Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Cancers, Vol. 10, Pages 86: New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma

Cancers doi: 10.3390/cancers10040086

Authors: Kathy Shair Akhil Reddy Vaughn Cooper

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity.

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Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma.

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Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma.

J Hepatol. 2018 Mar 15;:

Authors: Dong LQ, Shi Y, Ma LJ, Yang LX, Wang XY, Zhang S, Wang ZC, Duan M, Zhang Z, Liu LZ, Zheng BH, Ding ZB, Ke AW, Gao DM, Yuan K, Zhou J, Fan J, Xi R, Gao Q

Abstract
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aim to investigate its ITH in hope of helping develop new therapeutic strategies.
METHODS: We obtained 69 spatially distinct regions from 6 operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing(WES) and multi-level validation.
RESULTS: We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal "illusion", parallel evolution and chromosome instability. A median of 60.3% mutations were heterogeneous mutations, among which 85% of the driver mutations located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor-suppressor genes, such as TP53, SMARCB1 and PBRM1 that involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral subregions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, may be used for new treatment strategy. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be developed in 5/6 patients.
CONCLUSIONS: Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC.
LAY SUMMARY: We applied multiregional whole exome sequencing to investigate the evolution trajectory of ICC. The results revealed that many fuels, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found some clues of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, can be promising treatment targets for ICC patients.

PMID: 29551704 [PubMed - as supplied by publisher]

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Aluminum hydroxide colloid vaccine encapsulated in yeast shells with enhanced humoral and cellular immune responses.

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Aluminum hydroxide colloid vaccine encapsulated in yeast shells with enhanced humoral and cellular immune responses.

Biomaterials. 2018 Mar 12;167:32-43

Authors: Liu H, Jia Z, Yang C, Song M, Jing Z, Zhao Y, Wu Z, Zhao L, Wei D, Yin Z, Hong Z

Abstract
Aluminum salt (Alum) is one of the most important immune adjuvants approved for use in humans, however it is not suitable for vaccination against various chronic infectious diseases and cancers for not being able to induce cell-mediated (Th1) immunity. Here, we encapsulated an Alum colloid inside β-glucan particles (GPs), which are a type of natural particles derived from the yeast glucan shells, to prepare hybrid GP-Alum (GP-Al) adjuvant particles with a very uniform size of 2-4 μm. These hybrid particles can be used to load antigen proteins through a simple mixing procedure, and can be highly specifically targeted to antigen-presenting cells (APCs) and strongly activate dendritic cells (DCs) maturation and cytokine secretion. In an animal model, they elicit a strong Th1-biased immune response and extremely high antibody titer, and cause marked prophylactic and therapeutic effects against tumors. As Alum has been proven to be a safe adjuvant to induce strong humoral responses and β-glucans are safe for human use, this very uniform hybrid Alum particulate system could have important application as a vaccine carrier to stimulate humoral and cellular immune responses at the same time.

PMID: 29554479 [PubMed - as supplied by publisher]

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Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

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Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Ann Oncol. 2018 Mar 14;:

Authors: Rodríguez-Ruiz ME, Perez-Gracia JL, Rodríguez I, Alfaro C, Oñate C, Pérez G, Gil-Bazo I, Benito A, Inogés S, López-Diaz de Cerio A, Ponz-Sarvise M, Resano L, Berraondo P, Barbés B, Martin-Algarra S, Gúrpide A, Sanmamed MF, de Andrea C, Salazar AM, Melero I

Abstract
BACKGROUND: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.
PATIENTS AND METHODS: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered one week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.
RESULTS: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+immunotherapy. No objective responses were observed, while nine patients presented stable disease (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease (SD). IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.
CONCLUSIONS: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

PMID: 29554212 [PubMed - as supplied by publisher]

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Sensing Microbial Viability through Bacterial RNA Augments T Follicular Helper Cell and Antibody Responses.

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Sensing Microbial Viability through Bacterial RNA Augments T Follicular Helper Cell and Antibody Responses.

Immunity. 2018 Mar 09;:

Authors: Barbet G, Sander LE, Geswell M, Leonardi I, Cerutti A, Iliev I, Blander JM

Abstract
Live vaccines historically afford superior protection, yet the cellular and molecular mechanisms mediating protective immunity remain unclear. Here we found that vaccination of mice with live, but not dead, Gram-negative bacteria heightened follicular T helper cell (Tfh) differentiation, germinal center formation, and protective antibody production through the signaling adaptor TRIF. Complementing the dead vaccine with an innate signature of bacterial viability, bacterial RNA, recapitulated these responses. The interferon (IFN) and inflammasome pathways downstream of TRIF orchestrated Tfh responses extrinsically to B cells and classical dendritic cells. Instead, CX3CR1+CCR2- monocytes instructed Tfh differentiation through interleukin-1β (IL-1β), a tightly regulated cytokine secreted upon TRIF-dependent IFN licensing of the inflammasome. Hierarchical production of IFN-β and IL-1β dictated Tfh differentiation and elicited the augmented humoral responses characteristic of live vaccines. These findings identify bacterial RNA, an innate signature of microbial viability, as a trigger for Tfh differentiation and suggest new approaches toward vaccine formulations for coordinating augmented Tfh and B cell responses.

PMID: 29548673 [PubMed - as supplied by publisher]

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Can Optical Coherence Tomography Be Used to Guide Treatment Decisions in Adult or Pediatric Multiple Sclerosis?

Abstract

Purpose of review

With the recognition that neurodegeneration represents the principal substrate of disability in multiple sclerosis (MS), there has been increased strives towards identifying biomarkers for accurately quantifying and tracking neurodegeneration during the disease course. The retina provides an opportune "window" into the central nervous system (CNS) in MS, with retinal changes in MS reflecting not only local, but also global aspects of neurodegeneration and inflammation operative in the disease. Optical coherence tomography (OCT) is a rapid, inexpensive, reproducible, high-resolution imaging technique allowing accurate quantification of discrete retinal layers. OCT determined thinning of inner retinal layers such as the retinal nerve fiber layer (RNFL) and in particular the composite of the ganglion cell and inner plexiform (GCIP) layers, predominantly related to optic neuropathy, have been shown to not only correlate with high and low contrast visual function in MS, but also global MS disability scores, as well as whole brain and particularly gray matter volumes. Rates of GCIP thinning have been shown to be accelerated among MS patients exhibiting inflammatory activity outside of the visual pathways, as well as disability progression during follow-up. Moreover, baseline RNFL thickness in MS has been shown to have utility for predicting future disability accumulation. On the other hand, thickening of the inner nuclear layer (INL) in MS, the pathophysiologic basis of which remains to be elucidated, has been found to predict the development of clinical and radiological inflammatory activity, as well as subsequent disability progression in MS. Given the potential for OCT to provide insight into neurodegeneration and inflammation occurring in MS, this review focuses on the potential utility of OCT within the clinical setting to influence treatment decisions for MS patients.

Recent findings

The evolution of spectral domain-OCT technology, with improved resolution and reproducibility allowing intra-retinal layer segmentation, has facilitated the determination that the OCT derived measure GCIP thickness is a highly accurate measure for quantifying and tracking neurodegeneration, and conversely neuroprotection, in MS. The strong relationships between rates of GCIP and brain atrophy across MS subtypes over time underpin the insight derived regarding the global MS disease process from OCT and highlight OCT as an excellent complementary tool to magnetic resonance imaging (MRI) for tracking MS patients. More recently, longitudinal studies are emerging which support the utility of OCT for monitoring the differential effects of disease-modifying therapies (DMTs) in MS.

Summary

Although further work is required, there is mounting evidence supporting the utility of OCT in the clinical setting to monitor disease course in individual patients with MS and to aid in the prediction of disease course. As pharmacological treatment options in MS expand to also include potentially neuroprotective and/or remyelinating or neurorestorative drugs, OCT as a biomarker of neurodegeneration and neuroprotection (and neuroinflammation to a lesser degree) may become an invaluable tool in both the research and clinical settings.

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Biology of the Adrenal Gland Cortex Obviates Effective Use of Adeno-Associated Virus Vectors to Treat Hereditary Adrenal Disorders

Human Gene Therapy, Ahead of Print.


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Continuing Medical Education Exam: April 2018

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Self-expandable metal stents in malignant biliary obstruction: Back to the roots with uncovered stents as the “new” standard?

Biliary obstruction can arise from different types of malignant disease, including pancreatic cancer, intrinsic cholangiocarcinoma, gallbladder cancer, and metastatic disease. The most common cause of malignant distal biliary obstruction is pancreatic cancer; jaundice will develop in 70% to 90% of patients during the course of their disease. Pancreatic cancer is usually advanced at presentation, and curative intended resection is possible in less than 15% of patients.1 In the United States the incidence of pancreatic cancer is calculated at 12.5 per 100,000 women and men per year according to the SEERS database (National Cancer Institute, Surveillance, Epidemiology, and End Result Program, 2010-2014).

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Information for readers

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Response:

We thank Drs Baldaque-Silva and Omae1 for their comments on the recent articles2,3 published on the use of endoscopic submucosal dissection (ESD) for the treatment of early Barrett's neoplasia, and we commend them for the excellent results4 reported, which further strengthen the evidence base for this technique.

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Endoscopic submucosal dissection learning curve and role in the treatment of Barrett's neoplasia

We read with interest the articles by Yang et al1 and by Subramaniam et al2 on the role of endoscopic submucosal dissection (ESD) for the treatment of neoplastic Barrett's esophagus (NBE). Conventional multimodal endoscopic treatment has some limitations, such as recurrence of neoplasia and intestinal metaplasia in 4% and 8% of cases, respectively, and adverse events in 19% of patients.3

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Colorectal polyp snaring: the smaller, the colder, the bigger!

No doubt, one day we'll enjoy a tremendous minimization of the risk of postcolonoscopy colorectal cancer (CRC) resulting from our desperate effort to improve the quality of colonoscopy. We must admit, however, that the most immediately tangible effect is not so much represented by the desired increase in the diagnosis of clinically relevant (ie, advanced) lesions but rather by an unexpected upsurge in the detection of small colorectal polyps. When we couple an excellent level of cleansing with a meticulous exploration of the mucosa, the most likely outcome for a screening colonoscopy is indeed represented by our warmly anticipated improvement in the adenoma detection rate brought about by the detection of at least 1 diminutive or small polyp.

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Retraction notice to “Long-term outcomes of per-oral endoscopic myotomy in patients with achalasia with a minimum follow-up of 2 years: an international multicenter study”

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://ift.tt/2GNuKz7 article has been retracted due to overlapping/duplicate material.Data from some patients from this study have previously been published in other journals without cross-referencing. Twenty patients overlap with a paper by Kumbhari et al.1 Thirty-five patients overlap with the study by Ngamruengphong et al.2

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Unde venis? Geographic profiling for the prevention of gastric cancer

In the middle of the 14th century, when the Black Death was decimating the population in Asia and Europe, the Venetian Republic established a system of isolation for travelers arriving to the port of Ragusa (now Dubrovnik), then the gateway for Asian trade to Europe. Before these travelers were allowed to proceed to their destination, they had to spend a period of 40 days (hence quarantine, from the Italian word for 40, quaranta) in a nearby island. The insightful Venetian legislators preceded the concept of incubation, reasoning that those in whom any plague did not develop within 40 days were healthy and could move on.

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Fine-needle biopsy sampling under EUS guidance: Is one needle tip really better than the other?

We read with interest the article by Abdelfatah et al1 regarding the use of 2 new types of core biopsy devices in the sampling of solid lesions under EUS guidance. We commend the authors on their effort to study the sampling capabilities of 2 novel needles, each with a unique tip design. We and others have recently demonstrated a superior tissue yield over conventional FNA using either 1 of the 2 devices2-6; hence the concern over the substantially lower diagnostic yield rates reported by Abdelfatah et al.

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Editors

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In upcoming issues...

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ASGE update

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Focus on...

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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study, Published online: 21 March 2018; doi:10.1038/s41416-018-0057-2

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes, Published online: 21 March 2018; doi:10.1038/s41416-018-0030-0

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer, Published online: 21 March 2018; doi:10.1038/s41416-018-0053-6

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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Historical Datasets Support Genomic Selection Models for the Prediction of Cotton Fiber Quality Phenotypes Across Multiple Environments

Genomic selection (GS) has successfully been used in plant breeding to improve selection efficiency and reduce breeding time and cost. However, there has not been a study to evaluate GS prediction models that may be used for predicting cotton breeding lines across multiple environments. In this study, we evaluated the performance of Bayes Ridge Regression, BayesA, BayesB, BayesC and Reproducing Kernel Hilbert Spaces regression models. We then extended the single-site GS model to accommodate genotype x environment interaction (GxE) in order to assess the merits of multi- over single-environment models in a practical breeding and selection context in cotton, a crop for which this has not previously been evaluated. Our study was based on a population of 215 upland cotton (Gossypium hirsutum) breeding lines which were evaluated for fiber length and strength at multiple locations in Australia and genotyped with 13,330 single nucleotide polymorphic (SNP) markers. BayesB, which assumes unique variance for each marker and a proportion of markers to have large effects, while most other markers have zero effect, was the preferred model. GS accuracy for fiber length based on a single-site model varied across sites, ranging from 0.27 to 0.77 (mean = 0.38), while that of fiber strength ranged from 0.19 to 0.58 (mean = 0.35) using randomly selected sub-populations as the training population. Prediction accuracies from the MxE model were higher than those for single-site and across-site models, with an average accuracy of 0.71 and 0.59 for fiber length and strength, respectively. The use of the MxE model could therefore identify which breeding lines have effects that are stable across environments and which ones are responsible for GxE and so reduce the amount of phenotypic screening required in cotton breeding programs to identify adaptable genotypes.

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Comparative Transcriptomics Among Four White Pine Species

Conifers are the dominant plant species throughout the high latitude boreal forests as well as some lower latitude temperate forests of North America, Europe, and Asia. As such, they play an integral economic and ecological role across much of the world. This study focused on the characterization of needle transcriptomes from four ecologically important and understudied North American white pines within the Pinus subgenus Strobus. The populations of many Strobus species are challenged by native and introduced pathogens, native insects, and abiotic factors. RNA from the needles of western white pine (Pinus monticola), limber pine (Pinus flexilis), whitebark pine (Pinus albicaulis), and sugar pine (Pinus lambertiana) was sampled, Illumina short read sequenced, and de novo assembled. The assembled transcripts and their subsequent structural and functional annotations were processed through custom pipelines to contend with the challenges of non-model organism transcriptome validation. Orthologous gene family analysis of over 58,000 translated transcripts, implemented through Tribe-MCL, estimated the shared and unique gene space among the four species. This revealed 2025 conserved gene families, of which 408 were aligned to estimate levels of divergence and reveal patterns of selection. Specific candidate genes previously associated with drought tolerance and white pine blister rust resistance in conifers were investigated.

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Improved risk stratification by circulating tumor cell counts in pancreatic cancer

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3-5%. Here we investigated if circulating tumor cells (CTCs) may predict metastatic spread and survival in pancreatic cancer patients. Experimental Design: In a prospective study we enrolled 69 pancreatic cancer patients. In peripheral blood CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTCs) in bone marrow and clinical outcome (follow up time: 48 months). Results: Median patient survival was 11 months (0-48 months). Thirty-eight patients were male and 31 female, and the majority received gemcitabine (58/69). CTCs were present in 23/69 patients (33.3%) ranging from 1-19 cells (17 with >1CTC). While clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (p=0.009, PFS; p=0.030, OS, both logrank) and multivariate analysis (HR: 4.543; CI: 1.549-13.329; p=0.006, PFS; HR: 2.093; CI: 1.081-4.050; p=0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (p=0.013) and multivariate (HR: 4.203; CI: 1.416-12.471; p=0.010) analysis. Conclusions:  CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer life span who might profit from new adjuvant therapies.

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Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogs

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N=245), women with POLE-mutant ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=0.001-0.996, P=0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM for fludarabine; P <0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers.

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Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer

Purpose: We investigated the safety and antitumor activity of the anti-programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2^-) advanced breast cancer with programmed death ligand 1-positive (PD-L1-positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study. Experimental Design: Patients with ER+/HER2^- advanced breast cancer with PD-L1-positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity. Primary endpoints were safety and overall response rate (ORR), based on Response Evaluation Criteria in Solid Tumors, version 1 (RECIST v1.1) as assessed by investigator review. Results: Between April 2014 and January 2015, 25 patients were enrolled. Median number of prior therapies for breast cancer, including endocrine agents, was 9 (range, 3-15). Median follow-up was 9.7 months (range, 0.7-31.8 months). Three patients experienced partial response (PR) and none experienced complete response (CR), resulting in an ORR of 12.0% (95% CI, 2.5-31.2%); 16% of patients had stable disease (SD), and clinical benefit rate (CR + PR + [SD for ≥24 weeks]) was 20% (95% CI, 7-41). Median duration of response was 12.0 months (range, 7.4-15.9 months). The incidence of treatment-related adverse events was 64%; nausea (20%) and fatigue (12%) were most common and were predominantly grade 1/2. No treatment-related discontinuations or deaths occurred. Conclusions: Pembrolizumab was well-tolerated with modest but durable objective response in certain patients with previously treated, advanced, PD-L1-positive, ER+/HER2^- breast cancer.

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Phase I Study of MEDI3617, a Selective Angiopoietin-2 Inhibitor Alone and Combined With Carboplatin/Paclitaxel, Paclitaxel, or Bevacizumab for Advanced Solid Tumors

Purpose: This first-in-human study aimed to determine the maximum tolerated dose (MTD) and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) monoclonal antibody, alone and combined with bevacizumab or cytotoxic chemotherapy. Experimental Design: This phase I/Ib, multicenter, open-label, dose escalation and dose expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy (5-1500 mg every 3 weeks [Q3W]) or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed. Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer (prolonged grade 3 edema-associated adverse events [AEs] occurred). Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose expansion arms were 6% and 0%, respectively. Conclusions: Recommended MEDI3617 monotherapy dosage is 1500 mg Q3W or 1000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. Based on limited clinical activity, MEDI3617 development was discontinued.

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Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib. Results: NGS analysis of the primary tumor and ctDNA of a 39-year old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth. Conclusions: These findings implicate ALK activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP.

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The transition from HLA-I positive to HLA-I negative primary tumors: the road to escape from T-cell responses

Natalia Aptsiauri | Francisco Ruiz-Cabello | Federico Garrido

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Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease

Abstract

Currently, no reliable predictors of cognitive impairment in Parkinson's disease exist. We hypothesized that microstructural changes at grey matter T₁-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson's disease. We performed a cross-sectional comparison between patients with Parkinson's disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson's disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson's disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson's disease without cognitive impairment. These results were confirmed both with region of interest and voxel-based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson's disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson's disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.

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Characterization of EEG signals revealing covert cognition in the injured brain

Abstract

Patients with severe brain injury are difficult to assess and frequently subject to misdiagnosis. 'Cognitive motor dissociation' is a term used to describe a subset of such patients with preserved cognition as detected with neuroimaging methods but not evident in behavioural assessments. Unlike the locked-in state, cognitive motor dissociation after severe brain injury is prominently marked by concomitant injuries across the cerebrum in addition to limited or no motoric function. In the present study, we sought to characterize the EEG signals used as indicators of cognition in patients with disorders of consciousness and examine their reliability for potential future use to re-establish communication. We compared EEG-based assessments to the results of using similar methods with functional MRI. Using power spectral density analysis to detect EEG evidence of task performance (Two Group Test, P ≤ 0.05, with false discovery rate correction), we found evidence of the capacity to follow commands in 21 of 28 patients with severe brain injury and all 15 healthy individuals studied. We found substantial variability in the temporal and spatial characteristics of significant EEG signals among the patients in contrast to only modest variation in these domains across healthy controls; the majority of healthy controls showed suppression of either 8–12 Hz 'alpha' or 13–40 Hz 'beta' power during task performance, or both. Nine of the 21 patients with EEG evidence of command-following also demonstrated functional MRI evidence of command-following. Nine of the patients with command-following capacity demonstrated by EEG showed no behavioural evidence of a communication channel as detected by a standardized behavioural assessment, the Coma Recovery Scale – Revised. We further examined the potential contributions of fluctuations in arousal that appeared to co-vary with some patients' ability to reliably generate EEG signals in response to command. Five of nine patients with statistically indeterminate responses to one task tested showed a positive response after accounting for variations in overall background state (as visualized in the qualitative shape of the power spectrum) and grouping of trial runs with similar background state characteristics. Our findings reveal signal variations of EEG responses in patients with severe brain injuries and provide insight into the underlying physiology of cognitive motor dissociation. These results can help guide future efforts aimed at re-establishment of communication in such patients who will need customization for brain–computer interfaces.

http://ift.tt/2DGmFcA

An Infected Aortic Aneurysm After Successful Treatment of Nontyphoidal Salmonella Gastroenteritis

A 75-year-old man was admitted to our hospital with diarrhea. He had a history of mitral valve plasty for mitral regurgitation, chronic heart failure, cerebral infarction, and type 2 diabetes mellitus. C-reactive protein (12.5 mg/dL), blood urea nitrogen (142.6 mg/dL), and creatinine (10.9 mg/dL) levels were increased remarkably. Colonoscopy showed redness and edematous mucosa at the terminal ileum and the total colon (Figure A). Nontyphoidal Salmonella (NTS) with O8 antigen was identified from cultures of stool and mucosa of the terminal ileum, although blood cultures were negative.

http://ift.tt/2FPOIfB

Abdominal Pain Caused by a Second Gall Bladder and Separate Cystic Duct

A 35-year-old morbidly obese (body mass index, 40) woman presented with a few months of postprandial right upper-quadrant pain, nausea, and vomiting. Physical examination was positive for Murphy's sign, but otherwise unremarkable. Her laboratory values including liver chemistry were normal except for a mildly increased white count. Initial work-up with an abdominal ultrasound showed an intrahepatic cyst in addition to the gallbladder. Magnetic resonance cholangiopancreatography (Figure A) and subsequent endoscopic retrograde cholangiopancreatography performed for clarification showed the presence of a cyst with a separate duct draining into the common hepatic duct.

http://ift.tt/2FWNGub

Ampullary Dieulafoy: An Unusual Cause of Obscure Gastrointestinal Bleeding

A 65-year-old woman presented with multiple episodes of melena and a 5 g/mL decrease in hemoglobin level over a 6-month period. Three esophagogastroduodenoscopies and 2 colonoscopies were unremarkable. A capsule showed blood in the duodenum without an obvious source. Repeat upper endoscopy showed blood from the major papilla. Further studies were obtained including computed tomography, magnetic resonance imaging/magnetic resonance cholangiopancreatography, endoscopic ultrasound, bleeding scan, and an angiography—all were unremarkable.

http://ift.tt/2FPOHZ5

Hepatitis C Virus–Related Cryoglobulinemic Vasculitis

A 78-year-old woman with a history of chronic hepatitis C virus (HCV) infection presented to the hospital with a skin rash, diffuse arthralgias, and weakness. Physical examination showed a diffuse palpable purpuric rash (Figures A–C). Doppler examination showed an absence of perfusion, requiring amputation of the distal part of the fifth digit (Figure D). Serum protein electrophoresis and immunofixation showed the presence of an IgM κ monoclonal protein with markedly increased free κ chains. Cryoglobulin identification confirmed the presence of an IgM κ monoclonal spike and IgG polyclonal proteins, consistent with type II mixed cryoglobulinemia.

http://ift.tt/2HQcCnI

Epithelioid Sarcoma Presenting as Recurrent Thumb Ulcer: a Lesson to Learn

Abstract

Epithelioid sarcoma first described by Enzinger (Cancer 26:1029–41, 1970) is a rare soft-tissue sarcoma typically presenting as a subcutaneous or deep dermal mass in distal portions of the extremities of adolescents and young adults. They are frequently mistaken for ulcers, abscesses, or infected warts that fail medical management. Patients often develop multiple local recurrences of long duration, with subsequent metastases in 30 to 50% of cases (Chase and Enzinger (Am J Surg Pathol 9:241–63, 1985)). We here report a case of left thumb epithelioid sarcoma that presented as an ulcer and subsequently metastasized to forearm, arm, axillary lymph nodes, and lungs.

http://ift.tt/2prpHMI

Efficacy of anterior versus posterior per-oral endoscopic myotomy for treating achalasia: a randomized, prospective study

Per-oral endoscopic myotomy (POEM) has been demonstrated to be safe and effective for treating achalasia. Two approaches―anterior myotomy and posterior myotomy―are used during POEM. However, little is known about the comparison between the two different approaches. The objective of the study is to compare the safety and short-term efficacy of the 2 approaches for treating achalasia.

http://ift.tt/2DHG258

NF1 mutations in conjunctival melanoma

http://ift.tt/2DHUD0o

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

http://ift.tt/2DG9Yys

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

http://ift.tt/2powyr5

Adaptive Replanning for HPV-Associated N2b Oropharyngeal Squamous Cell Carcinoma in Response to Anatomic Changes During Radiation Therapy

Repeat CT simulation and dosimetric planning in response to weight loss or tumor response takes substantial resources. All published studies are compromised by heterogeneity of the study population, timing of replanning, and dosimetric endpoints. We report the first prospective evaluation of dosimetric changes from replanning at a uniform timepoint in a uniform patient population.

http://ift.tt/2prXBlm

Particle Radiation Therapy of Head and Neck Malignancies at the Shanghai Proton and Heavy Ion Center

To report initial experience of particle radiation therapy for head-and-neck malignant tumor in Shanghai Proton and Heavy Ion Center.

http://ift.tt/2DIBo6I

The Effect of MATE1 Polymorphisms on Cisplatin Efficacy in the Treatment of Head and Neck Cancer

MATE1 (multidrug and toxin extrusion protein 1/SLC47A1) has an important role in the renal and biliary excretion of endogenous and exogenous organic cations including a number of therapeutic drugs. We recently reported that homozygosity for a single nucleotide polymorphism in MATE1 (rs2289669) (A/A) was independently protective for cisplatin-related ototoxicity in patients with head and neck squamous cell carcinoma (HNSCC) receiving cisplatin-based chemoradiation. To evaluate whether MATE1 A/A status had any effect on treatment efficacy we examined cancer outcomes in a subset of our patients expected to have a poorer prognosis.

http://ift.tt/2ppWCC6

A Review of Quality of Life and Utility Determination Studies for Health Outcomes Research in the Management of Head and Neck Cancer

With multidisciplinary improvements in techniques, technologies, and systemic therapies with multiple approaches to successful outcomes, there is a need to help patients and practitioners understand different healthcare states to tailor treatment to patients' priorities. Utilities are a quality of life metric for patient preference of health states and are essential for cost-effectiveness analysis (CEA). To best inform future CEAs of head and neck squamous cell cancer (HNSCC) with focus on oropharyngeal primaries (OPC) receiving definitive (chemo)radiation, we conducted a systematic review of the literature to identify recent publications that evaluate utilities for posttreatment health states.

http://ift.tt/2prWHoO

Incidence and Distribution of Nodal Metastases in Sinonasal Malignancy

Cervical lymph node drainage pathways of sinonasal malignancies (SNM) have not yet been well-established in the literature. We present the largest population-based cohort of SNM to investigate the frequency and pattern of cervical node involvement.

http://ift.tt/2DIhYPw

Index of Authors

Abdelhakiem, Mohamed162

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Withdrawn

http://ift.tt/2prBdIH

Withdrawn

http://ift.tt/2pquYVM

Extracapsular Nodal Extension Predicts Death and Recurrence in Merkel Cell Carcinoma (MCC)

Stage III Merkel cell carcinoma (MCC) constitutes a heterogeneous group of patients (pts). This study was performed to identify predictors of recurrence and survival among pts with stage III MCC.

http://ift.tt/2DIB3AY

Mutational Landscape of Human Papillomavirus–Associated Oropharynx Squamous Cell Carcinoma in Patients Treated on a Phase 2 De-intensified Chemoradiation Trial

Next-generation sequencing (NGS) technique was used to analyze the mutational landscape of a cohort of patients with favorable risk human papillomavirus (HPV)–associated OPSCC prospectively treated with de-intensified chemoradiation therapy.

http://ift.tt/2pxjC2j

Evaluation of Pre- and Post-IMRT FDG-PET SUV Values for the Prediction of Tumor Control In HPV-Positive Oropharyngeal Cancer Patients

To evaluate the predictive value of pre- and post-IMRT FDG-PET SUV for human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC) patients.

http://ift.tt/2pxjzDF

In Regard to Yang et al

To the Editor: We read with interest the article by Yang et al (1) that reported the pattern of androgen deprivation therapy (ADT) use with radiation therapy (RT) in men with low-risk prostate cancer (PC) in the US National Cancer Database between 2004 and 2012. Overall, they noted 18% of 82,352 men with low-risk PC, who underwent RT as primary treatment, received ADT. The addition of ADT had been shown in a subanalysis in the RTOG (Radiation Therapy Oncology Group) 9408 trial to confer no benefit in men with low-risk PC receiving RT (2).

http://ift.tt/2DHWySu

In Regard to Wortel et al

To the Editor: We read with great interest the article by Wortel et al (1), reporting the impact of rectal balloon and magnetic resonance imaging delineation on anorectal dose and gastrointestinal toxicity levels.

http://ift.tt/2pxjvDV

Patients Report Less Severe Symptoms With Unilateral Radiation Therapy Than Bilateral Radiation Therapy for Tonsillar Squamous Cell Carcinomas

The goal of this study was to examine the effects of radiation treatment volume on quality of life in patients with squamous cell carcinoma of the tonsil.

http://ift.tt/2DINEUN

Late and Long-Term Effects Among Survivors of Head and Neck Cancer at Least 5 Years Posttreatment: A Systematic Review

The identification and management of late- and long-term treatment effects in cancer survivors has become a national priority. Little is known about the prevalence of these effects in long-term head and neck cancer survivors. The aim of this study was to review the literature on late- and long-term treatment effects among head and neck cancer survivors at least 5 years posttreatment. Reported here is a description of the body of literature identified in this study.

http://ift.tt/2pxjkIL

A hairy polypoid lesion of the colon

http://ift.tt/2GPhk64

C-11 Choline and F-18 Fluciclovine PET/CT demonstration of annular pancreas

http://ift.tt/2HNhwSA

WHEN AND HOW SHOULD WE PERFORM A BIOPSY FOR HCC IN PATIENTS WITH LIVER CIRRHOSIS IN 2018? A REVIEW

The role of liver biopsy in the diagnosis of hepatocellular carcinoma (HCC) has changed over time. The diagnostic algorithm for this tumour is nowadays mainly based on radiological imaging, relegating histology to controversial cases, in which imaging techniques cannot establish a clear-cut diagnosis. This most commonly happens in small lesions, where biopsies frequently become mandatory, or in larger hypovascularized lesions. In this case however, the histological examination may not be reliable enough to grade the lesion, as different cell clones, deriving from sequential mutations, can originate heterogeneous cell populations.

http://ift.tt/2G9KFtG

P.09.17 PNPLA3 RS738409 POLYMORPHISM PREDICTS THE DEVELOPMENT AND THE SEVERITY OF HEPATIC STEATOSIS, BUT NOT METABOLIC SYNDROME, IN PATIENTS WITH CELIAC DISEASE

http://ift.tt/2FWpvvS

Comparative study of oxidative status in blood of asthmatic patients

Abstract

Bronchial asthma (BA) is a chronic inflammatory lungs disease, resulting in an airflow restriction, hyperactivity, and airway remodeling. The aim of present study is to investigate and compare the oxidative stress levels in blood of asthmatic patients differ in the disease control degree. In the current study were included 30 patients with bronchial asthma and 24 healthy volunteers. Patients were diagnosed with BA with allergic component longer than 1 year. For this purpose were explored the reactive oxygen species (ROS) and reactive nitrogen species (RNS), final products of lipids and proteins. Also, were studied the relationship between oxidative stress parameters and C-reactive protein (CRP) as a marker of inflammation degree. By using the electron paramagnetic resonance (EPR) spin trapping technique, ongoing the real-time oxidative processes were confirmed in blood samples isolated from asthmatic patients differing in the disease control degree. Moreover, positive correlation was found between the levels of studied oxidative stress (OS) biomarkers and CRP as a marker of inflammation degree. The oxidative processes in real time were demonstrated in BA patients. The correlation analysis results confirm the development and maintenance of inflammatory processes in respiratory tract is associated with the oxidative and nitrosative stress.

http://ift.tt/2IGnOEv

Implicit Physician Biases in Periviability Counseling

To assess whether neonatologists show implicit racial and/or socioeconomic biases and whether these are predictive of recommendations at extreme periviability.

http://ift.tt/2FPxbnN

Disparities in Access to Healthcare Transition Services for Adolescents with Down Syndrome

To compare healthcare transition planning in adolescents with Down syndrome with adolescents with other special healthcare needs.

http://ift.tt/2G0LqSU

Fidget Spinner Ingestions in Children—A Problem that Spun Out of Nowhere

The Consumer Product Safety Risk Management System's injury and potential injury database records 13 cases of fidget spinner ingestion since 2016. In addition to a database query, we report 3 additional cases of fidget spinner ingestion to describe patient presentations and subsequent management strategies.

http://ift.tt/2GbizOY

HABIT, a Randomized Feasibility Trial to Increase Hydroxyurea Adherence, Suggests Improved Health-Related Quality of Life in Youths with Sickle Cell Disease

To examine the effect of a community health worker (CHW) intervention, augmented by tailored text messages, on adherence to hydroxyurea therapy in youths with sickle cell disease, as well as on generic and disease-specific health-related quality of life (HrQL) and youth-parent self-management responsibility concordance.

http://ift.tt/2G0KVbu

Mortality Risk and Hospital Admission after a Brief Resolved Unexplained Event

In a meta-analysis in this volume of The Journal, Brand et al1 attempt to address a common problem faced by both parents and pediatricians. Should a child be admitted to the hospital after a brief resolved unexplained event (BRUE)?

http://ift.tt/2G5RPiV

Effectiveness of Pediatric Asthma Pathways for Hospitalized Children: A Multicenter, National Analysis

To determine if clinical pathways affect care and outcomes for children hospitalized with asthma using a multicenter study.

http://ift.tt/2GaM4jS

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT, Published online: 20 March 2018; doi:10.1038/s41419-018-0435-y

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

http://ift.tt/2FOOpl3

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial–mesenchymal transition in lung adenocarcinoma

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial–mesenchymal transition in lung adenocarcinoma

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial–mesenchymal transition in lung adenocarcinoma, Published online: 20 March 2018; doi:10.1038/s41419-018-0457-5

Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial–mesenchymal transition in lung adenocarcinoma

http://ift.tt/2HP5l7x

Evaluation of 99mTc-Labeled Bevacizumab–N-HYNIC Conjugate in Human Ovarian Tumor Xenografts

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


http://ift.tt/2DIDrYn

British Journal of Surgery, Ahead of Print.

British Journal of Surgery, Ahead of Print.


http://ift.tt/2FRNPTW

Germline mutations in lysine specific demethylase 1 (LSD1/KDM1A) confer susceptibility to multiple myeloma

Given the frequent and largely incurable occurrence of multiple myeloma (MM), identification of germline genetic mutations that predispose cells to MM may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell. Here we identified familial and early-onset MM kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. Additionally, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in MM patients unselected for family history compared to controls. Both monoclonal gammopathy of unknown significance (MGUS) and MM cells have significantly lower KDM1A transcript levels compared with normal plasma cells. Transcriptome analysis of MM cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacological inhibition of KDM1A promoted plasma cell expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show KDM1A is the first autosomal dominant MM germline predisposition gene, providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B cell differentiation.

http://ift.tt/2GMgJ4Q

Inhibition of Nr4a receptors enhances anti-tumor immunity by breaking Treg-mediated immune tolerance

Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin (CPT) and a common cyclooxygenase-2 (COX-2) inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted anti-tumor effects. Genetic inactivation or pharmacological inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent anti-tumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacological modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment.

http://ift.tt/2HOwJ5E

ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T cell therapy in mice

Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by major histocompatibility complex class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on non-cancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER). We show here that ERAP1 is critically involved in the process of tumor rejection and assumes a dual role by independently operating on both sides. Direct presentation of two MHC-I restricted epitopes of a cancer-driving transplantation rejection antigen through ERAP1 moderately affected tumor rejection by adoptively transferred T-cell receptor (TCR) gene-modified T cells in each case. ERAP1 expression by antigen cross-presenting cells of the ATT recipients was critical for expansion of therapeutic monospecific T cells and correlated with tumor rejection. Specifically, lack of ERAP1 expression in the ATT recipient's non-cancerous cells enabled progression of pMHC-I-positive, IFNγ-responsive tumors, despite the presence of antigen-specific functional cytotoxic T lymphocytes. These data reveal a decisive role for ERAP1 in T cell mediated tumor rejection and will enhance the choice of MHC-I-restricted epitopes targeted by adoptive T cell transfer.

http://ift.tt/2Gbcfac

Plk1-mediated phosphorylation of TSC1 enhances the efficacy of rapamycin

The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin.

http://ift.tt/2HQfGAm

Co-targeting BCL-2 and PI3K induces BAX-dependent mitochondrial apoptosis in AML cells

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients suggesting targeting BCL-2 alone is insufficient to yield durable responses. Here we assessed the efficacy of co-administration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 co-administration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.

http://ift.tt/2HMxpbR

Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible

Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers.Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 1–15. ©2018 AACR.

http://ift.tt/2GcqICH

Electronic Nose Technology Fails to Sniff Out Acute Mountain Sickness

High Altitude Medicine &Biology, Ahead of Print.


http://ift.tt/2pt5vtU

Investigation of Protein Recruitment to DNA Lesions Using 405 Nm Laser Micro-irradiation

Studying DNA damage repair kinetics requires a system to induce lesions at defined sub-nuclear regions. We describe a method to create localized double-stranded breaks using a laser-scanning confocal microscope equipped with a 405 nm laser and provide automated procedures to quantify the dynamics of repair factors at these lesions.

http://ift.tt/2u2L6kV

Education Outcomes in a Duty-Hour Flexibility Trial in Internal Medicine

In 2003, the Accreditation Council for Graduate Medical Education (ACGME) established resident duty-hour policies that limited resident workweeks to 80 hours and shifts to 30 hours. Further restrictions that limited shifts to 16 hours for first-year residents (interns) were implemented in 2011.…

http://ift.tt/2u4H0Zx

Managing the Most Precious Resource in Medicine

Many health care institutions appear to have lost sight of the truism that our health professionals are our most precious resource. With increasing commoditization, commercialization, productivity targets, and administrative burdens, the volunteerism and soul that have typified our profession for…

http://ift.tt/2GMJY7P

Abemaciclib Approval Expands Initial Treatment Options for Advanced Breast Cancer

FDA has approved the CDK4/6 inhibitor abemaciclib (Verzenio) as a first-line treatment in some women with advanced or metastatic breast cancer. Under the approval, the drug must be used in combination with an aromatase inhibitor.

http://ift.tt/2G8w9lZ

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling

Evaluating the potency of environmental chemicals and drugs, to be enzymatically bioactivated to intermediates generating covalent DNA adducts, is an important field in the development of cancer and its treatment. Methods are described for compound activation to form DNA adducts, as well as techniques for their detection and quantification.

http://ift.tt/2DFG79p

Multimodal Hierarchical Imaging of Serial Sections for Finding Specific Cellular Targets within Large Volumes

This protocol targets specific cells in tissue for imaging at nanoscale resolution using a scanning electron microscope (SEM). Large numbers of serial sections from resin-embedded biological material are first imaged in a light microscope to identify the target and then in a hierarchical manner in the SEM.

http://ift.tt/2pqWVN8

Colorectal cancer: research prioritisation needed in third most lethal malignancy worldwide

Prioritising research and funding could have a significant impact on reducing colorectal cancer disease burden over the next 5 years. The conclusions are included in a study recently published by Gut titled "Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer" and expanded in this podcast. In conversation with the journal's Education Editor Mairi McLean, the leading author of the study, Mark Lawler, identifies 15 critical research gaps which prioritisation and resolution could improve patient outcomes. Professor Mark Lawler works at the Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.

For more details on this Open Access article included in the January 2018 issue of Gut, visit http://ift.tt/2HRtmLn.

http://ift.tt/2FOCqnR

Systematic Assessment of Well-Being in Mice for Procedures Using General Anesthesia

We developed a protocol to assess well-being in mice during procedures using general anesthesia. A series of behavioral parameters indicating levels of well-being as well as glucocorticoid metabolites were analyzed. The protocol can serve as a general aid to estimate the degree of severity in a scientific, animal-centered manner.

http://ift.tt/2G6iiwG

A Simple Method for High Throughput Chemical Screening in Caenorhabditis Elegans

Here we describe a simple protocol for rapidly producing hundreds of nematode growth media agar, 96-well culture plates with consistent numbers of Caenorhhabditis elegans per well. These cultures are useful for the phenotypic screening of whole organisms. We focus here on using these cultures to screen chemicals for pro-longevity effects.

http://ift.tt/2HOPxBH

Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers, Vol. 10, Pages 84: Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

Cancers doi: 10.3390/cancers10030084

Authors: Celina Yang Kyle Bromma Devika Chithrani

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

http://ift.tt/2HQaInh

Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers, Vol. 10, Pages 85: Role of Pattern Recognition Receptors in KSHV Infection

Cancers doi: 10.3390/cancers10030085

Authors: Timsy Uppal Roni Sarkar Ranjit Dhelaria Subhash Verma

Kaposi's sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host's immune system are crucial to prevent KSHV infection. The host's immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as 'pathogen-associated molecular patterns (PAMPs)'. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.

http://ift.tt/2GaJr1y

"J BUON"[jour]; +53 new citations

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"J BUON"[jour]

These pubmed results were generated on 2018/03/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Antibacterial and Antioxidant Compounds from the Flower Extracts of Vernonia amygdalina

Vernonia amygdalina is traditionally used in Ethiopia to treat various diseases. This prompted us to isolate bioactive compounds from the flowers of this plant. The CHCl3 extract after silica gel column chromatography has led to the isolation of two compounds identified as tricosane (1) and vernolide (2), while the acetone extract furnished isorhamnetin (3) and luteolin (4). The acetone extract and isorhamnetin significantly scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical by 91.6 and 94%, respectively. It was also shown that the acetone extract and isorhamnetin inhibited lipid peroxidation by 74 and 80%, respectively. The extracts and isolated compounds were also evaluated for their antibacterial activity with the CHCl3 extract and vernolide showing strong activity against S. aureus with an inhibition zone of 21 and 19 mm, respectively. On the other hand, the acetone extract and isorhamnetin were active against all bacterial pathogens tested. The work presented herein has demonstrated that vernolide and isorhamnetin had antibacterial activity. The antioxidant activity displayed by the flowers of V. amygdalina is accounted to the presence of isorhamnetin. Therefore, the biological activities displayed by the extracts and isolated compounds from this plant corroborate the traditional uses of this plant by the local people against various diseases.

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Third-Generation Human Epidermal Growth Factor Receptor 2 Chimeric Antigen Receptor Expression on Human T Cells Improves with Two-Signal Activation

Human Gene Therapy, Ahead of Print.


http://ift.tt/2DFtwTC

Synthetic Adeno-Associated Viral Vector Efficiently Targets Mouse and Nonhuman Primate Retina In Vivo

Human Gene Therapy, Ahead of Print.


http://ift.tt/2ptxoCI

Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes

Human Gene Therapy, Ahead of Print.


http://ift.tt/2DFuWNZ

Physiological variations and the influence of age and sex on serum biochemical profile of hinnies

Abstract

There is little information about serum biochemistry in hinnies, animals that are usually confused with mules, so this is why specific diagnosis and treatment for these animals are difficult to obtain. Due to this fact, this study had the aim of offering elements to understand and determine references in serum biochemistry parameters specific for hinnies. To achieve this objective, biochemistry parameters from blood samples collected from 33 healthy animals (15 male hinnies with age between 7 and 84 months, and 18 female hinnies with age between 17 days and 84 months), from different farms in Brazil, were evaluated to verify the influence of age and sex of animals on these parameters. The analyzed elements were total protein, albumin, globulin, albumin:globulin (A:G) ratio, cholesterol, triglycerides, uric acid, creatinine, urea, calcium, phosphorus, calcium-phosphorus ratio (Ca:P), magnesium, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and creatine kinase (CK). Animal's ages had an influence on biochemistry parameters, as the younger animals (≤ 30 months) presented higher levels of phosphorus and higher albumin:globulin ratio. Males and females presented similar serum biochemistry profiles. The results of this study offer elements to determine the serum biochemistry profile of hinnies and have enormous importance for veterinary clinic since this is one of the first researches in this area.

http://ift.tt/2DHh6dG

Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. Despite surgical resection followed by radiotherapy and chemotherapy, the median survival rate is approximately 14 months. Although experimental therapies are in clinical trials for GBM, there is an urgent need for a peripheral GBM biomarker for measuring treatment response. As we have previously demonstrated that the long noncoding RNA HOX Transcript Antisense Intergenic RNA, or HOTAIR, is dysregulated in GBM and required for GBM cell proliferation, we hypothesized that HOTAIR expression may be utilized as a peripheral biomarker for GBM. HOTAIR expression was measured in serum from 43 GBM and 40 controls using quantitative real-time PCR (qRT-PCR). The PCR products were subsequently subcloned into pCR™4-TOPO®TA vectors for DNA sequencing. A ROC curve was also generated to examine HOTAIR's prognostic value. The amount of HOTAIR in serum exosomes and exosome-depleted supernatant was calculated by qRT-PCR. The relative HOTAIR expression was also investigated in 15 pairs of GBM serum and tumors. We detected HOTAIR in serum from GBM patients. HOTAIR levels in serum samples from GBM patients was significantly higher than in the corresponding controls (P < 0.0001). The area under the ROC curve distinguishing GBM patients from controls was 0.913 (95% CI: 0.845–0.982, P < 0.0001), with 86.1% sensitivity and 87.5% specificity at the cut-off value of 10.8. HOTAIR expression was significantly correlated with high grade brain tumors. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r = 0.734, P < 0.01). We confirmed via sequencing that the amplified HOTAIR from serum contained the HOTAIR sequence and maps to the known HOTAIR locus at 12q13. The serum-derived exosomes contain HOTAIR and the purified exosomes were validated by western blot and nanoparticle tracking analysis. Importantly, our results demonstrate that serum HOTAIR can be used as a novel prognostic and diagnostic biomarker for GBM.

http://ift.tt/2HRqfDf

The decade of exosomal long RNA species: an emerging cancer antagonist

Abstract

Exosomes have emerged as a novel approach for the treatment and diagnosis of cancer after RNA content was discovered in exosomes in 2007. As important meditators of intercellular communication, exosomes have become a strong focus of investigation for researchers in the past decade, as witnessed through the exponential increase of research on exosomes. The capability of exosomes to transfer functionally active cargo highlights their importance as promising biomarkers and diagnostic molecules, as well as prospective drug delivery systems. The accessibility of exosomes in nearly all biofluids additionally alludes to its unprecedented ability in various types of cancers due to its extensive impact on tumor formation and progression. This review analyzes the role of exosomal long RNA species, which is comprised of mRNA, lncRNA, and circRNA, in tumor formation and progression, with an emphasis on their potential as future diagnostic biomarkers and treatment vectors in cancer biology. Their alignment with the development of exosomal databases is further examined in this review, in view of the accumulation of studies published on exosomes in the past decade.

http://ift.tt/2GKIfQd

Extra-axial chordoma: a clinicopathologic analysis of six cases

Abstract

Extra-axial chordoma is an exceedingly rare tumor, with only 28 cases reported in the literature to date. Axial and extra-axial chordoma exhibits complete morphologic and immunophenotypic (expression of brachyury) overlap. However, in consideration of the non-canonical presentation, extra-axial chordoma is under-recognized and often misdiagnosed, most often as extraskeletal myxoid chondrosarcoma or myoepithelioma. To increase our understanding of the clinicopathologic features of extra-axial chordoma, six cases have been retrieved from the files of the Istituto Ortopedico Rizzoli and of the General Hospital of Treviso. The clinicoradiologic, morphologic, and molecular features have been analyzed, and the follow-up was updated. Our series included four female and two male patients; their ages ranged from 20 to 67 years (mean 45.8 years). All patients presented with a single mass localized in four cases in the soft tissue (posterior arm, left leg, dorsal aspect of the foot, and popliteal fossa), and in two cases in the bone (radius and second metacarpal bone). Grossly, the neoplasm was lobulated, with a fleshy cut surface and a diameter ranging between 0.8 and 8 cm (mean 3.4 cm). Morphologically, all six cases showed an epithelioid cell proliferation organized in nests and cords demarcated by fibrous septa and set in an abundant extracellular myxoid matrix. Neoplastic cells featured hyperchromatic nuclei and abundant vacuolated cytoplasm. Immunohistochemically, all six cases were strongly positive for EMA, cytokeratin AE1/AE3, S100, and brachyury. INI1 nuclear expression was retained. Smooth muscle actin, calponin, p63, and GFAP were all negative. Fluorescent in situ hybridization (FISH) analysis did not reveal rearrangements involving NR4A3, FUS, and EWSR1 genes. At follow-up (mean 55 months), all patients were alive without disease after local surgical treatment. One patient underwent thigh amputation following multiple local recurrences and inguinal node metastases treated with marginal resection. In conclusion, primary extra-axial chordoma is an extremely rare neoplasm with distinct morphological and immunohistochemical features. Immunomorphology and molecular analysis allow distinction from both extraskeletal myxoid chondrosarcoma and myoepithelioma. Complete surgical resection appears to be curative.

http://ift.tt/2G687rY

Mechanical Thrombectomy in Elderly Stroke Patients with Mild-to-Moderate Baseline Disability

Background: The number of elderly patients suffering from ischemic stroke is rising. Randomized trials of mechanical thrombectomy (MT) generally exclude patients over the age of 80 years with baseline disability. The aim of this study was to understand the efficacy and safety of MT in elderly patients, many of whom may have baseline impairment. Methods: Between January 2015 and April 2017, 96 patients ≥80 years old who underwent MT for stroke were selected for a chart review. The data included baseline characteristics, time to treatment, the rate of revascularization, procedural complications, mortality, and 90-day good outcome defined as a modified Rankin Scale (mRS) score of 0–2 or return to baseline. Results: Of the 96 patients, 50 had mild baseline disability (mRS score 0–1) and 46 had moderate disability (mRS score 2–4). Recanalization was achieved in 84% of the patients, and the rate of symptomatic hemorrhage was 6%. At 90 days, 34% of the patients had a good outcome. There were no significant differences in good outcome between those with mild and those with moderate baseline disability (43 vs. 24%, p = 0.08), between those aged ≤85 and those aged #x3e; 85 years (40.8 vs. 26.1%, p = 0.19), and between those treated within and those treated beyond 8 h (39 vs. 20%, p = 0.1). The mortality rate was 38.5% at 90 days. The Alberta Stroke Program Early CT Score (ASPECTS) and the National Institutes of Health Stroke Scale (NIHSS) predicted good outcome regardless of baseline disability (p #x3c; 0.001 and p = 0.009, respectively). Conclusion: Advanced age, baseline disability, and delayed treatment are associated with sub­optimal outcomes after MT. However, redefining good outcome to include return to baseline functioning demonstrates that one-third of this patient population benefits from MT, suggesting the real-life utility of this treatment.
Intervent Neurol 2018;7:246–255

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p27-V109G Polymorphism Is Not Associated with the Risk of Prostate Cancer: A Case-Control Study of Han Chinese Men in Central China

Objective. We conducted an update meta-analysis aiming to verify the association between p27-V109G polymorphism and cancer risk, particular for prostate cancer (PCa). Then, we conducted a case-control study of Han Chinese in central China to verify the evidence-based results. Methods. Relevant studies were collected from diverse databases up to March 2017. In addition, a hospital-based (H-B) case-control study enrolling 90 PCa patients and 140 healthy controls was included to verify these evidence-based findings. Genetic risk was calculated by odds ratio (OR) with its corresponding 95% confidence interval (CI). The p27-V109G polymorphism was determined by MassARRAY genotyping method. Results. Finally, twenty-four published studies comprising 9627 cases and 12,102 controls were enrolled for the current meta-analysis. Overall analysis suggested that p27-V109G polymorphism decreased overall cancer risk in allelic contrast, heterozygote, and dominant models. When stratified analysis was conducted by ethnicity, data revealed that p27-V109G polymorphism was associated with a decreased cancer risk in Caucasians. Highlighted in the subgroup analysis by cancer type, we uncovered a significantly decreased risk of PCa in allelic contrast, dominant, homogeneous, and recessive models. However, in the validation case-control study, we failed to uncover a positive association between p27-V109G polymorphism and PCa risk. In addition, negative results were also identified when subgroup analyses were stratified by age, tumor grade, tumor stage, PSA levels, and other measurements. Conclusion. Although evidence-based results suggest that p27-V109G polymorphism plays a protective role in overall cancer risk, particularly for PCa, our case-control study failed to validate any association between this particular polymorphism and PCa risk.

http://ift.tt/2FXFeuP

Clinicohistopathological Characteristics of Malignant Melanoma in the Gall Bladder: A Case Report and Review of the Literature

Objective. Primary gall bladder melanoma is a rare and controversial entity. So far, only 36 cases are documented in the literature. Metastatic melanoma targeting the gall bladder, however, has been reported to occur in about 15–20% of melanoma patients and is much more common. Methods. Based on the case of a 58-year-old woman presenting with multiple melanoma nodules in the gall bladder, we searched in the available literature in PubMed for articles describing a "primary melanoma of the gallbladder" regardless of language used. Results. We detected 33 papers that described 36 cases of primary gall bladder melanoma between 1907 and 2017. From different criteria distinguishing primary and secondary gall bladder melanoma, generally, the following were accepted: (1) exclusion of previous primary melanoma, (2) absence of synchronous involvement of other sites, (3) unicity of the lesion, (4) polypoid or papillary shape of the lesion, and (5) presence of junctional melanocitary component. Review of the 36 published cases revealed that only about one-fourth of them fulfilled all the five criteria. Conclusion. Primary gall bladder melanoma is even rarer than described in the literature, and the question whether this entity really exists remains open.

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Cancers, Vol. 10, Pages 83: The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It

Cancers, Vol. 10, Pages 83: The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It

Cancers doi: 10.3390/cancers10030083

Authors: Heather Armstrong Michael Bording-Jorgensen Stephanie Dijk Eytan Wine

Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from chronic microbial infections and damage brought on by chronic inflammation. A hallmark cancer-inducing microbe is Helicobacter pylori and its causation of peptic ulcers and potentially gastric cancer. This review discusses the recent developments in understanding microbes in health and disease and their potential role in the progression of cancer. To date, microbes can be linked to almost every cancer, including colon, pancreatic, gastric, and even prostate. We discuss the known mechanisms by which these microbes can induce cancer growth and development and how inflammatory cells may contribute to cancer progression. We also discuss new treatments that target the chronic inflammatory conditions and their associated cancers, and the impact microbes have on treatment success. Finally, we examine common dietary misconceptions in relation to microbes and cancer and how to avoid getting caught up in the misinterpretation and over inflation of the results.

http://ift.tt/2povX7U

N- acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner

Abstract

Therapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppresses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that impact the quality of TCR-transduced T cells and suggest that the addition of NAC to current clinical protocols should be considered.

http://ift.tt/2GGPdWb

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

http://ift.tt/2DHz0Oq

An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF)-β1. An interleukin (IL)-15 superagonist/IL-15 receptor α fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies. This in vitro study investigated the efficacy of IL-15SA/IL-15RA on TGF-β1-induced suppression of NK cell-cytotoxic function. IL-15SA/IL-15RA inhibited TGF-β1 from decreasing NK cell lysis of four of four tumor cell lines (H460, LNCap, MCF7, MDA-MB-231). IL-15SA/IL-15RA rescued healthy donor and cancer patient NK cell-cytotoxicity, which had previously been suppressed by culture with TGF-β1. TGF-β1 downregulated expression of NK cell-activating markers and cytotoxic granules, such as CD226, NKG2D, NKp30, granzyme B, and perforin. Smad2/3 signaling was responsible for this TGF-β1-induced downregulation of NK cell-activating markers and cytotoxic granules. IL-15SA/IL-15RA blocked Smad2/3-induced transcription, resulting in the rescue of NK cell-cytotoxic function from TGF-β1-induced suppression. These findings suggest that in addition to increasing NK cell function via promoting the IL-15 signaling pathway, IL-15SA/IL-15RA can function as an inhibitor of TGF-β1 signaling, providing a potential remedy for NK cell dysfunction in the immunosuppressive tumor microenvironment.

http://ift.tt/2FAQX1z

Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Abstract

The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.

http://ift.tt/2DG2SuG

Antibiotics for simple skin abscesses: the new evidence in perspective

Two studies, both published in New England Journal of Medicine in the last 2 years, go a long way in answering, once and for all, whether antibiotics are beneficial after incision and drainage (I&D) of simple skin abscesses. This is an age-old question in emergency medicine and one that grew more urgent with the emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in the late 1990s and early 2000s. While CA-MRSA can cause serious invasive infections, it predominantly causes skin and soft tissue abscesses, mostly simple furuncles in young, healthy patients. Between 1997 and 2005, for example, ED visits for skin and soft tissue infections rose more than 50%, with 59% of culturable infections due to MRSA.1 Do all these furuncles we are now seeing really require a prescription for MRSA-active antibiotics?

'A strategy of routinely treating all skin abscesses with adjunctive antibiotics seems perfectly justified'.

There have...

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Bet 1: Can induced hypertension improve outcome following acute traumatic spinal cord injury?

A shortcut review was carried out to establish whether augmentation of blood pressure to a high mean arterial pressure (MAP) target in the early phase of traumatic spinal cord injury (SCI) could lead to improvements in morbidity or mortality. 23 directly relevant papers were found using the reported search strategy. Of these, two systematic reviews collated the best evidence to answer the clinical question. The author, date and country of publication; patient group studied; study type; relevant outcomes; results and study weaknesses of the best papers are tabulated. It is concluded that data from observational cohort studies support high MAP targets and avoidance of hypotension in the early stages of traumatic SCI, but there are insufficient trial data to support routine use as best practice. Given the intervention carries risk, induced hypertension requires careful consideration on a case-by-case basis.

http://ift.tt/2GaQoj0

Abstracts from international Emergency Medicine journals

Editor's note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication.

http://ift.tt/2GaQmHU

Beyond prognostication: ambulance personnels lived experiences of cardiac arrest decision-making

Introduction

The purpose of this study was to explore ambulance personnel's decisions to commence, continue, withhold or terminate resuscitation efforts for patients with out-of-hospital cardiac arrest.

Method

Semistructured interviews with a purposive sample of 16 demographically diverse ambulance personnel, currently employed in a variety of emergency ambulance response roles, around New Zealand.

Results

Participants sought and integrated numerous factors, beyond established prognostic indicators, when making resuscitation decisions. Factors appeared to be integrated in four distinct phases, described under four main identified themes: prearrival impressions, immediate on-scene impressions, piecing together the big picture and transition to termination of resuscitation. Commencing or continuing resuscitation was sometimes a default action, particularly where ambulance personnel felt the context was uncertain, unfamiliar or overwhelming. Managing the impact of termination of resuscitation and resulting scene of a death required significant confidence, psychosocial skills and experience.

Conclusion

This unique, exploratory study provides new insights into ambulance personnel's experiences of prehospital resuscitation decision-making. Prognostication in out-of-hospital cardiac arrest is known to be challenging, but results from this study suggest that confidence in a poor prognosis for the cardiac arrested patient is only part of the resuscitation decision-making picture. Results suggest ambulance personnel may benefit from greater educational preparation and mentoring in managing the scene of a death to avoid inappropriate or prolonged resuscitation efforts.

http://ift.tt/2GckTFz

Issues and challenges for research in major trauma

The starting point for evidence-based guidelines is the systematic review and critical appraisal of the relevant literature. This review highlights the risk of bias identified while critically appraising the evidence to inform the National Institute of Health and Care Excellence guideline on the assessment and initial management of major trauma.

http://ift.tt/2GckT8x

Ketamine procedural sedation in the emergency department of an urban tertiary hospital in Dar es Salaam, Tanzania

Study objective

We describe ketamine procedural sedations and associated adverse events in low-acuity and high-acuity patients in a resource-limited ED.

Methods

This was a prospective observational study of ketamine procedural sedations at the Emergency Medical Department at the Muhimbili National Hospital in Dar es Salaam, Tanzania. We observed consecutive procedural sedations and recorded patient demographics, medications, vital signs, pulse oximetry, capnography and a priori defined adverse events (using standard definitions in emergency medicine sedation guidelines). All treatment decisions were at the discretion of the treating providers who were blinded to study measurements to simulate usual care. Data collection was unblinded if predefined safety parameters were met. For all significant adverse and unblinding events, ketamine causality was determined via review protocol. Additionally, providers and patients were assessed for sedation satisfaction.

Results

We observed 54 children (median 3 years, range 11 days–15 years) and 45 adults (median 33 years, range 18–79 years). The most common indications for ketamine were burn management in children (55.6%) and orthopaedic procedures in adults (68.9%). Minor adverse events included nausea/vomiting (12%), recovery excitation (11%) and one case of transient hypertension. There were nine (9%) patients who had decreased saturation readings (SpO₂ ≤92%). There were three deaths, all in severely injured patients. After review protocol, none of the desaturations or patient deaths were thought to be caused by ketamine. No patient experienced ketamine-related laryngospasm, apnoea or permanent complications. Overall, ketamine was well tolerated and resulted in high patient and provider satisfaction.

Conclusion

In this series of ketamine sedations in an urban, resource-limited ED, there were no serious adverse events attributable to ketamine.

http://ift.tt/2HNvO5u