Τετάρτη 24 Μαΐου 2017
PROPIONIBACTERIUM ACNES AND CHRONIC DISEASES : P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,post-neurosurgical infection,joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.
P. acnes bacteria live deep within follicles and pores, away from the surface of the skin. In these follicles, P. acnes bacteria use sebum, cellular debris and metabolic byproducts from the surrounding skin tissue as their primary sources of energy and nutrients. Elevated production of sebum by hyperactive sebaceous glands (sebaceous hyperplasia) or blockage of the follicle can cause P. acnes bacteria to grow and multiply.[6]
P. acnes bacteria secrete many proteins, including several digestive enzymes.[7] These enzymes are involved in the digestion of sebum and the acquisition of other nutrients. They can also destabilize the layers of cells that form the walls of the follicle. The cellular damage, metabolic byproducts and bacterial debris produced by the rapid growth of P. acnes in follicles can trigger inflammation.[8] This inflammation can lead to the symptoms associated with some common skin disorders, such as folliculitis and acne vulgaris.[9][10][11]
The damage caused by P. acnes and the associated inflammation make the affected tissue more susceptible to colonization by opportunistic bacteria, such as Staphylococcus aureus. Preliminary research shows healthy pores are only colonized by P. acnes, while unhealthy ones universally include the nonpore-resident Staphylococcus epidermidis, amongst other bacterial contaminants. Whether this is a root causality, just opportunistic and a side effect, or a more complex pathological duality between P. acnes and this particular Staphylococcus species is not known.[12]
P. acnes has also been found in corneal ulcers, and is a common cause of chronic endophthalmitis following cataract surgery. Rarely, it infects heart valves leading to endocarditis, and infections of joints (septic arthritis) have been reported.[5] Furthermore, Propionibacterium species have been found in ventriculostomy insertion sites, and areas subcutaneous to suture sites in patients who have undergone craniotomy. It is a common contaminant in blood and cerebrospinal fluid cultures.
P. acnes has been found in herniated discs.[13] The propionic acid which it secretes creates micro-fractures of the surrounding bone. These micro-fractures are sensitive and it has been found that antibiotics have been helpful in resolving this type of low back pain.[14]
P. acnes can be found in bronchoalveolar lavage of approximately 70% of patients with sarcoidosis and is associated with disease activity, but it can be also found in 23% of controls.[15][16] The subspecies of P. acnes that cause these infections of otherwise sterile tissues (prior to medical procedures), however, are the same subspecies found on the skin of individuals who do not have acne-prone skin, so are likely local contaminants. Moderate to severe acne vulgaris appears to be more often associated with virulent strains.[17]
P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,[18] post-neurosurgical infection,[19] joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,[20] SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.[21]
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Location of implant-retained fixed dentures affects oral health-related quality of life
Abstract
Background
The effects of the locations of dental implants on treatment outcomes, as evaluated by oral health-related quality of life (OHRQoL) assessment, remain controversial.
Purpose
To investigate the association between the locations of dental implants and changes in OHRQoL.
Materials and methods
Sixty-eight subjects received implant treatment in the anterior or posterior region and completed the Oral Health Impact Profile (OHIP) questionnaire before and after treatment. Change in OHIP summary scores and the 4 dimension scores were calculated to evaluate the effects of implant treatment on OHRQoL.
Results
The mean Oro-facial Appearance score for the anterior group was significantly higher than that for the posterior group (10.4 ± 5.1 and 7.2 ± 3.8, respectively; P ＝ .005; Effect size = 0.63) at baseline. All questionnaire scores were significantly improved following implant treatment in both groups, and no significant group differences were observed at follow-up. Regression analysis revealed a significant association between the locations of most anterior implants and changes in the Oro-facial Appearance score (adjusted R2 = 0.073; P = .015).
Conclusion
Our results suggest that the locations of dental implants influence OHRQoL impairments and improvements after treatment. This information might be useful in clinical decision-making.
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Dichotic Listening Deficit Associated With Solvent Exposure.Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes.
Dichotic Listening Deficit Associated With Solvent Exposure.
από Landry, Simon P.; Fuente, Adrian στο Otology & Neurotology Published Ahead-of-Print
Μετάφραση άρθρου
Hypothesis: A significant left ear deficit can be observed in solvent-exposed individuals using the dichotic digit test. Background: Solvents are ubiquitous in global industrial processes. Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes. Investigations in exposed populations suggest a decreased performance for dichotic listening. Methods: In this present study, we examined the lateralization of a dichotic digit test score for 49 solvent-exposed individuals along with 49 age- and sex-matched controls. We evaluated group differences between test scores and the right ear advantage using a laterality index (LI). Results: Individual ear results suggest that long-term workplace solvent exposure is associated with a significantly lower dichotic listening score for the left ear. A binaural compound score analysis using a laterality index supports this left-ear deficit. Conclusion: These results provide an insight on the effects of solvent exposure on dichotic listening abilities. Further research should investigate the importance of using dichotic listening tasks to screen for solvent-induced auditory dysfunction in exposed individuals. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
PARP Inhibitors in Prostate Cancer
Opinion Statement
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.
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Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses are associated with multiple sclerosis
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
No Evidence That Brain-Stimulation Technique Boosts Cognitive Training
Transcranial direct-current stimulation (tDCS)—a non-invasive technique for applying electric current to areas of the brain—may be growing in popularity, but new research suggests that it probably does not add any meaningful benefit to cognitive training. The study is published in Psychological Science, a journal of the Association for Psychological Science.
"Our findings suggest that applying tDCS while older participants engaged in daily working memory training over four weeks did not result in improved cognitive ability," explains researcher Martin Lövdén of Karolinska Institutet and Stockholm University.
"The study is important because it addresses what has arguably been the most promising cognitive application of tDCS: the possibility of long-term cognitive enhancement from relatively limited practice on select cognitive tasks," Lövdén adds. "Cognitive enhancement is of interest not just to scientists, but also to the student studying for final exams, the gamer playing online games, and the retiree remembering which pills to take. Because of this large audience, it is of utmost importance to conduct systematic research to disentangle hype from fact."
Working memory—our capacity for holding information in mind at any given moment—underlies many fundamental cognitive processes and is linked with some aspects of intelligence. Research has shown that working memory training improves working memory performance but it's unclear whether this specific training can yield improvements to broader cognitive abilities.
Recent interest and publicity surrounding the potential effects of tDCS—which involves conducting a weak electrical current to the brain via electrodes on the scalp—led Lövdén and colleagues to wonder: Could using tDCS during cognitive training enhance brain plasticity and enable transfer from working memory to other cognitive processes?
The researchers enrolled 123 healthy adults who were between 65 and 75 years old in a 4-week training program. All participants completed a battery of cognitive tests, which included tasks that were incorporated in the training and tasks that were not, at the beginning of the study and again at the end. Those randomly assigned to the experimental group trained on tasks that targeted their ability to update mental representations and their ability to switch between different tasks and rules, while those in the active control group trained on tasks that focused on perceptual speed.
As they completed the training tasks, some participants received 25 minutes of tDCS current to the left dorsolateral prefrontal cortex, an area of the brain that plays a central role in working memory; other participants were led to believe they were receiving 25 minutes of current, when in actuality the current was only active for a total 30 seconds.
Comparing participants' performance before and after training indicated that those who received working memory training did improve on the updating and switching tasks they had encountered during training and on similar tasks that they had not encountered previously.
But there was no evidence that tDCS produced any additional benefit to the working memory training—at the end of the study, participants who received tDCS did not show greater improvement than their peers.
When the researchers pooled the data from this study with findings from six other studies, they again found no evidence of any additional benefit from working memory training that was combined with tDCS.
Given strong public interest in cognitive enhancement, Lövdén and colleagues urge caution when it comes to this as-of-yet unproven application of tDCS:
"A growing number of people in the general public, presumably inspired by such uninhibited optimism, are now using tDCS to perform better at work or in online gaming, and online communities offer advice on the purchase, fabrication, and use of tDCS devices," the researchers write. "Unsurprisingly, commercial exploitation is rapidly being developed to meet this new public demand for cognitive enhancement via tDCS, often without a single human trial to support the sellers' or manufacturers' claims."
"These findings highlight exactly how limited our knowledge is of the mechanisms underlying the potential effects of tDCS on human cognition and encourages the research community to take a step back and focus its resources on developing strategies for uncovering such mechanisms before using the technique in more applied settings," Lövdén concludes.
Co-authors on the study include Jonna Nilsson, Alexander V. Lebedev, and Anders Rydström of Karolinska Institutet and Stockholm University.
This research received funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013) and ERC Grant No. 617280 -REBOOT. Martin Lövdén was also supported by a Distinguished Young Researchers grant from the Swedish Research Council (446-2013-7189).
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Automatic multimodal detection for long-term seizure documentation in epilepsy
Seizure documentation and quantification represents the primary outcome measure of epilepsy therapy including antiepileptic drug treatment, epilepsy surgery, and neurostimulation. Presently, patients document their seizures using seizure diaries without systematic and objective validation approach by physicians. Recent publications showed that manual seizure counting suffers from underreporting with sensitivities of 50% during day and as low as 30% during night and can therefore be considered as highly unreliable (Blachut et al., 2015).
http://ift.tt/2rSS8na
Myeloproliferative Neoplasms with t(8;22)(p11.2;q11.2)/BCR-FGFR1: A Meta-Analysis of 20 Cases Shows Cytogenetic Progression with B-Lymphoid Blast Phase
Rearrangements of FGFR1 result in the 8p11 myeloproliferative syndrome, a group of rare diseases that features a myeloproliferative neoplasm (MPN) that commonly progresses to lymphoblastic leukemia/lymphoma or acute myeloid leukemia. The most common partner of the FGFR1 is ZMYM2 and patients with the ZMYM2-FGFR1 fusion often present with MPN and T-lymphoblastic lymphoma. There are 14 other partners that can fuse with the FGFR1 and of interest is the BCR-FGFR1 fusion that results from t(8;22)(p11.2;q11.2).
http://ift.tt/2qYbeIi
T-cell transcription factor GATA-3 is an immunophenotypic marker of acute leukemias with T-cell differentiation
T cell transcription factor GATA-3, known to play a role in early T cell development and in the development of T cell neoplasms, is expressed at high levels in fetal and adult thymus, as well as in acute leukemias with T-cell differentiation, including T lymphoblastic leukemia/lymphoma (22/22 cases), early T cell precursor (ETP) lymphoblastic leukemia (11/11 cases), and mixed phenotype acute leukemia, T/myeloid (4/5 cases), but only rarely in acute myeloid leukemia/myeloid sarcoma (1/36 cases), and not in B lymphoblastic leukemia (0/16 cases).
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Histopathologic Evaluation of Atypical Neurofibromatous Tumors and Their Transformation into Malignant Peripheral Nerve Sheath Tumor in Neurofibromatosis 1 Patients – A Consensus Overview
Neurofibromatosis 1 (NF1) patients develop multiple neurofibromas, with 8-15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, following a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant trans-formation of neurofibromas. Nuclear atypia alone is generally insignificant.
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B7-H3 expression in NSCLC and its association with B7-H4, PD-L1 and Tumor Infiltrating Lymphocytes
Background and Purpose: <p>The immune checkpoint PD-1 and its receptor B7-H1 (PD-L1) are successful therapeutic targets in cancer but less is known about other B7 family members. Here, we determined the expression level of B7-H3 protein in non-small cell lung cancer (NSCLC) and evaluated its association with tumor infiltrating lymphocytes (TILs), PD-L1, B7-H4 and major clinico-pathological characteristics is in 3 NSCLC cohorts.</p> <p>Experimental design:</p> <p>We used multiplexed automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3, PD-L1, B7-H4 and TILs in 634 NSCLC cases with validated antibodies. Associations between the marker levels, major clinico-pathological variables and survival were analyzed.</p> <p>Results: </p> <p>Expression of B7-H3 protein was found in 80.4% (510/634) of the cases. High B7-H3 protein level (top 10 percentile) was associated with poor overall survival (p <0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage and histology. Co-expression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3, CD8 and CD20 positive TILs.</p> <p>Conclusion:</p> <p>B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High levels of B7-H3 protein has a negative prognostic impact in lung carcinomas. Co-expression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a non-redundant biological role of these targets.
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Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules
Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy, and to predict the likelihood of local control as a function of dose and treatment fractions.<br /><br />Experimental Design: We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and 2 unpublished early stage patient cohorts, totaling 2701 patients.<br /><br />Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α (0.305 Gy-1; 95% CI: 0.120-0.365), the α/β ratio (2.80 Gy; 95% CI: 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI: 1.55-2.25). All fractionation groups are well-fitted by a single dose-response curve with a high 2 p-value, indicating consistency with the fitted model. The analysis was further validated with additional 23 patient cohorts (n=1628). The model indicates that hypofractionation regimes overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimes allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.<br /><br />Conclusions: The mechanistic tumor response modeling can accurately predict over-treatment or under-treatment for various treatment regimes.
http://ift.tt/2qdL73b
Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma
Purpose: <p>Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes.</p> <br /><br />Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.<br /><br />Results: <p>Seventy-two patients (82%) had ≥ 1 ctDNA alteration(s); amongst these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% versus 61.5% (≤ 1 versus > 1 month between tests; P = 0.04)) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥ 1 ctDNA alteration(s); 72.3% (N=16/22) of the evaluable matched patients achieved stable disease ≥ 6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥ 1 alteration with ≥ 5% variant allele fraction (versus < 5%) had a significantly shorter median survival (P = 0.012).</p> <br /><br />Conclusions: <p>ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies.
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Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer (MBC)
Background: CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC in human breast cancer xenografts. This Phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). <p>Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a three-day run-in with reparixin oral tablets 3 times daily (t.i.d.), followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin tablets t.i.d. for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended Phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.</p> <p>Results: There were neither G4-5 adverse events nor serious adverse events related to study therapy, and no interactions between reparixin and paclitaxel to influence their respective PK profiles. A 30% response rate was recorded, with durable responses > 12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSC.</p> <p>Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally t.i.d., was selected for further study in a randomized Phase II trial. (NCT02370238)
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BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAF V600E mutant melanoma
Purpose: Many patients with BRAF V600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies. <br /><br />Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAF V600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAF V600E melanoma cell lines and its effect on drug sensitivity was evaluated.<br /><br />Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAF V600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of AGAP3-BRAF fusion in BRAF V600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAF V600E and AGAP3-BRAF only have a fitness advantage over parental BRAF V600E cells during active treatment with a BRAF inhibitor.<br /><br />Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma.
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Health Brokers: How Can They Help Deal with the Wickedness of Public Health Problems?
Background. The role of health broker is a relatively new one in public health. Health brokers aim to create support for efforts to optimise health promotion in complex or even "wicked" public health contexts by facilitating intersectoral collaborations and by exchanging knowledge with different stakeholders. The current study aimed to explore the role of health brokers, by examining the motivational, contextual, and behaviour-related factors they have to deal with. Methods. Fifteen professionals from various backgrounds and from various policy and practice organisations were recruited for a semistructured interview. To structure the interviews, we developed the "Health Broker Wheel" (HBW), a framework we then specified with more details derived from the interviews. Results. We identified seven primary types of behaviour that health brokers need to engage in: recognizing opportunities, agenda setting, implementing, network formation, intersectoral collaboration, adaptive managing, and leadership. Determinants of health brokers' behaviours were identified and categorised as capability, opportunities, motivation, and local or national contextual factors. Conclusion. The health brokers' role can be seen as an operational approach and is visualised in the HBW. This framework can assist further research to monitor and evaluate this role, and health promotion practitioners can use it as a tool to implement the health brokers' role and to facilitate intersectoral collaboration.
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Closer to a Uniform Language in Colposcopy: Study on the Potential Application of 2011 International Federation for Cervical Pathology and Colposcopy Terminology in Clinical Practice
As the newest colposcopic terminology, the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) classification provides standardized interpretation of colposcopic findings. In this study, we analyzed the colposcopic accuracy and the significance of individual findings according to the 2011 IFCPC classification in 525 patients, reviewed by 13 trained colposcopists. Results show that colposcopic diagnoses are in 64.95% perfect agreement with cervical pathology, with 63.64% sensitivity and 96.01% specificity for high-grade squamous intraepithelial lesion (HSIL+). And the accuracy is reproducible across different experienced examiners. Many individual findings, especially the two new signs, inner border sign and ridge sign, are proved to have good predictive accuracy, while iodine negativity demonstrates an inferior performance. However, the distribution of three cervical transformation zone (TZ) types is heterogeneous in examiners. A comparison was also made of the findings of another two colposcopists without nomenclature training according to the Reid Colposcopic Index (RCI), modified RCI, and Swede Score. Results show that colposcopic accuracies in them are lower than in those nomenclature trained colposcopists. The 2011 IFCPC nomenclature improves colposcopic accuracy in trained colposcopists, like speaking the same language. However, the reproducibility of TZ and the predictive value of a few signs remain to be discussed.
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Protective Effect of a Polyherbal Aqueous Extract Comprised of Nigella sativa (Seeds), Hemidesmus indicus (Roots), and Smilax glabra (Rhizome) on Bleomycin Induced Cytogenetic Damage in Human Lymphocytes
This study was carried out to determine the chemoprotective potential of a polyherbal aqueous decoction comprised of Nigella sativa (seeds), Hemidesmus indicus (roots), and Smilax glabra (rhizome) against bleomycin induced cytogenetic damage in human lymphocytes. Isolated peripheral blood lymphocytes (PBLs) were exposed to bleomycin at a dose of 40 µg/mL for 2 hrs in the presence or absence of different doses of the decoction (100, 300, and 600 µg/mL). Modulatory effect of the decoction on bleomycin induced cytogenetic damage was evaluated by (a) degree of chromosomal aberrations (CA), (b) formation of micronuclei (MN), and (c) induction of γH2AX foci in lymphocytes exposed to bleomycin. Lymphocytes pretreated with the decoction showed that a significant reduction () in bleomycin induced (a) stable and unstable chromosome aberrations (CA), (b) MN formation, and (c) formation of H2AX foci, when compared to lymphocytes treated only with bleomycin. The decoction by itself did not induce any significant cytogenetic damage in PBLs. Overall results of the present study confirm that the decoction can attenuate the cytogenetic damage mediated by bleomycin in human PBLs.
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A novel polytetrafluoroethylene-channel model, which simulates low levels of culturable bacteria in build-up biofilm after repeated endoscope reprocessing
Clinical studies have shown variable culture results from flexible endoscope channels possibly due to low levels of bacteria that are difficult to extract. The aim of this study was to develop a simulated-use buildup biofilm (BBF) model that mimics low levels of viable bacteria after repeated rounds of aldehyde fixation and accumulation.
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EUS-guided fine-needle core liver biopsy using a novel 19G needle with modified one pass, one actuation wet suction technique
EUS-guided fine-needle core biopsy is a safe and effective technique for diagnosis of focal liver lesions. However, data are limited in its role in parenchymal disease. We evaluated the utility of EUS-guided parenchymal liver biopsies (EUS-LB) with a modified one pass wet suction technique (EUS-MLB) in patients with unexplained increase in liver associated tests.
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Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice
Consumption of a high-fat high-fructose diet (western diet, [WD]) promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in women. Further, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and are also associated with vascular stiffness. In turn, uric acid levels lead to vascular stiffness and CVD in women. However, the mechanisms by which fructose contributes to vascular stiffness in females remain to be fully uncovered. We examined the role of XO inhibition on vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 weeks. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19±1.72 vs 5.21±0.54 kPa, p<0.05), as well as abnormal aortic endothelium-dependent and independent vasomotor responses. XO inhibition using allopurinol (widely utilized in the clinical setting) significantly improved vasomotor responses and stiffness (16.9±0.50 vs 3.44± 0.50 kPa, p<0.05), while simultaneously lowering serum uric acid levels (0.55±0.98 vs 0.21±0.04 mg/dL, p<0.05). Also, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation and aortic stiffness in females. Further, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD in females.
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Cerebral Oxygenation and Regional Cerebral Perfusion Responses with Resistance Breathing during Central Hypovolemia
Resistance breathing improves tolerance to central hypovolemia induced by lower body negative pressure (LBNP), but this is not related to protection of anterior cerebral blood flow (indexed by mean middle cerebral artery velocity, MCAv). We hypothesized that inspiratory resistance breathing improves tolerance to central hypovolemia by maintaining cerebral oxygenation (ScO2), and protecting cerebral blood flow in the posterior cerebral circulation (indexed by posterior cerebral artery velocity, PCAv). Eight subjects (4M/4F) completed two experimental sessions of a presyncopal-limited LBNP protocol (3 mmHg/min onset rate) with and without (Control) resistance breathing via an impedance threshold device (ITD). ScO2 (via near-infrared spectroscopy), MCAv and PCAv (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Hemodynamic responses were analyzed between the Control and ITD condition at baseline (T1) and the time representing 10-s prior to presyncope in the Control condition (T2). While breathing on the ITD increased LBNP tolerance from 1506±75 s to 1704±88 s (P=0.003), both mean MCAv and mean PCAv were similar between conditions at T2 (P≥0.46), and decreased by the same magnitude with and without ITD breathing (P≥0.53). ScO2 also decreased by approximately 9% with or without ITD breathing at T2 (P=0.972), and there were also no differences in deoxygenated (dHb) or oxygenated hemoglobin (HbO2) between conditions at T2 (P≥0.43). There was no evidence that protection of regional cerebral blood velocity (i.e., anterior or posterior cerebral circulation), nor cerebral oxygen extraction played a key role in the determination of tolerance to central hypovolemia with resistance breathing.
http://ift.tt/2qm2JF1
CRF and urocortin 3 protect the heart from hypoxia/reoxygenation-induced apoptosis in zebrafish
Fish routinely experience environmental hypoxia and have evolved various strategies to tolerate this challenge. Given the key role of the corticotropin-releasing factor (CRF) system in coordinating the response to stressors and its cardioprotective actions against ischemia in mammals, we sought to characterize the cardiac CRF system in zebrafish and its role in hypoxia tolerance. We established that all genes of the CRF system, the ligands CRFa, CRFb, urotensin 1 (UTS1) and urocortin 3 (UCN3), the two receptor subtypes (CRFR1 and CRFR2), and the binding protein (CRFBP) are expressed in the heart of zebrafish: crfr1 > crfr2 = crfbp > crfa > ucn3 > crfb > uts1. In vivo, exposure to 5% O2 saturation for 15 min and 90 min recovery resulted in 4-5 fold increases in whole heart crfb and ucn3 mRNA levels but did not affect the gene expression of other CRF system components. In vitro, as assessed by monitoring caspase 3 activity and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pre-treatment of excised whole hearts with CRF or UCN3 for 30 min prevented the increase in apoptosis associated with exposure to 1% O2 saturation for 30 min and 24 h recovery. Lastly, addition of the non-selective CRF receptor antagonist, αh-CRF(9-41), prevented the cytoprotective effects of CRF. We show that the CRF system is expressed in fish heart, is up-regulated by hypoxia, and is cytoprotective. These findings identify a novel role for the CRF system in fish and a new strategy to tolerate hypoxia.
http://ift.tt/2qm2Non
(P086) Success of Stereotactic Body Radiation Therapy in Central Versus Peripheral Retreatment of Non-Small Cell Lung Cancer
The majority of complications in our SBRT practice have occurred in patients with a history of prior treatment. We compared the outcomes of stereotactic body radiation therapy (SBRT) in the treatment of central versus peripheral recurrent or second primary non-small cell lung cancer (NSCLC).
http://ift.tt/2rSx1Bi
(P084) Stereotactic Ablative Radiotherapy for Stage I Non-Small-Cell Lung Cancer Tumors Greater Than 5 cm
Outcomes for treatment of large (>5 cm) primary non–small-cell lung cancer (NSCLC) tumors treated with stereotactic ablative radiotherapy (SABR) have not been well characterized. In this study we retrospectively analyzed a group of patients treated with SABR for large NSCLC and identify predictors of outcome.
http://ift.tt/2rjmnXu
(P088) Splenic Irradiation for Splenomegaly: A Meta-Analysis
Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly secondary to hematologic malignancies and disorders. Our purpose is to characterize SI patient selection, optimal technique, efficacy, and toxicities.
http://ift.tt/2rSLSfl
ETV1-positive cells give rise to BRAFV600E mutant gastrointestinal stromal tumors
Gastrointestinal Stromal Tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDGFRA-wild type GIST, including mutant BRAF-driven tumors, have been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse GI tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents.
http://ift.tt/2qYkDlt
"J BUON"[jour]; +45 new citations
45 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2017/05/24
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
http://ift.tt/2rj9wV6
Perinatal Risk and Protective Factors for Pediatric Abusive Head Trauma: A Multicenter Case-Control Study
To estimate associations between factors recorded in pregnancy and the first week of life and subsequent abusive head trauma.
http://ift.tt/2rWnOXU
First Trimester Influenza Vaccination and Risks for Major Structural Birth Defects in Offspring
To examine risks for major structural birth defects in infants after first trimester inactivated influenza vaccine (IIV) exposures.
http://ift.tt/2qYeHc6
Reply
The comments of Finsterer and Zarrouk-Mahjoub expand the discussion of premature ovarian failure (POF) in patients with French Canadian Leigh Syndrome (FCLS). Our publication focused on POF in FCLS, an important and highly treatable aspect of this mitochondrial disease. We did not attempt to review the broad area of the relationships between mitochondria and the ovary. As Finsterer and Zarrouk-Mahjoub state, ovarian failure can occur in other mitochondrial diseases. Luteinizing hormone and follicle-stimulating hormone (FSH) levels were appropriately increased in FCLS women, their thyroid-stimulating hormone and prolactin levels were normal, and it was, therefore, not indicated to further investigate pituitary function or anatomy.
http://ift.tt/2qYjM4j
Preserving the Fogarty International Center — Benefits for Americans and the World
In his proposed budget for fiscal year 2018, President Donald Trump recommended eliminating the Fogarty International Center (FIC) at the National Institutes of Health (NIH). Although the NIH actually received increased funding in the fiscal year 2017 budget that was signed on May 5, the FIC — a…
http://ift.tt/2rBs0Qu
Regional Differences in the Associations Between Prescribed Dialysate Sodium Concentration and Interdialytic Weight Gain in the Dialysis Outcomes and Practice Patterns Study
Higher dialysate sodium (DNa) prescription levels are associated with thirst and interdialytic weight gain (IDWG, reviewed in1). A recent analysis from the United States found that measured DNa may be considerably higher than prescribed DNa,2 contrasting the results of another study from Austria/Europe.3 In the US study, the magnitude of the differences (prescribed minus measured DNa) ranged from −13 to +6 mEq/L, and measured DNa concentrations were ±2 mEq/L of prescribed DNa concentrations in 57.0% of treatments.
http://ift.tt/2riRulQ
Dabigatran Reversal in a Patient With End-Stage Liver Disease and Acute Kidney Injury
Dabigatran, a direct thrombin inhibitor and one of the new class of direct oral anticoagulants, is increasingly used in preference to warfarin because of its efficacy and ease of administration. However, because the drug is cleared by the kidneys, it can accumulate in plasma and increase the risk for bleeding in patients with decreased kidney function. We report a patient with end-stage liver disease who developed life-threatening hemorrhage and acute kidney injury while taking dabigatran, 150mg, twice daily.
http://ift.tt/2rSnzhp
Relationships of Measured Iohexol GFR and Estimated GFR With CKD-Related Biomarkers in Children and Adolescents
2 valid and reliable estimated glomerular filtration rate (GFR) equations for the pediatric population have been developed from directly measured GFR data in the Chronic Kidney Disease in Children (CKiD) cohort: the full CKiD and bedside CKiD equations. Although adult GFR estimating equations replicate relationships of measured GFR with biomarkers, it is unclear whether similar patterns exist among children and adolescents with chronic kidney disease (CKD).
http://ift.tt/2rjdZqC
Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in the Elderly: AGES-Kidney and MESA-Kidney
Studies in chronic kidney disease populations suggest that the non–glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β2-microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine.
http://ift.tt/2rSfCZs
Undermining Genetic Privacy? Employee Wellness Programs and the Law
Genetic information is becoming ubiquitous in research and medicine. The cost of genetic analysis continues to fall, and its medical and personal value continues to grow. Anticipating this age of genetic medicine, policymakers passed laws and regulations years ago to protect Americans' privacy and…
http://ift.tt/2qXXJIA
Preserving the Fogarty International Center — Benefits for Americans and the World
In his proposed budget for fiscal year 2018, President Donald Trump recommended eliminating the Fogarty International Center (FIC) at the National Institutes of Health (NIH). Although the NIH actually received increased funding in the fiscal year 2017 budget that was signed on May 5, the FIC — a…
http://ift.tt/2rBs0Qu
Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides
Despite advances in the development of lipid-lowering therapies, clinical trials have shown that a substantial risk of cardiovascular disease persists after currently recommended medical therapy. For example, in one trial involving patients who had had an acute coronary syndrome, the lowering of…
http://ift.tt/2qdrSqm
Undermining Genetic Privacy? Employee Wellness Programs and the Law
Genetic information is becoming ubiquitous in research and medicine. The cost of genetic analysis continues to fall, and its medical and personal value continues to grow. Anticipating this age of genetic medicine, policymakers passed laws and regulations years ago to protect Americans' privacy and…
http://ift.tt/2qXXJIA
Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease
Angiopoietin-like proteins (ANGPTLs) have been established as important regulators of lipoprotein metabolism and have thus emerged as attractive targets for modulation of lipid levels and cardiovascular disease risk. Loss-of-function variants in ANGPTL4, a negative regulator of lipoprotein lipase…
http://ift.tt/2qdrd8l
Lipid levels and risk of venous thrombosis: results from the MEGA-study
Abstract
The relationship between lipid levels and risk of venous thrombosis is not well established. We aimed to assess the association between several lipids and risk of venous thrombosis using data from a population-based case–control study, and to evaluate the underlying mechanism, considering confounding by common risk factors and mediation via hemostatic factors and C-reactive protein. From the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study, 2234 patients with a first venous thrombosis and 2873 controls were included. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides, and apolipoproteins B and A1 were established in controls (<10th, 10th–25th, 25th–75th [reference], 75th–90th, >90th percentile). In age- and sex-adjusted models, decreasing levels of apolipoproteins B and A1 were dose-dependently associated with increased thrombosis risk, with odds ratios of 1.35 (95% confidence interval 1.12–1.62) and 1.50 (95% confidence interval 1.25–1.79) for the lowest category versus the reference category, respectively. The dose–response relation remained with further adjustment for body mass index, estrogen use, statin use, and diabetes. Although apolipoproteins B and A1 were associated with several hemostatic factors and C-reactive protein, none explained the increased risk in mediation analyses. The other lipids were not associated with venous thrombosis risk. In conclusion, decreasing levels of apolipoproteins B and A1 were associated with increased risk of venous thrombosis. Our findings are consistent with experimental data on the anticoagulant properties of apolipoproteins B and A1. These findings need to be confirmed and the underlying mechanism further investigated.
http://ift.tt/2qPsj92
Hopefully devoted to Q: targeting glutamine addiction in cancer
Hopefully devoted to Q: targeting glutamine addiction in cancer
British Journal of Cancer 116, 1375 (23 May 2017). doi:10.1038/bjc.2017.113
Authors: Emma R Still & Mariia O Yuneva
http://ift.tt/2oI09Zb
Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial
Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial
British Journal of Cancer 116, 1382 (23 May 2017). doi:10.1038/bjc.2017.111
Authors: Manuela Viviano, Rosa Catarino, Emilien Jeannot, Michel Boulvain, Manuela Undurraga Malinverno, Pierre Vassilakos & Patrick Petignat
http://ift.tt/2oWnGHA
Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer
Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer
British Journal of Cancer 116, 1462 (23 May 2017). doi:10.1038/bjc.2017.115
Authors: Michael Haas, Steffen Ormanns, Sibylle Baechmann, Anna Remold, Stephan Kruger, Christoph B Westphalen, Jens T Siveke, Patrick Wenzel, Anna Melissa Schlitter, Irene Esposito, Detlef Quietzsch, Michael R Clemens, Erika Kettner, Ruediger P Laubender, Andreas Jung, Thomas Kirchner, Stefan Boeck & Volker Heinemann
http://ift.tt/2ps1OGl
Long-term improvement of breast cancer survivors’ quality of life by a 2-week group physical and educational intervention: 5-year update of the ‘PACThe’ trial
Long-term improvement of breast cancer survivors' quality of life by a 2-week group physical and educational intervention: 5-year update of the 'PACThe' trial
British Journal of Cancer 116, 1389 (23 May 2017). doi:10.1038/bjc.2017.112
Authors: Fabrice Kwiatkowski, Marie-Ange Mouret-Reynier, Martine Duclos, François Bridon, Thierry Hanh, Isabelle Van Praagh-Doreau, Armelle Travade, Marie-Paule Vasson, Sylvie Jouvency, Christian Roques & Yves-Jean Bignon
http://ift.tt/2oWDxWV
Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer
Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer
British Journal of Cancer 116, 1444 (23 May 2017). doi:10.1038/bjc.2017.108
Authors: J H Park, H van Wyk, C S D Roxburgh, P G Horgan, J Edwards & D C McMillan
http://ift.tt/2oWELRW
Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators
Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators
British Journal of Cancer 116, 1394 (23 May 2017). doi:10.1038/bjc.2017.114
Authors: Delphine Héquet, Cyrille Huchon, Sandrine Baffert, Séverine Alran, Fabien Reyal, Thuy Nguyen, Alix Combes, Caroline Trichot, Karine Alves, Hélène Berseneff & Roman Rouzier
http://ift.tt/2oHQP7V
Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening
Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening
British Journal of Cancer 116, 1480 (23 May 2017). doi:10.1038/bjc.2017.107
Authors: M Román, M J Quintana, J Ferrer, M Sala & X Castells
http://ift.tt/2oWt6SY
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma
British Journal of Cancer 116, 1402 (23 May 2017). doi:10.1038/bjc.2017.119
Authors: Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Vivek Subbiah, Ralph Zinner & Nilofer S Azad
http://ift.tt/2oHPaix
The prognostic value of dynamic contrast-enhanced MRI contrast agent transfer constant Ktrans in cervical cancer is explained by plasma flow rather than vessel permeability
The prognostic value of dynamic contrast-enhanced MRI contrast agent transfer constant Ktrans in cervical cancer is explained by plasma flow rather than vessel permeability
British Journal of Cancer 116, 1436 (23 May 2017). doi:10.1038/bjc.2017.121
Authors: Ben R Dickie, Chris J Rose, Lucy E Kershaw, Stephanie B Withey, Bernadette M Carrington, Susan E Davidson, Gillian Hutchison & Catharine M L West
http://ift.tt/2prFZH9
Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial
Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial
British Journal of Cancer 116, 1408 (23 May 2017). doi:10.1038/bjc.2017.117
Authors: Yasemin Hirst, Hanna Skrobanski, Robert S Kerrison, Lindsay C Kobayashi, Nicholas Counsell, Natasha Djedovic, Josephine Ruwende, Mark Stewart & Christian von Wagner
http://ift.tt/2oHOglW
Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity
Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity
British Journal of Cancer 116, 1451 (23 May 2017). doi:10.1038/bjc.2017.110
Authors: Sofia Pruikkonen & Marko J Kallio
http://ift.tt/2ps1QxX
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity
British Journal of Cancer 116, 1415 (23 May 2017). doi:10.1038/bjc.2017.94
Authors: Didier Meulendijks, Linda M Henricks, Bart A W Jacobs, Abidin Aliev, Maarten J Deenen, Niels de Vries, Hilde Rosing, Erik van Werkhoven, Anthonius de Boer, Jos H Beijnen, Caroline M P W Mandigers, Marcel Soesan, Annemieke Cats & Jan H M Schellens
http://ift.tt/2oWyV30
Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk
Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk
British Journal of Cancer 116, 1470 (23 May 2017). doi:10.1038/bjc.2017.104
Authors: Kathryn Hughes Barry, Lee E Moore, Joshua N Sampson, Stella Koutros, Liying Yan, Ann Meyer, Mahitha Reddy, Andrew J Oler, Michael B Cook, Joseph F Fraumeni Jr, Meredith Yeager, Laufey T Amundadottir & Sonja I Berndt
http://ift.tt/2qvXUu5
Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers
Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers
British Journal of Cancer 116, 1425 (23 May 2017). doi:10.1038/bjc.2017.116
Authors: Concetta Di Mauro, Roberta Rosa, Valentina D'Amato, Paola Ciciola, Alberto Servetto, Roberta Marciano, Roberta Clara Orsini, Luigi Formisano, Sandro De Falco, Valeria Cicatiello, Maurizio Di Bonito, Monica Cantile, Francesca Collina, Angela Chambery, Bianca Maria Veneziani, Sabino De Placido & Roberto Bianco
http://ift.tt/2oHSURa
Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe
Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe
British Journal of Cancer 116, 1486 (23 May 2017). doi:10.1038/bjc.2017.106
Authors: Heinz Freisling, Melina Arnold, Isabelle Soerjomataram, Mark George O'Doherty, José Manuel Ordóñez-Mena, Christina Bamia, Ellen Kampman, Michael Leitzmann, Isabelle Romieu, Frank Kee, Konstantinos Tsilidis, Anne Tjønneland, Antonia Trichopoulou, Paolo Boffetta, Vassiliki Benetou, H B(as) Bueno-de-Mesquita, José María Huerta, Hermann Brenner, Tom Wilsgaard & Mazda Jenab
http://ift.tt/2oHydVw
A recessive mutation in beta-IV-spectrin ( SPTBN4 ) associates with congenital myopathy, neuropathy, and central deafness
Abstract
Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse. SPTBN4 mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.
http://ift.tt/2qPs8uy
A distal auxiliary element facilitates cleavage and polyadenylation of Dux4 mRNA in the pathogenic haplotype of FSHD
Abstract
The degenerative muscle disorder facioscapulohumeral dystrophy (FSHD) is thought to be caused by the inappropriate expression of the Double Homeobox 4 (Dux4) protein in muscle cells leading to apoptosis. Expression of Dux4 in the major form of FSHD is a function of two contributing molecular changes: contractions in the D4Z4 microsatellite repeat region where Dux4 is located and an SNP present within a region downstream of the D4Z4. This SNP provides a functional, yet non-consensus polyadenylation signal (PAS) is used for the Dux4 mRNA 3′ end processing. Surprisingly, the sequences flanking the Dux4 PAS do not resemble a typical cleavage and polyadenylation landscape with no recognizable downstream sequence element and a suboptimal cleavage site. Here, we conducted a systematic analysis of the cis-acting elements that govern Dux4 cleavage and polyadenylation. Using a transcriptional read-through reporter, we determined that sequences downstream of the SNP located within the β-satellite region are critical for Dux4 cleavage and polyadenylation. We also demonstrate the feasibility of using antisense oligonucleotides to target these sequences as a means to reduce Dux4 expression. Our results underscore the complexity of the region immediately downstream of the D4Z4 and uncover a previously unknown function for the β-satellite region in Dux4 cleavage and polyadenylation.
http://ift.tt/2qkjCQH
Are you smarter than the average paramedic? Test your EMS IQ!
Take our 10-question quiz to test your knowledge, then share your results and challenge your colleagues to prove their expertise
http://ift.tt/2qQK9Ze
Multidisciplinary Management of Mycosis Fungoides/Sézary Syndrome
Abstract
Purpose of Review
Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years.
Recent Findings
Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances. Concurrently, numerous genomic studies have enhanced understanding of disease pathogenesis. Advances in SDTs include topical resiquimod, a novel potent Toll-like receptor (TLR) agonist; consensus CTCL phototherapy guidelines; and use of low-dose radiation therapy. Novel systemic therapies for advanced disease of note include targeted antibody drug conjugates (brentuximab vedotin), immune checkpoint inhibitors, and allogeneic hematopoietic stem cell transplantation (HSCT).
Summary
Our "toolbox" to diagnose and treat the spectrum of MF/SS continues to expand. Further characterization of genomic data going forward will enable a rational approach to selecting and combining therapies to improve patient care.
http://ift.tt/2qdet1J
XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes
Abstract
Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereas XPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype in XPC Ala499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.
http://ift.tt/2qgc5mF
Surf's Up?
Do you ever daydream about living in Hawai'i? Are you curious if there would be opportunities for audiologists in this tropical paradise? If so, you may be interested in a recent article by Shaikh et al (2017) titled "Hearing and Balance Disorders in the State of Hawai'i: Demographics and Demand for Services."
http://ift.tt/2riiuSB
Comparing the Effects of Electronic Cigarette Vapor and Cigarette Smoke in a Novel In Vivo Exposure System
http://ift.tt/2rREm48
The central effect of 3-iodothyronamine on brain neuropeptides in mice
Abstract
3-Iodothyronamine (T1AM) is an endogenous metabolite of thyroid hormone with noticeable metabolic and neurological effects. Alteration of feeding behaviour by this compound was different at various doses in experimental models and it is not clear whether this effect is partially accounted by changes in neuropeptide secretion. In this study, we attempted to find out whether chronic low dose 3-iodothyronamine treatment could modulate some food intake regulatory neuropeptides such as leptin, ghrelin, and galanin in mice brain. Eighteen male mice were divided randomly into control (n = 8) and treatment (n = 10) groups. The experimental procedure was applied for 7 days during which treatment group received T1AM (i.p) whereas the control group received DMSO and normal saline. The brain was analyzed for leptin, ghrelin, and galanin concentrations. There were significant differences in leptin concentration (1.75 ± 0.05 versus 2.9 ± 0.07 ng/ml) and ghrelin concentration (8.4 ± 0.35 versus 5 ± 0.08 ng/ml) between control and treatment groups (P < 0.05). There was no significant difference in galanin concentration (745.87 ± 34.91 ng/l) in control group compared with the treatment group (698.05 ± 66.88 ng/l). Interestingly, the treatment group mice lost weight (~1 g) whereas non-significant increase in weight mean was seen in control group before (day 1) and after the procedure (day 8). Clearly, further works in this area will be required to delineate the central role of T1AM, but based on our findings described here, we propose that some of peripheral metabolic effects of this compound may be accomplished by brain peptide regulation.
http://ift.tt/2qQ5t12
Focused Ultrasound Presented at Milken Institute Global Conference
On May 3, Chairman Neal F. Kassell, MD, attended the Milken Institute Global Conference in Beverly Hills, CA, at the invitation of Chairman of the Milken Institute and Foundation Council member, Michael Milken.
http://ift.tt/2rRG9X9
Atomic Force Microscopy Investigations of DNA Lesion Recognition in Nucleotide Excision Repair
http://ift.tt/2qgTDuc
Detection of viral hepatitis E in clinical liver biopsies
Abstract
Aims
to determine the relative utility of in situ testing for hepatitis E virus (HEV) RNA and paraffin section PCR to diagnose HEV infection in paraffin-embedded clinical liver biopsies, and to correlate with clinico-pathological characteristics.
Methods and results
We evaluated in situ and quantitative PCR (qPCR)-based approaches to identifying HEV in clinical liver biopsies from infected patients from multiple centers, correlating with clinical setting (immunocompetent, allograft or immunosuppressed native liver) and histologic findings.
36 biopsies from 29 patients had histologic data, of which 27 and 23 biopsies had satisfactory material for in situ RNA testing and tissue qPCR respectively. Both approaches specifically identified HEV infection, but tissue qPCR was significantly more sensitive than in situ testing (P=0.035). In immunocompetent but not immunosuppressed patients the tissue qPCR yield correlated with the severity of lobular hepatitis (rho=0.94, P<0.001). qPCR viral yield was comparably high in allografts and immunosuppressed native livers and significantly greater than with native liver infection. Immunosuppressed patients showed reduced severity of hepatitis and cholestatic changes, compared with immunocompetent patients. Indeed, HEV-infected liver allografts could show minimal hepatitis for many months. In individual cases each technique was useful when serum was not available to retrospectively identify chronic infection (in biopsies taken 4-31 months before diagnosis), to identify persistent/residual infection when contemporary serum PCR was negative and to identify cleared infection.
Conclusions
qPCR is better than in situ RNA testing to identify HEV infection in paraffin-embedded liver biopsies and has diagnostic utility in selected settings.
This article is protected by copyright. All rights reserved.
http://ift.tt/2qhjXEs
Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas
Abstract
Aims
Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to comprehensively characterize the prevalence and variability of RSPO fusions in colorectal TSAs.
Methods and Results
We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions previously analyzed for WNT pathway gene mutations. Quantitative PCR analyses identified 3 and 43 TSAs overexpressing RSPO2 and RSPO3, respectively, whereas the expression of RSPO1 and RSPO4 was marginal or undetectable in all cases. RSPO overexpression was always mutually exclusive with other WNT pathway gene mutations. Known PTPRK-RSPO3 fusions were detected in 37 TSAs, all but one of which overexpressed RSPO3. In addition, rapid amplification of cDNA ends revealed three novel RSPO fusion transcripts, an NRIP1-RSPO2 fusion and two PTPRK-RSPO3 fusion isoforms, in six TSAs. Overall, 43 TSAs had RSPO fusions (33%), whereas four TSAs (3%) overexpressed RSPO in the absence of RSPO fusions. TSAs with RSPO fusions showed several clinicopathological features, including distal localization (p = 0.0063), larger size (p = 0.0055), prominent ectopic crypt foci (p = 8.4 x 10-4), association of a high-grade component (p = 1.1 x 10-4), and the presence of KRAS mutations (p = 4.5 x 10-5).
Conclusions
The present study identified RSPO fusion transcripts, including three novel transcripts, in one-third of colorectal TSAs and showed that PTPRK-RSPO3 fusions were the predominant cause of RSPO overexpression in colorectal TSA.
This article is protected by copyright. All rights reserved.
http://ift.tt/2rAmPQK
Inside EMS Podcast: How to recognize lazy students, bad instructors
<!--cke_bookmark_117S--><!--cke_bookmark_117E--> Download this podcast on iTunes, SoundCloud or via RSS feed In this Inside EMS Podcast episode, co-hosts Chris Cebollero and Kelly Grayson discuss a fan email regarding a student that is completing EMT school. The student explains that they are not comfortable in their skills, knowledge and ability to pass the National Registry ...
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A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders
Abstract
Micropulse laser treatment is an alternative to the conventional continuous-wave laser for the treatment of retinal or macular diseases. In contrast to the conventional laser, the therapeutic effect of the subthreshold micropulse laser is not accompanied by thermal retinal damage. This fact is of particular importance when a treatment near the fovea is required. Micropulse treatment is applied in indications such as central serous chorioretinopathy (CSC), diabetic macular edema (DME), or macular edema due to retinal vein occlusion (RVO). This review outlines and discusses the published literature of subthreshold micropulse laser treatment for CSC, DME, and macular edema after RVO.
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Nalmefene in Alcohol Use Disorder Subjects with Psychiatric Comorbidity: A Naturalistic Study
Abstract
Introduction
Nalmefene is the first drug to be approved for reducing alcohol consumption in alcohol use disorder (AUD) patients at high drinking risk. In real-world settings, there is a high prevalence of concurrent psychiatric disorders in AUD subjects, with associated increased morbidity and worse prognosis. This study evaluated the use of nalmefene in AUD patients with stabilized psychiatric comorbidity previously treated unsuccessfully for alcohol dependence, and assessed craving reduction and safety.
Methods
Sixty-five AUD outpatients treated with as-needed 18 mg nalmefene for 24 weeks were included. Primary outcome measures were: changes in heavy drinking days (HDDs) and total alcohol consumption (TAC, g/day). Secondary outcome measures were: changes in drinking risk level and craving (obsessive–compulsive drinking scale and visual analogue scale for craving).
Results
Forty-two AUD subjects (64.6%) had one or more stabilized psychiatric comorbidity. There was a significant reduction in HDDs, TAC and craving measures (p < 0.001), with no differences between subjects with and without psychiatric comorbidity. Nalmefene was safe and well tolerated in all patients.
Conclusion
As-needed nalmefene reduced drinking and craving in AUD subjects with and without psychiatric comorbidity. These findings suggest that nalmefene is a valid therapeutic option in real-world clinical settings, where comorbid conditions are common, and has the potential to engage AUD patients who may otherwise not have sought help.
Funding
Lundbeck Italia S.P.A.
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High neuronatin (NNAT) expression is associated with poor outcome in breast cancer
Abstract
Neuronatin (NNAT) is a proteolipid involved in cation homeostasis especially in the developing brain. Its expression has been associated with the progression of lung cancer, glioblastoma, and neuroblastoma as well as glucose induced apoptosis in pancreatic cells. We performed a retrospective study of 148 breast cancer specimens for NNAT expression by immunohistochemistry to evaluate this protein as a prognostic marker for breast cancer. We found a high NNAT immunoreactivity score (by multivariate cox regression) to be an independent prognostic marker for relapse-free (hazard ratio HR = 3.55, p = 0.002) and overall survival (HR = 6.29, p < 0.001). However, NNAT expression was not associated with classical parameters such as hormone receptor expression (p = 0.86) or lymph node metastasis (p = 0.83). Additional independent risk factors in this study population were tumor size (≤2 cm; overall survival: HR = 0.36, p = 0.023; relapse-free survival: HR = 0.26, p < 0.01) and blood vessel infiltration (overall survival: HR = 0.34 p < 0.01). NNAT expression determined by immunohistochemistry might therefore become a helpful additional biomarker to identify high-risk breast cancer patients.
http://ift.tt/2rQWlb5
Epidermoid cysts are a characteristic feature of intrapancreatic but not of extrapancreatic accessory spleens
Abstract
Accessory spleens (ASs), ectopic splenic tissue at intrapancreatic and extrapancreatic sites, rarely contain epidermoid cysts. Our aim was to analyze the incidence of epidermoid cysts in ASs and perform an immunohistochemical analysis of its epithelial lining. We included in the study 148 ASs from 135 patients, for which pathological data were available. Eleven were intrapancreatic ASs (IPASs) and 137 were extrapancreatic ASs (EPASs). Six of the eleven (55%) IPASs contained epidermoid cysts, but they were not detected in EPASs. Immunohistochemical analysis showed that both the superficial/luminal and basal layer of the epithelial lining of epidermoid cysts in IPASs are negative for MUC2, MUC5AC, MUC6, WT-1, calretinin, thrombomodulin, uroplakin-II, and uroplakin-III. The superficial/luminal layer was positive for MUC4, CK7, and CA19-9 in all cases (100%), for CEA and HBME-1 in three cases (50%), and for MUC1, CK5/6, and CK20 in two cases (33%). The superficial/luminal layer was negative for p63 and D2-40 in all cases. The basal layer was positive for MUC1, CK5/6, p63, and HBME-1 in all six cases (100%), for CK7 and D2-40 in two cases (33%), and for CEA in one case (17%). The basal layer was negative for MUC4, CK20, and CA19-9 in all cases. Epidermoid cysts are a characteristic feature of IPASs but not of EPASs. Immunohistochemical analysis showed that the epithelial lining of epidermoid cysts in IPASs has a mixed character of glandular, squamous, mesothelial, and urothelial epithelium.
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Tone identification behavior in Rattus Norvergicus: muscarinic receptor blockage lowers responsiveness in non-target selective neurons while nicotinic receptor blockage selectively lowers target responses
Abstract
Learning to associate a stimulus with reinforcement causes plasticity in primary sensory cortex. Neural activity caused by the associated stimulus is paired with reinforcement, but population analyses have not found a selective increase in response to that stimulus. Responses to other stimuli increase as much as, or more than, responses to the associated stimulus. Here, we applied population analysis at a new time point, and additionally evaluated whether cholinergic receptor blockers interacted with the plastic changes in cortex. Three days of tone identification behavior caused responsiveness to increase broadly across primary auditory cortex, and target responses strengthened less than overall responsiveness. In pharmacology studies, behaviorally impairing doses of selective acetylcholine receptor blockers were administered during behavior. Neural responses were evaluated on the following day while the blockers were absent. The muscarinic group, blocked by scopolamine, showed lower responsiveness, and an increased response to the tone identification target that exceeded both the three day control group and task-naïve controls. Also, a selective increase in the late phase of the response to the tone identification stimulus emerged. Nicotinic receptor antagonism, with mecamylamine, more modestly lowered responses the following day, and lowered target responses more than overall responses. Control acute studies demonstrated the muscarinic block did not acutely alter response rates, but the nicotinic block did. These results lead to the hypothesis that the decrease in the proportion of the population spiking response that is selective for the target may be explained by the balance between effects modulated by muscarinic and nicotinic receptors.
This article is protected by copyright. All rights reserved.
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Intracellular, In Vivo, Dynamics of Thalamocortical Synapses in Visual Cortex
Seminal studies of the thalamocortical circuit in the visual system of the cat have been central to our understanding of sensory encoding. However, thalamocortical synaptic properties remain poorly understood. We used paired recordings, in the lateral geniculate nucleus (LGN) and primary visual cortex (V1), to provide the first in vivo characterization of sensory-driven thalamocortical potentials in V1. The amplitudes of EPSPs we characterized were smaller than those previously reported in vitro. Consistent with prior findings, connected LGN-V1 pairs were only found when their receptive fields (RFs) overlapped, and the probability of connection increased steeply with degree of RF overlap and response similarity. However, surprisingly, we found no relationship between EPSP amplitudes and the similarity of RFs or responses, suggesting different connectivity models for intracortical and thalamocortical circuits. Putative excitatory regular-spiking (RS) and inhibitory fast-spiking (FS) V1 cells had similar EPSP characteristics, showing that in the visual system, feedforward excitation and inhibition are driven with equal strength by the thalamus. Similar to observations in the somatosensory cortex, FS V1 cells received less specific input from LGN. Finally, orientation tuning in V1 was not inherited from single presynaptic LGN cells, suggesting that it must emerge exclusively from the combined input of all presynaptic LGN cells. Our results help to decipher early visual encoding circuits and have immediate utility in providing physiological constraints to computational models of the visual system.
SIGNIFICANCE STATEMENT To understand how the brain encodes the visual environment, we must understand the transfer of visual signals between various regions of the brain. Therefore, understanding synaptic dynamics is critical to our understanding of sensory encoding. This study provides the first characterization of visually evoked synaptic potentials between the visual thalamus and visual cortex in an intact animal. To record these potentials, we simultaneously recorded the extracellular potential of presynaptic thalamic cells and the intracellular potential of postsynaptic cortical cells in input layers of primary visual cortex. Our characterization of synaptic potentials in vivo disagreed with prior findings in vitro. This study will increase our understanding of thalamocortical circuits and will improve computational models of visual encoding.
http://ift.tt/2qWw2C9
Feature-Selective Attention Adaptively Shifts Noise Correlations in Primary Auditory Cortex
Sensory environments often contain an overwhelming amount of information, with both relevant and irrelevant information competing for neural resources. Feature attention mediates this competition by selecting the sensory features needed to form a coherent percept. How attention affects the activity of populations of neurons to support this process is poorly understood because population coding is typically studied through simulations in which one sensory feature is encoded without competition. Therefore, to study the effects of feature attention on population-based neural coding, investigations must be extended to include stimuli with both relevant and irrelevant features. We measured noise correlations (rnoise) within small neural populations in primary auditory cortex while rhesus macaques performed a novel feature-selective attention task. We found that the effect of feature-selective attention on rnoise depended not only on the population tuning to the attended feature, but also on the tuning to the distractor feature. To attempt to explain how these observed effects might support enhanced perceptual performance, we propose an extension of a simple and influential model in which shifts in rnoise can simultaneously enhance the representation of the attended feature while suppressing the distractor. These findings present a novel mechanism by which attention modulates neural populations to support sensory processing in cluttered environments.
SIGNIFICANCE STATEMENT Although feature-selective attention constitutes one of the building blocks of listening in natural environments, its neural bases remain obscure. To address this, we developed a novel auditory feature-selective attention task and measured noise correlations (rnoise) in rhesus macaque A1 during task performance. Unlike previous studies showing that the effect of attention on rnoise depends on population tuning to the attended feature, we show that the effect of attention depends on the tuning to the distractor feature as well. We suggest that these effects represent an efficient process by which sensory cortex simultaneously enhances relevant information and suppresses irrelevant information.
http://ift.tt/2rUemEn
The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the performance of the Afirma gene expression classifier
BACKGROUND
A recent revision in thyroid tumor nomenclature has resulted in a change from a malignant diagnosis (noninvasive follicular variant of papillary thyroid carcinoma) to one that is nonmalignant (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]). The objective of the current study was to evaluate the impact of this change on the performance of the Afirma gene expression classifier (GEC).
METHODS
The authors retrospectively analyzed consecutive thyroid fine-needle aspiration specimens with indeterminate diagnoses on which GEC was performed. Surgical pathology material was reviewed with the reclassification of nodules into NIFTP.
RESULTS
GEC testing was performed on 384 fine-needle aspiration specimens diagnosed as atypia of undetermined significance (AUS) (304 cases) and suspicious for a follicular neoplasm (SFN) (80 cases) and yielded a suspicious result in 152 of the AUS cases (50%) and 50 of the SFN cases (63%). Thyroidectomy was performed on 177 patients. After reclassifying NIFTP, the positive predictive value of GEC decreased from 42% (95% confidence interval [95% CI], 39%-45%) to 24% (95% CI, 22%-26%) in the AUS group and from 23% (95% CI, 19%-27%) to 13% (95% CI, 9%-18%) in the SFN group. Total thyroidectomy was performed more frequently than a partial thyroidectomy in patients with AUS with a suspicious GEC result compared with pre-GEC controls (68% vs 49%; P = .037).
CONCLUSIONS
Reclassification of NIFTP significantly decreases the positive predictive value of GEC in indeterminate thyroid nodules. Nevertheless, the majority of patients with indeterminate thyroid nodules with a suspicious GEC result in the study institution have undergone total thyroidectomy. This finding raises concerns over reliance on a suspicious GEC result by clinicians to justify total thyroidectomy. Cancer Cytopathol 2017. © 2017 American Cancer Society.
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DC Fire and EMS celebrates EMS Week with CPR challenge
"May Madness" encourages responders to "own the code" and improve survival rates for cardiac arrest victims
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Mapping RNA-RNA Interactions Globally Using Biotinylated Psoralen
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Intensive Pre-Stem Cell Transplant Regimen May be Best for Younger Patients with AML, MDS
Results from a large phase III clinical trial suggest that a highly intensive preparatory regimen should be used for younger patients with acute myeloid leukemia or myelodysplastic syndromes preparing to undergo an allogeneic stem cell transplant.
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Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome
Objective
Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI.
DesignUltra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response.
ResultsSubjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria, Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone.
ConclusionsIn a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI.
Trial registration numberhttp://ift.tt/2qWIvWw
A metabolomics-based biomarker signature discriminates pancreatic cancer from chronic pancreatitis
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. The projection that it will surpass breast cancer to become the second-leading cause of cancer-related deaths by 2030 serves as a wake-up call to stakeholders, including healthcare systems and researchers.1 Earlier diagnosis is one factor that could alter this trajectory. Correspondingly, the research community has made substantial efforts to find biomarkers that will enable the diagnosis of pancreatic cancer at a stage where it can be successfully treated.2 There are however, significant challenges. Pancreatic cancer is a very heterogeneous disease with great interindividual variation, as well as significant heterogeneity within the tumours of individuals.3 4 This calls for large sample sizes to ensure adequate representation of subtypes. Moreover, biomarker development programmes require samples to be separated into independent training and test sets, further increasing the quantity of samples needed. However, the number of...
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High-energy particle beam and gamma radiation exposure, familial relatedness and cancer in mice
High-energy particle beam and gamma radiation exposure, familial relatedness and cancer in mice
British Journal of Cancer advance online publication, May 23 2017. doi:10.1038/bjc.2017.141
Authors: Pavel Chernyavskiy, Elijah F Edmondson, Michael M Weil & Mark P Little
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A meta-analysis of CXCL12 expression for cancer prognosis
A meta-analysis of CXCL12 expression for cancer prognosis
British Journal of Cancer advance online publication, May 23 2017. doi:10.1038/bjc.2017.134
Authors: Harsh Samarendra, Keaton Jones, Tatjana Petrinic, Michael A Silva, Srikanth Reddy, Zahir Soonawalla & Alex Gordon-Weeks
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Randomised controlled trial of early prophylactic feeding vs standard care in patients with head and neck cancer
Randomised controlled trial of early prophylactic feeding vs standard care in patients with head and neck cancer
British Journal of Cancer advance online publication, May 23 2017. doi:10.1038/bjc.2017.138
Authors: Teresa E Brown, Merrilyn D Banks, Brett G M Hughes, Charles Y Lin, Lizbeth M Kenny & Judith D Bauer
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Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach
Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach
British Journal of Cancer advance online publication, May 23 2017. doi:10.1038/bjc.2017.144
Authors: Yukinori Kurokawa, Han-Kwang Yang, Haruhiko Cho, Min-Hee Ryu, Toru Masuzawa, Sook Ryun Park, Sohei Matsumoto, Hyuk-Joon Lee, Hiroshi Honda, Oh Kyoung Kwon, Takashi Ishikawa, Kyung Hee Lee, Kazuhito Nabeshima, Seong-Ho Kong, Toshio Shimokawa, Jeong-Hwan Yook, Yuichiro Doki, Seock-Ah Im, Seiichi Hirota, Seokyung Hahn, Toshirou Nishida & Yoon-Koo Kang
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Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells
Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells
British Journal of Cancer advance online publication, May 23 2017. doi:10.1038/bjc.2017.133
Authors: Jenni Nikkilä, Rahul Kumar, James Campbell, Inger Brandsma, Helen N Pemberton, Fredrik Wallberg, Kinga Nagy, Ildikó Scheer, Beata G Vertessy, Artur A Serebrenik, Valentina Monni, Reuben S Harris, Stephen J Pettitt, Alan Ashworth & Christopher J Lord
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Circadian clustering of spontaneous epileptic seizures emerges after pilocarpine-induced status epilepticus
Summary
Objective
Seizures in mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis are thought to develop with various latency intervals after an initial transient brain insult. To study seizure dynamics after an initial transient precipitating insult in a systematic fashion, we utilized continuous video–electroencephalography (EEG) monitoring after the induction of status epilepticus (SE) in a mouse MTLE model.
Methods
Continuous 24/7 video/telemetric hippocampal EEG recordings in the systemic pilocarpine MTLE mouse model.
Results
After SE, we observed emerging seizures interfering with the circadian EEG rhythms. The physiologic circadian EEG pattern of mice was transiently suppressed for 2.9 (mean) ± (SEM) 0.5 days after SE. This period was accompanied predominately by nonconvulsive seizure activity, followed by convulsive seizures at later stages. After the circadian rhythm was restored, spontaneous generalized seizures occurred mainly in a clustered manner in a narrow time window between 4 and 7 p.m. (light cycle 7 a.m./7 p.m.). Moreover, we demonstrate that depth-electrode implantation surgery transiently disturbs the physiologic EEG circadian cycle; variation of the time point of SE induction after electrode insertion surgery revealed a substantial impact on the epilepsy phenotype, which was more severe when SE occurred after postsurgical reappearance of EEG circadian cycling.
Significance
These data have several experimental and pathophysiologic implications. The impact of depth-electrode surgery on the phenotype has to be tightly controlled. In mice monitored after pilocarpine-induced SE, the "epileptogenesis" period is characterized by the dynamics of epileptiform activity toward behavioral recurrent seizure patterns. The striking clustering of spontaneous seizures at the transition from sleep to activity stages of mice has to be taken into account for future studies on the model. Improving our understanding of the molecular mechanisms that determine the circadian dynamics of seizure threshold remains an intriguing task for the future.
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Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein-bound concentrations
Summary
Objective
Given that only the free non–protein-bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine-epoxide and N-desmethyl clobazam), using standardized methodology and under set conditions.
Methods
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein-bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Results
Gabapentin and pregabalin are non–protein-bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N-desmethyl-clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).
Significance
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.
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Structural Similarities between Neuregulin 1-3 Isoforms Determine Their Subcellular Distribution and Signaling Mode in Central Neurons
The Neuregulin (NRG) family of ErbB ligands is comprised of numerous variants originating from the use of different genes, alternative promoters, and splice variants. NRGs have generally been thought to be transported to axons and presynaptic terminals where they signal via ErbB3/4 receptors in paracrine or juxtacrine mode. However, we recently demonstrated that unprocessed pro-NRG2 accumulates on cell bodies and proximal dendrites, and that NMDAR activity is required for shedding of its ectodomain by metalloproteinases. Here we systematically investigated the subcellular distribution and processing of major NRG isoforms in rat hippocampal neurons. We show that NRG1 isotypes I and II, which like NRG2 are single-pass transmembrane proteins with an Ig-like domain, share the same subcellular distribution and ectodomain shedding properties. We furthermore show that NRG3, like CRD-NRG1, is a dual-pass transmembrane protein that harbors a second transmembrane domain near its amino terminus. Both NRG3 and CRD-NRG1 cluster on axons through juxtacrine interactions with ErbB4 present on GABAergic interneurons. Interestingly, although single-pass NRGs accumulate as unprocessed proforms, axonal puncta of CRD-NRG1 and NRG3 are comprised of processed protein. Mutations of CRD-NRG1 and NRG3 that render them resistant to BACE cleavage, as well as BACE inhibition, result in the loss of axonal puncta and in the accumulation of unprocessed proforms in neuronal soma. Together, these results define two groups of NRGs with distinct membrane topologies and fundamentally different targeting and processing properties in central neurons. The implications of this functional diversity for the regulation of neuronal processes by the NRG/ErbB pathway are discussed.
SIGNIFICANCE STATEMENT Numerous Neuregulins (NRGs) are generated through the use of different genes, promoters, and alternative splicing, but the functional significance of this evolutionary conserved diversity remains poorly understood. Here we show that NRGs can be categorized by their membrane topologies. Single-pass NRGs, such as NRG1 Types I/II and NRG2, accumulate as unprocessed proforms on cell bodies, and their ectodomains are shed by metalloproteinases in response to NMDA receptor activation. By contrast, dual-pass CRD-NRG1 and NRG3 are constitutively processed by BACE and accumulate on axons where they interact with ErbB4 in juxtacrine mode. These findings reveal a previously unknown functional relationship between membrane topology, protein processing, and subcellular distribution, and suggest that single- and dual-pass NRGs regulate neuronal functions in fundamentally different ways.
http://ift.tt/2rUks7G
Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex
We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6–8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (~5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.
SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.
http://ift.tt/2rUm95o
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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...
