Medicine by Alexandros G.Sfakianakis: 11/03/18

Σάββατο 3 Νοεμβρίου 2018

Bundled payments in spine surgery

Publication date: Available online 31 October 2018

Source: Seminars in Spine Surgery

Author(s): Peter G. Passias, Samantha R. Horn, Tiffany Liu, Frank A. Segreto, Cole A. Bortz, John A. Bendo

Abstract

Interest in the application of bundled payments to the field of spine surgery continues to grow. There may be great potential for cost-savings for spinal procedures under bundled payments. However, challenges such as heterogeneity of DRGs, complex procedures requiring lengthy recoveries, and appropriate outcomes measurement pose barriers to successful bundled payment design. In this paper, we review the challenges and opportunities posed by bundled payments in spine surgery. We also present several key considerations for policymakers interested in payment reform within spine surgery. Surgeon involvement will be critical in providing guidance for generating effective alternative payment models.

https://ift.tt/2D1UAQo

Value based spine care: Paying for outcomes, not volume

Publication date: Available online 27 September 2018

Source: Seminars in Spine Surgery

Author(s): Jeffrey M. Hills, Benjamin Weisenthal, Ahilan Sivaganesan, Mohamad Bydon, Kristin R. Archer, Clinton J. Devin

Abstract

Spine pathology is among the most common, most disabling, and costliest disorders in the US health care system. Traditional reimbursement models in which volume of service rather than quality is incentivized has resulted in an unsustainable rise in cost. The focus for all stakeholders is now on value-based health care. Value is determined by the outcomes achieved per dollar spent to achieve those outcomes. Clinical registries and validated outcome tools are now making it possible for all spine practitioners to define and develop value-based care. Accurate measurement of outcomes and cost and identifying outliers are essential to improving the value in spine surgery.

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Spinescope

Publication date: Available online 27 September 2018

Source: Seminars in Spine Surgery

Author(s): Scott D. Boden

https://ift.tt/2D0O1xl

Contributors to authors

Publication date: September 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 3

Author(s):

https://ift.tt/2P9qiCr

Clinical presentation and treatment of melioidosis in the head and neck region.

Clinical presentation and treatment of melioidosis in the head and neck region.

J Laryngol Otol. 2018 Sep 05;:1-5

Authors: Mahawerawat K, Kasemsiri P

Abstract
BACKGROUND: Although melioidosis in the head and neck region is uncommon, it is a potentially life-threatening infection. Thus, early diagnosis and proper management are very important.
OBJECTIVES: To report the clinical presentation and management of melioidosis in the head and neck.
METHOD: A retrospective study was conducted from 1 January 2013 to 31 October 2016 in Mukdahan Hospital, Thailand. Case records of patients who had presented with culture-positive melioidosis were analysed.
RESULTS: Medical records of 49 patients (23 males and 26 females) were analysed. Patients ranged in age from 1 to 75 years. Clinical presentations included 22 parotid abscesses, 16 neck abscesses and 11 suppurative lymphadenitis cases. Only 35 patients (71 per cent) had high indirect haemagglutination assay titres of ≥ 1:160 (95 per cent confidence interval = 45.35-88.28). Almost half of the patients received intravenous ceftazidime and subsequently oral co-trimoxazole. Oral antibiotic regimens were prescribed for mild localised melioidosis. Overall, 95.65 per cent of patients were in remission and no relapses were observed (95 per cent confidence interval = 85.47-98.80).
CONCLUSION: Careful clinical correlation and proper investigation are required to establish an early diagnosis of melioidosis and to initiate appropriate treatment.

PMID: 30180912 [PubMed - as supplied by publisher]

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State-of-the-art strategies for targeting the DNA damage response in cancer.

State-of-the-art strategies for targeting the DNA damage response in cancer.

Nat Rev Clin Oncol. 2018 Oct 24;:

Authors: Pilié PG, Tang C, Mills GB, Yap TA

Abstract
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

PMID: 30356138 [PubMed - as supplied by publisher]

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BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer.

BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer.

Gene. 2018 Dec 15;678:302-311

Authors: M JR, S V

Abstract
BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance and cancer stemness. Overexpression is observed in various cancer types such as breast, primary hepatocellular carcinoma (HCC), gastric, ovarian, head and neck, pancreatic and lung cancer. Studies have shown that experimental reduction of BMI protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increases susceptibility to cytotoxic agents and radiation therapy. Thus, inhibition of BMI1 expression particularly in breast cancer stem cells can be used as a potential strategy for the complete elimination of tumor and to prevent disease relapse. On other hand PTEN is known to be an important tumor suppressor next to p53. In many cancers particularly in breast cancer, p53 and PTEN undergo mutations. Studies have indicated the functional and mechanistic link between the BMI-1oncoprotein and tumor suppressor PTEN in the development and progression of cancer. The current review focuses on recent findings of how oncogenicity and chemo-resistance are caused by BMI1. It also highlights the transcriptional regulation between BMI1 and PTEN that dictates the therapeutic outcome in cancers where the functional p53 is absent. Herein, we have clearly demonstrated the regulation of transcription at genomic loci of BMI1 and PTEN in cancerous tissue or cells and the possible epigenetic regulation by histone deacetylase inhibitors (HDACi) at BMI1 and PTEN loci that may provide some clue for the possible therapy against TNBC in near future.

PMID: 30096458 [PubMed - indexed for MEDLINE]

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Effects of electromagnetic field, cisplatin and morphine on cytotoxicity and expression levels of DNA repair genes.

Effects of electromagnetic field, cisplatin and morphine on cytotoxicity and expression levels of DNA repair genes.

Mol Biol Rep. 2018 Oct;45(5):807-814

Authors: Sanie-Jahromi F, Saadat M

Abstract
Morphine (Mor) is widely used as an analgesic drug in cancers and in combination with chemotherapy is known to have DNA damaging effects on non-targeted cell. This study surveyed the effect of Mor in combination with 50-Hz electromagnetic field (EMF) and co-treatment of cisplatin in combination with Mor and EMF on the expression of genes involved in DNA repair pathways. MCF-7 and SH-SY5Y cells were treated with 5.0 µM Mor and then exposed to 50-Hz 0.50 mT EMF in the intermittent pattern of 15 min field-on/15 min field-off. Gene expression, cisplatin and bleomycin cytotoxicity were measured using real-time PCR and MTT assay. Mor treated cells showed significant down-regulation of the examined genes, while in "Mor + EMF" treatments the genes were not significantly changed. IC50 of cisplatin was significantly elevated in both cell lines when co-treated with "Mor + EMF" compared with Mor treated cells. Non-homologous end joining (NHEJ) related genes were significantly decreased in co-treatment of cisplatin and "Mor + EMF" which led to bleomycin higher cytotoxicity in SH-SY5Y not in MCF-7. Our data is promising for providing a cell line-specific sensitization by combination of cisplatin and "Mor + EMF" treatment with local administration of double strand breaking agents.

PMID: 29968116 [PubMed - indexed for MEDLINE]

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Novel biomarkers in bladder cancer.

Novel biomarkers in bladder cancer.

Urol Oncol. 2018 03;36(3):115-119

Authors: Cheng ML, Iyer G

Abstract
A sea change has occurred in the treatment options available for metastatic urothelial bladder cancer with the recent Food and Drug Administration approval of 5 immune checkpoint blockade agents for patients who have progressed on platinum-based chemotherapy or are not candidates for cisplatin. Additionally, comprehensive characterization of the landscape of genomic alterations in this disease through The Cancer Genome Atlas and other efforts has detected numerous potential targets for small molecule inhibitors. Detailed analysis of the urothelial carcinoma transcriptome has allowed for molecular subtyping of the disease and the ramifications of these subtypes upon treatment response is an active area of investigation. Coupled with these advances is a critical unmet need to define predictive biomarkers of response to therapy. Here, we highlight select research relevant to the validation and continued discovery of novel biomarkers to advance precision oncology in bladder cancer.

PMID: 29472156 [PubMed - indexed for MEDLINE]

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Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells.

Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells.

Genome Med. 2018 01 04;10(1):2

Authors: Kundu S, Ali MA, Handin N, Padhan N, Larsson J, Karoutsou M, Ban K, Wiśniewski JR, Artursson P, He L, Hellström M, Sjöblom T

Abstract
BACKGROUND: The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway.
METHODS: To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted.
RESULTS: Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells.
CONCLUSIONS: This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

PMID: 29301589 [PubMed - indexed for MEDLINE]

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The development of PARP as a successful target for cancer therapy.

The development of PARP as a successful target for cancer therapy.

Expert Rev Anticancer Ther. 2018 02;18(2):161-175

Authors: Ferrara R, Simionato F, Ciccarese C, Grego E, Cingarlini S, Iacovelli R, Bria E, Tortora G, Melisi D

Abstract
INTRODUCTION: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents.

PMID: 29260919 [PubMed - indexed for MEDLINE]

https://ift.tt/2BS2ETE

NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies.

NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies.

Front Immunol. 2018;9:2290

Authors: Flórez-Álvarez L, Hernandez JC, Zapata W

Abstract
NK cells play a key role in immune response against HIV infection. These cells can destroy infected cells and contribute to adequate and strong adaptive immune responses, by acting on dendritic, T, B, and even epithelial cells. Increased NK cell activity reflected by higher cytotoxic capacity, IFN-γ and chemokines (CCL3, CCL4, and CCL5) production, has been associated with resistance to HIV infection and delayed AIDS progression, demonstrating the importance of these cells in the antiviral response. Recently, a subpopulation of NK cells with adaptive characteristics has been described and associated with lower HIV viremia and control of infection. These evidences, together with some degree of protection shown in vaccine trials based on boosting NK cell activity, suggest that these cells can be a feasible option for new treatment and vaccination strategies to overcome limitations that, classical vaccination approaches, might have for this virus. This review is focus on the NK cells role during the immune response against HIV, including all the effector mechanisms associated to these cells; in addition, changes including phenotypic, functional and frequency modifications during HIV infection will be pointed, highlighting opportunities to vaccine development based in NK cells effector functions.

PMID: 30386329 [PubMed - in process]

https://ift.tt/2Oninfp

Development of a TCR multimer with high avidity for detecting a naturally presented tumor-associated antigen on osteosarcoma cells.

Development of a TCR multimer with high avidity for detecting a naturally presented tumor-associated antigen on osteosarcoma cells.

Cancer Sci. 2018 Oct 30;:

Authors: Watanabe K, Tsukahara T, Toji S, Saitoh S, Hirohashi Y, Nakatsugawa M, Kubo T, Kanaseki T, Kameshima H, Terui T, Sato N, Torigoe T

Abstract
For the efficacy of peptide vaccination immunotherapy for patients with cancer, endogenous expression of the target peptide/HLA on cancer cells is required. However, it is difficult to evaluate the expression status of a peptide/HLA complex because of the lack of a soluble T cell receptor (TCR) that reacts with TAA with high avidity. In this study, we developed two soluble TCR-multimers that were each directed to tumor-associated antigens (TAAs), survivin2B and PBF in the context of HLA-A24 (SVN-2B TCR-multimer and PBF TCR-multimer, respectively), from CTL clones that were established from peptide-vaccinated patients. Both TCR multimers could recognize cognate peptide-pulsed antigen presenting cells, C1R-A24 cells, in a CD8-independent manner. Moreover, the PBF TCR-multimer successfully recognized a PBF peptide naturally presented on HLA-A24+ PBF+ osteosarcoma cells. Taken together, the results indicated that a TCR-multimer might be useful for detection of a TAA-derived peptide presented by HLA in patients receiving immunotherapy. This article is protected by copyright. All rights reserved.

PMID: 30375705 [PubMed - as supplied by publisher]

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Anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) liposomes induce antigen-specific regulatory T cells and prevent atherosclerosis in mice.

Anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) liposomes induce antigen-specific regulatory T cells and prevent atherosclerosis in mice.

J Control Release. 2018 Oct 23;291:135-146

Authors: Benne N, van Duijn J, Lozano Vigario F, Leboux RJT, van Veelen P, Kuiper J, Jiskoot W, Slütter B

Abstract
Atherosclerosis is the predominant underlying pathology of many types of cardiovascular disease and is one of the leading causes of death worldwide. It is characterized by the retention of oxidized low-density lipoprotein (ox-LDL) in lipid-rich macrophages (foam cells) in the intima of arteries. Autoantigens derived from oxLDL can be used to vaccinate against atherosclerosis. However, a major challenge is the induction of antigen-specific Tregs in a safe and effective way. Here we report that liposomes containing the anionic phospholipid 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) induce Tregs that are specific for the liposomes' cargo. Mechanistically, we show a crucial role for the protein corona that forms on the liposomes in the circulation, as uptake of DSPG-liposomes by antigen-presenting cells is mediated via complement component 1q (C1q) and scavenger receptors (SRs). Vaccination of atherosclerotic mice on a western-type diet with DSPG-liposomes encapsulating an LDL-derived peptide antigen significantly reduced plaque formation by 50% and stabilized the plaques, and reduced serum cholesterol concentrations. These results indicate that DSPG-liposomes have potential as a delivery system in vaccination against atherosclerosis.

PMID: 30365993 [PubMed - as supplied by publisher]

https://ift.tt/2DlcMp1

Class-B CpG-ODN Formulated With a Nanostructure Induces Type I Interferons-Dependent and CD4+ T Cell-Independent CD8+ T-Cell Response Against Unconjugated Protein Antigen.

Class-B CpG-ODN Formulated With a Nanostructure Induces Type I Interferons-Dependent and CD4+ T Cell-Independent CD8+ T-Cell Response Against Unconjugated Protein Antigen.

Front Immunol. 2018;9:2319

Authors: Chiodetti AL, Sánchez Vallecillo MF, Dolina JS, Crespo MI, Marin C, Schoenberger SP, Allemandi DA, Palma SD, Pistoresi-Palencia MC, Morón G, Maletto BA

Abstract
There is a need for new vaccine adjuvant strategies that offer both vigorous antibody and T-cell mediated protection to combat difficult intracellular pathogens and cancer. To this aim, we formulated class-B synthetic oligodeoxynucleotide containing unmethylated cytosine-guanine motifs (CpG-ODN) with a nanostructure (Coa-ASC16 or coagel) formed by self-assembly of 6-0-ascorbyl palmitate ester. Our previous results demonstrated that mice immunized with ovalbumin (OVA) and CpG-ODN formulated with Coa-ASC16 (OVA/CpG-ODN/Coa-ASC16) elicited strong antibodies (IgG1 and IgG2a) and Th1/Th17 cellular responses without toxic systemic effects. These responses were superior to those induced by a solution of OVA with CpG-ODN or OVA/CpG-ODN formulated with aluminum salts. In this study, we investigated the capacity of this adjuvant strategy (CpG-ODN/Coa-ASC16) to elicit CD8+ T-cell response and some of the underlying cellular and molecular mechanisms involved in adaptive response. We also analyzed whether this adjuvant strategy allows a switch from an immunization scheme of three-doses to one of single-dose. Our results demonstrated that vaccination with OVA/CpG-ODN/Coa-ASC16 elicited an antigen-specific long-lasting humoral response and importantly-high quality CD8+ T-cell immunity with a single-dose immunization. Moreover, Coa-ASC16 promoted co-uptake of OVA and CpG-ODN by dendritic cells. The CD8+ T-cell response induced by OVA/CpG-ODN/Coa-ASC16 was dependent of type I interferons and independent of CD4+ T-cells, and showed polyfunctionality and efficiency against an intracellular pathogen. Furthermore, the cellular and humoral responses elicited by the nanostructured formulation were IL-6-independent. This system provides a simple and inexpensive adjuvant strategy with great potential for future rationally designed vaccines.

PMID: 30364187 [PubMed - in process]

https://ift.tt/2JCjgQK

Empowering dendritic cell cancer vaccination: the role of combinatorial strategies.

Empowering dendritic cell cancer vaccination: the role of combinatorial strategies.

Cytotherapy. 2018 Oct 22;:

Authors: Galati D, Zanotta S

Abstract
Dendritic cells (DCs) are bone marrow-derived immune cells that play a crucial role in inducing the adaptive immunity and supporting the innate immune response independently from T cells. In the last decade, DCs have become a hopeful instrument for cancer vaccines that aims at re-educating the immune system, leading to a potent anti-cancer immune response able to overcome the immunosuppressive tumor microenvironment (TME). Although several studies have indicated that DC-based vaccines are feasible and safe, the clinical advantages of DC vaccination as monotherapy for most of the neoplasms remain a distant target. Recently, many reports and clinical trials have widely used innovative combinatorial therapeutic strategies to normalize the immune function in the TME and synergistically enhance DC function. This review will describe the most relevant and updated evidence of the anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines.

PMID: 30360963 [PubMed - as supplied by publisher]

https://ift.tt/2DlcVJ5

A Novel Human Papillomavirus 16 L1 Pentamer-Loaded Hybrid Particles Vaccine System: Influence of Size on Immune Responses.

A Novel Human Papillomavirus 16 L1 Pentamer-Loaded Hybrid Particles Vaccine System: Influence of Size on Immune Responses.

ACS Appl Mater Interfaces. 2018 Oct 15;:

Authors: Jia C, Yang T, Liu Y, Zhu A, Yin F, Wang Y, Xu L, Wang Y, Yan M, Cai Q, Liang X, Ju R, Chen J, Wang L

Abstract
Cervical cancer remains the second-most prevalent female malignancy around the world, leading to a great majority of cancer-related mortality that occurs mainly in developing countries. Developing an effective and low-cost vaccine against human papillomavirus (HPV) infection, especially in medically underfunded areas, is urgent. Compared with vaccines based on HPV L1 viruslike particles (VLPs) in the market, recombinant HPV L1 pentamer expressed in Escherichia coli represents a promising and potentially cost-effective vaccine for preventing HPV infection. Hybrid particles comprising a polymer core and lipid shell have shown great potential compared to conventional aluminum salts adjuvant and is urgently needed for HPV L1 pentamer vaccines. It is well-reported that particle sizes are crucial in regulating immune responses. Nevertheless, reports on the relationship between the particulate size and the resultant immune response have been in conflict, and there is no answer to how the size of particles regulates specific immune response for HPV L1 pentamer-based candidate vaccines. Here, we fabricated HPV 16 L1 pentamer-loaded poly(d,l-lactide- co-glycolide) (PLGA)/lecithin hybrid particles with uniform sizes (0.3, 1, and 3 μm) and investigated the particle size effects on antigen release, activation of lymphocytes, dendritic cells (DCs) activation and maturation, follicular helper CD4+ T (TFH) cells differentiation, and release of pro-inflammatory cytokines and chemokines. Compared with the other particle sizes, 1 μm particles induced more powerful antibody protection and yielded more persistent antibody responses, as well as more heightened anamnestic responses upon repeat vaccination. The superior immune responses might be attributed to sustainable antigen release and robust antigen uptake and transport and then further promoted a series of cascade reactions, including enhanced DCs maturation, increased lymphocytes activation, and augmented TFH cells differentiation in draining lymph nodes (DLNs). Here, a powerful and economical platform for HPV vaccine and a comprehensive understanding of particle size effect on immune responses for HPV L1 pentamer-based candidate vaccines are provided.

PMID: 30360122 [PubMed - as supplied by publisher]

https://ift.tt/2RkdKEV

Further clinical advancement of dendritic cell vaccination against ovarian cancer.

Further clinical advancement of dendritic cell vaccination against ovarian cancer.

Ann Res Hosp. 2018 Aug;2:

Authors: Morehead LC, Cannon MJ

PMID: 30345421 [PubMed]

https://ift.tt/2DlyGID

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time.

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time.

Front Immunol. 2018;9:2265

Authors: van Willigen WW, Bloemendal M, Gerritsen WR, Schreibelt G, de Vries IJM, Bol KF

Abstract
Immune checkpoint inhibitors propelled the field of oncology with clinical responses in many different tumor types. Superior overall survival over chemotherapy has been reported in various metastatic cancers. Furthermore, prolonged disease-free and overall survival have been reported in the adjuvant treatment of stage III melanoma. Unfortunately, a substantial portion of patients do not obtain a durable response. Therefore, additional strategies for the treatment of cancer are still warranted. One of the numerous options is dendritic cell vaccination, which employs the central role of dendritic cells in activating the innate and adaptive immune system. Over the years, dendritic cell vaccination was shown to be able to induce an immunologic response, to increase the number of tumor infiltrating lymphocytes and to provide overall survival benefit for at least a selection of patients in phase II studies. However, with the success of immune checkpoint inhibition in several malignancies and considering the plethora of other treatment modalities being developed, it is of utmost importance to delineate the position of dendritic cell therapy in the treatment landscape of cancer. In this review, we address some key questions regarding the integration of dendritic cell vaccination in future cancer treatment paradigms.

PMID: 30327656 [PubMed - in process]

https://ift.tt/2PGG2ZI

Immunodiagnostics and Immunotherapy Possibilities for Prostate Cancer.

Immunodiagnostics and Immunotherapy Possibilities for Prostate Cancer.

Adv Exp Med Biol. 2018;1096:185-194

Authors: Schatten H

Abstract
Despite significant progress in early detection and improved treatment modalities prostate cancer remains the second leading cause of cancer death in American men which results in about 30,000 deaths per year in the USA. An aggressive phenotype leading to 2.58% risk of dying from prostate cancer still exists and immunotherapy has offered new possibilities to treat metastatic prostate cancer that cannot be treated by other modalities. Cancer immunotherapy is a rapidly growing field of research aimed at identifying biomarkers in immunodiagnosis and to develop new therapies by enabling the immune system to detect and destroy cancer cells. Immunotherapy falls into three different broad categories which are checkpoint inhibitors, cytokines, and vaccine immunotherapy. While immunotherapy to treat prostate cancer is still limited progress has been made; for treatment of advanced prostate cancer sipuleucel-T has been administered to patients in personalized doses to destroy prostate cancer cells which is promising and invites further research to determine immunotherapies for advanced prostate cancer. Antibody-based targeted immunotherapy and dendritic-cell-based vaccination are among the therapies that are currently being evaluated as promising approaches to treat prostate cancer. Combination immunotherapies include prostate cancer vaccines and radiotherapy for castration resistant prostate cancer. Microbial vectors for prostate cancer immunotherapy have been developed and bacterial strains have been engineered to express cancer-specific antigens, cytokines, and prodrug-converting cytokines. These approaches are addressed in the present review.

PMID: 30324354 [PubMed - in process]

https://ift.tt/2Dl2FjN

The Nontoxic Cholera B Subunit Is a Potent Adjuvant for Intradermal DC-Targeted Vaccination.

The Nontoxic Cholera B Subunit Is a Potent Adjuvant for Intradermal DC-Targeted Vaccination.

Front Immunol. 2018;9:2212

Authors: Antonio-Herrera L, Badillo-Godinez O, Medina-Contreras O, Tepale-Segura A, García-Lozano A, Gutierrez-Xicotencatl L, Soldevila G, Esquivel-Guadarrama FR, Idoyaga J, Bonifaz LC

Abstract
CD4+ T cells are major players in the immune response against several diseases; including AIDS, leishmaniasis, tuberculosis, influenza and cancer. Their activation has been successfully achieved by administering antigen coupled with antibodies, against DC-specific receptors in combination with adjuvants. Unfortunately, most of the adjuvants used so far in experimental models are unsuitable for human use. Therefore, human DC-targeted vaccination awaits the description of potent, yet nontoxic adjuvants. The nontoxic cholera B subunit (CTB) can be safely used in humans and it has the potential to activate CD4+ T cell responses. However, it remains unclear whether CTB can promote DC activation and can act as an adjuvant for DC-targeted antigens. Here, we evaluated the CTB's capacity to activate DCs and CD4+ T cell responses, and to generate long-lasting protective immunity. Intradermal (i.d.) administration of CTB promoted late and prolonged activation and accumulation of skin and lymphoid-resident DCs. When CTB was co-administered with anti-DEC205-OVA, it promoted CD4+ T cell expansion, differentiation, and infiltration to peripheral nonlymphoid tissues, i.e., the skin, lungs and intestine. Indeed, CTB promoted a polyfunctional CD4+ T cell response, including the priming of Th1 and Th17 cells, as well as resident memory T (RM) cell differentiation in peripheral nonlymphoid tissues. It is worth noting that CTB together with a DC-targeted antigen promoted local and systemic protection against experimental melanoma and murine rotavirus. We conclude that CTB administered i.d. can be used as an adjuvant to DC-targeted antigens for the induction of broad CD4+ T cell responses as well as for promoting long-lasting protective immunity.

PMID: 30319653 [PubMed - in process]

https://ift.tt/2JAtn8t

Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.

Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.

Cancer Immunol Immunother. 2018 Oct 10;:

Authors: Zhang W, Lu X, Cui P, Piao C, Xiao M, Liu X, Wang Y, Wu X, Liu J, Yang L

Abstract
Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-γ assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.

PMID: 30306202 [PubMed - as supplied by publisher]

https://ift.tt/2DlcG0D

Visualisation and characterisation of mononuclear phagocytes in the chicken respiratory tract using CSF1R-transgenic chickens.

Visualisation and characterisation of mononuclear phagocytes in the chicken respiratory tract using CSF1R-transgenic chickens.

Vet Res. 2018 Oct 10;49(1):104

Authors: Sutton K, Costa T, Alber A, Bryson K, Borowska D, Balic A, Kaiser P, Stevens M, Vervelde L

Abstract
The respiratory tract is a key organ for many avian pathogens as well as a major route for vaccination in the poultry industry. To improve immune responses after vaccination of chickens through increased uptake of vaccines and targeting to antigen presenting cells, a better understanding of the avian respiratory immune system is required. Transgenic MacReporter birds were used expressing a reporter gene (eGFP or mApple) under the control of the CSF1R promoter and enhancer in cells of the mononuclear phagocyte (MNP) lineage to visualize the ontogeny of the lymphoid tissue, macrophages and dendritic cells, in the trachea, lung and air sac of birds from embryonic day 18-63 weeks of age. Small aggregates of CSF1R-transgene+ cells start to form at the openings of the secondary bronchi at 1 week of age, indicative of the early development of the organised bronchus-associated lymphoid tissue. Immunohistochemical staining revealed subpopulations of MNPs in the lung, based on expression of CSF1R-transgene, CD11, TIM4, LAMP1, and MHC II. Specialised epithelial cells or M cells covering the bronchus-associated lymphoid tissue expressed CSF1R-transgene and type II pneumocytes expressed LAMP1 suggesting that these epithelial cells are phagocytic and transcytose antigen. Highly organised lymphoid tissue was seen in trachea from 4 weeks onwards. Throughout the air sacs at all ages, CSF1R-transgene+ cells were scattered and at later stages, CSF1R-transgene+ cells lined capillaries. These results will serve as a base for further functional characterization of macrophages and dendritic cells and their role in respiratory diseases and vaccine responses.

PMID: 30305141 [PubMed - in process]

https://ift.tt/2JCzR6F

System immunology-based identification of blood transcriptional modules correlating to antibody responses in sheep.

System immunology-based identification of blood transcriptional modules correlating to antibody responses in sheep.

NPJ Vaccines. 2018;3:41

Authors: Braun RO, Brunner L, Wyler K, Auray G, García-Nicolás O, Python S, Zumkehr B, Gaschen V, Stoffel MH, Collin N, Barnier-Quer C, Bruggmann R, Summerfield A

Abstract
Inactivated vaccines lack immunogenicity and therefore require potent adjuvants. To understand the in vivo effects of adjuvants, we used a system immunology-based analysis of ovine blood transcriptional modules (BTMs) to dissect innate immune responses relating to either antibody or haptoglobin levels. Using inactivated foot-and-mouth disease virus as an antigen, we compared non-adjuvanted to liposomal-formulated vaccines complemented or not with TLR4 and TLR7 ligands. Early after vaccination, BTM relating to myeloid cells, innate immune responses, dendritic cells, and antigen presentation correlated positively, whereas BTM relating to T and natural killer cells, as well as cell cycle correlated negatively with antibody responses. Interestingly, similar BTM also correlated with haptoglobin, but in a reversed manner, indicating that acute systemic inflammation is not beneficial for early antibody responses. Analysis of vaccine-dependent BTM modulation showed that liposomal formulations induced similar responses to those correlating to antibody levels. Surprisingly, the addition of the TLR ligands appeared to reduce early immunological perturbations and mediated anti-inflammatory effects, despite promoting antibody responses. When pre-vaccination BTM were analyzed, we found that high vaccine responders expressed higher levels of many BTM relating to cell cycle, antigen-presenting cells, and innate responses as compared with low responders. In conclusion, we have transferred human BTM to sheep and identified early vaccine-induced responses associated with antibody levels or unwanted inflammation in a heterogeneous and small group of animals. Such readouts are applicable to other veterinary species and very useful to identify efficient vaccine adjuvants, their mechanism of action, and factors related to low responders.

PMID: 30302283 [PubMed]

https://ift.tt/2A5FeIH

Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial.

Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial.

Cancers (Basel). 2018 Oct 05;10(10):

Authors: Buchroithner J, Erhart F, Pichler J, Widhalm G, Preusser M, Stockhammer G, Nowosielski M, Iglseder S, Freyschlag CF, Oberndorfer S, Bordihn K, von Campe G, Hoffermann M, Ruckser R, Rössler K, Spiegl-Kreinecker S, Fischer MB, Czech T, Visus C, Krumpl G, Felzmann T, Marosi C

Abstract
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3⁻20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436⁻671 versus control: 568 days, 95% CI: 349⁻680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.

PMID: 30301187 [PubMed]

https://ift.tt/2JGbMMA

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion.

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion.

Cancer Immunol Immunother. 2018 Oct;67(10):1545-1558

Authors: Löhr M, Freitag B, Technau A, Krauss J, Monoranu CM, Rachor J, Lutz MB, Hagemann C, Kessler AF, Linsenmann T, Wölfl M, Ernestus RI, Engelhardt S, Gelbrich G, Schlegel PG, Eyrich M

Abstract
High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ+ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4+/CD8+ T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (Treg). In parallel to Treg-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8+VLA-4+ T-cells with CNS-homing properties, but not of CD4+ VLA-4+ T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.

PMID: 30054667 [PubMed - indexed for MEDLINE]

https://ift.tt/2LKpktD

pH Sensitive phosphorylated chitosan hydrogel as vaccine delivery system for intramuscular immunization.

pH Sensitive phosphorylated chitosan hydrogel as vaccine delivery system for intramuscular immunization.

J Biomater Appl. 2017 05;31(10):1358-1369

Authors: Wei J, Xue W, Yu X, Qiu X, Liu Z

Abstract
In the field of immunotherapy, immune vaccinations have received more and more attention for disease prevention and treatment. In immune vaccination, efficient vaccine adjuvants are necessary due to the weak immunogenicity of vaccines. Some traditional vaccine adjuvants have been widely used but have shown obvious limitations such as poor biosafety. Therefore, researchers make a great effort to develop more functional novel immune adjuvants such as chitosan-based immune adjuvants. However, chitosan is poorly water soluble, which greatly limits its application as immune adjuvants, regardless of its good biocompatibility, biodegradability, and other biological activities. In this work, we prepared a water-soluble chitosan derivative phosphorylated chitosan (PCS) and evaluated its potential as a novel immune adjuvant. PCS was found to be pH sensitive: specifically, it was water soluble at pH < 7.0 but began to gel at pH >7.0. By virtue of this, neutral PCS aqueous solutions containing ovalbumin (OVA) antigen was intramuscularly injected into test mice, which would transform to an OVA-containing gel network for OVA immunization. The results showed that the use of 30 mg/mL PCS-based hydrogel as vaccine delivery system contributed to significantly higher level of antigen-specific immune responses, including higher level of antigen-specific IgG antibodies, IFN-γ and IL-4 cytokines secretion by splenocytes, as well as memory CD4+ and CD8+ T cells. In vivo imaging and immunohistochemistry assays suggest that the improved immunization efficacy may be attributed to the controlled release of antigen from injection site by PCS gel network, and then prolonged antigen stimuli to the immune system. From the results, PCS could be developed as a promising vaccine delivery system for immunotherapy.

PMID: 28387574 [PubMed - indexed for MEDLINE]

https://ift.tt/2QFqxBk

An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity.

An Engineered Herpesvirus Activates Dendritic Cells and Induces Protective Immunity.

Sci Rep. 2017 02 02;7:41461

Authors: Ma Y, Chen M, Jin H, Prabhakar BS, Valyi-Nagy T, He B

Abstract
Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. While attenuated HSV is explored for vaccine, the underlying event remains poorly defined. Here we report that recombinant HSV-1 with a mutation in the γ134.5 protein, a virulence factor, stimulates dendritic cell (DC) maturation which is dependent on TANK-binding kinase 1 (TBK1). When exposed to CD11+ DCs, the mutant virus that lacks the amino terminus of γ134.5 undergoes temporal replication without production of infectious virus. Mechanistically, this leads to sequential phosphorylation of interferon regulatory factor 3 (IRF3) and p65/RelA. In correlation, DCs up-regulate the expression of co-stimulatory molecules and cytokines. However, selective inhibition of TBK1 precludes phosphorylation of IRF3 and subsequent DC activation by the γ134.5 mutant. Herein, the γ134.5 mutant is immune-stimulatory and non-destructive to DCs. Remarkably, upon immunization the γ134.5 mutant induces protection against lethal challenge by the wild type virus, indicative of its vaccine potential. Furthermore, CD11+ DCs primed by the γ134.5 mutant in vivo mediate protection upon adoptive transfer. These results suggest that activation of TBK1 by engineered HSV is crucial for DC maturation, which may contribute to protective immunity.

PMID: 28150813 [PubMed - indexed for MEDLINE]

https://ift.tt/2k58IM8

Intein-mediated backbone cyclization of VP1 protein enhanced protection of CVB3-induced viral myocarditis.

Intein-mediated backbone cyclization of VP1 protein enhanced protection of CVB3-induced viral myocarditis.

Sci Rep. 2017 02 02;7:41485

Authors: Qi X, Xiong S

Abstract
CVB3 is a common human pathogen to be highly lethal to newborns and causes viral myocarditis and pancreatitis in adults. However, there is no vaccine available for clinical use. CVB3 capsid protein VP1 is an immunodominant structural protein, containing several B- and T-cell epitopes. However, immunization of mice with VP1 protein is ineffective. Cyclization of peptide is commonly used to improve their in vivo stability and biological activity. Here, we designed and synthesizd cyclic VP1 protein by using engineered split Rma DnaB intein and the cyclization efficiency was 100% in E. coli. As a result, the cyclic VP1 was significantly more stable against irreversible aggregation upon heating and against carboxypeptidase in vitro and the degradation rate was more slowly in vivo. Compared with linear VP1, immunization mice with circular VP1 significantly increased CVB3-specific serum IgG level and augmented CVB3-specific cellular immune responses, consequently afforded better protection against CVB3-induced viral myocarditis. The cyclic VP1 may be a novel candidate protein vaccine for preventing CVB3 infection and similar approaches could be employed to a variety of protein vaccines to enhance their protection effect.

PMID: 28148910 [PubMed - indexed for MEDLINE]

https://ift.tt/2JCY7pg

High frequency and molecular epidemiology of metallo-β-lactamase-producing gram-negative bacilli in a tertiary care hospital in Lahore, Pakistan

Metallo-β-lactamase (MBL)-producing isolates have a strong impact on diagnostic and therapeutic decisions. A high frequency of MBL-producing gram-negative bacilli has been reported worldwide. The current study...

https://ift.tt/2D1LXVZ

Low self-reported sports activity before stroke predicts poor one-year-functional outcome after first-ever ischemic stroke in a population-based stroke register

Physical activity (PA) is associated with lower risk of stroke. We tested the hypothesis that lack of pre-stroke PA is an independent predictor of poor outcome after first-ever ischemic stroke.

https://ift.tt/2P6C28F

Posterior reversible encephalopathy syndrome complicated with subarachnoid hemorrhage in an eclamptic pregnant patient: case report

Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic condition which comprises various neurological symptoms. This syndrome could be complicated by intracranial hemorrhage including subarachnoid...

https://ift.tt/2D1Yd8D

Bacteremia by Leuconostoc mesenteroides in an immunocompetent patient with chronic Chagas disease: a case report

The Leuconostoc mesenteroides are members of the Streptococcae family and currently has been recognized as potential pathogens. This case describes a bacteremia caused by L. mesenteroides in an immunocompetent pa...

https://ift.tt/2qrKpwI

Epidemiology of HIV, syphilis, and hepatitis B and C among manual cane cutters in low-income regions of Brazil

In recent decades the epidemic of asymptomatic sexually transmitted infections has extended deep into Brazil, including small towns and rural areas. The purpose of this study was to investigate the epidemiolog...

https://ift.tt/2QduRYF

Outbreak of yellow fever in central and southwestern Uganda, February–may 2016

On 28 March, 2016, the Ministry of Health received a report on three deaths from an unknown disease characterized by fever, jaundice, and hemorrhage which occurred within a one-month period in the same family ...

https://ift.tt/2qtKAI4

Zoonotic disease research in East Africa

The East African region is endemic with multiple zoonotic diseases and is one of the hotspots for emerging infectious zoonotic diseases with reported multiple outbreaks of epidemic diseases such as Ebola, Marb...

https://ift.tt/2QisZht

Brief summary of French guidelines for the prevention, diagnosis and treatment of hospital-acquired pneumonia in ICU

The French Society of Anaesthesia and Intensive Care Medicine and the French Society of Intensive Care edited guidelines focused on hospital-acquired pneumonia (HAP) in intensive care unit. The goal of 16 Fren...

https://ift.tt/2QhZZXj

CX-3543 Promotes Cell Apoptosis through Downregulation of CCAT1 in Colon Cancer Cells

Aim. Colon cancer-associated transcript-1 (CCAT1), located in the vicinity of transcription factor c-Myc, was first identified in colon cancer. A small-molecule compound CX3543 (Quarfloxin) selectively targeting Myc G-quadruplexes has entered phase II clinical trials for neuroendocrine carcinomas. The aim of the study was to explore the relationship between CX3543, CCAT1, and cell apoptosis in colon cancer cells. Methods. Semiquantitative PCR was used to detect the relative expression of CCAT1 in colon cancer (CC) tissues and HT29 cell lines. Real-time PCR (RT-PCR) was also used to investigate the expression of CCAT1 and c-Myc after HT29 cells being treated by CX3543 for 24 h. Cell apoptosis assay and cell proliferation assay were conducted in HT29 cells after being treated by CX3543. Results. The results showed that the expression of CCAT1 was remarkably increased in CC tissues and HT29 cells compared to controls. CX3543 treatment reduced the expression of c-Myc and CCAT1 and promoted cell apoptosis and inhibited cell proliferation. After the expression of CCAT1 was inhibited by sh-CCAT1 transfection, the cell apoptosis rate was higher than that of control group. After the cells were treated by CCAT1 overexpression plasmid transfection and CX3543, the cell apoptosis rate was lower than that of control group. In vivo results showed that CX3543 inhibited the xenograft tumor growth of rats through downregulation of CCAT1. Conclusion. Our study demonstrated that CX3543 could inhibit the progression of colon cancer by downregulating CCAT1 expression and might be a potential drug for the treatment of colon cancer.

https://ift.tt/2OnS09a

The Effect of Vitamin E and Metallothionein on the Antioxidant Capacities of Cadmium-Damaged Liver in Grass Carp Ctenopharyngodon idellus

Cadmium (Cd) causes a broad spectrum of toxicological effects to animals. Aquatic animals were more likely to accumulate Cd than terrestrial animals because of the living environment. Clearance of Cd in aquatic animals has become an important part of aquatic food safety. The present study was focused on the oxidative damage induced by Cd in the liver of grass carp Ctenopharyngodon idellus and the protective effect of vitamin E (VE) and metallothionein (MT). Grass carp were divided into four groups: the control group, Cd+phosphate-buffered saline (PBS) group, Cd+VE group, and Cd+MT group. All fish were injected with CdCl2 on the first day and then VE, MT, and PBS were given 4 days after injection, respectively. The liver function and antioxidant capacity of grass carp were evaluated. Cd administration resulted in damage of liver function and morphology in liver, which was expressed as the increased content of AST and ALT, rupture of organelles, and decrease of CAT, SOD, and GSH-Px activity. However, VE and MT treatments protected against Cd-induced damage of liver in grass carp by decreasing AST and ALT content, repairing organelles, and maintained the antioxidant system by elevating CAT, SOD, and GSH-Px activity and regulating related mRNA transcript expression. The results revealed that VE and MT might play an important role in the treatment of heavy metal poisoning through their antioxidative effects.

https://ift.tt/2yPcDpI

Kinetic characterization of acetone monooxygenase from Gordonia sp. strain TY-5

Acetone monooxygenase (ACMO) is a unique member of the Baeyer–Villiger monooxygenase (BVMO) family based on its ability to act on small ketones, such as acetone. Herein, we performed a kinetic analysis of ACMO...

https://ift.tt/2OnzPAE

Palliative Care Use and Patterns of End-of-Life Care in Hospitalized Patients with Calciphylaxis

Calciphylaxis is a rare, debilitating condition characterized by extremely painful ischemic skin lesions and is associated with a one year mortality of 25-80% at the time of diagnosis.1 End stage renal disease (ESRD) patients with calciphylaxis have a worse prognosis than non-ESRD patients with the same condition.1 Additionally, nearly 50% of calciphylaxis patients suffer from limited mobility due to severe pain and more than 70% are hospitalized for severe skin ulcers.1,2 Furthermore, calciphylaxis does not have any approved treatments although agents such as sodium thiosulfate have been reported to ameliorate skin lesions with varying efficacy.

https://ift.tt/2P9zruy

Moderating effects of forgiveness on relationship between empathy and health-related quality of life in hemodialysis patients: a structural equation modeling approach

Health-related quality of life (QOL) is a recommended clinical tool to assess hemodialysis patients and a primary end point to observe the effectiveness of overall disease management. Empathy is associated with positive outcomes such as pain relief and reduced anxiety and distress. Numerous studies have tested the relationships among empathy, forgiveness and QOL; however, a mechanism of forgiveness has not been fully explored in hemodialysis patients.

https://ift.tt/2D1ADsD

Concomitant therapy with direct-acting antivirals and chemoimmunotherapy in HCV-associated diffuse large B-cell lymphoma

The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL.

https://ift.tt/2P5iHog

Long-term follow-up of children and young adults with autoimmune hepatitis treated with cyclosporine

Cyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use.

https://ift.tt/2CXkYL7

FOXRED1 silencing in mice: a possible animal model for Leigh syndrome

Abstract

Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantia nigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for Leigh syndrome due to defective CI, which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.

https://ift.tt/2OnGD0R

A Purification and In Vitro Activity Assay for a (p)ppGpp Synthetase from Clostridium difficile

Here, we describe a method for purifying histidine-tagged pyrophosphokinase enzymes and utilizing thin layer chromatography of radiolabelled substrates and products to assay for the enzymatic activity in vitro. The enzyme activity assay is broadly applicable to any kinase, nucleotide cyclase, or phosphor-transfer reaction whose mechanism includes nucleotide triphosphate hydrolysis.

https://ift.tt/2AJFrla

Database-guided Flow-cytometry for Evaluation of Bone Marrow Myeloid Cell Maturation

The MDS diagnosis is difficult in the absence of morphological criteria or non-informative cytogenetics. MFC could help refine the MDS diagnostic process. To become useful for clinical practice, the MFC analysis must be based on parameters with sufficient specificity and sensitivity, and data should be reproducible between different operators.

https://ift.tt/2OoZicX

Metal Corrosion and the Efficiency of Corrosion Inhibitors in Less Conductive Media

The testing of processes associated with material corrosion can often be difficult especially in non-aqueous environments. Here, we present different methods for short-term and long-term testing of corrosion behavior of non-aqueous environments such as biofuels, especially those containing bioethanol.

https://ift.tt/2CZtjOl

Evaluation of Hot Nodules of Thyroid Gland Using Tc-99m Pertechnetate: a Novel Approach Using Quantitative Single-Photon Emission Computed Tomography/Computed Tomography

Abstract

Planar scintigraphy using Tc-99m pertechnetate is useful for snapshot evaluation of hot thyroid nodules, which are pathologically follicular adenoma and seldom, if ever, malignant. The autonomy of the hot nodules has been demonstrated by the presence of thyroid-stimulating hormone-dependent extra-nodular thyroid tissue besides the hot nodules. Here, we present two cases of hot thyroid nodules in patients who underwent quantitative single-photon emission computed tomography/computed tomography (SPECT/CT). In addition to the nodules, contralateral normal thyroid parenchyma was evaluated based on standardized uptake values. One patient had a traditional follicular adenoma suppressing other thyroid tissue, whereas the other patient seemed to have a nodule erupting from underlying hyperfunctioning, not suppressed, thyroid tissue. This novel approach using quantitative SPECT/CT unveils a new pathology of hot thyroid nodule that does not suppress, but coincides with hyperfunctioning thyroid tissue.

https://ift.tt/2qpUc6H

The Impact of Health Literacy on Health Status and Resource Utilization in Lumbar Degenerative Disease

Publication date: Available online 3 November 2018

Source: The Spine Journal

Author(s): Steven D. Glassman, Leah Y. Carreon, Morgan E. Brown, Jeffrey S. Jones, Jean Edward, Jing Li, Mark V. Williams

ABSTRACT

Background Context

Health literacy, defined as "the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions," has been demonstrated to affect access to care and appropriate healthcare utilization.

Purpose

To determine the impact of health literacy in the evaluation and management of patients with chronic low back pain.

Study design

Cross sectional

Patient sample

Patients seen at a multi-surgeon spine specialty clinic

Outcome measures

Oswestry Disability Index, EQ-5D and Numeric Rating Scales (0 to 10) for back and leg pain

Methods

The Newest Vital Sign (NVS) and Health Literacy Survey (HealthLitt) ODI, EQ-5D and pain scales were administered to patients undergoing evaluation and treatment for lumbar degenerative disease in the outpatient setting. Patients were surveyed regarding their use of medication, therapy and pain management modalities.

Results

Of 201 patients approached for participation, 186 completed the health literacy surveys. Thirty (17%) were assessed as having limited literacy, 52 (28%) as possibly having limited literacy and 104 (56%) having adequate literacy based on their NVS scores. The cohort with low NVS scores also had low HealthLitt Scores. Patients with limited literacy had worse back and leg pain scores compared to patients with possibly limited literacy and adequate literacy.Patients with adequate health literacy were more likely to use medications (80% vs 53%, p=0.017) and were more likely to see a specialist (34% vs. 17%) compared to those with limited literacy. Patients with limited health literacy were not more likely to see a chiropractor (7% vs. 7%), but reported more average visits (19 vs 8).

Conclusion

Patients with lower health literacy reported worse back and leg pain scores, indicating either more severe disease or a fundamental difference in their responses to standard health-related quality of life measures. This study also suggests that patients with limited health literacy may under-utilize some resources and over-utilize other resources. Further study is needed to clarify these patterns, and to examine their impact on health status and clinical outcomes.

https://ift.tt/2zshJHY

Prolonged pain reducing effect of Sodium Hyaluronate-CarboxyMethyl Cellulose solution in the Selective Nerve Root Block(SNRB) of lumbar radiculopathy: A Prospective, Double-Blind, Randomized Controlled Clinical Trial

Publication date: Available online 2 November 2018

Source: The Spine Journal

Author(s): Sangbong Ko, Seungbum Chae, Wonkee Choi, Jaibum Kwon

Abstract

Background

The pattern of linear graph schematized by visual analogue scale (VAS) score displaying pain worsening between 2 days and 2 weeks after selective nerve root block is called rebound pain.

Purpose

The purpose of this study was to determine if sodium hyaluronate and carboxymethyl cellulose solution(HA-CMC sol) injection could reduce the occurrence of rebound pain at 3 days to 2 weeks after selective nerve root block in patients with radiculopathy compared to injection with corticosteroids and local anesthetics alone.

Study Design/Setting

https://ift.tt/2SG2qUZ

A longitudinal study of perinatal depression among Chinese high-risk pregnant women

Publication date: December 2018

Source: Women and Birth, Volume 31, Issue 6

Author(s): Ying Zhao, Michelle L. Munro-Kramer, Shenxun Shi, Jing Wang, Xinli Zhu

Abstract

Background

Information is needed on the prevalence of depression in Chinese women with medically defined complications across the perinatal period, as well as key risk factors to develop appropriate perinatal mental health services and ensure the services target those most in need.

Aim

The goal of this study was to examine whether women's perinatal depression scores change across the perinatal period and evaluate risk factors associated with postnatal depression at 6-weeks after delivery.

Methods

A sample of 167 Chinese pregnant women with medically defined complications and an Edinburgh Postnatal Depression Scale ≥ 9 and/or a Postpartum Depression Screening Scale ≥ 60 were followed throughout early pregnancy (<28 weeks), late pregnancy (>28 weeks), 3-days and 6-weeks after delivery.

Findings

Repeated measures analysis of variance showed that there were significant differences on the Edinburgh Postnatal Depression Scale and Postpartum Depression Screening Scale scores at each time point between high-risk depressed and low-risk depressed groups. Binary logistic regression indicated a significant association between postnatal depression at 6-weeks after delivery and depression in late pregnancy and 3-days after delivery, postnatal stress events, postnatal complications, and concerns about the fetus.

Conclusions

Postnatal depression is a common condition with limited research among Chinese pregnant women with medically defined complications. Additional research is warranted to develop strategies to identify high-risk depressed pregnant women as well as effective treatment options during the perinatal period.

https://ift.tt/2F27yQE

Women’s experiences of having depression during pregnancy and receiving acupuncture treatment—A qualitative study

Publication date: December 2018

Source: Women and Birth, Volume 31, Issue 6

Author(s): Simone M. Ormsby, Hannah G. Dahlen, Caroline A. Smith

Abstract

Background

Research indicates some women experiencing depression during pregnancy are dissatisfied with conventional depression treatments due to incomplete effectiveness, dislike of side effects, unsatisfactory experiences with providers and concerns regarding in-utero and breastfeeding safety. Consequently, many explore alternative options including acupuncture. To further understand women's views, preferences and motivations in this regard, as well as their experiences of receiving acupuncture as part of a three-armed pragmatic randomised controlled trial evaluating acupuncture for antenatal depression in Sydney, Australia, in-depth interviews were conducted with a group of acupuncture recipients.

Methods

Eight participants who had completed the eight-treatment intervention were interviewed. Data was analysed using thematic analysis.

Results

The overarching theme to emerge was that women 'felt trapped between a rock and a hard place', in not wanting to feel the way they did, but also not knowing what else to do, as conventional treatments had been inadequate or unsatisfactory, or were now unacceptable during pregnancy. With a mixture of curiosity and open-mindedness, or scepticism and desperation, the women in this study decided to try acupuncture, to 'give it a go', in the hope of receiving benefits. After treatment, these women reported being surprised by 'gaining relief' from symptoms, that they also felt were cumulative and ongoing.

Conclusions

The women in this study described gaining benefits from acupuncture that they felt enabled them to better manage their lives and the changes that pregnancy brings. These findings provide new understanding regarding the possible role acupuncture could provide as a supportive treatment for antenatal depression.

https://ift.tt/2AJ311p

Getting evidence into practice – Managing hares and tortoises

Publication date: December 2018

Source: Women and Birth, Volume 31, Issue 6

Author(s): Caroline Homer

https://ift.tt/2EYggiE

Pregnant women’s choice of birthing hospital: A qualitative study on individuals’ preferences

Publication date: December 2018

Source: Women and Birth, Volume 31, Issue 6

Author(s): Nasrin Tayyari Dehbarez, Stina Lou, Niels Uldbjerg, Anne Møller, Dorte Gyrd-Hansen, Rikke Søgaard

Abstract

Objective

To investigate pregnant women's decision making in relation to their choice of birthing hospital and, in particular, their priorities regarding hospital characteristics.

Methods

The focus of this study was the choice of birthing hospital among pregnant women. A qualitative interview design was used and women were recruited during their first pregnancy-related visit to a general practitioner. The interviews were conducted using a semi-structured interview guide, and a thematic analysis of the data was carried out.

Results

Women made their hospital choice decision independently and they relied extensively on their own or peers' experiences. Travel distance played a role, but some women were willing to incur longer travel times to give birth at a specialized hospital in order to try to reduce the risks (in case of unexpected events). The women associated the presence of specialized services and staff that were more qualified and experienced with increased safety. Other priorities included continuity of care (i.e., being seen by the same midwife) as well as service availability, which in this case referred to the possibility of a water birth and postnatal hoteling services.

Conclusions

The choice of hospital provider appears to be strongly influenced by experience, whether personal experience or the experience of peers. However, there appears to be room for more information to be provided on safety and service attributes as an instrument for making an informed decision.

https://ift.tt/2AKWQKl

Barriers and enablers for smoking cessation amongst pregnant women: An Umbrella Review

Publication date: Available online 3 November 2018

Source: Women and Birth

Author(s): Melinda J. Barnett, Shanna Fealy, Amanda Wilson

Abstract

Aim

The aim of this study is to summarise the qualitative findings from systematic reviews to identify what pregnant women perceive as barriers and enablers to smoking cessation during pregnancy.

Background

Smoking during pregnancy is a predictor of adverse maternal and infant outcomes. Despite known health risks, less than half of pregnant smokers quit during pregnancy.

Methods

An umbrella review using the Johanna Briggs Institute methodology was conducted. A comprehensive literature review was completed in July 2017. All included papers were subject to an eligibility criterion and checked for quality by at least two reviewers.

Findings

A total of n = 529 papers were identified and screened. Of these, only two met all inclusion and quality criteria and were included for review. More barriers than facilitators were identified from the available literature.

Conclusion

An enabler or barrier to smoking cessation for pregnant women is not a fixed entity but dependent on the context of an individual's life. What is an enabler for one woman may be considered a barrier for another, and these are dependent on support provided by family and friends. Further research is needed to optimise ways of addressing these barriers.

https://ift.tt/2F2RJcy

Synchronous discordant Epstein-Barr virus (EBV)–positive nodal T/NK-cell lymphoma and EBV-positive diffuse large B cell lymphoma in a patient with a history of EBV-positive Burkitt lymphoma

Abstract

In rare cases, patients present with multiple simultaneous lymphomas at one or more anatomic sites. These may be described as composite (occurring at one anatomic site) or discordant (occurring at different anatomic sites). Although the Epstein-Barr virus (EBV) is often implicated in the development of composite lymphoma, its role in the pathogenesis of discordant lymphoma is less clear. We report a case of discordant Epstein-Barr virus–associated lymphoma consisting of nodal T/NK-cell lymphoma and diffuse large B cell lymphoma in a patient with a history of EBV-positive Burkitt lymphoma post treatment. Simultaneous biopsies of the left and right femoral lymph nodes showed a synchronous nodal T/NK-cell lymphoma (left) and diffuse large B cell lymphoma (right). The nodal T/NK-cell lymphoma was morphologically and immunohistochemical distinct from the diffuse large B cell. Both the T/NK-cell component and the B cell component showed bright nuclear positivity with in situ hybridization for EBER. Molecular studies for C-myc were negative. The role played by the Epstein-Barr virus (EBV) in the pathogenesis of discordant T cell and B cell lymphoma is uncertain but may be clinically significant, particularly in the setting of prior EBV-positive lymphoma. Additional testing for immunodeficiency should be considered in these patients.

https://ift.tt/2CZWgd5

MYO18B promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR signaling pathway

MYO18B has been identified as a novel tumor suppressor gene in several cancers. However, its specific roles in the progression of hepatocellular carcinoma (HCC) has not been well defined.

https://ift.tt/2DjYogx

Effects of high fat diet-induced obesity on mammary tumorigenesis in the PyMT/MMTV murine model

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https://ift.tt/2JAchYv

Fingolimod augments Pemetrexed killing of non-small cell lung cancer and overcomes resistance to ERBB inhibition

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https://ift.tt/2DlJ7fr

Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report

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https://ift.tt/2DksLnm

Squamous cell carcinoma-A rare pancreatic exocrine malignancy

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https://ift.tt/2JAc9rZ

Dutch combat operation experiences in Iraq and Afghanistan: The conundrum of low surgical workload deployments

Publication date: Available online 3 November 2018

Source: Injury

Author(s): Christine F.W. Vermeulen, Peter J. Keijzers, Erik H.W.M. Fredriks, Peter van der Hee, Oscar van Waes, Rigo Hoencamp

Abstract

Introduction

The Combined Joined Task Force - Operation Inherent Resolve is the military intervention of Iraq and Coalition Forces in the battle against Islamic State of Iraq and Syria (ISIS). Al Assad Airbase (AAAB) is one of the key airbases. It contains a Role 2 Medical Treatment Facility, primarily to perform Damage Control Surgery in Coalition Forces, Iraqi National Security Forces and Local Nationals. We present a six month medical exposure in order to provide insight into the treatment of casualties and to optimize medical planning of combat operations and (pre-/post-) deployment training.

Patients and Methods

This is a cohort study of casualties that were admitted to the Role 2 Medical Treatment Facility AAAB from November 2017 to April 2018. Their mechanisms and types of injury are described and compared to those sustained in Uruzgan, Afghanistan between 2006-2010. Additionally, they are compared to the caseload in the Dutch civilian medical centers of the medical specialist team at AAAB.

Results

There were significant differences in both mechanism and type of injury between Coalition Forces and Iraqi Security Forces (p = 0.0001). Coalition Forces had 100% disease and non-battle injuries, where Iraqi Security Forces had 86% battle injuries and 14% non-battle casualties. The most common surgical procedures performed were debridement of wounds (38%), (exploratory) laparotomy (10%) and genital procedures (7%). The surgical caseload in Uruzgan, Afghanistan was significantly different in aspect and quantity, being 4.1 times higher. When compared to the workload at home all team members had at least a tenfold lower workload than in their civilian hospitals.

Discussion

The deployed surgical teams were scarcely exposed to casualties at AAAB, Iraq. These low workload deployments could cause a decline in surgical skills. Military medical planning should be tailormade and should include adjusting length of stay, (pre-/post-)deployment refresher training and early consultation of military medical specialists. Future research should focus on optimizing this process by investigating fellowships in combat matching trauma centers, regional and international collaboration and refresher training possibilities to maintain the expertise of the acute military care provider.

https://ift.tt/2CZADJK

Outcomes and Predictors of mortality following periprosthethic proximal femoral fractures

Publication date: Available online 2 November 2018

Source: Injury

Author(s): Adam Tucker, Graham Finlayson, Nicholas D. Black, Sinead McDonald, Mary Molloy, Darrin Wilson

Abstract

Background

Periprosthetic fractures are a well-documented, serious complication of joint arthroplasty, occurring in up to 11% of hip replacements. We examined periprosthetic femoral fractures over an 8 year period to determine the demographics, fracture pattern and management options and associated outcomes. Furthermore, we sought to determine which comorbidities resulted in increased risk of 12 month mortality after periprosthetic fractures about hip replacements

Methods

A retrospective review of a prospective fracture database was conducted for the years 2007-2015. The Fracture Outcomes Research Database (FORD) was interrogated for patients aged >60 years, admitted with periprosthetic hip fracture. Radiographic and Electronic Clinical Record review was performed to classify fractures, record treatments, comorbidies and 12 month mortality. A multivariate analysis was performed to determine comorbidities that significantly increased the risk of 12 month mortality.

Results

A total of 189 patients were identified. The majority were Vancouver B1 fractures (61.9%); the operations were primarily cable plating (75.1%), with a smaller number of revision arthroplasties (21.2%) and only three proximal femoral replacement (1.6%). Four patients (2.1%) died before surgery. Only 27.3% returned to their usual residence post-discharge. Overall 30-day mortality was 2.1%, and one-year mortality was 11.6%. Patients who died tended to be older. In the multivariate analysis, ASA grade III/IV and active neoplasia were significant contributors to 12 month mortality.

Conclusion(s)

Our 12 month mortality (11.6%) is at the lower end of existing reported literature, and serves as a benchmark for UK practice. In the multivariate analysis, only ASA grade III/IV and an active neoplastic process were significantly associated with increased risk of mortality. Whilst large, multicenter trials, utilizing standardized treatment techniques are required to fully assess risk factors for 12-month mortality, it appears that those at significant risk are elderly, frail individuals with an active malignancy.

https://ift.tt/2PbljkQ

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Αναζήτηση αυτού του ιστολογίου

Σάββατο 3 Νοεμβρίου 2018

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