No abstract available
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Τρίτη 19 Σεπτεμβρίου 2017
Early effects of renal replacement therapy on cardiovascular comorbidity in children with end-stage kidney disease: findings from the 4C-T Study.
Background: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective 4C study and focuses on the early effects of RRT modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis. Methods: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n=76 transplantation, n=90 dialysis). Results: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity ([latin sharp s]=-0.67; p
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Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company (GlaxoSmithKline) that manufactures mepolizumab (Nucala®) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42–0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36–0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust.
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Safety, Tolerability, and Pharmacokinetics of Radavirsen (AVI-7100), an Antisense Oligonucleotide Targeting Influenza A M1/M2 translation
Summary
Aims
To assess the safety, tolerability, and pharmacokinetics (PK) of radavirsen following single ascending doses and multiple doses given as IV infusions in healthy adults.
Methods
A Phase 1 safety and pharmacokinetic (PK) study of radavirsen was performed in healthy volunteers. The study was divided into 2 parts. The first was a single-ascending dose study of 5 cohorts of 8 subjects each, randomized 6:2 to receive single intravenous doses of radavirsen ranging from 0.5 to 8 mg/kg or placebo. The second was a multiple dose study of 16 subjects randomized 12:4 to receive 8 mg/kg or placebo once daily for 5 days.
Results
66 subjects were screened and 56 subjects were dosed between 2013 and 2015. At least one adverse event occurred in 31/42 (74%) who received radavirsen, and 13/14 (93%) receiving placebo. The most common adverse events were headache and proteinuria, and were similar among those receiving radavirsen or placebo. Single dose PK demonstrated relatively linear and dose-proportional increases in maximal concentration and area-under-the-concentration-time curve (AUC0-24). At 8 mg/kg in the multiple dose cohort, the Day 4 geometric mean AUC0-24 was 57.9 μg*h/mL.
Conclusion
Single infusions of radavirsen up to 8 mg/kg, and multi-dosing at 8 mg/kg once daily for 5 days, appear to be safe and well-tolerated in healthy subjects. The multi-dose Day 4 AUC0-24 this study is comparable to the AUC which was associated with protection from viral infection in a preclinical ferret influenza model. Further evaluation of radavirsen for the treatment of influenza infections is warranted.
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Accelerated Wound Healing on Skin by Electrical Stimulation with a Bioelectric Plaster
Wound healing on skin involves cell migration and proliferation in response to endogenous electric current. External electrical stimulation by electrical equipment is used to promote these biological processes for the treatment of chronic wounds and ulcers. Miniaturization of the electrical stimulation device for wound healing on skin will make this technology more widely available. Using flexible enzymatic electrodes and stretchable hydrogel, a stretchable bioelectric plaster is fabricated with a built-in enzymatic biofuel cell (EBFC) that fits to skin and generates ionic current along the surface of the skin by enzymatic electrochemical reactions for more than 12 h. To investigate the efficacy of the fabricated bioelectric plaster, an artificial wound is made on the back skin of a live mouse and the wound healing is observed for 7 d in the presence and absence of the ionic current of the bioelectric plaster. The time course of the wound size as well as the hematoxylin and eosin staining of the skin section reveals that the ionic current of the plaster leads to faster and smoother wound healing. The present work demonstrates a proof of concept for the electrical manipulation of biological functions by EBFCs.
Wound healing on skin is accelerated by a plaster device with a built-in enzymatic biofuel cell that drives ionic current on the wound. Cells in the skin respond to electric current during wound healing processes. A stretchable bioelectric plaster fits to skin and generates ionic current on the wound by enzymatic electrochemical reactions to promote these processes.
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UWB pulse detection and TOA estimation using GLRT
In this paper, a novel statistical approach is presented for time-of-arrival (TOA) estimation based on first path (FP) pulse detection using a sub-Nyquist sampling ultra-wide band (UWB) receiver. The TOA measu...
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Impact of IL-12 in Cancer
Background: Interleukin 12 (IL-12) is a pleiotropic cytokine that plays an essential role in Th1-type immune response against cancer, a condition where cells in a particular part of the body grow and reproduce uncontrollably.
Methods: In this review, we describe the structural features of IL-12 family and their roles involved in cancer.
Results: IL-12 has been demonstrated to regulate both innate (natural killer cells) and adaptive (cytotoxic T lymphocytes) immunities in cancer therapy. This cytokine has been proposed as a potential new agent to be developed in cancer immunotherapy studies due to its impressive antitumor effects in many animal models. In addition, the antitumor activity of IL-12 can be efficiently induced by itself as well as significantly improved by its combination with various treatment modalities including antibodies, antiangiogenic agents, radiotherapy, adoptive therapy, and anti-tumor vaccines.
Conclusion: IL-12 has potential roles in anticancer therapy. The advantages of using immunotherapeutic approaches in clinical trials have been reported recently. However, the mechanisms to underlay the immunoregulation and antitumor activities of IL-12 itself, as well as its combination, remain under investigation.
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Method to Assess Interactivity of Drugs with Nonparallel Concentration Effect Relationships
Background: Commonly used methods for analyzing interactivity between drugs (e.g. synergy, antagonism) such as isobologram, combination index, and curve shift are based on the Loewe Additivity principle of dose equivalence and the inherent assumption of similar concentration- effect (C-E) including parallel curves and equal maximum effects (Emax), and therefore are not suitable for drugs with dissimilar C-E. This study describes a new method that is without this limitation and has the additional advantage of enabling statistical analysis.
Methods and Results: The method comprises two steps. First, based on the dose equivalence principle, the experimentally obtained C-E of one drug was used to calculate the equally effective C-E of the other drug at no interactivity; the resulting two zero-interactivity C-E formed the upper and lower boundaries of Additivity Envelope. Next, 95% confidence intervals calculated from experimental data were added to Additivity Envelope to obtain Uncertainty Envelope (UE). Experimentally observed effects of drug combinations (C-Ecomb,observed) located within UE indicate additivity whereas C-Ecomb,observed located above or below UE indicate statistically significant (p
Conclusion: UE is a broadly applicable method for analysis, including statistical significance assessment, of drug interactivity.
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Epithelial-to-Mesenchymal Transition: A Mediator of Sorafenib Resistance in Advanced Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC.
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In-silico & In-vitro Identification of Structure-Activity Relationship Pattern of Serpentine & Gallic Acid Targeting PI3Kγ as Potential Anticancer Target
Background: Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3-kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer.
Objective: To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kγ, a detail structure-activity relationship study was performed.
Method: In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kγ isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity.
Results: A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kγ.
Conclusion: The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In-silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation.
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Potential Therapeutic Targets in Energy Metabolism Pathways of Breast Cancer
Background: Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions.
Objective: This paper summarizes the isozymes overexpressed in breast cancer, their roles of energy metabolism and cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer.
Method: Information has been collected from recently published literature available on Google Scholar and PubMed. Where available, in vivo results were given more importance over in vitro works.
Result: Like many other cancers, breast cancer shows increased dependence on glycolysis rather than mitochondrial respiration, the main energy source in healthy cells. Cancer cells alter the cellular energy system in a way that helps minimize level of reactive oxygen species and simultaneously produce enough macromolecules- proteins, lipids and nucleotides for cellular proliferation. The altered system enables the cells to grow, proliferate, metastasize and to develop drug resistance. Certain isozymes of metabolic enzymes are overexpressed in breast cancer and the degree of expression of these enzymes vary among subtypes.
Conclusion: A clear understanding of the variations of energy metabolism in different molecular subtypes of breast cancer would help in treating each type with a very customized, safer and efficient treatment regimen. Anti-cancer drugs or RNAi or combination of both targeting cancer cell specific isozymes of metabolic enzymes mentioned in this article could offer a great treatment modality for breast cancer.
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The β 2-Adrenergic Agonist Salbutamol Inhibits Migration, Invasion and Metastasis of the Human Breast Cancer MDA-MB- 231 Cell Line
Background: Breast cancer is the most diagnosed and the major cause of cancer death in women worldwide. Metastasis is the main cause of these deaths. The metastatic cascade involves multiple steps and it has been described that adrenergic receptors can modulate this process at multiple levels. However, β -adrenergic action in breast cancer is controversial. We have previously shown that β-adrenergic agonists inhibit cell proliferation and tumor growth of numerous breast cancer models.
Objective: The purpose of the present investigation was to evaluate adrenergic effect in parameters related to tumor progression (migration, invasion and metastases) in two human breast cancer cell lines. Methods: Migration was assessed in IBH-6 and MDA-MB-231 cells by time-lapse videomicroscopy and modified Boyden chambers. Invasion was evaluated by Transwells coated with Matrigel and expression of pro-metastatic genes was determined by RT-qPCR. Experimental metastases studies were performed by injection of the cells in the tail vein of NSG immuno-deficient mice.
Results: In both cell lines, salbutamol (β2-agonist) and propranolol (β-blocker) significantly diminished cell migration while epinephrine exerted opposite effects. Moreover, salbutamol inhibited invasion of both breast cancer cell lines and enhanced adhesion to extracellular matrix. Salbutamol treatment was also able to decrease the expression of pro-metastatic genes in MDA-MB-231 cells. Finally, this compound decreased the number and size of MDA-MB-231 lung experimental metastases in NSG immuno- deficient mice. No effect on the establishment of IBH-6 metastases was observed.
Conclusion: Our results suggest that salbutamol could be an effective adjuvant drug for the treatment of metastatic breast cancer.
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Automatic sleep staging using ear-EEG
Sleep and sleep quality assessment by means of sleep stage analysis is important for both scientific and clinical applications. Unfortunately, the presently preferred method, polysomnography (PSG), requires co...
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Modification of C-Terminus Provides New Insights into the Mechanism of -Synuclein Aggregation
Aggregation of neuronal protein α-synuclein leads to the formation of amyloid fibrils, which are associated with the development of Parkinson's disease. The mechanism of α-synuclein pathology is not fully understood and is a subject of active research in the field. To tackle this problem, the fusions of fluorescent proteins to α-synuclein C-terminus are often used in cellular and animal studies. The effects induced by such α-synuclein sequence extension on α-synuclein aggregation propensity are, however, not systematically examined despite the evidence that the negatively charged C-terminus plays a critical role in the regulation of α-synuclein aggregation.
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Genomics and 3-Dimensional Brachytherapy for Cervical Cancer: Significant Steps Forward
In this issue of Oncology Scan, the Gynecologic Cancer editors discuss publications of molecular analysis of primary cervical cancer as part of the Cancer Genome Atlas project and advancements in 3-dimensional (3D) brachytherapy (BT) for cervical cancer. The genomic study highlights a specific type of cervical cancer classified as keratin-low, which has lower survival with surgery, and further work needs to be done to determine whether this difference in outcome holds true for patients treated with definitive chemoradiation therapy.
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A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery
Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose-volume predictors.
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Doing the Right Thing for the Wrong Reason
In this issue of the International Journal of Radiation Oncology • Biology • Physics (the Red Journal), Tao et al (1) report the results of a phase 3, randomized, placebo-controlled trial of a glycosaminoglycan analog (OTD70DERM) for reduction of radiation-associated skin toxicity in patients treated with radiation and concurrent cetuximab. The authors should be commended for the rigor of the study, which included a double-blinded design, independent review of photographs by an expert panel, and longitudinal patient-reported quality of life measures.
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Salvage Treatment Options for Recurrent Seminoma?
A 58-year-old patient without comorbidities was diagnosed with a seminoma of the right testis. An inguinal orchiectomy was performed with a primary tumor stage T2N0MS0, stage IB (tumor markers α-fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase were within normal ranges). A surveillance strategy was decided without adjuvant treatment.
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A House Divided: The Irradiation Versus Prostatectomy Debate Continues
We read with interest the recent Red Journal article "Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?" by Roach et al (1). This was a thoughtful and critical analysis of the complex literature relating to irradiation versus prostatectomy in men with localized prostate cancer. Overall, the authors assigned low reliability scores to many of the studies evaluated, citing an inadequate (or unreported) duration of androgen deprivation therapy (ADT) with radiation therapy for intermediate- or high-risk disease, unadjusted survival metrics, or incomplete reporting of patient or disease features.
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Adaptive Radiation Therapy: Off-Line, On-Line, and In-Line?
In a recent critical review by Lim-Reinders et al (1), published online in the Red Journal, the authors are applauded for tackling an important and relevant critical review about on-line adaptive radiation therapy (ART). The authors provide a rationale for ART, differentiate between on-line and off-line approaches, and review the concepts and challenges associated with the various workflow procedures underlying on-line ART. They present examples of how different on-line approaches have been implemented at various treatment centers, and they also summarize the literature relevant to the application of on-line ART for different treatment sites.
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ProtecTing Low-Risk Prostate Cancer
The landmark Prostate Testing for Cancer and Treatment (ProtecT) study was published in September 2016 (1). This is the first randomized trial to answer the question of which treatment among surgery, radiation therapy, and active surveillance is best for low-risk prostate cancer. The fact that the authors were able to perform and complete this study deserves immense credit.
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Addressing the Challenges of Narrow Network Plans in Oncology
The breadth of a health insurance plan's network typically dictates the level of access that a consumer will have to primary care physicians, specialists, and other types of health care providers. Thus, the comprehensiveness of plan networks—including whether consumers have access to in-network cancer centers—is a critical component of quality health insurance. In response to increased health care costs and pressure to keep premiums down, health plans have begun to adopt "narrow network" plans. A narrow network plan has been typically defined as a plan with a more limited number of providers as compared with typical insurance plans (1).
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The Problem of Establishing Standards of Care in an Uncommon Malignancy: Brachytherapy for Invasive Penile Carcinoma
In this issue of the International Journal of Radiation Oncology • Biology • Physics, Escande et al (1) report a phenomenal single-institution experience with interstitial 192Ir low-dose-rate or pulsed-dose-rate brachytherapy for squamous cell carcinoma of the glans penis. Their experience, which spans 45 years and involves more than 200 patients with a median follow-up of more than 10 years, indisputably establishes interstitial brachytherapy as an effective penile-sparing modality for squamous cell carcinoma of the glans.
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Optimizing Dose Per Fraction: A New Chapter in the Story of the Abscopal Effect?
I had the privilege to be mentored by Rodney Withers and Jack Fowler, two of the many scientific giants who dedicated their lives to the subject of radiation dose and fractionation (D&F). I also always remember Norman Coleman's sentence that "Radiation is a different drug at different doses and fractionation schedules." It is not then a surprise that when we ventured into exploring the immune effects of radiation therapy, I encouraged the laboratory to focus on investigating the optimal D&F.
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Perspectives on Postmastectomy Radiation Therapy for Persistent Nodal Disease After Neoadjuvant Chemotherapy: Is Hindsight 20/20?
Postmastectomy radiation therapy (PMRT) generally improves locoregional control and overall survival in patients with pathologic lymph node-positive breast cancer, as evidenced by meta-analyses of randomized trials (1). Nevertheless, controversy persists regarding whether PMRT is indicated for all such patients, especially those with clinical T1-T3N1 who receive neoadjuvant chemotherapy (NAC) with a complete pathologic response in the involved axillary lymph nodes (ypN0). For such patients, the current standard recommendation is to offer entry into clinical trials comparing regional nodal irradiation (RNI) versus no RNI (2), such as the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51/Radiation Therapy Oncology Group 1304 trial.
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In Reply to van der Steen-Banasik et al
To the Editor: We appreciate the comments by Dr van der Steen-Banasik and colleagues (1). We agree with the assessment that the work previously conducted by van der Steen-Banasik et al and Nieuwenhuijzen et al included the critical component of brachytherapy in the radiation cohorts (2, 3). This information was not included in our Table 1 because we focused more attention on the number of patients who required salvage treatment. For out meta-analysis data, we believed that limiting information regarding salvage treatment, particularly salvage cystectomy, could fail to identify cross-over between different treatment arms.
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Modification of C-Terminus Provides New Insights into the Mechanism of α-Synuclein Aggregation
Aggregation of neuronal protein α-synuclein leads to the formation of amyloid fibrils, which are associated with the development of Parkinson's disease. The mechanism of α-synuclein pathology is not fully understood and is a subject of active research in the field. To tackle this problem, the fusions of fluorescent proteins to α-synuclein C-terminus are often used in cellular and animal studies. The effects induced by such α-synuclein sequence extension on α-synuclein aggregation propensity are, however, not systematically examined despite the evidence that the negatively charged C-terminus plays a critical role in the regulation of α-synuclein aggregation.
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Roles for Innate Immunity in Combination Immunotherapies
Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Here we review antitumor activities of innate immune cells, mechanisms of their synergy with adaptive immune responses against tumors, and discuss recent studies highlighting the potential of combination therapies recruiting both innate and adaptive immune effectors to eradicate established tumors. Cancer Res; 77(19); 1–7. ©2017 AACR.
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New Advances and Challenges of Targeting Cancer Stem Cells
The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20–23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. The reported advances of CSC research and therapies fostered new collaborations across national and international borders, and inspired the next generation's young scientists. Cancer Res; 77(19); 1–6. ©2017 AACR.
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Detection of bacterial pathogens from clinical specimens using conventional microbial culture and 16S metagenomics: a comparative study
Infectious disease is the leading cause of death worldwide, and diagnosis of polymicrobial and fungal infections is increasingly challenging in the clinical setting. Conventionally, molecular detection is stil...
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Variation in loss of immunity shapes influenza epidemics and the impact of vaccination
Protective antibody immunity against the influenza A virus wanes in 2–7 years due to antigenic drift of the virus' surface proteins. The duration of immune protection is highly variable because antigenic evolu...
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The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of Both Centromeric and Two Micron Plasmids in Saccharomyces cerevisiae
Protein degradation by the ubiquitin-proteasome system is essential to many processes. We sought to assess its involvement in the turnover of mitochondrial proteins in Saccharomyces cerevisiae. We find that deletion of a specific ubiquitin ligase (E3), Psh1p, increases the abundance of a temperature-sensitive mitochondrial protein, mia40-4pHA, when it is expressed from a centromeric plasmid. Deletion of Psh1p unexpectedly elevates the levels of other proteins expressed from centromeric plasmids. Loss of Psh1p does not increase the rate of turn-over of mia40-4pHA, affect total protein synthesis, or increase the protein levels of chromosomal genes. Instead, psh1 appears to increase the incidence of missegregation of centromeric plasmids relative to their normal 1:1 segregation. After generations of growth with selection for the plasmid, ongoing missegregation would lead to elevated plasmid DNA, mRNA, and protein, all of which we observe in psh1 cells. The only known substrate of Psh1p is the centromeric histone H3 variant Cse4p, which is targeted for proteasomal degradation after ubiquitination by Psh1p. However, Cse4p overexpression alone does not phenocopy psh1 in increasing plasmid DNA and protein levels. Instead, elevation of Cse4p leads to an apparent increase in 1:0 plasmid segregation events. Further, two micron high-copy yeast plasmids also missegregate in psh1, but not when Cse4p alone is overexpressed. These findings demonstrate that Psh1p is required for the faithful inheritance of both centromeric and two micron plasmids. Moreover, the effects that loss of Psh1p has on plasmid segregation cannot be accounted for by increased levels of Cse4p.
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Benchmarking against the National Emergency Laparotomy Audit recommendations
Background
The Royal College of Anaesthetists published the National Emergency Laparotomy Audit (NELA) to describe and compare inpatient care and outcomes of major emergency abdominal surgery in England and Wales in 2015 and 2016. The purpose of this article is to compare emergency abdominal surgical care and mortality in a regional hospital (Logan Hospital, Queensland, Australia) with NELA results.
Methods
Data were extracted from two databases. All deaths from May 2010 to April 2015 were reviewed and patients who had an emergency abdominal operation within 30 days of death were identified. The health records of all patients who underwent abdominal surgery were extracted and those who had an emergency laparotomy were identified for analysis.
Results
Three hundred and fifty patients underwent emergency laparotomy and were included in the analysis. The total 30-day mortality during this 5-year period was 9.7%. Factors affecting mortality included age, Portsmouth-Physiological and Operative Severity Score (P-POSSUM) and admission source. Timing of antibiotic administration, use of perioperative medical service and frequency of intensive care admission were the same in patients who died and survived.
Conclusion
Mortality in patients following emergency laparotomy at Logan Hospital compares favourably with 11.1% reported by NELA. This may be partly attributable to case mix distribution as for each P-POSSUM risk Logan Hospital mortality was at the upper end of that reported by NELA. Further Australia data are required. Improved compliance with NELA recommendations may improve outcomes.
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HIGH BCR-ABL/GUSIS LEVELS AT DIAGNOSIS OF CHRONIC PHASE CML ARE ASSOCIATED WITH UNFAVORABLE RESPONSES TO STANDARD-DOSE IMATINIB
Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate Imatinib responses. Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABLIS transcripts at diagnosis with the outcome - defined by the 2013 European LeukemiaNet recommendations - of 272 newly diagnosed CML patients receiving Imatinib 400 mg/daily. Applying Receiver Operating Characteristic curves we defined BCR-ABL/GUSIS and BCR-ABL/ABLIS levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS) and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings", 22.4% failed Imatinib and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (p<0.001), FFS (p<0.001) and EFS (p<0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (p=0.029) but not with OS (p=0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (p=0.03), FFS (p=0.001) and EFS (p=0.005), but not with TFS (p=0.167) or OS (p=0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured employing GUS as a reference gene identify CML patients unlikely to benefit from standard dose Imatinib.
http://ift.tt/2ypjy7B
ImmunoPET of malignant and normal B cells with 89Zr- and 124I-labeled obinutuzumab antibody fragments reveals differential CD20 internalization in vivo
Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20. Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab (Rx) and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89Zr) versus non-residualizing (124I) radionuclides by region of interest (ROI) analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to asses antigen modulation in vivo. Results: 124I-GAcDb and 124I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers. ImmunoPET imaging of huCD20TM showed specific uptake in lymphoid tissues. The use of the radiometal 89Zr as alternative label for GAcDb and GAcMb yielded greater target-specific uptake and retention compared with 124I-labeled tracers. Pairwise comparison of 89Zr- and 124I-labeled GAcDb and GAcMb allowed assessment of in vivo internalization of CD20/antibody complexes and revealed that CD20 internalization differs between malignant and endogenous B cells. Conclusions: These obinutuzumab-based PET tracers have the ability to noninvasively and quantitatively monitor CD20-expression and have revealed insights into CD20 internalization upon antibody binding in vivo. Because they are based on a humanized mAb they have the potential for direct clinical translation and could improve patient selection for targeted therapy, dosimetry prior to radioimmunotherapy (RIT), and prediction of response to therapy.
http://ift.tt/2xPhzvU
The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-derived IL-6
Purpose: Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAM in colorectal cancer (CRC) are contradictory. We therefore investigated the functions, mechanisms and clinical significance of TAMs in CRC. Experimental Design: We measured the macrophage infiltration (CD68), P-gp and Bcl2 expression in CRC tissues using Immunohistochemistry staining. Co-culture of TAMs and CRC cells both in vitro and in vivo models was used to evaluate the effects of TAMs on CRC chemoresistance. Cytokine Antibody Arrays, enzyme linked immunosorbent assay, neutralizing antibody and luciferase reporter assay were performed to uncover the underlying mechanism. Results: TAM infiltration was associated with chemoresistance in CRC patients. CRC-conditioned macrophages increased CRC chemoresistance and reduced drug-induced apoptosis by secreting IL-6, which could be blocked by a neutralizing anti-IL-6 antibody. Macrophage-derived IL-6 activated the IL-6R/STAT3 pathway in CRC cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced CRC chemoresistance. miR-155-5p, a key microRNA regulating C/EBPβ, was frequently downregulated in TAM, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL-6 in TAM, and TAM-secreted IL-6 then induced chemoresistance by activating the IL-6R/STAT3/miR-204-5p pathway in CRC cells. Conclusions: Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL-6 signaling in TAM could induce chemoresistance in CRC cells by regulating the IL-6R/STAT3/miR-204-5p axis, revealing a new crosstalk between immune cells and tumor cells in CRC microenvironment.
http://ift.tt/2yoe9xx
BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer.
Purpose: Bladder cancer (BC) is a current clinical and social problem. At diagnosis, most patients present non-muscle invasive tumors, characterized by a high recurrence rate, which could progress to muscle invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in BC is still unclear. Experimental Design: Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed in vitro by experiments with BC cell lines and peripheral blood monocyte-derived macrophages. Results: We observed BMP4 expression is associated and favored type-2 macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from BC cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL-10. Using a series of human BC patient samples we also observed increased expression of BMP4 in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced BMPR2 expression. Conclusions: These findings suggest that BMP4 secretion by BC cells provides the M2 signal necessary for a pro-tumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the pro-differentiating actions mediated by BMP ligands, favoring tumor growth.
http://ift.tt/2xPV0Hw
Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients using an IVIVE-PBPK Modeling Approach
Purpose: AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a 4-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in glioblastoma patients, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors.
http://ift.tt/2yoe3Gb
Therapeutic drug monitoring of carboplatin in high-dose protocol (TI-CE) for advanced germ cell tumors: pharmacokinetic results of a phase 2 multicenter study
PURPOSE: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling inter-patient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. EXPERIMENTAL DESIGN: Eighty nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. RESULTS: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentile, respectively). The new covariate equation [CL (mL/min) = 130.7 x (Scr/83)–0.826 x (BW/76)+0.907 x (Age/36)–0.223 with Scr in μM, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared to other equations. CONCLUSION: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young males patients could be used if TDM cannot be implemented.
http://ift.tt/2xQc9B9
Characterization of the Immune Microenvironment in Hepatocellular Carcinoma (HCC)
Purpose: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. Experimental Design: To characterize the immune microenvironment in HCC, immunohistochemical (IHC) staining was performed for CD8 positive T lymphocytes, PD-1 positive and LAG-3 positive lymphocytes, CD163 positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. Results: Expression of CD8 was reduced in tumor and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24/29 cases (83%) and positive expression of LAG-3 on tumor infiltrating lymphocytes was identified in 19/29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted. Conclusions: LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC.
http://ift.tt/2yodWKL
Laboratory markers of cardiac and metabolic complications after generalized tonic-clonic seizures
Generalized tonic-clonic seizures (GTCS) frequently lead to emergency inpatient referrals. Laboratory blood values are routinely performed on admission to detect underlying causes and metabolic or cardiac comp...
http://ift.tt/2ynAICt
Morinda Officinalis Polysaccharides Stimulate Hypothalamic GnRH Secretion in Varicocele Progression
Varicoceles (VCs) are the predominant cause of male infertility and are a risk factor for chronic venous disease. Morinda officinalis (M. officinalis) is a traditional Chinese medicine used to tonify the kidney and strengthen yang. In this study, we evaluated the effects of water-soluble polysaccharides extracted from M. officinalis (MOPs) on gonadotropin-release hormone (GnRH) secretion in a classic experimental left VC (ELV) rat model. Intragastric administration of MOPs at a dose ranging from 50 mg kg−1 to 100 mg kg−1 facilitated improvements in sperm parameters and seminiferous epithelial structures, modulated serum hormone profiles, and stimulated GnRH synthesis and release in the hypothalamus. MOPs also promoted spinogenesis and functional spine maturation in the arcuate nuclei (Arc), wherein they acted mainly on Kiss1 and GnRH neurons. Moreover, MOP-mediated Kisspeptin-GPR54 pathway upregulation and MAPK phosphorylation activation may have been responsible for increases in GnRH synthesis and release. Collectively, the findings of this study indicate that MOPs were effective in stimulating GnRH secretion, possibly by upregulating the Kiss1/GPR54 pathway and enhancing synaptic plasticity, and that MOPs can serve as a therapy for early VCs.
http://ift.tt/2hdL0AX
Andrographolide Promotes Neural Differentiation of Rat Adipose Tissue-Derived Stromal Cells through Wnt/β-Catenin Signaling Pathway
Adipose tissue-derived stromal cells (ADSCs) are a high-yield source of pluripotent stem cells for use in cell-based therapies. We explored the effect of andrographolide (ANDRO, one of the ingredients of the medicinal herb extract) on the neural differentiation of rat ADSCs and associated molecular mechanisms. We observed that rat ADSCs were small and spindle-shaped and expressed multiple stem cell markers including nestin. They were multipotent as evidenced by adipogenic, osteogenic, chondrogenic, and neural differentiation under appropriate conditions. The proportion of cells exhibiting neural-like morphology was higher, and neurites developed faster in the ANDRO group than in the control group in the same neural differentiation medium. Expression levels of the neural lineage markers MAP2, tau, GFAP, and β-tubulin III were higher in the ANDRO group. ANDRO induced a concentration-dependent increase in Wnt/β-catenin signaling as evidenced by the enhanced expression of nuclear β-catenin and the inhibited form of GSK-3β (pSer9). Thus, this study shows for the first time how by enhancing the neural differentiation of ADSCs we expect that ANDRO pretreatment may increase the efficacy of adult stem cell transplantation in nervous system diseases, but more exploration is needed.
http://ift.tt/2hfW3cS
Angelica sinensis Suppresses Body Weight Gain and Alters Expression of the FTO Gene in High-Fat-Diet Induced Obese Mice
The root of Angelica sinensis (RAS) is a traditional Chinese medicine used for preventing and treating various diseases. In this study, we assessed RAS supplementation effects on body weight and the FTO gene expression and methylation status in a high-fat-diet (HFD) induced obese mouse model. Female obese mice were divided into groups according to RAS dosage in diet as follows: normal diet, HFD diet (HC), HFD with low-dosage RAS (DL), HFD with medium-dosage RAS (DM), and HFD with high-dosage RAS (DH). After RAS supplementation for 4 weeks, body weight suppression and FTO expression in DH mice were significantly higher than in HC mice, whereas no significant change in FTO expression was detected between DM and DL mice or in their offspring. Bisulfite sequencing PCR (BSP) revealed that the CpG island in the FTO promoter was hypermethylated up to 95.44% in the HC group, 91.67% in the DH group, and 90.00% in the normal diet group. Histological examination showed that adipocytes in the DH group were smaller than those in the HC group, indicating a potential role of RAS in obesity. This study indicated that RAS could ameliorate obesity induced by HFD and that the molecular mechanism might be associated with the expression of the FTO gene.
http://ift.tt/2hhKmyz
Impact of patient audio-visual re-education through a smartphone on quality of bowel preparation before colonoscopy; a single-blinded randomized study
Preparation education is essential for successful colonoscopy. This study aimed to evaluate the impact of audio-visual (AV) re-education through a smartphone before colonoscopy on bowel preparation quality.
http://ift.tt/2wv8x7f
Effect of a mentor-based, supportive-expressive program, Be Resilient to Breast Cancer, on survival in metastatic breast cancer: a randomised, controlled intervention trial
Effect of a mentor-based, supportive-expressive program, Be Resilient to Breast Cancer, on survival in metastatic breast cancer: a randomised, controlled intervention trial
British Journal of Cancer advance online publication, September 19 2017. doi:10.1038/bjc.2017.325
Authors: Zeng Jie Ye, Hong Zhong Qiu, Mu Zi Liang, Mei Ling Liu, Peng Fei Li, Peng Chen, Zhe Sun, Yuan Liang Yu, Shu Ni Wang, Zhang Zhang, Kun Lun Liao, Cai Fen Peng, Hui Huang, Guang Yun Hu, Yun Fei Zhu, Zhen Zeng, Qu Hu & Jing Jing Zhao
http://ift.tt/2xdHWeF
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia
The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia
British Journal of Cancer advance online publication, September 19 2017. doi:10.1038/bjc.2017.310
Authors: Jon D Emery, Victoria Gray, Fiona M Walter, Shelley Cheetham, Emma J Croager, Terry Slevin, Christobel Saunders, Timothy Threlfall, Kirsten Auret, Anna K Nowak, Elizabeth Geelhoed, Max Bulsara & C D'Arcy J Holman
http://ift.tt/2xdfdWY
Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death
Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death
British Journal of Cancer advance online publication, September 19 2017. doi:10.1038/bjc.2017.323
Authors: Sainan Li, Jingjing Li, Weiqi Dai, Qinghui Zhang, Jiao Feng, Liwei Wu, Tong Liu, Qiang Yu, Shizan Xu, Wenwen Wang, Xiya Lu, Kan Chen, Yujing Xia, Jie Lu, Yingqun Zhou, Xiaoming Fan, Wenhui Mo, Ling Xu & Chuanyong Guo
http://ift.tt/2xdf5Xu
Group interventions to reduce emotional distress and fatigue in breast cancer patients: a 9-month follow-up pragmatic trial
Group interventions to reduce emotional distress and fatigue in breast cancer patients: a 9-month follow-up pragmatic trial
British Journal of Cancer advance online publication, September 19 2017. doi:10.1038/bjc.2017.326
Authors: Charlotte Grégoire, Isabelle Bragard, Guy Jerusalem, Anne-Marie Etienne, Philippe Coucke, Gilles Dupuis, Dominique Lanctôt & Marie-Elisabeth Faymonville
http://ift.tt/2xf57CI
First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH: final results of the GISCAD (Italian Group for the Study of Digestive Tract Cancers) CENTRAL (ColorEctalavastiNTRiAlLdh) trial
First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH: final results of the GISCAD (Italian Group for the Study of Digestive Tract Cancers) CENTRAL (ColorEctalavastiNTRiAlLdh) trial
British Journal of Cancer advance online publication, September 19 2017. doi:10.1038/bjc.2017.234
Authors: Riccardo Giampieri, Marco Puzzoni, Bruno Daniele, Daris Ferrari, Sara Lonardi, Alberto Zaniboni, Luigi Cavanna, Gerardo Rosati, Nicoletta Pella, Maria Giulia Zampino, Pietro Sozzi, Domenico Germano, Vittorina Zagonel, Carla Codecà, Michela Libertini, Roberto Labianca, Stefano Cascinu, The Italian Group for the Study of Gastrointestinal Cancer (GISCAD) & Mario Scartozzi
http://ift.tt/2xfrUhE
Optimal MRI sequences for 68 Ga-PSMA-11 PET/MRI in evaluation of biochemically recurrent prostate cancer
Abstract
Background
PET/MRI can be used for the detection of disease in biochemical recurrence (BCR) patients imaged with 68Ga-PSMA-11 PET. This study was designed to determine the optimal MRI sequences to localize positive findings on 68Ga-PSMA-11 PET of patients with BCR after definitive therapy. Fifty-five consecutive prostate cancer patients with BCR imaged with 68Ga-PSMA-11 3.0T PET/MRI were retrospectively analyzed. Mean PSA was 7.9 ± 12.9 ng/ml, and mean PSA doubling time was 7.1 ± 6.6 months. Detection rates of anatomic correlates for prostate-specific membrane antigen (PSMA)-positive foci were evaluated on small field of view (FOV) T2, T1 post-contrast, and diffusion-weighted images. For prostate bed recurrences, the detection rate of dynamic contrast-enhanced (DCE) imaging for PSMA-positive foci was evaluated. Finally, the detection sensitivity for PSMA-avid foci on 3- and 8-min PET acquisitions was compared.
Results
PSMA-positive foci were detected in 89.1% (49/55) of patients evaluated. Small FOV T2 performed best for lymph nodes and detected correlates for all PSMA-avid lymph nodes. DCE imaging performed the best for suspected prostate bed recurrence, detecting correlates for 87.5% (14/16) of PSMA-positive prostate bed foci. The 8-min PET acquisition performed better than the 3-min acquisition for lymph nodes smaller than 1 cm, detecting 100% (57/57) of lymph nodes less than 1 cm, compared to 78.9% (45/57) for the 3-min acquisition.
Conclusion
PSMA PET/MRI performed well for the detection of sites of suspected recurrent disease in patients with BCR. Of the MRI sequences obtained for localization, small FOV T2 images detected the greatest proportion of PSMA-positive abdominopelvic lymph nodes and DCE imaging detected the greatest proportion of PSMA-positive prostate bed foci. The 8-min PET acquisition was superior to the 3 min acquisition for detection of small lymph nodes.
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Modelling Zika Virus Infection of the Developing Human Brain In Vitro Using Stem Cell Derived Cerebral Organoids
http://ift.tt/2wEYrvM
Analysis of microRNA (miRNA) expression profiles reveals 11 key biomarkers associated with non-small cell lung cancer
Abstract
Background
Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer cases which cause most of cancer-related deaths globally. However, the results vary largely in different studies due to different platforms and sample sizes. Here, we aim to identify the key miRNAs in the carcinogenesis of NSCLC that might be potential biomarkers for this cancer.
Methods
Meta-analysis was performed on miRNA profile using seven datasets of NSCLC studies. Furthermore, we predicted and investigated the functions of genes regulated by key miRNAs.
Results
Eleven key miRNAs were identified, including 2 significantly upregulated ones (hsa-miR-21-5p and hsa-miR-233-3p) and 9 downregulated ones (hsa-miR-126-3p, hsa-miR-133a-3p, hsa-miR-140-5p, hsa-miR-143-5p, hsa-miR-145-5p, hsa-miR-30a-5p, hsa-miR-30d-3p, hsa-miR-328-3pn, and hsa-miR-451). The functional enrichment analysis revealed that both up- and downregulated miRNAs were proportionally associated with regulation of transcription from RNA polymerase II promoter. According to transcription factor analysis, there were 65 (43.9%) transcription factors influenced by both up- and downregulated miRNAs.
Conclusions
In this study, 11 meta-signature miRNAs, as well as their target genes and transcription factors, were found to play significant role in carcinogenesis of NSCLC. These target genes identified in our study may be profitable to diagnosis and prognostic prediction of NSCLC as biomarkers.
http://ift.tt/2yaYy3q
Single-molecule Manipulation of G-quadruplexes by Magnetic Tweezers
http://ift.tt/2xeo34r
Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure
Objective
The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients.
DesignThe clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria.
ResultsOf the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741xINR+0.523xHBV-SOFA+0.026xage+0.003xTB) for short-term mortality was superior to five other scores based on both discovery and external validation studies.
ConclusionsRegardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.
http://ift.tt/2fhSna1
Randomized controlled trial of increasing physical activity on objectively measured and self-reported cognitive functioning among breast cancer survivors: The memory & motion study
BACKGROUND
Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12-week physical activity intervention, compared with a control condition, on objective and self-reported cognition among breast cancer survivors.
METHODS
Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self-reported cognition using the Patient-Reported Outcomes Measurement Information System scales. Linear mixed-effects regression models tested intervention effects for changes in cognition scores.
RESULTS
On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P < .05). The between-group differences in improvement on self-reported cognition were not statistically significant but were suggestive of potential group differences. Time since surgery moderated the correlation, and participants who were ≤2 years post surgery had a significantly greater improvement in Oral Symbol Digit score (exercise vs control (b = 4.00; P < .01), but no significant improvement was observed in patients who were >2 years postsurgery (b = −1.19; P = .40). A significant dose response was observed with greater increased physical activity associated with objective and self-reported cognition in the exercise arm.
CONCLUSIONS
The exercise intervention significantly improved processing speed, but only among those who had been diagnosed with breast cancer within the past 2 years. Slowed processing speed can have substantial implications for independent functioning, supporting the potential importance of early implementation of an exercise intervention among patients with breast cancer. Cancer 2017. © 2017 American Cancer Society.
http://ift.tt/2ynuan8
Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate
Abstract
Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous etiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top-associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft-susceptibility locus in our genome-wide association study (GWAS). Mega-analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variants are associated with the risk of nsCL/P. Two SNPs, rs338217 and rs7649443, were statistically significant even at the genome-wide level (ptrend = 9.70E-10 and ptrend = 8.96E-09, respectively). Three other SNPs, rs9826379, rs6805920 and rs6583202, reached a suggestive genome-wide significance threshold (ptrend < 1.00E-05). The location of the strongest individual SNP in the intronic sequence of the gene encoding DLG1 antisense RNA suggests that the true causal variant implicated in the risk of nsCL/P may affect the DLG1 gene expression level rather than structure of the encoded protein. In conclusion, we identified a novel cleft-susceptibility locus at chromosome 3q29 with a DLG1 as a novel candidate gene for this common craniofacial anomaly.
http://ift.tt/2xejirz
Precise, High-throughput Analysis of Bacterial Growth
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Dry Film Photoresist-based Electrochemical Microfluidic Biosensor Platform: Device Fabrication, On-chip Assay Preparation, and System Operation
http://ift.tt/2xuiYYb
Mucinous adenocarcinoma on perianal fistula. A rising entity?
Abstract
Introduction
Mucinous adenocarcinoma on perianal fistula is a rare entity; it could be underdiagnosed because it behaves often as a regular perianal fistula.
Materials and methods
We have recently treated four cases in our unit. We present them and review the literature, emphasizing on clinical characteristic and therapeutic options. The four patients were male with a mean age of 64. Three of them were classified as locally advances cases and therefore treated with neoadjuvant therapy.
Results
All of them underwent laparoscopic abdominoperineal escisión. Surgical specimens are described and clinical characteristic specified. Review of the literature shows that this disease has a very high potential risk of local recurrence and we must be aggressive with the resection. Sometimes plastic surgery is needed to reconstruct the perianal wound.
Conclusions
Mucinous adenocarcinoma associated with anal fistula is a rare disease. Neoadjuvant chemoradiotherapy followed by an adequate abdominoperineal excision may result in favourable outcomes.
http://ift.tt/2xusnPp
Long-Term Nerve Damage Possible after Chemotherapy for Breast Cancer
Many women who receive taxane-based chemotherapy to treat breast cancer experience long-term nerve damage, or peripheral neuropathy, data from a large clinical trial show.
http://ift.tt/2jGRmJZ
Special Issue on Liposomes, Exosomes, and Virosomes
This special issue of the Biophysical Journal hosts a collection of articles submitted by participants of the Biophysical Society Thematic Meeting "Liposomes, Exosomes, Virosomes: From Modeling Complex Membrane Processes to Medical Diagnostics and Drug Delivery", which took place in September 2016 in Ascona, Switzerland. All articles deal with aspects of generating or characterizing membrane vesicles, proteins or lipids in them, and interactions between them. Not only have membrane vesicles become useful tools to study fundamental properties of biomembranes and cellular organelles and viruses, but they have also been frequently employed in diagnostics and drug or gene delivery and thus have become important tools for practical applications.
http://ift.tt/2xbSGtF
Sterilization of Biofilm on a Titanium Surface Using a Combination of Nonthermal Plasma and Chlorhexidine Digluconate
Nosocomial infections caused by opportunistic bacteria pose major healthcare problem worldwide. Out of the many microorganisms responsible for such infections, Pseudomonas aeruginosa is a ubiquitous bacterium that accounts for 10–20% of hospital-acquired infections. These infections have mortality rates ranging from 18 to 60% and the cost of treatment ranges from $20,000 to $80,000 per infection. The formation of biofilms on medical devices and implants is responsible for the majority of those infections. Only limited progress has been made to prevent this issue in a safe and cost-effective manner. To address this, we propose employing jet plasma to break down and inactivate biofilms in vitro. Moreover, to improve the antimicrobial effect on the biofilm, a treatment method using a combination of jet plasma and a biocide known as chlorhexidine (CHX) digluconate was investigated. We found that complete sterilization of P. aeruginosa biofilms can be achieved after combinatorial treatment using plasma and CHX. A decrease in biofilm viability was also observed using confocal laser scanning electron microscopy (CLSM). This treatment method sterilized biofilm-contaminated surfaces in a short treatment time, indicating it to be a potential tool for the removal of biofilms present on medical devices and implants.
http://ift.tt/2ynvpD2
Glecaprevir/Pibrentasvir for HCV Genotype 3 Patients with Cirrhosis and/or Prior Treatment Experience: A Partially Randomized Phase III Clinical Trial
ABSTRACT
Background: This study assessed the efficacy and safety of ribavirin (RBV)-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus (HCV) genotype (GT) 3 infection with either prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options.
Methods: SURVEYOR-II, Part 3 was a partially-randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon (IFN) or pegIFN ± ribavirin or SOF plus ribavirin ± pegIFN therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naïve or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at post-treatment week 12 (SVR12). Safety was evaluated throughout the study.
Results: There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; CI 72-97) and 95% (21/22; CI 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; CI 87-99) of treatment-naïve patients treated for 12 weeks, and 96% (45/47; CI 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events (AEs) led to discontinuation of study drug and no serious AEs were related to study drug.
Conclusions: Patients with HCV GT3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. This article is protected by copyright. All rights reserved.
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CHOP-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury
Abstract
Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP-/-) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7 to 14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL-induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation and M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP-/- mice. In addition, intestinal organoids derived from CHOP-/- mice contain more and longer crypt structures than those from WT mice, which is consistent with the upregulation of stem cell markers (Lgr5, Olfm4 and Sox9) and in vivo findings that CHOP-/- mice have longer villi and crypts as compared to WT mice. Similarly, the mRNA levels of CD14, IL-1β, TNF-α and MCP-1 are increased and stem cell proliferation is suppressed in the duodenum of cirrhotic patients. Conclusion: Activation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL-induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases This article is protected by copyright. All rights reserved.
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New pediatric percentiles of liver enzyme serum levels (ALT, AST, GGT): Effects of age, sex, BMI and pubertal stage
Abstract
The present study aims to clarify the effects of sex, age, BMI and puberty on transaminase serum levels in children and adolescents and to provide new age- and sex-related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non-normal BMI (BMI < 10th or > 90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age- and sex-related reference intervals were established by using an LMSP-type method. Serum levels of transaminases follow age-specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. The ALT percentiles showed similar shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI-SDS (β = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (β = -1.42) and BMI-SDS (β = -0.15). The GGT percentiles revealed significant sex-specific differences, correlated positively with age (β = 0.37) and showed significant association with BMI-SDS (β = 1.16). Conclusion: Current reference values of ALT, AST and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on the serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. This article is protected by copyright. All rights reserved.
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Radiation therapy versus surgery for patients with cervical squamous cell carcinoma who have undergone neoadjuvant chemotherapy revisited
Abstract
Background
The therapeutic significance of neoadjuvant chemotherapy (NAC) followed by radiation therapy (RT) was negated during the early 1990s. Here, we compared post-NAC RT to surgery for chemo-sensitive cervical squamous cell carcinoma (SCC).
Methods
This study included 79 consecutive patients with cervical SCC who were treated by NAC followed by surgery (n = 49) or by definitive RT (n = 30). We compared characteristics and survival outcomes between the surgery and RT groups by their responses to NAC.
Results
Of the 79 patients, 70 (89%) had stage II–IV disease and 41 (52%) had radiological pelvic lymph node enlargement. The 5-year disease-specific survival (DSS) rate of the entire cohort was 66.4% (median follow-up 54 months). Fifty-five patients (70%) achieved sufficient (complete or partial) responses to NAC. Among patients with insufficient NAC responses, the 5-year DSS rate of the surgery group (55.6%) was significantly higher than the RT group (20.0%; P = 0.044). However, among patients with sufficient responses to NAC, 5-year DSS rates did not significantly differ between the surgery and RT groups (82.3 vs 78.6%; P = 0.79) even though the RT group had many more unfavorable prognostic factors and received fewer subsequent treatments than the surgery group.
Conclusions
Post-NAC survival outcomes among patients with chemo-sensitive cervical SCC who then underwent RT were not inferior to those treated with surgery, and NAC did not detract from the efficacy of subsequent RT. Among selected patients who respond favorably to NAC, RT could be a less invasive substitute for surgery without compromising treatment outcomes.
http://ift.tt/2fwKzho
Profiling microRNA from Brain by Microarray in a Transgenic Mouse Model of Alzheimer’s Disease
MicroRNAs (miRNAs) are small noncoding RNAs, which regulate numerous cell functions by targeting mRNA for cleavage or translational repression, and have been found to play an important role in Alzheimer's disease (AD). Our study aimed to identify differentially expressed miRNAs in AD brain as a reference of potential therapeutic miRNAs or biomarkers for this disease. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and age-matched wild-type (WT) littermates to determine the expression of miRNAs in the brain. MiRNAs were profiled by microarray, and differentially expressed miRNAs underwent target prediction and enrichment analysis. Microarray analysis revealed 56 differentially expressed miRNAs in AD mouse brain, which involved 39 miRNAs that were significantly upregulated and 19 that were downregulated at different ages. Among those miRNAs, a total of 11 miRNAs, including miR-342-3p, miR-342-5p, miR-376c-3p, and miR-301b-3p, were not only conserved in human but also predicted to have targets and signaling pathways closely related to the pathology of AD. In conclusion, in this study, differentially expressed miRNAs were identified in AD brain and proposed as biomarkers, which may have the potential to indicate AD progression. Despite being preliminary, these results may aid in investigating pathological hallmarks and identify effective therapeutic targets.
http://ift.tt/2hffwXD
Current Methods to Define Metabolic Tumor Volume in Positron Emission Tomography: Which One is Better?
Abstract
Numerous methods to segment tumors using 18F-fluorodeoxyglucose positron emission tomography (FDG PET) have been introduced. Metabolic tumor volume (MTV) refers to the metabolically active volume of the tumor segmented using FDG PET, and has been shown to be useful in predicting patient outcome and in assessing treatment response. Also, tumor segmentation using FDG PET has useful applications in radiotherapy treatment planning. Despite extensive research on MTV showing promising results, MTV is not used in standard clinical practice yet, mainly because there is no consensus on the optimal method to segment tumors in FDG PET images. In this review, we discuss currently available methods to measure MTV using FDG PET, and assess the advantages and disadvantages of the methods.
http://ift.tt/2xeKvKN
Mother’s education and offspring asthma risk in 10 European cohort studies
Abstract
Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3–8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mother's age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalence's of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.
http://ift.tt/2xujjKc
Spiral Fracture in Young Infant Causing a Diagnostic Dilemma: Nutritional Rickets versus Child Abuse
Fractures are uncommon in young, nonambulatory infants. The differential diagnosis includes nonaccidental injury (NAI) and metabolic bone disease, including rickets. While rickets typically present after six months of age, multiple cases have been reported in younger infants. We report a case of an 11-week-old male infant who presented with a spiral fracture of the humerus and no radiologic evidence of rickets. A detailed psychosocial assessment failed to reveal any risk factors for NAI. The patient had elevated alkaline phosphatase and PTH with low 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D levels. Additionally, the mother was noncompliant with prenatal vitamins, exclusively breastfeeding without vitamin D supplementation, and had markedly low vitamin D levels 15 weeks postpartum. The biochemical data and history were consistent with rickets. Given the diagnostic dilemma, the working diagnosis was rickets and the patient was started on ergocalciferol with subsequent normalization of his laboratory values and healing of the fracture. These findings are consistent with nutritional rickets largely due to maternal-fetal hypovitaminosis D. This case highlights that in young infants rickets should be considered even in the absence of positive radiologic findings. Additionally, it illustrates the importance of maintaining adequate vitamin D supplementation during pregnancy and early infancy.
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Seven tips for wisdom teeth pain relief
Wisdom teeth often emerge in early adulthood and can cause a lot of pain as they push through the gums. We look at seven tips to relieve the pain.
http://ift.tt/2jE7604
Gastrointestinal Motility, Mucosal Mast Cell, and Intestinal Histology in Rats: Effect of Prednisone
Our aim was to verify the effects of prednisone related to gastrointestinal motility, intestinal histology, and mucosal mast cells in rats. Two-month-old male Wistar rats were randomly assigned to control group (vehicle) animals receiving saline 0.9% () or treated orally with 0.625 mg/kg/day of prednisone () or 2.5 mg/kg/day of prednisone () during 15 days. Mast cells and other histologic analyses were performed in order to correlate to gastric emptying, cecum arrival, and small intestine transit evaluated by Alternating Current Biosusceptometry. Results showed that prednisone in adult rats increased the frequency of gastric contractions, hastened gastric emptying, slowed small intestinal transit, and reduced mucosal mast cells. Histologically, the treatment with both doses of prednisone decreased villus height, whereas longitudinal and circular muscles and crypt depth were not affected. These findings indicate an impairment of intestinal absorption which may be linked to several GI dysfunctions and symptoms. The relationship between gastrointestinal motor disorders and cellular immunity needs to be clarified in experimental studies since prednisone is one of the most prescribed glucocorticoids worldwide.
http://ift.tt/2wt3kgh
Quantifying Laryngopharyngeal Reflux in Singers: Perceptual and Objective Findings
This study examines the relationship between laryngopharyngeal reflux (LPR) symptoms and oropharyngeal pH levels in singers. We hypothesized that reported symptoms would correlate with objective measures of pH levels from the oropharynx, including the number and total duration of reflux episodes. Twenty professional/semiprofessional singers completed the Reflux Symptom Index (RSI) and underwent oropharyngeal pH monitoring. Mild, moderate, or severe pH exposure was recorded during oropharyngeal pH monitoring. Correlations were performed to examine potential relationships between reflux symptoms and duration of LPR episodes. Symptom severity did not correlate with pH levels; however, we found a number of covariances of interest. Large sample sizes are necessary to determine if true correlations exist. Our results suggest that singers may exhibit enhanced sensitivity to LPR and may therefore manifest symptoms, even in response to subtle changes in pH. This study emphasizes the importance of sensitive and objective measures of reflux severity as well as consideration of the cumulative time of reflux exposure in addition to the number of reflux episodes.
http://ift.tt/2xNCXC6
Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures
Abstract
Objective
We compared the tolerability and efficacy of intranasal sub-dissociative ketamine to intranasal fentanyl for analgesia of children with acute traumatic pain and investigated the feasibility of a larger non-inferiority trial that could investigate the potential opioid sparing effects of intranasal ketamine.
Methods
This randomized controlled trial compared intranasal ketamine 1 mg/kg to intranasal fentanyl 1.5 μg/kg in children 4–17 years old with acute pain from suspected, isolated extremity fractures presenting to an urban level II pediatric trauma center from December 2015 to November 2016. Patients, parents, treating physicians, and outcome assessors were blinded to group allocation. The primary outcome, a tolerability measure, was the frequency of cumulative side effects and adverse events within 60 minutes of drug administration. The secondary outcomes included the difference in mean pain score reduction at 20 minutes, the proportion of patients achieving a clinically significant reduction in pain in 20 minutes, total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the emergency department (ED) stay, and the feasibility of enrolling children presenting to the ED in acute pain into a randomized trial conducted under US regulations. All patients were monitored until 6 hours after their last dose of study drug, or until admission to the hospital ward or operating room.
Results
Of 629 patients screened, 87 received the study drug and 82 had complete data for the primary outcome (41 patients in each group). The median age (interquartile range) was 8 (3) years and 62% were male. Baseline pain scores were similar among patients randomized to receive ketamine (73 ± 26) and fentanyl (69 ± 26) [mean difference (95% CI): 4 (-7 to 15)]. The cumulative number of side effects was 2.2 times higher in the ketamine group, but there were no serious adverse events and no patients in either group required intervention. The most common side effects of ketamine were bad taste in the mouth (37; 90.2%), dizziness (30; 73.2%), and sleepiness (19; 46.3%). The most common side effects of fentanyl were sleepiness (15; 36.6%), bad taste in the mouth (9; 22%), and itchy nose (9; 22%). No patients experienced respiratory side effects. At 20 minutes, the mean pain scale score reduction was 44 ± 36 for ketamine and 35 ± 29 for fentanyl [mean difference: 9 (95% CI: -4 to 23)]. Procedural sedation with ketamine occurred in 28 ketamine patients (65%) and 25 fentanyl patients (57%) prior to completing the study.
Conclusions
Intranasal ketamine was associated with more minor side effects than intranasal fentanyl. Pain relief at 20 minutes was similar between groups. Our data support the feasibility of a larger, non-inferiority trial to more rigorously evaluate the safety, efficacy, and potential opioid sparing benefits of intranasal ketamine analgesia for children with acute pain.
This article is protected by copyright. All rights reserved.
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Identification of a molecular cause of a neurodevelopmental disorder
Video summarises research in Genome Medicine, read the full article: http://ift.tt/2esiczT
https://www.youtube.com/watch?v=tIYTN-pLcXQ
Legacy effects of continuous chloropicrin-fumigation for 3-years on soil microbial community composition and metabolic activity
Chloropicrin is widely used to control ginger wilt in China, which have an enormous impact on soil microbial diversity. However, little is known on the possible legacy effects on soil microbial community compo...
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The biodiversity of Lactobacillus spp. from Iranian raw milk Motal cheese and antibacterial evaluation based on bacteriocin-encoding genes
Lactobacilli, as the largest group of lactic acid bacteria, produce large amounts of antimicrobial metabolites such as organic acids, fatty acids, ammonia, hydrogen peroxide, diacetyl and...
http://ift.tt/2w4HH1r
Construction of an HRP-streptavidin bound antigen and its application in an ELISA for porcine circovirus 2 antibodies
A fusion protein SBP-Cap∆41, consisting of Cap∆41 (without 41 amino acids at the N-terminus) protein of porcine circovirus 2 (PCV2) and a streptavidin binding peptide (SBP), was constructed. This fusion protei...
http://ift.tt/2f7Ux8o
Randomized clinical trial of antibiotic therapy for uncomplicated appendicitis
Background
Uncomplicated appendicitis may resolve spontaneously or require treatment with antibiotics or appendicectomy. The aim of this randomized trial was to compare the outcome of a non-antibiotic management strategy with that of antibiotic therapy in uncomplicated appendicitis.
Methods
Patients presenting to a university teaching hospital with CT-verified uncomplicated simple appendicitis (appendiceal diameter no larger than 11 mm and without any signs of perforation) were randomized to management with a no-antibiotic regimen with supportive care (intravenous fluids, analgesia and antipyretics as necessary) or a 4-day course of antibiotics with supportive care. The primary endpoint was rate of total treatment failure, defined as initial treatment failure within 1 month and recurrence of appendicitis during the follow-up period.
Results
Some 245 patients were randomized within the trial, and followed up for a median of 19 months. The duration of hospital stay was shorter (mean 3·1 versus 3·7 days; P < 0·001) and the medical costs lower (€1181 versus 1348; P < 0·001) among those randomized to therapy without antibiotics. There was no difference in total treatment failure rate between the groups: 29 of 124 (23·4 per cent) in the no-antibiotic group and 25 of 121 (20·7 per cent) in the antibiotic group (P = 0·609). Eighteen patients (9 in each group) had initial treatment failure, 15 of whom underwent appendicectomy and three received additional antibiotics. Thirty-six patients (20 in the no-antibiotic group, 16 in the antibiotic group) experienced recurrence, of whom 30 underwent appendicectomy and six received further antibiotics.
Conclusion
Treatment failure rates in patients presenting with CT-confirmed uncomplicated appendicitis appeared similar among those receiving supportive care with either a no-antibiotic regimen or a 4-day course of antibiotics. Registration number: KCT0000124 ( http://cris.nih.go.kr).
http://ift.tt/2wDsB2l
Weekend admission and mortality for gastrointestinal disorders across England and Wales
Background
Little has been reported on mortality following admissions at weekends for many gastrointestinal (GI) disorders. The aim was to establish whether GI disorders are susceptible to increased mortality following unscheduled admission on weekends compared with weekdays.
Methods
Record linkage was undertaken of national administrative inpatient and mortality data for people in England and Wales who were hospitalized as an emergency for one of 19 major GI disorders.
Results
The study included 2 254 701 people in England and 155 464 in Wales. For 11 general surgical and medical GI disorders there were little, or no, significant weekend effects on mortality at 30 days in either country. There were large consistent weekend effects in both countries for severe liver disease (England: 26·2 (95 per cent c.i. 21·1 to 31·6) per cent; Wales: 32·0 (12·4 to 55·1 per cent) and GI cancer (England: 21·8 (19·1 to 24·5) per cent; Wales: 25·0 (15·0 to 35·9) per cent), which were lower in patients managed by surgeons. Admission rates were lower at weekends than on weekdays, most strongly for severe liver disease (by 43·3 per cent in England and 51·4 per cent in Wales) and GI cancer (by 44·6 and 52·8 per cent respectively). Both mortality and the weekend mortality effect for GI cancer were lower for patients managed by surgeons.
Discussion
There is little, or no, evidence of a weekend mortality effect for most major general surgical or medical GI disorders, but large weekend effects for GI cancer and severe liver disease. Lower admission rates at weekends indicate more severe cases. The findings for severe liver disease may suggest a lack of specialist hepatological resources. For cancers, reduced availability of end-of-life care in the community at weekends may be the cause.
http://ift.tt/2xjqvbF
SinusCor: an advanced tool for heart rate variability analysis
Heart rate variability (HRV) is a widespread non-invasive technique to assess cardiac autonomic function. Time and frequency domain analyses have been used in HRV studies, and their interpretations are linked ...
http://ift.tt/2xe6hOV
Intracranial Hemorrhage Complicating Herpes Simplex Encephalitis on Antiviral Therapy: A Case Report and Review of the Literature
Herpes simplex virus (HSV) encephalitis is the most common cause of nonendemic sporadic encephalitis in the USA. Decreased mortality with early treatment with acyclovir has been documented. Although common complications include cortical petechial hemorrhages, frank intracerebral hematomas are considered very rare. Only few cases have been reported in the literature. We report a case of HSV encephalitis complicated by intracerebral hemorrhage 12 days after initiation of acyclovir therapy.
http://ift.tt/2xbtHqz
Pharyngoesophageal diverticula simulating thyroid nodules: An unusual occurrence with unique features
Pharyngoesophageal diverticula (PED) of the Zenker's and Killian-Jamieson types arise in close proximity to the thyroid gland, and may rarely be confused with a thyroid nodule on ultrasonography. In this brief report, we detail the cytologic, clinical, and radiologic findings of three PED that were thought to be thyroid nodules, and were subjected to fine-needle aspiration (FNA). The patients were females with an age range of 51-64 years. All three patients had multiple thyroid nodules, and two patients reported symptoms attributable to the diverticulum. Nodule sizes ranged from 1.0 to 2.7 cm, and either the right or left thyroid lobe could be involved. Microcalcifications were present by ultrasonography in all three cases. FNA of these thyroid nodule mimics showed squamous cells with granular or amorphous debris, bacterial and/or fungal colonies, inflammation, and food particles. These cytologic features, particularly the presence of vegetable or meat fragments, are characteristic, and have also been reported in the few previous reports of PED. The presence of a diverticulum was confirmed with imaging studies in all our patients. Although a rare occurrence, the inadvertent FNA of a PED masquerading as a thyroid nodule is important to recognize, as a recommendation for appropriate radiologic studies could potentially avoid inappropriate therapy for thyroid disease.
http://ift.tt/2fgkmHa
Fine needle aspiration biopsy diagnosis of primary clear cell chondrosarcoma: A case report
Abstract
Clear cell chondrosarcoma is a rare chondrosarcoma variant often involving the long bone epiphyses of young to middle aged adults. We report herein a case involving the left femoral head in a 25-year-old female with a 3-month history of worsening left hip pain. Radiographs revealed a complex, multifocal and lytic lesion centered in the left proximal femoral epiphysis with involvement of the femoral neck. Computed tomography-guided fine needle aspiration biopsy with concomitant core needle biopsy was performed, and a diagnosis of clear cell chondrosarcoma was rendered. Cytologic smears revealed aggregates of matrix material accompanied by a population of mostly uniform spindled to epithelioid and histiocytoid cells, rarely accompanied by osteoclast-type giant cells. The patient underwent surgical resection with -total hip replacement, and subsequent pathologic examination confirmed the initial needle biopsy diagnosis. There has been no evidence of local recurrence or distant metastases with 3-years follow-up. To our knowledge, this is the first reported example of a primary clear cell chondrosarcoma initially evaluated by fine needle aspiration biopsy.
http://ift.tt/2xu2ChT
Somatic health effects of Chernobyl: 30 years on
Abstract
2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.
http://ift.tt/2f7msoS
Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/ transient receptor potential vanilloid 4 (TRPV4)- and calmodulin-mediated mechanism
Abstract
Human aquaporin 4 (AQP4) is the primary water channel protein in brain astrocytes. Hypothermia is known to cause astrocyte swelling in culture, but the precise role of AQP4 in this process is unknown. Primary human cortical astrocytes were cultured under hypothermic (32°C) or normothermic (37°C) conditions. AQP4 transcript, total protein and surface localized protein were quantified using RT-qPCR, sandwich ELISA with whole cell lysates, or cell-surface biotinylation followed by ELISA analysis of the surface-localized protein, respectively. Four-hour mild hypothermic treatment increased the surface localization of AQP4 in human astrocytes to 155 ± 4% of normothermic controls, despite no change in total protein expression levels. The hypothermia-mediated increase in AQP4 surface abundance on human astrocytes was blocked using either calmodulin antagonist (trifluoperazine; TFP); TRPV4 antagonist, HC-067047 or calcium chelation using EGTA-AM. The TRPV4 agonist (GSK1016790A) mimicked the effect of hypothermia compared with untreated normothermic astrocytes. Hypothermia led to an increase in surface localization of AQP4 in human astrocytes through a mechanism likely dependent on the TRPV4 calcium channel and calmodulin activation. Understanding the effects of hypothermia on astrocytic AQP4 cell-surface expression may help develop new treatments for brain swelling based on an in-depth mechanistic understanding of AQP4 translocation.
This article is protected by copyright. All rights reserved.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
