results of second-line treatment, including intensive chemotherapy and HSCT, show that salvage treatment is still disappointing in controlling refractory forms. Early identification of patients at high risk of relapse is mandatory, allowing earlier intensification. Valid prognostic parameters, such as biological markers, are needed. International cooperation is warranted to collect more data on these rare diagnoses.



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Survey and analysis of simple sequence repeats in the Ustilaginoidea virens genome and the development of microsatellite markers

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Publication date: 1 July 2016
Source:Gene, Volume 585, Issue 1
Author(s): Mina Yu, Junjie Yu, Huanhuan Li, Yahui Wang, Xiaole Yin, Huiwen Bo, Hui Ding, Yuxin Zhou, Yongfeng Liu
Ustilaginoidea virens is the causal agent of rice false smut, causing quantitative and qualitative losses in rice industry. However, the development and application of simple sequence repeat (SSR) markers for genetic diversity studies in U. virens were limited. This study is the first to perform large-scale development of SSR markers of this pathogen at the genome level, to (1) compare these SSR markers with those of other fungi, (2) analyze the pattern of the SSRs, and (3) obtain more informative genetic markers. U. virens is rich in SSRs, and 13,778 SSRs were identified with a relative abundance of 349.7SSRs/Mb. The most common motifs in the genome or in noncoding regions were mononucleotides, whereas trinucleotides in coding sequences. A total of 6 out of 127 primers were randomly selected to be used to analyze 115 isolates, and these 6 primers showed high polymorphism in U. virens. This study may serve as an important resource for molecular genetic studies in U. virens.



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Transcriptome analysis of phycocyanin inhibitory effects on SKOV-3 cell proliferation

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Publication date: 1 July 2016
Source:Gene, Volume 585, Issue 1
Author(s): Jun Ying, Jian Wang, Huijuan Ji, Chaoqing Lin, Ruowang Pan, Li Zhou, Yulong Song, Enyong Zhang, Ping Ren, Jishun Chen, Qian Liu, Teng Xu, Huiguang Yi, Jinsong Li, Qiyu Bao, Yunliang Hu, Peizhen Li
Phycocyanin (PC) from Spirulina platensis has inhibitory effects on tumor cell growth. In this research, the transcriptome study was designed to investigate the underlying molecular mechanisms of PC inhibition on human ovarian cancer cell SKOV-3 proliferation. The PC IC50 was 216.6μM and 163.8μM for 24h and 48h exposure, respectively, as determined by CCK-8 assay. The morphological changes of SKOV-3 cells after PC exposure were recorded using HE staining. Cells arrested in G2/M stages as determined by flow cytometry. The transcriptome analysis showed that 2031 genes (with > three-fold differences) were differentially expressed between the untreated and the PC-treated cells, including 1065 up-regulated and 966 down-regulated genes. Gene ontology and KEGG pathway analysis identified 18 classical pathways that were remarkably enriched, such as neurotrophin signaling pathway, VEGF signaling pathway and P53 signaling pathway. qPCR results further showed that PTPN12, S100A2, RPL26, and LAMA3 increased while HNRNPA1P10 decreased in PC-treated cells. Molecules and genes in those pathways may be potential targets to develop treatments for ovarian cancer.



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Comparative analyses of the complete mitochondrial genomes of the two murine pinworms Aspiculuris tetraptera and Syphacia obvelata

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Publication date: 1 July 2016
Source:Gene, Volume 585, Issue 1
Author(s): Chun-Ren Wang, Yan Lou, Jun-Feng Gao, Jian-Hua Qiu, Yan Zhang, Yuan Gao, Qiao-Cheng Chang
Pinworms Aspiculuris tetraptera and Syphacia obvelata are important parasitic nematodes of laboratory mice, rat and other rodents. However, the mitochondrial (mt) genome of these parasites have not been known yet. In the present study, the complete mt genomes of A. tetraptera and S. obvelata were sequenced, which were 13,669bp and 14,235bp in size, respectively. Both genomes included 12 protein-coding genes, two rRNA genes, 22 tRNA genes and one non-coding region. The mt genomes of A. tetraptera and S. obvelata preferred bases A and T, with the highest for T and the lowest for C. The mt gene arrangements of the two pinworms were the same as that of the GA8 type. Phylogenetic analysis using mtDNA data revealed that the Bayesian inference (BI) trees contained two big branches: species from Oxyuridomorpha, Rhabditomorpha and Ascaridomorpha formed one branch, and those from Spiruromorpha formed another branch with high statistical support. The two murine pinworms A. tetraptera and S. obvelata have closer relationship than to other pinworms. This study provides a foundation for studying the population genetics, systematics and molecular phylogeny of pinworms.



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The potential function of microRNA in chordomas

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Publication date: 1 July 2016
Source:Gene, Volume 585, Issue 1
Author(s): Sukru Gulluoglu, Emre Can Tuysuz, Aysegul Kuskucu, Ugur Ture, Basar Atalay, Fikrettin Sahin, Omer Faruk Bayrak
Little is known about the molecular biology of chordomas, which are rare, chemoresistant tumors with no well-established treatment. miRNAs regulate gene networks and pathways. We aimed to evaluate the effects of dysregulated miRNA in chordomas would help reveal the underlying mechanisms of chordoma initiation and progression. In this study, miR-31, anti-miR-140-3p, anti-miR148a, and miR-222 were transiently transfected to chordoma cell lines and an MTS assay, apoptosis assay, and cell-cycle analysis were conducted to evaluate the effects. The mRNA level of predicted and confirmed targets of each miRNA, as well as the EMT and MET markers of U-CH1 and MUG-Chor1, were assessed with real-time polymerase chain reaction. Transient transfection of miRNA mimics was achieved, as each mimic increased or decreased the level of its corresponding miRNA. miR-31 decreased cell viability in MUG-Chor1 and U-CH2 after 72h, which is consistent with previous findings for U-CH1. Both miR-31 and anti-miR-148a induced apoptosis in all three cell lines. Although each miRNA had a similar pattern, miR-31 had the most effective S-phase arrest in all three cell lines. RDX, MET, DNMT1, DNMT3B, TRPS1, BIRC5, and KIT were found to be targeted by the selected miRNAs. The level of miR-222 in chordoma cell lines U-CH1 and MUG-Chor1 correlated positively with EMT markers and negatively with MET markers. This study uncovered the potential of miR-31, miR-140-3p, miR-148a, and miR-222-3p to be key molecules in the cell viability, cell cycle, and apoptosis in chordomas, as well as initiation, differentiation, and progression.



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Editorial Board

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Publication date: 10 June 2016
Source:Gene, Volume 584, Issue 1





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Editorial Board

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Publication date: 25 May 2016
Source:Gene, Volume 583, Issue 1





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Eksepsjonelt sykdomsforløp ved bruk av alternativ behandling?

I møte med alternativ behandling opplever pasienten tidvis en uforklarlig endring.

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PD-1 blockade — a therapeutic option for treatment of metastatic Merkel cell carcinoma

Abstract

Background

The immune system is extremely important in the development and progression of Merkel cell carcinoma (MCC). Immune checkpoint blockade has recently been shown to enable efficacious treatment of a variety of tumours. We report use of an anti-PD-1 antibody for treatment of a patient with metastatic MCC.

Case Report

An 80-year-old patient with metastatic MCC received off-label treatment with the anti-PD-1 antibody pembrolizumab after the disease had progressed during therapy with oral etoposide. A PET-CT scan performed after three cycles of pembrolizumab revealed response to therapy with reduced size of the adrenal gland metastases and less PET activity in the adrenal gland and lymph node metastases. Further on, treatment was resumed due to disease progression in a treatment-free interval of more than four months. During subsequent months of treatment size of the metastases stabilized and uptake of nuclide by all tumour sites once again decreased.

Conclusions

These results reveal the potential efficacy of an anti-PD-1 antibody for treatment of metastatic MCC. They thus contribute to currently limited data on use of anti-PD-1 antibodies for treatment of MCC. This is, moreover, the first report of successful resumption of treatment of metastatic MCC with an anti-PD-1 antibody. Results from ongoing trials will contribute to determination of the relevance of PD-1 blockade in metastatic MCC.

This article is protected by copyright. All rights reserved.



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Clinical repigmentation patterns in paediatric vitiligo

Abstract

Background

Repigmentation is an essential outcome measure in vitiligo. However, clinical studies describing vitiligo repigmentation patterns are lacking.

Objectives

To assess and clearly define the repigmentation patterns in a series of vitiligo patients, correlating these with clinico-epidemiological characteristics.

Methods

Patients with vitiligo seen at least at twice (initial consultation and follow-up visit) in the Department of Paediatric Dermatology, Hôpital Pellegrin des Enfants, Bordeaux University Hospital from 2006 to 2014, were included. Clinical photographs and case records were reviewed.

Results

There were 109 patients (64 females, 45 males) with mostly Fitzpatrick skin type III (n=67, 61%). The majority had non-segmental (n=71, 65%) or segmental vitiligo (n=29, 27%). A total of 172 representative vitiligo lesions were analysed. Overall, a combined pattern of repigmentation was most commonly seen (n=106, 62%). The combined pattern occurred more frequently in patients with segmental compared to non-segmental vitiligo (p=0.009); whereas, the diffuse pattern was more frequent in the latter (p=0.007). Diffuse repigmentation was the predominant pattern on the eyelids (p<0.001). We observed a new pattern in sites with few to absent hair follicles, which we propose to call “medium spotted repigmentation”. This begins as circular macules of repigmentation, wider than 5mm in diameter, which are from the outset, larger than the initial macules of perifollicular repigmentation. This study is limited by its retrospective nature and small sample size for subgroup assessment.

Conclusions

The combined pattern of repigmentation was most frequently observed. Medium spotted repigmentation is a new pattern, which will benefit from larger studies for better understanding.

This article is protected by copyright. All rights reserved.



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Risk of self-harm and non-fatal suicide attempts, and completed suicide in patients with psoriasis – a population-based cohort study

Abstract

Background

Psoriasis is a common inflammatory skin disease, and inflammation may affect suicidal behavior. Current data on the incidence and risk of suicidal behavior in patients with psoriasis are scarce.

Objective

We investigated the association between psoriasis and the risk of self-harm and suicide attempts, and suicides, respectively.

Methods

All Danish patients aged ≥18 years with mild or severe psoriasis (cases) from January 1, 1997 to December 31, 2011 were matched on age, sex, and calendar time 1:5 with healthy controls. The outcome was a diagnosis of self-harm or non-fatal suicide attempt, or completed suicide, respectively. Incidence rates per 10,000 person-years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression models.

Results

The study cohort comprised 408,663 individuals, including 57,502 and 11,009 patients with mild and severe psoriasis, respectively. A total of 280 cases of self-harm or suicide attempts, and 574 suicides, respectively, occurred during follow up. There was no increased risk of self-harm or suicide attempts in patients with mild psoriasis (IRR 1.01, 95% CI 0.17-2.01), but this risk was significantly increased in severe psoriasis (IRR 1.69, 95% CI 1.00-2.84). There was no increased risk of suicides in mild (IRR 1.05, 95% CI 0.84-1.32), or severe psoriasis (IRR 0.78, 95% CI 0.45-1.36), respectively. Similar results were found when suicides were confirmed by official forensic investigations, and when psoriasis was compared with atopic dermatitis.

Conclusions

We found limited evidence to suggest an increased risk of self-harm and non-fatal suicide attempts in psoriasis patients and, importantly, after adjustment for psoriatic arthritis this risk was no longer significantly increased. The risk of completed suicide was also not increased, regardless of psoriasis severity.

This article is protected by copyright. All rights reserved.



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Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor

Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): V.R. Belum, B. Benhuri, M.A. Postow, M.D. Hellmann, A.M. Lesokhin, N.H. Segal, R.J. Motzer, S. Wu, K.J. Busam, J.D. Wolchok, M.E. Lacouture
BackgroundDermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known.MethodsWe conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented.ResultsRash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab.ConclusionWe found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.



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CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma

Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): Hagma H. Workel, Fenne L. Komdeur, Maartje C.A. Wouters, Annechien Plat, Harry G. Klip, Florine A. Eggink, G. Bea A. Wisman, Henriette J.G. Arts, Maaike H.M. Oonk, Marian J.E. Mourits, Refika Yigit, Marco Versluis, Evelien W. Duiker, Harry Hollema, Marco de Bruyn, Hans W. Nijman
IntroductionIntraepithelial CD8+ tumour-infiltrating T-lymphocytes (TIL) are associated with a prolonged survival in endometrial cancer (EC). By contrast, stromal infiltration of CD8+ TIL does not confer prognostic benefit. A single marker to discriminate these populations would therefore be of interest for rapid assessment of the tumour immune contexture, ex vivo analysis of intraepithelial and stromal T-cells on a functional level and/or adoptive T-cell transfer. Here we determined whether CD103, the αE subunit of the αEβ7integrin, can be used to specifically discriminate the epithelial and stromal CD8+ TIL populations in EC.MethodsCD103+ TIL were quantified in a cohort of 305 EC patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 were assessed by immunofluorescence. Further phenotyping of CD103+ cells was performed by flow cytometry on primary endometrial tumour digests.ResultsCD8+CD103+ cells were preferentially located in endometrial tumour epithelium, whereas CD8+CD103− cells were located in stroma. CD103+ lymphocytes were predominantly CD3+CD8+ T-cells and expressed PD1. The presence of a high CD103+ cell infiltration was associated with an improved prognosis in patients with endometrial adenocarcinoma (p = 0.035). Moreover, this beneficial effect was particularly evident in high-risk adenocarcinoma patients (p = 0.031).ConclusionsBecause of the restricted expression on intraepithelial CD8+ T-cells, CD103 may be a suitable biomarker for rapid assessment of immune infiltration of epithelial cancers. Furthermore, this intraepithelial tumour-reactive subset might be an interesting T-cell subset for adoptive T-cell transfer and/or target for checkpoint inhibition therapy.



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Response to letter ‘A cumulative meta-analysis on the association of toll-like receptor 4 gene Asp299Gly polymorphism with cancer risk’

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Kui Zhang, Bin Zhou, Yanyun Wang, Li Rao, Lin Zhang




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High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Fabian Finkelmeier, Özge Canli, Andrea Tal, Thomas Pleli, Jörg Trojan, Michael Schmidt, Bernd Kronenberger, Stefan Zeuzem, Albrecht Piiper, Florian R. Greten, Oliver Waidmann
AimImmunotherapy in cancer is a recent and very promising approach, namely the inhibition of the PD/programmed death-ligand 1 (PD-L1) axis. Here we aimed to investigate the prognostic value of a soluble form of PD-L1 in hepatocellular carcinoma (HCC) patients.MethodsHCC patients were prospectively recruited and soluble programmed death-ligand 1 (sPD-L1) levels were determined. sPD-L1 levels were compared to stages of cirrhosis and HCC. The association of the sPD-L1 levels and overall survival (OS) was assessed.ResultsTwo hundred fifteen patients with HCC were prospectively included. The median serum sPD-L1 concentration in patients with HCC was 0.5 ng/ml (range 0.03–6.04). Soluble PD-L1 levels positively correlated with the stage of cirrhosis and with stages of HCC. Furthermore, sPD-L1 correlated positively with a marker of macrophage activation (sCD163) and inflammation (C-reactive protein). The cut-off for high-level sPD-L1 (>0.8 ng/ml) was defined by sPD-L1 levels determined in a healthy control cohort. Patients with high serum sPD-L1 concentrations had an increased mortality risk (hazard ratio 3.340, 95 % confidence interval 1.609–6.934, P<0.001), while very low PD-L1 levels seem to come along with better prognosis. High sPD-L1 levels were associated with mortality independently from cirrhosis stage, alpha-fetoprotein and sCD163 levels in a multivariate Cox regression model.ConclusionsWe conclude that a high sPD-L1 level is a possible prognostic indicator for a poor outcome in HCC patients. The predictive value of sPD-L1 levels for a successful anti-PD1/PD-L1 therapy should be investigated in the future.



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Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Markus Moehler, Maike Delic, Katrin Goepfert, Daniela Aust, Heike I. Grabsch, Niels Halama, Bernd Heinrich, Catherine Julie, Florian Lordick, Manfred P. Lutz, Murielle Mauer, Maria Alsina Maqueda, Hansjoerg Schild, Carl C. Schimanski, Anna-Dorothea Wagner, Arnaud Roth, Michel Ducreux
The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient’s tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.



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A cumulative meta-analysis on the association of toll-like receptor 4 gene Asp299Gly polymorphism with cancer risk

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Haiyan Yang, Teng Pan, Guangcai Duan, Yadong Wang




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Clinical characteristics and outcomes of pediatric patients with desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) is a rare malignancy that typically affects pediatric and young adult patients. There are limited data on the clinical features of pediatric DSRCT. We selected patients aged 0-21 years reported to the Surveillance, Epidemiology and End Results Program from 1991-2011. We estimated overall survival using Kaplan-Meier approaches and compared outcomes using the log rank test. The median age of the 95 pediatric patients was 15.3 years (range: 0-21). The majority of tumors originated in the abdomen and pelvis (84.4%) and the majority of patients had distant metastasis (72.6%). A minority of patients received radiation (34%). Overall survival at 5 years was poor (18.1%; 95% confidence interval 10.1-27.9%). Radiation therapy was associated with superior survival. Pediatric patients with DSRCT have significant disease burden. Outcomes for children are poor, though patients selected for radiation appear to have improved survival.

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Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Wenwei Zhang, So Young Bu, Mara T. Mashek, InSug O-Sullivan, Zakaria Sibai, Salmaan A. Khan, Olga Ilkayeva, Christopher B. Newgard, Douglas G. Mashek, Terry G. Unterman
Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid metabolism downstream of FoxO proteins.

Graphical abstract

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Teaser

FoxO proteins are major targets of insulin that regulate hepatic glucose metabolism. Zhang et al. report that FoxO proteins also promote triacylglycerol catabolism through regulation of ATGL and its inhibitor, G0S2, and that ATGL-dependent lipolysis plays an important role in mediating the effects of FoxO on liver glucose and lipid metabolism.


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Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Wei Wang, Sang Joon Lee, Patrick A. Scott, Xiaoqin Lu, Douglas Emery, Yongqin Liu, Toshihiko Ezashi, Michael R. Roberts, Jason W. Ross, Henry J. Kaplan, Douglas C. Dean
Most retinitis pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nighttime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE) and, thus, is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment-rich outer segments (OSs), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.

Graphical abstract

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Teaser

Wang et al. show RPE glucose release requires rod outer segment extension. Glucose induces Txnip in cones to direct outer segment synthesis. With rod degeneration in retinitis pigmentosa, cones starve for glucose causing outer segment loss and diminished central vision. Rod transplant or glucose therapy restores synthesis and cone function.


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Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Cédric G. Geoffroy, Brett J. Hilton, Wolfram Tetzlaff, Binhai Zheng
How aging impacts axon regeneration after CNS injury is not known. We assessed the impact of age on axon regeneration induced by Pten deletion in corticospinal and rubrospinal neurons, two neuronal populations with distinct innate regenerative abilities. As in young mice, Pten deletion in older mice remains effective in preventing axotomy-induced decline in neuron-intrinsic growth state, as assessed by mTOR activity, neuronal soma size, and axonal growth proximal to a spinal cord injury. However, axonal regeneration distal to injury is greatly diminished, accompanied by increased expression of astroglial and inflammatory markers at the injury site. Thus, the mammalian CNS undergoes an age-dependent decline in axon regeneration, as revealed when neuron-intrinsic growth state is elevated. These results have important implications for developing strategies to promote axonal repair after CNS injuries or diseases, which increasingly affect middle-aged to aging populations.

Graphical abstract

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Teaser

Working on two different axonal pathways, Geoffroy et al. show an age-dependent decline in axon regeneration after injury in the adult mammalian CNS. Their data implicate changes in neuron-extrinsic influences at the injury site in this age-dependent decline.


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Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Benjamin Cieply, Juw Won Park, Angela Nakauka-Ddamba, Thomas W. Bebee, Yang Guo, Xuequn Shang, Christopher J. Lengner, Yi Xing, Russ P. Carstens
Alternative splicing (AS) plays a critical role in cell fate transitions, development, and disease. Recent studies have shown that AS also influences pluripotency and somatic cell reprogramming. We profiled transcriptome-wide AS changes that occur during reprogramming of fibroblasts to pluripotency. This analysis revealed distinct phases of AS, including a splicing program that is unique to transgene-independent induced pluripotent stem cells (iPSCs). Changes in the expression of AS factors Zcchc24, Esrp1, Mbnl1/2, and Rbm47 were demonstrated to contribute to phase-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS during reprogramming by different RNA-binding proteins. Ectopic expression of Esrp1 enhanced reprogramming, in part by modulating the AS of the epithelial specific transcription factor Grhl1. These data represent a comprehensive temporal analysis of the dynamic regulation of AS during the acquisition of pluripotency.

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Cieply et al. show that post-transcriptional gene regulation during induced pluripotency of mouse embryo fibroblasts involves temporally coordinated changes in alternative splicing that is mediated by multiple splicing factors. One such factor, Esrp1, which is activated at the critical MET phase, and its target gene, Grhl1, enhance reprogramming efficiency.


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Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Zachary C. Poss, Christopher C. Ebmeier, Aaron T. Odell, Anupong Tangpeerachaikul, Thomas Lee, Henry E. Pelish, Matthew D. Shair, Robin D. Dowell, William M. Old, Dylan J. Taatjes
Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report a large-scale identification of Mediator kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence Mediator kinase targets within 64 proteins, including DNA-binding transcription factors and proteins associated with chromatin, DNA repair, and RNA polymerase II. Although RNA-seq data correlated with Mediator kinase targets, the effects of CA on gene expression were limited and distinct from CDK8 or CDK19 knockdown. Quantitative proteome analyses, tracking around 7,000 proteins across six time points (0–24 hr), revealed that CA selectively affected pathways implicated in inflammation, growth, and metabolic regulation. Contrary to expectations, increased turnover of Mediator kinase targets was not generally observed. Collectively, these data support Mediator kinases as regulators of chromatin and RNA polymerase II activity and suggest their roles extend beyond transcription to metabolism and DNA repair.

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Taking advantage of a recently characterized Mediator kinase (CDK8 and CDK19) inhibitor, Poss et al. use SILAC-based proteomics and phosphoproteomics, RNA-seq, and biochemical assays to provide an extensive analysis of human Mediator kinase function. The methods applied and targets identified provide a valuable resource for future studies.


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An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Sara Della Torre, Nico Mitro, Roberta Fontana, Monica Gomaraschi, Elda Favari, Camilla Recordati, Federica Lolli, Fabiana Quagliarini, Clara Meda, Claes Ohlsson, Maurizio Crestani, Nina Henriette Uhlenhaut, Laura Calabresi, Adriana Maggi
Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism.

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Della Torre et al. show that ERα activity in the mouse female liver is essential for balanced lipid and cholesterol metabolism. Lack of liver ERα activation in the case of ovarian failure leads to metabolic dysfunction that may be linked to post-menopausal disease.


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Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Maria-Paz Garcia-Cuellar, Christian Büttner, Christoph Bartenhagen, Martin Dugas, Robert K. Slany
MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, revealing 165 direct target genes separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on DOT1L-mediated histone methylation, and coded preferentially for transcription factors, including many homeobox genes. A distinct ME3 group accumulated MLL-ENL beyond the termination site, was dependent on P-TEFb-mediated phosphorylation of RNA Pol II for transcription, and translated mainly into proteins involved in RNA biology and ribosome assembly. This dichotomy was reflected by a differential sensitivity toward small molecule inhibitors, suggesting the possibility of a combinatorial strategy for treatment of MLL-induced leukemia.

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In this article, Garcia-Cuellar et al. use nascent RNA and ChIP sequencing to identify genes controlled by the leukemogenic oncoprotein MLL-ENL. Two target gene categories can be classified that differ by the MLL-ENL binding mode used, respective co-factor requirements, and pharmacological sensitivity toward specific inhibitors.


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Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Tania Løve Aaes, Agnieszka Kaczmarek, Tinneke Delvaeye, Bram De Craene, Stefaan De Koker, Liesbeth Heyndrickx, Iris Delrue, Joachim Taminau, Bartosz Wiernicki, Philippe De Groote, Abhishek D. Garg, Luc Leybaert, Johan Grooten, Mathieu J.M. Bertrand, Patrizia Agostinis, Geert Berx, Wim Declercq, Peter Vandenabeele, Dmitri V. Krysko
Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. We have developed a genetic model in which direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release damage-associated molecular patterns and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells. Our study broadens the current concept of immunogenic cell death and opens doors for the development of new strategies in cancer therapy.

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Teaser

Løve Aaes et al. show that necroptotic cancer cells induce the maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using RIPK3 induction systems, the authors further demonstrate efficient prophylactic vaccination with immunogenic necroptotic cells.


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Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Mitchell D’Rozario, Ting Zhang, Edward A. Waddell, Yonggang Zhang, Cem Sahin, Michal Sharoni, Tina Hu, Mohammad Nayal, Kaveesh Kutty, Faith Liebl, Wenhui Hu, Daniel R. Marenda
Proneural proteins of the class I/II basic-helix-loop-helix (bHLH) family are highly conserved transcription factors. Class I bHLH proteins are expressed in a broad number of tissues during development, whereas class II bHLH protein expression is more tissue restricted. Our understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as regulators of neurogenesis. Here, we show that the class I bHLH proteins Daughterless and Tcf4 are expressed in postmitotic neurons in Drosophila melanogaster and mice, respectively, where they function to restrict neurite branching and synapse formation. Our data indicate that Daughterless performs this function in part by restricting the expression of the cell adhesion molecule Neurexin. This suggests a role for these proteins outside of their established roles in neurogenesis.

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Teaser

Class I bHLH proneural proteins are highly conserved transcription factors generally recognized as critical for neurogenesis. D’Rozario et al. show that the Drosophila and mouse class I bHLH proteins Daughterless and Tcf4 are present in postmitotic, differentiated neurons and function to restrict neurite branch and synapse number.


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Mesolimbic Dopamine Encodes Prediction Errors in a State-Dependent Manner

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Georgios K. Papageorgiou, Mathieu Baudonnat, Flavia Cucca, Mark E. Walton
Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal’s current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet.

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Teaser

Dopamine signals information about reward value used for learning and decision making. Papageorgiou et al. show that mesolimbic dopamine coding of reward prediction errors rapidly updates to reflect current state-dependent values.


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Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Xueting Luo, Marcio Ribeiro, Eric R. Bray, Do-Hun Lee, Benjamin J. Yungher, Saloni T. Mehta, Kinjal A. Thakor, Francisca Diaz, Jae K. Lee, Carlos T. Moraes, John L. Bixby, Vance P. Lemmon, Kevin K. Park
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, STAT3 translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various STAT3 mutants demonstrate that STAT3′s transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth. STAT3′s localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on STAT3 transcriptional activity, with mitochondrial STAT3 providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse STAT3 functions and axon regrowth.

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Teaser

Luo et al. provide mechanistic insights into how STAT3 induces axon regeneration and sprouting after injury. They demonstrate that exploiting STAT3′s effects in combination with modulation of MEK and PTEN promotes extensive CNS axon regrowth.


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High-Content Quantification of Single-Cell Immune Dynamics

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Michael Junkin, Alicia J. Kaestli, Zhang Cheng, Christian Jordi, Cem Albayrak, Alexander Hoffmann, Savaş Tay
Cells receive time-varying signals from the environment and generate functional responses by secreting their own signaling molecules. Characterizing dynamic input-output relationships in single cells is crucial for understanding and modeling cellular systems. We developed an automated microfluidic system that delivers precisely defined dynamical inputs to individual living cells and simultaneously measures key immune parameters dynamically. Our system combines nanoliter immunoassays, microfluidic input generation, and time-lapse microscopy, enabling study of previously untestable aspects of immunity by measuring time-dependent cytokine secretion and transcription factor activity from single cells stimulated with dynamic inflammatory inputs. Employing this system to analyze macrophage signal processing under pathogen inputs, we found that the dynamics of TNF secretion are highly heterogeneous and surprisingly uncorrelated with the dynamics of NF-κB, the transcription factor controlling TNF production. Computational modeling of the LPS/TLR4 pathway shows that post-transcriptional regulation by TRIF is a key determinant of noisy and uncorrelated TNF secretion dynamics in single macrophages.

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Junkin et al. have developed a method to quantitatively probe single-cell input-output dynamics with an automated microfluidic system. They conduct coupled measurements of transcription factor and cytokine secretion dynamics from the same single cells to enable modeling, which uncovers dynamic and noise-based roles of TRIF in the NF-κB-TNF pathway.


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H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Dezhi Zhao, Qian Zhang, Yiqi Liu, Xia Li, Kai Zhao, Yuanyuan Ding, Zhiqing Li, Qicong Shen, Chunmei Wang, Nan Li, Xuetao Cao
The H3K4me3 demethylase Kdm5a regulates gene transcription and is implicated in carcinogenesis. However, the role of Kdm5a in innate immune response remains poorly understood. Here, we demonstrate that Kdm5a deficiency impairs activation of natural killer (NK) cells, with decreased IFN-γ production. Accordingly, Kdm5a−/− mice are highly susceptible to Listeria monocytogenes (Lm) infection. During NK cell activation, loss of Kdm5a profoundly impairs phosphorylation and nuclear localization of STAT4, along with increased expression of suppressor of cytokine signaling 1 (SOCS1). Mechanistic studies reveal that Kdm5a associates with p50 and binds to the Socs1 promoter region in resting NK cells, leading to a substantial decrease in H3K4me3 modification and repressive chromatin configuration at the Socs1 promoter. Thus, Kdm5a is required for priming activation of NK cells by suppressing the suppressor, SOCS1. Our study provides insights into the epigenetic regulation of innate immune response of NK cells.

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Teaser

Zhao et al. show that the H3K4me3 demethylase Kdm5a is recruited to the SOCS1 promoter by p50 to maintain a repressive chromatin configuration. Kdm5a-mediated suppression of SOCS1 is required for NK cell activation and initiation of innate immune responses to infection. These results reveal a role for histone demethylation in NK cell activation.


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The Rules of War, 1916

Reported in Scientific American, This Week in World War I: April 1, 1916

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IJMS, Vol. 17, Pages 486: The Impact of Specific Viruses on Clinical Outcome in Children Presenting with Acute Heart Failure

The presence and type of viral genomes have been suggested as the main etiology for inflammatory dilated cardiomyopathy. Information on the clinical implication of this finding in a large population of children is lacking. We evaluated the prevalence, type, and clinical impact of specific viral genomes in endomyocardial biopsies (EMB) collected between 2001 and 2013 among 63 children admitted to our hospital for acute heart failure (median age 2.8 years). Viral genome was searched by polymerase chain reaction (PCR). Patients underwent a complete two-dimensional echocardiographic examination at hospital admission and at discharge and were followed-up for 10 years. Twenty-seven adverse events (7 deaths and 20 cardiac transplantations) occurred during the follow-up. Viral genome was amplified in 19/63 biopsies (35%); PVB19 was the most commonly isolated virus. Presence of specific viral genome was associated with a significant recovery in ejection fraction, compared to patients without viral evidence (p < 0.05). In Cox-regression analysis, higher survival rate was related to virus-positive biopsies (p < 0.05). When comparing long-term prognosis among different viral groups, a trend towards better prognosis was observed in the presence of isolated Parvovirus B19 (PVB19) (p = 0.07). In our series, presence of a virus-positive EMB (mainly PVB19) was associated with improvement over time in cardiac function and better long-term prognosis.

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IJMS, Vol. 17, Pages 487: Optical Absorption Spectra and Electronic Properties of Symmetric and Asymmetric Squaraine Dyes for Use in DSSC Solar Cells: DFT and TD-DFT Studies

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The electronic absorption spectra, ground-state geometries and electronic structures of symmetric and asymmetric squaraine dyes (SQD1–SQD4) were investigated using density functional theory (DFT) and time-dependent (TD-DFT) density functional theory at the B3LYP/6-311++G** level. The calculated ground-state geometries reveal pronounced conjugation in these dyes. Long-range corrected time dependent density functionals Perdew, Burke and Ernzerhof (PBE, PBE1PBE (PBE0)), and the exchange functional of Tao, Perdew, Staroverov, and Scuseria (TPSSh) with 6-311++G** basis set were employed to examine optical absorption properties. In an extensive comparison between the optical data and DFT benchmark calculations, the BEP functional with 6-311++G** basis set was found to be the most appropriate in describing the electronic absorption spectra. The calculated energy values of lowest unoccupied molecular orbitals (LUMO) were 3.41, 3.19, 3.38 and 3.23 eV for SQD1, SQD2, SQD3, and SQD4, respectively. These values lie above the LUMO energy (−4.26 eV) of the conduction band of TiO2 nanoparticles indicating possible electron injection from the excited dyes to the conduction band of the TiO2 in dye-sensitized solar cells (DSSCs). Also, aromaticity computation for these dyes are in good agreement with the data obtained optically and geometrically with SQD4 as the highest aromatic structure. Based on the optimized molecular geometries, relative positions of the frontier orbitals, and the absorption maxima, we propose that these dyes are suitable components of photovoltaic DSSC devices.

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Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events



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Whi2 enhances methylmercury toxicity in yeast via inhibition of Akr1 palmitoyltransferase activity

Publication date: June 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 6
Author(s): Gi-Wook Hwang, Toru Fukumitsu, Yousuke Ogiwara, Tsutomu Takahashi, Nobuhiko Miura, Shusuke Kuge, Akira Naganuma
BackgroundWe have previously reported that Whi2 enhances the toxicity of methylmercury in yeast. In the present study we examined the proteins known to interact with Whi2 to find those that influence the toxicity of methylmercury.MethodsGene disruption and site-directed mutagenesis were employed to examine the relationship of mercury toxicity and palmitoylation. Protein palmitoylation was examined using the acyl-biotinyl exchange method. Protein–protein interactions were detected by immunoprecipitation and immunoblotting.ResultsWe found that deletion of Akr1, a palmitoyltransferase, rendered yeast cells highly sensitive to methylmercury, and Akr1 is necessary for the methylmercury resistance of Whi2-deleted yeast. Palmitoyltransferase activity of Akr1 has an important role in the alleviation of methylmercury toxicity. Whi2 deletion or methylmercury treatment enhanced the palmitoyltransferase activity of Akr1, and methylmercury treatment reduced the binding between Akr1 and Whi2.ConclusionsWhi2 bonds to Akr1 (a protein that is able to alleviate methylmercury toxicity) and thus inhibits Akr1's palmitoyltransferase activity, which leads to enhanced methylmercury toxicity. In contrast, methylmercury might break the bond between Whi2 and Akr1, which enhances the palmitoyltransferase activity of Akr1 to alleviate methylmercury toxicity.General significanceThis study's findings propose that the Whi2/Akr1 system can be regarded as a defense mechanism that detects methylmercury incorporation of yeast cells and alleviates its toxicity.



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Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium

Publication date: June 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 6
Author(s): M.E. Solesio, L. Demirkhanyan, E. Zakharian, E.V. Pavlov
BackgroundCalcium signaling plays a key role in the regulation of multiple processes in mammalian mitochondria, from cellular bioenergetics to the induction of stress-induced cell death. While the total concentration of calcium inside the mitochondria can increase by several orders of magnitude, the concentration of bioavailable free calcium in mitochondria is maintained within the micromolar range by the mitochondrial calcium buffering system. This calcium buffering system involves the participation of inorganic phosphate. However, the mechanisms of its function are not yet understood. Specifically, it is not clear how calcium-orthophosphate interactions, which normally lead to formation of insoluble precipitates, are capable to dynamically regulate free calcium concentration. Here we test the hypothesis that inorganic polyphosphate, which is a polymerized form of orthophosphate, is capable to from soluble complexes with calcium, playing a significant role in the regulation of the mitochondrial free calcium concentration.MethodsWe used confocal fluorescence microscopy to measure the relative levels of mitochondrial free calcium in cultured hepatoma cells (HepG2) with variable levels of inorganic polyphosphate (polyP).ResultsThe depletion of polyP leads to the significantly lower levels of mitochondrial free calcium concentration under conditions of pathological calcium overload. These results are coherent with previous observations showing that inorganic polyphosphate (polyP) can inhibit calcium-phosphate precipitation and, thus, increase the amount of free calcium.ConclusionsInorganic polyphosphate plays an important role in the regulation of mitochondrial free calcium, leading to its significant increase.General significanceInorganic polyphosphate is a previously unrecognized integral component of the mitochondrial calcium buffering system.



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IJERPH, Vol. 13, Pages 399: Effects of 20 Selected Fruits on Ethanol Metabolism: Potential Health Benefits and Harmful Impacts

The consumption of alcohol is often accompanied by other foods, such as fruits and vegetables. This study is aimed to investigate the effects of 20 selected fruits on ethanol metabolism to find out their potential health benefits and harmful impacts. The effects of the fruits on ethanol metabolism were characterized by the concentrations of ethanol and acetaldehyde in blood, as well as activities of alcohol dehydrogenase and acetaldehyde dehydrogenase in liver of mice. Furthermore, potential health benefits and harmful impacts of the fruits were evaluated by biochemical parameters including aspartate transaminase (AST), alanine transferase (ALT), malondialdehyde, and superoxide dismutase. Generally, effects of these fruits on ethanol metabolism were very different. Some fruits (such as Citrus limon (yellow), Averrhoa carambola, Pyrus spp., and Syzygium samarangense) could decrease the concentration of ethanol in blood. In addition, several fruits (such as Cucumis melo) showed hepatoprotective effects by significantly decreasing AST or ALT level in blood, while some fruits (such as Averrhoa carambola) showed adverse effects. The results suggested that the consumption of alcohol should not be accompanied by some fruits, and several fruits could be developed as functional foods for the prevention and treatment of hangover and alcohol use disorder.

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MLKL forms cation channels

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MLKL forms cation channels

Cell Research advance online publication, April 1 2016. doi:10.1038/cr.2016.26

Authors: Bingqing Xia, Sui Fang, Xueqin Chen, Hong Hu, Peiyuan Chen, Huayi Wang & Zhaobing Gao



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Positive selection rather than relaxation of functional constraint drives the evolution of vision during chicken domestication

Positive selection rather than relaxation of functional constraint drives the evolution of vision during chicken domestication

Cell Research advance online publication, April 1 2016. doi:10.1038/cr.2016.44

Authors: Ming-Shan Wang, Rong-wei Zhang, Ling-Yan Su, Yan Li, Min-Sheng Peng, He-Qun Liu, Lin Zeng, David M Irwin, Jiu-Lin Du, Yong-Gang Yao, Dong-Dong Wu & Ya-Ping Zhang



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Tribute to Peter D. Grimm, DO

Publication date: Available online 1 April 2016
Source:Brachytherapy
Author(s): John C. Blasko




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Spacetime Opera: Janna Levin on LIGO and the Hunt for Gravitational Waves

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The astrophysicist and author talks about her new book, Black Hole Blues and Other Songs from Outer Space

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How Cultural Differences Affect Autism Diagnoses

Behaviors that are considered red flags in the U.S. and Western Europe are considered normal, even desirable, in other parts of the world

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