Using FRET, raft/liquid ordered domain formation was assessed in asymmetric vesicles containing outer leaflets composed of high-Tm saturated phosphatidylcholines (diC18:0PC, diC16:0PC, diC15:0PC or diC14:0PC), low-Tm unsaturated dioleoylphosphatidylcholine (DOPC) and cholesterol, and inner leaflets composed of lipids which by themselves would not form ordered domains, DOPC and cholesterol. Ordered domain formation in the outer leaflet was compared to that in symmetric vesicles with the same lipid composition as the asymmetric vesicle outer leaflets.
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Τετάρτη 18 Ιουλίου 2018
Lipid Structure and Composition Control Consequences of Interleaflet Coupling in Asymmetric Vesicles
Factors affecting time off work in patients with traumatic hand injuries – a bio-psycho-social perspective
Publication date: Available online 18 July 2018
Source: Injury
Author(s): A. Eisele, C. Dereskewitz, S. Kus, C. Oberhauser, K.-D. Rudolf, M. Coenen, C. Best, B. Dölz, N. Drummer, A. Franz, K. Weißenberg, W.-L. Müller, F. Siemers, C. Betz, A. Franz, G. Hanebuth, M. Sauerbier, B. Bickert, V. Struckmann, U. Kneser
Abstract
Hand injuries are common and can result in a long time off work. To analyse and identify factors affecting time of work, a holistic view on patients is needed. World Health Organization's International Classification of Functioning, Disability and Health (ICF) with its bio-psycho-social perspective provides such a holistic view. The purpose of this study is to analyse time off work in patients with traumatic hand injuries and to identify factors affecting time off work from a bio-psycho-social perspective. We used factors derived from the ICF Core Set for Hand Conditions to predict time off work by applying Cox regression analyses and Kaplan-Meier method using data of a multicentre prospective study in nine German Level 1 hand trauma centres. In total, 231 study participants with a broad range of hand injuries were included. From these, 178 patients (77%) returned to work within 200 days. Impairments in mobility of joint functions and sensory functions related to temperature and other stimuli as well as higher hand strain at work led to extended time off work. Gender, fine hand use and employment status additionally influenced time off work in sub-models. Our results demonstrate that a bio-psycho-social perspective is recommended when investigating time off work.
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A Biomechanical Study Comparing Minimally Invasive Anterior Pelvic Ring Fixation Techniques to External Fixation
Publication date: Available online 18 July 2018
Source: Injury
Author(s): Lauren M. MacCormick, Frank Chen, Jeff Gilbertson, Sikandar Khan, Lisa K. Schroder, Joan E. Bechtold, Peter A. Cole
Abstract
Introduction
INFIX and Pelvic Bridge are two new minimally invasive surgical techniques for unstable pelvic ring injuries, and they have demonstrated early clinical success in small, single-center case-series. The primary objective of this study is to gather evidence speaking to the biomechanical stability of internal bridging methods relative to external fixation, with the expectation of biomechanical equivalence.
Methods
Ten human cadaveric pelvic specimens were dissected free of all skin, fat, organs, and musculature and were prepared with a partially unstable pelvic ring injury (OTA/AO 61-B). The specimens were randomized to two groups and were repaired and tested with anterior pelvic external fixation (APEF) and INFIX sequentially, or APEF and Pelvic Bridge sequentially. Testing was performed with each specimen mounted onto a servo-hydraulic testing frame with axial compression applied to the superior base of the sacrum under five axial loading/unloading sinusoidal cycles between 10 N and 1,000 N at 0.1 Hz. Relative translational motion and rotation across the osteotomy site was reported as our primary outcome measures. Outcome measures were further analyzed using a Wilcoxon signed-rank test to determine differences between non-parametric data sets with significance defined as a p value < 0.05.
Results
We found no statistical difference in translation (p = 0.237, 0.228) or rotation (p = 0.278, 0.873) at the fracture site when comparing both new constructs to external fixation. Under the imposed loading protocol, no episodes of implant failure or failure at the bone-implant interface occurred.
Discussion
Our study provides the biomechanical foundation necessary to support future clinical trial implementation for pelvic fracture patients. While biomechanical stability of these newer, subcutaneous techniques is equivalent to APEF, the surgeon must take into account their technical abilities and knowledge of pelvic anatomy, patient-specific factors including body habitus, and the potential complications associated with each implant and the ability to avoid them.
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Unified performance measures in network localization
With the evolving Internet of Things, location-based services have recently become very popular. For modern wireless sensor networks (WSNs), ubiquitous positioning is elementary. Hence, the demand of everlasti...
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A clean signal reconstruction approach for coherently combining multiple radars
Distributed radars have the potential to combine coherently for achieving a high signal-to-noise ratio (SNR) while maintaining a moderate antenna size. The key to coherently combining multiple radars is obtain...
https://ift.tt/2uTCB99
Biologics of Lumbar Interbody Fusion
Publication date: Available online 17 July 2018
Source: Seminars in Spine Surgery
Author(s): Gurmit Singh, Wellington K. Hsu, Clifford C. Raisbeck
ABSTRACT
Lumbar interbody spine fusion is increasingly utilized for treatment of a variety of spinal pathologies. The utilization of biologics in this space has gained significant interest from both—a research and clinical perspective. Historically, iliac crest bone graft has been the gold standard for lumbar interbody spine fusion, however, to avoid donor site morbidity, other options for bone graft substitutes are now commercially available. These include allograft, demineralized bone matrix, ceramics, and recombinant growth factors. More data is needed to assess clinical efficacy of mesenchymal stem cells, platelet rich plasma and peptides.
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Mini-open ALIF for Degenerative Spine and Adult Deformity: Surgical Technique and the Evidence
Publication date: Available online 17 July 2018
Source: Seminars in Spine Surgery
Author(s): I. David Kaye, Karim Shafi, Alex R. Vaccaro
ABSTRACT
With advances in surgical technique and spinal instrumentation, the mini-open anterior approach has become increasingly utilized for lumbar interbody placement. The anterior approach is not only less disruptive regarding muscular dissection, but also provides excellent visualization of the entire disc space and a large bed for fusion. Anterior lumbar interbody fusion (ALIF) provides indirect decompression through restoration of foraminal height and has been found to produce the most potential segmental correction. Although ALIF is associated with some unique complications, it is now routinely used in cases of degenerative and isthmic spondylolisthesis, pseudarthrosis after posterior fusions, adult spinal deformity, and cases of degenerative disc disease.
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Posterior Based Lumbar Interbody Fusion Devices: Static and Expandable Technology
Publication date: Available online 17 July 2018
Source: Seminars in Spine Surgery
Author(s): Yazeed M. Gussous, Nikhil Jain, Safdar N. Khan
Abstract
Utilization of minimally invasive surgery (MIS) to achieve interbody fusion has increased tremendously over recent years. Distraction of the interbody space and inserting an adequately sized cage can be challenging when utilizing a minimally invasive approach, thus the advent of expandable cages. The purpose of this article is to review the characteristics, technique, and indications of both expandable and traditional lumbar interbody fusion cages.
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The experience of vasa praevia for Australian midwives: A qualitative study
Publication date: Available online 18 July 2018
Source: Women and Birth
Author(s): Nasrin Javid, Jon A. Hyett, Caroline S.E. Homer
Abstract
Background
Vasa praevia can cause stillbirth or early neonatal death if it is not diagnosed antenatally and managed appropriately. Experiencing undiagnosed vasa praevia during labour is challenging and traumatic for women and their care providers. Little is known about the experiences of midwives who care for these women.
Aim
To investigate the experience of Australian midwives caring for women with undiagnosed vasa praevia during labour and birth.
Methods
A qualitative descriptive study was conducted with midwives in Australia who had cared for at least one woman with vasa praevia during 2010–2016. Semi-structured in-depth telephone interviews were conducted and analysed using thematic analysis.
Findings
Twelve of the 20 midwives interviewed were involved in a neonatal death and/or near-miss due to vasa praevia. There was one over-arching theme, which described the 'devastating and dreadful experience' for the midwives. This had two inter-related categories of feeling the personal impacts and addressing the professional processes. Feeling scared, shocked, and guilty described how the experience took its toll on the midwives personally. The professional processes included working in organised chaos; feeling for the parents; finding communication to be hard; and, doing their best to save the baby.
Discussion
Caring for women who experienced ruptured vasa praevia had a profound impact on the emotional and professional well-being of midwives even when the baby survived.
Conclusion
Ruptured vasa praevia was recognised as a traumatic experience that warrants serious considerations from maternity care providers, managers and policy makers. Midwives should be supported and adequately prepared to cope with traumatic events.
https://ift.tt/2mquRaF
Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.
 | Related Articles |
Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.
J Pathol. 2018 Jul 17;:
Authors: Chedgy EC, Vandekerkhove G, Herberts C, Annala M, Donoghue AJ, Sigouros M, Ritch E, Struss W, Konomura S, Liew J, Parimi S, Vergidis J, Hurtado-Coll A, Sboner A, Fazli L, Beltran H, Chi KN, Wyatt AW
Abstract
Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment-related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM or MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options. This article is protected by copyright. All rights reserved.
PMID: 30015382 [PubMed - as supplied by publisher]
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A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia.
 | Related Articles |
A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia.
Mol Cancer Ther. 2017 Oct;16(10):2058-2068
Authors: Garcia TB, Snedeker JC, Baturin D, Gardner L, Fosmire SP, Zhou C, Jordan CT, Venkataraman S, Vibhakar R, Porter CC
Abstract
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies, including cytarabine in acute myeloid leukemia (AML) and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine whether AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal. AZD1775 impaired homologous recombination in olaparib-treated cells, resulting in enhanced DNA damage accumulation and apoptosis induction. This combination enhanced disease control and increased survival in a murine AML model. Furthermore, we demonstrated that combined treatment with AZD1775 and olaparib reduces proliferation and colony formation and increases apoptosis in AML patient samples. In aggregate, these studies raise the possibility of rational combinations of targeted agents for leukemia in patients for whom conventional chemotherapeutics may not be effective or well tolerated. Mol Cancer Ther; 16(10); 2058-68. ©2017 AACR.
PMID: 28655785 [PubMed - indexed for MEDLINE]
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Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma
Metastasis-associated in colon cancer 1 (MACC1) has been reported to promote tumor cell invasion and metastasis. Cancer stem cells and epithelial-mesenchymal transition (EMT) have also been reported to promote...
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No evidence for human papillomavirus having a causal role in salivary gland tumors
Salivary gland malignancies are a very heterogeneous group of cancers, with histologically > 20 different subtypes, and prognosis varies greatly. Their etiology is unknown, however, a few small studies show pr...
https://ift.tt/2L9PqXC
Immunology and efficacy of MF59-adjuvanted vaccines.
 | Related Articles |
Immunology and efficacy of MF59-adjuvanted vaccines.
Hum Vaccin Immunother. 2018 Jul 17;:
Authors: Ko EJ, Kang SM
Abstract
Adjuvants are included in vaccine formulations to enhance the immunogenicity and efficacy of vaccines. MF59® is an oil-in-water emulsion adjuvant and licensed for use in pandemic and seasonal influenza vaccines in many countries. MF59 is safe and well tolerated in humans. MF59-adjuvanted vaccination spares vaccine dose and enhances hemagglutination inhibiting antibodies against homologous and heterologous influenza virus strains. The mechanisms of MF59 involve rapid induction of chemokines, inflammatory cytokines, recruiting multiple immune cells, uric acid and benign apoptosis of certain innate immune cells. The adjuvant effects of MF59 on generating vaccine-specific isotype-switched IgG antibodies, effector CD8 T cells, and protective immunity were retained even in a CD4-deficient condition by inducing effective immune-competent microenvironment with various innate and antigen presenting cells in a mouse model. CD4-independent adjuvant effects of MF59 might contribute to improving the vaccine efficacy in children, the elderly, and immunocompromised patients as well as in healthy adults. Further studies will be needed to broaden the use of MF59 in various vaccine antigens and populations as well as lead to better understanding of the action mechanisms of MF59 adjuvant.
PMID: 30015572 [PubMed - as supplied by publisher]
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A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor.
 | Related Articles |
A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor.
Front Immunol. 2018;9:1528
Authors: Yang F, Fan X, Huang H, Dang Q, Lei H, Li Y
Abstract
A single epitope of Leishmania analog of the receptors for activated C kinase (LACK) from Leishmania major, the polypeptide LACK156-173, is recognized by Vβ4+/Vα8+ T cells, and activate these cells that drives the subsequent T helper (Th)2 response. This study was undertaken to investigate the therapeutic potential of the LACK156-173 epitope in murine autoimmune arthritis models. To explore the influence of the LACK156-173 epitope on murine collagen antibody-induced arthritis, as well as its immunological mechanism, we vaccinated or treated mice with a LACK156-173 epitope expression plasmid or polypeptide. The effect of LACK156-173 epitope was then evaluated by clinical scores, histopathology, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Using flow cytometry, we measured the subsets and maturity of CD11c+ dendritic cells (DCs), as well as T cell polarization, in co-culture experiments. We also measured cytokine gene expression and production. The murine macrophage-like cell line RAW264.7 was used to identify the receptor for the epitope. Vaccination or treatment of the mice with the LACK156-173 epitope expression plasmid or polypeptide ameliorated the severity of arthritis. qRT-PCR analysis revealed that the LACK156-173 epitope improved the balance of effector T cells in synovial tissue compared to that in untreated arthritis controls. Toll-like receptor (TLR) 4 expression was diminished by LACK156-173. The epitope also influenced T cell polarization by regulating the differentiation, maturation, and functions of CD11c+ DCs and upregulating Jagged1 ligand expression. Blocking the mannose receptor (MR) significantly attenuated LACK156-173 epitope-induced macrophage activation. Our data indicate that vaccination or treatment with a single microorganism epitope, LACK156-173, is a highly efficient therapy for murine autoimmune arthritis. The therapeutic effects are mediated by the regulation of the differentiation, maturation, and functions of DCs via MR, resulting in the upregulation of Jagged1 expression and Th2 cell polarization. Our results demonstrate the therapeutic potential of the LACK156-173 epitope in rheumatoid arthritis.
PMID: 30013572 [PubMed]
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Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy.
| Related Articles |
Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy.
Front Immunol. 2018;9:1499
Authors: Guo Y, Lei K, Tang L
Abstract
Cancer neoantigens derived from random somatic mutations in tumor tissue represent an attractive type of targets for the cancer immunotherapies including cancer vaccine. Vaccination against the tumor-specific neoantigens minimizes the potential induction of central and peripheral tolerance as well as the risk of autoimmunity. Neoantigen-based cancer vaccines have recently showed marked therapeutic potential in both preclinical and early-phase clinical studies. However, significant challenges remain in the effective and faithful identification of immunogenic neoepitopes and the efficient and safe delivery of the subunit vaccine components for eliciting potent and robust anticancer T cell responses. In this mini review, we provide a brief overview of the recent advances in the development of neoantigen-based cancer vaccines focusing on various vaccine delivery strategies for targeting and modulating antigen-presenting cells. We discuss current delivery approaches, including direct injection, ex vivo-pulsed dendritic cell vaccination, and biomaterial-assisted vaccination for enhancing the efficiency of neoantigen vaccines and present a perspective on future directions.
PMID: 30013560 [PubMed]
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Targeting of Immune Cells by Dual TLR2/7 Ligands Suppresses Features of Allergic Th2 Immune Responses in Mice.
  | Related Articles |
Targeting of Immune Cells by Dual TLR2/7 Ligands Suppresses Features of Allergic Th2 Immune Responses in Mice.
J Immunol Res. 2017;2017:7983217
Authors: Laiño J, Wangorsch A, Blanco F, Wolfheimer S, Krause M, Flaczyk A, Möller TM, Tsai M, Galli S, Vieths S, Toda M, Scheurer S, Schülke S
Abstract
Background: TLR ligands can promote Th1-biased immune responses, mimicking potent stimuli of viruses and bacteria.
Aim: To investigate the adjuvant properties of dual TLR2/7 ligands compared to those of the mixture of both single ligands.
Methods: Dual TLR2/7 ligands: CL401, CL413, and CL531, including CL264 (TLR7-ligand) and Pam2CysK4 (TLR2-ligand), were used. Immune-modulatory capacity of the dual ligands with the individual ligands alone or as a mixture in mouse BMmDCs, BMmDC:TC cocultures, or BMCMCs was compared and assessed in naïve mice and in a mouse model of OVA-induced intestinal allergy.
Results: CL413 and CL531 induced BMmDC-derived IL-10 secretion, suppressed rOVA-induced IL-5 secretion from OVA-specific DO11.10 CD4+ TCs, and induced proinflammatory cytokine secretion in vivo. In contrast, CL401 induced considerably less IL-10 secretion and led to IL-17A production in BMmDC:TC cocultures, but not BMCMC IL-6 secretion, or IL-6 or TNF-α production in vivo. No immune-modulating effects were observed with single ligands. All dual TLR2/7 ligands suppressed DNP-induced IgE-and-Ag-specific mast cell degranulation. Compared to vaccination with OVA, vaccination with the mixture CL531 and OVA, significantly suppressed OVA-specific IgE production in the intestinal allergy model.
Conclusions: Based on beneficial immune-modulating properties, CL413 and CL531 may have utility as potential adjuvants for allergy treatment.
PMID: 29204451 [PubMed - indexed for MEDLINE]
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A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity.
 | Related Articles |
A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity.
J Transl Med. 2017 Oct 06;15(1):201
Authors: Rai PK, Chodisetti SB, Zeng W, Nadeem S, Maurya SK, Pahari S, Janmeja AK, Jackson DC, Agrewala JN
Abstract
BACKGROUND: The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice.
METHODS: In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA.
RESULTS: Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44hiCD62LhiCD127hi) and effector memory (CD44hiCD62LloCD127lo) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ+TNF-α+) and Th17 cells (IFN-γ+IL-17A+) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91.
CONCLUSIONS: Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against Mtb. This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.
PMID: 28985739 [PubMed - indexed for MEDLINE]
https://ift.tt/2JAdL36
Testing Epinephrine for Out-of-Hospital Cardiac Arrest
The administration of epinephrine has been part of the resuscitation of patients with cardiac arrest since the 1960s. The rationale for the use of epinephrine includes evidence from studies in animals and from clinical trials in humans that increasing vasomotor tone during circulatory collapse and…
https://ift.tt/2JBcEAj
A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest
In attempting to reduce the rate of death and disability associated with cardiac arrest worldwide, emergency medical workers have few effective treatments other than early initiation of cardiopulmonary resuscitation (CPR) and prompt defibrillation. For more than 50 years, treatment strategies have…
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Parenteral Opioid Shortage — Treating Pain during the Opioid-Overdose Epidemic
https://ift.tt/2zRKnWt
Algorithm for comorbidities, associations, length of stay and mortality (ACALM)
Future Oncology, Ahead of Print.
https://ift.tt/2uyj0fh
The next generation of therapy for multiple myeloma: a review of ongoing clinical trials utilizing ClinicalTrials.gov
Future Oncology, Ahead of Print.
https://ift.tt/2LuLmxo
Optimal prophylaxis of chemotherapy-induced nausea and vomiting for moderately emetogenic chemotherapy: a meta-analysis
Future Oncology, Ahead of Print.
https://ift.tt/2uvOAtM
Effects of SOX15 on the colorectal cancer cells via downregulation of the Wnt/β-catenin signaling pathway
Future Oncology, Ahead of Print.
https://ift.tt/2Lr4ImT
Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 1)
Future Oncology, Ahead of Print.
https://ift.tt/2uvOylE
Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 2)
Future Oncology, Ahead of Print.
https://ift.tt/2zSwuYj
miRNA in a multiomic context for diagnosis, treatment monitoring and personalized management of metastatic breast cancer
Future Oncology, Ahead of Print.
https://ift.tt/2uvOxhA
Analysis of risk factors of lymph node metastasis in rectal neuroendocrine neoplasms using multicenter data
Future Oncology, Ahead of Print.
https://ift.tt/2zTca98
Parenteral Opioid Shortage — Treating Pain during the Opioid-Overdose Epidemic
https://ift.tt/2zRKnWt
Radical Changes for Reproductive Health Care — Proposed Regulations for Title X
On June 1, 2018, the Department of Health and Human Services (HHS) proposed new regulations for the Title X Family Planning Program. If enacted, these regulations will radically alter the mix of health care providers and the range, quality, and effectiveness of services offered to support the…
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A Remembrance of Life before Roe v. Wade
https://ift.tt/2JwIVIR
Parenteral Opioid Shortage — Treating Pain during the Opioid-Overdose Epidemic
https://ift.tt/2zRKnWt
Accurately genotyping CYP2D6: not for the faint of heart
Pharmacogenomics, Ahead of Print.
https://ift.tt/2LaGDF6
Genetic polymorphisms of CYP2S1, CYP2J2 and CYP2R1 genes in three Chinese populations: Han, Tibetan and Uighur
Pharmacogenomics, Ahead of Print.
https://ift.tt/2L3Fejr
Beta-1,4-galactosyltransferase 2 c.909C>T gene variant is predictive of on-clopidogrel platelet reactivity
Pharmacogenomics, Ahead of Print.
https://ift.tt/2JzR0fL
Different Prognostic Implications of Aquaporin-1 and Aquaporin-5 Expression among Different Histological Types of Ovarian Carcinoma
Abstract
The aquaporins (AQPs) are a family of transmembrane water channel proteins that are distributed in various human tissues. Recent studies have suggested that AQP expression correlates with various aspects of cancer biology that determine the aggressiveness of different cancers. Ovarian carcinoma is one of the most lethal gynecological cancers. Some studies have suggested that AQPs are expressed in ovarian carcinoma, and are associated with cancer cell growth and migration. In this study, we immunohistochemically evaluated the expression of AQP1, 3, 5, and 9 in a total of 300 ovarian carcinomas using tissue microarrays. In our analyses of correlations between aquaporin expression and overall survival, high AQP5 expression was significantly associated with poorer prognosis (P = 0.029). For AQP1, the low expression group trended towards poorer prognosis than the high expression group, but the difference was not statistically significant. When ovarian carcinomas were divided by histological types, high AQP5 expression correlated with poorer prognosis in serous carcinoma (P = 0.015), and low AQP1 expression correlated with poorer prognosis in clear cell carcinomas (P = 0.0055). By contrast, high AQP1 expression correlated with poorer prognosis in mucinous carcinoma (P = 0.0001) and endometrioid carcinoma (P = 0.021). Our studies suggest that AQPs can be useful prognostic markers in ovarian carcinoma, but their correlation with prognosis depends on the histological type of ovarian carcinoma.
https://ift.tt/2LaGsJW
Parenteral Opioid Shortage — Treating Pain during the Opioid-Overdose Epidemic
https://ift.tt/2zRKnWt
Cell Cycle Arrest and Apoptosis Induction of Phloroacetophenone Glycosides and Caffeoylquinic Acid Derivatives in Gastric Adenocarcinoma (AGS) Cells
Introduction: In the present study, we analyzed anti-proliferative and apoptosis induction activity of five phenolic compounds: echisoside, pleoside, chlorogenic acid, 4,5-Di-O-caffeoylquinic acid, and cynarin on AGS (adenocarcinoma gastric) cell line.
Method: These phenolic compounds were isolated from methanol extract of Dorema glabrum root. An MTT assay was conducted to evaluate the inhibitory effect on cancer cells. EB/AO staining was done to assess the mode of cell death and morphological changes of the cells' nuclei. Cell cycle distribution of the cells was analyzed by flow cytometry, and for further confirmation of the pathway, mRNA levels of apoptosis cascade players were quantified by qRT-PCR.
Result: We found that echisoside, pleoside, chlorogenic acid, 4,5-Di-O-caffeoylquinic acid, and cynarin inhibited the proliferation of AGS cancer cells in vitro. Our data revealed that these compounds triggered morphological changes characteristic of apoptotic cell death. These compounds up-regulated bax and caspase3 expression and down-regulated cyclin D1, bcl2, VEGFA, c-myc and survivin. Moreover, cell population increased at the G1 phase, and a number of cells at the G2/M phase of the cell cycle decreased after treatment.
Conclusion: All these data suggest that phenolic compounds have a cytotoxic effect on gastric cancer cells and could trigger apoptosis. Besides cytotoxic activity, they could potentially arrest the cell cycle at the G1 phase.
https://ift.tt/2Nt3B70
Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2- Thioxoimidazolidinones
Background: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target.
Objective: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38).
Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 – 186.9 and 24.6 – 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 – 198.5 and 16.9 – 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38.
Conclusion: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.
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Synthesis and Evaluation of 2-Naphthaleno trans-Stilbenes and Cyanostilbenes as Anticancer Agents
Background: Naphthalene is a good structural replacement for the isovanillin moiety (i.e. the 3- hydroxy-4-methoxyphenyl unit) in the combretastatin A-4 molecule, a natural product structurally related to resveratrol, which consistently led to the generation of highly cytotoxic naphthalene analogues when combined with a 3,4,5-trimethoxyphenyl or related aromatic system. Also, the naphthalene ring system is present in many current drug molecules that are utilized for anti-tumor, anti-arrhythmia and antioxidant therapy.
Objective: In our continuing quest to improve the potencies of naturally occurring anti-cancer molecules through chemical modification, we have now synthesized a small library of 2-naphthaleno trans- stilbenes and cyanostilbenes that are structurally related to both resveratrol and DMU-212, and have evaluated these novel analogs against a panel of 54 human tumor cell lines.
Method: A series of 2-naphthaleno-containing trans-stilbenes 3a-3h (Scheme 1) were synthesized by Wittig reaction of a variety of aromatic substituted benzyl-triphenylphosphonium bromide reactants with 2- naphthaldehyde using n-BuLi as a base in THF. A second series of 2-naphthaleno trans-cyanostilbenes analogs 5a-5h was synthesized by reaction of 2-naphthaldehyde (2; 1 mmol) with an appropriately substituted 2- phenylacrylonitrile 4a-4h; 1 mmol) in 5% sodium methoxide/methanol. The reaction mixture was stirred at room temperature for 2-3 hours and the reaction allowed to go to completion (TLC monitoring), during which time the desired product precipitated out of the solution as a solid. The resulting precipitate was filtered off, washed with water and dried to yield the desired compound in yields ranging from 70-95% (Scheme 2).
Results: The percentage growth inhibition of 54 human cancer cell lines in a primary NCI screen after exposure to compounds 3a, 3d, 5b and 5c was carried out. The results showed that only compounds 5b and 5c met the criteria for subsequent testing to determine growth inhibition values (GI50) in dose-response studies. At 10-5 M concentration, compounds 5b and 5c exhibited cytotoxic activity against leukemia cell lines HL-60(TB) and SR, lung cancer cell line NCI-H522, colon cancer cell lines COLO 205 and HCT-116, CNS-cancer cell line SF-539, melanoma cell line MDA-MB-435, and breast cancer cell line BT-549. The naphthalene trans-stilbene analogue 3a, exhibited significant growth inhibition against only one cell line, melanoma cell line MDA-MB-435 (96 % growth inhibition). Compound 3d was inactive in the 10-5 M single dose screen.
Conclusion: We have synthesized a small set of novel 2-naphthaleno stilbenes and cyanostilbenes and evaluated several of these compounds for their anticancer properties against a panel of 54 human tumor cell lines. The most active analogs, 5b and 5c, showed significantly improved growth inhibition against the human cancer cells in the NCI panel when compared to DMU-212. Of these compounds, analog 5c was found to be the most potent anticancer agent and exhibited significant growth inhibitory effects against COLO 205, CNS SF 539 and melanoma SK-MEL 5 and MDA-MB-435 cell lines with GI50 values ≤ 25 nM. Analog 5b also exhibited GI50 values in the range 25-41 nM against CNS SF 295 and melanoma MDA-MB-435 and UACC-62 cell lines. Compounds 5b and 5c were also cytotoxic towards the MV4-11 leukemia cell line with LD50 value of 450 nM and 200 nM, respectively, and demonstrated >50% inhibition of tubulin polymerization at concentrations below their LD50 values in these cells. In silico docking studies suggest that compounds 5b and 5c bind favorably at the colchicine- binding pocket of the tubulin dimer, indicating that both 5b and 5c may inhibit tubulin polymerization through a mechanism similar to that exhibited by colchicine. Derivative 5c demonstrated more favorable binding based on the docking score and buried surface area, as compared to compound 5b, in agreement with the higher observed potency of 5c against a broader range of tumor cell lines. Based on these results, analog 5c is considered to be a lead compound for further optimization as a clinical candidate for treating a variety of cancers.
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AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells
Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies.
Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth.
Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.
https://ift.tt/2NXPhEm
Potential Future of New Glutamate Agonists and Antagonists Development
Receptors of glutamic acid are known for over 30 years for their action and for about 20 years for their structure. Presence of at least three classes of ionotropic receptors was confirmed at the beginning of 80'. Recognition of the sequence and first cloning were done at the beginning of 90'. In 1994 ligand binding site was recognized at the junction of two subunits S1-S2 in the ligand-binding domain.
Since then, many subtypes of ionotropic and metabotropic glutamate receptors were recognized, together with their localization and functions.
In the meantime numerous orthosteric ligands, both agonists and antagonists were developed especially for NMDA ion channels. Their usefulness as drugs was rather low, due to the involvement in the excitatory tract. More interest was focused on metabotropic receptors, which are GPSR's and can be modulated both by orthosteric and allosteric modulators.
It seems like allosterism could be considered as promising future for glutamate receptors and ion channels, especially when first allosteric negative modulators of the mGluR2 went close into the clinical trial.
https://ift.tt/2NsI6TI
Riluzole Inhibits Proliferation, Migration and Cell Cycle Progression and Induces Apoptosis in Tumor Cells of Various Origins
Background: Regardless of contemporary improvements in cancer treatment, the results of drug treatment are not always efficacious. Thus, the development of novel approaches that affect cancer cell-specific metabolic pathways is needed. Since much evidence has shown that tumor cell proliferation and motility are stimulated by glutamate via activation of its receptors, use of antagonists to these receptors may be the key to control cancer cell progression. Riluzole noncompetitive metabotropic glutamate receptor 1 (mGluR1) antagonist, commonly used to treat patients with amyotrophic lateral sclerosis (ALS), has shown some antineoplastic properties against melanoma, breast and prostate cancer. Yet little is known about its molecular mode of action.
Aims: The current study aims at evaluating the abilities of Riluzole to inhibit proliferation of several cancer cell lines, as well as resolve the mechanism of its action.
Method: We demonstrated antiproliferative and antimigrative properties of Riluzole in rhabdomyosarcomamedulloblastoma, neuroblastoma, astrocytoma, glioma, colon cancer, lung cancer, thyroid carcinoma, leukemia, erythroleukemia and multiple myeloma. Our studies revealed apoptosis induction and G2-M cell cycle arrest in Riluzole treated A549, C6 and HT-29 cells.
Result: At the molecular level, we found that these cells treated with Riluzole had a decrease of Cyclin B and an increase of p21 Waf1/Cip1 and p53 expression. We also observed an enhancement of CDK1 and Chk2 phosphorylation. Reported changes may suggest the involvement of these proteins in G2-M arrest, observed in flow cytometry analysis. These data indicated the potential use of Riluzole in the treatment of different types of cancers.
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Halilectin-3, a Lectin from the Marine Sponge Haliclona caerulea, Induces Apoptosis and Autophagy in Human Breast Cancer MCF7 Cells Through Caspase-9 Pathway and LC3-II Protein Expression
Background: An ideal strategy for cancer treatment is the specific induction of tumor cell death, sparing normal cells. Marine sponges are rich biological reservoirs of biomolecules, especially lectins, which have attracted considerable attention due to potential biological effect on human cells. Lectins are proteins that bind specific carbohydrate signatures and some gained further interest for their capacity to bind tumor associated carbohydrates antigens and induce tumor cell apoptosis.
Objective: This study aimed to evaluate the antitumor potential of H3, a lectin, recently reported from marine sponge Haliclona caerulea on the human breast cancer cell line MCF7.
Results: H3 reduced MCF7 cell viability with an IC50 of 100 µg/ml, without a significant effect on normal cells. At 24 h, H3 induced a significant arrest in the G1 cell cycle phase. Consistently, almost 50% of the cells were in early apoptosis and showed remarkable increased expression of caspase-9 (CASP 9). H3 impaired dramatically the adhesiveness of MCF7 cells in culture. Assays conducted with Lysotracker Red probe showed increased organelle acidity, suggesting autophagic cell death, which was further supported by increased expression of microtubuleassociated protein light chain 3 (LC3) and observable conversion of LC3-I in LC3-II by western blot.
Conclusion: The apoptotic effect of H3 may be related to a balance between apoptotic and autophagic cell death, mediated by increased expression of CASP 9 and LC3-II. To the best of our knowledge this is the first report about a sponge lectin triggering both apoptosis and autophagy in MCF7 cell.
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Oleanolic Acid Inhibits Colorectal Cancer Angiogenesis by Blocking the VEGFR2 Signaling Pathway
Background: Angiogenesis is a crucial process that regulated by multiple intracellular signaling pathways including MEK/ERK and JNK/SAPK. Thus, many inhibitors have developed to these pathways as anti-cancer therapeutic strategies. Oleanolic acid (OA) is a natural pentacyclic triterpenoic acid compound that present in various herbal medicines. It has been used as antitumor agent for various cancers including colorectal cancer (CRC), which attenuates angiogenesis.
Objective: To study the molecular mechanism of OA suppressing angiogenesis.
Method: The proliferation of human umbilical vein endothelial cells (HUVECs) was determined by MTT and the invasion and migration of them were measured by wound-healing Assay, transwell migration assay and tube formation assay. The xenograft mouse model was used to study the effect of OA blocking angiogenesis in vivo. The Western blot was used to checked the phosphorylation of VEGFR2.
Results: OA attenuates HUVECs invasion, migration, tube formation and vascular sprouting. Moreover, OA suppresses HUVECs sprout and tube formation. Importantly, OA also blocks angiogenesis in HUVECs and colorectal cancer cells (HCT-116) both in vitro and in vivo. OA-dependent suppression of tumor angiogenesis mediated by blocking the phosphorylation of the vascular endothelial growth factor receptor-2 (VEGFR2) that results in inhibition of MEK/ERK/JNK pathway.
Conclusion: Our results suggest that inhibition of tumor angiogenesis via the suppression VEGFR2 phosphorylation may be one of the underlying mechanisms by which OA exerts its anti-cancer effect.
https://ift.tt/2NXPXto
Antineoplastic Effects of NF-κB Inhibition by DHMEQ (Dehydroxymethylepoxyquinomicin) Alone and in Co-treatment with Radio-and Chemotherapy in Medulloblastoma Cell Lines
Background: NF-κB is a transcription factor involved in the transcriptional regulation of a large number of genes related to tumorigenesis in several cancer cell types, and its inhibition has been related to anticancer effect. DHMEQ (Dehydroxymethylepoxyquinomicin) is a compound that blocks the translocation of NF-κB from the cytoplasm to the nucleus, thus inhibiting its activity as a transcriptional activator. Several studies have shown the antineoplastic effects of DHMEQ in numerous tumor types, however, there are no surveys that tested their effects in MB.
Objectives: The aim of the present study was to evaluate the effects of DHMEQ as NF-κB inhibitor in pediatric MB cell lines.
Method: We used the UW402, UW473 and ONS-76 medulloblastoma (MB) cell lines to verify the effect of DHMEQ on proliferation, clonogenic capacity, apoptosis, cell invasion and migration, and evaluated the effect of the combination with other drugs and the potential as a radiosensitizator.
Results: A significant decrease in the cell growth, a strong inhibition of the clonogenic capacity, migration and cell invasion was observed after NF-κB inhibition in the three MB cell lines. Conversely, increased level of apoptosis rates were demonstrated. Additionally, treatments with DHMEQ combined with other chemotherapeutic agents were synergic in most points, and a strong radiosensitization by this compound was observed in the three MB cell lines.
Conclusion: DHMEQ has potential antitumor effect on MB cells, and it may be considered a new therapeutic agent to improve treatment approaches in MB.
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Comparison of Physicochemical Properties of Generic Doxorubicin HCl Liposome Injection with the Reference Listed Drug
Background: Liposomal doxorubicin is widely used for treating ovarian cancer and Kaposi's sarcoma. Encapsulation of doxorubicin in highly complex polyethylene glycol–coated (stealth) liposomes prolongs residence time and avoids the systemic toxicity associated with administration of the free drug. Small variations in physicochemical properties introduced during manufacture of liposomes can influence the payload of encapsulated drug, stability of liposomes under physiological conditions, and release of drug at the target tissue. Accordingly, the US Food and Drug Administration and the European Medicines Agency have issued guidance for manufacturers of generic liposomal doxorubicin that is designed to ensure that more than 30 physicochemical parameters that influence its safety and efficacy should be similar in the generic and reference listed drugs.
Objective: This study aims to describe the physicochemical characterization procedures used to ensure consistency between batches of generic liposomal doxorubicin and with the reference listed drug.
Methods: A range of spectroscopic, chromatographic, and other physicochemical tests was used to compare relative concentrations of liposome components, liposome morphology, ratios of free/entrapped doxorubicin, stability, and in vitro doxorubicin release rates in physiologically and clinically relevant media.
Results: The tests established that generic and reference liposomes contained similar concentrations of drug, lipids, and excipients and that their physical forms were also similar.
Conclusion: The results of the tests demonstrate the physicochemical equivalence of generic liposomal doxorubicin hydrochloride and the reference listed drug, Doxil®/Caelyx®. Biochemical and clinical equivalence must also be demonstrated to fully meet regulatory requirements for generic liposomal medicines, and these are the subjects of separate studies.
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Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells
Background: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients.
Objective: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism.
Method: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay. The gene was silenced by small interfering RNA. The cellular morphology was observed by using an optical microscope. The viable cell numbers were counted by trypan blue staining assay.
Results: The OSI-resistant HCC827/OSIR cells were established on HCC827 cells with naive EGFR-sensitive mutation, and the resistant effects of HCC827/OSIR cells were confirmed through MTT and colony formation assays. The IC50s of HCC827/OSIR cells to other EGFR TKIs, such as gefitinib, erlotinib, afatinib, and rociletinib was higher than that of the HCC827 cells. The anti-proliferative effects of paclitaxel, pemetrexed, doxorubicin, and fluorouracil in HCC827 and HCC827/OSIR cells were similar. The expression of inositolrequiring enzyme 1α (IRE1α) was increased after the cells developed resistance to OSI. The number of viable cells in both cell lines, particularly in HCC827/OSIR cells, was decreased through knockdown of IRE1α or pretreatment with STF-083010, an IRE1α inhibitor.
Conclusion: An increased expression of IRE1α may be one of the resistant mechanisms for OSI-resistant NSCLC.
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Novel Fluorinated Porphyrins Sensitize Tumor Cells to Photodamage in Normoxia and Hypoxia: Synthesis and Biocompatible Formulations
Background: Hypoxia renders tumor cells refractory to treatment. One way to overcome this problem is the design of drug delivery systems that contain the antitumor agent within an oxygen supply medium.
Objective: to evaluate whether the perfluorocarbon liquids (capable of retaining up to 50% v/v amounts of O2 gas) can be tools for delivery of photosensitizers to hypoxic tumors.
Method: We synthesized a series of compounds in which fluoroaliphatic or fluoroaromatic moieties were conjugated to the porphyrin ring in meso-positions. Two derivatives were tested as the solutions prepared either from a dimethylformamide stock ('free' formulation) or from a perfluorocarbon emulsion in which the photosensitizer is entrapped in the oxygenated medium.
Results: In the emulsion the hydrophobic photosensitizer and the gas transporting liquid represented a biocompatible composition. Free formulations or perfluorocarbon emulsions of fluorinated porphyrins evoked little-to-null dark cytotoxicity. In contrast, each formulation triggered cell death upon light activation. Photodamage in the presence of fluorinated porphyrins was achievable not only at normoxic (20.9% O2 v/v) conditions but also in hypoxia (0.5% O2). With new compounds dissolved in the medium the cell photodamage in hypoxia was negligible whereas a significant photodamage was achieved with the emulsions of fluorinated porphyrins. The derivative with the fluoroalkyl substituent was more potent than its structurally close analog carrying the fluoroaryl moiety.
Conclusion: Our new fluorinated porphyrin derivatives, especially their emulsions in which the photosensitizer and the oxygenated medium are coupled into one phase, can be perspective for photoelimination of hypoxic tumor cells.
https://ift.tt/2NXPMOK
Knowledge, attitudes and practices of malaria transmission and preventive measures in Woreta town, Northwest Ethiopia
Despite a high public health burden of malaria in endemic regions of Ethiopia, there are limitations on the availability of data concerning public awareness about the disease and its preventive measures. The p...
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In vitro activity of Morinda citrifolia Linn. fruit juice against the axenic amastigote form of Leishmania amazonensis and its hydrogen peroxide induction capacity in BALB/c peritoneal macrophages
The current treatment of leishmaniasis induces strong side effects and increasing numbers of cases of resistance to reference drugs have been reported. The discovery of the therapeutic properties of active sub...
https://ift.tt/2JAYhvI
Role of imitation and limited rehabilitation capacity on the spread of drug abuse
We formulate a mathematical model for the spread of drug abuse using non linear ordinary differential equations. The model seeks to investigate both peer influence and limited rehabilitation effects on the dyn...
https://ift.tt/2LuGHLU
Conceptions of sleep experience: a layman perspective
To date, there is little information on how lay people understand and discuss sleep in the context of daily life. Efforts to conceptualize sleep quality have been largely driven by clinical considerations of s...
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Antiviral RNA interference in mammals
Shou-Wei Ding | Qingxia Han | Jinyan Wang | Wan-Xiang Li
https://ift.tt/2NsCR6A
CRISPR-Cas13 Precision Transcriptome Engineering in Cancer
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated genes (Cas) system has been rapidly harnessed to perform various genomic engineering tasks. Recently, it has been demonstrated that a novel RNA-targeting CRISPR effector protein, called Cas13, binds and cleaves RNA rather than DNA substrates analogously to the eukaryotic RNA interference system. The known Cas13a–Cas13d effectors are able to efficiently cleave complementary target single-stranded RNAs, which represent a potentially safer alternative to deoxyribonuclease Cas9, because it induces loss-of-function phenotypes without genomic loss of the targeted gene. Furthermore, through the improvement in Cas13 effector functionalities, a system called REPAIR has been developed to edit full-length transcripts containing pathogenic mutations, thus providing a promising opportunity for precise base editing. Moreover, advanced engineering of this CRISPR effector also permits nucleic acid detection, allowing the identification of mutations in cell-free tumor DNA through a platform termed Specific High Sensitivity Enzymatic Reporter Unlocking. All of these properties give us a glimpse about the potential of the CRISPR toolkit for precise transcriptome engineering, possibly leading to an expansion of CRISPR technologies for cancer therapeutics and diagnostics. Here, we examine previously unaddressed aspects of the CRISPR-based RNA-targeting approach as a feasible strategy for globally interrogating gene function in cancer in a programmable manner. Cancer Res; 78(15); 1–7. ©2018 AACR.
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Identification of the Novel Nup188-brr7 Allele in a Screen for Cold-Sensitive mRNA Export Mutants in Saccharomyces cerevisiae
The maturation and export of mRNA from the nucleus through the nuclear pore complex is critical for maintaining an appropriate proteome in all eukaryotic cells. Here we summarize a previously unpublished screen in S. cerevisiae that utilized an established dT50 in situ hybridization assay to identify cold-sensitive mutants that accumulated bulk poly A RNA in the nucleus. The screen identified seven mutants in six complementation groups, including the brr6-1 strain that we described previously. In addition to brr6-1, we identified novel alleles of the key transport gene GLE1 and NUP188, a component of the Nic96 nucleoporin complex. Notably, we show that the nup188-brr7 allele causes defects in select protein import pathways as well as mRNA export. Given recent structural and functional evidence linking the Nic96 complex to transport components, this mutant may be particularly useful to the transport community.
https://ift.tt/2LwqcPw
Event Analysis: Using Transcript Events To Improve Estimates of Abundance in RNA-seq Data
Alternative splicing leverages genomic content by allowing the synthesis of multiple transcripts and, by implication, protein isoforms, from a single gene. However, estimating the abundance of transcripts produced in a given tissue from short sequencing reads is difficult and can result in both the construction of transcripts that do not exist, and the failure to identify true transcripts. An alternative approach is to catalog the events that make up isoforms (splice junctions and exons). We present here the Event Analysis (EA) approach, where we project transcripts onto the genome and identify overlapping/unique regions and junctions. In addition, all possible logical junctions are assembled into a catalog. Transcripts are filtered before quantitation based on simple measures: the proportion of the events detected, and the coverage. We find that mapping to a junction catalog is more efficient at detecting novel junctions than mapping in a splice aware manner. We identify 99.8% of true transcripts while iReckon identifies 82% of the true transcripts and creates more transcripts not included in the simulation than were initially used in the simulation. Using PacBio Iso-seq data from a mouse neural progenitor cell model, EA detects 60% of the novel junctions that are combinations of existing exons while only 43% are detected by STAR. EA further detects ~5,000 annotated junctions missed by STAR. Filtering transcripts based on the proportion of the transcript detected and the number of reads on average supporting that transcript captures 95% of the PacBio transcriptome. Filtering the reference transcriptome before quantitation, results in is a more stable estimate of isoform abundance, with improved correlation between replicates. This was particularly evident when EA is applied to an RNA-seq study of type 1 diabetes (T1D), where the coefficient of variation among subjects (n = 81) in the transcript abundance estimates was substantially reduced compared to the estimation using the full reference. EA focuses on individual transcriptional events. These events can be quantitate and analyzed directly or used to identify the probable set of expressed transcripts. Simple rules based on detected events and coverage used in filtering result in a dramatic improvement in isoform estimation without the use of ancillary data (e.g. ChIP, long reads) that may not be available for many studies.
https://ift.tt/2L4SZyd
A Bayesian Decision Theory Approach for Genomic Selection
Plant and animal breeders are interested in selecting the best individuals from a candidate set for the next breeding cycle. In this paper, we propose a formal method under the Bayesian decision theory framework to tackle the selection problem based on genomic selection (GS) in single- and multi-trait settings. We proposed and tested three univariate loss functions (Kullback-Leibler, KL; Continuous Ranked Probability Score, CRPS; Linear-Linear loss, LinLin) and their corresponding multivariate generalizations (Kullback-Leibler, KL; Energy Score, EnergyS; and the Multivariate Asymmetric Loss Function, MALF). We derived and expressed all the loss functions in terms of heritability and tested them on a real wheat dataset for one cycle of selection and in a simulated selection program. The performance of each univariate loss function was compared with the standard method of selection (Std) that does not use loss functions. We compared the performance in terms of the selection response and the decrease in the population's genetic variance during recurrent breeding cycles. Results suggest that it is possible to obtain better performance in a long-term breeding program using the single-trait scheme by selecting 30% of the best individuals in each cycle but not by selecting 10% of the best individuals. For the multi-trait approach, results show that the population mean for all traits under consideration had positive gains, even though two of the traits were negatively correlated. The corresponding population variances were not statistically different from the different loss function during the 10-th selection cycle. Using the loss function should be a useful criterion when selecting the candidates for selection for the next breeding cycle.
https://ift.tt/2JAvO9H
Upping Enrollment of Veterans in Trials [News in Brief]
NCI/VA initiative to increase participation in NCI-sponsored clinical cancer research.
https://ift.tt/2uImzif
Serum sex steroids as prognostic biomarkers in patients receiving androgen deprivation therapy for recurrent prostate cancer: a post-hoc analysis of the PR.7 trial
Purpose: Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Experimental Design: Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence post-radiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable cox regression analyses adjusted for baseline prognostic factors assessed time to castration resistance prostate cancer(CRPC), prostate cancer survival and overall survival according to tertile of sex steroid measured by mass spectrometry. Results: Post-ADT initiation, we measured samples in 219 patients as well as 2 subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and dihydrotestosterone (DHT), while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA) and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone(E1) and estradiol(E2) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups. Conclusions: Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E1 and E2 and rising DHEA and AST levels which predict a shorter time to CRPC.
https://ift.tt/2mtXlk0
A novel, fully human anti-fucosyl-GM1 antibody demonstrates potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer
Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1. Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors. Results: BMS-986012 showed high binding affinity for FcRIIIa, which resulted in enhanced antibody-dependent cellular cytotoxicity against FucGM1-expressing tumor cells. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis assays. In mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, responses significantly improved. Conclusions: Single agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase 1 clinical trial of patients with relapsed, refractory SCLC.
https://ift.tt/2zQZsI2
Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis
Purpose: Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematological malignancies, but have limited efficacy in solid tumors. This study aimed to identify combination therapies that exploit clinical BH3 mimetics for prostate cancer (PCa). Experimental Design: PCa cells or xenografts were treated with BH3 mimetics as single agents or in combination with other agents, and effects on MCL1 and apoptosis were assessed. MCL1 was also targeted directly using RNAi, CRISPR, or an MCL1 specific BH3 mimetic, S63845. Results: We initially found that MCL1 depletion or inhibition markedly sensitized PCa cells to apoptosis mediated by navitoclax, but not venetoclax, in vitro and in vivo, indicating that they are primed to undergo apoptosis and protected by MCL1 and BCLXL. Small molecule EGFR kinase inhibitors (erlotinib, lapatinib) also dramatically sensitized to navitoclax-mediated apoptosis, and this was associated with markedly increased proteasome-dependent degradation of MCL1. This increased MCL1 degradation appeared to be through a novel mechanism as it was not dependent upon GSK3b-mediated phosphorylation and subsequent ubiquitylation by the ubiquitin ligases bTRCP and FBW7, or through other previously identified MCL1 ubiquitin ligases or deubiquitinases. Inhibitors targeting additional kinases (cabozantinib and sorafenib) similarly caused GSK3b-independent MCL1 degradation, and in combination with navitoclax drove apoptosis in vitro and in vivo. Conclusions: These results show that PCa cells are primed to undergo apoptosis, and that co-targeting BCLXL and MCL1, directly or indirectly through agents that increase MCL1 degradation, can induce dramatic apoptotic responses.
https://ift.tt/2mqrTCV
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of anti-PD-1 Therapies in Metastatic Melanoma
Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients, therefore, biomarkers of response are needed. We hypothesized quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD1 response. Methods: Pre-treatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker positive cells and their co-localization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis (AQUA) algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score and IDO-1/HLA-DR co-expression were evaluated for anti-PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR co-expression was strongly associated with anti-PD-1 response (P = .0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = .0096). These patients also experienced significantly improved progression free survival (PFS; hazard ratio [HR] = 0.36; P = .0004) and overall survival (OS; HR = 0.39; P = .0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = .000004). In contrast, PD-L1 expression was not predictive of survival. Conclusion: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy.
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Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells
Horm Metab Res
DOI: 10.1055/a-0633-2706
Peroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Working Through the Paradox of Methotrexate Toxicity
SEE RELATED ARTICLE, P. 128.
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Exposed
The harsh tones of my pager broke the silence on a slow morning in Fast Track. That overcast spring day, the waiting room had slowed to a trickle and our urgent care area was empty.
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A Woman With Severe Rash
A 65-year-old woman was prescribed a new medication for rheumatoid arthritis. She unintentionally took this medication daily rather than weekly. On day 3, she developed a painful pruritic rash with a diffuse erosive process. Initial examination on day 10 noted a diffuse (70% body surface area) rash, mucositis (Figures 1 and 2), and pancytopenia.
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Construction Worker With Chest Pain
A 32-year-old male construction worker with no medical history presented to our emergency department with chest pain after an accidental discharge from a nail gun into the left side of his chest. The patient was hemodynamically stable, alert, oriented, and without dyspnea. He complained only of mild chest wall pain at the site of injury. Secondary survey result was unremarkable, with the exception of a small puncture wound in the fourth intercostal space, without active hemorrhage.
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What Role Has Emergency Medicine Played in the Opioid Epidemic? Partner in Crime or Canary in the Coal Mine?
Q1. Jeffery et al1 reference the 5 key questions proposed in the 2016 Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids for chronic pain.5
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Eleven-Year-Old Male With Weakness
A previously healthy 11-year-old boy presented to the emergency department with 3 weeks of progressive muscle weakness. He initially had weakness and fatigability of the lower extremities. He then developed left eye ptosis, slurring of his words, and difficulty chewing. Laboratory results obtained by his pediatrician, including those for CBC count, creatine phosphokinase level, erythrocyte sedimentation rate, and thyroid studies, were unremarkable. He denied fever, weight loss, or rash. On physical examination, his muscles had normal bulk; however, he had generalized hypotonia and weakness, with proximal muscles affected more than distal ones.
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Five Days at Memorial: Life and Death in a Storm-Ravaged Hospital
Five Days at Memorial: Life and Death in a Storm-Ravaged Hospital by Sheri Fink (@sherifink) invites the reader to examine what is expected of the medical community during times of disaster; specifically, what is demanded by our emergency medicine training in triage, disaster management, and end-of-life care, and what ethics form the foundation of our practice when preexisting systems around us fail. Dr. Fink's book offers an opportunity for us as health care practitioners to seriously consider what actions we would take if faced with a situation of conflict in settings of unfathomable duress and insufficient resources resulting from the near immediate and immense disparity between our usual practice and the severe, disaster-induced lack of basic resources confronting us.
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Human Mistake
"It's positive," the tech declared with disappointment, walking out of the utilities room.
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Young Man With Unilateral Neck Swelling
A 36-year-old male patient presented to our emergency department with a newly expanding mass in his neck. He had recently undergone a posterior cranial fossa resection of multiple schwannomas. He did not complain of neck pain, fever, headache, or new neurologic deficits. He was alert and oriented, with normal vital signs. The right-sided lesion extended from the base of the skull down the length of his neck and was fluctuant. There was no overlying warmth or erythema and no discharge was noted. All laboratory markers, including erythrocyte sedimentation rate and C-reactive protein, were normal.
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Girl With Chest Pain
A 13-year-old girl presented to the emergency department with sharp left upper quadrant abdominal pain, irradiating to the back and worsening with deep breathing or reclining. The pain had arisen suddenly 2 days before while she was swimming and was accompanied by low-grade fever (37.5°C [99.5° F]) and mild cough. Physical examination was remarkable for dullness and decreased breath sounds at the left lung base. Laboratory tests showed neutrophilic leukocytosis and elevated c-reactive protein level.
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In reply:
We thank Drs. Norii, Crandall, and Braude for their thoughtful comments suggesting that intraosseous access may be a proxy for longer time to return of spontaneous circulation compared with intravenous access.1 We have performed the suggested sensitivity analysis: we modified our multivariable logistic regression model to also include duration of out-of-hospital resuscitation among patients with return of spontaneous circulation or termination of resuscitation in the out-of-hospital setting (measured from the 911 call until either return of spontaneous circulation or termination of resuscitation, standardized data that were collected during clinical trials2) as one of the covariates.
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Wilderness EMS
There have been hundreds of field guides written about wilderness medicine. Wilderness EMS is not one of them. Seth Hawkins, MD, an emergency and emergency medical services (EMS) physician who has devoted much of his career to shaping the practice of medicine in places where "the surrounding environment has…more power over us than does the infrastructure of our civilization," has crafted a unique reference specifically authored for wilderness EMS professionals. Unlike typical wilderness medicine texts and guides that generally target the layperson whose hiking buddy breaks a leg or climber experiencing the first symptoms of altitude sickness, Wilderness EMS details an evidence-based approach to the practice of out-of-hospital medicine in austere environments.
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Classified
FLORIDA, Port Charlotte: Stable, 22 year old, progressive independent group seeking residency trained, board certified emergency physicians for expansion to second facility. 27k and 22k volume EDs. Full specialty backup. Excellent compensation based on productivity with full time income potential exceeding 350k. Flexible scheduling. Documentation by EMR. Malpractice, Health Insurance, Dental provided. Located on Charlotte Harbor with saltwater access to the Gulf. Short drive to Tampa, Sarasota, Fort Myers, Naples.
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Breaking Down Silos: The Joint Statement About the Clinical Use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Warrants Revision
Brenner et al1 recently published a joint statement between the American College of Surgeons Committee on Trauma and the American College of Emergency Physicians on the clinical use of resuscitative endovascular balloon occlusion of the aorta (REBOA). The statement created concern in both civilian and military communities by its—in our opinion—overly restrictive message and notable omissions.
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Classified 2018 Advertising Rates & Information
Ads and complete payments must be received in writing by the issue's deadline date. These deadlines apply to insertions, cancellations, and changes.
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Calendar
▮ Symposium by the Sea 2018. August 2–5, 2018. Fort Myers, FL. Contact: Evan Buckley. Email: ebuckley@emlrc.org. Url: http://www.cvent.com. (15.0)
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Is Procalcitonin-Guided Antibiotic Therapy Working in Emergency Department Outpatients?
We thank Drs. Tupchong and Chien for their summary comment1 in regard to our recent metanalysis.2,3
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Towards a personalized benefit-risk balance for immunosuppressive therapy in inflammatory bowel disease
Infections, cancers and cardiovascular events are the main events that may be attributable to inflammatory bowel disease (IBD) and/or IBD treatment. Immunosuppressive drugs have been shown to promote immunosuppression-related infections and cancers. Via mucosal healing, immunosuppressive drugs should be able to reduce the incidence of infections related to intestinal lesions, malnutrition, intravenous devices and IBD surgery, and to reduce the incidence of cancers attributable to chronic mucosal inflammation.
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Environmental factors, gut microbiota, and colorectal cancer prevention
The substantial burden of colorectal cancer and increasing trend in young adults highlight the importance of lifestyle modification as a complement to screening for colorectal cancer prevention. Several dietary and lifestyle factors have been implicated in the development of colorectal cancer, possibly through the intricate metabolic and inflammatory mechanisms. Likewise, as a key metabolic and immune regulator, the gut microbiota has been recognized to play an important role in colorectal tumorigenesis.
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Mental Health No Different for Offspring of Lesbian Parents
WEDNESDAY, July 18, 2018 -- Mental health does not differ significantly between offspring with sexual minority parents from the community-based National Longitudinal Lesbian Family Study (NLLFS) and a matched normative population-based sample,...
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Mechanical and aesthetics compatibility of Brazilian red propolis micellar nanocomposite as a cavity cleaning agent
Propolis is a natural substance produced by bees and is known to have antimicrobial activity. Our aim was to evaluate the antimicrobial effect of micellar nanocomposites loaded with an ethyl acetate extract of...
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Anti-cancer activity of Angelica gigas by increasing immune response and stimulating natural killer and natural killer T cells
The polysaccharide component of Angelica gigas induces immuno-stimulatory effects on innate immune cells. However, it is unclear whether A. gigas' adjuvant activity on the immune system can elicit anti-cancer res...
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Identification of LETM1 as a marker of cancer stem-like cells and predictor of poor prognosis in esophageal squamous cell carcinoma
Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is closely related to the occurrence and development of malignant tumors. This study discusses the expression of LETM1 in esophageal squamous carcinoma (ESCC) and its association with cancer stem-like cells (CSC). We used immunohistochemistry in 166 ESCC tissue samples, as well as western blot, and immunofluorescent methods in ESCC cell lines to study the role of LETM1 and its association with CSC in ESCC. The expression of LETM1 was significantly higher in ESCC, and it was closely related to the primary tumor (pT) stage and clinical stage.
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Immunohistochemical characteristics of Renomedullary interstitial cell tumor: a study of 41 tumors with emphasis on differential diagnosis of mesenchymal neoplasms
Renomedullary interstitial cell tumors (RMICT) are almost always incidentally identified either at autopsy or resection of the kidney for other reasons. However, rare cases have been reported which are large, resulting in a clinical mass. The immunohistochemical phenotype of usual, incidental RMICT using modern soft tissue tumor markers in is largely unknown, however, providing little information to aid in classification of larger or atypical tumors. We retrieved 41 RMICTs from 36 patients, and studied pathologic characteristics including morphology, immunohistochemistry (S100, keratin AE1/AE3, smooth muscle actin, desmin, estrogen and progesterone receptors, calponin, CD34, CD35), and histochemical staining.
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Metastatic breast Cancer simulating well-differentiated neuroendocrine neoplasms of visceral organs
A series of metastatic breast carcinoma (MBC) mimicking visceral well-differentiated neuroendocrine neoplasms has not previously been reported. We identified five consultation cases originally submitted as neuroendocrine neoplasms in females but which were found to be MBC on subsequent review. All 5 neoplasms demonstrated nested architecture and relatively uniform nuclei. Four patients had a known history of breast cancer (remote in 3 and concurrent in 1), but the metastases (3 liver, 1 lung) labeled for chromogranin and/or synaptophysin, prompting misdiagnosis as neuroendocrine neoplasm.
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Role of complement system in patients with biopsy-proven IgG4 related kidney disease
Hypocomplementaemia has been frequently reported in IgG4 related kidney disease (IgG4-RKD). However, studies on the role of complement system in IgG4-RKD are lacking. A total of 40429 renal biopsies from January 2010 to January 2018 were re-examined in the present study, and 17 patients were confirmed to meet the criteria of IgG4-RKD. According to the serum C3 levels, they were divided into two groups: the low C3 group (C3<0.8g/L, n=7) and the normal C3 group (C3≥0.8g/L, n=10). Compared with the normal C3 level group, the patients in the low C3 level group had lower serum C4 concentrations (P=.025), higher serum IgG4 concentrations (P=.003), higher positive rates in rheumatoid factor (P=.033), more severe storiform fibrosis (P=.007) at diagnosis, and higher blood urea nitrogen levels at the latest test (P=.04).
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PD-1, PD-L1 and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1 and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extra-pancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas (ACs) were immunostained using antibodies against PD-1, PD-L1 and CD163.
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Histomorphometric Evaluation of the Ki-67 Proliferation Rate and CD34 Microvascular and D2-40 Lymphovascular Densities Drives the Pulmonary Typical Carcinoid Outcome
Ki-67 has shown promise as a prognostic factor in pulmonary carcinoids. In this study, we sought to validate the importance of Ki-67 and study the relationships between Ki-67 and other stromal biomarkers of vascular density. We examined Ki-67, CD34 and D2-40 in tumor tissues from 128 patients with surgically excised typical carcinoid of the lung. We used immunohistochemistry and morphometry to evaluate the amount of tumor staining for cellular proliferation (Ki-67), microvascular density (CD34-MVD) and lymphovascular density (D2-40-LVD).
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IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma
Malignant peritoneal mesothelioma (MPeM) is an incurable cancer with poor prognosis and several biomarkers have been suggested for screening of MPeM. The aim of our study was to evaluate the prognostic significanceas of IMP3 and Fli-1 in MPeM. Diagnostic biopsies of 44 MPeM patients were centrally collected and were immunohistochemically analyzed for expression of IMP3, Fli-1, and Ki-67. Labelling was assessed by two pathologists. Complete clinical information and follow up were obtained from patients' records.
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TFE3 is a diagnostic marker for solid pseudopapillary neoplasms of the pancreas
Aberrant Wnt signaling is a hallmark of solid pseudopapillary neoplasms of the pancreas (SPN). Transcription factor E3 (TFE3) plays a critical role in activation and regulation of the Wnt pathway, and is predicted to be a candidate gene implicated in SPN by gene regulatory network analysis. The aim of this study was to evaluate TFE3 as a marker for SPN. Paraffin embedded tissues of SPN (n = 75) and other primary pancreatic tumors were analyzed, including pancreatic neuroendocrine tumors (PanNET) (n = 17), pancreatic ductal adenocarcinomas (PDAC) (n = 14), pancreatic neuroendocrine carcinomas (PanNEC) (n = 4) and acinar cell carcinomas (ACC) (n = 3).
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Seven Strategies Can Help Practices Manage Staff Time Off
WEDNESDAY, July 18, 2018 -- Several strategies can be implemented to help address management of staff time off, allowing mutual respect for the employee and employer requests, according to an article published in Medical Economics. Noting that when...
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Australian Researchers Develop First Blood Test for Melanoma
WEDNESDAY, July 18, 2018 -- The first blood test to detect melanoma skin cancer in its early stages has been created, according to a study published in the July 17 issue of Oncotarget. Pauline Zaenke, of Edith Cowan University in Perth, Australia,...
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Overall Cancer Mortality Rates Decreasing for Men and Women
WEDNESDAY, July 18, 2018 -- Cancer incidence rates have decreased among men but remained stable among women, while cancer death rates are decreasing for both men and women, according to a report published in the July 1 issue of Cancer. Kathleen A....
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Salmonella Outbreak Linked to Hy-Vee Spring Pasta Salad
WEDNESDAY, July 18, 2018 -- A Salmonella outbreak that's sickened 21 people in five states has been linked to Hy-Vee Spring Pasta Salad. Five people have been hospitalized. No deaths have been reported, the U.S. Centers for Disease Control and...
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The Association Between Inhaled Nitric Oxide Treatment and ICU Mortality and 28-Day Ventilator-Free Days in Pediatric Acute Respiratory Distress Syndrome
Objectives: To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome. Design: Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the analysis. Setting: Two quaternary care PICUs. Patients: Children with pediatric acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: There were 499 children enrolled in this study with 143 (28.7%) receiving inhaled nitric oxide treatment. Children treated with inhaled nitric oxide were more likely to have a primary diagnosis of pneumonia (72% vs 54.8%; p 0.2) Conclusions: Treatment with inhaled nitric oxide in pediatric acute respiratory distress syndrome is not associated with improvement in either mortality or ventilator-free days and may be associated with harm. Further prospective trials are required to define the role of inhaled nitric oxide treatment in pediatric acute respiratory distress syndrome. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by Institutional funds from the Children's Hospital Los Angeles Department of Critical Care and Anesthesiology. Dr. Bhalla disclosed that the work described in this application has been submitted as a master's thesis at the University of Southern California and she disclosed off-label product use of inhaled nitric oxide treatment in acute respiratory distress syndrome and she is supported through a grant from National Center for Advancing Translational Sciences (NCATS) (UL1TR001855). Dr. Yehya's institution received funding from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Wilson received funding from the Global Collaboration (collaborative group that provides funding to attend annual executive meeting). Drs. Mack and Wilson are supported through grants from NCATS (UL1TR001855 and UL1TR000130). Dr. Khemani received funding from Orange Med (consulting work unrelated to this project). Dr. Newth received funding from Philips Research North America and Covidien. For information regarding this article, E-mail: abhalla@chla.usc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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Moderate and Severe Acute Respiratory Distress Syndrome: Hemodynamic and Cardiac Effects of an Open Lung Strategy With Recruitment Maneuver Analyzed Using Echocardiography
Objectives: Open lung ventilation with a recruitment maneuver could be beneficial for acute respiratory distress syndrome patients. However, the increased airway pressures resulting from the recruitment maneuver may induce cardiac dysfunction, limiting the benefit of this maneuver. We analyzed the effect of a recruitment maneuver and decremental positive end-expiratory pressure titration on cardiac function. Settings: Medical ICU Amiens, France. Patients: Twenty patients with moderate to severe acute respiratory distress syndrome Interventions: Patients underwent a stepwise recruitment maneuver with respiratory evaluation and echocardiography assessment of cardiac function including longitudinal strain at baseline, peak positive end-expiratory pressure of recruitment maneuver (positive end-expiratory pressure 40 cm H2O), and at "optimal" positive end-expiratory pressure. The patients were divided into two groups based on change on the PaO2/FIO2 ratio (nonresponders
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Systemic High-Mobility Group Box-1: A Novel Predictive Biomarker for Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage
Objectives: To investigate the release of proinflammatory damage-associated molecular pattern molecule "high-mobility group box-1" in the serum of patients after aneurysmal subarachnoid hemorrhage and its association with cerebral vasospasm. Design: Retrospective observational study. Setting: University hospital. Patients: Aneurysmal subarachnoid hemorrhage patients admitted within 24 hours of ictus. Interventions: Standard subarachnoid hemorrhage treatment after clipping or coiling of aneurysm. Measurements and Main Results: We enrolled 53 aneurysmal subarachnoid hemorrhage patients from which peripheral venous blood was withdrawn on days 1, 3, 5, 7, 9, 11, and 13 and once from the controls to obtain the serum. Serum high-mobility group box-1 concentration was quantified by enzyme-linked immunosorbent assay. Serum interleukin-6 and peripheral blood leukocytes were also determined over the first 2 weeks after subarachnoid hemorrhage. Patients' data were recorded prospectively. Serum high-mobility group box-1 was significantly elevated in subarachnoid hemorrhage patients from day 1 to day 13 when compared with nonsubarachnoid hemorrhage patients (p
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New Morbidity and Discharge Disposition of Pediatric Acute Respiratory Distress Syndrome Survivors
Objectives: Much of the research related to pediatric acute respiratory distress syndrome has focused on inhospital mortality and interventions affecting this outcome. Limited data exist on survivors' morbidity, hospital disposition, and 1-year survival. The aim of this study was to determine new morbidity rate, discharge disposition, and 1-year mortality for survivors of pediatric acute respiratory distress syndrome. Design: Secondary analysis of prospective cohort study. Setting: Quaternary children's hospital. Patients: Three-hundred sixteen mechanically ventilated children with pediatric acute respiratory distress syndrome (Berlin and Pediatric Acute Lung Injury Consensus Conference criteria) between July 2011 and December 2014. Interventions: None. Measurements and Main Results: We performed secondary analysis of a prospectively recruited cohort of 316 mechanically ventilated children with pediatric acute respiratory distress syndrome between July 2011, and December 2014. Preillness and hospital discharge Functional Status Scale score were determined via chart review, and factors associated with new morbidity, defined as an increase of Functional Status Scale score of 3 or more, were analyzed. Demographic variables, pediatric acute respiratory distress syndrome characteristics, and ventilator management were tested for association with development of new morbidity, discharge disposition, and 1-year mortality. Inhospital mortality of pediatric acute respiratory distress syndrome was 13.3% (42/316). Of 274 survivors to hospital discharge, new morbidity was seen in 63 patients (23%). Discharge to rehabilitation rate was 24.5% (67/274) and associated with development of new morbidity. One- and 3-year mortality of survivors was 5.5% (15 deaths) and 8% (22 deaths) and was associated with baseline Functional Status Scale, immunocompromised status, Pediatric Risk of Mortality III, and organ failures at pediatric acute respiratory distress syndrome onset, but not with pediatric acute respiratory distress syndrome severity. Conclusions: New morbidity was common after pediatric acute respiratory distress syndrome and appears to be intermediate phenotype between survival without morbidity and death, making it a useful metric in future interventional and outcome studies in pediatric acute respiratory distress syndrome. Dr. Keim assisted in the conceptualization of the study, preformed the majority of the data collection, and drafted the initial article. Dr. Watson and Thomas contributed their expertise in long-term outcome studies, reviewed the data, and assisted in the revision of the article. Dr. Yehya originally conceptualized the study, assisted in data collection, preformed the initial data analysis, and contributed to the initial article review and revision of the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by grants from the National Institutes of Health K12-HL109009 and K23-HL136688 (to Dr. Yehya). Dr. Keim received support for article research from the National Institutes of Health (NIH). Dr. Thomas reports personal fees from Therabron and CareFusion and grants from the Federal Drug Association, all outside of the submitted work. Dr. Thomas' institution received funding from GeneFluidics, and he received funding from CareFusion and Therabron. Dr. Yehya's institution received funding from the NIH/National Heart, Lung, and Blood Institute, and he received support for article research from the NIH. Dr. Watson has disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: keimg@email.chop.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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