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Κυριακή 18 Μαρτίου 2018

Lethal endomyocarditis caused by chronic “Krokodil” intoxication

Abstract

"Krokodil" is a home-made opioid drug obtained by synthesizing desomorphine from codeine and combining it with other low-cost additives. Initially introduced in the former Soviet countries, it was then imported to Western Europe as a heroin substitute. To our knowledge, this is the first report of an Italian case of lethal krokodil abuse, that occurred in a 39-year-old man, who died suddenly after transportation to the Emergency Department (ED) for hyperthermia associated with sweating, dyspnoea and tachycardia. Post-mortem examination revealed extensive necrotic ulcerative lesions on the forearms, and autopsy showed a hypertrophic heart with ample endocardial vegetation on the aortic valve and patency of the foramen ovale. Histopathological examination of the heart showed ulcero-vegetative lesions of the aortic valve with an abscess on the annulus and extension to the periaortic adipose tissue, as well as diffuse myocardial interstitial inflammatory neutrophilic infiltrates. Toxicological analysis demonstrated a desomorphine metabolite in urine. On the basis of all these findings the cause of death was ruled to be congestive heart failure caused by endocarditis and myocarditis, correlated with chronic abuse of krokodil.



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Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice.

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Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice.

Diabetologia. 2018 Mar 15;:

Authors: Chen Y, Wu J, Wang J, Zhang W, Xu B, Xu X, Zong L

Abstract
AIMS/HYPOTHESIS: The intestinal immune system is an ideal target to induce immune tolerance physiologically. However, the efficiency of oral protein antigen delivery is limited by degradation of the antigen in the gastrointestinal tract and poor uptake by antigen-presenting cells. Gut dendritic cells (DCs) are professional antigen-presenting cells that are prone to inducing antigen-specific immune tolerance. In this study, we delivered the antigen heat shock protein 65-6×P277 (H6P) directly to the gut DCs of NOD mice through oral vaccination with H6P-loaded targeting nanoparticles (NPs), and investigated the ability of this antigen to induce immune tolerance to prevent autoimmune diabetes in NOD mice.
METHODS: A targeting NP delivery system was developed to encapsulate H6P, and the ability of this system to protect and facilitate H6P delivery to gut DCs was assessed. NOD mice were immunised with H6P-loaded targeting NPs orally once a week for 7 weeks and the onset of diabetes was assessed by monitoring blood glucose levels.
RESULTS: H6P-loaded targeting NPs protected the encapsulated H6P from degradation in the gastrointestinal tract environment and significantly increased the uptake of H6P by DCs in the gut Peyer's patches (4.1 times higher uptake compared with the control H6P solution group). Oral vaccination with H6P-loaded targeting NPs induced antigen-specific T cell tolerance and prevented diabetes in 100% of NOD mice. Immune deviation (T helper [Th]1 to Th2) and CD4+CD25+FOXP3+ regulatory T cells were found to participate in the induction of immune tolerance.
CONCLUSIONS/INTERPRETATION: In this study, we successfully induced antigen-specific T cell tolerance and prevented the onset of diabetes in NOD mice. To our knowledge, this is the first attempt at delivering antigen to gut DCs using targeting NPs to induce T cell tolerance.

PMID: 29546475 [PubMed - as supplied by publisher]



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Cancer Vaccine Therapy Using Carcinoembryonic Antigen - expressing Dendritic Cells generated from Induced Pluripotent Stem Cells.

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Cancer Vaccine Therapy Using Carcinoembryonic Antigen - expressing Dendritic Cells generated from Induced Pluripotent Stem Cells.

Sci Rep. 2018 Mar 15;8(1):4569

Authors: Kitadani J, Ojima T, Iwamoto H, Tabata H, Nakamori M, Nakamura M, Hayata K, Katsuda M, Miyajima M, Yamaue H

Abstract
Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model. We differentiated hiPSDCs from iPSCs of three healthy donors and transduced CEA cDNA into the hiPSDCs. The surface marker expression, cytokine secretion and migratory capacity of the hiPSDCs were equivalent to those of human monocyte-derived DCs (hMoDCs). Cytotoxic T cells activated by hiPSDCs-CEA exhibited CEA-specific cytotoxic activity against the target cells expressing CEA. Furthermore, in the CEA transgenic mouse model, cytotoxic T cells activated in mice immunized with miPSDCs-CEA displayed CEA-specific cytotoxic activity against MC38-CEA. In the subcutaneous tumour model, vaccination with miPSDCs-CEA achieved a significant growth inhibitory effect on MC38-CEA. No adverse events caused by the administration of miPSDCs were observed. Genetic modification of iPSDCs, inducing the expression of CEA, is a promising tool for clinical applications of vaccine therapy for treating gastrointestinal cancer patients.

PMID: 29545628 [PubMed - in process]



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In silico prediction of cancer immunogens: current state of the art.

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In silico prediction of cancer immunogens: current state of the art.

BMC Immunol. 2018 Mar 15;19(1):11

Authors: Doytchinova IA, Flower DR

Abstract
Cancer kills 8 million annually worldwide. Although survival rates in prevalent cancers continue to increase, many cancers have no effective treatment, prompting the search for new and improved protocols. Immunotherapy is a new and exciting addition to the anti-cancer arsenal. The successful and accurate identification of aberrant host proteins acting as antigens for vaccination and immunotherapy is a key aspiration for both experimental and computational research. Here we describe key elements of in silico prediction, including databases of cancer antigens and bleeding-edge methodology for their prediction. We also highlight the role dendritic cell vaccines can play and how they can act as delivery mechanisms for epitope ensemble vaccines. Immunoinformatics can help streamline the discovery and utility of Cancer Immunogens.

PMID: 29544447 [PubMed - in process]



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Interactions of Cryptococcus with Dendritic Cells.

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Interactions of Cryptococcus with Dendritic Cells.

J Fungi (Basel). 2018 Mar 15;4(1):

Authors: Wozniak KL

Abstract
The fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening infections in immune compromised and immune competent hosts. These pathogens enter the host via inhalation, and respiratory tract innate immune cells such as dendritic cells (DCs) are one of the first host cells they encounter. The interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease in the host. This review will focus specifically on the interactions between Cryptococcus and dendritic cells (DCs), including recognition/processing by DCs, effects of immune mediators on DC recruitment and activity, and the potential for DC vaccination against cryptococcosis.

PMID: 29543719 [PubMed]



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An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination.

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An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination.

J R Soc Interface. 2018 Mar;15(140):

Authors: Brown LV, Gaffney EA, Wagg J, Coles MC

Abstract
Tumour immunotherapy is dependent upon activation and expansion of tumour-targetting immune cells, known as cytotoxic T-lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterized. To elucidate these mechanisms, we developed a human-parametrized, in silico, agent-based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour-specific immune response-inducing peptides (cognate antigen) from the major histocompatibility class I (MHC-I) receptors of dendritic cells (DCs) originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of DCs and T cells that interact subsequent to DC migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.

PMID: 29540543 [PubMed - in process]



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Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells.

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Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells.

Front Immunol. 2018;9:385

Authors: Lichtenegger FS, Rothe M, Schnorfeil FM, Deiser K, Krupka C, Augsberger C, Schlüter M, Neitz J, Subklewe M

Abstract
Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor-ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting programmed cell death protein 1 (PD-1), HVEM, CD244, TIM-3, and lymphocyte activation gene 3 (LAG-3) on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured DCs. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways, including PD-1/PD-L1. This result was consistent across different methods to measure T cell stimulation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and seen for both CD4+ and CD8+ T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by peripheral blood mononuclear cells with low concentrations of peptides, we observed the highest T cell stimulation with dual blockade of LAG-3 and PD-1 blockade. We conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or dual blockade of LAG-3 and PD-1, depending on the strength of the antigenic stimulus.

PMID: 29535740 [PubMed]



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Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development.

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Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development.

Front Immunol. 2018;9:263

Authors: Zimara N, Chanyalew M, Aseffa A, van Zandbergen G, Lepenies B, Schmid M, Weiss R, Rascle A, Wege AK, Jantsch J, Schatz V, Brown GD, Ritter U

Abstract
Resistant mouse strains mount a protective T cell-mediated immune response upon infection with Leishmania (L.) parasites. Healing correlates with a T helper (Th) cell-type 1 response characterized by a pronounced IFN-γ production, while susceptibility is associated with an IL-4-dependent Th2-type response. It has been shown that dermal dendritic cells are crucial for inducing protective Th1-mediated immunity. Additionally, there is growing evidence that C-type lectin receptor (CLR)-mediated signaling is involved in directing adaptive immunity against pathogens. However, little is known about the function of the CLR Dectin-1 in modulating Th1- or Th2-type immune responses by DC subsets in leishmaniasis. We characterized the expression of Dectin-1 on CD11c+ DCs in peripheral blood, at the site of infection, and skin-draining lymph nodes of L. major-infected C57BL/6 and BALB/c mice and in peripheral blood of patients suffering from cutaneous leishmaniasis (CL). Both mouse strains responded with an expansion of Dectin-1+ DCs within the analyzed tissues. In accordance with the experimental model, Dectin-1+ DCs expanded as well in the peripheral blood of CL patients. To study the role of Dectin-1+ DCs in adaptive immunity against L. major, we analyzed the T cell stimulating potential of bone marrow-derived dendritic cells (BMDCs) in the presence of the Dectin-1 agonist Curdlan. These experiments revealed that Curdlan induces the maturation of BMDCs and the expansion of Leishmania-specific CD4+ T cells. Based on these findings, we evaluated the impact of Curdlan/Dectin-1 interactions in experimental leishmaniasis and were able to demonstrate that the presence of Curdlan at the site of infection modulates the course of disease in BALB/c mice: wild-type BALB/c mice treated intradermally with Curdlan developed a protective immune response against L. major whereas Dectin-1-/- BALB/c mice still developed the fatal course of disease after Curdlan treatment. Furthermore, the vaccination of BALB/c mice with a combination of soluble L. major antigens and Curdlan was able to provide a partial protection from severe leishmaniasis. These findings indicate that the ligation of Dectin-1 on DCs acts as an important checkpoint in adaptive immunity against L. major and should therefore be considered in future whole-organism vaccination strategies.

PMID: 29535708 [PubMed]



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An autologous tumor vaccine for CLL.

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An autologous tumor vaccine for CLL.

Leuk Res. 2018 Mar 02;68:40-47

Authors: Zhu F, Khatri I, Spaner D, Gorczynski RM

Abstract
Chronic Lymphocytic Leukemia B cells (CLL) are malignant cells which retain at least some functions of normal B cells. Paramount amongst the latter is that when such cells are appropriately stimulated, they are able to present antigens, including any potential tumor antigens, making them excellent choices as a candidate tumor vaccine. We show that following stimulation of CLL cells with Phorbol myristic acetate, IL-2, the TLR7 agonist imiquimod (P2I) and ionomycin (P2Iio), markedly increased expression of CD54 and CD83 was seen, indicative of B cell activation and a transition to antigen-presenting cells. However, this occurred in the context of augmented expression of the known immunoregulatory molecule, CD200. Accordingly we explored the effect of stimulation of CLL cells with P2Iio, followed by coating of cells with a non-depleting anti-CD200mAb, on the ability of those cells to immunize PBL in vitro to become cytotoxic to CLL cells, or to protect NOD-SCIDγcnull (NSG) mice from subsequent CLL tumor challenge. Our data indicate that this protocol is effective in inducing CD8+ CTL able to lyse CLL cells in vitro, and decrease tumor burden in vivo in spleen and marrow of mice injected with CLL cells. Pre-treatment of mice with a CD8 depleting antibody before vaccination with P2Iio/anti-CD200 coated cells abolished any protection seen. These data suggest a potential role for blockade of CD200 expression on CLL cells as a component of a tumor vaccination strategy.

PMID: 29525600 [PubMed - as supplied by publisher]



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The influence of interferon-β supplemented human dendritic cells on BCG immunogenicity.

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The influence of interferon-β supplemented human dendritic cells on BCG immunogenicity.

J Immunol Methods. 2018 Mar 06;:

Authors: El-Sahrigy SAF, Rahman AMOA, Samaha DY, Mohamed NA, Saber SM, Talkhan HA, Ismail GA, Ibraheem EM, Riad EM

Abstract
INTRODUCTION: Tuberculosis (TB) remains a huge worldwide burden, despite extensive vaccination coverage with the Bacillus Calmette-Guérin (BCG), the only vaccine available against this disease, indicating that BCG-driven immunity is inadequate to protect the human population against TB. This underscore the critical necessitate to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection.
AIM OF THE WORK: To examine whether the exogenous addition of IFN-β could improve dendritic cell (DC) response to Mycobacterium bovis (M. bovis) and to evaluate the effect induced by the infection of human DCs with M. bovis (with and without IFN-β) and Mycobacterium tuberculosis (Mtb) on DC viability as well as to compare the ability of BCG and Mtb to provide DCs with a Th1-polarizing capacity through the assessment of the immunoregulatory cytokines interleukin (IL)-12, IL-10 and interferon-gamma (IFN-γ).
METHODS: Immature DCs (iDCs) were generated in vitro using peripheral blood monocytes separated by anti-CD14-conjugated microbeads in the presence of granulocyte-macrophage-colony-stimulating factor (GM-CSF) and IL-4, cultured cells were analyzed using flow cytometry, then we tested DC viability after inoculation with M. bovis (with and without IFN-β pretreatment) and Mtb using light microscopic examination and trypan blue exclusion method. Additionally, supernatants from infected-DCs cultures were analyzed for IFN-γ, IL-12 and IL-10 by ELISA.
RESULTS: The viability of BCG-infected DCs was significantly higher than that of Mtb-infected DCs (61.55% vs 52.10%). BCG-infected DC produced significantly more IL-12 (p = 0.02) and less IL-10 (p = 0.01) compared with Mtb-infected cells. IFN-β-pretreated BCG-infected DCs produced significantly larger amounts of IL-12 than did BCG-infected DCs (p = 0.03) and Mtb-infected cells (p < 0.001).
CONCLUSION: IFN-β improves DC functions following BCG infection, thus assuming that IFN-β could be used as a vaccine adjuvant.

PMID: 29522775 [PubMed - as supplied by publisher]



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The Influence of Invariant Natural Killer T Cells on Humoral Immunity to T-Dependent and -Independent Antigens.

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The Influence of Invariant Natural Killer T Cells on Humoral Immunity to T-Dependent and -Independent Antigens.

Front Immunol. 2018;9:305

Authors: Lang ML

Abstract
Vaccination with CD1d-binding glycolipid adjuvants and co-administered protein, lipid, and carbohydrate antigens leads to invariant natural killer T (NKT) cell-dependent enhancement of protective B cell responses. NKT cell activation boosts the establishment of protein antigen-specific B cell memory and long-lived plasma cell (LLPC) compartments. NKT cells may exert a similar effect on some carbohydrate-specific B cells, but not lipid-specific B cells. The mechanisms of action of NKT cells on B cell responsiveness and subsequent differentiation into memory B cells and LLPC is dependent on CD1d expression by dendritic cells and B cells that can co-present glycolipids on CD1d and antigen-derived peptide on MHCII. CD1d/glycolipid-activated NKT cells are able to provide help to B cells in a manner dependent on cognate and non-cognate interactions. More recently, a glycolipid-expanded subset of IL-21-secreting NKT cells known as NKT follicular helper cells has been suggested to be a driver of NKT-enhanced humoral immunity. This review summarizes established and recent findings on how NKT cells impact humoral immunity and suggests possible areas of investigation that may allow the incorporation of NKT-activating agents into vaccine adjuvant platforms.

PMID: 29520280 [PubMed]



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Vulnerable populations: an area CMAJ will continue to champion [Editorial]



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The authors respond to "Bill S-206 is ill-suited to achieve its stated objectives" [Letters]



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Exploring the concept of vulnerability in health care [Commentary]



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Bannock as medicine [Humanities]



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Food insecurity and breastfeeding [Commentary]



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Federal budget invests heavily in research, Indigenous health [News]



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Relation between household food insecurity and breastfeeding in Canada [Research]

BACKGROUND:

Qualitative studies have suggested that food insecurity adversely affects infant feeding practices. We aimed to determine how household food insecurity relates to breastfeeding initiation, duration of exclusive breastfeeding and vitamin D supplementation of breastfed infants in Canada.

METHODS:

We studied 10 450 women who had completed the Maternal Experiences — Breastfeeding Module and the Household Food Security Survey Module of the Canadian Community Health Survey (2005–2014) and who had given birth in the year of or year before their interview. We used multivariable Cox proportional hazards models and logistic regression to examine the relation between food insecurity and infant feeding practices, adjusting for sociodemographic characteristics, maternal mood disorders and diabetes mellitus.

RESULTS:

Overall, 17% of the women reported household food insecurity, of whom 8.6% had moderate food insecurity and 2.9% had severe food insecurity (weighted percentages). After adjustment for sociodemographic factors, women with food insecurity were no less likely than others to initiate breastfeeding or provide vitamin D supplementation to their infants. Half of the women with food insecurity ceased exclusive breastfeeding by 2 months, whereas most of those with food security persisted with breastfeeding for 4 months or more. Relative to women with food security, those with marginal, moderate and severe food insecurity had significantly lower odds of exclusive breastfeeding to 4 months, but only women with moderate food insecurity had lower odds of exclusive breastfeeding to 6 months, independent of sociodemographic characteristics (odds ratio 0.60, 95% confidence interval 0.39–0.92). Adjustment for maternal mood disorder or diabetes slightly attenuated these relationships.

INTERPRETATION:

Mothers caring for infants in food-insecure households attempted to follow infant feeding recommendations, but were less able than women with food security to sustain exclusive breastfeeding. Our findings highlight the need for more effective interventions to support food-insecure families with newborns.



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Aspergilloma [Practice]



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Cancer incidence and survival among Metis adults in Canada: results from the Canadian census follow-up cohort (1992-2009) [Research]

BACKGROUND:

Métis people are 1 of 3 Aboriginal groups recognized by the Canadian constitution. We estimated site-specific incidence rates and survival for the most common cancers among Métis adults in Canada and compared these with rates among non-Aboriginal adults in Canada.

METHODS:

We examined responses to the 1991 long-form census, including self-reported Métis ancestry linked to national mortality and cancer databases for followup from 1992 to 2009. We estimated age-standardized incidence rates and 5-year relative survival. We determined relative risk (RR) of cancer among Métis and non-Aboriginal adults using Poisson regression, and estimated excess mortality rate ratios using ethnicity-specific life tables.

RESULTS:

For all cancers and both sexes combined, cancer incidence was similar for Métis and non-Aboriginal adults. However, incidence was significantly higher among Métis adults than among non-Aboriginal adults for the following cancers: female breast (RR 1.18, 95% confidence interval [CI] 1.02–1.37), lung (RR 1.34, 95% CI 1.18–1.52), liver (RR 2.09, 95% CI 1.30–3.38), larynx (RR 1.60, 95% CI 1.03–2.48), gallbladder (RR 2.35, 95% CI 1.12–4.96) and cervix (RR 1.84, 95% CI 1.23–2.76). Métis people had poorer survival for prostate cancer (excess mortality rate ratio 2.60, 95% CI 1.52–4.46).

INTERPRETATION:

We found higher incidence for several cancers and poorer survival after prostate cancer among Métis adults. Several of these disparities may be related to lifestyle factors (including tobacco use, obesity and lack of cancer screening), providing evidence to support development of public health policy and health care to address cancer burden in the Métis people of Canada.



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Bill S-206 is ill-suited to achieve its stated objectives [Letters]



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Sugar-sweetened beverages as the new tobacco: examining a proposed tax policy through a Canadian social justice lens [Analysis]



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Responding to inflight medical emergencies can be stressful for doctors [News]



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Proctocolitis caused by lymphogranuloma venereum [Practice]



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Mostly praise for 2018 federal budget from science and health care communities [News]



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A shift from papillary to reticular fibroblasts enables tumour–stroma interaction and invasion

A shift from papillary to reticular fibroblasts enables tumour–stroma interaction and invasion

A shift from papillary to reticular fibroblasts enables tumour–stroma interaction and invasion, Published online: 19 March 2018; doi:10.1038/s41416-018-0024-y

A shift from papillary to reticular fibroblasts enables tumour–stroma interaction and invasion

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Reply to ‘Comment on ‘MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma’’

Reply to 'Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma''

Reply to 'Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma'', Published online: 19 March 2018; doi:10.1038/s41416-018-0031-z

Reply to 'Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma''

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Comment on ‘MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma’

Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma'

Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma', Published online: 19 March 2018; doi:10.1038/s41416-018-0013-1

Comment on 'MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma'

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Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial, Published online: 19 March 2018; doi:10.1038/s41416-018-0020-2

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

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Adults’ Political Leanings Linked With Early Personality Traits

Our political attitudes in adulthood have roots in early childhood temperament, according to new findings published in Psychological Science, a journal of the Association for Psychological Science. Analyses of data from more than 16,000 participants in two longitudinal studies in the United Kingdom reveal links between conduct problems at ages 5 and 7 and economic and political discontent 25 years later.

"Findings from both studies indicate that children who showed higher levels of conduct problems — that is, aggression, fighting, stealing from peers — were more likely to be economically left leaning and distrustful of the political system as adults," says study author Gary J. Lewis of Royal Holloway, University of London. "Some, but not all, of this link was explained by educational attainment and socioeconomic status in adulthood."

The findings shed light on the relationship between personality traits and political sentiment, suggesting a link that spans more than two decades.

Lewis investigated this link by analyzing data from the British Cohort Study and the National Child Development Study, two longitudinal cohort studies following individuals in the United Kingdom.

Participants' parents completed an assessment of their children's behavior when the children were either 5 or 7 years old, reporting on behaviors related to anxiety, conduct problems, and hyperactivity.

At age 30 or 33, the participants completed measures that gauged their economic conservatism, political cynicism, racism, authoritarianism, and attitudes about gender inequality. These measures cohered into two broad factors: economic/political discontent and social conservatism.

The studies also included data about the parents' social class and the participants' childhood intelligence, educational attainment, and social class in adulthood.

Modeling the relationships among these variables, Lewis found that childhood conduct problems were associated with economic/political discontent in adulthood, even after parental social class and childhood intelligence were taken into account. It is possible, Lewis notes, that conduct problems in childhood may reflect difficulty with self-control and long-term planning or early rejection of authority, either of which could lead to economic/political discontent.

The models also indicated indirect pathways in both cohorts, by which conduct problems were associated with lower educational attainment and adult social class and, ultimately, greater economic/political discontent.

These associations may be modest in strength, says Lewis, but they are stable over a 25-year span, suggesting early foundations of later political attitudes. Future research with more detailed and frequent assessments will help to illuminate the exact nature of these long-term associations.

"We all wonder from time to time why it is that those on the other side of the fence came to be that way," Lewis notes. "These findings take us a little further down the road to answering that question."



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Aortic stent graft injury over active blood flow: over the fence

Description

A 72-year-old woman was admitted to our hospital complaining of chest pain at rest. She underwent thoracic endovascular repair (TER) using three stent grafts (GORE TAG 34x150, 34x200 and 26x200 mm; W. L. Gore & Associates, Flagstaff, Arizona, USA) with type B aortic dissection 5 years earlier (figure 1A). Coronary CT angiography (CTA) findings were inconclusive because of remarkable massive calcification in all coronary arteries. As a low-density area suspected of mural thrombus inside the second stent graft was detected (figure 1B), non-obstructive angioscopy was performed to evaluate graft failure besides invasive coronary angiography.1 No significant stenosis was found using invasive coronary angiography; however, suspicious blood flow through the graft was observed at the aneurysmal descending aorta in the middle of the second graft (figure 2 and video 1). Being uninfluenced by aortic blood flow, it was thought to exist...



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Cancers, Vol. 10, Pages 79: Erratum: Roche, J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers, 2018, 10, 52

Cancers, Vol. 10, Pages 79: Erratum: Roche, J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers, 2018, 10, 52

Cancers doi: 10.3390/cancers10030079

Authors: Joëlle Roche

The author wishes to make the following correction to the paper[...]



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Book Review—Diagnostic Pathology: Lymph Nodes and Extranodal Lymphomas, 2nd Edition



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Prognostic value of zymographic gelatinase activity of MMP-2 and MMP-9 in tumor recurrence of canine intrascrotal hemangiomas

Abstract

There is limited information about intrascrotal hemangioma tumors and their gelatinase activity in the dogs. This study was planned to identify the serum gelatinases in male dogs affected by intrascrotal hemangioma and determine their prognostic value in tumor recurrence. Ten dogs with intrascrotal hemangioma were diagnosed among a total of 65 testicular excision samples. According to the incidence of recurrence, the patients divided into two groups: tumors with recurrence and tumors with no-recurrence. Serum gelatinase activity was assayed by semi-quantitative zymography to determinate their prognostic value in canine intrascrotal hemangioma. Both latent and active MMP-9 and only latent MMP-2 appeared in the gels. Gelatinases showed a significant higher serum activity in dogs with hemangioma than those of the normal dogs. There was a significant association between increased serum activity of gelatinase A and gelatinase B and tumor recurrence. The dogs with hemangioma had a shorter disease-free survival time; however, multivariate analysis showed that serum activity of MMP-2 and MMP-9 was not an independent prognostic factor. According to the findings, MMP-2 and MMP-9 may cause a progressive angiogenesis in canine intrascrotal hemangioma and tumor recurrence subsequently. Our results showed that serum activity of MMP-2 and MMP-9 may be used as a non-invasive prognostic marker for tumor recurrence prediction in dogs affected by intrascrotal hemangioma.



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European cancer mortality predictions for the year 2018 with focus on colorectal cancer

Abstract
Background
We projected cancer mortality statistics for 2018 for the European Union (EU) and its six more populous countries, using the most recent available data. We focused on colorectal cancer.
Materials and methods
We obtained cancer death certification data from stomach, colorectum, pancreas, lung, breast, uterus, ovary, prostate, bladder, leukaemia, and total cancers from the World Health Organisation database and projected population data from Eurostat. We derived figures for France, Germany, Italy, Poland, Spain, the UK, and the EU in 1970–2012. We predicted death numbers by age group and age-standardized (world population) rates for 2018 through joinpoint regression models.
Results
EU total cancer mortality rates are predicted to decline by 10.3% in men between 2012 and 2018, reaching a predicted rate of 128.9/100 000, and by 5.0% in women with a rate of 83.6. The predicted total number of cancer deaths is 1 382 000 when compared with 1 333 362 in 2012 (+3.6%). We confirmed a further fall in male lung cancer, but an unfavourable trend in females, with a rate of 14.7/100 000 for 2018 (13.9 in 2012, +5.8%) and 94 500 expected deaths, higher than the rate of 13.7 and 92 700 deaths from breast cancer. Colorectal cancer predicted rates are 15.8/100 000 men (−6.7%) and 9.2 in women (−7.5%); declines are expected in all age groups. Pancreatic cancer is stable in men, but in women it rose +2.8% since 2012. Ovarian, uterine and bladder cancer rates are predicted to decline further. In 2018 alone, about 392 300 cancer deaths were avoided compared with peak rates in the late 1980s.
Conclusion
We predicted continuing falls in mortality rates from major cancer sites in the EU and its major countries to 2018. Exceptions are pancreatic cancer and lung cancer in women. Improved treatment and—above age 50 years—organized screening may account for recent favourable colorectal cancer trends.

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TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis

Abstract
The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.

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Disrupted dynamic network reconfiguration of the language system in temporal lobe epilepsy

Abstract
Temporal lobe epilepsy tends to reshape the language system causing maladaptive reorganization that can be characterized by task-based functional MRI, and eventually can contribute to surgical decision making processes. However, the dynamic interacting nature of the brain as a complex system is often neglected, with many studies treating the language system as a static monolithic structure. Here, we demonstrate that as a specialized and integrated system, the language network is inherently dynamic, characterized by rich patterns of regional interactions, whose transient dynamics are disrupted in patients with temporal lobe epilepsy. Specifically, we applied tools from dynamic network neuroscience to functional MRI data collected from 50 temporal lobe epilepsy patients and 30 matched healthy controls during performance of a verbal fluency task, as well as during rest. By assigning 16 language-related regions into four subsystems (i.e. bilateral frontal and temporal), we observed regional specialization in both the probability of transient interactions and the frequency of such changes, in both healthy controls and patients during task performance but not rest. Furthermore, we found that both left and right temporal lobe epilepsy patients displayed reduced interactions within the left frontal 'core' subsystem compared to the healthy controls, while left temporal lobe epilepsy patients were unique in showing enhanced interactions between the left frontal 'core' and the right temporal subsystems. Also, both patient groups displayed reduced flexibility in the transient interactions of the left temporal and right frontal subsystems, which formed the 'periphery' of the language network. Importantly, such group differences were again evident only during task condition. Lastly, through random forest regression, we showed that dynamic reconfiguration of the language system tracks individual differences in verbal fluency with superior prediction accuracy compared to traditional activation-based static measures. Our results suggest dynamic network measures may be an effective biomarker for detecting the language dysfunction associated with neurological diseases such as temporal lobe epilepsy, specifying both the type of neuronal communications that are missing in these patients and those that are potentially added but maladaptive. Further advancements along these lines, transforming how we characterize and map language networks in the brain, have a high probability of altering clinical decision making in neurosurgical centres.

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Corrigendum

Patricia Rodriguez-Rodriguez, Anna Sandebring-Matton, Paula Merino-Serrais, Cristina Parrado-Fernandez, Alberto Rabano, Bengt Winblad, Jesús Ávila, Isidre Ferrer, Angel Cedazo-Minguez. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain 2017; 140: 3269–3285; 10.1093/brain/awx256.

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Axis-Guided Vessel Segmentation Using a Self-Constructing Cascade-AdaBoost-SVM Classifier

One major limiting factor that prevents the accurate delineation of vessel boundaries has been the presence of blurred boundaries and vessel-like structures. Overcoming this limitation is exactly what we are concerned about in this paper. We describe a very different segmentation method based on a cascade-AdaBoost-SVM classifier. This classifier works with a vessel axis + cross-section model, which constrains the classifier around the vessel. This has the potential to be both physiologically accurate and computationally effective. To further increase the segmentation accuracy, we organize the AdaBoost classifiers and the Support Vector Machine (SVM) classifiers in a cascade way. And we substitute the AdaBoost classifier with the SVM classifier under special circumstances to overcome the overfitting issue of the AdaBoost classifier. The performance of our method is evaluated on synthetic complex-structured datasets, where we obtain high overlap ratios, around 91%. We also validate the proposed method on one challenging case, segmentation of carotid arteries over real clinical datasets. The performance of our method is promising, since our method yields better results than two state-of-the-art methods on both synthetic datasets and real clinical datasets.

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Comment on ‘MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma’



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A shift from papillary to reticular fibroblasts enables tumour–stroma interaction and invasion



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Reply to ‘Comment on ‘MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma’’



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Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial



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Celastrol inhibits colorectal cancer cell proliferation and migration through suppression of MMP3 and MMP7 by the PI3K/AKT signaling pathway

Colorectal cancer (CRC) is one of the most frequent malignant tumors. Signaling by the PI3K/AKT pathway is crucial for CRC development and progression, including proliferation and migration. Celastrol has an anticancer effect, but its mechanism needs to be determined. Here, we showed that celastrol suppressed CRC cell proliferation and migration. Celastrol treatment also decreased the PI3K/AKT pathway components, and MMP3 and MMP7 expression levels. In addition, knockdown of AKT, not mTOR, inhibited MMP3 and MMP7 expression levels and AKT silencing promoted the celastrol-induced effects on CRC cell proliferation and migration. Taken together, these findings indicated that the celastrol-induced antitumor effects were mediated through MMP3 and MMP7 by the PI3K/AKT signaling pathway. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ Correspondence to Wang Ling, PhD, PhD Program for Immunology, Department of Oncology, the First Affiliated Hospital of Dalian Medical University, No. 193, Lian-He Road, Dalian 116011, People's Republic of China Tel: +86 180 9887 6728; fax: +86 411 8363 5963; e-mail: 516245530@qq.com Received October 2, 2017 Accepted February 26, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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AMR aims to standardize new cardiac arrest approach

The message now to medical personnel – and the public – is to stay on the scene and focus on high-quality CPR

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Ginsenoside Rg3 Sensitizes Colorectal Cancer to Radiotherapy through Downregulation of Proliferative and Angiogenic Biomarkers

Background. Radiation therapy is an important mode of colorectal cancer treatment. However, most people die of local recurrence after tumors become resistant to radiotherapy, and little progress has been made in treating radiotherapy-resistant colorectal cancer. Hence, novel agents that are nontoxic and can sensitize colorectal cancer to radiotherapy are urgently needed. Ginsenoside Rg3, a saponin extracted from ginseng, shows cytotoxicity against a variety of cancer cells through suppression of pathways linked to oncogenesis, including cell survival, proliferation, invasion, and angiogenesis. In this article, we investigated whether Rg3 can sensitize colorectal cancer to radiation in vivo. Methods and Materials. We established CT-26 xenografts in BALB/c mice and treated them with vehicle, Rg3, radiation, and combined Rg3 + radiation. Mouse quality of life, survival, tumor volumes, and inhibitive rates were estimated. NF-κB activation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. We also tested for markers of proliferation, angiogenesis, and invasion using immunohistochemistry and Western blot analysis. Results. Rg3 significantly enhanced the efficacy of fractionated radiotherapy by improving the quality of life of mice. Moreover, tumors from mice xenografted with CT-26 cells and treated with combined Rg3 + radiotherapy showed significantly lower tumor volumes ( versus controls; versus radiation alone), NF-κB activation, and expression of NF-κB-regulated gene products (cyclin D1, survivin, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF)) compared with controls. The combination treatment was also effective in suppressing angiogenesis, as indicated by lower CD31+ microvessel density compared with controls (). Conclusion. Our results suggest that Rg3 enhances the antitumor effects of radiotherapy for colorectal cancer by suppressing NF-κB and NF-κB-regulated gene products, leading to inhibition of tumors and prolongation of the lifespan of CT-26 xenograft BALB/c mice.

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Medicinal Plants Used for Treatment of Diarrhoeal Related Diseases in Ethiopia

This paper presents a review of relevant antidiarrhoeal medicinal plants based on the fundamental knowledge accumulated by indigenous people of Ethiopia. The review includes an inventory carried out on the phytochemical and pharmacological analysis of plant species used in the treatments of diarrhoeal diseases. This study is based on a review of the literature published in scientific journals, books, theses, proceedings, and reports. A total of 132 medicinal plants used by local people of Ethiopia are reported in the reviewed literature. Herbs (43.6%) were the primary source of medicinal plants, followed by trees (27%). Some findings include the predominance of leaf material used (78%), as well as the frequent use of crushing of the plant parts (38%) as a mode of preparation. This study demonstrates the importance of traditional medicines in the treatment of basic human ailments such as diarrhoeal diseases in Ethiopia. Baseline information gaps were observed in different regions of Ethiopia. Thus, documentation of the knowledge held by other regions of Ethiopia that have so far received less attention and urban ethnobotany is recommended for future ethnobotanical studies. In addition, phytochemical studies are recommended mainly on frequently utilized medicinal plants for treatment of diarrhoeal diseases which can serve as a basis for future investigation of modern drug development. Although societies in Ethiopia have long used medicinal plants for diarrhoeal diseases treatment, it is also a good practice to perform toxicological tests.

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Effects of Chinese Dietary Pattern of Fat Content, n-6/n-3 Polyunsaturated Fatty Acid Ratio, and Cholesterol Content on Lipid Profile in Rats

This study aims to investigate the effect of Chinese diet pattern of fat content (30% or 36.06%), n-6/n-3 polyunsaturated fatty acid (PUFA) ratio (5 : 1 or 9 : 1), and cholesterol content (0.04 or 0.057 g/kg total diet) on lipid profile using a rat model. Results showed that rats' body weights (BWs) were controlled by the simultaneous intakes of cholesterol level of 0.04 g/kg total diet and n-6/n-3 ratio of 5 : 1. In addition, under high-fat diet, increased cholesterol feeding led to increased total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels and decreased triacylglycerols (TG) in rats' plasma. However, high density lipoprotein cholesterol (HDL-C) level and the ratios of HDL-C/LDL-C and HDL-C/TC in rats' plasma increased in response to simultaneous intakes of low n-6/n-3 ratio (5 : 1) and cholesterol (0.04 g/kg total diet) even under high-fat diet. Moreover, as the n-6/n-3 PUFA ratio in the diet decreased, the proportion of n-3 PUFAs increased in plasma, liver, and muscle and resulted in the decrease of n-6/n-3 PUFA ratio.

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Metamorphopsia Score and Central Visual Field Outcomes in Diabetic Cystoid Macular Edema

Aim. To detect abnormality of the visual function in naïve patients with cystoid diabetic macular edema (DME) using M-charts, Amsler test, and white on white (W/W) and blue on yellow (B/Y) perimetry. Methods. There were 64 eyes included in the study: 30 eyes with DME, 22 eyes with diabetes without DME, and 12 eyes of normal subjects. Conventional W/W perimetry and B/Y perimetry were performed within the central 10° of the visual field. To assess metamorphopsia, Amsler test and M-charts were used. Results. The rate of detection of metamorphopsia was 37% with Amsler test examination and 50% with M-charts. Specificity of both tests was 100%. We found a significant difference between vertical scores of M-charts in all groups, but not in horizontal scores (). Mean defect (MD) was 8.9 dB and 3.6 dB and loss variance (LV) 4.8 dB and 3.3 dB (). Conclusions. M-chart is more sensitive than Amsler test method for detection of metamorphopsia. The MD and LV are higher in b/y in comparison to W/W perimetry. B/Y perimetry and M-charts are more sensitive than conventional methods for detecting the visual function loss in cystoid DME.

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Donation after Circulatory Death in Paediatric Liver Transplantation: Current Status and Future Perspectives in the Machine Perfusion Era

Efforts have been made by the transplant community to expand the deceased donor pool in paediatric liver transplantation (LT). The growing experience on donation after circulatory death (DCD) for adult LT has encouraged its use also in children, albeit in selective cases, opening new perspectives for paediatric patients. Even though there has recently been a slight increase in the number of DCD livers transplanted in children, with satisfactory graft and patient outcomes, the use of DCD grafts in paediatric recipients is still controversial due to morbid outcomes associated with DCD grafts. In this context, recent advances in the optimization of donor support by extracorporeal membrane oxygenation and in the graft preservation by liver machine perfusion could find application in order to expand the donor pool in paediatric LT. In the present study we review the current literature on DCD liver grafts transplanted in children and on the use of extracorporeal donor support and liver perfusion machines in paediatrics, with the aim of defining the current status and future perspectives of paediatric LT.

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Herbal Medicine for Oligomenorrhea and Amenorrhea: A Systematic Review of Ancient and Conventional Medicine

Introduction. Menstrual bleeding cessation is one of the most frequent gynecologic disorders among women in reproductive age. The treatment is based on hormone therapy. Due to the increasing request for alternative medicine remedies in the field of women's diseases, in present study, it was tried to overview medicinal plants used to treat oligomenorrhea and amenorrhea according to the pharmaceutical textbooks of traditional Persian medicine (TPM) and review the evidence in the conventional medicine. Methods. This systematic review was designed and performed in 2017 in order to gather information regarding herbal medications of oligomenorrhea and amenorrhea in TPM and conventional medicine. This study had several steps as searching Iranian traditional medicine literature and extracting the emmenagogue plants, classifying the plants, searching the electronic databases, and finding evidences. To search traditional Persian medicine references, Noor digital library was used, which includes several ancient traditional medical references. The classification of plants was done based on the repetition and potency of the plants in the ancient literatures. The required data was gathered using databases such as PubMed, Scopus, Google Scholar, Cochrane Library, Science Direct, and web of knowledge. Results. In present study of all 198 emmenagogue medicinal plants found in TPM, 87 cases were specified to be more effective in treating oligomenorrhea and amenorrhea. In second part of present study, where a search of conventional medicine was performed, 12 studies were found, which had 8 plants investigated: Vitex agnus-castus, Trigonella foenum-graecum, Foeniculum vulgare, Cinnamomum verum, Paeonia lactiflora, Sesamum indicum, Mentha longifolia, and Urtica dioica. Conclusion. Traditional Persian medicine has proposed many different medicinal plants for treatment of oligomenorrhea and amenorrhea. Although just few plants have been proven to be effective for treatment of menstrual irregularities, the results and the classification in present study can be used as an outline for future studies and treatment.

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Gear Shifting of Quadriceps during Isometric Knee Extension Disclosed Using Ultrasonography

Ultrasonography has been widely employed to estimate the morphological changes of muscle during contraction. To further investigate the motion pattern of quadriceps during isometric knee extensions, we studied the relative motion pattern between femur and quadriceps under ultrasonography. An interesting observation is that although the force of isometric knee extension can be controlled to change almost linearly, femur in the simultaneously captured ultrasound video sequences has several different piecewise moving patterns. This phenomenon is like quadriceps having several forward gear ratios like a car starting from rest towards maximal voluntary contraction (MVC) and then returning to rest. Therefore, to verify this assumption, we captured several ultrasound video sequences of isometric knee extension and collected the torque/force signal simultaneously. Then we extract the shapes of femur from these ultrasound video sequences using video processing techniques and study the motion pattern both qualitatively and quantitatively. The phenomenon can be seen easier via a comparison between the torque signal and relative spatial distance between femur and quadriceps. Furthermore, we use cluster analysis techniques to study the process and the clustering results also provided preliminary support to the conclusion that, during both ramp increasing and decreasing phases, quadriceps contraction may have several forward gear ratios relative to femur.

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Genetic Diversity and Distribution of Blastocystis Subtype 3 in Human Populations, with Special Reference to a Rural Population in Central Mexico

Blastocystis subtype 3 (ST3) is a parasitic protist found in the digestive tract of symptomatic and asymptomatic humans around the world. While this parasite exhibits a high prevalence in the human population, its true geographic distribution and global genetic diversity are still unknown. This gap in knowledge limits the understanding of the spread mechanisms, epidemiology, and impact that this parasite has on human populations. Herein, we provided new data on the geographical distribution and genetic diversity of Blastocystis ST3 from a rural human population in Mexico. To do so, we collected and targeted the SSU-rDNA region in fecal samples from this population and further compared its genetic diversity and structure with that previously observed in populations of Blastocystis ST3 from other regions of the planet. Our analyses reveled that diversity of Blastocystis ST3 showed a high haplotype diversity and genetic structure to the world level; however, they were low in the Morelos population. The haplotype network revealed a common widespread haplotype from which the others were generated recently. Finally, our results suggested a recent expansion of the diversity of Blastocystis ST3 worldwide.

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A role for pericytes in chronic pain?

Purpose of review The importance of the blood–brain barrier (BBB) and neuroinflammation in neurodegenerative conditions is becoming increasingly apparent, yet very little is known about these neurovascular functions in nonmalignant disease chronic pain. Neural tissue pericytes play critical roles in the formation and maintenance of the BBB. Herein, we review the important roles of neural pericytes and address their potential role in chronic pain. Recent findings Pericytes are implicated in the function of neural microvasculature, including BBB permeability, neuroimmune factor secretion and leukocyte transmigration. In addition, the multipotent stem cell nature of pericytes affords pericytes the ability to migrate into neural parenchyma and differentiate into pain-associated cell types. These recent findings indicate that pericytes are key players in pathological BBB disruption and neuroinflammation, and as such pericytes may be key players in chronic pain states. Summary Pericytes play key roles in pathological processes associated with chronic pain. We propose that pericytes may be a therapeutic target for painful diseases that have associated neural vascular dysfunction. Given the paucity of new pharmacotherapies for chronic pain conditions, we hope that this review inspires researchers to unearth the potential role(s) of pericytes in chronic pain sowing the seeds for future new chronic pain therapies. Correspondence to Nicholas Beazley-Long, Arthritis Research UK Pain Centre and School of Life Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK. E-mail: nicholas.beazley-long@nottingham.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Chronic postsurgical pain and cancer: the catch of surviving the unsurvivable

Purpose of review Chronic postsurgical pain (CPSP) is an important and well recognized cause of much long-term suffering, which in some cases may be preventable and affects many people living with cancer. Unfortunately, general consensus is lacking as to how best reduce the risk of developing CPSP. Recent findings Cancer is now not always a short-lived, fatal disease and is now moving towards a chronic illness. Poorly managed perioperative pain is the greatest risk factor for CPSP. Recent trials have examined preventive strategies for CPSP associated with breast surgery and thoracotomy, two operations used in cancer treatment. Standard antinociceptive drugs, 5% lidocaine patches and ketamine do not prevent CPSP. The evidence for gabapentinoids is conflicting. Intravenous lidocaine and, separately, regional anaesthesia appear beneficial. Summary Well-managed pain, irrespective of technique, reduces the risk of CPSP. The literature is inconclusive regarding an 'optimal approach.' Regional anaesthesia, intravenous lidocaine and the aggressive management of perioperative pain using multimodal analgesia including antineuropathic pain agents such as gabapentinoids and certain antidepressants are recommended. Clinicians should not rely on general anaesthesia, opioids, NSAIDs and ketamine to prevent CPSP. A blanket approach using gabapentinoids for all patients undergoing major surgery is not indicated. Instead, the presence of perioperative neuropathic pain should be checked for regularly. Correspondence to Dr Stephen R. Humble, Honorary Senior Lecturer Imperial College, Imperial College Healthcare NHS Trust, Pain Management Clinic, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. Tel: +44 203 311 1234; e-mail: Stephen.humble@nhs.net Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Role of the Immune Response in the Pathogenesis of Bronchiectasis

Bronchiectasis is a prevalent respiratory condition characterised by permanent and abnormal dilation of the lung airways (bronchi). There are a large variety of causative factors that have been identified for bronchiectasis; all of these compromise the function of the immune response to fight infection. A triggering factor may lead to the establishment of chronic infection in the lower respiratory tract. The bacteria responsible for the lower respiratory tract infection are usually found as commensals in the upper respiratory tract microbiome. The consequent inflammatory response to infection is largely responsible for the pathology of this condition. Both innate and adaptive immune responses are activated. The literature has highlighted the central role of neutrophils in the pathogenesis of bronchiectasis. Proteases produced in the lung by the inflammatory response damage the airways and lead to the pathological dilation that is the pathognomonic feature of bronchiectasis. The small airways demonstrate infiltration with lymphoid follicles that may contribute to localised small airway obstruction. Despite aggressive treatment, most patients will have persistent disease. Manipulating the immune response in bronchiectasis may potentially have therapeutic potential.

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Effect of Lavender (Lavandula angustifolia) Essential Oil on Acute Inflammatory Response

Lavandula angustifolia is a plant of Lamiaceae family, with many therapeutic properties and biological activities, such as anticonvulsant, anxiolytic, antioxidant, anti-inflammatory, and antimicrobial activities. The aim of this study was to evaluate the effect of Lavandula angustifolia Mill. essential oil (LEO) on acute inflammatory response. LEO was analyzed using gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR) methods and showed predominance of 1,8-cineole (39.83%), borneol (22.63%), and camphor (22.12%). LEO at concentrations of 0.5, 1, 3, and 10 μg/ml did not present in vitro cytotoxicity. Additionally, LEO did not stimulate the leukocyte chemotaxis in vitro. The LEO topical application at concentrations of 0.25, 0.5, and 1 mg/ear reduced edema formation, myeloperoxidase (MPO) activity, and nitric oxide (NO) production in croton oil-induced ear edema model. In carrageenan-induced paw edema model, LEO treatment at doses of 75, 100, and 250 mg/kg reduced edema formation, MPO activity, and NO production. In dextran-induced paw edema model, LEO at doses of 75 and 100 mg/kg reduced paw edema and MPO activity. In conclusion, LEO presented anti-inflammatory activity, and the mechanism proposed of LEO seems to be, at least in part, involving the participation of prostanoids, NO, proinflammatory cytokines, and histamine.

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Stereotactic Body Radiation Therapy (SBRT) for Hepatocellular Carcinoma: High Rates of Local Control With Low Toxicity

Objectives: Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. Materials and Methods: Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT. Results: Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity. Conclusions: SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted. The authors declare no conflicts of interest. Reprints: Brian C. Baumann, MD, Department of Radiation Oncology, Washington University in St. Louis, 4921 Parkview Place, Lower Level, St. Louis, MO 63110. E-mail: brian.baumann@wustl.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Comparing Simultaneous Liver-Kidney Transplant Strategies: A Modified Cost-Effectiveness Analysis

Background The proportion of patients with kidney failure at time of liver transplantation is at an historic high in the United States. The optimal timing of kidney transplantation with respect to the liver transplant is unknown. Methods We used a modified cost-effectiveness analysis to compare four strategies: the old system ("pre-OPTN"), the new Organ Procurement Transplant Network (OPTN) system since August 10, 2017 ("OPTN"), and two strategies which restrict simultaneous liver-kidney transplants ("safety net" and "stringent"). We measured "cost" by deployment of deceased donor kidneys (DDKs) to liver transplant recipients and effectiveness by life years (LYs) and quality-adjusted life years (QALYs) in liver transplant recipients. We validated our model against Scientific Registry for Transplant Recipients data. Results The OPTN, safety net and stringent strategies were on the efficient frontier. By rank order, OPTN > safety net > stringent strategy in terms of LY, QALY and DDK deployment. The pre-OPTN system was dominated, or outperformed, by all alternative strategies. The incremental LY per DDK between the strategies ranged from 1.30 to 1.85. The incremental QALY per DDK ranged from 1.11 to 2.03. Conclusion These estimates quantify the "organ"-effectiveness of various kidney allocation strategies for liver transplant candidates. The OPTN system will likely deliver better liver transplant outcomes at the expense of more frequent deployment of DDKs to liver transplant recipients. Corresponding Authors: Jane C. Tan, 750 Welch Rd, Suite 200, MC 5785, Palo Alto CA 94304, 650-725-9891. janetan@stanford.edu; W. Ray Kim, 300 Pasteur Drive, Always M211, Stanford CA 94305, 650-725-6511. wrkim@stanford.edu Authorship: X.S.C.: Research design, data acquisition, data analysis, results interpretation, paper writing. W.R.K.: Research design, results interpretation, paper writing. J.C.T.: Research design, data acquisition, results interpretation, paper writing. G.M.C.: Research design, results interpretation, paper writing. J.G.: Research design, data analysis, results interpretation, paper writing. The authors declare no conflict of interest. Research reported here was supported by the John M. Sobrato Gift Fund (J.C.T.) and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K24DK092336 (W.R.K.) and K24 DK085446 (G.M.C.). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Microtubule-Associated Protein 4 Is a Prognostic Factor and Promotes Tumor Progression in Lung Adenocarcinoma

Microtubule-associated protein 4 (MAP4) plays an important role in microtubule assembly and stabilization. The purpose of this study was to investigate the level of expression of MAP4 in lung adenocarcinoma (LADC) samples and to evaluate its prognostic value and the influence on cancer progression in LADC patients. The expression of MAP4 protein was analyzed using immunohistochemistry. The clinical significance and the prognostic significance of MAP4 expression were assessed by Kaplan-Meier analysis and Cox regression analysis. The roles of MAP4 in the migration and invasion of LADC cells were detected by wound-healing assays and transwell assays, respectively. We found the expression levels of MAP4 protein in LADC tissues to be significantly higher than those in noncancerous tissues. MAP4 expression was significantly correlated with differentiation, pathological T stage, and TNM stage. Kaplan-Meier survival analysis indicated that patients with high MAP4 expression had significantly poorer overall survival (OS). Cox regression analysis revealed that MAP4 expression level was an independent prognostic factor for OS. Functionally, in vitro studies showed that MAP4 knockdown efficiently suppressed the migration and invasion of LADC cells. Our data indicated that MAP4 protein may represent a novel prognostic biomarker and a potential therapeutic target for LADC.

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Vitamin D and Incidence of Prediabetes or Type 2 Diabetes: A Four-Year Follow-Up Community-Based Study

Aim. To examine whether the baseline 25-hydroxyvitamin D [25(OH)D] level was predictive of the onset of prediabetes or type 2 diabetes (T2DM) in the Chinese population. Methods. This was a 4-year follow-up study that was conducted in the Chengdu region of China as part of the China National Diabetes and Metabolic Disorders Study. The study included 490 participants that were free of prediabetes and type 2 diabetes mellitus (T2DM) at baseline and had complete data by follow-up examinations. Glucose, insulin, and 25(OH)D levels were measured at baseline and at 4 years later. Prediabetes and T2DM were defined by results obtained from an oral glucose tolerance test. Results. Over a 4-year follow-up, 95 (48.5‰) developed prediabetes and 31 (15.8‰) individuals developed diabetes. Low 25(OH)D status was significantly associated with the risk of developing prediabetes [OR 3.01 (95% CI: 1.50–6.06), ] and T2DM [OR 5.61 (95% CI: 1.73–18.27), ] after adjustment for multiple potential confounders. In a multiple linear regression analysis, low baseline levels of 25(OH)D were an independent predictor of increased insulin resistance over a 4-year period (). Conclusions. The current prospective study suggests that low 25(OH)D levels might have contributed to the incidence of prediabetes or T2DM in Chinese individuals. This trial is registered with TR-CCH-ChiCTR-OCS-09000361.

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Cell Fragmentation and Permeabilization by a 1 ns Pulse Driven Triple-Point Electrode

Ultrashort electric pulses (ns-ps) are useful in gaining understanding as to how pulsed electric fields act upon biological cells, but the electric field intensity to induce biological responses is typically higher than longer pulses and therefore a high voltage ultrashort pulse generator is required. To deliver 1 ns pulses with sufficient electric field but at a relatively low voltage, we used a glass-encapsulated tungsten wire triple-point electrode (TPE) at the interface among glass, tungsten wire, and water when it is immersed in water. A high electric field (2 MV/cm) can be created when pulses are applied. However, such a high electric field was found to cause bubble emission and temperature rise in the water near the electrode. They can be attributed to Joule heating near the electrode. Adherent cells on a cover slip treated by the combination of these stimuli showed two major effects: (1) cells in a crater (

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Identification of Gastric Cancer-Related Circular RNA through Microarray Analysis and Bioinformatics Analysis

Gastric cancer is one of the common malignant tumors worldwide. Increasing studies have indicated that circular RNAs (circRNAs) play critical roles in the cancer progression and have shown great potential as useful markers and therapeutic targets. However, the precise mechanism and functions of most circRNAs are still unknown in gastric cancer. In the present study, we performed a microarray analysis to detect circRNA expression changes between tumor samples and adjacent nontumor samples. The miRNA expression profiles were obtained from the National Center of Biotechnology Information Gene Expression Omnibus (GEO). The differentially expressed circRNAs and miRNAs were identified through fold change filtering. The interactions between circRNAs and miRNAs were predicted by Arraystar's home-made miRNA target prediction software. After circRNA-related miRNAs and dysregulated miRNAs were intersected, 23 miRNAs were selected. The target mRNAs of miRNAs were predicted by TarBase v7.0. Gene ontology (GO) enrichment analysis and pathway analysis were performed using standard enrichment computational methods for the target mRNAs. The results of pathway analysis showed that p53 signaling pathway and hippo signal pathway were significantly enriched and CCND2 was a cross-talk gene associated with them. Finally, a circRNA-miRNA-mRNA regulation network was constructed based on the gene expression profiles and bioinformatics analysis results to identify hub genes and hsa_circRNA_101504 played a central role in the network.

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Antioxidant, Hepatoprotective, and Antidepression Effects of Rumex tingitanus Extracts and Identification of a Novel Bioactive Compound

Over the last few decades, Rumex species have been recognized as a promising source of new compounds with numerous pharmacological activities. Therefore, the antioxidant activity of Rumex tingitanus (R. tingitanus) leaves extracts was evaluated in vitro and then confirmed in vivo as well as the antidepressant-like and toxicological effects of the extracts. The ethyl acetate fraction (Rt EtOAcF) followed by hydroalcoholic extract (Rt EtOH-H2O) showed a remarkable in vitro antioxidant activity. The hydroalcoholic extract (Rt EtOH-H2O) showed significant hepatoprotective activity against carbon tetrachloride- (CCl4-) induced liver toxicity which is seen from inhibition of the malondialdehyde (MDA) accumulation and enhancement of the liver antioxidant enzymes activities. The Rt EtOH-H2O and Rt EtOAcF extracts were able to reduce the immobility time in mice and then elicited a significant antidepressant-like effect. The ethyl acetate fraction (Rt EtOAcF) was purified and resulted in the identification of a new antioxidant component called 4′-p-acetylcoumaroyl luteolin. The Rt EtOAcF and the 4′-p-acetylcoumaroyl luteolin revealed a strong antioxidant activity using DPPH test with IC50 of 11.7 ± 0.2 and 20.74 ± 0.6 μg/ml, respectively, and AAI of 3.39 and 1.92 better than that of BHT, used as control.

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The Role of Cardiokines in Heart Diseases: Beneficial or Detrimental?

Cardiovascular disease remains the leading cause of morbidity and mortality, imposing a major disease burden worldwide. Therefore, there is an urgent need to identify new therapeutic targets. Recently, the concept that the heart acts as a secretory organ has attracted increasing attention. Proteins secreted by the heart are called cardiokines, and they play a critical physiological role in maintaining heart homeostasis or responding to myocardial damage and thereby influence the development of heart diseases. Given the critical role of cardiokines in heart disease, they might represent a promising therapeutic target. This review will focus on several cardiokines and discuss their roles in the pathogenesis of heart diseases and as potential therapeutics.

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Cancers, Vol. 10, Pages 78: New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

Cancers, Vol. 10, Pages 78: New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

Cancers doi: 10.3390/cancers10030078

Authors: Klaudia Szymonowicz Sebastian Oeck Nathalie Malewicz Verena Jendrossek

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt's activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.



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Cancers, Vol. 10, Pages 77: Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy

Cancers, Vol. 10, Pages 77: Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy

Cancers doi: 10.3390/cancers10030077

Authors: Anna-Laura Kretz Silvia von Karstedt Andreas Hillenbrand Doris Henne-Bruns Uwe Knippschild Anna Trauzold Johannes Lemke

Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment.



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Outcomes of Computed Tomography-Guided Image-Based Interstitial Brachytherapy for Cancer of the Cervix Using GEC-ESTRO Guidelines

Abstract

Locally advanced cancer of the cervix is treated by concurrent chemoradiation followed by brachytherapy. Interstitial brachytherapy is used to treat large tumors with involvement of parametrium, post-hysterectomy, and narrow, conical vagina. The GYN GEC-ESTRO working group described target volume delineation and also 3D image-based planning using MRI and 3D dose-volume parameters for brachytherapy of carcinoma cervix. CT-based as compared to MR-based image-guided brachytherapy (IGBT) is much more feasible and practical because MR access is still difficult for most departments. This is a retrospective study done to assess the local control in cancer of the cervix, treated based on these guidelines and dose received by 2 cm3 of the rectum as defined by the GEC-ESTRO guidelines and its correlation with long-term toxicity. Sixty-three patients of cancer of the cervix received 45 Gy/25 fractions of external beam radiotherapy with concurrent weekly cisplatin followed by interstitial brachytherapy. A central tandem was inserted into the uterine cavity. The needles were inserted based on the concept of gross tumor volume (GTV), high-risk clinical target volume (HRCTV), and intermediate-risk CTV (IR CTV) as defined by the GYN GEC-ESTRO guidelines. All patients underwent CT-based planning. A dose of 6.5 Gy × 4 fractions was delivered in two sessions such that the HRCTV received a total dose of 26 Gy. Dose optimization was done to prevent 2 cm3 of rectum from receiving > 400 cGy (60% of prescribed dose) per fraction and 2 cm3 of bladder from receiving 500 cGy per fraction. At a median follow-up of 41.5 months (range 6–106 months), 74.6% (47/63) of the patients were alive, with no local, loco-regional, or distant metastasis. Loco-regional control rate was 88% (56/63). Eight percent (5/63) of the patients developed grade I proctitis which was managed conservatively. There was no grades II, III, or IV proctitis. There was no bladder or sigmoid toxicity. GEC-ESTRO guidelines can be modified for CT-based planning also with very minimal late toxicity without compromising local control.



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