Measurement of Gender Differences of Gastrocnemius Muscle and Tendon Using Sonomyography during Calf Raises: A Pilot Study

Skeletal muscles are essential to the gender-specific characteristics of human movements. Sonomyography, a new signal for quantifying muscle activation, is of great benefit to understand muscle function through monitoring the real-time muscle architectural changes. The purpose of this pilot study was to investigate gender differences in the architectural changes of gastronomies muscle and tendon by using sonomyography during performing two-legged calf raising exercises. A motion analysis system was developed to extract sonomyography from ultrasound images together with kinematic and kinetic measurements. Tiny fascicle length changes among seven male subjects were observed at the initial part of calf raising, whereas the fascicle of seven female subjects shortened immediately. This result suggested that men would generate higher mechanical power output of plantar flexors to regulate their heavier body mass. In addition, the larger regression coefficient between the fascicle length and muscle force for the male subjects implied that higher muscle stiffness for the men was required in demand of maintaining their heavier body economically. The findings from the current study suggested that the body mass might play a factor in the gender difference in structural changes of muscle and tendon during motion. The sonomyography may provide valuable information in the understanding of the gender difference in human movements.

http://ift.tt/2CveDEc

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate

Abstract

Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins.

http://ift.tt/2iE9mkh

Use of genetic and chemical synthetic lethality as probes of complexity in bacterial cell systems

Abstract

Different conditions and genomic contexts are known to have an impact on gene essentiality and interactions. Synthetic lethal interactions occur when a combination of perturbations, either genetic or chemical, result in a more profound fitness defect than expected based on the effect of each perturbation alone. Synthetic lethality in bacterial systems has long been studied; however, during the past decade, the emerging fields of genomics and chemical genomics have led to an increase in the scale and throughput of these studies. Here, we review the concepts of genomics and chemical genomics in the context of synthetic lethality and their revolutionary roles in uncovering novel biology such as the characterization of genes of unknown function and in antibacterial drug discovery. We provide an overview of the methodologies, examples and challenges of both genetic and chemical synthetic lethal screening platforms. Finally, we discuss how to apply genetic and chemical synthetic lethal approaches to rationalize the synergies of drugs, screen for new and improved antibacterial therapies and predict drug mechanism of action.

http://ift.tt/2q22x2V

Environmental factors influencing the development and spread of antibiotic resistance

Abstract

Antibiotic resistance and its wider implications present us with a growing healthcare crisis. Recent research points to the environment as an important component for the transmission of resistant bacteria and in the emergence of resistant pathogens. However, a deeper understanding of the evolutionary and ecological processes that lead to clinical appearance of resistance genes is still lacking, as is knowledge of environmental dispersal barriers. This calls for better models of how resistance genes evolve, are mobilized, transferred and disseminated in the environment. Here, we attempt to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission. Although mobilization of resistance genes likely occurs continuously, the great majority of such genetic events do not lead to the establishment of novel resistance factors in bacterial populations, unless there is a selection pressure for maintaining them or their fitness costs are negligible. To enable preventative measures it is therefore critical to investigate under what conditions and to what extent environmental selection for resistance takes place. In addition, understanding dispersal barriers is not only key to evaluate risks, but also to prevent resistant pathogens, as well as novel resistance genes, from reaching humans.

http://ift.tt/2EmnKYH

The effect of bacterial chemotaxis on host infection and pathogenicity

Abstract

Chemotaxis enables microorganisms to move according to chemical gradients. Although this process requires substantial cellular energy, it also affords key physiological benefits, including enhanced access to growth substrates. Another important implication of chemotaxis is that it also plays an important role in infection and disease, as chemotaxis signalling pathways are broadly distributed across a variety of pathogenic bacteria. Furthermore, current research indicates that chemotaxis is essential for the initial stages of infection in different human, animal and plant pathogens. This review focuses on recent findings that have identified specific bacterial chemoreceptors and corresponding chemoeffectors associated with pathogenicity. Pathogenicity-related chemoeffectors are either host and niche-specific signals or intermediates of the host general metabolism. Plant pathogens were found to contain an elevated number of chemotaxis signalling genes and functional studies demonstrate that these genes are critical for their ability to enter the host. The expanding body of knowledge of the mechanisms underlying chemotaxis in pathogens provides a foundation for the development of new therapeutic strategies capable of blocking infection and preventing disease by interfering with chemotactic signalling pathways.

http://ift.tt/2EixHpT

Metals in fungal virulence

Abstract

Metals are essential for life, and they play a central role in the struggle between infecting microbes and their hosts. In fact, an important aspect of microbial pathogenesis is the 'nutritional immunity', in which metals are actively restricted (or, in an extended definition of the term, locally enriched) by the host to hinder microbial growth and virulence. Consequently, fungi have evolved often complex regulatory networks, uptake and detoxification systems for essential metals such as iron, zinc, copper, nickel and manganese. These systems often differ fundamentally from their bacterial counterparts, but even within the fungal pathogens we can find common and unique solutions to maintain metal homeostasis. Thus, we here compare the common and species-specific mechanisms used for different metals among different fungal species—focusing on important human pathogens such as Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans, but also looking at model fungi such as Saccharomyces cerevisiae or A. nidulans as well-studied examples for the underlying principles. These direct comparisons of our current knowledge reveal that we have a good understanding how model fungal pathogens take up iron or zinc, but that much is still to learn about other metals and specific adaptations of individual species—not the least to exploit this knowledge for new antifungal strategies.

http://ift.tt/2q13kkH

Protein kinase C in fungi—more than just cell wall integrity

Abstract

Human protein kinase C (PKC) isoforms have been implicated in diseases such as Alzheimer's, diabetes and cancers. In contrast to mammals, which have at least nine genes, fungi have only one or two. The yeast Saccharomyces cerevisiae produces only a single Pkc1 and is employed in the study of specific human isozymes, including their susceptibility to pharmacological drugs. Vice versa, the domain structure and regulation of yeast and other fungal PKCs yield insights into the function of human isozymes. Therefore, human PKCs are briefly reviewed herein and related to the yeast enzyme. The latter was originally implicated in the regulation of cell wall synthesis through a conserved MAP kinase pathway, but many more targets have now been described in S. cerevisiae and other fungi. These implicate PKC in the control of such diverse processes as the organization of the actin cytoskeleton, autophagy and apoptosis, nutrient sensing and ribosome biogenesis, cell cycle control, cytokinesis and genetic stability. PKC is a promising target for the development of antifungal drugs against pathogenic fungi such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Thus, fungal PKCs are drawing increased attention and the accumulating literature on the enzymes from different species is summarized herein.

http://ift.tt/2Ejnk56

Thalassemia

Over the years, an increase in understanding of the underlying molecular and cellular mechanisms as well as the pathophysiology of thalassemia has caused a paradigm shift in diagnosis and treatment.

http://ift.tt/2Ej75oG

Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)

Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence.We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo.

http://ift.tt/2Cr7Hbd

ACCURACY OF FECAL CALPROTECTIN FOR THE PREDICTION OF ENDOSCOPIC ACTIVITY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Fecal calprotectin is a noninvasive marker of inflammatory bowel disease.

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Duodenal invasion of hepatocellular carcinoma following transarterial chemoembolization

http://ift.tt/2CsbC7K

A Review on Ethnopharmacological Applications, Pharmacological Activities, and Bioactive Compounds of Mangifera indica (Mango)

Mangifera indica (family Anacardiaceae), commonly known as mango, is a pharmacologically, ethnomedically, and phytochemically diverse plant. Various parts of M. indica tree have been used in traditional medicine for the treatment of different ailments, and a number of bioactive phytochemical constituents of M. indica have been reported, namely, polyphenols, terpenes, sterols, carotenoids, vitamins, and amino acids, and so forth. Several studies have proven the pharmacological potential of different parts of mango trees such as leaves, bark, fruit peel and flesh, roots, and flowers as anticancer, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antifungal, anthelmintic, gastroprotective, hepatoprotective, immunomodulatory, antiplasmodial, and antihyperlipemic. In the present review, a comprehensive study on ethnopharmacological applications, pharmacological activities, and bioactive compounds of M. indica has been described.

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Integrative Approach to Facilitate Fracture Healing: Topical Chinese Herbal Paste with Oral Strontium Ranelate

Strontium ranelate (SrR) is one of the pharmaceutical agents reported to be effective on the promotion of fracture healing. This study aimed to evaluate the integrative effect of the oral SrR with a topical Chinese herbal paste, namely, CDR, on facilitation of bone healing. The in vivo efficacy was evaluated using rats with tibial fracture. They were treated with either CDR topically, or SrR orally, or their combined treatments. The in vivo results illustrated a significant additive effect of CDR on SrR in increasing the yield load of the fractured tibia. The in vitro results showed that neither SrR nor CDR exhibited a cytotoxic effect on UMR106 and bone-marrow stem cell (BMSC), but both of them increased the proliferation of BMSC at low concentrations. The combination of CDR at 200 μg/mL with SrR at 200 or 400 μg/ml also showed an additive effect on increasing the ALP activity of BMSC. Both SrR and CDR alone reduced osteoclast formation, and the effective concentration of SrR to inhibit osteoclastogenesis was reduced in the presence of CDR. This integrative approach by combining oral SrR and topical CDR is effective in promoting fracture healing properly due to their additive effects on proosteogenic and antiosteoclastogenic properties.

http://ift.tt/2Cr7GEb

In Vitro Phagocytosis of Myelin Debris by Bone Marrow-Derived Macrophages

We present methods to assess the phagocytic capacity of primary murine bone marrow-derived macrophages using fluorescently labeled myelin debris and intracellular lipid droplet staining.

http://ift.tt/2CencGX

A Rapid and Efficient Method to Dissect Pupal Wings of Drosophila Suitable for Immunodetections or PCR Assays

The ability to accurately detect transcripts or proteins in Drosophila tissues is critical for studying their abundance and localization related to the development process. Here is the description of a straightforward procedure to dissect pupal wings. These wings can be used as samples in several techniques (immunohistochemistry, PCR assay, etc.).

http://ift.tt/2Ej1uyD

Texas college aims to bring medical students of different fields together

By Ruth Campbell Odessa American ODESSA, Texas — Odessa College's Health Sciences Building is being renovated to allow everyone from emergency medical services students to nursing and radiologic technology pupils to mingle and cooperate. Vice President for Business Affairs Virginia Chisum said the two-story, 57,000-square-foot building is being remodeled in stages. Chisum said they started ...

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Effect of Telemedicine Education and Telemonitoring on Continuous Positive Airway Pressure Adherence. The Tele-OSA Randomized Trial

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 117-126, January 1, 2018.


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The Impact of the ASAP Trial: Maybe We Shouldn’t Act So Quickly

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 142-143, January 1, 2018.


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We Have to Learn to Do without Knowing Enough: Antieosinophilic Treatments for Severe Asthma

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 1-2, January 1, 2018.


http://ift.tt/2Elzhr1

Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 104-116, January 1, 2018.


http://ift.tt/2q2KCt7

Diagnosis of peritoneal tuberculosis via endosonography assisted through the needle forceps biopsy of peritoneum: First case in the literature (with video)

Abstract

Ascites can pose a difficult problem in diagnosis of peritoneal tuberculosis, and diagnostic laparoscopy or laparotomy is eventually required in some patients. Herein, we reported the diagnosis of peritoneal tuberculosis in a patient with ascites by using endosonography (EUS) assisted through the needle biopsy forceps (TTNB). The patient was immediately started on the tuberculosis treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Ej9kbG

Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

Abstract

Purpose

In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC).

Methods

In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant.

Results

Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%).

Conclusions

In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

http://ift.tt/2CrpgYL

The large mouth of largemouth bass is of interest to scientists trying to understand how joints work

Inside the bass's mouth is a system of linked muscle and bone that resembles the mechanism of an oil rig. NYTimes:



Read more here: http://ift.tt/2DAmX4W

Posted at Clinical Cases and Images. Stay updated and subscribe, follow us on Twitter and connect on Facebook.

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Introduction: Antibody-Mediated Therapy Special Issue Part 2

Antibodies have been used therapeutically for well over a century but the breadth and depth of their applications are increasing so rapidly and successfully that clinical studies are informing mechanistic questions while basic research continues to interrogate how antibodies are made and function, so their properties can be further refined. The first part of this Special Issue comprised five review articles (1); this second part includes four more reviews. Once again, we thank the authors for their excellent contributions. This issue also includes an original research article that builds on observations from patients with hyper-IgM syndrome to further define the mechanism for antibody class-switch recombination (CSR).

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Cover

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Table of Contents

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A pro-inflammatory role of Fcα/μR on marginal zone B cells in sepsis

Abstract

Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcγ and Fcε receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors for IgA and IgM, including Fcα/μ receptor (Fcα/μR) (CD351), polymeric immunoglobulin receptor (poly-IgR), Fcα receptor (FcαRI) (CD89) and Fcμ receptor (FcμR). In this review, we summarize the molecular and functional characteristics of Fcα/μR in comparison with poly-IgR, FcμR and FcαRI, and focus particularly on the pro-inflammatory function of Fcα/μR expressed on marginal zone B cells in sepsis.

http://ift.tt/2lu5Pqj

Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination

Abstract

Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild-type (WT) AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and a null mutation on the other allele in a mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome-editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AID^JP41/∆/AIDER CH12F3-2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed that the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID-deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1 and hnRNP U). Together, these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA-binding proteins from WT AID.

http://ift.tt/2lnxLwG

Targeted antibody therapy and relevant novel biomarkers for precision medicine for rheumatoid arthritis

Abstract

Over the past two decades, the management of rheumatoid arthritis (RA) has progressed remarkably, encompassing the development of new diagnostic tools and efficacious biological agents, such as monoclonal antibodies against inflammatory cytokines and surface markers on immune cells. In addition to the significant efficacy of these biological agents, biomarkers for RA are under consideration for their potential to classify heterogeneous patients into several groups based on clinical and immunological phenotypes for the prediction of clinical course and prognosis and the facilitation of appropriate and precise treatment with the appropriate therapeutic monoclonal antibodies. Biomarkers, particularly those for the prediction and monitoring of the responses to therapeutic monoclonal antibodies for RA, are in demand, with many approaches examined in recent years. In this article, we have summarized the background research on biomarkers and introduced recent topics in the field that enable the possible clinical applications of biomarkers, especially those related to pathogenic cytokines, to guide the treatment of RA.

http://ift.tt/2lwKn46

Sweet SIGNs: IgG glycosylation leads the way in IVIG-mediated resolution of inflammation

Abstract

A hallmark of many chronic inflammatory and autoimmune diseases is that there is an impaired resolution of inflammation and return to the steady state. The infusion of high doses of pooled serum IgG preparations from thousands of donors [intravenous immunoglobulin (IVIG) therapy] has been shown to induce resolution of inflammation in a variety of chronic inflammatory and autoimmune diseases, suggesting that IgG molecules can instruct the immune system to stop inflammatory processes and initiate the return to the steady state. The aim of this review is to discuss how insights into the mechanism of IVIG activity may help to understand the molecular and cellular pathways underlying resolution of inflammation. We will put a special emphasis on pathways dependent on the IgG F_C domain and IgG sialylation, as several recent studies have provided new insights into how this glycosylation-dependent pathway modulates innate and adaptive immune responses through different sets of C-type or I-type lectins.

http://ift.tt/2lnWNf4

IVIG-mediated effector functions in autoimmune and inflammatory diseases

Abstract

Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab′)₂ fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.

http://ift.tt/2ltQy8N

Incidence, risk and prognostic role of anti-epidermal growth factor receptor-induced skin rash in biliary cancer: a meta-analysis

Abstract

Background

Anti-epidermal growth factor receptor (EGFR)-induced skin rash is a common adverse event and is considered a prognostic factor of various cancers. However, the role of rash is rarely known in biliary cancer, possibly owing to the low incidence of this frequently fatal malignancy. We thus performed a meta-analysis to investigate the incidence, risk and prognostic significance of skin rash related to anti-EGFR treatment for biliary cancer.

Methods

Eligible studies were enrolled after a systematic search of electronic databases. A fixed-effects or random-effects model was utilized according to the heterogeneity.

Results

Fourteen clinical trials published between 2006 and 2017 comprising 1,106 patients with advanced biliary cancer were included. The overall incidence of all-grade and high-grade (grade ≥3) rash was 78.2% [95% confidence interval (CI) 70.4–84.3] and 11.3% (7.6–16.5), respectively. Anti-EGFR treatment correlates with a significantly increased risk of all-grade [risk ratio (RR) 7.37, 95% CI 5.11–10.64, p < 0.0001] and high-grade (RR 6.94, 95% CI 1.89–25.45, p = 0.0035) rash compared with control medication. Higher grades of skin rash correlate with a higher objective response rate (RR 3.50, 95% CI 1.47–8.33, p = 0.0048), and a longer overall [hazard ratio (HR) 0.47, 95% CI 0.31–0.71, p = 0.0003) and progression-free survival (HR 0.51, 95% CI 0.36–0.72, p = 0.0001) compared with lower grades or no rash in patients who received anti-EGFR treatment.

Conclusions

Anti-EGFR treatment correlates with an increased risk of skin rash in advanced biliary cancer. Stratifying patients by the severity of rash may have major implications for survival benefit regarding anti-EGFR treatment for biliary cancer.

http://ift.tt/2CclN3E

Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA tool

Abstract

Objectives

To develop a patient decision aid to promote shared decision-making for stable, alert patients who present to the emergency department (ED) with syncope.

Methods

Using input from patients, clinicians, and experts in the field of syncope, health care design, and shared decision-making, we created a prototype of a paper-based decision aid to engage patients in the disposition decision (admission vs. discharge) after an unremarkable ED evaluation for syncope. In phase 1, we conducted 1-on-1 semi-structured exploratory interviews with 10 emergency physicians and 10 ED syncope patients. In phase 2, we conducted 1-on-1 directed interviews with 15 emergency care clinicians, 5 cardiologists, and 12 ED syncope patients to get detailed feedback on decision aid content and design. We iteratively modified the aid using feedback from each interviewee until clarity and usability had been optimized.

Results

The 11- x 17-inch, paper-based decision aid, titled SynDA, includes 4 sections: 1) Explanation of syncope, 2) Explanation of future risks, 3) Personalized 30-day risk estimate, and 4) Disposition options. The personalized risk estimate is calculated using a recently published syncope risk-stratification tool. This risk estimate is stated in natural frequency and graphically displayed using a 100-person color-coded pictogram. Patient-oriented questions are included to stimulate dialogue between patient and clinician. At the end of the development process, patient and physician participants expressed satisfaction with the clarity and usability of the decision aid.

Conclusions

We iteratively developed an evidence-based decision aid to facilitate shared decision-making for alert syncope patients after an unremarkable ED evaluation. Further testing is required to determine its effects on patient care. This decision aid has the potential to improve care for syncope patients and promote patient-centered care in emergency medicine.

This article is protected by copyright. All rights reserved.

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Different applicabilities of the etch-bleach-seal technique for treating opacities on permanent incisor damage by molar incisor hypomineralisation in three young patients

Enamel opacity on anterior teeth can be prejudicial for the aesthetic appearance of affected patients. Patients with molar incisor hypomineralisation, for example, present opacities that can range from discrete white mottling to extensive yellow-brown discolourations. They can request a treatment to improve their aesthetic conditions. Many techniques have been considered to manage this condition. Wright developed a technique called etch–bleach–seal, which showed promising results for the management of anterior enamel opacities. The aims of this report are to present this technique and to analyse its benefits and inconveniences.

http://ift.tt/2pZMXVy

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Summary

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, where the majority of patients experienced no or minimum clinical benefits. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations which are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity such as neoantigens, the likelihood of toxic effects is likely to be very limited. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

This article is protected by copyright. All rights reserved.

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Pretreatment of Probiotic Bifico Ameliorates Colitis-Associated Cancer in Mice: Transcriptome and Gut Flora Profiling

Abstract

Individuals with inflammatory bowel disease (IBD) are at a high risk for developing colitis-associated cancer (CAC). Strategies to block the process from IBD to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane (AOM) and dextran sodium sulphate (DSS) induced colitis-associated cancer in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of thirty-five C57BL/6 mice were collected and examined for degree of inflammation and tumorigenesis. Methods of cDNA microarray, comparative 16S rRNA sequencing were performed to observe Bifico-target alterations in gene expression and microbiota structure. We found pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including chemokine C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL3, and CXCL5, which were all ligands of C-X-C motif receptor 2 (CXCR2). 16S rRNA sequencing demonstrated that Bifico decreased the abundance of genus Desulfovibrio, Mucispirillum and Odoribacter, while a bloom of genus Lactobacillus was detected. Notably, we found abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies demonstrate that oral administration of Bifico can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus and CXCR2 signaling.

This article is protected by copyright. All rights reserved.

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Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

Abstract

Cdc37 is an important partner for HSP90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulated cell survival remained unclear in colorectal carcinoma. Here, we investigated the expression of Cdc37 and its clinical significance in colorectal carcinoma, and systematically explored the role of Cdc37 in colorectal carcinoma cell survival both in vitro and in vivo and the underlying mechanism. Our results showed that Cdc37 was remarkably up-regulated in colorectal carcinoma, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of CDK4 to activate the RB1 signaling pathway, followed by the increased expression of Bcl-2 and Bcl-xL, which ultimately promoted the cell survival in colorectal carcinoma. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings demonstrated that Cdc37 played a critical role in promoting colorectal carcinoma cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patient.

This article is protected by copyright. All rights reserved.

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Dietary acrylamide intake and risk of breast cancer: the Japan Public Health Center-based Prospective Study

Abstract

Acrylamide forms during cooking and is classified as a probable carcinogen in humans, mandating the need for epidemiological studies of dietary acrylamide and cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japanese women has not been assessed. We investigated the association between dietary acrylamide intake and risk of breast cancer in the Japan Public Health Center-based Prospective Study. The present study included 48,910 women aged 45-74 years who responded to a 5-year follow-up survey questionnaire. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. During an average of 15.4 years of follow up, 792 breast cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest tertile=0.95, 95% confidence intervals: 0.79-1.14, p-trend=0.58). Further, no significant associations were observed when stratified analyses were conducted by smoking status, coffee consumption, alcohol consumption, body mass index, menopausal status, estrogen receptor status, and progesterone receptor status. In conclusion, dietary acrylamide intake was not associated with the risk of breast cancer in this population-based prospective cohort study of Japanese women.

This article is protected by copyright. All rights reserved.

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CCL5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment

Summary

Chemokines and their receptors have key roles in cancer progression. This study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when CCL5 neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

This article is protected by copyright. All rights reserved.

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IL-6/STAT3 promotes prostate cancer resistance to androgen deprivation therapy via regulating PTTG1 expression

Summary

Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration-resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44⁺CD24^- cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by IL-6 via activated STAT3 directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that IL-6/STAT3 activation can increase PTTG1 expression and consequently promote the resistance to ADT in CRPC via inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.

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A third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

Summary

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

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Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

Summary

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in an MHC-unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

http://ift.tt/2lkucHJ

FDA Permits Marketing of Device to Treat Diabetic Foot Ulcers

December 28, 2017 -- Today, the U.S. Food and Drug Administration permitted the marketing of the Dermapace System, the first shock wave device intended to treat diabetic foot ulcers. "Diabetes is the leading cause of lower limb amputations,"...

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Bone response to functionally loaded, two-piece zirconia implants: A preclinical histometric study

Abstract

Objective

To evaluate the bone response to a two-piece zirconia implant in comparison with a control titanium implant in the canine mandible 4 and 16 weeks after restoration.

Material and Methods

Zirconia and titanium implants were alternately placed bilaterally in healed mandibular molar and premolar sites of five canines. Full-ceramic single-tooth restorations were cemented after 6 weeks of transmucosal healing, allowing for full functional loading of the implants. Histologic and histometric analyses were performed on orofacial and mesiodistal undecalcified sections of the specimens obtained upon sacrifice after 4 and 16 weeks of functional loading. Bone-to-implant contact (BIC), multinucleated giant cells-to-implant contact (MIC), crestal bone level, and peri-implant bone density were histometrically assessed.

Results

All 60 implants and 60 restorations were still in function after 4 and 16 weeks of loading in both test and control groups. No implant loss, no implant or abutment fracture, and no chipping of the restorations could be detected. Histometric analysis showed no statistically significant differences between zirconia and titanium implants in BIC, crestal bone level, and peri-implant bone density at both time points. Between 4 and 16 weeks, the crestal bone level around zirconia implants showed a small but statistically significant increase in its distance from the implant shoulder. MIC was very low on both implant types and both time points and decreased statistically significantly overtime.

Conclusion

The present two-piece zirconia implant showed a similar bone integration compared to the titanium implant with similar surface morphology after 4 and 16 weeks of loading.

http://ift.tt/2EfTIpn

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

http://ift.tt/2lkucHJ