Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Δευτέρα 12 Ιουνίου 2017

Sensitivity to Shared Information in Social Learning

Abstract

Social learning has been shown to be an evolutionarily adaptive strategy, but it can be implemented via many different cognitive mechanisms. The adaptive advantage of social learning depends crucially on the ability of each learner to obtain relevant and accurate information from informants. The source of informants' knowledge is a particularly important cue for evaluating advice from multiple informants; if the informants share the source of their information or have obtained their information from each other, then their testimony is statistically dependent and may be less reliable than testimony from informants who do not share information. In this study, we use a Bayesian model to determine how rational learners should incorporate the effects of shared information when learning from other people, conducting three experiments that examine whether human learners behave similarly. We find that people are sensitive to a number of different patterns of dependency, supporting the use of a sophisticated strategy for social learning that goes beyond copying the majority, and broadening the situations in which social learning is likely to be an adaptive strategy.



http://ift.tt/2rq9Gpb

An insight into the EANM technologist committee benchmark document on nuclear medicine technologists’ competencies



http://ift.tt/2s5561L

A Comparison of Yttrium-90 Microsphere Radioembolization to Hepatic Arterial Infusional Chemotherapy for Patients with Chemo-refractory Hepatic Colorectal Metastases

Opinion statement

Patients with unresectable hepatic colorectal metastases who become chemo-refractory have limited treatment options. Systemic chemotherapies such as TAS102 and regorafenib have been used in the refractory setting, but with only modest improvement in overall survival compared to best supportive care. In patients with liver-only or liver-dominant disease, direct chemotherapy to the liver such as hepatic artery infusional (HAI) chemotherapy and radioembolization (yttrium-90 (Y90)) should be considered. Due to the difficulty of HAI therapy post Y90 for technical reasons, we recommend HAI therapy prior to Y90.



http://ift.tt/2rULBdK

Gastric outlet obstruction secondary to parastomal hernia: case report and literature review



http://ift.tt/2sn2VJQ

Portomesenteric thrombosis post laparoscopic cholecystectomy: a case report



http://ift.tt/2sWbWGH

Systematic differences between ultrasound and pathological evaluation of thyroid nodules: a method comparison study

Background

The size of thyroid nodules as measured by ultrasound (ultrasound size, USS) is routinely used in clinical decision-making. Reports of discrepancy between USS and pathological size (PS) evaluation have not analysed their systematic differences. The objective of this study was to uncover the lack of agreement (bias) between USS and PS measurements.

Methods

A retrospective study was performed on 121 patients who had a total or hemi-thyroidectomy for a solitary nodule. Ordinary least product regression was used to detect and distinguish constant and proportional bias in unidimensional size measurements between USS and PS evaluation. Three-dimensional volume measurements were compared in a subgroup of 31 patients. Pre-specified acceptable limits of interchange were defined as 20% difference.

Results

Ordinary least product regression demonstrated no constant or proportional bias between the two methods; regression equation: USS = (0.863) + (1.040) × PS. When nodules were grouped by size, discrepancies between the two methods were observed in nodules <10 mm (P = 0.004). However, potential overtreatment of patients with USS >10 mm but PS <10 mm only accounted for 4.1% of total patients. Subgroup analysis of volume measurements showed no bias between USS and PS evaluation.

Conclusions

USS and PS measurements were interchangeable, as there was no evidence of constant or proportional bias between the two measurements. However, USS may misclassify the size for smaller nodules and potentially lead to unnecessary workup and treatment. Discrepancy in size measurements between USS and PS should be taken into account in clinical practice, particularly in smaller nodules.



http://ift.tt/2smYzCh

Intramuscular myxoma and fibrous dysplasia of bone presents as Mazabraud's syndrome



http://ift.tt/2sWtiTZ

Accelerated atherosclerosis in ANCA-associated vasculitis

Objectives

Cardiovascular disease, including myocardial infarction and stroke, is a major cause of mortality in ANCA-associated vasculitis (AAV). Although AAV affects small vessels, an accelerated atherosclerosis not explained by traditional cardiovascular risk factors (CVRF) has been demonstrated. We aimed to investigate the association of atherosclerosis measured by carotid intima-media thickness (CIMT) and cerebral small vessel disease in AAV-patients.

Materials & Methods

Twenty-three AAV-patients in complete remission were recruited. Carotid ultrasonography (US), transcranial Doppler (TCD), brain magnetic resonance imaging (MRI), and SPECT after intravenous administration of tracer 99mTc-HMPAO (dose: 720MBq) were performed.

Results

AAV-patients presented higher CIMT compared to normative population. Multivariate linear regression analysis demonstrated an association of higher CIMT with increased pulsatility index in middle cerebral artery (PI-MCA) (P=.011), higher lesion load on ARWMC scale (P=.011) and abnormal SPECT (P=.008). No association between higher CIMT and CVRF (diabetes or hypertension) was demonstrated. Increasing internal carotid artery pulsatility index (PI-ICA) was associated with decreasing mean flow velocity (MFV)-MCA (P=.038), increasing PI-MCA (P=.008) and increasing white matter lesions on MRI (P=.011).

Conclusions

Our study adds weight to the presence of increased atherosclerosis in AAV-patients. The association observed between CIMT and PI-ICA with small vessel cerebral disease, points the possible association of easy to use carotid US in predicting microvascular brain injury.



http://ift.tt/2smLNDO

Pregnancy in CADASIL

Objectives

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients.

Materials and methods

We reviewed records of 50 CADASIL females followed in our center, and we collected prospective information in six patients for a total of 93 pregnancies.

Results

No woman had the disease onset or suffered from cerebral vascular ischemic events during pregnancy. Sixteen miscarriages (17.2%) were recorded. There were 72 vaginal births, and five cesarean sections. Considering the six patients followed prospectively (for a total of eight pregnancies), data on fetal growth and newborns weight were in line with those from the general population. Considering gestational complications, we recorded mild proteinuria without hypertension in one patient and hyperinsulinemia and pre-eclampsia in another affected by a known nephropathy. Antithrombotic drugs were used in three patients, in one for an unrelated coexisting prothrombotic condition.

Conclusions

CADASIL does not seem to be associated with an unfavorable outcome of pregnancy either for women and fetuses. Patients and treating physicians should be reassured that pregnancy can be safely initiated in CADASIL, as there is no evidence to support a specific preventive antithrombotic treatment during pregnancy in CADASIL. Larger studies are needed to definitively confirm these conclusions.



http://ift.tt/2sWvCKx

Neurocognitive function in HIV-infected persons with asymptomatic cryptococcal antigenemia: a comparison of three prospective cohorts

HIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive fun...

http://ift.tt/2rcWip0

Protocol for a randomised controlled trial evaluating the effects of providing essential medicines at no charge: the Carefully seLected and Easily Accessible at No Charge Medicines (CLEAN Meds) trial

Introduction

Cost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence.

Methods and analysis

This is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO's Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months.

Ethics and dissemination

Ethics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers.

Trial registration number

NCT02744963.



http://ift.tt/2s5jPcP

Comparison of chemical profiles between the root and aerial parts from three Bupleurum species based on a UHPLC-QTOF-MS metabolomics approach

Bupleuri Radix (Chaihu) represents one of the most successful and widely used herbal medicines in Asia for the treatment of many diseases such as inflammatory disorders and infectious diseases over the past 20...

http://ift.tt/2tfWKn0

Modulatory influence of Acacia hydaspica R. Parker ethyl acetate extract against cisplatin inveigled hepatic injury and dyslipidemia in rats

Cisplatin (CP) is recommended as a first-line chemotherapeutic agent for solid tumors, however its usage outcomes in severe adverse effects. Acacia hydaspica possesses various phytochemicals and pharmacological a...

http://ift.tt/2sicBo9

Wogonin suppresses stem cell-like traits of CD133 positive osteosarcoma cell via inhibiting matrix metallopeptidase-9 expression

Several efforts have been deployed to cure osteosarcoma, a high-grade malignant bone tumour in children and adolescents. However, some challenges such as drug resistance, relapse, and tumour metastasis remain ...

http://ift.tt/2sibRPH

Isolation of anti-mycobacterial compounds from Curtisia dentata (Burm.f.) C.A.Sm (Curtisiaceae)

Tuberculosis is counted amongst the most infectious and lethal illnesses worldwide and remains one of the major threats to human health. The aim of the current study was to isolate and characterize anti-mycoba...

http://ift.tt/2tfK6EV

Early impairment of intracranial conduction time predicts mortality in deeply sedated critically ill patients: a prospective observational pilot study

Somatosensory (SSEP) and brainstem auditory (BAEP) evoked potentials are neurophysiological tools which, respectively, explore the intracranial conduction time (ICCT) and the intrapontine conduction time (IPCT...

http://ift.tt/2s5gqe3

Venoarterial PCO2-to-arteriovenous oxygen content difference ratio is a poor surrogate for anaerobic metabolism in hemodilution: an experimental study

The identification of anaerobic metabolism in critically ill patients is a challenging task. Observational studies have suggested that the ratio of venoarterial PCO2 (Pv–aCO2) to arteriovenous oxygen content diff...

http://ift.tt/2rl1Jq3

Frequency, associated factors and outcome of multi-drug-resistant intensive care unit-acquired pneumonia among patients colonized with extended-spectrum β-lactamase-producing Enterobacteriaceae

We assessed prevalence, associated factors and prognosis of extended-spectrum beta-lactamase-producing Enterobacteriaceae pneumonia acquired in intensive care unit (ESBL-PE pneumonia) among carriers. Variable...

http://ift.tt/2s57FAK

Red blood cell transfusion in the resuscitation of septic patients with hematological malignancies

Indications for red blood cell (RBC) transfusion in septic acute circulatory failure remain unclear. We addressed the practices and the prognostic impact of RBC transfusion in the early resuscitation of severe...

http://ift.tt/2rkPg5P

Can proportional ventilation modes facilitate exercise in critically ill patients? A physiological cross-over study

Early exercise of critically ill patients may have beneficial effects on muscle strength, mass and systemic inflammation. During pressure support ventilation (PSV), a mismatch between demand and assist could i...

http://ift.tt/2s5eW3L

Cytonuclear Epistasis Controls the Density of Symbiont Wolbachia pipientis in Non-gonadal Tissues of Mosquito Culex quinquefasciatus

Wolbachia pipientis, a bacterial symbiont infecting arthropods and nematodes, is vertically transmitted through the female germline and manipulates its host's reproduction to favor infected females. Wolbachia also infects somatic tissues where it can cause non-reproductive phenotypes in its host, including resistance to viral pathogens. Wolbachia-mediated phenotypes are strongly associated with the density of Wolbachia in host tissues. Little is known, however, about how Wolbachia density is regulated in native or heterologous hosts. Here, we measure the broad-sense heritability of Wolbachia density among families in field populations of the mosquito Culex pipiens, and show that densities in ovary and non-gonadal tissues of females in the same family are not correlated, suggesting that Wolbachia density is determined by distinct mechanisms in the two tissues. Using introgression analysis between two different strains of the closely-related species Culex quinquefasciatus, we show that Wolbachia densities in ovary tissues are determined primarily by cytoplasmic genotype, while densities in non-gonadal tissues are determined by both cytoplasmic and nuclear genotypes and their epistatic interactions. Quantitative-trait locus mapping identified two major-effect quantitative-trait loci in the Culex quinquefasciatus genome explaining a combined 23% of variance in Wolbachia density specifically in non-gonadal tissues. A better understanding of how Wolbachia density is regulated will provide insights into how Wolbachia density can vary spatiotemporally in insect populations, leading to changes in Wolbachia-mediated phenotypes such as viral pathogen resistance.



http://ift.tt/2shNXns

The impact of clinical and genetic factors on ticagrelor and clopidogrel antiplatelet therapy

Pharmacogenomics Ahead of Print.


http://ift.tt/2rlcgl9

NP108, an antimicrobial polymer with activity against methicillin and mupirocin resistant Staphylococcus aureus. [PublishAheadOfPrint]

Staphylococcus aureus is a clinically significant human pathogen that causes infectious diseases ranging from skin and soft tissue infections (SSTI), healthcare associated infections (HAI) to potentially fatal bacteraemia and endocarditis. Nasal carriage of S. aureus, especially persistent carriage, is associated with an increased risk of subsequent infection, particularly nosocomial and surgical site infections (SSI), usually via autoinfection. NP108 is a cationic antimicrobial polymer composed of Generally Recognized as Safe (GRAS) amino acid building blocks. NP108 is broad-spectrum and rapidly bactericidal (3 log kill in ≤3 h); killing bacteria by membrane disruption and cell lysis. NP108, contrary to many antibiotics, shows equally effective antimicrobial activity versus a variety of S. aureus (MIC100 = 8 – 500 mg/L) and S. epidermidis (MIC100 = 4 - 8 mg/L), whether exponentially growing or in stationary phase. NP108 is antimicrobially active under nutrient limiting conditions similar to those found in the anterior nares (MIC100 = 8 mg/L), kills antibiotic resilient small colony variants (MIC100 = 32 mg/L)) and S. aureus biofilms (prevention (1 – 4 mg/L) and eradication (>31.25 mg/L)). NP108 is active against isolates of S. aureus resistant to the current standard of care decolonisation agent, mupirocin, with no significant increase in MIC100. NP108 is water-soluble and has been formulated into compatible aqueous gel vehicles for human use in which antimicrobial efficacy is retained (2.0% (w/v)). NP108 is a potential non-antibiotic antimicrobial alternative to antibiotics for the nasal decolonisation of S. aureus with clear advantages in its mechanism of action over the existing gold standard mupirocin.



http://ift.tt/2rprvVB

Peripheral neuropathy in 30 duodopa patients with vitamins B supplementation

Objectives

Peripheral neuropathy (PN) is a significant concern and potential cause of withdrawal in patients with Parkinson's disease (PD) treated with Levodopa/Carbidopa Intestinal Gel (LCIG) infusion. Vitamin B deficiency and/or hyperhomocysteinemia levodopa-related are considered possible causative factors. In this study, we evaluated PN incidence in LCIG-PD patients treated since the beginning of infusion with vitamins B supplementation.

Materials & Methods

In this prospective open-label pilot study, 30 consecutive patients with PD on LCIG infusion were evaluated with clinical, neurophysiological, and biochemical assessments for a mean follow-up of 42.4 months (range 24-72). All evaluations were repeated every 6 months.

Results

At baseline, 21 of 30 presented no signs or symptoms of PN, and 9 of 30 had pre-existing chronic PN. In whole population, a progressive worsening in nerve conduction studies of sural sensory and peroneal motor nerves was observed during the long-term follow-up. 4 of 21 patients, with normal clinical, electrophysiological assessment at baseline, developed distal symmetrical axonal polyneuropathy that remained asymptomatic during the long-term follow-up. Patients with pre-existing PN (9 of 30) showed a mild worsening of electrophysiological features during the period of observation. In none PN was cause of discontinuation of LCIG therapy. No incident cases of acute-subacute PN were documented. No correlation was found with age, sex, Levodopa dosage, duration of levodopa exposure, and homocysteine plasma levels.

Conclusion

In this consecutive series of 30 patients with PD on LCIG infusion, with early and continuous vitamins B integration, we observed a low rate (19%) of new onset peripheral polyneuropathy that remained stable after long-term follow-up. Larger studies, controlled, with blinded evaluation, are needed to confirm these findings.



http://ift.tt/2rUBYvu

Correction: Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer [Correction]



http://ift.tt/2rlah0b

Antibiotic-mediated modulations of outer membrane vesicles in enterohemorrhagic Escherichia coli O104:H4 and O157:H7 [PublishAheadOfPrint]

Ciprofloxacin, meropenem, fosfomycin, and polymyxin B strongly increase production of outer membrane vesicles (OMVs) in Escherichia coli O104:H4 and O157:H7. Ciprofloxacin also upregulates OMV-associated Shiga toxin 2a, the major virulence factor of these pathogens, whereas the other antibiotics increase OMV production without the toxin. Both these effects might worsen the clinical outcome of infections caused by Shiga toxin-producing E. coli. Our data support the existing recommendations to avoid antibiotics for treatment of these infections.



http://ift.tt/2rpqAEz

Comparison of two phenotypic algorithms to detect carbapenemase-producing Enterobacteriaceae [PublishAheadOfPrint]

A novel algorithm designed for the screening of carbapenemase producing Enterobactericeae (CPE), based on faropenem and temocillin disks was compared to that of the French Society of Microbiology (CA-SFM), which is based on ticarcillin-clavulanate, imipenem and temocillin disks. Both algorithms presented comparable negative predictive values (98.6% vs 97.5%) for the CPE screening among carbapenem non-susceptible Enterobacteriaceae. However, since 46.2% (n=49) of the CPEs were correctly identified as OXA-48-like producers by the faropenem/temocillin-based algorithm, it significantly decreased the number of complementary tests needed (42.2% vs 62.6% with the CA-SFM algorithm).



http://ift.tt/2rUEj9U

Drug sensitivity and resistance mechanism in Aspergillus section Nigri strains from Japan [PublishAheadOfPrint]

Aspergillus niger and its related species, known as Aspergillus section Nigri, are ubiquitously distributed across the globe and are often isolated from clinical specimens. In Japan, Aspergillus section Nigri is the second-most often isolated from clinical specimens following A. fumigatus. We determined the species of Aspergillus section Nigri isolated in Japan by DNA sequencing of partial β-tubulin genes and investigated drug susceptibility by CLSI M38-A2 method. The collection contained 20 A. niger, 59 A. welwitschiae, and 39 A. tubingensis strains. Drug susceptibility testing revealed 30-55% of A. niger, 6.8-18.6% of A. welwitschiae, and 79.5-89.7% of A. tubingensis to be less susceptible (so-called resistant) to itraconazole (ITC) and/or voriconazole (VRC) according to the epidemiologic cutoff values (ECVs) proposed for A. niger previously. Minimum inhibitory concentrations distributions of ITC or VRC showed no remarkable differences between clinical and environmental isolates. When the cyp51A sequences were compared between susceptible and resistant strains, 18 amino acid mutations were specific for resistant isolates of A. niger and A. tubingensis, however none of them were confirmed to be associated with azole resistance. Three non-related A. welwitschiae isolates possessed a partial deletion in cyp51A, likely attributable to being more susceptible to azoles when compared to other isolates. 1 of 5 ITC-resistant A. tubingensis isolates showed higher expression level of cyp51A than those of susceptible strains. Our results show that cyp51A point mutations may have no association with azole resistance but in some cases the over-expression of cyp51A might lead the azole-resistance in these species.



http://ift.tt/2rph0Bq

PenA, ponA, porB1 and mtrR mutations and molecular epidemiological typing of Neisseria gonorrhoeae with decreased susceptibility to cephalosporin [PublishAheadOfPrint]

In recent years, N. gonorrhoeae strains with decreased susceptibilities (DS; MIC > 0.064 mg/L) or resistance to cefixime (CFM) or ceftriaxone (CRO), have been classed as a "superbug" and have spread worldwide, resulting in treatment failures for gonorrhea (1-3)....



http://ift.tt/2rUuatU

Pharmacodynamic evaluation of fosfomycin against E. coli and Klebsiella spp. from urinary tract infections and the influence of pH on fosfomycin activities [PublishAheadOfPrint]

Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI) and recently have been recommended for treating multidrug-resistant (MDR) gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimen has not been analyzed. Minimal inhibitory concentration (MIC) was determined using agar dilution in pH 6.0 and 7.0 for 245 Gram negative bacterial isolates, consisting of 158 E. coli and 87 Klebsiella spp. which were collected from patients with UTI. Monte Carlo simulation of urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3000 mg fosfomycin and MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against E. coli (MIC90 ≤ 16 μg/mL) but not against Klebsiella spp. (MIC90 > 512 μg/mL). Acidification of pH environment increased bacterial susceptibility in 71% of the isolates and resulted in a statistically significant decrease in bacterial survival. Fosfomycin oral single dose regimen against E. coli isolate with MIC ≤64 mg/L was able to achieve ≥90% PTA for a target pharmacodynamic index of 23 AUC/MIC in the urine; PTA was not achieve when MIC is higher than 64 mg/L. Cumulative fractions of responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in an acidic urine pH of 6.0. Decreased pH from 7.0 to 6.0 improves PTA and CFR of the target PD index in both E. coli and Klebsiella isolates.



http://ift.tt/2rpwcOT

Carbapenemase-producing Enterobacteriaceae-isolates from Edo State, Nigeria [PublishAheadOfPrint]

The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) is a global health problem which is of great concern to public health services (1, 2)....



http://ift.tt/2rUDnlV

Resistance to the cyclotide cycloviolacin O2 in Salmonella enterica caused by different mutations that often confer cross-resistance or collateral sensitivity to other antimicrobial peptides [PublishAheadOfPrint]

Antimicrobial peptides (AMPs) are essential components of innate immunity in all living organisms, and these potent broad-spectrum antimicrobials have inspired several antibacterial development programs in the past two decades. In this study, resistance development to the Gram-negative specific peptide cycloviolacin O2 (cyO2), a member of the cyclotide family of plant mini-proteins, was characterized in Salmonella enterica serovar Typhimurium LT2. Mutants isolated from serial passaging experiments at increasing concentration of cyO2 were characterized by whole genome sequencing. Identified mutations were genetically reconstituted in a wild type background. The additive effect of mutations was studied in double mutants. Fitness costs, levels of resistance and cross-resistance to another cyclotide, other peptide and non-peptide antibiotics and AMPs were determined. A variety of resistance mutations were identified, where some reduced fitness and others had no effect on fitness in vitro, in the absence of cyO2. In mouse competition experiments, four of the cyO2 resistant mutants showed a significant fitness advantage whereas the others appeared neutral. The level of resistance was increased by combining several individual resistance mutations. Several cases of cross-resistance and collateral sensitivity between cyclotides, other AMPs and antibiotics were identified. These results show that resistance to cyclotides can evolve via several different types of mutations with only minor fitness costs and that these mutations often affect resistance to other AMPs.



http://ift.tt/2rUIEcU

High accumulation and in vivo recycling of the new antimalarial albitiazolium rapidly condemn the parasite to death [PublishAheadOfPrint]

Albitiazolium is the lead compound of bis-thiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits a rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei-infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio > 150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect.

We also established a new viability assay in the P. vinckei-infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 hours at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.



http://ift.tt/2rpqAo3

Efficacy of a Paromomycin plus Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis [PublishAheadOfPrint]

The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q-fever, as it enhances the activity of the antibiotic against the causative Coxiella burnetii bacteria residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could be also the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activity of combinations of CQ with standard drugs paromomycin (PM), miltefosine and amphotericin B against Leishmania major and Leishmania mexicana. In 72-hour intracellular anti-leishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced EC50 values by over 5-fold against L. major and against the normally insensitive L. mexicana. In murine models of L. major and L. mexicana CL, daily co-administration of 50 mg/kg PM and 25 mg/kg CQ for 10 days resulted in significant reduction in lesion size but not in parasite load compared to mice given the same doses of PM alone. Overall, our data indicates that a PM plus CQ combination therapy is unlikely to be a potential candidate for further preclinical development.



http://ift.tt/2rUEiTo

Potent In Vitro Synergism of Fluconazole and Osthole against Fluconazole-Resistant Candida albicans [PublishAheadOfPrint]

Osthole is a natural coumarin that exhibits wide biological and pharmacological activities such as neuroprotective, osteogenic, immunomodulation, anti-tumor and anti-inflammatory effects. In this study, we investigated the antifungal effects of osthole in vitro. Checkerboard microdilution assay showed that osthole has significant synergistic effect with fluconazole against fluconazole-resistant Candida albicans. Similar results was obtained from growth curve assay. Meanwhile, XTT reduction assay demonstrated the synergism of fluconazole and osthole against C. albicans biofilm formation. Microarray results showed that the expression of genes involved in oxidation-reduction process, energy metabolism and transportation changed significantly after the combined treatment with fluconazole and osthole, and further results showed that endogenous reactive oxygen species (ROS) was significantly increased in the combination group. In conclusion, these results demonstrated the synergism of fluconazole and osthole against fluconazole-resistant C. albicans and indicated that endogenous ROS augmentation might contribute to the synergism of fluconazole and osthole.



http://ift.tt/2rpxiKE

Chemoenzymatic synthesis, nanotization and anti-Aspergillus activity of optically enriched fluconazole analogues [PublishAheadOfPrint]

Despite recent advances in diagnostic and therapeutic advances in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogs. Anti-Aspergillus activity was observed for an optically enriched derivative, (-)-S-2-(2' ,4' -difluorophenyl)-1-hexyl-amino-3-(1''',2''',4''') triazol-1'''-yl-propan-2-ol, which exhibits MIC values of 15.6 μg/mL and 7.8 μg/disc in microbroth dilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1000 μg/mL. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analog exhibited improved antifungal activity against Aspergillus fumigatus (MIC = 1.63 μg/mL). These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotised counterparts, exhibiting anti-Aspergillus activity may have reduced toxicity.



http://ift.tt/2rUID8Q

Liposomal Amphotericin B Nephrotoxicity in Patients with Hematological Malignancies: A Retrospective Cohort Analysis [PublishAheadOfPrint]

We retrospectively examined the incidence, onset, risk factors, and outcomes of renal injury during 103 treatment courses of liposomal amphotericin B (L-AMB) in 97 adult patients with hematological malignancies. All patients were analyzed before, during and after the administration of L-AMB, and renal injury was graded per the RIFLE criteria. Most patients (87.3%) received L-AMB at 3 mg/kg/day. Nearly two-thirds (61.7%) of treatment courses did not meet any RIFLE category for renal injury, while 19.4% of patients were classified at risk, 13.6% met an injury classification, and 5.8% were categorized as developing renal failure. However,15% of patients developed renal injury within 48 hours of the onset of multiorgan failure associated with sepsis, bleeding or progressing malignancy. When these patients were analyzed as a competing risk for L-AMB associated renal injury (RIFLE category "I" or above) in a multivariate Cox regression model, receipt of cyclosporine (subhazard ratio 2.62, 95% CI 1.10-6.27; P=0.03), cyclosporine plus furoseminde ≥ 40 mg/day (SHR 5.46,1.89-15.74;P=0.002) or cyclosporine plus foscarnet (SHR 9.03, 3.68-22.14; P<0.0001) were the only comedications significantly associated with increased rates of renal injury. The cumulative incidence of L-AMB renal injury during the first 10 days of therapy was 7% overall, but only 3% in patients who were not receiving cyclosporine. Hence, the renal risks of L-AMB therapy may be lessened if patients are switched to alternative agents after 7-10 days, or aggressive diuresis and/or foscarnet are avoided, especially among patients receiving calcineurin inhibitors.



http://ift.tt/2rptoBz

Pharmacokinetics of Pyrazinamide: optimising dosing regimens for drug-sensitive and -resistant tuberculosis [PublishAheadOfPrint]

Pyrazinamide is used in the treatment of tuberculosis(TB) because its sterilising effect against tubercle bacilli allows treatment shortening. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multi-drug resistant tuberculosis(MDR-TB). Pyrazinamide pharmacokinetic(PK) data from 61 HIV/TB co-infected patients in South Africa was used in the analysis. They were administered weight adjusted doses of pyrazinamide, rifampicin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on day 1, 8, 15, and 29. The data was interpreted using nonlinear mixed-effects modelling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted AUC0-24 of 363 mg⋅h/L. Among patients with drug susceptible TB, adding 400 mg to the dose for those weighing 30-54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1500 mg, 1750 mg and 2000 mg to patients in the 33-50 kg, 51-70 kg and greater than 70 kg weight-bands respectively.



http://ift.tt/2rUuado

In Vitro - In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-{beta}-Lactam-Susceptible Klebsiella pneumoniae [PublishAheadOfPrint]

Recent findings have identified K. pneumoniae strains that are pan-β-lactam-susceptible (PBL-S), but piperacillin-tazobactam-resistant (TZP-R) in vitro. We assessed the efficacy of a humanized exposure of TZP against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications these TZP-R/PBL-S strains.



http://ift.tt/2rpkXWZ

Pharmacokinetic Assessment of Vancomycin Loading Dose in Critically Ill Patients [PublishAheadOfPrint]

Background: The vancomycin loading dose (LD) of 25-30 mg/kg is a frequently practiced strategy to achieve effective concentrations from the first-treatment dose. However, considering only the body weight for dosing might be inadequate in critically ill patients due to pharmacokinetics changes.

Objective: Assess achieving optimal trough serum levels of vancomycin and AUC0–24/MIC in the first 24-hours of treatment, by using a LD based on population pharmacokinetic parameters of critically ill patients.

Methods: We performed a concurrent cohort study over 22 months of patients with severe sepsis who received intravenous vancomycin. The patients were treated with three different strategies to initiate vancomycin: without LD (Group A), with LD of 25-30 mg/kg (Group B), and with LD based on population pharmacokinetic parameters of the critically ill patient (Group C).

Results: An optimal trough serum concentration was achieved in 5%, 9% and 83% of patients in Group A, B and C, respectively. The number of patients that reached optimal AUC0–24, was 2 out of 18 (11%), 5 out of 11 (46%), and 11 out of 12 (92%) on Groups A, B and C, respectively. The statistical analysis for both parameters revealed significant differences in Group C, with respect to other groups.

Conclusions: The administration of LD calculated from population pharmacokinetic parameters from the beginning of therapy is a more efficient strategy to obtain adequate trough serum concentrations and AUC0–24/MIC in critical patients.



http://ift.tt/2rUzywO

Selective Killing Of Dormant Mycobacterium tuberculosis By Marine Natural Products [PublishAheadOfPrint]

The dormant phenotype acquired by Mycobacterium tuberculosis (Mtb) during infection poses a major challenge in disease treatment since these bacilli are tolerant to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent Mtb under both replicating and non-replicating conditions we have identified compounds that are selectively active against dormant Mtb. This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassay guided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant Mtb we used a luciferase reporter assay and CFU enumeration. The structures of five purified active compounds were defined by NMR and mass spectrometry. We identified two lipid compounds with potent activity towards dormant and actively growing Mtb. One of these was commercially obtained and showed similar activity against Mtb in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant Mtb. In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target Mtb pathways conditionally essential for dormancy survival.



http://ift.tt/2rpAO81

Targeting quorum sensing signal biosynthesis to fight antibiotic resistant infections: Ambuic acid as a model inhibitor [PublishAheadOfPrint]

There has been major interest by the scientific community in anti-virulence approaches against bacterial infections. However, partly due to a lack of viable lead compounds, anti-virulence therapeutics have yet to reach the clinic. Here we investigate the development of an anti-virulence lead targeting quorum sensing signal-biosynthesis, a process that is conserved in Gram positive bacterial pathogens. Some preliminary studies suggest that the small molecule ambuic acid is a signal biosynthesis inhibitor. To confirm this, we construct a methicillin-resistant Staphylococcus aureus (MRSA) strain that decouples AIP production from regulation, and demonstrate that AIP production is inhibited in this mutant. Quantitative mass spectrometric measurements show that ambuic acid inhibits signal biosynthesis (IC50 of 2.5 ± 0.1 μM) against a clinically relevant USA 300 MRSA strain. Quantitative real-time PCR confirms that this compound selectively targets the quorum sensing regulon. We show that a 5 μg dose of ambuic acid reduces MRSA-induced abscess formation in a mouse model, and verify its quorum sensing inhibitory activity in vivo. Finally, we employ mass spectrometry to identify or confirm the structure of quorum sensing signaling peptides in three strains of S. aureus, three strains of Staphylococcus epidermidis, Enterococcus faecalis, Listeria monocytogenes, Staphylococcus saphrophyticus, and Staphylococcus lugdunensis. By measuring AIP production by these strains, we show that ambuic acid possesses broad-spectrum efficacy against multiple Gram positive bacterial pathogens, but does not inhibit quorum sensing in some commensal bacteria. Collectively, these findings demonstrate the promise of ambuic acid as a lead for the development of anti-virulence therapeutics.



http://ift.tt/2rUu99k

Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells

Purpose: <p>Leptomeningeal metastases (LM) are more common in non-small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of LM.</p> <br />Experimental Design: <p>We compared the CellSearch Assay™, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected LM. Next-Generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTCs) of 19 patients.</p> <br />Results: <p>Twenty-one patients were diagnosed with LM, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/ 7.5 mL; range, 27-14,888). CellSearch had a sensitivity of 95.2% for LM diagnosis, which was higher than that of TCT(12/21, 57.1%), MRI(10/21, 47.6%), and MRI plus TCT(19/21, 90.5%), respectively. CTCs were found in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2-4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was only detected in 1 of 14 CSFCTC samples. Other potential resistant mutations such as MET amplification and ERBB2 mutation were also identified in CSFCTCs.</p> <br />Conclusions: <p>CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose LM, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with LM.



http://ift.tt/2sW7hEE

Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.<br /><br />Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.<br /><br />Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P<0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P =0.002), lymph node metastasis (P =0.004) and advanced clinical stage (P =0.001). LUAD patients with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for LUAD patients. Moreover, forced expression of RCC2 promoted intra-pulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion and proliferation in vitro. Further study found that RCC2 induced epithelial-mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP -9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT and the expression of MMP-2 and MMP-9.<br /><br />Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK-JNK signaling.



http://ift.tt/2smxGPb

In situ vaccination after accelerated hypofractionated radiation and surgery in a mesothelioma mouse model

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated non-ablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.<br /><br />Experimental Design: We therefore assessed the impact of non-ablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short term impact and radical surgery (R0 resection) was used to analyze the long-term impact of this radiation protocol before surgery. <br /><br />Results: Non-ablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8+ T cells limiting the negative impact of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long term antitumor immune protection that was primarily driven by CD4+ T cells. Radical surgery alone or radical surgery with a short course of non-ablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.     <br /><br />Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Non-ablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting.



http://ift.tt/2sWpDpk

Age and gender associations of virus positivity in Merkel cell carcinoma characterized using a novel RNA in situ hybridization assay

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection. <p>Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMAs) and whole tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, quantitative PCR (qPCR) was performed on 57 cases of MCC from 52 patients.   </p> <p>Results: RNA-ISH demonstrated the presence of MCPyV in 37/75 (49.3%) cases. Notably, tumors from younger patients (< 73 years) had a significantly higher virus positivity than those from elderly patients (≥ 73 years) (64.9% vs. 34.2%, P =0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P =0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman's correlation coefficient R2 = 0.932, P < 0.0001).  </p> <p>Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. 



http://ift.tt/2smtfUb

Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer

Purpose: Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes, and investigated mechanisms of sensitivity. <p>Experimental design: A panel of cell lines representative of TNBC were tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging.</p> <p>Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0.001 LAR vs. basal-like] and in vivo in MDAMB453 LAR cell line xenografts. Single cell analysis of CDK2 activity demonstrated differences in cell cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell cycle re-entry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity post-mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes.</p> <p>Conclusion: Cell cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC.



http://ift.tt/2sW4KKO

Expression and Therapeutic Potential of SOX9 in Chordoma

Purpose: Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma. <br /><br />Experimental Design: <p>SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescence assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound healing assay and a transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell cycle arrest as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by a MTT assay.</p> <br /><br />Results: <p>Tissue microarray (TMA) and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells.</p> <br /><br />Conclusions: <p>Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma.



http://ift.tt/2smtEpH

Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early stage non-small-cell lung cancer using next-generation sequencing

Purpose: <br />To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma (AC) and squamous cell carcinoma (SCC) as a non-invasive method in the early diagnosis of non-small-cell lung cancer (NSCLC). <br /><br />Experimental Design: <br />Tumor-derived exosomes from the plasma of early stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate AC- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.<br /><br />Results: <br />There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in AC and SCC patients, respectively, compared to healthy volunteers. Distinct AC- and SCC-specific  exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24 and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p were AC-specific, and miR-10b-5p, miR-15b-5p and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, AC and SCC, respectively.<br /><br />Conclusions:<br /> <p> Tumor-derived exosomal miRNAs, AC-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p and miR-320b, were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, non-invasive biomarkers for early NSCLC diagnosis.



http://ift.tt/2rpqsEN

Dental extraction from an appendix: a case report and review of the literature



http://ift.tt/2rpgPpT

Out-of-office hours’ elective surgical intensive care admissions and their associated complications

Background

The 'weekend' effect is a controversial theory that links reduced staffing levels, staffing seniority and supportive services at hospitals during 'out-of-office hours' time periods with worsening patient outcomes. It is uncertain whether admitting elective surgery patients to intensive care units (ICU) during 'out-of-office hours' time periods mitigates this affect through higher staffing ratios and seniority.

Methods

Over a 3-year period in Western Australia's largest private hospital, this retrospective nested-cohort study compared all elective surgical patients admitted to the ICU based on whether their admission occurred 'in-office hours' (Monday–Friday 08.00–18.00 hours) or 'out-of-office hours' (all other times). The main outcomes were surgical complications using the Dindo-Clavien classification and length-of-stay data.

Results

Of the total 4363 ICU admissions, 3584 ICU admissions were planned following elective surgery resulting in 2515 (70.2%) in-office hours and 1069 (29.8%) out-of-office hours elective ICU surgical admissions. Out-of-office hours ICU admissions following elective surgery were associated with an increased risk of infection (P = 0.029), blood transfusion (P = 0.020), total parental nutrition (P < 0.001) and unplanned re-operations (P = 0.027). Out-of-office hours ICU admissions were also associated with an increased hospital length-of-stay, with (1.74 days longer, P < 0.0001) and without (2.8 days longer, P < 0.001) adjusting for severity of acute and chronic illnesses and inter-hospital transfers (12.3 versus 9.8%, P = 0.024). Hospital mortality (1.2 versus 0.7%, P = 0.111) was low and similar between both groups.

Conclusion

Out-of-office hours ICU admissions following elective surgery is common and associated with serious post-operative complications culminating in significantly longer hospital length-of-stays and greater transfers with important patient and health economic implications.



http://ift.tt/2rUnMCO

The secrets of tooth calcium revealed

Two studies on calcium isotopes in teeth have provided new insights into both the extinction of the marine reptiles and weaning age in humans. The findings open new avenues for research in anthropology and paleontology, say researchers.

http://ift.tt/2rknt5D

Multi-linear sparse reconstruction for SAR imaging based on higher-order SVD

This paper focuses on the spotlight synthetic aperture radar (SAR) imaging for point scattering targets based on tensor modeling. In a real-world scenario, scatterers usually distribute in the block sparse pat...

http://ift.tt/2smapg2

The Role of Cold-inducible RNA binding protein (CIRP) in Cell Stress Response

Abstract

Cold-inducible RNA binding protein (CIRP) was discovered after the cells were exposed to a moderate cold shock because its production was induced. Other cellular stresses such as UV radiation and hypoxia also could increase its expression. Under stress conditions, CIRP could up regulate its own expression by self-transcriptional activation of alternative promoters. After relocating into cytoplasm from nucleus, CIRP assists cells in adapting to novel environmental conditions via stabilizing specific mRNAs and facilitating their translation. It not only participates in anti-apoptosis processes under mild hypothermia condition, but also protects cells from ultraviolet radiation and hypoxia induced senescence process. This article focuses on the possible mechanisms of its inducible expression, cytoprotective functions and carcinogenesis. In addition, extracellular CIRP has been shown to be a novel danger-associated molecular patter (DAMP) member and is able to induce inflammatory response. Finally, based on the distinct roles of CIRP in intracellular and extracellular conditions, a possible model of CIRP-mediated cell fate has been proposed. This article is protected by copyright. All rights reserved.



http://ift.tt/2rp48vm

Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling

Abstract

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. This article is protected by copyright. All rights reserved.



http://ift.tt/2rUfeM1

Role of ATP-Sensitive K + Channels in Myocardial Infarct Size-Limiting Effect of Chronic Continuous Normobaric Hypoxia

The role of KATP channels in myocardial infarct size-limiting effect of chronic continuous normobaric hypoxia was examined in a rat model based on a 20-min coronary occlusion and subsequent 3-h reperfusion. Rats were adapted to normobaric hypoxia (12% O2) for 21 days. This hypoxia produced a pronounced infarct size-limiting effect, which had been prevented by 0.3 mg/kg glibenclamide, a non-selective inhibitor of entire pool of KATP channels, or 5 mg/kg 5-hydroxydecanoate, an inhibitor of mitochondrial KATP channels. The study highlighted the important role of mitochondrial KATP channels in myocardial infarct size-limiting effect of chronic normobaric hypoxia.



http://ift.tt/2rugELx

Structure of Rat Lungs after Administration of Magnetomicelles Based on the Carbon-Coated Iron Nanoparticles

We studied the effects of single administration of a suspension of magnetomicelles based on carbon-coated iron nanoparticles on the structure of rat lungs within 40 days. Histological analysis revealed a complex of hemodynamic alterations in the lungs. Described changes persisted in the lung stroma from day 1 until day 40, but their intensity decreased by the end of the experiment. Using immunohistochemical Perls reaction we identified cells morphologically corresponding to alveolar and interstitial lung macrophages. The number of Perls+ cells decreased by day 40 of the experiment. Ultrastructural analysis showed endocytosis of modified iron nanoparticles and their accumulation in intracellular digestionorganelles (endo- and lysosomes) of mononuclear phagocyte system cells. Accumulation of magnetomicelles in the lungs was not associated with damage to pneumocytes, macrophages, and blood-air barrier.



http://ift.tt/2qL6wRs

Low levels of physiological interstitial flow eliminate morphogen gradients and guide angiogenesis

Abstract

Convective transport can significantly distort spatial concentration gradients. Interstitial flow is ubiquitous throughout living tissue, but our understanding of how interstitial flow affects concentration gradients in biological processes is limited. Interstitial flow is of particular interest for angiogenesis because pathological and physiological angiogenesis is associated with altered interstitial flow, and both interstitial flow and morphogen gradients (e.g., vascular endothelial growth factor, VEGF) can potentially stimulate and guide new blood vessel growth. We designed an in vitro microfluidic platform to simulate 3D angiogenesis in a tissue microenvironment that precisely controls interstitial flow and spatial morphogen gradients. The microvascular tissue was developed from endothelial colony forming cell-derived endothelial cells extracted from cord blood and stromal fibroblasts in a fibrin extracellular matrix. Pressure in the microfluidic lines was manipulated to control the interstitial flow. A mathematical model of mass and momentum transport, and experimental studies with fluorescently labeled dextran were performed to validate the platform. Our data demonstrate that at physiological interstitial flow (0.1–10 μm/s), morphogen gradients were eliminated within hours, and angiogenesis demonstrated a striking bias in the opposite direction of interstitial flow. The interstitial flow-directed angiogenesis was dependent on the presence of VEGF, and the effect was mediated by αvβ3 integrin. We conclude that under physiological conditions, growth factors such as VEGF and fluid forces work together to initiate and spatially guide angiogenesis.



http://ift.tt/2suA8Tf

JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin

Abstract

Purpose

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Methods

The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.

Results

We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.

Conclusions

JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.



http://ift.tt/2s4Dwl1

Etiology and Perinatal Outcome of Nonimmune Hydrops Fetalis in Southern China

AJP Rep 2017; 07: e111-e115
DOI: 10.1055/s-0037-1603890

Objective This study aims to analyze the etiology and perinatal outcome of nonimmune hydrops fetalis (NIHF) in Southern China. Methods All cases with NIHF diagnosed antenatally from January 1, 2007 to December 31, 2014 were identified and analyzed. Results Total 482 cases of NIHF were identified during the study period. The most common cause of NIHF was hemoglobin (Hb) Bart's disease (61.8%), followed by chromosomal abnormalities (13.5%), idiopathic etiology (13.1%), cardiac abnormalities (6.4%), and others (5.2%). After 20 weeks' gestation, a total of 408 cases of NIHF presented, including Hb Bart's disease (279 cases), cardiac abnormalities (27 cases), and infection (7 cases). NIHF caused by chromosomal abnormalities mainly presented between 15 and 19 weeks' gestation. Of the 482 cases, 459 cases elected termination of pregnancy. The remaining 23 cases elected to continue their pregnancy. Among them, 14 (60.9%) resulted in intrauterine fetal death, 6 had neonatal death, 3 infants survived to 1 year of age. Of the three infants, one has cerebral palsy, and the remaining two are normal. Conclusions Hb Bart's disease is the most common cause of NIHF in Southern China. An effective prenatal screening and counseling program for thalassemia in this region may be the most effective way to lower the incidence NIHF.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text



http://ift.tt/2s42DVd

Monochorionic-Triamniotic Triplet Pregnancy Complicated by Twin Reversed Arterial Perfusion Sequence: Case Report and Literature Review

AJP Rep 2017; 07: e106-e110
DOI: 10.1055/s-0037-1603917

Background Monochorionic-triamniotic pregnancies are rare and fraught with complications. Case A case of monochorionic-triamniotic triplet pregnancy complicated by twin reversed arterial perfusion (TRAP) sequence is presented. The patient declined termination or selective fetal reduction. Triplet C was acardiac. At 24 weeks, triplet B developed polyhydramnios. At 30 weeks, polyhydramnios was seen in all three amniotic sacs, but without signs of fetal hydrops and with normal Doppler velocimetry measurements in the umbilical artery, middle cerebral artery, and ductus arteriosus of triplets A and B. At 322/7 weeks, the patient presented with preterm premature rupture of membranes and preterm labor. Two live male infants were delivered by cesarean delivery weighing 1,350 and 1,390 g, respectively; the acardiac fetus weighed 1,460 g. Pathology examination revealed a single placenta weighing1,250 g, with evidence of direct vascular connections between triplets A and C as well as between triplets A and B. Conclusion Monochorionic-triamniotic triplet pregnancy with TRAP sequence is rare. Although the risk of complications is high, such pregnancies can be managed conservatively in select cases.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text



http://ift.tt/2s4AxJm

Chemical Composition and Cytotoxic and Antibacterial Activities of the Essential Oil of Aloysia citriodora Palau Grown in Morocco

The aim of this work is to investigate the in vitro cytotoxic and antibacterial effects of the essential oils of Aloysia citriodora Palau, harvested in different regions of Morocco. The chemical profile was established using gas chromatography-mass spectrometry analysis. The cytotoxic activity against P815, MCF7, and VERO cell lines as well as the normal human peripheral blood mononuclear cells (PBMCs) was evaluated using the MTT assay. Standard, ATCC, strains of bacteria (Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa) were cultivated in Muller Hinton media. Then, agar disc diffusion, minimum inhibitory concentrations (MICs), and minimal bactericidal concentrations (MBCs) were determined using microdilution method. The essential oils obtained were predominantly composed of -spathulenol (15.61%), Ar-curcumene (14.15%), trans-caryophyllene oxide (14.14%), and neral (10.02%). The results of the assays showed that the cytotoxic effect of the essential oil of A. citriodora was high on P815 and moderate on MCF7 and on VERO cell lines. However, no cytotoxic effect was observed on PBMCs. On the other hand, essential oils showed a significant antimicrobial activity against both Gram-negative and Gram-positive bacteria. MICs ranged between 2.84 and 8.37 mg/ml. Essential oil of A. citriodora leaves possesses significant antibacterial effect and cytotoxic activity against tumor cell lines.

http://ift.tt/2seAMUb

Stanford Professor Peter Koltai to Speak at ORL Frontiers 2017

Peter J. Koltai, MD will be the guest speaker at Otorhinolaryngology Frontiers 2017, which highlights research endeavors and emerging technology... Read the full article...

http://ift.tt/2smahxi

Laryngotracheal Reconstruction: A Long-awaited Resolution for Jayda Hector

Pediatric otolaryngologist Sancak Yuksel, MD has provided care for Jayda Hector since shortly after she was born in October 2010... Read the full article...

http://ift.tt/2sVK05Q

Dr. Michael Byrd Named Chief of Surgery

Michael Byrd, MD has been elected chief of surgery at Memorial Hermann Southeast Hospital, a 274-bed facility serving families in... Read the full article...

http://ift.tt/2slXCKC

Dr. Ibrahim Alava Recognized as a Texas Super Doctors Rising Star

Ibrahim "Trey" Alava, MD, an assistant professor in the Department of Otorhinolaryngology-Head & Neck Surgery at McGovern Medical School at... Read the full article...

http://ift.tt/2sVC2cX

Computer-Aided Systematic Review Screening Comes of Age

Shekelle and colleagues describe important refinements to machine-learning software designed to reduce the need for human activity to identify relevant studies for a systematic review update. The editorialists discuss their findings and call on reviewers to evaluate these efficiency-boosting methods and reevaluate their approach to updating reviews.

http://ift.tt/2teIQSc

Variability in the Relationship of Hemoglobin A 1c and Average Glucose Concentrations: How Much Does Race Matter?

Bergenstal and colleagues report a study that contributes to our understanding of racial differences in hemoglobin A1c (HbA1c). The editorialists discuss the findings, explain why they do not suggest limited utility of HbA1c in blacks, and call for studies that enable better understanding of populations that may be prone to discordant HbA1c and glucose measures.

http://ift.tt/2sgMKwK

The Past, Present, and Future of Dual-Antiplatelet Therapy Duration in Percutaneous Coronary Intervention

In this issue, Piccolo and colleagues evaluate the dual-antiplatelet therapy (DAPT) score to assist in decision making about the duration of DAPT after implantation of cardiac stents. The editorialist discusses the history of DAPT in percutaneous coronary intervention, the findings of the current study, and strategies that could help to better individualize future decision making about DAPT duration.

http://ift.tt/2tePo3p

Machine Learning Versus Standard Techniques for Updating Searches for Systematic Reviews: A Diagnostic Accuracy Study



http://ift.tt/2shgGsJ

Hyperammonemia After Blood Transfusion: A Case Report



http://ift.tt/2teyLVi

Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention

Background:
The dual-antiplatelet therapy (DAPT) score was developed to identify patients more likely to derive harm (score Objective:

http://ift.tt/2sgVcMv

Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A 1c Levels

Background:
Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin.
Objective:
To determine whether a racial difference exists in the relationship of mean glucose and HbA1c.
Design:
Prospective, 12-week observational study.
Setting:
10 diabetes centers in the United States.
Participants:
104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%.
Measurements:
Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values.
Results:
The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons).
Limitation:
There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals.
Conclusion:
On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes.
Primary Funding Source:
Helmsley Charitable Trust.

http://ift.tt/2ter6q7

Comparison of subsequent infection in methicillin-resistant Staphylococcus aureus nasal carriers between ST72 community-genotype and hospital genotypes: a retrospective cohort study

Carriage of methicillin-resistant Staphylococcus aureus (MRSA) is an important risk factor of subsequent infection. The purpose of our study was to compare the rates of subsequent infection among newly-admitted p...

http://ift.tt/2rbPh7S

Peripheral neuropathy in a diabetic child treated with linezolid for multidrug-resistant tuberculosis: a case report and review of the literature

Extensively drug-resistant (XDR) tuberculosis (TB) and multidrug resistant (MDR)-TB with additional resistance to injectable agents or fluoroquinolones are challenging to treat due to lack of available, effect...

http://ift.tt/2s3noR2

Bacteremia due to Gordonia polyisoprenivorans: case report and review of literature

Gordonia polyisoprenivorans is a ubiquitous aerobic actinomycetes bacterium that rarely cause infections in humans. Here, we report a case of G. polyisoprenivorans catheter-related bac...

http://ift.tt/2rjHucv

Risk factors of lower limb cellulitis in a level-two healthcare facility in Cameroon: a case-control study

Cellulitis is a common infection of the skin and subcutaneous tissues. It is associated with significant morbidity from necrosectomies and amputations especially in sub-Saharan Africa. We aimed at identifying ...

http://ift.tt/2s3JVgn

In Situ Immunofluorescent Staining of Autophagy in Muscle Stem Cells

55908fig1.jpg

Active autophagy is associated with productive muscle regeneration, which is essential for Muscle Stem Cell (MuSC) activation. Here, we provide a protocol for the in situ detection of LC3, an autophagy marker in MyoD-positive MuSCs of muscle tissue sections from control and injured mice.

http://ift.tt/2sVi8yX

Colo. paramedics receive 75 donated ballistic vests

The North Colorado Medical Center's volunteer services team raised $44,000 for the vests

http://ift.tt/2sg7Xa7

Dallas 911 system remains a gamble for callers

The 911 center is so severely understaffed that the city has spent more than $400,000 in overtime in recent months just to get the phones answered

http://ift.tt/2tdXnO0

One More Controversy: Adeno-Associated Virus in Stem Cells

Human Gene Therapy Jun 2017, Vol. 28, No. 6: 449-449.


http://ift.tt/2su3iBY

Adeno-Associated Virus Vectors and Stem Cells: Friends or Foes?

Human Gene Therapy Jun 2017, Vol. 28, No. 6: 450-463.


http://ift.tt/2rb0KER

Rod Outer Segment Development Influences AAV-Mediated Photoreceptor Transduction After Subretinal Injection

Human Gene Therapy Jun 2017, Vol. 28, No. 6: 464-481.


http://ift.tt/2suxNI7

Video Tracking Protocol to Screen Deterrent Chemistries for Honey Bees

55603fig1.jpg

The loss of honey bee colonies presents a challenge to crop pollination services. Current pollinator protection practices warrant an alternative approach to minimize the contact of honey bees to harmful pesticides using repellent chemistries. Here, we provide detailed methods for a visual tracking protocol to screen deterrents for bees.

http://ift.tt/2te0RQI

Practical Tips for Working as an Expedition Doctor on High-Altitude Expeditions

High Altitude Medicine & Biology , Vol. 0, No. 0.


http://ift.tt/2sUiiX0

The somatic mutation landscape of premalignant colorectal adenoma

Objective

There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma.

Design

Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC.

Results

Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941.

Conclusion

The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.



http://ift.tt/2sl2box

Rapid Deletion Production in Fungi via Agrobacterium Mediated Transformation of OSCAR Deletion Constructs

55239fig1.jpg

Gene deletion mutants generated through homologous recombination are the gold standard for gene function studies. The OSCAR (One Step Construction of Agrobacterium-Recombination-ready-plasmids) method for rapid generation of deletion constructs is described. Agrobacterium mediated fungal transformation follows. Finally, a PCR based confirmation method of gene deletions in fungal transformants is presented.

http://ift.tt/2sfMjCT

Assessing Working Memory in Children: The Comprehensive Assessment Battery for Children – Working Memory (CABC-WM)

55121fig1.jpg

Working memory predicts a significant amount of variance for a variety of cognitive tasks, including speaking, reading, and writing. However, few tools are available to assess working memory in children. We present an innovative, computer-based battery that comprehensively assesses different components of working memory in school-age children.

http://ift.tt/2sfR2EH

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 106, 12.5 × 106 and 25 × 106 cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.



http://ift.tt/2su9QjW

Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC

Abstract

Background

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.

Methods

We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.

Results

Seventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.

Conclusions

ALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study.



http://ift.tt/2sl5zzP

Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

Abstract

Background

Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.

Methods

R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.

Results

Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.

Conclusions

Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.



http://ift.tt/2riP9YG

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 106, 12.5 × 106 and 25 × 106 cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.



http://ift.tt/2su9QjW

Erratum to: Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: a useful contributor to cutaneous disease control



http://ift.tt/2rb71Av

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

Abstract

Background

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.

Methods

The levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.

Results

We found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.

Conclusions

Underexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.



http://ift.tt/2tdwkm9

Teen cardiac arrest survivor raising money for AEDs

Caleb Perkins, 18, is working with his family to raise awareness about CPR and AEDs

http://ift.tt/2s3fF5h

Calcium binding protein 39 promotes hepatocellular carcinoma growth and metastasis by activating ERK signaling pathway

Abstract

Calcium binding protein (CAB39) is a key regulator of a group of STE20 kinases. Here we report that CAB39 was frequently up-regulated in hepatocellular carcinoma (HCC), which was significantly associated with tumor metastasis (P=0.000), poorer disease-free survival rate (P=0.027) and poor prognosis (P=0.000). Ectopic expression of CAB39 in immortalized human liver cell line LO2 and HCC cell lines QGY-7703 and BEL-7402 could increase foci formation, colony formation in soft agar, tumor formation in nude mice and cell motility. Silencing CAB39 expression in two HCC cell lines Huh7 and MHCC97H with short hairpin RNA could effectively abolish its oncogenic function. Further study found that CAB39 contributed to the ERK pathway activation and mutations of the key sites of CAB39 markedly decrease the level of the phosphorylated ERK. In addition, CAB39 could promote epithelial-mesenchymal transition (EMT) by up-regulating N-cadherin and Fibronectin, and down-regulating E-cadherin and α-E-catenin. As a result, β-catenin nuclear translocation was increased and its downstream target gene MMP-9 was up-regulated. Taken together, our findings suggested that CAB39 play very important oncogenic roles in HCC pathogenesis and progression by activating ERK signaling pathway. Better understanding of CAB39 may lead to its clinical application as a biomarker for prognosis predictor and a novel therapeutic target. This article is protected by copyright. All rights reserved.



http://ift.tt/2riRjrd

Acute Hepatic Porphyrias: Recommendations for Evaluation and Long Term Management

ABSTRACT

The acute hepatic porphyrias (AHPs) are a group of four inherited disorders, each resulting from the deficient activity of a specific enzyme in the heme biosynthetic pathway. They present clinically with acute neurovisceral symptoms which may be sporadic or recurrent, and which, when severe, can be life-threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic or recurrent acute attacks, asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow-up and long-term management are needed, particularly since no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the NIH's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific AHP, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long term complications. These guidelines provide a framework for monitoring patients with AHPs to ensure optimal outcomes. This article is protected by copyright. All rights reserved.



http://ift.tt/2s36bqN

The challenge of cholangiocarcinoma diagnosis: the turning point is in extracellular vesicles?



http://ift.tt/2s3jEPv

Modelling the benefits and harms of surveillance for hepatocellular carcinoma: information to support informed choices

Abstract

Surveillance by ultrasonography for hepatocellular carcinoma (HCC) for individuals with cirrhosis is recommended. There is debate regarding the effectiveness of surveillance in reducing mortality and there is little information on the harms available to patients considering surveillance. The aim of this study was to provide estimates of both the benefit and harms of surveillance. A Markov model was built to simulate outcomes of individuals entering surveillance. Following identification of a focal lesion by ultrasound surveillance further investigations were defined by the EASL-EORTC recall policy. Benefit and harm outcomes are expressed per 1000 patients over 5 years. For every 1000 patients in surveillance over 5 years there are 13 fewer deaths (95% confidence interval 12-14) compared with no surveillance, equating to a number needed to screen to prevent one death from HCC of 77. In comparison, many more individuals experienced harm through surveillance. For every 1000 patients, 150 (95% confidence interval 146-154) had one or more false positive tests equating to a number needed to harm from surveillance of 7. As a consequence of a false positive test, 65 individuals required at least one additional unnecessary CT scan or MRI and 39 required an unnecessary liver biopsy according to the recall policy. Surveillance benefits were sensitive to the incidence of HCC and the mortality benefit achieved by treatment. Harms were sensitive to the rates of false positive testing and the frequency of liver biopsy. Conclusion. There is a balance between the small absolute mortality benefit to surveillance for HCC and the numerically more frequent harms resulting from false positive testing. Implementation of the recently revised AASLD recommendations is predicted to reduce harms from unnecessary liver biopsy. This article is protected by copyright. All rights reserved.



http://ift.tt/2rjbtRI

Ablative Therapies in Metastatic Breast Cancer: A Systematic Review

Abstract

Purpose

Patients with oligometastatic breast cancer are being increasingly offered ablative therapies, yet it is unclear which subpopulations may derive long-term benefit. This study sought to explore factors that could define a clinically relevant oligometastatic breast cancer population that benefits from ablative therapies.

Methods

A systematic review using MEDLINE for English language articles published between 1985 and April 2014 was undertaken. Criteria for review included studies that reported overall survival (OS) or progression-free survival (PFS) in breast cancer patients with distant metastases which also: quantified the extent of disease, had metachronous presentation of metastases, and reported on at least 5 patients.

Results

Of 59 674 screened studies, 41 studies of 1813 individual patients were identified. All studies were observational cohort studies (level 2B or 4 evidence) and underwent critical review. All outcomes pertaining to OS and PFS were extracted. Extracted data were too heterogeneous to facilitate a meta-analysis. The only factor that suggested worse outcomes was positive margins post-metastasectomy. There was no clear signal for improved outcomes in regards to age, disease extent, disease-free interval, or receptor status.

Conclusion

Existing evidence does not provide meaningful direction on which metastatic breast cancer patients should have ablation of their residual disease due to heterogeneous reporting of disease factors, patient factors, and outcomes. Thorough demonstration of the absence of high- or moderate-level evidence and the absence of clinical data to guide patient selection suggests that metastatic breast cancer patients being treated with ablative modalities should be placed on clinical trial.



http://ift.tt/2s2Xpca

Immediate tissue expander or implant-based breast reconstruction does not compromise the oncologic delivery of post-mastectomy radiotherapy (PMRT)

Abstract

Purpose

Increasingly, women are choosing immediate breast reconstruction (IBR) following mastectomy. Reports have indicated IBR may compromise post-mastectomy radiotherapy (PMRT). We investigated the impact of IBR on timing of PMRT, target coverage, and doses to organs at risk in a modern radiotherapy practice using advanced planning techniques.

Methods

Between 2013 and 2015, PMRT was delivered to 116 patients (66 mastectomy alone, 50 IBR). PMRT was delivered with a median dose of 50 Gy in 25 fractions. Left-sided patients were treated in breath-hold under image guidance. Differences in dosimetric parameters and time to the initiation of PMRT were assessed between patients with and without reconstruction.

Results

Reconstructed patients were younger and had lower clinical stage disease. Reconstruction did not significantly increase the mean time to PMRT initiation (51 days reconstructed vs. 45 days non-reconstructed, p = 0.14) or the number of patients who initiated PMRT within 12 weeks of the last therapeutic intervention (48/50 [96.0] vs. 61/66 [92.4%], p = 0.41). There was no significant difference in the percentage of patients in whom the internal mammary lymph nodes (IMNs) were targeted (72 vs. 80%, p = 0.29) or in IMN target coverage (mean IMN V40.5 Gy 92.6 vs. 94.1%, p = 0.62). Reconstruction did not significantly affect the mean ipsilateral lung V20 (25.4 vs. 26.4%, p = 0.37) or the mean heart dose (2.2 vs. 2.1 Gy, p = 0.63).

Conclusions

In a specialized breast multidisciplinary practice, immediate breast reconstruction did not significantly delay PMRT, compromise target coverage, or increase dose to organs at risk.



http://ift.tt/2rj2X5e

Squamous cell carcinoma of the breast in the United States: incidence, demographics, tumor characteristics, and survival

Abstract

Purpose

Squamous cell carcinoma of breast accounts for less than 0.1% of all breast cancers. The purpose of this study is to describe the epidemiology and survival of this rare malignancy.

Methods

Data were extracted from the National Cancer Institute's Surveillance, Epidemiology and End Results Registry to identify women diagnosed with squamous cell carcinoma of breast between 1998 and 2013. SEER*Stat 8.3.1 was used to calculate age-adjusted incidence, age-wise distribution, and annual percentage change in incidence. Kaplan–Meier curves were plotted for survival analysis. Univariate and multivariate Cox proportional hazard regression model was used to determine predictors of survival.

Results

A total of 445 cases of squamous cell carcinoma of breast were diagnosed during the study period. The median age of diagnosis was 67 years. The overall age-adjusted incidence between 1998 and 2013 was 0.62 per 1,000,000 per year, and the incidence has been on a decline. Approximately half of the tumors were poorly differentiated. Stage II was the most common stage at presentation. Majority of the cases were negative for expression of estrogen and progesterone receptor. One-third of the cases underwent breast conservation surgery while more than half of the cases underwent mastectomy (unilateral or bilateral). Approximately one-third of cases received radiation treatment. The 1-year and 5-year cause-specific survival was 81.6 and 63.5%, respectively. Excluding patient with metastasis or unknown stage at presentation, in multivariate Cox proportional hazard model, older age at diagnosis and higher tumor stage (T3 or T4) or nodal stage at presentation were significant predictors of poor survival.

Conclusions

Our study describes the unique characteristics of squamous cell carcinoma of breast and demonstrates that it is an aggressive tumor with a poor survival. Older age and higher tumor or nodal stages at presentation were independent predictors of poor survival for loco-regional stages.



http://ift.tt/2s2OibK

Sleep quality, duration, and breast cancer aggressiveness

Abstract

Purpose

Epidemiological studies suggest that short sleep duration and poor sleep quality may increase breast cancer risk. However, whether sleep is associated with breast tumor aggressiveness characteristics has largely been unexplored.

Methods

The study included 4171 non-Hispanic whites (NHW) and 235 African Americans (AA) diagnosed with incident, primary, invasive breast cancer in the Women's Health Initiative (WHI) Observational Study (1994–2013). We used logistic regression to examine the association of baseline sleep (sleep duration, sleep quality, WHI Insomnia Rating Scale) with tumor grade, stage, hormone receptor status, HER2 status.

Results

In NHW, women who reported 6 h of sleep/night were more likely to have tumors classified as regional/distant stage at diagnosis compared to women who slept 7–8 h/night (adjusted odds ratio (OR): 1.25, 95% confidence interval (CI): 1.05–1.48). AA women who reported their typical night's sleep as 'average quality' or 'restless or very restless sleep' were more likely to be diagnosed with triple-negative tumors than those who reported 'sound or restful' sleep (adjusted ORs: 2.91 (1.11, 7.63) and 3.74 (1.10, 12.77), respectively).

Conclusions

Our findings provide indications that aspects of sleep (sleep duration and quality), partially modifiable health behaviors, may be associated with development of aggressive tumor characteristics in postmenopausal women. The role of these sleep attributes may differ for NHW and AA women; however, further study in robust, racial diverse samples is needed. This study provides evidence that facets of sleep behavior are associated with the development of aggressive tumor features and these associations differ by race.



http://ift.tt/2riPr1F