Medicine by Alexandros G.Sfakianakis: 05/25/18

Παρασκευή 25 Μαΐου 2018

Found in Translation: Late Bilinguals Do Automatically Activate Their Native Language When They Are Not Using It

Cognitive Science, EarlyView.

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Effect of sex on haemocytobiochemical profiling of silver tiger fish ( Datnioides polota Hamilton, 1822)

Abstract

This investigation presents an overview of the effect of sex on haematobiochemical and haemocytomorphometrical aspects of Datnioides polota. For the present study, 15 males and 15 females of Datnioides polota were collected from Balugaon, the central sector of Chilika lagoon of Odisha. Two millilitres of blood samples was collected from each sex through the caudal vein. One millilitre of collected blood was transferred from the syringe into ethylenediaminetetraacetic acid (EDTA) containing vials, for haematological studies and other 1 ml was taken in Eppendorf tube without anticoagulant for analyses of biochemical parameters. Haematological parameters like red blood cell count (RBC), white blood cells count (WBC), haemoglobin, haematocrit, mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), biochemical parameters such as glucose, protein, albumin, globulin, cholesterol, and morphometrical parameters namely length, breadth, area, and N/C ratio of erythrocytes, lymphocytes, monocytes, eosinophils, and neutrophils are analysed in relation to the sex of the fish. Statistical analysis reveals the sex wise significant difference in some haematological parameters like Hb which varies at P < 0.01 level while WBC deviate at P < 0.05 level. All the biochemical parameters show higher value in females in comparison to males except albumin but sex wise significant variation recorded in protein and globulin at P < 0.01 level. In males, the concentration of Hb is positively correlated with RBC and PCV while in females negatively correlated. RBC is positively correlated with PCV in both the sexes at R² = 0.008 and R² = 0.9 in male and female, respectively. The morphometry of blood cells such as monocytes and lymphocytes shows significant sexual dimorphism. The cellular length and area of monocytes deviate at the level of P < 0.01 and breadth at P < 0.05 level. The cellular and nuclear breadth of lymphocyte vary significantly at the level of P < 0.05 and P < 0.001, respectively. The results of this study may serve as a reference value for haemocytological and biochemical parameters of this species which in turn helps in diagnosing diseases and increasing fish production.

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Antifungal activity of selected natural preservatives against the foodborne molds Penicillium verrucosum and Aspergillus westerdijkiae

Abstract

The present study examines the inhibitory effect of the essential oil (EO) of Origanum vulgare, its active components carvacrol and thymol, and a few active components of other EOs, namely, eugenol, trans-cinnamaldehyde and 1,8-cineole, against Penicillium verrucosum CBS 302.48, Aspergillus westerdijkiae CBS 112803 and Aspergillus westerdijkiae CBS 112804. Therefore, the minimum inhibitory concentration (MIC) was determined by broth macrodilution of each antifungal agent. Regarding their antifungal activity, the following ranking in order of decreasing inhibitory action is: trans-cinnamaldehyde > carvacrol = thymol > O. vulgare EO > eugenol > 1,8-cineole.The combined effects of the natural preservatives were studied by checkerboard assay. The results are based on the fractional inhibitory concentration indices (FICIs), which are interpreted as 'synergy', 'no interaction' or 'antagonism'. The indices ranging from 0.8 to 1.3 and thus show no interaction.In addition, the dependence of the natural inhibitors on different pH values (pH 7.0, 5.6, 4.5 and 3.5) and water activity (0.99, 0.92, 0.90 and 0.87 a_w) was investigated. All tested natural preservatives are tolerant to the different examined milieu conditions, with the lowest MICs recorded at pH 3.5 and 0.87 a_w.

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Antimicrobial activity of fusidic acid in Escherichia coli is dependent on the relative levels of ribosome recycling factor (RRF) and elongation factor G (EFG)

Abstract

During protein synthesis, elongation factor G (EFG) participates at the steps of translocation and ribosome recycling. Fusidic acid (FA) is a bacteriostatic antibiotic, which traps EFG on ribosomes, stalling them on mRNAs. How the bacterial susceptibility to FA is determined, and which of the two functions of EFG (translocation or ribosome recycling) is more vulnerable, has remained debatable. The in vivo studies addressing these aspects of FA mediated inhibition of protein synthesis are lacking. Here, we used a system of Escherichia coli strains and their complementation/supplementation with the plasmid borne copies of the inducible versions of EFG and RRF genes. Additionally, we investigated FA sensitivity in a strain with increased proportion of stalled ribosomes. We show that the cells with high EFG/RRF (or low RRF/EFG) ratios are more susceptible to FA than those with low EFG/RRF (or high RRF/EFG) ratios. Our in vivo observations are consistent with the recent in vitro reports of dependence of FA susceptibility on EFG/RRF ratios, and the notion that an overriding target of FA is the translocation function of EFG. An applied outcome of our in vivo study is that FA mediated growth inhibition could be facilitated by depletion or inactivation of cellular RRF.

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Cold adaptation and replicable microbial community development during long-term low temperature anaerobic digestion treatment of synthetic sewage

Abstract

The development and, activity of a cold-adapting microbial community was monitored during low temperature anaerobic digestion (LtAD) treatment of wastewater. Two replicate hybrid anaerobic sludge bed-fixed-film reactors treated a synthetic sewage wastewater at 12°C, at organic loading rates of 0.25–1.0 kg Chemical Oxygen Demand (COD) m⁻³ d⁻¹, over 889 days. The inoculum was obtained from a full-scale AD reactor, which was operated at 37˚C. Both LtAD reactors readily degraded the influent with COD removal efficiencies regularly exceeding 78% for both the total and soluble COD fractions. The biomass from both reactors was sampled temporally and tested for activity against hydrolytic and methanogenic substrates at 12˚C and 37˚C. Data indicated that significantly enhanced low-temperature hydrolytic and methanogenic activity developed in both systems. For example, the hydrolysis rate constant (K) at 12°C had increased 20–30-fold by comparison to the inoculum by day 500. Substrate affinity also increased for hydrolytic substrates at low temperature. Next generation sequencing demonstrated that a shift in community structure occurred over the trial, involving a 1-log-fold change in 25 SEQS (OTU-free approach) from the inoculum. Microbial community structure changes and process performance were replicable in the LtAD reactors.

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Maternal depression and cortisol in pregnancy predict offspring emotional reactivity in the preschool period

Developmental Psychobiology, EarlyView.

https://ift.tt/2LxfwAs

Neratinib: Inching up on the cure rate of HER2+ breast cancer?

Neratinib was recently approved by FDA for extended adjuvant treatment of HER-2 positive breast cancer. ExteNET trial showed improvement in invasive disease-free survival (iDFS) in the neratinib arm compared to placebo. The benefit was more pronounced in patients with ER+/HER2+ tumors, suggesting bidirectional crosstalk between the two pathways.

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NRG1 Fusions in KRAS Wild-type Pancreatic Cancer [Research Briefs]

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 PDAC patients enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASwt) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in two patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASwt tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of PDAC patients.

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MLL3 Mutations Disrupt COMPASS Recruitment to Enhancer Chromatin [Research Watch]

Mutations in the MLL3 PHD domain promote oncogenesis by disrupting its interaction with BAP1.

https://ift.tt/2kqpdnP

Microbial Signals Promote Preleukemic Myeloproliferation in Tet2-/- Mice [Research Watch]

TET2 deficiency increases systemic bacterial dissemination to promote preleukemic myeloproliferation (PMP).

https://ift.tt/2sc8NDb

Endoplasmic Reticulum Stress Drives Latent Pancreatic Tumor Metastases [Research Watch]

Unresolved ER stress promotes quiescence and immune escape of latent disseminated PDAC.

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KLHL22 Promotes MTORC1 Activation and Breast Tumorigenesis [Research Watch]

Amino acids promote CUL3-KLHL22–mediated DEPDC5 degradation to relieve mTORC1 inhibition.

https://ift.tt/2sc8NmF

ICU Mortality Similar for Patients With Hematologic CA ± Chemo

FRIDAY, May 25, 2018 -- Short-term mortality is similar among patients with hematologic cancer who receive chemotherapy while in the intensive care unit (ICU) versus those who do not, according to a study published online May 4 in Cancer. Stephen M....

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American Urological Association, May 18-21

The American Urological Association's 2018 Annual Meeting The annual meeting of the American Urological Association was held from May 18 to 21 in San Francisco and attracted more than 12,000 participants from around the world, including clinicians,...

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CDC IDs Outbreak Trends Tied to Treated Recreational Water

FRIDAY, May 25, 2018 -- Outbreaks associated with treated recreational water with confirmed infectious etiology are usually caused by Cryptosporidium, Legionella, or Pseudomonas, according to research published in the May 18 issue of the U.S....

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FDA Approves Palynziq for Phenylketonuria

FRIDAY, May 25, 2018 -- Palynziq (pegvaliase-pqpz) has been approved by the U.S. Food and Drug Administration to treat phenylketonuria, or PKU. Palynziq is a novel enzyme therapy for adult patients with PKU with uncontrolled blood phenylalanine...

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Increase in Tx Candidates With 2017 Hypertension Guidelines

FRIDAY, May 25, 2018 -- The 2017 American College of Cardiology/American Heart Association hypertension guideline is associated with an increase in the proportion of adults recommended for antihypertensive treatment compared with the 2014 guideline,...

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Giant Colonic Cavernous Hemangioma Causing Hematochezia in a 14-Year-Old Boy

A 14-year-old boy presented with intermittent hematochezia for 2 weeks. He reported a similar episode of hematochezia 1 year ago that was regarded as colitis. His medical history was unremarkable. Physical examination showed a nontender, soft, palpable mass at the upper right quadrant of the abdomen. His hemoglobin level was 7.3 g/dL (normal range, 13.0–16.0 g/dL). A computed tomography scan of his abdomen showed asymmetric segmental wall thickening with scattered punctuate calcification (Figure A, white arrow) and heterogeneous enhancement from the midtransverse colon to the hepatic flexure (Figure A, black arrow).

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Another new organ! is this a golden age of discovery in anatomy?

Clinical Anatomy, EarlyView.

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Response to: Gross anatomy examination performances in relation to medical students' knowledge of classical Latin and Greek

Clinical Anatomy, EarlyView.

https://ift.tt/2KU4K63

Overview of Systematic Reviews of Advance Care Planning: Summary of Evidence and Global Lessons

Advance care planning (ACP) involves important decision-making about future medical needs. The high volume and disparate nature of ACP research make it difficult to grasp the evidence and derive clear policy lessons for policymakers and clinicians.

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Comparison of EORTC QLQ-C30 and PRO-CTCAETM questionnaires on six symptom items

Clinical studies have over the past decade paid increasing attention to health-related quality of life(HRQOL) data. Multiple questionnaires are often administered resulting in overlapping questions increasing patient burden.

https://ift.tt/2GNGC2J

The impact of spasticity on diaphragm contraction: electrophysiological assessment

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease in which ventilatory insufficiency and other respiratory complications account for the majority of deaths. Respiratory failure is a presenting feature in about 3-5% of the patients (de Carvalho et al., 1996).

https://ift.tt/2GSyEoS

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogues and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of somatostatin receptor (SSTR) 2A and 5 in a cohort of 40 ONBs.

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Immunohistological analysis of the duodenal bulb: a new method for celiac disease diagnosis in children

Anti-tissue transglutaminase antibodies (anti-tTG) have simplified celiac disease (CD) diagnosis. However, in atypical forms of CD, intestinal biopsy is still required. This prospective study investigates whether histological analysis of the duodenal bulb combined with intestinal IgA anti-tTG deposit immunoassay makes CD diagnosis possible in at-risk children with low concentrations of serum anti-tTG.

https://ift.tt/2IOCKnR

On the performance of parallelisation schemes for particle filtering

Considerable effort has been recently devoted to the design of schemes for the parallel implementation of sequential Monte Carlo (SMC) methods for dynamical systems, also widely known as particle filters (PFs)...

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eIF2β, a subunit of translation‐initiation factor EIF2, is a potential therapeutic target for non‐small cell lung cancer

Cancer Science, EarlyView.

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Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin

Cancer Science, EarlyView.

https://ift.tt/2LsJzt0

Non-Nutritive Sweeteners Don't Up Blood Glucose Levels

FRIDAY, May 25, 2018 -- Consumption of non-nutritive sweeteners (NNSs) does not increase blood glucose levels, according to a review published online May 15 in the European Journal of Clinical Nutrition. Alexander D. Nichol, from the University of...

https://ift.tt/2s6AduK

Mortality Still High After Surgery for Congenital Heart Defects

FRIDAY, May 25, 2018 -- Long-term mortality after congenital heart surgery is higher than that of the general population for all forms of congenital heart defects (CHDs), according to a study published in the May 29 issue of the Journal of the...

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60-Day Mortality Not Significantly Lower With ECMO in ARDS

FRIDAY, May 25, 2018 -- For patients with very severe acute respiratory distress syndrome (ARDS), 60-day mortality is not significantly lower with venovenous extracorporeal membrane oxygenation (ECMO) than with continued conventional treatment,...

https://ift.tt/2s6AbTE

Laws Allowing Service Denial to Sexual Minorities Tied to Distress

FRIDAY, May 25, 2018 -- Laws permitting denial of services to same-sex couples are associated with an increase in sexual minority adults experiencing mental distress, according to a study published online May 23 in JAMA Psychiatry. Julia Raifman,...

https://ift.tt/2KTZWh2

Antidepressant Prescribing Linked to Lasting Weight Gain

FRIDAY, May 25, 2018 -- Antidepressant prescribing is associated with long-term increased risk of weight gain, according to a study published online May 23 in The BMJ. Rafael Gafoor, Ph.D., from King's College London, and colleagues examined the...

https://ift.tt/2s6Aa22

Higher Seafood Intake May Shorten Time to Pregnancy

FRIDAY, May 25, 2018 -- Higher seafood intake is tied to a shorter time to pregnancy (TTP), according to a study published online May 23 in the Journal of Clinical Endocrinology & Metabolism. Audrey J. Gaskins, Sc.D., from Harvard University in...

https://ift.tt/2KTZTBS

CPAP Use May Improve Sexual QOL in Those With Sleep Apnea

FRIDAY, May 25, 2018 -- Successful continuous positive airway pressure (CPAP) use for obstructive sleep apnea may be associated with improved sexual quality of life (QOL), according to a study published online May 24 in JAMA Otolaryngology-Head...

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Early-Life Weight Associated With Cognitive Factors

FRIDAY, May 25, 2018 -- Early-life weight status has an inverse association with some cognitive abilities in children, according to a study published online May 23 in Obesity. Nan Li, Ph.D., from Brown University in Providence, R.I., and colleagues...

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Severe Atopic Eczema Tied to Higher CV Disease Risk

FRIDAY, May 25, 2018 -- Adults with severe atopic eczema are at increased risk of cardiovascular disease, according to a study published online May 23 in The BMJ. Richard J. Silverwood, Ph.D., from the London School of Hygiene and Tropical Medicine,...

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Certolizumab Looks Promising for Moderate-to-Severe Psoriasis

FRIDAY, May 25, 2018 -- Twice-weekly certolizumab biologic appears to be both safe and effective for the treatment of moderate-to-severe chronic plaque psoriasis, according to a study published online April 13 in the Journal of the American Academy...

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Single Molecule Fluorescence In Situ Hybridization (smFISH) Analysis in Budding Yeast Vegetative Growth and Meiosis

This single molecule fluorescence in situ hybridization protocol is optimized to quantify the number of RNA molecules in budding yeast during vegetative growth and meiosis.

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Utilization of Ultrasound Guided Tissue-directed Cellular Implantation for the Establishment of Biologically Relevant Metastatic Tumor Xenografts

Here, we present a protocol to utilize ultrasound-guided injection of neuroblastoma (NB) and Ewing's sarcoma (ES) cells (established cell lines and patient-derived tumor cells) at biologically relevant sites to create reliable preclinical models for cancer research.

https://ift.tt/2IQCP6B

CARIP-Seq and ChIP-Seq: Methods to Identify Chromatin-Associated RNAs and Protein-DNA Interactions in Embryonic Stem Cells

Here, we describe methods to perform ChIP-Seq and CARIP-Seq, including library preparation for next-generation sequencing, to generate global epigenomic and chromatin-associated RNA maps in ES cells.

https://ift.tt/2IRkiXB

The Determination of Protease Specificity in Mouse Tissue Extracts by MALDI-TOF Mass Spectrometry: Manipulating PH to Cause Specificity Changes

Here, we present a protocol to determine protease specificity in crude mouse tissue extracts using MALDI-TOF spectrometry.

https://ift.tt/2IPk2g8

Associations between the use of herbal medicines and adverse pregnancy outcomes in rural Malawi: a secondary analysis of randomised controlled trial data

The use of herbal medicines during pregnancy is very high globally and previous studies have pointed out possible associations with adverse pregnancy outcomes. Nevertheless, the safety of herbal medicines in p...

https://ift.tt/2xaQ804

Varicella zoster virus infections in neurological patients: a clinical study

Varicella zoster virus (VZV) reactivation is a common infectious disease in neurology and VZV the second most frequent virus detected in encephalitis. This study investigated characteristics of clinical and la...

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Treating schistosomiasis among South African high school pupils in an endemic area, a qualitative study

Schistosomiasis, a neglected tropical disease caused by parasites that infest open water sources such as rivers and dams may increase susceptibility to HIV. Mass-treatment with praziquantel tablets, recommende...

https://ift.tt/2xaGqLa

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial

Objective

There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.

Design and results

A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI –12.59 to –2.50; p=0.0018), respectively.

Conclusions

This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.

Trial registration

NCT01770431; Post-results.

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Long-term proton pump inhibitor use after Helicobacter pylori eradication may create a gastric environment for N-nitrosamine formation and gastric cancer development

I read with great interest the recent article by Cheung et al reporting a duration-dependent association between the long-term use proton pump inhibitors (PPI) and an increased risk of gastric cancer in patients, even after Helicobacter pylori (HP) eradication therapy.1 Chronic gastritis due to HP infection induces mutagenesis through deamination and nitration of DNA, via a reaction with inducible nitric oxide synthase (iNOS)-derived NO and superoxide from inflammatory cells.2 However, Cheung et al further demonstrated that continued PPI treatment, even after HP eradication, could also increase the risk for gastric cancer. I support the findings of this paper from the perspective of the importance of physiological acidity in the formation of carcinogenic N-nitroso compounds (NOC) in the stomach.

Gastric acidity does not solely contribute to the digestion of food and as a first-line host defence against swallowed pathogens but also suppresses NOC formation in the stomach.

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Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: a randomised controlled trial

Objectives

In the management of patients with bleeding peptic ulcers, recurrent bleeding is associated with high mortality. We investigated if added angiographic embolisation after endoscopic haemostasis to high-risk ulcers could reduce recurrent bleeding.

Design

After endoscopic haemostasis to their bleeding gastroduodenal ulcers, we randomised patients with at least one of these criteria (ulcers≥20 mm in size, spurting bleeding, hypotensive shock or haemoglobin<9 g/dL) to receive added angiographic embolisation or standard treatment. Our primary endpoint was recurrent bleeding within 30 days.

Results

Between January 2010 and July 2014, 241 patients were randomised (added angiographic embolisation n=118, standard treatment n=123); 22 of 118 patients (18.6%) randomised to angiography did not receive embolisation. In an intention-to-treat analysis, 12 (10.2%) in the embolisation and 14 (11.4%) in the standard treatment group reached the primary endpoint (HR 1.14, 95% CI 0.53 to 2.46; p=0.745). The rate of reinterventions (13 vs 17; p=0.510) and deaths (3 vs 5, p=0.519) were similar. In a per-protocol analysis, 6 of 96 (6.2%) rebled after embolisation compared with 14 of 123 (11.4%) in the standard treatment group (HR 1.89, 95% CI 0.73 to 4.92; p=0.192). None of 96 patients died after embolisation compared with 5 (4.1%) deaths in the standard treatment group (p=0.108). In a posthoc analysis, embolisation reduced recurrent bleeding only in patients with ulcers≥15 mm in size (2 (4.5%) vs 12 (23.1%); p=0.027).

Conclusions

After endoscopic haemostasis, added embolisation does not reduce recurrent bleeding.

Trial registration number

NCT01142180.

https://ift.tt/2IQiQVD

Canalostomy As a Surgical Approach to Local Drug Delivery into the Inner Ears of Adult and Neonatal Mice

Here we describe canalostomy procedure which allows local drug delivery into the inner ears of adult and neonatal mice through the semicircular canal with minimum damage to hearing and vestibular function. This method can be used to inoculate viral vectors, pharmaceuticals, and small molecules into the mouse inner ear.

https://ift.tt/2KQxahp

Enhanced Genome Editing with Cas9 Ribonucleoprotein in Diverse Cells and Organisms

Utilizing a preassembled Cas9 ribonucleoprotein complex (RNP) is a powerful method for precise, efficient genome editing. Here, we highlight its utility across a broad range of cells and organisms, including primary human cells and both classic and emerging model organisms.

https://ift.tt/2Lsmab8

Dallas paramedics offering free CPR training at airport

Paramedics from several EMS agencies teaching hands-only CPR to passengers at the Dallas/Fort Worth International Airport

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Payor Logic celebrates hidden superheroes during EMS Week 2018

EMS practitioners and billing administrators acknowledged for industry impact

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The Dantastic Mr. Tox & Howard Episode 12 – Isbister Bitsy Spider

holger-link-636245-unsplash.jpg?resize=7

https://ift.tt/2KRMfzc Join Dan (@drusyniak) &howard (@heshiegreshie) as they palaver with Dr. Geoff Isbister (@geoff_isbister) about the poison playground that is Australia. Snakes, spiders and quetiapine, oh my! Learn what color of snake to look out for (hint: all of them), learn how Australians do research (on themselves), and why generally leaving your house down under […]

EMCrit Project by Tox & Hound.

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Corrigendum

Maya L. Henry, H. Isabel Hubbard, Stephanie M. Grasso, Maria Luisa Mandelli, Stephen M. Wilson, Mithra T. Sathishkumar, Julius Fridriksson, Wylin Daigle, Adam L. Boxer, Bruce L. Miller and Maria Luisa Gorno-Tempini. Retraining speech production and fluency in non-fluent/agrammatic primary progressive aphasia. Brain 2018; 141: 1799–1814.

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Correction to: Ret is essential to mediate GDNF’s neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

Correction to: Ret is essential to mediate GDNF's neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

Correction to: Ret is essential to mediate GDNF's neuroprotective and neuroregenerative effect in a Parkinson disease mouse model, Published online: 25 May 2018; doi:10.1038/s41419-018-0636-4

Correction to: Ret is essential to mediate GDNF's neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

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Annexin A5 regulates hepatocarcinoma malignancy via CRKI/II-DOCK180-RAC1 integrin and MEK-ERK pathways

Annexin A5 regulates hepatocarcinoma malignancy via CRKI/II-DOCK180-RAC1 integrin and MEK-ERK pathways

Annexin A5 regulates hepatocarcinoma malignancy via CRKI/II-DOCK180-RAC1 integrin and MEK-ERK pathways, Published online: 25 May 2018; doi:10.1038/s41419-018-0685-8

Annexin A5 regulates hepatocarcinoma malignancy via CRKI/II-DOCK180-RAC1 integrin and MEK-ERK pathways

https://ift.tt/2s813mi

Neuroglobin mediates neuroprotection of hypoxic postconditioning against transient global cerebral ischemia in rats through preserving the activity of Na+/K+ ATPases

Neuroglobin mediates neuroprotection of hypoxic postconditioning against transient global cerebral ischemia in rats through preserving the activity of Na⁺/K⁺ ATPases

Neuroglobin mediates neuroprotection of hypoxic postconditioning against transient global cerebral ischemia in rats through preserving the activity of Na<sup>+</sup>/K<sup>+</sup> ATPases, Published online: 25 May 2018; doi:10.1038/s41419-018-0656-0

Neuroglobin mediates neuroprotection of hypoxic postconditioning against transient global cerebral ischemia in rats through preserving the activity of Na⁺/K⁺ ATPases

https://ift.tt/2IQWTpd

Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78

Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78

Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78, Published online: 25 May 2018; doi:10.1038/s41419-018-0669-8

Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78

https://ift.tt/2s8jUxO

Dabrafenib–Trametinib Combination Approved for Melanoma, Anaplastic Thyroid Cancer

FDA recently approved the targeted-drug combination to treat patients with advanced melanoma and a subset of patients with a rare and aggressive form of thyroid cancer whose tumors have a specific mutation in the BRAF gene.

https://ift.tt/2INfrXx

Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo

Epilepsia, EarlyView.

https://ift.tt/2ILeao4

Cancers, Vol. 10, Pages 162: p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations

Cancers, Vol. 10, Pages 162: p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations

Cancers doi: 10.3390/cancers10060162

Authors: Tsukasa Oikawa Yutaro Otsuka Hisataka Sabe

In addition to its classical roles as a tumor suppressor, p53 has also been shown to act as a guardian of epithelial integrity by inducing the microRNAs that target transcriptional factors driving epithelial–mesenchymal transition. On the other hand, the ENCODE project demonstrated an enrichment of putative motifs for the binding of p53 in epithelial-specific enhancers, such as CDH1 (encoding E-cadherin) enhancers although its biological significance remained unknown. Recently, we identified two novel modes of epithelial integrity (i.e., maintenance of CDH1 expression): one involves the binding of p53 to a CDH1 enhancer region and the other does not. In the former, the binding of p53 is necessary to maintain permissive histone modifications around the CDH1 transcription start site, whereas in the latter, p53 does not bind to this region nor affect histone modifications. Furthermore, these mechanisms likely coexisted within the same tissue. Thus, the mechanisms involved in epithelial integrity appear to be much more complex than previously thought. In this review, we describe our findings, which may instigate further experimental scrutiny towards understanding the whole picture of epithelial integrity as well as the related complex asymmetrical functions of p53. Such understanding will be important not only for cancer biology but also for the safety of regenerative medicine.

https://ift.tt/2xcxSUb

Cancers, Vol. 10, Pages 163: Epstein Barr Virus-Associated Hodgkin Lymphoma

Cancers, Vol. 10, Pages 163: Epstein Barr Virus-Associated Hodgkin Lymphoma

Cancers doi: 10.3390/cancers10060163

Authors: Antonino Carbone Annunziata Gloghini

Abstract: Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein–Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level. This review paper focuses on EBV-related cHL highlighting pathogenetic and pathological features that may impact pathobiology-driven treatment for the affected patients.

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EM Nerd-The Case of the Deceptive Beacon

Let's face it, we have an unhealthy relationship with antibiotics. We are all aware that we are currently in an antibiotic resistance crisis that is driven by overuse. And despite our enlightenment we cannot seem to stop prescribing antibiotics for complaints that have been clearly shown not to require antibiotics. And so, given our appalling […]

EMCrit Project by Rory Spiegel.

https://ift.tt/2J67aBq

Patient-derived multicellular tumor spheroids towards optimized treatment for patients with hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has poor prognosis. Specially, patients with HCC usually have poor tolerance of systemic chemotherapy, because HCCs develop from chronically damaged tissue that contains considerable inflammation, fibrosis, and cirrhosis. Since HCC exhibits highly heterogeneous molecular characteristics, a proper in vitro system is required for the study of HCC pathogenesis. To this end, we have established two new hepatitis B virus (HBV) DNA-secreting HCC cell lines from infected patients.

Methods

Based on these two new HCC cell lines, we have developed chemosensitivity assays for patient-derived multicellular tumor spheroids (MCTSs) in order to select optimized anti-cancer drugs to provide more informative data for clinical drug application. To monitor the effect of the interaction of cancer cells and stromal cells in MCTS, we used a 3D co-culture model with patient-derived HCC cells and stromal cells from human hepatic stellate cells, human fibroblasts, and human umbilical vein endothelial cells to facilitate screening for optimized cancer therapy.

Results

To validate our system, we performed a comparison of chemosensitivity of the three culture systems, which are monolayer culture system, tumor spheroids, and MCTSs of patient-derived cells, to sorafenib, 5-fluorouracil, and cisplatin, as these compounds are typically standard therapy for advanced HCC in South Korea.

Conclusion

In summary, these findings suggest that the MCTS culture system is the best methodology for screening for optimized treatment for each patients with HCC, because tumor spheroids not only mirror the 3D cellular context of the tumors but also exhibit therapeutically relevant pathophysiological gradients and heterogeneity of in vivo tumors.

https://ift.tt/2LtFHIf

Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis

Abstract

Purpose

After surgical resection, an ample prognosis variability among stages is observed. Multiple prognostic factors are individually studied and some CRC classifiers have been proposed. Not one have been implemented into clinical practice.

Methods/patients

We classified 105 patients with resected CRC (stage I–III) into five molecular subtypes using BRAF^V600E and RAS (KRAS; NRAS) status, and the expression of DNA mismatch repair (MMR) proteins (MLH1 and MSH2). Clinicopathological features and DFS) of distincts groups were evaluated.

Results and conclusions

RAS and BRAF^V600E mutations were detected in 43.8 and 11.4% of patients, respectively. 19% of tumours had lack of expression of any MMR proteins reflecting a system deficiency (dMMR). Patients with any RAS mutation had lower DFS that patients with RAS wild type (wt) (40.23 vs 45.26 months; p value = 0.035). Of a total of five molecular subtypes, three were MMR proficient (pMMR): RAS mutated (39%), BRAF^V600E mutated (6.7%) and RAS/BRAF^V600E wt (35.2%); and two were dMMR: BRAF^V600E mutated (4.8%) and BRAF^V600E wt (14.3%). Left side tumours were more frequently observed in pMMR/RAS and BRAF^V600E wt subtype, and right side tumours in dMMR subtypes. Among the three pMMR subtypes, a benefit survival was observed for patients without any mutation in BRAF^v600E or RAS oncogenes (median of DFS = 45.5 vs 40.98 months in RAS mutated group; p = 0.084 and vs 34.13 in BRAF^v600E mutated group; p = 0.031). Molecular classification using these biomarkers can be useful to identify groups with differences in prognosis.

https://ift.tt/2IIEOxC

Acute myeloid leukemia—current data from the 2017 American Society of Hematology meeting

Summary

Purpose

To review data on acute myeloid leukemia (AML) presented at the 2017 meeting of the American Society of Hematology (ASH) and to discuss these data within the framework of future developments for the disease.

Results and conclusion

Data generated by next generation sequencing (NGS) may be used for primary diagnosis, therapy selection and monitoring as well as characterization of persons at risk for AML development. After validation, this method will need to be implemented in general practice in the future. For treatment more targeted therapies—single agent or in combination with standard chemotherapy or low-dose treatment approaches—will become available and complement our armamentarium against AML. Among others interesting targets discussed are FLT-3, IDH1 and 2, BCL-2, MEK, E‑selectin, MDM2 and JAK1. Furthermore, maintenance after induction chemotherapy is again being considered for the management of AML.

https://ift.tt/2GMCxfa

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC.

Methods

The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma.

Results

A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis.

Conclusion

The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

https://ift.tt/2IPAcSx

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

Abstract

In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model

Abstract

Background

The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including cancer. Recently, the synthesis and initial evaluation of two high-potential radiolabelled irreversible TG2 inhibitors were reported by us. In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo.

Results

The metabolic stability of [¹¹C]1 and [¹⁸F]2 in SCID mice was comparable to the previously reported stability in Wistar rats. Quantitative real-time polymerase chain reaction analysis on MDA-MB-231 cells and isolated tumours showed a high level of TG2 expression with very low expression of other transglutaminases. PET imaging showed low tumour uptake of [¹¹C]1 (approx. 0.5 percentage of the injected dose per gram (%ID/g) at 40–60 min p.i.) and with relatively fast washout. Tumour uptake for [¹⁸F]2 was steadily increasing over time (approx. 1.7 %ID/g at 40–60 min p.i.). Pretreatment of the animals with the TG2 inhibitor ERW1041E resulted in lower tumour activity concentrations, and this inhibitory effect was enhanced using unlabelled 2.

Conclusions

Whereas the TG2 targeting potential of [¹¹C]1 in this model seems inadequate, targeting of TG2 using [¹⁸F]2 was achieved. As such, [¹⁸F]2 could be used in future studies to clarify the role of active tissue transglutaminase in disease.

https://ift.tt/2Lwo3n9

Cancers, Vol. 10, Pages 161: KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

Cancers, Vol. 10, Pages 161: KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

Cancers doi: 10.3390/cancers10060161

Authors: Azra Memon Woon Kyu Lee

Krüppel-like factor 10 (KLF10), originally named TGF-β (Transforming growth factor beta) inducible early gene 1 (TIEG1), is a DNA-binding transcriptional regulator containing a triple C2H2 zinc finger domain. By binding to Sp1 (specificity protein 1) sites on the DNA and interactions with other regulatory transcription factors, KLF10 encourages and suppresses the expression of multiple genes in many cell types. Many studies have investigated its signaling cascade, but other than the TGF-β/Smad signaling pathway, these are still not clear. KLF10 plays a role in proliferation, differentiation as well as apoptosis, just like other members of the SP (specificity proteins)/KLF (Krüppel-like Factors). Recently, several studies reported that KLF10 KO (Knock out) is associated with defects in cell and organs such as osteopenia, abnormal tendon or cardiac hypertrophy. Since KLF10 was first discovered, several studies have defined its role in cancer as a tumor suppressor. KLF10 demonstrate anti-proliferative effects and induce apoptosis in various carcinoma cells including pancreatic cancer, leukemia, and osteoporosis. Collectively, these data indicate that KLF10 plays a significant role in various biological processes and diseases, but its role in cancer is still unclear. Therefore, this review was conducted to describe and discuss the role and function of KLF10 in diseases, including cancer, with a special emphasis on its signaling with TGF-β.

https://ift.tt/2LuFDYB

In vitro-induced erythromycin resistance facilitates cross-resistance to the novel fluoroketolide, solithromycin, in Staphylococcus aureus

Abstract

The aim of this study was to determine whether in vitro induced erythromycin resistance facilitates the cross-resistance to the novel fluoroketolide, solithromycin, in Staphylococcus aureus. Four strains of methicillin-susceptible S. aureus strains S2, S3, S5 and S7 were successfully induced to establish erythromycin-resistant strains by continuous in vitro culture with erythromycin. Mutations at drug binding sites were shown to increase the minimal inhibitory concentrations for ketolides, including telithromycin and the novel compound solithromycin, but did not increase for lincosamides, chloramphenicols or oxazolidinones. In S2-, S5- and S7-derived strains, L22 protein mutations occurred first, resulting in a low level of cross-resistance to ketolides (≤4 μg/mL). The L4 protein mutations were dependent on the L22 protein, resulting in high-level cross-resistance to ketolides (≥8 μg/mL). In S3-derived strains, high levels of cross-resistance occurred concurrently in the 23S rRNA domains II/V and the L22 protein. Hence, long-term exposure of erythromycin results in resistance to ketolides in S. aureus through drug binding site mutations. These results demonstrate that since erythromycin has been used clinically for a long time, it is necessary to carefully evaluate the rewards and risks when prescribing solithromycin for the treatment of infectious diseases.

https://ift.tt/2x7k0dQ

Automated Pulmonary Embolism Risk Classification and Guideline Adherence for Computed Tomography Pulmonary Angiography Ordering

Academic Emergency Medicine, EarlyView.

https://ift.tt/2s8Fxgo

Slow Infusion of Low‐dose Ketamine Reduces Bothersome Side Effects Compared to Intravenous Push: A Double‐blind, Double‐dummy, Randomized Controlled Trial

Academic Emergency Medicine, EarlyView.

https://ift.tt/2kpEWDB

The Banner of Hope and Solidarity After Mass Murder

Academic Emergency Medicine, EarlyView.

https://ift.tt/2s8FsJC

In Reply:

Academic Emergency Medicine, EarlyView.

https://ift.tt/2knSv6z

Accuracy of axial length measurements obtained by optical biometry and acoustic biometry in rhegmatogenous retinal detachment: a prospective study

Bringing medication prescribing out of the dark: Time for full disclosure [Editorials]

https://ift.tt/2J6br7L

Reduction of anxiety after treatment with transdermal clonidine [Letter]

https://ift.tt/2GMupet

Summaries of safety labeling changes approved by FDA--Boxed warnings highlights, January-March 2018 [News]

https://ift.tt/2J5umzS

Drug shortages roundtable: Minimizing the impact on patient care [ASHP Report]

https://ift.tt/2GNudM8

Preparation times and costs for various solutions used for continuous renal replacement therapy [Practice Research Report]

Purpose

Results of a study to determine time and cost requirements for final preparation of continuous renal replacement therapy (CRRT) products are reported.

Methods

A 3-phase observational study was conducted at a tertiary care university hospital to evaluate costs associated with manual addition of phosphate and/or potassium to 3 commercial 5-L CRRT products. In the first phase of the study, pharmacy workflow processes for solution preparation were established; in the second phase, pharmacist and pharmacy technician time spent in the CRRT workflow and all materials used were observed and recorded. In the third phase, time and personnel requirements were analyzed in economic terms to estimate final preparation costs.

Results

Through direct observation over 35 days, the CRRT workflow was observed and work times recorded for 511 bag preparations. The main cost contributors were the base CRRT solution and electrolyte additive prices. Technician compounding time differed substantially by solution brand and the need for electrolyte addition. Pharmacist verification time did not differ meaningfully by product.

Conclusion

Preparation and verification of premade CRRT solutions that contained physiological electrolyte concentrations required less technician and pharmacist time than solutions that needed addition of electrolytes in the pharmacy. Personnel costs, which were a small part of the total cost of dispensed CRRT bags, were higher for technicians than pharmacists. The baseline costs of the solutions and the electrolyte additives, if needed, were the main contributors to total cost.

https://ift.tt/2J8hkSa

Tools of the trade: Creativity, innovation, influence, and advocacy [John W. Webb Lecture]

https://ift.tt/2KUiPk2

Summaries of safety labeling changes approved by FDA--Boxed warnings highlights, January-March 2018 [News]

Conclusion

The emergence of universal electronic prescribing and content knowledge vendors has laid the groundwork for incorporating indications into the CPOE prescribing process. As medication prescribing moves in the direction of inclusion of the indication, it is imperative to design CPOE systems to efficiently and effectively incorporate indications into prescriber workflows and optimize ways this can best be accomplished.

https://ift.tt/2Lt2IuI

News brief [News]

https://ift.tt/2GP6g6Z

Educator, editor Harvey A. K. Whitney Jr. dies at 87 [News]

https://ift.tt/2LvPjlU

Pharmacists say public awareness could aid 340B program [News]

https://ift.tt/2GQ6TgC

New drugs and dosage forms [News]

https://ift.tt/2J0n2pd

Illinois hospitals cope with outbreak of bleeding linked to tainted cannabinoids [News]

https://ift.tt/2GMumPP

Primary adrenal diffuse large B cell lymphoma: a clinicopathological and molecular study from China

Abstract

Primary adrenal lymphoma is a rare entity that, in most cases, is derived from B cells. The most commonly seen primary adrenal lymphoma is diffuse large B cell lymphoma (DLBCL). To better understand the clinicopathological and molecular features of these tumors, we studied 14 Chinese patients with DLBCL who initially presented with an adrenal tumor. The clinicopathological features of the 14 primary adrenal DLBCL cases were retrospectively reviewed using immunohistochemistry, immunoglobulin gene rearrangement analysis, evaluation of Epstein-Barr virus status, and fluorescence in situ hybridization. Patient age ranged from 43 to 69 years, with a mean age of 58 years. The patients most commonly presented with abdominal pain and adrenal mass. Ten patients exhibited bilateral adrenal masses, and four had unilateral adrenal masses (three left, one right). Thirteen of 14 DLBCLs were DLBCL not otherwise specified, and one was an intravascular large B cell lymphoma. According to the algorithm of Hans et al. (Blood 103:275–282, 2004), 13 and 1 cases were classified as the non-germinal center B-cell-like subtype and the germinal center B-cell-like subtype, respectively. The Ki-67 index ranged from 35 to 80%. Epstein-Barr virus-encoded RNA was detected by in situ hybridization in 6 of the 12 available cases. Two patients showed BCL-6 rearrangements. The follow-up period ranged from 1 to 87 months. During the follow-up period, four patients died of the disease, five were alive with the disease, four were alive without disease, and one was lost during the follow-up period. In summary, most primary adrenal lymphomas are non-germinal-center B-cell-like subtype DLBCLs, which have high proliferative activity and a poor prognosis.

https://ift.tt/2xaBOoy

Cancers, Vol. 10, Pages 160: A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Cancers, Vol. 10, Pages 160: A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Cancers doi: 10.3390/cancers10060160

Authors: Devalingam Mahalingam Sanjay Goel Santiago Aparo Sukeshi Patel Arora Nicole Noronha Hue Tran Romit Chakrabarty Giovanni Selvaggi Andres Gutierrez Matthew Coffey Steffan T. Nawrocki Gerard Nuovo Monica M. Mita

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

https://ift.tt/2xbPU8Z

Cancers, Vol. 10, Pages 159: Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Cancers, Vol. 10, Pages 159: Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Cancers doi: 10.3390/cancers10060159

Authors: Jiaqi Tang Cody C. Gifford Rohan Samarakoon Paul J. Higgins

The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

https://ift.tt/2J48IMl

Hunting the G-unit in Huntington’s

This scientific commentary refers to 'Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes', by Song et al. (doi:10.1093/brain/awy081).

https://ift.tt/2IPabCR

Editorial

'A Colledge for the promoting of Physico-Mathematicall Experimental Learning' was founded on 28 November 1660 by 12 individuals who met after a lecture by Christopher Wren (1632–1723) at Gresham College in London. They suggested a further 41 names for inclusion of whom 15 were physicians. On 12 December 1660, it was agreed that the membership be limited to 45 but with barons, Fellows of the Royal College of Physicians, and professors of mathematics, physic and natural philosophy based in Oxford or Cambridge being eligible as supernumeraries. John Wilkins (1614–72) acted initially as chairman. The 'Colledge' received its Royal Charter from Charles II on 15 July 1662, being renamed the 'Royal Society for improving Natural Knowledge'. These events were the culmination of activities that had begun in the 1640s. But where and to whom the credit lies is disputed. John Wallis (1616–1703) who, as one of the founding Fellows of the Royal Society was directly involved, writes that in about 1645, at a time when academic life was disrupted in 'both Universities' (Oxford and Cambridge), he became involved with a group interested in natural philosophy. They met each week to discuss and carry out experiments. Mention of divinity, state-affairs and current news was prohibited.

https://ift.tt/2LvHpJg

Synaptic assays: using biophysical models to infer neuronal dysfunction from non-invasive EEG

This scientific commentary refers to 'Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis', by Symmonds et al. (doi:10.1093/brain/awy107).

https://ift.tt/2IKjbJq

Can we use regional grey matter atrophy sequence to stage neurodegeneration in multiple sclerosis?

This scientific commentary refers to 'Progression of regional grey matter atrophy in multiple sclerosis', by Eshagi et al. (doi:10.1093/brain/awy088).

https://ift.tt/2Lsak0E

Figure 1

https://ift.tt/2ILYdJY

Cerebello-cortical network fingerprints differ between essential, Parkinson’s and mimicked tremors

Abstract

Cerebello-thalamo-cortical loops play a major role in the emergence of pathological tremors and voluntary rhythmic movements. It is unclear whether these loops differ anatomically or functionally in different types of tremor. We compared age- and sex-matched groups of patients with Parkinson's disease or essential tremor and healthy controls (n = 34 per group). High-density 256-channel EEG and multi-channel EMG from extensor and flexor muscles of both wrists were recorded simultaneously while extending the hands against gravity with the forearms supported. Tremor was thereby recorded from patients, and voluntarily mimicked tremor was recorded from healthy controls. Tomographic maps of EEG-EMG coherence were constructed using a beamformer algorithm coherent source analysis. The direction and strength of information flow between different coherent sources were estimated using time-resolved partial-directed coherence analyses. Tremor severity and motor performance measures were correlated with connection strengths between coherent sources. The topography of oscillatory coherent sources in the cerebellum differed significantly among the three groups, but the cortical sources in the primary sensorimotor region and premotor cortex were not significantly different. The cerebellar and cortical source combinations matched well with known cerebello-thalamo-cortical connections derived from functional MRI resting state analyses according to the Buckner-atlas. The cerebellar sources for Parkinson's tremor and essential tremor mapped primarily to primary sensorimotor cortex, but the cerebellar source for mimicked tremor mapped primarily to premotor cortex. Time-resolved partial-directed coherence analyses revealed activity flow mainly from cerebellum to sensorimotor cortex in Parkinson's tremor and essential tremor and mainly from cerebral cortex to cerebellum in mimicked tremor. EMG oscillation flowed mainly to the cerebellum in mimicked tremor, but oscillation flowed mainly from the cerebellum to EMG in Parkinson's and essential tremor. The topography of cerebellar involvement differed among Parkinson's, essential and mimicked tremors, suggesting different cerebellar mechanisms in tremorogenesis. Indistinguishable areas of sensorimotor cortex and premotor cerebral cortex were involved in all three tremors. Information flow analyses suggest that sensory feedback and cortical efferent copy input to cerebellum are needed to produce mimicked tremor, but tremor in Parkinson's disease and essential tremor do not depend on these mechanisms. Despite the subtle differences in cerebellar source topography, we found no evidence that the cerebellum is the source of oscillation in essential tremor or that the cortico-bulbo-cerebello-thalamocortical loop plays different tremorogenic roles in Parkinson's and essential tremor. Additional studies are needed to decipher the seemingly subtle differences in cerebellocortical function in Parkinson's and essential tremors.

https://ift.tt/2IK6um3

Effects of the SGLT-2 Inhibitor Empagliflozin on Renal Tissue Oxygenation in Non-Diabetic Subjects: A Randomized, Double-Blind, Placebo-Controlled Study Protocol

Abstract

Introduction

Empagliflozin is an SGLT-2 inhibitor (SGLT-2i) which belongs to a new class of hypoglycemic drugs with the unique property of decreasing blood glucose independently from insulin, through an increase in glycosuria. In addition to decreasing cardiovascular morbidity and mortality, empagliflozin has nephroprotective properties in high cardiovascular risk patients with type 2 diabetes. Decreased hyperfiltration and shifting towards more favorable renal fuel energetics with improved renal oxygenation may explain some of these properties. With this study, we propose to explore the effects of empagliflozin on renal tissue oxygenation using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI).

Methods

This is a double-blind, randomized, placebo-controlled study examining the acute and chronic renal effects of empagliflozin 10 mg. The primary outcome is the effects of empagliflozin on renal tissue oxygenation as measured by BOLD-MRI. The secondary outcomes include the effects of empagliflozin on tubular function, 24 h blood pressure control, and the influence of body mass index (BMI) on the renal response to empagliflozin. Fifteen normal weight, 15 overweight, and 15 obese non-diabetic subjects (men and women) will be recruited. Each participant will undergo 24 h urine collections and blood pressure measurements on day − 1, followed by an investigation day at the study center with blood and urine sampling and renal BOLD-MRI measurements before and 180 min after the administration of 10 mg empagliflozin or placebo. This sequence of measurements will be repeated after 1 month of a daily empagliflozin or placebo intake. To investigate renal oxygenation, the renal cortical and medullary R2*, as a marker of oxygenation, will be assessed by BOLD-MRI under standardized hydration conditions: the higher R2*, the lower oxygenation.

Conclusion

SGLT-2 inhibitors have a profound effect on renal physiology. This is an important study that will explore for the first time whether inhibiting SGLT-2 with empagliflozin in healthy volunteers affects renal tissue oxygenation as determined by BOLD-MRI.

Funding

Boehringer Ingelheim Pharma GmbH & Co.

Trial registration

ClinicalTrials.gov identifier, NCT03093103.

https://ift.tt/2scMT2z

Conjunctival Melanoma - Epidemiological Trends and Features

Abstract

Conjunctival melanoma is a rare but sight and life threatening malignancy. It accounts for 2%–5% of all ocular tumours and 5%–7% of all ocular melanomas with an incidence of 0.2–0.8 per million in the Caucasian population with rare cases reported in the non-Caucasians. In recent decades the incidence of uveal melanoma has been relatively stable whilst conjunctival and cutaneous melanoma have shown increasing incidence which may be connected to the result of environmental exposure to ultraviolet light. The dissimilarity in incidence between light and dark pigmented individuals observed in conjunctival melanomas compared to uveal and cutaneous melanomas may be related to differences in their histological structures and genetic profile. Recent molecular biological studies support the fact that each type of melanoma undergoes its own molecular changes and has characteristic biological behaviour. Further studies are required for each type of melanoma in order to ascertain their individual etiology and pathogenesis and based on this knowledge develop relevant preventative and treatment procedures.

https://ift.tt/2s5FLFV

Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel

Abstract

Background

A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.

Methods

Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1–14, a treatment break on days 15–20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.

Results

14 patients were enrolled and treated with median 3.5 cycles (range 0–12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUV_max decreased by − 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUV_max decreased − 44% (p = 0.03).

Conclusions

The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.

https://ift.tt/2LtnZVa

IL13Rα2 expression identifies tissue‐resident IL‐22‐producing PLZF+ innate T cells in the human liver

European Journal of Immunology, EarlyView.

https://ift.tt/2s9w7S1

Assessing the Recall Rate for Screening Mammography: Comparing the Medicare Hospital Compare Dataset With the National Mammography Database

American Journal of Roentgenology, Ahead of Print.

https://ift.tt/2kpOKxH

Interpretation Time Using a Concurrent-Read Computer-Aided Detection System for Automated Breast Ultrasound in Breast Cancer Screening of Women With Dense Breast Tissue

American Journal of Roentgenology, Ahead of Print.

https://ift.tt/2x95J08

Screening Mammography Findings From One Standard Projection Only in the Era of Full-Field Digital Mammography and Digital Breast Tomosynthesis

American Journal of Roentgenology, Ahead of Print.

https://ift.tt/2kmWmAV

High-Resolution CT Findings of Obstructive and Restrictive Phenotypes of Chronic Lung Allograft Dysfunction: More Than Just Bronchiolitis Obliterans Syndrome

American Journal of Roentgenology, Ahead of Print.

https://ift.tt/2J1Q5IX

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Παρασκευή 25 Μαΐου 2018

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