Corrigendum to “Simulating Radiotherapy Effect in High-Grade Glioma by Using Diffusive Modeling and Brain Atlases”

http://ift.tt/2GPQSbc

High-Density Stretchable Electrode Grids for Chronic Neural Recording

Abstract

Electrical interfacing with neural tissue is key to advancing diagnosis and therapies for neurological disorders, as well as providing detailed information about neural signals. A challenge for creating long-term stable interfaces between electronics and neural tissue is the huge mechanical mismatch between the systems. So far, materials and fabrication processes have restricted the development of soft electrode grids able to combine high performance, long-term stability, and high electrode density, aspects all essential for neural interfacing. Here, this challenge is addressed by developing a soft, high-density, stretchable electrode grid based on an inert, high-performance composite material comprising gold-coated titanium dioxide nanowires embedded in a silicone matrix. The developed grid can resolve high spatiotemporal neural signals from the surface of the cortex in freely moving rats with stable neural recording quality and preserved electrode signal coherence during 3 months of implantation. Due to its flexible and stretchable nature, it is possible to minimize the size of the craniotomy required for placement, further reducing the level of invasiveness. The material and device technology presented herein have potential for a wide range of emerging biomedical applications.

An inert, soft, and stretchable composite based on gold-coated titanium dioxide nanowires is developed for biomedical applications. It shows outstanding conductivity, electromechanical properties, and long-term stability. High-density stretchable electrode grids based on the material can resolve high spatiotemporal neural signals from the surface of the cortex in freely moving rats with stable recording quality during 3 months of implantation.

http://ift.tt/2sZo7qv

Alcohol and injury among attendees at a busy inner city New Zealand emergency department

Publication date: Available online 27 February 2018
Source:Injury
Author(s): Bridget Kool, Sarah Buller, Ron Kuriyan, Charlotte M Jones-Todd, David Newcombe, Peter Jones
IntroductionWe present a study that provides a contemporary view of alcohol-related injury prevalence amongst patients presenting to a New Zealand (NZ) emergency department (ED).MethodsAdult injury patients presenting to Auckland City Hospital ED within 6 h of injury were invited to participate during three recruitment periods (2015–2016). An interviewer-administered questionnaire obtained information on demographic, injury, general health, and lifestyle factors. Breath alcohol samples were obtained. Descriptive and logistic regression analyses were conducted.Results501 patients participated (71% response rate), 21% had consumed alcohol within 6 h of their injury. The majority were male, and overall falls were the most common mechanism of injury among all patients. Alcohol-related injuries most commonly occurred at home, and were significantly more likely to occur during the weekend (Friday-Sunday) and night hours (23:00 − 06:59). After controlling for the effects of confounding; 'poor' general health, engaging in leisure activities at the time of injury, and injuries resulting from assaults were associated with increasing the odds of alcohol-related injury.ConclusionsAcute alcohol use continues to play a considerable role in ED injury presentations in NZ. Continued policy, health promotion, and injury prevention efforts are required to reduce the harms associated with alcohol use.



http://ift.tt/2owKSNE

The risk of cardiovascular disease following breast cancer by Framingham risk score

Abstract

Objectives

This study evaluates the risk of cardiovascular disease (CVD) following breast cancer, accounting for baseline CVD risk.

Methods

Within the EPIC-NL (Dutch part of the European Prospective Investigation into Nutrition and Cancer) cohort, 1103 women were diagnosed with breast cancer. For every breast cancer patient, 3–4 women without breast cancer (n = 4328) were selected matched for age, year, and time since cohort enrollment. Based on CVD risk factors at cohort enrollment, 10-year risk of CVD was calculated and categorized: low (< 10%), intermediate (10–20%), high (> 20%). Cox proportional hazard models assessed the risk of CVD events (hospitalization or mortality) and CVD mortality of women with versus without breast cancer, adjusted for baseline CVD risk.

Results

After median follow-up of 5 and 6 years, 92 (8.3%) and 325 (7.5%) CVD events occurred in women with and without breast cancer, respectively. In the low CVD risk group, women with breast cancer had 1.44 (95% CI 1.00–2.06) times higher risk of CVD events than women without breast cancer. In the intermediate and high CVD risk categories, risk of CVD events was similar in women with and without breast cancer. Overall, women with breast cancer had 1.77 (95% CI 1.10–2.86) times higher risk of CVD mortality than women without breast cancer.

Conclusions

Among women with low CVD risk, women with breast cancer have a higher risk of CVD event than women without breast cancer. Overall, women with breast cancer have a higher risk of CVD mortality than women without breast cancer.

http://ift.tt/2EZnSxa

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors, Published online: 27 February 2018; doi:10.1038/s41419-018-0340-4

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

http://ift.tt/2FDEWtB

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression, Published online: 27 February 2018; doi:10.1038/s41419-018-0347-x

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

http://ift.tt/2t1zpuf

AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-β pathway

AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-β pathway

AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-β pathway, Published online: 27 February 2018; doi:10.1038/s41419-018-0338-y

AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-β pathway

http://ift.tt/2FC3HGH

Benzodiazepine and Z-drug prescribing in Ireland: analysis of national prescribing trends from 2005-2015

Abstract

Aims

To examine prescribing trends for benzodiazepines and Z-drugs to General Medical Services (GMS) patients in Ireland.

Methods

A repeated cross-sectional analysis of the national pharmacy claims database was conducted for GMS patients aged ≥16 years from 2005-2015. Prescribing rates per 1000 eligible GMS population were calculated with 95% confidence intervals (CIs). Negative binomial regression was used to determine longitudinal trends and compare prescribing rates across years, gender and age groups. Duration of supply and rates of concomitant benzodiazepine and Z-drug prescribing were determined. Age (16-44, 45-64, ≥65 years) and gender trends were investigated.

Results

Benzodiazepine prescribing rates significantly decreased from 225.92/1000 population (95% CI 224.94-226.89) in 2005 to 166.07/1000 population (95% CI 165.38-166.75) in 2015 (p<0.0001). Z-drug prescribing rates significantly increased from 95.36/1000 population (95% CI 94.73-96.00) in 2005 to 109.11/1000 population (95% CI 108.56-109.67) in 2015 (p=0.048). Approximately one third of individuals were receiving long-term prescriptions (>90 days) for either benzodiazepines or Z-drugs. The proportion of those receiving >1 benzodiazepine and/or Z-drug concomitantly increased from 11.9% in 2005 to 15.3% in 2015. Benzodiazepine and Z-drug prescribing rates were highest for older women (≥65 years) throughout the study period.

Conclusions

Benzodiazepine prescribing to the GMS population in Ireland significantly decreased from 2005 to 2015, and was coupled with significant increases in Z-drug prescribing. The study shows that benzodiazepine and Z-drug prescribing is common in this population, with a third receiving long-term prescriptions. Targeted interventions are needed to reduce potentially inappropriate long-term prescribing and use of these medications in Ireland.

http://ift.tt/2t5Wv2Y

Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2EZvIXt

First reported case in Australia: a rare case of lymphangioma of the gallbladder

http://ift.tt/2COlWFG

Corrigendum

http://ift.tt/2F7fW09

Autoimmune postural orthostatic tachycardia syndrome

Abstract

The aim of this study was to evaluate the association between postural orthostatic tachycardia syndrome (POTS) and circulating antiganglionic acetylcholine receptor (gAChR) antibodies. We reviewed clinical assessments of Japanese patients with POTS, and determined the presence of gAChR antibodies in serum samples from those patients. Luciferase immunoprecipitation systems detected anti-gAChRα3 and β4 antibodies in the sera from POTS (29%). Antecedent infections were frequently reported in patients in POTS patients. Moreover, autoimmune markers and comorbid autoimmune diseases were also frequent in seropositive POTS patients. Anti-gAChR antibodies were detectable in significant number of patients with POTS, and POTS entailed the element of autoimmune basis.

http://ift.tt/2F30jUg

Enhancing the fatty acid profile of milk through forage-based rations, with nutrition modeling of diet outcomes

Abstract

Consumer demand for milk and meat from grass-fed cattle is growing, driven mostly by perceived health benefits and concerns about animal welfare. In a U. S.-wide study of 1,163 milk samples collected over 3 years, we quantified the fatty acid profile in milk from cows fed a nearly 100% forage-based diet (grassmilk) and compared it to profiles from a similar nationwide study of milk from cows under conventional and organic management. We also explored how much the observed differences might help reverse the large changes in fatty acid intakes that have occurred in the United States over the last century. Key features of the fatty acid profile of milk fat include its omega-6/omega-3 ratio (lower is desirable), and amounts of total omega-3, conjugated linoleic acid, and long-chain omega-3 polyunsaturated fatty acids. For each, we find that grassmilk is markedly different than both organic and conventional milk. The omega-6/omega-3 ratios were, respectively, 0.95, 2.28, and 5.77 in grassmilk, organic, and conventional milk; total omega-3 levels were 0.049, 0.032, and 0.020 g/100 g milk; total conjugated linoleic acid levels were 0.043, 0.023, and 0.019 g/100 g milk; and eicosapentaenoic acid levels were 0.0036, 0.0033, and 0.0025 g/100 g milk. Because of often high per-capita dairy consumption relative to most other sources of omega-3 fatty acids and conjugated linoleic acid, these differences in grassmilk can help restore a historical balance of fatty acids and potentially reduce the risk of cardiovascular and other metabolic diseases. Although oily fish have superior concentrations of long-chain omega-3 fatty acids, most fish have low levels of α-linolenic acid (the major omega-3), and an omega-6/omega-3 ratio near 7. Moreover, fish is not consumed regularly, or at all, by ~70% of the U. S. population.

From a 3-year, U.S.-wide study, we report the fatty acid profile from 1,163 samples of milk from nearly 100% forage-fed cows (grass milk) and compare it to profiles from a similar study of conventional and organic milk. We find increases in omega-3 fatty acids and conjugated linoleic acid and a decrease in omega-6 fatty acids. In model human diets, these changes are sufficient to substantially reduce historically high omega-6/omega-3 ratios in modern diets.

http://ift.tt/2HNB9L3

Associations of Metabolic syndrome and C-reactive protein with Mortality from total cancer, obesity-linked cancers and Breast Cancer among Women in NHANES III

Abstract

Although metabolic syndrome (MetS) is a prognostic factor for cancer occurrence, the association of MetS and cancer mortality remains unclear. The purpose of this study was to evaluate whether MetS, components of MetS and C-reactive protein (CRP) are associated with cancer mortality in women.

A total of 400 cancer deaths, with 140 deaths from obesity-linked-cancers (OLCas), [breast (BCa), colorectal, pancreatic and endometrial], linked through the National Death Index, were identified from 10,104 eligible subjects aged ≥18 years. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) for cancer mortality.

MetS was associated with increased deaths for total-cancer [HR=1.33, 95% confidence interval (CI) 1.04-1.70] and BCa [HR=2.1, 95% CI, 1.09-4.11]. The risk of total-cancer [HR=1.7, 95% CI, 1.12-2.68], OLCas [HR=2.1, 95% CI, 1.00-4.37] and BCa [HR=3.8, 95% CI, 1.34-10.91] mortality was highest for women with all MetS components abnormal, compared to those without MetS. Linear associations of blood-pressure [HR=2.5, 1.02-6.12, Quartile (Q) 4 vs Q1, p-trend=0.004] and blood-glucose [HR=2.2, 1.04-4.60, Q4 vs Q1, p-trend=0.04] with total-OLCas mortality were observed. A three-fold increased risk of BCa mortality was observed for women with enlarged waist circumference, ≥100.9cm, [HR=3.5, 1.14-10.51, p-trend=0.008] and in those with increased blood glucose, ≥101mg/dL, [HR=3.2, 1.11-9.20, p-trend=0.03] compared to those in Q1. None of the components of MetS were associated with total-cancer mortality. CRP was not associated with cancer mortality.

In conclusion, MetS is associated with total-cancer and breast-cancer mortality, with waist circumference, blood pressure and blood glucose as independent predictors of OLCas and BCa mortality. This article is protected by copyright. All rights reserved.

http://ift.tt/2ovwpBD

Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women

Abstract

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes, and homeostasis model-insulin resistance (HOMA-IR – a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0, and ≥30.0 kg/m²) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. This article is protected by copyright. All rights reserved.

http://ift.tt/2oBIV1J

Pharmacological Inhibition of the Notch Pathway Enhances the Efficacy of Androgen Deprivation Therapy for Prostate Cancer

Abstract

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In this study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch Pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. This article is protected by copyright. All rights reserved.

http://ift.tt/2Co63KB

Quantification of the duodenal eosinophil content in adults: a necessary step for an evidence-based diagnosis of duodenal eosinophilia

Summary

Background

The normal content of eosinophils in the adult duodenum remains undefined. Therefore, there is no foundation for evidence-based criteria to diagnose eosinophilic duodenitis.

Aim

This study aimed at: (1) establishing the range of the eosinophil density in the mucosa of the duodenum of normal adults, and (2) determining the biopsy-based prevalence of isolated eosinophilic duodenitis in a large population of adults.

Methods

We counted intact eosinophils in three separate high-power fields (hpf area = 0.237 mm² each) with the highest densities of eosinophils from the duodenal biopsy specimens of 370 consecutive adults (60% women) with no history of small intestinal disease and a normal duodenal histology. From a large database we also extracted patients with a diagnosis of elevated duodenal eosinophilia and reviewed their biopsies and clinical history.

Results

The mean eosinophil count for the 370 patients was 8.2 eos/hpf with a standard deviation of ± 6.3. Twenty-seven of the 370 had eosinophil counts outside the 95% range, which was calculated as: mean + 1.96 × SD = 20.4 eos/hpf. In a database of 458 668 adult subjects, 31 patients (6.8/100 000) had elevated duodenal eosinophilia; 21 of these had other gastrointestinal organs involved by eosinophilia, suggesting eosinophilic gastroenteritis. No significant association between duodenal eosinophilia and any specific symptom was observed.

Conclusions

This study suggests that in this diverse US population, a cut-off count of 20 eos/hpf would be useful to separate patients with normal from those with elevated duodenal eosinophilic infiltrations. The clinical implications of duodenal eosinophilia, particularly when it is not an expression of eosinophilic gastroenteritis, remain to be established.

http://ift.tt/2BURDQV

Cost-utility analysis of cervical deformity surgeries using one-year outcome

Publication date: Available online 27 February 2018
Source:The Spine Journal
Author(s): Gregory W. Poorman, Peter G. Passias, Rabia Qureshi, Hamid Hassanzadeh, Samantha Horn, Cole Bortz, Frank Segreto, Amit Jain, Michael Kelly, Richard Hostin, Christopher Ames, Justin Smith, Virginie LaFage, Douglas Burton, Shay Bess, Chris Shaffrey, Frank Schwab, Munish Gupta
ObjectCost-utility analysis, a special case of cost-effectiveness analysis, estimates the ratio between the cost of an intervention to the benefit it produces in number of quality-adjusted life years. Cervical deformity correction has not been evaluated in terms of cost-utility and in the context of value-based health care. Our objective, therefore, was to determine the cost-utility ratio of cervical deformity correction.MethodsRetrospective review of a prospective, multicenter cervical deformity database. Patients with 1-year follow-up after surgical correction for cervical deformity were included. Cervical deformity was defined as the presence of at least one of the following: kyphosis (C2-7 Cobb angle >10°), cervical scoliosis (coronal Cobb angle >10°), positive cervical sagittal malalignment (C2-C7 sagittal vertical axis >4cm or T1-C6 >10 ^o), or horizontal gaze impairment (chin-brow vertical angle >25^o). Quality adjusted life years were calculated by both EuroQol 5D (EQ5D) quality of life and NDI mapped to SF6D index. Costs were assigned using Medicare 1-year average reimbursement for: 9+ level posterior fusions (PF), 4-8 level PF, 4-8 level PF with anterior fusion (AF), 2-3 level PF with AF, 4-8 level AF, and 4-8 level posterior refusion. Reoperations and deaths were added to cost and subtracted from utility respectively. QALY per dollar spent was calculated using standardized methodology at 1-year time point and subsequent time-points relying on maintenance of 1-year utility.Results84 patients (average age: 61.2 years, 60% female, BMI: 30.1) were analyzed after cervical deformity correction (average levels fused: 7.2, osteotomy used: 50%. Costs associated with index procedures were: 9+ level PF ($76,617), 4-8 level PF ($40,596), 4-8 level PF with AF ($67,098), 4-8 level AF ($31,392) and 4-8 level posterior refusion ($35,371). Average 1-year reimbursement of surgery was $55,097 at 1-year with 8 revisions and 3 deaths accounted for. Cost per QALY gained to 1-year follow-up was $646,958 by eq5d and $477,316 by NDI SF6D. If 1-year benefit is sustained, upper threshold of cost-effectiveness is reached 3-4.5 years after intervention.ConclusionsMedicare 1-year average reimbursement compared to 1-year quality adjusted life year described $646,958 by eq5d and $477,316 by NDI SF6D. Cervical deformity surgeries reach accepted costeffectiveness thresholds when benefit is sustained 3-4.5 years. Longer follow-up is needed for a more definitive cost-analysis, but this data is an important first step in justifying cost-utility ratio for cervical deformity correction.



http://ift.tt/2CNGm1s

Balanced Crystalloids versus Saline in Critically Ill Adults

Intravenous crystalloid solutions are commonly administered in critical care, yet the question of whether crystalloid composition affects patient outcomes remains unanswered. Historically, 0.9% sodium chloride (saline) has been the most commonly administered intravenous fluid. Data suggest that…

http://ift.tt/2CM1UM4

Patient-Centered Outcomes and Resuscitation Fluids

During the past 50 years, the use of intravenous resuscitation fluids in critically ill patients has been based on physiological principles rather than on evidence from clinical trials. None of the current proprietary resuscitation fluids have been formally evaluated for safety and efficacy, and…

http://ift.tt/2CLusp2

Balanced Crystalloids versus Saline in Noncritically Ill Adults

Administration of intravenous isotonic crystalloids is one of the most common medical therapies, with routine use in emergency departments, hospital wards, intensive care units (ICUs), and operating rooms. However, it is not known whether the composition of isotonic crystalloid fluid has an effect…

http://ift.tt/2Fa8X6w

Efficacy and safety of the trastuzumab biosimilar candidate CT-P6

Future Oncology, Ahead of Print.


http://ift.tt/2F3F7gN

Nicotine extracted from ancient dental plaque for the first time

A team of scientists has shown for the first time that nicotine residue can be extracted from dental plaque on the teeth of ancient tobacco users. Their research provides a new method for determining who was consuming tobacco in the ancient world and could help trace the use of tobacco and other intoxicating plants further back into prehistory.

http://ift.tt/2CqxqDC

EFFECT OF KCNQ1 G229D MUTATION ON CARDIAC PUMPING EFFICACY AND REENTRANT DYNAMICS IN VENTRICLES: COMPUTATIONAL STUDY

Abstract

There is growing interest in genetic arrhythmia since mutations in gene which encodes the ion channel underlie numerous arrhythmias. Hasegawa et al. reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential (AP) duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared to the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behavior (not considered in previous studies). We compared AP shapes under wild-type and mutant conditions, after applying the Hasegawa et al. modified I_Ks equation to the O'Hara et al. [1] ventricular cell models. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. I_Ks enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intra-ventricular pressure, and increase in end-systolic volume 17%, end-diastolic volume 7%, and end-diastolic pressure 11%, which further resulted in reduction in stroke volume as well as cardiac output (28%), ejection fraction 33% stroke work 44%, and ATP consumption 28%. In short, using computational model of the ventricle, we predicted that G229D mutation decreased cardiac pumping efficacy and increased the vulnerability of ventricular fibrillation.

http://ift.tt/2CMW25r

A quasi-3D compartmental multi-scale approach to detect and quantify diseased regional lung constriction using spirometry data.

Abstract

Spirometry is a widely used pulmonary function test to detect the airflow limitations associated with various obstructive lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and even obesity-related complications. These conditions arise due to the change in the airway resistance, alveolar compliance, and inductance values. Currently, zero-dimensional (0D) compartmental models are commonly used for calibrating these resistance, compliance, and inductance values, i.e., solving the inverse spirometry problem. However, 0D compartments cannot capture the flow physics or the spatial geometry effects, thereby generating a low fidelity prediction of the diseased lung. Computational fluid dynamics (CFD) models offer higher fidelity solutions but may be impractical for certain applications due to the duration of these simulations. Recently, a novel, fast-running and robust Quasi-3D (Q3D) wire model for simulating the airflow in the human lung airway was developed by CFD Research Corporation (CFDRC). This Q3D method preserved the 3D spatial nature of the airways and was favorably validated against CFD solutions. In the present study, the Q3D compartmental multi-scale combination is further improved to predict regional lung constriction of diseased lungs using spirometry data. The Q3D mesh is resolved up to the eighth lung airway generation. The remainder of the airways and the alveoli sections are modeled using a compartmental approach. The Q3D geometry is then split into different spatial sections and the resistance values in these regions are obtained using parameter inversion. Finally, the airway diameter values are then reduced to create the actual diseased lung model, corresponding to these resistance values. This diseased lung model can be used for patient-specific drug deposition predictions and the subsequent optimization of the orally inhaled drug products.

http://ift.tt/2CMIYNp

A Genetic Screen Identifies PRP18a, a Putative Second Step Splicing Factor Important for Alternative Splicing and a Normal Phenotype in Arabidopsis thaliana

Splicing of pre-mRNA involves two consecutive trans-esterification steps that take place in the spliceosome, a large dynamic ribonucleoprotein complex situated in the nucleus. In addition to core spliceosomal proteins, each catalytic step requires step-specific factors. Although the Arabidopsis thaliana genome encodes around 430 predicted splicing factors, functional information about these proteins is limited. In a forward genetic screen based on an alternatively-spliced GFP reporter gene in Arabidopsis thaliana, we identified a mutant impaired in putative step II factor PRP18a, which has not yet been investigated for its role in pre-mRNA splicing in plants. Step II entails cleavage at the 3' splice site accompanied by ligation of the 5' and 3' exons and intron removal. In the prp18 mutant, splicing of a U2-type intron with non-canonical AT-AC splice sites in GFP pre-mRNA is reduced while splicing of a canonical GT-AG intron is enhanced, resulting in decreased levels of translatable GFP mRNA and GFP protein. These findings suggest that wild-type PRP18a may in some cases promote splicing at weak, non-canonical splice sites. Analysis of genome-wide changes in alternative splicing in the prp18a mutant identified numerous cases of intron retention and a preponderance of altered 3' splice sites, suggesting an influence of PRP18a on 3' splice selection. The prp18a mutant featured short roots on synthetic medium and small siliques, illustrating that wild-type PRP18a function is needed for a normal phenotype. Our study expands knowledge of plant splicing factors and provides foundational information and resources for further functional studies of PRP18 proteins in plants.

http://ift.tt/2F86eum

Transcriptome Analysis of Litsea cubeba Floral Buds Reveals the Role of Hormones and Transcription Factors in the Differentiation Process

Background: Litsea cubeba (Lour.) Pers. is an important economic plant that is rich in valuable essential oil. The essential oil is often used as a raw material for perfumes, food additives, insecticides and bacteriostats. Most of the essential oil is contained in the fruit, and the quantity and quality of fruit are dependent on the flowers. To explore the molecular mechanism of floral bud differentiation, high-throughput RNA sequencing was used to detect differences in the gene expression of L. cubeba female and male floral buds at three differentiation stages. Results: This study obtained 160.88 Gbp of clean data that were assembled into 100,072 unigenes, and a total of 38,658 unigenes were annotated. A total of 27,521 simple sequence repeats (SSRs) were identified after scanning the assembled transcriptome, and the mono-nucleotide repeats were predominant, followed by di-nucleotide and tri-nucleotide repeats. A total of 12,559 differentially expressed genes (DEGs) were detected from the female (F) and male (M) floral bud comparisons. The gene ontology (GO) databases revealed that these DEGs were primarily contained in "metabolic processes", "cellular processes", and "single-organism processes". The Kyoto Encyclopedia of Genes and Genomes (KEGG) databases suggested that the DEGs belonged to "plant hormone signal transduction" and accounted for a relatively large portion in all of these comparisons. We analyzed the expression level of plant hormone-related genes and detected the contents of several relevant plant hormones in different stages. The results revealed that the dynamic changes in each hormone content were almost consistent with the expression levels of relevant genes. The transcription factors selected from the DEGs were analyzed. Most DEGs of MADS-box were upregulated and most DEGs of bZIP were downregulated. The expression trends of the DEGs were nearly identical in female and male floral buds, and qRT-PCR analysis revealed consistency with the transcriptome data. Conclusions: We sequenced and assembled a high-quality L. cubeba floral bud transcriptome, and the data appeared to be well replicated (n=3) over three developmental time points during flower development. Our study explored the changes in the contents of several plant hormones during floral bud differentiation using biochemical and molecular biology techniques, and the changes in expression levels of several flower development related transcription factors. These results revealed the role of these factors (i.e., hormones and transcription factors) and may advance our understanding of their functions in flower development in L. cubeba.

http://ift.tt/2COgnXJ

Genetic Interactions Between BOB1 and Multiple 26S Proteasome Subunits Suggest a Role for Proteostasis in Regulating Arabidopsis Development

Protein folding and degradation are both required for protein quality control, an essential cellular activity that underlies normal growth and development. We investigated how BOB1, an Arabidopsis thaliana small heat shock protein, maintains normal plant development. bob1 mutants exhibit organ polarity defects and have expanded domains of KNOX gene expression. Some of these phenotypes are ecotype specific suggesting that other genes function to modify them. Using a reverse genetic approach we identified an interaction between BOB1 and FIL, a gene required for abaxial organ identity. We also performed an EMS enhancer screen using the bob1-3 allele to identify pathways that are sensitized by a loss of BOB1 function. This screen identified genetic, but not physical, interactions between BOB1 and the proteasome subunit RPT2a. Two other proteasome subunits, RPN1a and RPN8a, also interact genetically with BOB1. Both BOB1 and the BOB1-interacting proteasome subunits had previously been shown to interact genetically with the transcriptional enhancers AS1 and AS2, genes known to regulate both organ polarity and KNOX gene expression. Our results suggest a model in which BOB1 mediated protein folding and proteasome mediated protein degradation form a functional proteostasis module required for ensuring normal plant development.

http://ift.tt/2ouKWh8

A Genomic Reference Panel for Drosophila serrata

Here we describe a collection of re-sequenced inbred lines of Drosophila serrata, sampled from a natural population situated deep within the species endemic distribution in Brisbane, Australia. D. serrata is a member of the speciose montium group whose members inhabit much of south east Asia and has been well studied for aspects of climatic adaptation, sexual selection, sexual dimorphism, and mate recognition. We sequenced 110 lines that were inbred via 17-20 generations of full-sib mating at an average coverage of 23.5x with paired-end Illumina reads. 15,228,692 biallelic SNPs passed quality control after being called using the Joint Genotyper for Inbred Lines (JGIL). Inbreeding was highly effective and the average levels of residual heterozygosity (0.86%) were well below theoretical expectations. As expected, linkage disequilibrium decayed rapidly, with r² dropping below 0.1 within 100 base pairs. With the exception of four closely related pairs of lines which may have been due to technical errors, there was no statistical support for population substructure. Consistent with other endemic populations of other Drosophila species, preliminary population genetic analyses revealed high nucleotide diversity and, on average, negative Tajima's D values. A preliminary GWAS was performed on a cuticular hydrocarbon trait, 2-MeC₂₈ revealing 4 SNPs passing Bonferroni significance residing in or near genes. One gene Cht9 may be involved in the transport of CHCs from the site of production (oenocytes) to the cuticle. Our panel will facilitate broader population genomic and quantitative genetic studies of this species and serve as an important complement to existing D. melanogaster panels that can be used to test for the conservation of genetic architectures across the Drosophila genus.

http://ift.tt/2CLnGzF

A Metagenome-Wide Association Study and Arrayed Mutant Library Confirm Acetobacter Lipopolysaccharide Genes Are Necessary for Association with Drosophila melanogaster

A metagenome wide association (MGWA) study of bacterial host association determinants in Drosophila predicted that LPS biosynthesis genes are significantly associated with host colonization. We were unable to create site-directed mutants for each of the predicted genes in Acetobacter, so we created an arrayed transposon insertion library using Acetobacter fabarum DsW_054 isolated from Drosophila. Creation of the A. fabarum DsW_054 gene knock-out library was performed by combinatorial mapping and Illumina sequencing of random transposon insertion mutants. Transposon insertion locations for 6,418 mutants were successfully mapped, including hits within 63% of annotated genes in the A. fabarum DsW_054 genome. For 45/45 members of the library, insertion sites were verified by arbitrary PCR and Sanger sequencing. Mutants with insertions in four different LPS biosynthesis genes were selected from the library to validate the MGWA predictions. Insertion mutations in two genes biosynthetically upstream of Lipid-A formation, lpxC and lpxB, show significant differences in host association, whereas mutations in two genes encoding LPS biosynthesis functions downstream of Lipid-A biosynthesis had no effect. These results suggest an impact of bacterial cell surface molecules on the bacterial capacity for host association. Also, the transposon insertion mutant library will be a useful resource for ongoing research on the genetic basis for Acetobacter traits.

http://ift.tt/2ovkpjI

Lutetium Lu 177 Dotatate Approved by FDA [News in Brief]

Radiopharmaceutical becomes treatment option for patients with certain neuroendocrine tumors.

http://ift.tt/2t13ASn

NIH Offers Funding for Genome-Editing Projects [News in Brief]

Agency to award $190 million for technology development over next 6 years.

http://ift.tt/2Ct1CxO

A Resource for Managing Immunotherapy Side Effects [News in Brief]

Comprehensive guidelines aim to help clinicians diagnose and treat side effects of checkpoint inhibitors.

http://ift.tt/2t1DXAW

Heterochromatin protein 1{alpha} mediates development and aggressiveness of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.

http://ift.tt/2oy9a9g

Interleukin-30/IL-27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization

Prostate cancer (PC) stem-like cells (PCSLCs) are believed to be responsible for PC onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In PC patients, interleukin(IL)-30/IL-27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here we asked whether IL-30 may favor PC progression by conditioning PCSLCs and assessed the value of blocking IL-30 to suppress tumor growth. IL-30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL-30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL-30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL-30 knockdown or knockout in PCSLCs. Collectively, these results mark IL-30 as a key driver of PCSLC behavior. Targeting IL-30 signaling may be a potential therapeutic strategy against PC progression and recurrence.

http://ift.tt/2CpPYnE

Targeting the SUMO pathway primes all-trans retinoic acid-induced differentiation of non-promyelocytic acute myeloid leukemias

Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a post-translational modification related to ubiquitination, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with pharmacological inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA-induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-APL AML cells. This activated ATRA-induced terminal myeloid differentiation and reduced cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation via overexpression of SUMO-conjugating enzyme Ubc9 dampened expression of ATRA-responsive genes and prevented differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor-prognosis cancer.

http://ift.tt/2oAK9dz

Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy

Abstract

Background

To evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients.

Methods

Two groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re-planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test.

Results

Both SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V₂₀, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST.

Conclusions

This study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice.

http://ift.tt/2ovfr6y

Response criteria in solid tumors (PERCIST/RECIST) and SUV max in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy

Abstract

Background

The purpose of this study was to evaluate the prognostic impact of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) and of pre- and post-treatment maximum Standard Uptake Value (SUV_max) in regards to survival and tumor control for patients treated for early-stage non-small cell lung cancer (ES-NSCLC) with stereotactic body radiotherapy (SBRT).

Methods

This is a retrospective review of patients with ES-NSCLC treated at our institution using SBRT. Lobar, locoregional, and distant failures were evaluated based on PERCIST/RECIST and clinical course. Univariate analysis of the Kaplan-Meier curves for overall survival (OS), progression free survival (PFS), lobar control (LC), locoregional control (LRC), and distant control (DC) was conducted using the log-rank test. Pre- and post-treatment SUV_max were evaluated using cutoffs of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3. ∆SUV_max was also evaluated at various cutoffs. Cox regression analysis was conducted to evaluate survival outcomes based on age, gender, pre-treatment gross tumor volume (GTV), longest tumor dimension on imaging, and Charlson Comorbidity Index (CCI).

Results

This study included 95 patients (53 female, 42 male), median age 75. Lung SBRT was delivered in 3–5 fractions to a total of 48–60 Gy, with a BED_{α/β = 10Gy} of at least 100 Gy. Median OS and PFS from the end of SBRT was 15.4 and 11.9 months, respectively. On univariate analysis, PERCIST/RECIST response correlated with PFS (p = 0.039), LC (p = 0.007), and LRC (p = 0.015) but not OS (p = 0.21) or DC (p = 0.94). Pre-treatment SUV_max and post-treatment SUV_max with cutoff values of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3 did not predict for OS, PFS, LC, LRC, or DC. ∆SUV_max did not predict for OS, PFS, LC, LRC, or DC. On multivariate analysis, pre-treatment GTV ≥ 30 cm³ was significantly associated with worse survival outcomes when accounting for other confounding variables.

Conclusions

PERCIST/RECIST response is associated with improved LC and PFS in patients treated for ES-NSCLC with SBRT. In contrast, pre- and post-treatment SUV_max is not predictive of disease control or survival.

http://ift.tt/2ozZc7a

Construct validity of the Spanish Versions of the Memorial Symptom Assessment Scale Short Form (MSAS-SF) and Condensed Form (CMSAS): Rasch Analysis of Responses in Oncology Outpatients

The Memorial Symptom Assessment Scale (MSAS) is a self-rating instrument for the assessment of symptom distress in cancer patients. The Spanish version of the MSAS has recently been validated. However, we lack evidence of the internal construct validity of the shorter versions (MSAS-SF and CMSAS). In addition, rigorous testing of these scales with modern psychometric methods is needed.

http://ift.tt/2FCEziO

Family Caregivers’ Preparations for Death: A Qualitative Analysis

Many family caregivers are not prepared for the death of their family member or friend. Palliative care services tend to emphasise the patients' preparation for death rather than caregivers' preparation for, or living after, death. Caregivers' perspectives on anticipating and preparing for death are under-researched, despite preparation being associated with better bereavement outcomes.

http://ift.tt/2F0cvFg

Effects of Xin-Ji-Er-Kang on Anticardiovascular Remodeling in L-NAME Induced Hypertensive Mice and Its Potential Mechanisms

Background. Xin-Ji-Er-Kang (XJEK) shows protective effects on the myocardial ischemic diseases in our previous reports. We hypothesized that XJEK may exert preventing effects on L-NAME induced hypertensive mice by ameliorating oxidative stress (OS) and endothelial dysfunction (ED). Methods. After treatment with XJEK for four weeks, cardiac function and cardiovascular pathology changes were evaluated. Then, endothelial-dependent vascular relaxation and serum NO, eNOS, AMDA, SOD, MDA content, and cardiac tissue eNOS expression were detected. Results. The hypertensive mice displayed distinct cardiovascular remodeling including increased HW/BW index (4.7 ± 0.33 versus 5.2 ± 0.34), cross-section area, and collagen deposition. In addition, ED was found manifested by decreased serum NO (20.54 ± 8.05 versus 6.29 ± 2.33), eNOS (28.34 ± 2.36 versus 20.37 ± 2.30), content, and decreased eNOS expression in cardiac tissue and damaged endothelium-dependent diastolic function. Moreover, OS was detected confirmed by decreased SOD activity and increased MDA content in serum. However, treatment with XJEK for 4 wk could reverse cardiovascular remodeling (HW/BW index normalized from 5.2 ± 0.34 to 4.59 ± 0.25), ameliorate and preserve endothelial function (NO: 16.67 ± 7.24 versus 6.29 ± 2.33; eNOS: 16.67 ± 7.24 versus 6.29 ± 2.33), and suppress OS. Conclusion. XJEK has protective effects against cardiovascular remodeling in L-NAME induced hypertensive mice.

http://ift.tt/2FciZ72

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy, Published online: 27 February 2018; doi:10.1038/bjc.2017.467

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

http://ift.tt/2t0EOSf

Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours, Published online: 27 February 2018; doi:10.1038/bjc.2017.460

Systemic immune-inflammation index in germ-cell tumours

http://ift.tt/2Cq5qA6

PulmCrit- Get SMART: Nine reasons to quit using normal saline for resuscitation

Saline vs. balanced solutions has been a topic of ongoing debate.  Two fresh studies will illuminate this: the SMART and SALT-ED trials.  This post summarizes current knowledge, beginning with physiology and working our way to fresh trials. Reason #1.  There is no physiologic rationale for using "normal" saline (NS). Saline is a hypertonic, acidotic fluid […]

EMCrit Project by Josh Farkas.

http://ift.tt/2EZGQYn

Correlation Between Tumor Metabolism and Semiquantitative Perfusion MRI Metrics in Non-small Cell Lung Cancer

Balance between vascularity and glucose metabolism in tumor could prove to be an important indicator of its biological status and resistance to treatment. This study evaluates the use of semiquantitative dynamic contrast-enhanced MRI parameters for predicting the 18F-FDG-PET maximum standardized uptake value in non-small cell lung cancer (NSCLC). It was found that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Investigating vascular-metabolic relationship will help in guiding personalized targeted therapy in NSCLC.

http://ift.tt/2ozSrT2

Glycogen storage disease type Ia: adult presentation with microcytic anemia and liver adenomas

http://ift.tt/2EYDBws

Hepatic diagnostics in pregnancy: Biopsy, biomarkers and beyond

http://ift.tt/2FCySlb

Transient elastography is useful in diagnosing biliary atresia and predicting prognosis after hepatoportoenterostomy

Abstract

We investigated the utility of transient elastography for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty-eight cholestatic infants (9-87 days of age) with direct bilirubin level > 1 mg/dL were enrolled. Liver stiffness measurement (LSM) by transient elastography was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non-BA cholestatic infants. A receiver operating characteristic curve analysis showed that an LSM >7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%, specificity = 97%, area under the curve = 85.3%, P = 0.0001). Cholestatic infants with an LSM >7.7 kPa were more likely to be diagnosed with BA (odds ratio = 128, P < 0.001). Very early measurement of LSM after hepatoportoenterostomy is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months after hepatoportoenterostomy. Five of the BA subjects were awaiting or had received liver transplantation, and they had a significantly higher LSM measured 1 week after hepatoportoenterostomy than that in the other BA subjects (26.0 vs. 10.8 kPa, P = 0.006). A Cox proportional analysis demonstrated that the need for liver transplantation was significantly higher in BA subjects with LSM > 16 kPa measured 1 week after hepatoportoenterostomy than other BA subjects (hazard ratio = 10.16, P = 0.04). Conclusions: LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM after hepatoportoenterostomy may predict complications and the need for early liver transplantation in infants with BA. This article is protected by copyright. All rights reserved.

http://ift.tt/2F2oL8g

Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism

Abstract

Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are co-expressed in the enteroendocrine L cells but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid (TLCA), increased fibroblast growth factor 15 (FGF15) and FGF21 and GLP-1 secretion, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and LCA-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX-induced metabolic phenotypes and inhibited TLCA synthesis, adipose tissue browning, and liver bile acid synthesis gene expression, but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice. This study uncovered a novel mechanism in which activation of intestinal FXR shaped the gut microbiota to activate TGR5/GLP-1 signaling to improve hepatic glucose and insulin sensitivity and increase adipose tissue browning. The gut microbiota plays a critical role in bile acid metabolism and signaling to regulate metabolic homeostasis in health and disease. This article is protected by copyright. All rights reserved.

http://ift.tt/2FF7kvy

Submucosal tunnel endoscopic resection for extraluminal tumors: a novel endoscopic method for en bloc resection of predominant extraluminal growing subepithelial tumors or extra-gastrointestinal tumors (with videos)

The management of subepithelial tumors with a predominant extraluminal growth pattern or extra-gastrointestinal (GI) tumors can be challenging and traditionally requires a surgical resection that is not only invasive but may carry a significant risk of morbidity and mortality. We aim to assess the feasibility, safety and efficacy of a novel endoscopic technique termed as submucosal tunnel endoscopic resection for Extraluminal Tumors (STER-ET).

http://ift.tt/2F5QurV

Patient-Centered Outcomes and Resuscitation Fluids

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2FAGpAX

Patient-Centered Outcomes and Resuscitation Fluids

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2FAGpAX

Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel

.


http://ift.tt/2t0A1QF

The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality

To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort.

http://ift.tt/2F9wggD

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

http://ift.tt/2HRMvNW

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

http://ift.tt/2GPeoVy

Systemic immune-inflammation index in germ-cell tumours

http://ift.tt/2HNPdE6

Size Matters: Measurement of Capsule Diameter in Cryptococcus neoformans

The polysaccharide capsule is the primary virulence factor in Cryptococcus neoformans, and its size correlates with strain virulence. Capsule diameter measurements are used in phenotypic testing and to gauge therapeutic efficacy. Here a standard method of capsule induction is presented, and two methods of staining and measuring diameter are compared.

http://ift.tt/2t5bj1O

Hepatitis C: When high drug prices preclude patient benefit

Currently, there are at least 6 drug companies that have developed curative treatments for hepatitis C. Drugs that cure hepatitis C can save up to one-half million individuals every year, but these therapies are neither accessible nor affordable. See also pages 000-000.

http://ift.tt/2BSV8HI

Prevention of liver cancer with new curative hepatitis C antivirals: Real-world challenges

New antiviral therapies cure most patients with hepatitis C and prevent the development of cirrhosis and hepatocellular carcinoma. The major challenges for global hepatitis C virus eradication are the identification of patients with chronic hepatitis C, referrals to treatment, and elevated drug prices. See also pages 000-000.

http://ift.tt/2EWwnNj

Individualized Stem-positioning in Calcar-guided Short-stem Total Hip Arthroplasty

This protocol describes the round-the-corner technique and the individualized stem-positioning of calcar-guided short stems alongside the medial calcar, depending on the level of the osteotomy. This differs from conventional total hip arthroplasty and includes a learning curve.

http://ift.tt/2CLU8lo

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

A method is described for fractionation of insoluble and soluble mutant huntingtin species from mouse brain and cell culture. The method described is useful for characterization and quantification of huntingtin protein flux and aids in analyzing protein homeostasis in disease pathogenesis and in the presence of perturbations

http://ift.tt/2FbIWDM

Endodontic applications of 3D printing

Abstract

Computer-aided design (CAD) and computer-aided manufacturing (CAM) technologies can leverage cone beam computed tomography (CBCT) data for production of objects used in surgical and nonsurgical endodontics and in educational settings. The aim of this article is to review all current applications of 3D printing in endodontics and to speculate upon future directions for research and clinical use within the specialty. A literature search of PubMed, Ovid and Scopus was conducted using the following terms: stereolithography, 3D printing, computer aided rapid prototyping, surgical guide, guided endodontic surgery, guided endodontic access, additive manufacturing, rapid prototyping, autotransplantation rapid prototyping, computer aided design (CAD), computer aided manufacturing (CAM). Inclusion criteria were articles in the English language documenting endodontic applications of 3D printing. Fifty-one articles met inclusion criteria and were utilized. The endodontic literature on 3D printing is generally limited to case reports and pre-clinical studies. Documented solutions to endodontic challenges include: guided access with pulp canal obliteration, applications in autotransplantation, pre-surgical planning and educational modeling and accurate location of osteotomy perforation sites. Acquisition of technical expertise and equipment within endodontic practices present formidable obstacles to widespread deployment within the endodontic specialty. As knowledge advances, endodontic postgraduate programmes should consider implementing 3D printing into their curriculums. Future research directions should include clinical outcomes assessments of treatments employing 3D printed objects.

This article is protected by copyright. All rights reserved.

http://ift.tt/2BUtPwu

Reply to "Lumbar Transforaminal Epidural Steroid Injection in Patients With Chronic Unilateral Radicular Pain"

No abstract available

http://ift.tt/2CM6LNl

Retraction Re: Expression of Concern. Am J Phys Med Rehabil 2017;96:761

No abstract available

http://ift.tt/2F9iKcT

Injury of the Hypothalamus in Patients With Hypoxic–Ischemic Brain Injury: A Diffusion Tensor Imaging Study

Objectives The survival rate for hypoxic–ischemic brain injury (HI-BI) is less than 20%. Several brain regions, including the caudate, hippocampus, and hypothalamus, are vulnerable to HI-BI. Hypothalamus is involved in regulation of temperature, sleep-wakefulness cycle, emotional behavior, and memory function. Using diffusion tensor imaging, we examined injury of the hypothalamus in patients with HI-BI. Methods Twelve patients with HI-BI and 27 healthy control subjects were recruited. The region of interest was defined for the hypothalamus and the fractional anisotropy and apparent diffusion coefficient were measured. Results The fractional anisotropy value was significantly lower in the patient group compared with the control group (P

http://ift.tt/2CM4GkD

Three-Year Changes in Physical Activity and Subsequent Loss of Ability to Walk 400 m in Older Adults: The InCHIANTI Study

We examined the associations of maintaining or increasing physical activity (PA) for a 3-yr follow-up with subsequent incident inability to complete the 400-m walk test (i.e., mobility disability) for 6 yrs of follow-up in older adults. This study included 421 participants 65 yrs and older. The 400-m walk test was assessed at baseline and at 3-, 6-, and 9-yr follow-up. Physical activity was self-reported through a 6-point rating scale at baseline and 3-yr follow-up. Three-year cumulative PA (i.e., average at baseline and at 3-yr follow-up) and its changes (i.e., from baseline to 3-yr follow-up) were linked to subsequent incidence of mobility disability for 6 yrs of follow-up (i.e., from 3- to 9-yr follow-up), after adjustment for potential covariates. After the 3-yr period, incidence of mobility disability for the subsequent 6 yrs of follow-up occurred in 129 participants. The odds ratio (95% confidence interval) of incident mobility disability associated with 1-category increase in cumulative PA was 0.63 (0.41–0.97, P = 0.036). The odds ratio (95% confidence interval) of incident mobility disability associated with 1-category increase in changes in PA was 0.56 (0.38–0.84, P = 0.005). Hence, maintaining or increasing PA levels is associated with a reduced risk of mobility disability among older adults.

http://ift.tt/2FbeTw8

Efficacy of Armeo® Robotic Therapy Versus Conventional Therapy on Upper Limb Function in Children With Hemiplegic Cerebral Palsy

Objective The aim of this study was to examine the efficacy of Armeo robotic therapy, compared with conventional therapy, on upper limb function in children with hemiplegic cerebral palsy. Design Thirty children with hemiplegic cerebral palsy, with ages ranging from 6 to 8 yrs, were selected for this randomized controlled study and randomly assigned to two groups. The study group (n = 15) received 12 wks of Armeo robotic therapy (45 min/session, 3 days/wk) and the control group (n = 15) received conventional therapy for the same period. The measured outcomes were the Modified Ashworth Scale and the Quality of Upper Extremity Skills Test, measured at baseline and after 12 wks of intervention. Results Children in the study group showed significant improvement in the mean values of all the measured variables, compared with those in the control group (P

http://ift.tt/2CLHiUd

Ultrasound-Guided S1 Transforaminal Epidural Injection Using the In-Plane Approach and Color Doppler Imaging

Recently, several studies have investigated the effectiveness of the ultrasound-guided lumbosacral transforaminal epidural injection. However, the ultrasound-guided S1 transforaminal epidural injection using an out-of-plane approach, which was previously reported, may cause an intestinal injury or intravascular injection because the needle tip tends to be invisible in the out-of-plane approach. In this study, therefore, we report a new method of ultrasound-guided S1 transforaminal epidural injection using the in-plane approach and color Doppler. In addition, we also report the usefulness of color Doppler imaging for finding the S1 foramen and confirming the accuracy of the injection.

http://ift.tt/2F9AEwh

Intervertebral Disc Degeneration in a Percutaneous Mouse Tail Injury Model

Objectives Intervertebral disc (IVD) degenerates progressively with age and after injuries. In this study, we aimed to characterize early molecular events underlying disc degeneration using a mouse tail IVD injury model. Design We have established a transcutaneous minimally invasive approach to induce mouse tail IVD injury under fluoroscopic guidance. Morphological and molecular changes in the injured IVDs are compared with the baseline features of adjacent intact levels. Results After needle puncture, tail IVDs exhibited time-dependent histological changes. The aggrecan neoepitope VDIPEN was evident from 2 days to 4 wks after injury. A disintegrin and metalloproteinase domain-containing protein 8 (adam8) is a surface protease known to cleave fibronectin in the IVD. Gene expression of adam8 was elevated at all time points after injury, whereas the increase of C-X-C motif chemokine ligand (cxcl)-1 gene expression was statistically significant at 2 days and 2 wks after injury. Type 1 collagen gene expression decreased initially at day 2 but increased at 2 wks after injury, whereas no significant change in type 2 collagen gene expression was observed. The extracellular matrix gene expression pattern is consistent with fibrocartilage formation after injury. Conclusions Mouse tail IVDs degenerate after needle puncture, as demonstrated by histological changes and aggrecan degradation. The minimally invasive tail IVD injury model should prove useful to investigators studying mechanisms of IVD degeneration and repair.

http://ift.tt/2CNarOW

Trunk Exercises Improve Gait Symmetry in Parkinson Disease: A Blind Phase II Randomized Controlled Trial

Objective Deficits in step-to-step symmetry and trunk muscle activations have been linked to falls in Parkinson disease. Given such symptoms are poorly managed with anti-parkinsonian medications, alternate therapies are needed. This blind phase II randomized controlled trial sought to establish whether exercise can improve step-to-step symmetry in Parkinson disease. Design Twenty-four Parkinson disease patients with a falls history completed baseline assessments of symptom severity, balance confidence, mobility, and quality of life. Step-to-step symmetry was assessed by deriving harmonic ratios from three-dimensional accelerations collected for the head and trunk. Patients were randomly assigned to either 12 wks of exercise and falls prevention education or falls prevention education only. Both groups repeated the baseline tests 12 and 24 wks after the initial assessment. The Australian and New Zealand Clinical Trials Registry number is ACTRN12613001175763. Results At 12 wks, the exercise group had statistically significant and clinically relevant improvements in anterior-posterior step-to-step trunk symmetry. In contrast, the education group recorded statistically significant and clinically meaningful reductions in medial-lateral and vertical step-to-step trunk symmetry at 12 wks. Conclusions Given that step-to-step symmetry improved for the exercise group and declined for the education group after intervention, active interventions seem more suited to increasing independence and quality of life for people with Parkinson disease. To Claim CME Credits Complete the self-assessment activity and evaluation online at http://ift.tt/1l80W45 CME Objectives Upon completion of this article, the reader should be able to do the following: (1) Describe the effect deficits in trunk muscle function have on gait in individuals with Parkinson disease; (2) Identify the benefits of targeted trunk exercises on step-to-step symmetry; and (3) Discuss the benefits of improving step-to-step symmetry in individuals with Parkinson disease. Level Advanced Accreditation The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

http://ift.tt/2owesTz

Effectiveness of Shortwave Diathermy for Subacromial Impingement Syndrome and Value of Night Pain for Patient Selection: A Double-Blinded, Randomized, Placebo-Controlled Trial

Objective The aim of this study was to investigate the effectiveness of short wave diathermy (SWD) in patients with subacromial impingement syndrome. Design In this double-blinded, randomized, placebo-controlled trial, 57 patients (aged 35–65 yrs) were classified into night pain positive (NP[+]) (n = 28) and night pain negative (NP[−]) (n = 29) groups. Both groups were randomly assigned to SWD (NP[+], n = 14; NP[−], n = 14) and sham (NP[+], n = 15; NP[−], n = 14) subgroups. Visual analog scale, Constant-Murley Scale (CS), and Shoulder Disability Questionnaire (SDQ) scores were used for evaluation. Results There was only a significant difference in pain with activity at 1-mo (mean difference [MD], −1.65; 95% confidence interval, −3.01 to −0.28]) and 2-mo evaluations (MD, −2.1; 95% confidence interval, −3.51 to −0.69) between SWD versus sham groups. In the NP(+) SWD group, the CS pain score was significantly higher than in the NP(+) sham group at all evaluations after treatment. At 1 mo, the NP(−) SWD group showed significantly better pain, strength, total CS, and SDQ scores than the NP(−) sham group. At 2 mos, the pain, range of motion, strength, and total CS and SDQ scores were better in the NP(−) SWD group than in the NP(−) sham group (P

http://ift.tt/2FcYXtr

Graduate Medical Education Funding and Curriculum in Physical Medicine and Rehabilitation: A Survey of Physical Medicine and Rehabilitation Department Chairs

This national survey highlights graduate medical education funding sources for physical medicine and rehabilitation (PM&R) residency programs as well as perceived funding stability, alignment of the current funding and educational model, the need of further education in postacute care settings, and the practice of contemporary PM&R graduates as perceived by PM&R department/division chairs. Approximately half of the reported PM&R residency positions seem to be funded by Centers of Medicare and Medicaid Services; more than 40% of PM&R chairs believe that their residency program is undersized and nearly a quarter feel at risk for losing positions. A total of 30% of respondents report PM&R resident experiences in home health, 15% in long-term acute care, and 52.5% in a skilled nursing facility/subacute rehabilitation facility. In programs that do not offer these experiences, most chairs feel that this training should be included. In addition, study results suggest that most PM&R graduates work in an outpatient setting. Based on the results that chairs strongly feel the need for resident education in postacute care settings and that most graduates go on to practice in outpatient settings, there is a potential discordance for our current Centers of Medicare and Medicaid Services graduate medical education funding model being linked to the acute care setting.

http://ift.tt/2CKJV8T

Effect of Stretching on Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model

Objective Stretching of fascia is an important component of manual and movement therapies. We previously showed that in pigs, a unilateral thoracolumbar fascia injury combined with movement restriction (hobble) produced contralateral loss of fascia mobility (shear strain during passive trunk flexion measured with ultrasound) similar to findings in human subjects with chronic low back pain. We now tested whether such abnormalities could be reversed by removing the hobble with or without daily stretching for 1 mo. Design Thirty pigs were randomized to control, injury, or injury + hobble for 8 wks. The hobble restricted hip extension ipsilateral to the injury. At week 8, the injury + hobble group was subdivided into continued hobble, removed hobble, and removed hobble + stretching (passively extending the hip for 10 min daily). Results Removing hobbles restored normal gait speed but did not restore fascia mobility. Daily passive stretching was not superior to removing hobbles, as there was no significant improvement in fascia mobility with either treatment group (removed hobble or stretching). Conclusions Reduced fascia mobility in response to injury and movement restriction worsens over time and persists even when movement is restored. Reversing fascia abnormalities may require either longer than 1 mo or a different treatment "dose" or modality.

http://ift.tt/2FcYOWV

The Emergence of the Rehabilitative Strategy: The Driving Forces in the United States

The aim of this essay was to show the impact that driving forces have had on the emergence of rehabilitation as a health strategy in the United States. Specifically, this essay (1) identifies the driving forces that have addressed the development of rehabilitation, (2) examines how the rehabilitative strategy has been driven by the driving forces through turning points and facilitators, and (3) identifies the barriers of each force against the development of rehabilitation. Critical and scoping review of the literature was conducted from the late 1910s until the end of the century. War, economy, the power of the state, and science were identified as the driving forces that led rehabilitation to become a health strategy complementing prevention, promotion, cure, and palliation. World War I and II played as a stimulus for rehabilitation, federal funding facilitated its development, acts, amendments, and governmental programs enabled its implementation, and the acknowledgment of physical medicine and rehabilitation as medical field contributed to its international recognition as health strategy. World Health Organization's International Classification of Functioning, Disability and Health is also identified as an emerging facilitator of rehabilitation. Based on the example of United States, this article closes with recommendations toward the implementation of rehabilitation as a health strategy in countries where so far this has not occurred.

http://ift.tt/2CKPSmc

Effect of Full-Length Carbon Fiber Insoles on Lower Limb Kinetics in Patients With Midfoot Osteoarthritis: A Pilot Study

Objectives We investigated the effects of full-length carbon fiber (FCF) insoles on gait, muscle activity, kinetics, and pain in patients with midfoot osteoarthritis (OA). Design We enrolled 13 patients with unilateral midfoot OA (mild: Visual Analog Scale [VAS] range, 1–3; moderate, VAS range, 4–7) and healthy controls. All participants were asked to walk under two conditions: with and without FCF insole. The outcome measures were ground reaction force, quantitative gait parameters, electromyography activities and pain severity (VAS). Results In the patients with moderate midfoot OA, significantly longer gait cycle and higher muscle activity of lower limb during loading-response phase were observed while walking without FCF insoles. In the mild midfoot OA group, there was no significant difference in VAS score (without, 2.0 ± 1.0 vs. with, 2.0 ± 0.5) with FCF insole use. However, significantly reduced VAS score (without, 5.5 ± 1.4 vs. with, 2.0 ± 0.5) and muscle activity of the tibialis anterior and increased muscle activity of gastrocnemius were observed in the moderate midfoot OA group by using an FCF insole (P

http://ift.tt/2FbExRg

Lumbar Transforaminal Epidural Steroid Injection in Patients With Chronic Unilateral Radicular Pain

No abstract available

http://ift.tt/2CLHtis

Association Between Sensorimotor Impairments and Functional Brain Changes in Patients With Low Back Pain: A Critical Review

Low back pain (LBP) coincides with sensorimotor impairments, for example, reduced lumbosacral tactile and proprioceptive acuity and postural control deficits. Recent functional magnetic resonance imaging studies suggest that sensorimotor impairments in LBP may be associated with brain changes. However, no consensus exists regarding the relationship between functional brain changes and sensorimotor behavior in LBP. Therefore, this review critically discusses the available functional magnetic resonance imaging studies on brain activation related to nonnociceptive somatosensory stimulation and motor performance in individuals with LBP. Four electronic databases were searched, yielding nine relevant studies. Patients with LBP showed reduced sensorimotor-related brain activation and a reorganized lumbar spine representation in higher-order (multi)sensory processing and motor regions, including primary and secondary somatosensory cortices, supplementary motor area, and superior temporal gyrus. These results may support behavioral findings of sensorimotor impairments in LBP. In addition, patients with LBP displayed widespread increased sensorimotor-evoked brain activation in regions often associated with abnormal pain processing. Overactivation in these regions could indicate an overresponsiveness to sensory inputs that signal potential harm to the spine, thereby inducing overgeneralized protective responses. Hence, functional brain changes could contribute to the development and recurrence of LBP. However, future studies investigating the causality between sensorimotor-related brain function and LBP are imperative.

http://ift.tt/2owe2MZ

Battlefield Acupuncture: An Emerging Method for Easing Pain

No abstract available

http://ift.tt/2CKPRPa

The Pilocarpine Model of Temporal Lobe Epilepsy and EEG Monitoring Using Radiotelemetry System in Mice

This manuscript describes a method of inducing status epilepticus by systemic pilocarpine injection and of monitoring spontaneous recurrent seizures in live animals using a wireless telemetry video and electroencephalogram system. This protocol can be utilized for studying the pathophysiologic mechanisms of chronic epilepsy, epileptogenesis, and acute seizures.

http://ift.tt/2EYAwk9

A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration

This protocol describes a mouse model of orthopedic surgery that has been used to study mechanisms of postoperative neuroinflammation and behavioral changes, and when combined with parabiosis, to study tissue regeneration during aging.

http://ift.tt/2BUdwzQ

Bella Diet Capsules by Bella All Natural: Recall - Presence of Sibutramine

Audience: Consumer [Posted 02/27/2018] ISSUE: Bella All Natural is voluntarily recalling its Diet Capsules labeled as Bella, Lot Number MFD:10.15.2017 EXP: 10.14.2019, to the consumer level. This recall has been initiated due to presence of...

http://ift.tt/2GRcPqn

Bella Diet Capsules by Bella All Natural: Recall - Presence of Sibutramine

Audience: Consumer [Posted 02/27/2018] ISSUE: Bella All Natural is voluntarily recalling its Diet Capsules labeled as Bella, Lot Number MFD:10.15.2017 EXP: 10.14.2019, to the consumer level. This recall has been initiated due to presence of...

http://ift.tt/2GRcPqn

A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset (Callithrix jacchus)

We report a surgical method to administrate drugs to the inner ear of a non-human primate, the common marmoset (Callithrix jacchus), via the round window membrane.

http://ift.tt/2EZFuZI

Cabozantinib Approval Expands Initial Treatment Options for Advanced Kidney Cancer

The Food and Drug Administration has approved cabozantinib (Cabometyx®) as an initial treatment for patients with advanced renal cell carcinoma, the most common type of kidney cancer.

http://ift.tt/2otWOQu

Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers doi: 10.3390/cancers10030061

Authors: Sergio Lamprecht Ina Sigal-Batikoff Shraga Shany Naim Abu-Freha Eduard Ling George Delinasios Keren Moyal-Atias John Delinasios Alexander Fich

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells.

http://ift.tt/2BUbHCR

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers doi: 10.3390/cancers10030060

Authors: Urska Kamensek Natasa Tesic Gregor Sersa Maja Cemazar

Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU.

http://ift.tt/2EXtiwG

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers doi: 10.3390/cancers10030059

Authors: David Corujo Marcus Buschbeck

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.

http://ift.tt/2CqAXC7

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Abstract

Background

In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results

Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions

This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.

http://ift.tt/2oumtIK

Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis

Abstract

Background

Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis.

Results

Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h.

No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO₃⁻ were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h.

Conclusion

Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

http://ift.tt/2CLGWwO

Revival of anti-angiogenic therapies in cancer

http://ift.tt/2FAUA9f

JC Virus-DNA Detection Is Associated with CD8 Effector Accumulation in Peripheral Blood of Patients with Multiple Sclerosis under Natalizumab Treatment, Independently from JC Virus Serostatus

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (0), 1–12 (12), 13–24 (24), 25–36 (36), and over 36 () infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the 0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV−) ( and , resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve ). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for 12 and 24 groups (). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

http://ift.tt/2CMeoDi

Issue Information - Editorial Board

http://ift.tt/2owfnmQ

The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models

Abstract

Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF–VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.

http://ift.tt/2FyshrP

Defective HLA class I antigen processing machinery in cancer

Abstract

Malignant transformation of cells is frequently associated with defective HLA class I antigen processing machinery (APM) component expression. This abnormality may have functional relevance, since it may have a negative impact on tumor cell recognition by cognate T cells. Furthermore, HLA class I APM abnormalities appear to have clinical significance, since they are associated with poor prognosis in several malignant diseases and may play a role in the resistance to immune checkpoint inhibitor-based immunotherapy. In this paper, we have reviewed the literature describing abnormalities in HLA class I APM component expression in many types of cancer. These abnormalities have been reported in all types of cancer analyzed with a frequency ranging between a minimum of 35.8% in renal cancer and a maximum of 87.9% in thyroid cancer for HLA class I heavy chains. In addition, we have described the molecular mechanisms underlying defects in HLA class I APM component expression and function by malignant cells. Lastly, we have discussed the clinical significance of HLA class I APM component abnormalities in malignant tumors.

http://ift.tt/2FBe0KS

Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders

Abstract

Background

Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients.

Methods

We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab.

Results

41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%).

Conclusion

This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.

http://ift.tt/2EZEcxG

Should catheter-directed thrombolysis be the standard of care for pregnancy-related iliofemoral deep vein thrombosis?

A 33-year-old, 8-week pregnant woman presented with mottling, pain and swelling of her left leg. Ultrasound Doppler scan revealed a large left iliofemoral deep vein thrombosis and the patient was diagnosed with phlegmasia cerulea dolens. After 24 hours of treatment with unfractionated heparin, there were minimal improvements in her symptoms. Catheter-directed thrombolysis was performed, following multidisciplinary consultation with the patient. An underlying May-Thurner lesion was identified and successfully stented. Radiation exposure to the fetus was minimised with the use of intravenous ultrasound and very low-dose fluoroscopy. Total radiation exposure to the fetus is 1.38 mGy, which is equivalent to 8 months of background radiation exposure. No immediate complication occurred and patient's symptoms completely resolved. On further follow-up, her iliofemoral veins remained patent with good flow and there were no recurrence of symptoms. A healthy infant was successfully delivered at 40 weeks gestation.

http://ift.tt/2sX7w6B

Primary spontaneous pneumothorax in conjunction with Marfan syndrome

A 25-year-old man with a history of Marfan syndrome, asthma and smoking presented with worsening dyspnoea and right-sided chest pain worsened with deep breathing after a fall 2 days prior. Diagnostic imaging revealed a spontaneous right-sided pneumothorax due to ruptured subpleural bullae in the apex of the right lung. Smaller subpleural bullae were also noted in the apex of the left lung. A chest tube was placed to reduce the right pneumothorax successfully.

http://ift.tt/2ozKmgZ

Persistent wrist monarthritis: down to the bone

A minority of osteoid osteomas are found to be juxta-articular and within the small bones of the wrist. We present a 30-year-old man diagnosed with an osteoid osteoma of the lunate bone, presenting with 3 years of left wrist pain, swelling and reduced range of motion. Given the patient's background and laboratory testing, consideration was given to both inflammatory and infectious causes and the diagnosis was delayed, requiring repeat interval imaging and assisted by multiple imaging modalities. Management by surgical excision led to resolution of pain and swelling. In cases of a prolonged isolated monarthritis, juxta-articular osteoid osteoma should be considered in the differential.

http://ift.tt/2ou1Dch