Free Fatty Acid Receptor 4 Mediates the Beneficial Effects of n-3 Fatty Acids on Body Composition in Mice

Abstract

As populations continue to age worldwide, sarcopenic obesity has heightened interest due to its medical importance. Although much evidence now indicates that n-3 fatty acids (FAs) may have beneficial effects on body composition including fat and muscle, their exact mechanisms have not yet been elucidated. Because free FA receptor 4 (FFA4) has been reported to be a receptor for n-3 FAs, we hypothesized that the protective role of n-3 FAs on body composition could be mediated by FFA4. To test this possibility, we generated mice overexpressing n-3 FAs but lacking FFA4 by crossing fat-1 transgenic (fat-1 ^Tg+) and FFA4 knockout (Ffar4 ^−/−) mice. Because fat-1 ^Tg+ mice, in which n-6 is endogenously converted into n-3 FAs, contain high n-3 FA levels, they could be a good animal model for studying the effects of n-3 FAs in vivo. Male and female littermates were included in high-fat-diet- (HFD) and ovariectomy-induced models, respectively. In the HFD model, male fat-1 ^Tg+ mice had a lower percentage of fat mass and a higher percentage of lean mass than their wild-type littermates only when they had the Ffar4 ^+/+ not the Ffar4 ^−/− background. Female fat-1 ^Tg+ mice showed less increase of fat mass percentage and less decrease of lean mass percentage after ovariectomy than wild-type littermates. However, these effects on body composition were attenuated in the Ffar4 ^−/− background. Taken together, our results indicate that the beneficial effects of n-3 FAs on body composition were mediated by FFA4 and thus suggest that FFA4 may be a potential therapeutic target for modulating sarcopenic obesity.

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Bone Disease in Connective Tissue Disease/Systemic Lupus Erythematosus

Abstract

This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2–4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies.

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Evaluation of a fever-management algorithm in a pediatric cancer center in a low-resource setting

Abstract

Background

In low- and middle-income countries (LMICs), inconsistent or delayed management of fever contributes to poor outcomes among pediatric patients with cancer. We hypothesized that standardizing practice with a clinical algorithm adapted to local resources would improve outcomes. Therefore, we developed a resource-specific algorithm for fever management in Davao City, Philippines. The primary objective of this study was to evaluate adherence to the algorithm.

Procedure

This was a prospective cohort study of algorithm adherence to assess the types of deviation, reasons for deviation, and pathogens isolated. All pediatric oncology patients who were admitted with fever (defined as an axillary temperature  >37.7°C on one occasion or ≥37.4°C on two occasions 1 hr apart) or who developed fever within 48 hr of admission were included. Univariate and multiple linear regression analyses were used to determine the relation between clinical predictors and length of hospitalization.

Results

During the study, 93 patients had 141 qualifying febrile episodes. Even though the algorithm was designed locally, deviations occurred in 70 (50%) of 141 febrile episodes on day 0, reflecting implementation barriers at the patient, provider, and institutional levels. There were 259 deviations during the first 7 days of admission in 92 (65%) of 141 patient episodes. Failure to identify high-risk patients, missed antimicrobial doses, and pathogen isolation were associated with prolonged hospitalization.

Conclusions

Monitoring algorithm adherence helps in assessing the quality of pediatric oncology care in LMICs and identifying opportunities for improvement. Measures that decrease high-frequency/high-impact algorithm deviations may shorten hospitalizations and improve healthcare use in LMICs.

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Pathology and genomics of pediatric melanoma: A critical reexamination and new insights

Abstract

The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors.

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Posttransplantation relapse of pediatric chronic myelomonocytic leukemia cured using donor lymphocyte infusion

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Strategies for research engagement of clinicians in allied health (STRETCH): a mixed methods research protocol

Introduction

Allied health professionals (AHPs) report positive attitudes to using research evidence in clinical practice, yet often lack time, confidence and skills to use, participate in and conduct research. A range of multifaceted strategies including education, mentoring and guidance have been implemented to increase AHPs' use of and participation in research. Emerging evidence suggests that knowledge brokering activities have the potential to support research engagement, but it is not clear which knowledge brokering strategies are most effective and in what contexts they work best to support and maintain clinicians' research engagement.

Methods and analysis

This protocol describes an exploratory concurrent mixed methods study that is designed to understand how allied health research fellows use knowledge brokering strategies within tailored evidence-based interventions, to facilitate research engagement by allied health clinicians. Simultaneously, a realist approach will guide a systematic process evaluation of the research fellows' pattern of use of knowledge brokering strategies within each case study to build a programme theory explaining which knowledge brokering strategies work best, in what contexts and why. Learning and behavioural theories will inform this critical explanation.

Ethics and dissemination

An explanation of how locally tailored evidence-based interventions improve AHPs use of, participation in and leadership of research projects will be summarised and shared with all participating clinicians and within each case study. It is expected that local recommendations will be developed and shared with medical and nursing professionals in and beyond the health service, to facilitate building research capacity in a systematic and effective way.

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Protocol for a systematic review of instruments for the assessment of quality of life and well-being in children and adolescents with cerebral palsy

Introduction

Cerebral palsy is the most common cause of physical disability in children and adolescents and is associated with impairments that may reduce the quality of life (QOL) of this population. Patient-reported outcome measures (PROMs) can facilitate the assessment of the effect of disease and treatment on QOL, from a patient viewpoint. The purpose of this systematic review is to identify PROMs that are used to measure QOL and subjective well-being (SWB) outcomes in young people with cerebral palsy and to evaluate the suitability of these PROMs for application in economic evaluations within this population.

Methods and analysis

MEDLINE, Scopus, the Cochrane Library, Web of Science Core Collection, EconLit, PsycINFO, CINAHL, EMBASE and Informit will be systematically searched from inception to date of search. Published peer-reviewed, English-language articles reporting PROMs measuring QOL or SWB outcomes in children and adolescents with cerebral palsy will be included. One reviewer will conduct the initial search and screen titles and abstracts for potentially eligible studies. The search will be performed in November 2017. To reduce the likelihood of reviewer selection bias, two other reviewers will independently screen a randomly selected subsample (10%) of the citations. Two reviewers will then retrieve full texts of potentially eligible studies and assess them against predefined inclusion criteria. The suitability of selected PROMs for use in economic evaluations of young people with cerebral palsy will be assessed using the International Society of Quality of Life Research recommended Minimum Standards and the Patient-Centered Outcomes and Comparative Effectiveness Research checklist. A narrative synthesis of extracted data will be presented including study descriptive data, PROMs measurement properties, settings in which they were applied and the valuation methods. Recommendations for practice on the selection of PROMs for use in economic evaluations of children and adolescents with cerebral palsy will be presented.

Ethics and dissemination

Ethical approval is not required as the proposed systematic review will not use primary data. The results of this study will be widely disseminated through publication in a peer-reviewed journal and conference presentation(s).

Systematic review registration number

International Prospective Register of Systematic Reviews number: CRD42016049746.

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Does internet-based cognitive behaviour therapy reduce healthcare costs and resource use in treatment of social anxiety disorder? A cost-minimisation analysis conducted alongside a randomised controlled trial

Objectives

Social anxiety disorder (SAD) can be effectively treated with internet-delivered cognitive behavioural therapy (ICBT), but studies on long-term cost minimisation from a healthcare provider perspective in comparison to an evidence-based control treatment of therapeutic equivalence are lacking. The objective of the study was to determine whether ICBT reduces healthcare costs and use of healthcare resources compared with cognitive behavioural group therapy (CBGT).

Design

A cost-minimisation study alongside a randomised controlled trial where participants (n=126) with SAD were randomised to ICBT or to CBGT. Costs measured from a healthcare provider perspective were estimated using time-driven activity-based costing alongside health status over 4 years from baseline measured with EQ-5D.

Setting

A psychiatric outpatient clinic in Stockholm, Sweden.

Participants

Participants were 126 individuals with SAD.

Primary outcome measures

Changes in EQ-5D and costs.

Interventions

Participants received either CBGT or ICBT for a duration of 15 weeks.

Results

ICBT minimised healthcare costs and demonstrated health improvements within the non-inferiority margin. Assuming a practical work capacity for personnel varying between 100%, 80% and 50% of theoretical full capacity, the cost for ICBT varied in the range between 400, 463 and 654 , while the cost for CBGT varied between 699, 806 and 1134. Within-group effect size was –0.36 (95% CI –0.70 to –0.01) for ICBT and –0.25 (95% CI –0.60 to 0.10) for CBGT. Mean use of effective psychologist time in ICBT was 189.60 (SD=53.77) minutes compared with 499.78 (SD=30.91) in the CBGT group.

Conclusions

In treatment of SAD, ICBT is equally effective but is associated with more efficient staff utilisation and less costs compared with CBGT. From a healthcare provider perspective, ICBT is an advantageous treatment option.

Trial registration number

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Effect of anesthesia depth on postoperative clinical outcome in patients with supratentorial tumor (DEPTH): study protocol for a randomized controlled trial

Introduction

Recent studies have shown that deep anaesthesia is associated with poor outcomes. However, no randomised controlled trials have been conducted to test the causality in patients undergoing brain tumour resection.

Methods and analysis

DEPTH is a multicenter, randomised, parallel-group, blind trial. The depth of general anaesthesia will be monitored using the bispectral index (BIS). Patients elected for supratentorial tumour resection will be randomly allocated to the deep or the light anaesthesia group in which the target BIS value is 35 or 50, respectively. BIS will be maintained at the target value for more than 90% of the total anaesthesia period. The primary outcome is the disability-free survival rate at postoperative 30 days and 1 year. The secondary outcomes are the mortality and morbidity within 30 days after surgery.

Ethics approval and dissemination

Ethical approval has been granted by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medicine University. The reference number is KY2016-059-02. The results of this study will be disseminated through presentations at scientific conferences and publication in scientific journals.

Trial registration

NCT03033693.

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What is the impact of research champions on integrating research in mental health clinical practice? A quasiexperimental study in South London, UK

Objectives

Key challenges for mental health healthcare professionals to implement research alongside clinical activity have been highlighted, such as insufficient time to apply research skills and lack of support and resources. We examined the impact of employing dedicated staff to promote research in community mental health clinical settings.

Design

Quasiexperiment before and after study.

Setting

South London and Maudsley National Health Service Foundation Trust.

Participants

4455 patients receiving care from 15 community mental health teams between 1 December 2013 and 31 December 2014.

Outcome measures

The proportion of patients approached for research participation in clinical services where research champions were present (intervention group), and where research champions were not present (comparison group).

Results

Patients in the intervention group were nearly six times more likely to be approached for research participation (Adj. OR=5.98; 95% CI 4.96 to 7.22).

Conclusions

Investing in staff that promote and drive research in clinical services increases opportunities for patients to hear about and engage in clinical research studies. However, investment needs to move beyond employing short-term staff.

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Outcomes of Bone Anchored Hearing Aid Implant at Universiti Kebangsaan Malaysia Medical Centre (UKMMC)

Abstract

The cross sectional study was conducted in Universiti Kebangsaan Malaysia Medical Center (UKMMC), Malaysia from August 2012 to December 2013. All patients implanted with in UKMMC from December 2001 until December 2012 was included. Glasgow Benefit Inventory (GBI) questionnaires and UKMMC questionnaires were used as part of the assessment tool. The GBI is a scoring which measures the change in health status produced by surgical interventions. UKMMC questionnaires was invented by our department to assess questions related to social and life style of patients and also the cosmetic perspective Baha implant and other daily related activities. The audiological assessment was assessed using hearing aid gain threshold. Complication with regards to skin reaction was graded using Holger Skin Classification. A total of 40 patients underwent Baha implant were recruited but only 35 patients fulfilled the criteria and included in this study for analysis. Age of patients ranged from 5 year old to 38 year old, with median of 13 years old. There were 22 patients (62.8%) were male and 13 patients (37.1%) were females. Almost all cases were canal atresia except one adult patient was a case of bilateral chronic discharging ear with chronic irritation with ear mould. Majority of patients 21 (60%) have hearing level of moderate to severe hearing loss (40–89 dB) and 14 patients (40%) have mild to moderate hearing loss (20–39 dB). The level of hearing was retested post operatively. All of the patients have improvement in their aided hearing with the range of 10–25 dBL which is statistically significant at p value of <0.05. The GBI was scored positively in all subscales. Majority of patients (91.4%) used BAHA more than 4 h per day and 88.6% agreed that BAHA is cosmetically acceptable. All patients experienced some form of skin irritation (Holger grade 1–2) however only 20% required surgical intervention. All our patients have range of 10–25 dB improvement of their aided hearing which is statistically significant at p value of <0.05. BAHA has been proven to show significant benefit in audiological improvement and quality of life.

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Big Brother star strips naked as she flaunts plastic surgery t...

The Big Brother starlet went under the knife at the beginning of the summer, in an effort to overhaul her image. And Daily Star Online was there every step of the way as Charlie embarked on her head-to-toe transformation .

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Physiochemical properties of rice starch for production of vermicelli with premium quality

Abstract

Rice vermicelli is a main food consumed in China and Southeast Asia. Quality of rice vermicelli varies with rice cultivars. Parameters including amylose content, amylopectin distribution, thermal and pasting characteristics, gel texture and starch granules of three rice cultivars "Zhongjiazao 17", "Xiangzaoxian 24" and "Thai Jasmine Rice", were studied for their impacts on vermicelli quality. Results showed significant differences for the measurements of the quality traits and indicated that a favorable quality of vermicelli was not determined by any single factor instead of a combination of multi-parameters. A vermicelli with a favorable quality could be produced from a rice variety with a high apparent amylose content (>25%), a protein content of 11%, an intermediate gelatinization temperature and gel consistency, and a gel hardness (~3 N for a Rapid Viscosity Analyzer pasting) and moderate retrogradation capacity (a setback viscosity of 30–100 RVU).

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Enzymatic pectic oligosaccharides (POS) production from sugar beet pulp using response surface methodology

Abstract

Pectic oligosaccharides (POS) have been indicated as novel candidate prebiotics. Traditionally, POS are produced from pectin-rich by-products using a two-step process involving extraction of the pectin, followed by its hydrolysis into POS. A one-step approach, in which the POS is directly produced from the raw material, might provide a more efficient alternative. Thus, the main aim of this paper was to investigate a one-step enzymatic hydrolysis approach to directly produce POS from sugar beet pulp (SBP). The POS yield was investigated as a function of the process parameters, as well as raw material characteristics. A statistically-based response surface methodology, using a central composite design was applied, to investigate the individual as well as the combined influences of the diverse parameters. The model was confirmed by a validation experiment, carried out at 135 g/l substrate concentration, 0.75 FPU/g SBP enzyme concentration, 0.8 mm particle size and 3 h hydrolysis time. Under these conditions, a POS-rich hydrolysate was obtained, containing rhamnose, arabinose, galactose, xylose and galacturonic acid, at 0.9, 15.2, 5.1, 1.4, and 13.2 g/l, respectively, enzymes were added each at 20 FPU/g dry matter (DM).

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Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999–2014

Drug resistance limits options for antiretroviral therapy (ART) and results in poorer health outcomes among HIV-infected persons. We sought to characterize resistance patterns and to identify predictors of res...

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Supraventricular tachycardia diagnosed by smartphone ECG

Diagnosis of paroxysmal supraventricular tachycardia (PSVT) may be difficult due to its episodic nature, which can be brief and self-limited, limiting the ability for clinicians to diagnose the specific rhythm disorder in a timely manner. We present a case of PSVT, which was unable to be diagnosed through typical evaluation with an event monitor despite several years of symptoms. The patient was ultimately diagnosed using the AliveCor Mobile ECG, a smartphone-based ECG device and application, which he purchased himself and captured a typical atrioventricular node re-entrant tachycardia. The patient was then able to email his cardiologist the tracing, which led to an electrophysiology study and successful slow pathway ablation procedure. Smartphone-based technology has the potential to push diagnostic evaluations outside of the healthcare system and empower patients.

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Dilation of epidural space and posterior soft tissue veins in Hirayama disease

Description

An 18-year-old man presented with distal weakness and amyotrophy of the right hand for a few months. He had no familial or personal medical history. Clinical examination showed atrophy and a marked weakness of right hypothenar and interossei muscles (grade 1/5 on Medical Research Council scale) and a mild weakness of right thumb abduction and wrist extension (4/5). Biceps, brachioradial and triceps tendon reflexes were normal and symmetric. There were no fasciculation, sensory abnormality or pain. Motor nerve conduction studies showed a reduced amplitude of compound muscle action potential of the right ulnar nerve but normal parameters of left ulnar and two median nerves. No focal slowing or conduction block was found. Studies of bilateral median, ulnar and right medial antebrachial cutaneous sensory nerves were normal. Electromyographic examination found active denervation (fibrillation potentials and neurogenic recruitment) in right C8-T1 innervated muscles (abductor pollicis brevis, first dorsal interosseus, extensor...

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Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection

A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.

Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.

Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame.

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Hyperemesis gravidarum

Hyperemesis gravidarum: Extreme, excessive, and persistent vomiting in early pregnancy that may lead to dehydration and malnutrition. It is usually associated with weight loss of more than 5%of the woman's prepregnancy weight. Hyperemesis gravidarum affects about 1 in every 300 pregnant women and is most common in young women, in first pregnancies, and in women carrying multiple fetuses. Hyperemesis gravidarum usually stops on its own by the 20th week of pregnancy. Treatment of mild hyperemesis gravidarum usually involves dietary measures, rest, and use of antacids. Very severe hyperemesis gravidarum may call for the use of intravenous fluids and nutrition.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Radiographic evaluation of condylar positioning in patients undergoing orthognathic surgery

Abstract

Objective

The aim of this study was to evaluate alterations in condylar positioning through submentovertex projection (Hirtz Radiographic Technique) in patients who underwent orthognathic surgery for maxillary advancement and mandibular setback with stable internal fixation.

Methods

A prospective longitudinal clinical study of 40 surgical patients presenting dentofacial deformity admitted in the Oral and Maxillofacial Surgery Department of Federal University of Paraná (UFPR) in the period between March 2013 and December 2015. We performed two submentovertex digital radiographs, one 7 days before surgery and the other one 30 days after the procedure. Cephalometric tracings were made using Radiocef® Studio 2 Software and measured the intercondylar and condylar angles (right and left).

Results

There was a decrease in the intercondylar angle (p < 0.001) and an increase in condylar angles both the right and the left side (p < 0.001) when compared with the pre and postoperative period. There was a larger increase in condylar angle on the right side in males (p = 0.007).

Conclusion

There is a tendency of decreasing of the intercondylar angle after orthognathic surgery, regardless of the alteration in the condylar angles, creating a new position of the condyle in the glenoid fossa. Patients with asymmetry may present greater alterations in the positioning of the opposite condylar to the deviation of the mandibular midline.

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Jury finds Worcester dentist not guilty of indecent assault on patient

A Lincoln Street dentist charged with indecently assaulting a female patient during a dental procedure was found not guilty Monday by a Central District Court jury. The jury of five women and one man deliberated for about 40 minutes before finding Dr. Nikhilkumar "Nikhil" M. Patel not guilty of a single count of indecent assault and battery.

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Did BoJack Horsemana s clown dentists steal Pennywisea s thunder?

This weekend, two unbearably creepy clown phenomena were unleashed on the viewing public. One was Pennywise the clown, the shapeshifting villain of the box office-breaking It , which has just had the best opening weekend for any horror film ever .

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Shrinkage in oral squamous cell carcinoma: An analysis of tumor and margin measurements in vivo, post-resection, and post-formalin fixation

To quantify changes in tumor size and tumor-free margins following surgical resection and formalin fixation of oral cavity squamous cell carcinoma.

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Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways

iPSC-MSCs protect against oxidative stress-induced mitochondrial dysfunction, apoptosis, hyper-responsiveness and inflammation in the airways. These findings highlight the potential use of iPSC-MScs as a novel cell-based therapy for COPD.

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The effects of house dust mite sublingual immunotherapy (SLIT)-tablet effects on immunological biomarkers and nasal allergen challenge symptoms

SQ HDM SLIT-tablet significantly increased serum HDM-specific IgG4 and IgE blocking factor, and significantly decreased early phase nasal symptoms after nasal allergen challenge. No significant effects on cytokines or gene expression in nasal mucosa were observed.

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Intussusception caused by heterotopic gastric mucosa in small intestine: a case report

Intestinal intussusception is the most frequent cause of small bowel obstruction in children between the ages of 2 months and 5 years and often remains idiopathic in etiology, even after surgery. On microscopi...

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Functional dynamics in cyclic nucleotide signaling and amyloid inhibition

Publication date: Available online 11 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Bryan VanSchouwen, Rashik Ahmed, Julijana Milojevic, Giuseppe Melacini
It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation. The dynamic exchange between non-toxic monomeric species and toxic oligomers of amyloidogenic proteins provides a foundation to understand amyloid inhibition. NMR ideally probes both types of dynamic exchange at atomic resolution. Specifically, we will show how NMR was utilized to reveal the dynamical basis of cyclic nucleotide affinity, selectivity, agonism and antagonism in multiple eukaryotic cAMP and cGMP receptors. We will also illustrate how NMR revealed the mechanism of action of plasma proteins that act as extracellular chaperones and inhibit the self-association of the prototypical amyloidogenic Aβ peptide. The examples outlined in this review illustrate the widespread implications of functional dynamics and the power of NMR as an indispensable tool in molecular pharmacology and pathology.



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Relationships between residue Voronoi volume and sequence conservation in proteins

Publication date: Available online 11 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Jen-Wei Liu, Chih-Wen Cheng, Yu-Feng Lin, Shao-Yu Chen, Jenn-Kang Hwang, Shih-Chung Yen
BackgroundFunctional and biophysical constraints can cause different levels of sequence conservation in proteins. Previously, structural properties, e.g., relative solvent accessibility (RSA) and packing density of the weighted contact number (WCN), have been found to be related to protein sequence conservation (CS). The Voronoi volume has recently been recognized as a new structural property of the local protein structural environment reflecting CS. However, for surface residues, it is sensitive to water molecules surrounding the protein structure. Herein, we present a simple structural determinant termed the relative space of Voronoi volume (RSV); it uses the Voronoi volume and the van der Waals volume of particular residues to quantify the local structural environment.MethodsRSV (range, 0–1) is defined as (Voronoi volume−van der Waals volume)/Voronoi volume of the target residue. The concept of RSV describes the extent of available space for every protein residue.ResultsRSV and Voronoi profiles with and without water molecules (RSVw, RSV, VOw, and VO) were compared for 554 non-homologous proteins. RSV (without water) showed better Pearson's correlations with CS than did RSVw, VO, or VOw values. The mean correlation coefficient between RSV and CS was 0.51, which is comparable to the correlation between RSA and CS (0.49) and that between WCN and CS (0.56).ConclusionsRSV is a robust structural descriptor with and without water molecules and can quantitatively reflect evolutionary information in a single protein structure. Therefore, it may represent a practical structural determinant to study protein sequence, structure, and function relationships.

Graphical abstract

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Stem Cells and Other Emerging Agents as Innovative “Drugs” in Neurodegenerative Diseases: Benefits and Limitations

Rejuvenation Research , Vol. 0, No. 0.


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Effect of brewing conditions on antioxidant properties of rosehip tea beverage: study by response surface methodology

Abstract

The aim of this study was to investigate the effects of brewing conditions (infusion time and temperature) on the antioxidant properties of rosehip tea beverage. The ascorbic acid content, total phenolic content (TPC), and ferric reducing antioxidant power (FRAP) of rosehip tea beverage were analysed. A two-factor and three-level central composite design was applied to evaluate the effects of the variables on the responses. The best quadratic models were obtained for all responses. The generated models were validated under the optimal conditions. At the optimal conditions, the rosehip tea beverage had 3.15 mg 100 mL⁻¹ of ascorbic acid, 61.44 mg 100 mL⁻¹ of TPC, and 2591 µmol of FRAP. The best brewing conditions for the rosehip tea beverage were found to be an infusion time of 6–8 min at temperatures of 84–86 °C.

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Atta (whole wheat flour) with multi-wholegrains: flour characterization, nutritional profiling and evaluation of chapati making quality

Abstract

Non-wheat grains, complementing the nutritional profile of wheat were utilized for the development of atta with multi-whole grains. Based on the dimensions, selected grains were segregated and the grinding techniques were applied for the production of multi whole grains flour. Multi whole grains flour was replaced with whole wheat flour to obtain five different formulations and further compared with control atta. With the increase in incorporation of the multi whole grain flours reduction in brightness (L*) from 79.73 to 78.47 and redness (a*) from 2.47 to 12.12 while the increase in yellowness (b*) was observed (12.10–12.70). Protein content increased from 13.44 to 14.83% while dietary fibre content was also found to be increased in all the formulations compared to control atta. Ash content, an indicator of mineral content showed an increasing trend with the increase in the level of non-wheat grains. Shear force required for tearing the chapatis at 0 h was observed to be in the range of 15.6 and 10.1 N and moisture content between 32.6 and 30.4%. Mineral analysis carried out for the 10% replacement showed an increase in the level of the estimated minerals. An overall eating quality of the chapatis was found to be acceptable up to 10% replacement compared to control atta chapati.

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Characterization of molecular structures of theaflavins and the interactions with bovine serum albumin

Abstract

In this study, theaflavins (TF1, TF2A, TF2B and TF3) were prepared from black tea and their interaction with bovine serum albumin (BSA) was explored by fluorescence and CD spectroscopy. The results showed that the structures of theaflavins exhibited significant effects on the binding/quenching process, and the binding affinity increased with the increase of molecular weight of theaflavins and the presence of galloyl moiety. The quenching effects showed a sequence as TF3 > TF2A > TF2B > TF1, demonstrating the important role of the galloyl moiety on the C-3 position of theaflavins. CD spectra indicated that TF3 in high concentration could change the skeleton structure of BSA and induce the unfolding of BSA secondary structure. The present results provide a new perspective for better understanding of the likely physiological fate of theaflavins and help to control the functional characteristics of food.

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κ-Casein as a source of short-chain bioactive peptides generated by Lactobacillus helveticus

Abstract

This paper explores the ability of Lactobacillus helveticus strains to release sequences of short biologically active peptides (containing 2–10 amino acid residues) from casein. The proteolytic enzymes of the tested strains exhibit different patterns of cleavage of CN fractions. The modification of κ-casein (κ-CN) with pyrrolidone carboxylic acid inhibits the proteolytic activity of strains L. helveticus 141 and the reference strain (DSMZ 20075), while the modification with phosphothreonine inhibits enzymes of all the tested bacteria. The peptide sequencing analysis indicated that the examined strains produced functional peptides very efficiently. κ-CN proved to be the main source of short peptides released by bacterial enzymes, and the hydrolysis of κ-CN yielded eighty-two bioactive peptides. The hydrolysis of α_S2-casein, α_S1-casein, and β-casein yielded six, two, and one short-chain bioactive peptides, respectively. The isolated bioactive peptides exhibited antioxidative, opioid, stimulating, hypotensive, immunomodulating, antibacterial, and antithrombotic activities. A vast majority of the isolated bioactive peptides caused inhibition of the angiotensin-converting enzyme and dipeptidyl peptidase IV. The role of hydrolysis products as neuropeptides is also pointed out. The highest number of cleavage sites in κ-casein and functional activities of short-chain peptides were obtained in hydrolyzates produced by L. helveticus strain T105.

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Preservation of orange juice using propolis

Abstract

Orange juice is one of the most popular and the most consumed fruit juices all over the world, especially in Europe and the chemical food preservatives, such as sodium benzoate, potassium sorbate and their mixtures, have long been used in orange juice sold on the market. Excessive consumption of these preservatives may be hazardous to human health. Propolis, composed of resins collected from plant buds and exudates and mixed with salivary gland secretions and beeswax by honey bee workers, has been used as a human medicine and natural food preservative. We hypothesis that propolis, without alcohol, can serve as an alternative and non-synthetic preservative of orange juice. In this study, the preservative effect of propolis emulsion on orange juice was determined up to 35 days. Propolis emulsion (0.02 g/mL propolis, 12 mL), emulsion control (12 mL containing Tween-80, hydrophilic phospholipid and polyethylene glycol 400), sodium benzoate (0.4 g) and potassium sorbate (0.4 g) was each added to 388, 388, 400 and 400 mL orange juice respectively. Propolis emulsion showed significant inhibition of bacteria growth and l-ascorbic acid degradation. Orange juice pH value, titratable acidity, total phenolic content, color and antioxidant capacity were effectively maintained by propolis emulsion. A control solution with all the same emulsifying agents without propolis did not show these properties. It was concluded that propolis can be used as a natural additive agent in orange juice or other fruit juices as an alternative to chemical preservatives.

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Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy

Abstract

Here we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)) and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca²⁺ concentrations, showed a reduced Ca²⁺-dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca²⁺-dependent aggregation for the p.Ile385Thr. Accordingly, limited trypsin proteolysis assay showed that p.Asp44Asn and p.Gly103Asp were more susceptible to trypsin cleavage in presence of Ca²⁺ in comparison to WT and p.Ile385Thr. Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in the response to caffeine stimulation, compared to normal control fibers. Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca²⁺ and a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca²⁺ entry. These results widen the spectrum of skeletal muscle diseases associated to CASQ1 and indicate that these mutations affect properties critical for correct Ca²⁺ handling in skeletal muscle fibers.

This article is protected by copyright. All rights reserved

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Outpatient management of pediatric acute mastoiditis

Evaluate the Montreal Children's Hospital experience with outpatient management of uncomplicated acute mastoiditis with parenteral antibiotic therapy alone and determine if it is a safe alternative to inpatient management.

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Practice patterns in the management of post-tonsillectomy hemorrhage: An American Society of Pediatric Otolaryngology survey

To evaluate practice patterns amongst pediatric otolaryngologists in the management of post-tonsillectomy hemorrhage.

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Preoperative Panel Testing for Hereditary Cancer Syndromes Does Not Significantly Impact Time to Surgery for Newly Diagnosed Breast Cancer Patients Compared with BRCA1/2 Testing

Abstract

Background

This study seeks to determine whether there is a delay in time to surgery in breast cancer patients with panel tests compared with traditional BRCA testing.

Methods

This study was a retrospective review of women diagnosed with breast cancer who underwent genetic evaluation from our institution's Genetic Counselor Database from January 2013 to August 2015. Patients were excluded if they were male, clinical information was unavailable, the patient underwent neoadjuvant chemotherapy, had a diagnosis of recurrent breast cancer during time of study, or had postoperative genetics evaluation.

Results

Included in the study were 138 patients. The time from diagnosis to surgery for BRCA1/2 tested patients was 43.5 days compared with 51.0 days in the panel group (p = 0.186). Turnaround time for genetic testing decreased during the period studied and was approximately 6 days longer for panel testing than BRCA testing. It took 12.2 days for BRCA results and 18.9 days for the panel results (p < 0.01). Turnaround time for BRCA1/2 testing in 2014 and 2015 was 12.4 and 10.5 days respectively, whereas panel testing was 20.5 and 18.2 days (p ≤ 0.001). Of the variables included in multivariable linear regression, only mastectomy significantly contributed to time to surgery (p < 0.001).

Discussion

Panel genetic testing did not delay time to surgery compared with BRCA testing alone. The use of panel testing has increased over time, and lab turnaround time has decreased. Mastectomy was the only clinical variable contributing to longer time to surgery.

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The Androgen Receptor: Is It a Promising Target?

Abstract

A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant therapeutic target for patients with AR-driven breast cancer. This has been most apparent in the subset of patients with triple-negative breast cancer (TNBC), in whom approximately 50% of tumors may have androgen dependence. Recent phase 2 clinical trials of agents that antagonize AR or reduce androgen production have shown clinical benefit and efficacy to varying degrees. This review highlights three of these recent trials of AR⁺ TNBC and acknowledge ongoing research in this exciting area.

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Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database

Abstract

Background

Occult breast cancer (OBC) is rare and optimal local–regional (LR) management has not been defined. Using a patient registry database, we examine factors associated with treatment and outcomes in OBC.

Methods

Female patients with cT0 N1/2 M0 BC were selected from the National Cancer Database (2004–2013) and categorized into four treatment groups: MAST = mastectomy with axillary lymph node dissection (ALND) ± radiation (RT); RT + ALND = RT with ALND, no breast surgery; ALND = ALND alone; OBS = no breast surgery, RT, or ALND. Patient characteristics and overall survival (OS) were compared between groups, and multivariable analysis was used to identify factors associated with treatment and OS.

Results

Among 2.03 million BC cases, 1853 females (0.09%) with cT0 N1/2 M0 disease were identified and 1231 patients were categorized into a treatment group: MAST = 592, RT + ALND = 342, ALND = 106, OBS = 191. On logistic regression, care at an academic center was associated with a higher likelihood of RT + ALND compared with MAST (odds ratio 2.03, 95% confidence interval [CI] 1.50–2.74, p < 0.001). Patients treated with RT + ALND had significantly better OS on univariate survival analysis compared with patients treated with MAST (hazard ratio [HR] 0.475, 95% CI 0.306–0.736, p = 0.001). RT + ALND was independently associated with OS on multivariable survival analysis (HR 0.509, 95% CI 0.321–0.808, p = 0.004), after adjusting for covariates.

Conclusions

Patients with OBC were more likely to undergo RT + ALND if they received care at an academic center. Patients treated with RT + ALND had significantly better OS compared with patients treated with MAST, after adjusting for covariates. This supports the use of RT + ALND as LR treatment for patients with OBC.

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Breast Cancer-Related Lymphedema Risk is Related to Multidisciplinary Treatment and Not Surgery Alone: Results from a Large Cohort Study

Abstract

Background

Breast cancer-related lymphedema (BCRL) is a significant complication for women undergoing treatment. We assessed BCRL incidence and risk factors in a large population-based cohort.

Methods

We utilized the Olmsted County Rochester Epidemiology Project Breast Cancer Cohort from 1990–2010 and ascertained BCRL and risk factors. The cumulative incidence estimator was used to estimate the rate of BCRL; competing risks regression was used for multivariable analysis.

Results

A total of 1794 patients with stage 0–3 breast cancer with a median of 10 years follow-up were included. The cumulative incidence of BCRL diagnosis within 5 years was 9.1% [95% confidence interval (CI) 7.8–10.5%]. No BCRL events occurred among patients without axillary surgery. In the axillary surgery subset (n = 1512), the 5-year incidence of BCRL was 5.3% in sentinel lymph node (SLN) surgery and 15.9% in axillary dissection (ALND) patients (p < 0.001). In patients treated with surgery only, BCRL rates were not different between ALND versus SLN (3.5 and 4.1% at 5 years, p = 0.36). Addition of breast or chest wall radiation more than doubled the BCRL rate in ALND patients (3.5 vs. 9.5% at 5 years, p = 0.01). The groups with highest risk (>25% at 5 years) all involved ALND with nodal RT and/or anthracycline/cytoxan + taxane chemotherapy. In multivariable analysis of patients with any axillary surgery factors significantly associated with BCRL were ALND, chemotherapy, radiation, and obesity.

Conclusions

BCRL is a sequelae of multimodal breast cancer treatment and risk is multifactorial. BCRL rates are higher in patients receiving chemotherapy, radiation, ALND, more advanced disease stage, and higher body mass index.

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Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes

Abstract

Background

How diagnosis with a variant of uncertain significance (VUS) in a BRCA gene impacts clinical decision-making is not well known.

Methods

We queried for all patients attending Mayo Clinic Rochester from 2004 to 2016 who tested positive for BRCA1 or BRCA2 VUS and reviewed patient management choices. Groups were compared by using Wilcoxon rank-sum and Chi-square tests.

Results

We identified 97 patients (95 females, 2 males) with BRCA VUS. For patients without cancer history (n = 20), 80% had a mother or sister with breast cancer, and median Tyrer-Cuzick (IBIS) lifetime breast cancer risk score was 27% (range 16–62%). Management included bilateral prophylactic mastectomy (BPM) in 39%, where choice for BPM was significantly associated with IBIS score (median 32 vs. 24%, p = 0.02) and first-degree family history of breast cancer (100 vs. 64%, p = 0.03) but not Gail score or total number of family members with cancer. For patients with breast cancer who had known VUS status prior to surgery (n = 9), the rate of contralateral prophylactic mastectomy (CPM) was 22% compared with 25% without known VUS and 83% with known BRCA pathogenic mutation. In 21 of 97 (22%) patients, the BRCA VUS has been reclassified (95% benign, 5% deleterious).

Conclusions

BRCA VUS carriers with cancer elected surgical choices similar to average-risk breast cancer patients. However, VUS carriers without cancer had high rates of BPM, associated with first-degree family history and IBIS score. Over time, a significant proportion of BRCA VUS were reclassified, illustrating the importance of appropriate counseling regarding VUS.

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Contralateral Prophylactic Mastectomy with Immediate Breast Reconstruction Increases Healthcare Utilization and Cost

Abstract

Background

The rates of contralateral prophylactic mastectomy (CPM) in women with unilateral breast cancer continue to rise, especially in women undergoing immediate breast reconstruction (IBR).

Methods

We utilized administrative claims data from a large US commercial insurance database (OptumLabs) to identify women age 18–64 years who underwent IBR between January 2004 and December 2013. We compared 2-year unadjusted utilization rates and total costs of care between unilateral mastectomy (UM) and bilateral mastectomy (BM) for implant-based and autologous reconstruction. Comparisons were tested using t-test and differences in cost were estimated using the Wilcoxon rank-sum test.

Results

Overall, 11,235 women undergoing mastectomy with IBR were identified; 7319 with implant reconstruction [1923 UM (26%) and 5396 BM (74%)] and 3916 with autologous reconstruction [1687 UM (43%) and 2229 BM (57%)]. The overall rate of office visits (2386 vs. 2391 per 100 women, p = 0.42) and hospital readmission rate (29.1 per 100 women vs. 27.4, p = 0.06) were similar between BM + IBR and UM + IBR. Women undergoing BM + IBR had a higher emergency room (ER) visit rate (34.1 per 100 women vs. 29.8, p < 0.0001). The total 2-year cost of care was higher for BM + IBR than UM + IBR for implant reconstruction ($106,711 vs. $97,218, p < 0.0001) and for autologous reconstruction ($114,725 vs. $87,874, p < 0.0001).

Conclusions

BM + IBR (autologous or implant) was associated with increased ER visits and higher total cost of care over 2 years compared with UM + IBR. Patients considering CPM should be counseled on the additional risks and costs associated with BM + IBR.

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Evaluating the Risk of Upstaging HER2-Positive DCIS to Invasive Breast Cancer

Abstract

Background

Overexpression of human epidermal growth factor 2 (HER2) in invasive breast cancer (IBC) is an independent poor prognostic factor. However, the significance of HER2 overexpression in ductal carcinoma in situ (DCIS) is not well defined. The current study assessed the correlation of HER2⁺ DCIS with the rate of upstaging to IBC on the final pathology.

Methods

The study retrospectively analyzed patients with the diagnosis of DCIS on core needle biopsy (CNB) at the authors' institution from 2009 to 2016. Data were analyzed using two-sample t tests. Multivariate analysis was performed using logistic regression.

Results

The study found that HER2⁺ DCIS had significantly higher rates of upstaging to IBC than HER2⁻ DCIS (odds ratio [OR] 1.89; p = 0.012). In addition, triple-positive disease was more than two times more likely to be upstaged (OR 2.5; p = 0.01), whereas patients with estrogen (ER)-positive, progesterone (PR)-positive, and HER2⁻ diseases were half as likely to be upstaged (OR 0.5; p = 0.04). Upstaging did not differ for patients with triple-negative disease (OR 0.89; p = 0.8). Additionally, patients with HER2⁺ DCIS were significantly younger regardless of ER/PR status (p = 0.03). The overexpression of HER2 in patients with an initial diagnosis of DCIS on CNB were twice as likely to have IBC on the final pathology as those who did not.

Conclusion

The results suggest that overexpression of HER2 may serve as a biomarker for risk stratification of patients with DCIS and may help to guide treatment strategies in the future. For institutions in which HER2 testing may be performed on DCIS, patients should be counseled appropriately about the risk of upgrade to IBC.

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A 10-Year Experience with Mastectomy and Tissue Expander Placement to Facilitate Subsequent Radiation and Reconstruction

Abstract

Background

An integrated approach to skin sparing mastectomy with tissue expander placement followed by radiotherapy and delayed reconstruction was initiated in our institution in 2002. The purpose of this study was to assess the surgical outcomes of this strategy.

Methods

Between September 2002 and August 2013, a total of 384 reconstructions had a tissue expander placed at the time of mastectomy and subsequently underwent radiotherapy. Rates and causes of tissue expander explantation before, during, and after radiotherapy, as well as tumor specific outcomes and reconstruction approaches, were collected.

Results

Median follow-up after diagnosis was 5.6 (range 1.3–13.4) years. In the study cohort, 364 patients (94.8%) had stage II–III breast cancer, and 7 patients (1.8%) had locally recurrent disease. The 5-year rates of actuarial locoregional control, disease-free survival, and overall survival were 99.2, 86.1, and 92.4%, respectively. The intended delayed-immediate reconstruction was subsequently completed in 325 of 384 mastectomies (84.6% of the study cohort). Of the remaining 59 tissue expanders, 1 was explanted before radiotherapy, 1 during radiotherapy, and 7 patients (1.8%) were lost to follow-up. Fifty patients (13.0%) required tissue expander explantation after radiation and before their planned final reconstruction, primarily due to cellulitis. Nonetheless, the cumulative rate of completed reconstructions was 89.6%. The median time from placement of the tissue expander until reconstruction was 12 (interquartile range 9–15) months.

Conclusions

Tissue expander placement at skin-sparing mastectomy in patients who require radiotherapy appears to be a viable strategy for combining reconstruction and radiotherapy.

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Lobular Neoplasia and Atypical Ductal Hyperplasia on Core Biopsy: Current Surgical Management Recommendations

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Predicting Nodal Positivity in Women 70 Years of Age and Older with Hormone Receptor-Positive Breast Cancer to Aid Incorporation of a Society of Surgical Oncology Choosing Wisely Guideline into Clinical Practice

Abstract

Purpose

One of the Society of Surgical Oncology Choosing Wisely guidelines recommends avoiding routine sentinel lymph node (SLN) surgery in clinically node-negative women ≥70 years of age with hormone receptor-positive (HR+) breast cancer. We sought to assess the impact of tumor stage and grade on nodal positivity, and to develop a model to identify patients at low-risk of nodal positivity to aid adoption of the guideline.

Methods

We identified women ≥70 years of age with HR+ cN0 invasive breast cancer in the National Cancer Database (NCDB; 2010–2013) and examined the impact of tumor stage and grade on nodal positivity to identify low-risk combinations. A multivariable logistic regression model was developed to incorporate additional factors. The area under the curve (AUC) and relative risks (RR) were used to assess performance.

Results

Among 71,834 cases, the pathologic nodal positivity (pN+) rate was 15.3%. We identified low-risk criteria as grade 1, cT1mi-T1c (≤2.0 cm), or grade 2, cT1mi-T1b (≤1.0 cm), with pN+ rates of 7.8% compared with 22.3% in patients not meeting these criteria (RR 2.86, p < 0.001). On multivariable analysis, factors associated with pN+ status included clinical T stage, grade, and histology (each p < 0.001). The resulting model had AUC 0.70 and identified women with low predicted probability (<10%) of positive nodes, of whom 6.3% were pN+, versus 21.2% in those with predicted probability ≥10% (RR 3.34, p < 0.001).

Conclusion

The simple clinical rule (grade 1, cT1mi-T1c, or grade 2, cT1mi-T1b), as well as the predictive model, both identify women at low risk of nodal positivity where SLN surgery can be omitted.

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Influence of Distance to Hospital and Insurance Status on the Rates of Contralateral Prophylactic Mastectomy, a National Cancer Data Base study

Abstract

Introduction

We evaluated the impact of travel distance and insurance status on contralateral prophylactic mastectomy (CPM) rates in breast cancer.

Methods

We queried the National Cancer Data Base (NCDB) for women >18 years of age with a nonmetastatic primary breast cancer of ductal, lobular, or mixed histology. Patient- and facility-specific CPM rates were calculated based on insurance, race, and distance to treatment center. Standard univariable and multivariable regression analysis was performed.

Results

Overall, the CPM rate was 6.5% for the 864,105 patients identified. Most patients traveled <20 miles to a treatment center (79.5%) and had private insurance or Medicare (58.3 and 33.4%, respectively). In general, younger, White, non-Hispanic, and privately insured patients residing further from a treatment center was associated with increased rates of CPM. However, distance to the treatment center and insurance type had a greater absolute impact on rates of CPM for Black and Hispanic patients. Absolute CPM rate increases for patients >100 miles from a treatment center compared with those <20 miles from a treatment center were observed to be greater for Black and Hispanic patients (3.5 and 3.9%, respectively) compared with White and non-Hispanic patients (2.5 and 2.6%). Additionally, further patient travel distance was associated with higher treatment center-specific CPM rates.

Conclusion

Increased travel distance is independently associated with increased rates of CPM for all patients and increased facility-specific rates of CPM. Black and Hispanic patients were found to be more vulnerable to the impact of travel distance and insurance status on rates of CPM.

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Challenging Atypical Breast Lesions Including Flat Epithelial Atypia, Radial Scar, and Intraductal Papilloma

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Intraoperative Radiation Using Low-Kilovoltage X-Rays for Early Breast Cancer: A Single Site Trial

Abstract

Introduction

Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative to whole breast radiation therapy following breast-conserving surgery for selected low-risk patients. However, minimal data are available about the clinical effectiveness of this modality of treatment using the Xoft^® Axxent^® Electronic Brachytherapy (eBx^®) System^®.

Methods

A total of 201 patients with 204 early-stage breast cancers were enrolled in a prospective X-ray IORT trial from June 2010 to September 2013. All tumors were treated with breast-conserving surgery and IORT. Data were collected at 1 week, 1 month, 6 months, 1 year, and yearly thereafter.

Results

With a median follow-up of 50 months, there have been seven ipsilateral breast tumor events (IBTE), no regional or distant recurrences, and no breast cancer-related deaths. One IBTE was within the IORT field, four outside of the IORT field but within the same quadrant as the index cancer, and two were new biologically different cancers in different quadrants. Three events were in patients who deviated from the protocol criteria. Kaplan–Meier analysis projects that 2.9% of patients will recur locally at 4 years.

Conclusions

Recurrence rates observed in this trial were comparable to those of the TARGIT-A and ELIOT trials as well as the retrospective TARGIT-R trial. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of IORT in selected women with low-risk breast cancer.

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Differences Among a Modern Cohort of BRCA Mutation Carriers Choosing Bilateral Prophylactic Mastectomies Compared to Breast Surveillance

Abstract

Background

Women with a BRCA mutation have significantly elevated breast cancer risk, which can be reduced by >90% with bilateral prophylactic mastectomy (BPM). We sought to compare a cohort of BRCA mutation carriers choosing BPM versus breast surveillance to better elucidate factors that may impact decision making.

Methods

Women with a BRCA mutation were retrospectively identified from a prospectively maintained database. The surveillance cohort (n = 313) consisted of women seen in a high-risk clinic between 2014 and 2016, while the surgery cohort (n = 142) consisted of women who underwent BPM between 2010 and 2016. Clinical and familial factors were compared between the groups.

Results

Women choosing BPM were more likely to have a BRCA1 than BRCA2 mutation compared with the surveillance group (57 vs. 45%, p = 0.02) and were less likely to have a personal history of ovarian cancer (10 vs. 20%, p = 0.01). Furthermore, women undergoing BPM were more likely to be married (78 vs. 62%, p = 0.01), to have more children (median 2 vs. 1, p < 0.001), and to have undergone a prophylactic oophorectomy (61 vs. 37%, p < 0.001). Women choosing BPM had more first-degree relatives (63 vs. 48%, p = 0.01) or a sister (23 vs. 14%, p = 0.02) with a history of breast cancer and were more likely to have a family member with ovarian cancer under the age of 40 years (9 vs. 4%, p = 0.03). There was no difference in the number of prior breast biopsies or history of atypia/lobular carcinoma in situ.

Conclusion

The decision to undergo BPM appears multifactorial, with gene mutation, family history, and relationships appearing to have the strongest influence on decision making.

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MACRA and the Changing Medicare Payment Landscape

Abstract

Background

The Medicare Access and CHIP Reauthorization Act (MACRA) is being implemented in 2017 by the Centers for Medicare and Medicaid Services (CMS) as the Quality Payment Program (QPP) and will have important and far reaching effects on how physicians are reimbursed and on how they practice. The QPP modifies the Medicare physician payment system by eliminating the Sustainable Growth Rate formula and incorporating the existing Physician Quality Reporting System, EHR Incentive Program, and the Value Modifier into a single new Merit-based Incentive Payment System (MIPS).

Methods

The authors reviewed the MACRA legislation as well as the CMS resources on the QPP and other sources to summarize the regulations pertaining to the new program, particularly for the first performance period.

Results

CMS has taken great care to create a smooth transition for Medicare physicians. Clinicians can avoid any penalty for performance in 2017 by submitting a minimal amount of quality data, attesting to a single improvement activity, or successfully attaining the base score for the advancing care information portion of MIPS. The reduced reporting period also makes it possible for participants to begin collecting data as late as October 2nd and still achieve the full possible score in the program.

Conclusions

Surgeons should be taking steps now to ensure that they are prepared to succeed in the QPP. The transition period creates a clear pathway for avoiding penalties while providing an opportunity to test one's ability to participate and improve performance.

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Selective Use of Sentinel Lymph Node Surgery in Patients Undergoing Prophylactic Mastectomy Using Intraoperative Pathology

Abstract

Background

Routine sentinel lymph node (SLN) surgery during prophylactic mastectomy (PM) is unnecessary, because most PMs do not contain cancer. Our institution utilizes intraoperative pathology to guide the surgical decision for resection of SLNs in PM. The purpose of this study was to review the effectiveness of this approach.

Methods

We identified all women aged ≥18 years who underwent bilateral PM (BPM) or contralateral PM (CPM) at our institution from January 2008 to July 2016. We evaluated the frequency of SLN resection and rate of occult breast cancer (DCIS or invasive disease) in the PM. We used the following definitions: over-treatment—SLN surgery in patients without cancer; under-treatment—no SLN surgery in patients with cancer; appropriate treatment—no SLN in patients without cancer or SLN surgery in patients with cancer.

Results

PM was performed on 1900 breasts: 1410 (74.2%) CPMs and 490 (25.8%) BPMs. Cancer was identified in 58 (3.0%) cases (32 invasive disease and 26 DCIS) and concurrent SLN surgery was performed in 44 (75.9%) of those cases. Overall, SLN surgery guided by intraoperative pathology resulted in appropriate treatment of 1787 (94.1%) cases: 1319 (93.5%) CPMs and 468 (95.5%) BPMs, by avoiding SLN in 1743/1842 cases without cancer (94.6%), and performing SLN surgery in 44/58 cases with cancer (75.9%).

Conclusions

Use of intraoperative pathology to direct SLN surgery in patients undergoing PM minimizes over-treatment from routine SLN in PM and minimizes under-treatment from avoiding SLN in PM, demonstrating the value of intraoperative pathology in this era of focus on appropriateness of care.

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Positive Ultrasound-guided Lymph Node Needle Biopsy in Breast Cancer may not Mandate Axillary Lymph Node Dissection

Abstract

Background

The ACOSOG Z0011 (Z11) trial demonstrated that in patients with nonpalpable axillary lymph nodes (LN) and one to two positive sentinel LN (SLN), axillary LN dissection (ALND) is unnecessary.JAMA 305:569–575, [2011], Ann Surg 264:413–42, [2016] The Z11 trial did not require preoperative axillary ultrasound (axUS). In many centers, preoperative axUS is part of the standard workup of a newly diagnosed breast cancer patient, but in light of the Z11 results, its role is now questioned.

Methods

We retrospectively analyzed newly diagnosed breast cancer patients at two institutions. Inclusion criteria were patients with (1) no palpable lymphadenopathy, (2) abnormal axUS, (3) axillary LN metastasis confirmed preoperatively by axUS-lymph node needle biopsy, (4) no neoadjuvant therapy, and (5) ALND. LN disease burden was dichotomized as N1 versus N2-3. We examined relationships between clinicopathologic factors, including axUS characteristics, and LN disease burden.

Results

Of 129 included cases, 67 had N1 disease (51.9%) and 62 had N2-3 disease (48.1%). Factors significantly associated with N1 disease were tumor size ≤2 cm (p = 0.012), nonlobular histology (p = 0.013), and one suspicious LN on axUS (p = 0.008). For patients with both tumor size on imaging ≤2 cm and one abnormal LN on axUS, only 27% had N2-3 disease (p = 0.007).

Conclusions

More than half of patients without palpable adenopathy but with preoperative US-guided biopsy proven axillary LN metastases had N1 disease. For patients with both tumor size ≤2 cm and only 1 abnormal LN on axUS, 73% had N1 disease. This suggests that such patients, if they are otherwise analogous to Z11 patients, may undergo attempt at SLNB.

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Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo

Publication date: Available online 11 September 2017
Source:Biochimie
Author(s): Yunhu Yu, Xiaohong Fu, Qishan Ran, Kaihua Yang, Yuanchao Wen, Hang Li, Fei Wang
Gliomas are the most recurrently occurring primary malignancies in the central nervous system. Despite surgical interventions, chemo- and radiotherapy, the results are unfortunately poor. Therefore, there is pressing need to explore more effective and efficient treatment options for treatment of glioma. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 μM against glioma U87 cells as against the IC50 of 65 μM against human astrocytes. The molecule exerted its anticancer activity through induction of apoptosis as evident from the Bid-, and Bax controlled cytochrome c and Omi/HtrA2 release, XIAP suppression, and caspase-9 and 3 signalling cascade. Additionally, it also caused cell cycle arrest of human glioma U87 cancer cells in the S phase of the cell cycle. Interestingly, globularifolin also caused significant inhibition of Akt/mTOR/p70S6K and MEK/ERK pathways. Globularifolin also inhibits cell migration and invasion by regulating the expression of matrix metalloproteinases (MMPs) in U87 glioma cells. We further investigated whether globularifolin exhibits the same effectiveness against glioma cell xenografts in nude mice in vivo and it was observed that globularifolin significantly reduced the tumor growth and volume in vivo indicating the potential of globularifolin as lead molecule for glioma chemotherapy.

Graphical abstract

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Lentiviral gene delivery to plasmolipin-expressing cells using Mus caroli endogenous retrovirus envelope protein

Publication date: Available online 11 September 2017
Source:Biochimie
Author(s): M.M. Prokofjeva, G.M. Proshkina, T.D. Lebedev, A.A. Shulgin, P.V. Spirin, V.S. Prassolov, S.M. Deyev
Gene therapy is a promising method for treating malignant diseases. One of the main problems is target delivery of therapeutic genes. Here we show that lentiviral vector particles pseudotyped with Mus caroli endogenous retrovirus (McERV) envelope protein can be used for selective transduction of PLLP-expressing cells. As a therapeutic gene in McERV-pseudotyped vector particles we used miniSOG encoding the cytotoxic FMN-binding protein, which can generate reactive oxygen species under illumination. Significant cytotoxic effect (up to 80% of dead cells in population) was observed in PLLP-expressing cells transduced with McERV-pseudotyped vector particles and subjected to illumination. We demonstrated that the McERV-pseudotyped HIV-1 based lentiviral vector particles are an effective tool for selective photoinduced destruction of PLLP-expressing cells.



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Selection of PD1/PD-L1 X-Aptamers

Publication date: Available online 11 September 2017
Source:Biochimie
Author(s): Hongyu Wang, Curtis H. Lam, Xin Li, Derek L. West, Xianbin Yang
Specific, chemically modified aptamers (X-Aptamers) were identified against two immune checkpoint proteins, recombinant Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1). Selections were performed using a bead-based X-Aptamer (XA) library containing several different amino acid functional groups attached to dU at the 5-position. The binding affinity and specificity of the selected XA-PD1 and XA-PDL1 were validated by hPD-1 and hPD-L1 expression cells, as well as by binding to human pancreatic ductal adenocarcinoma tissue. The selected PD1 and PDL1 XAs can mimic antibody functions in in vitro assays.



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Protonation equilibria and pore-opening structure of the dual-histidine influenza B virus M2 transmembrane proton channel from solid-state NMR [Molecular Biophysics]

The influenza A and B viruses are the primary cause of seasonal flu epidemics. Common to both viruses is the M2 protein, a homo-tetrameric transmembrane (TM) proton channel that acidifies the virion after endocytosis. Although influenza A M2 (AM2) and B M2 (BM2) are functional analogs, they have little sequence homology, except for a conserved HxxxW motif, which is responsible for proton selectivity and channel gating. Importantly, BM2 contains a second titratable histidine, His27, in the TM domain, which forms a reverse WxxxH motif with the gating tryptophan. To understand how His27 affects the proton conduction property of BM2, we have used solid-state NMR (SSNMR) to characterize the pH-dependent structure and dynamics of His27. In cholesterol-containing lipid membranes mimicking the virus envelope, 15N NMR spectra show that the His27 tetrad protonates with higher pKa's than His19, indicating that the solvent-accessible His27 facilitates proton conduction of the channel by increasing the proton dissociation rates of His19. AM2 is inhibited by the amantadine class of antiviral drugs while BM2 has no known inhibitors. We measured the N-terminal interhelical separation of the BM2 channel using fluorinated Phe5. The interhelical 19F-19F distances show a bimodal distribution of a short distance of 7 Å and a long distance of 15-20 Å, indicating that the phenylene rings do not block small-molecule entry into the channel pore. These results give insights into the lack of amantadine inhibition of BM2 and reveal structural diversities in this family of viral proton channels.

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Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility [Microbiology]

Myosin A (MyoA) is a Class XIV myosin implicated in gliding motility and host cell and tissue invasion by malaria parasites. MyoA is part of a membrane-associated protein complex called the glideosome, which is essential for parasite motility and includes the MyoA light chain MTIP, and several glideosome-associated proteins (GAPs). However, most studies of MyoA have focused on single stages of the parasite life cycle. We examined MyoA expression throughout the Plasmodium berghei life cycle in both mammalian and insect hosts. In extracellular ookinetes, sporozoites and merozoites, MyoA was located at the parasite periphery. In the sexual stages, zygote formation and initial ookinete differentiation precede MyoA synthesis and deposition, which occurred only in the developing protuberance. In developing intracellular asexual blood stages, MyoA was synthesized in mature schizonts and was located at the periphery of segmenting merozoites, where it remained throughout maturation, merozoite egress and host cell invasion. Besides the known GAPs in the malaria parasite, the complex included GAP40, an additional myosin light chain designated essential light chain (ELC) and several other candidate components. This ELC bound the MyoA neck region adjacent to the MTIP binding site, and both myosin light chains co-located to the glideosome. Co-expression of MyoA with its two light chains revealed that the presence of both light chains enhances MyoA-dependent actin motility. In conclusion, we have established a system to study the interplay and function of the three glideosome components, enabling the assessment of inhibitors that target this motor complex to block host cell invasion.

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Processive searching ability varies among members of the gap-filling DNA polymerase X family [DNA and Chromosomes]

DNA repair proteins must locate rare damaged sites within the genome. DNA polymerase beta (Pol β), a member of the DNA polymerase X family that is involved in base excision repair, uses a processive hopping search mechanism to locate substrates. This effectively enhances its search footprint on DNA, increasing the probability of locating damaged sites. Processive searching has been reported or proposed for many DNA-binding proteins, raising the question of how widespread or specific to certain enzymes the ability to perform this function is. To provide insight into this question, we compared the ability of three homologous DNA Pol X family members to perform a processive search for 1-nucleotide gaps in DNA using a previously developed biochemical assay. We found that at near-predicted physiological ionic strengths, the intramolecular searching ability of Pol β is at least 4-fold higher than that of Pol μ, and ~2-fold higher than that of Pol λ. Pol β also was able to perform intersegmental transfer, with the intersegmental searching ability of Pol β being at least 6-fold and ~2-fold higher than that of Pols μ and λ, respectively. Mutational analysis suggested that differences in the N-terminal domains of these polymerases are responsible for the varying degrees of searching competence. Of note, the differences in processive searching ability observed among the DNA Pol X family members correlated with their proposed biological functions in base excision repair and nonhomologous end joining.

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The intrinsically disordered N-terminal domain of galectin-3 dynamically mediates multisite self-association of the protein through fuzzy interactions [Molecular Biophysics]

Galectins are a family of lectins that bind β-galactosides through their conserved carbohydrate recognition domain (CRD) and can induce aggregation with glycoproteins or glycolipids on the cell surface and thereby regulate cell activation, migration, adhesion, and signaling. Galectin-3 has an intrinsically disordered N-terminal domain (NTD) and a canonical CRD. Unlike the other 14 known galectins in mammalian cells, which have dimeric or tandem-repeated CRDs enabling multivalency for various functions, galectin-3 is monomeric, and its functional multivalency therefore is somewhat of a mystery. Here, we used NMR spectroscopy, mutagenesis, small-angle X-ray scattering (SAXS), and computational modeling to study the self-association-related multivalency of galectin-3 at the residue-specific level. We show that the disordered NTD (~residues 20-100) interacts with itself and with a part of the CRD not involved in carbohydrate recognition (β-strands 7-9; residues ~200-220), forming a fuzzy complex via inter- and intramolecular interactions, mainly through hydrophobicity. These fuzzy interactions are characteristic of intrinsically disordered proteins to achieve liquid-liquid phase separation, and we demonstrated that galectin-3 can also undergo liquid-liquid phase separation. We propose that galectin-3 may achieve multivalency through this multisite self-association mechanism facilitated by fuzzy interactions.

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N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms [Molecular Biophysics]

The MYO1C gene produces three alternatively spliced isoforms, differing only in their N−terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nucleo−cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we over−expressed and purified the three full−length human isoforms from suspension−adapted HEK cells. MYO1CC favored the actomyosin closed state (AMC), MYO1C16 populated the actomyosin open state (AMO) and AMC equally, and MYO1C35 favored the AMO state. Moreover, the full−length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1CC constructs. Furthermore, global numerical simulation analysis predicted that MYO1C35 populated the actomyosin·ADP closed state (AMDC) 5−fold more than actomyosin·ADP open state (AMDO) and to a greater degree than MYO1CC and MYO1C16 (4−fold and 2−fold, respectively). On the basis of a homology model of the 35−amino acid NTR of MYO1C35 (NTR35) docked to the X−ray structure of MYO1CC, we predicted that a MYO1C35 NTR residue Arg−21 engages in a specific interaction with post−relay helix residue Glu−469 that affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR35 peptide to MYO1CC yielded a protein that transiently mimics MYO1C35 kinetic behavior. By contrast, NTR35 harboring the R21G mutation was unable to confer MYO1C35−like kinetic behavior. Therefore, the NTRs affect the specific nucleotide−binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine−tuning within MYO1C broadens its adaptability within cells.

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Lysine acetylation stoichiometry and proteomics analyses reveal pathways regulated by sirtuin 1 in human cells. [Genomics and Proteomics]

Lysine acetylation is a widespread posttranslational modification (PTM) affecting many biological pathways. Recent studies indicate that acetylated lysine residues mainly exhibit low acetylation occupancy, but challenges in sample preparation and analysis make it difficult to confidently assign these numbers, limiting understanding of their biological significance. Here, we tested three common sample preparation methods to determine their suitability for assessing acetylation stoichiometry in three human cell lines, identifying the acetylation occupancy in more than 1,300 proteins from each cell line. The stoichiometric analysis in combination with quantitative proteomics also enabled us to explore their functional roles. We found that higher abundance of the deacetylase sirtuin 1 (SIRT1) correlated with lower acetylation occupancy and lower levels of ribosomal proteins including those involved in ribosome biogenesis and rRNA processing. Treatment with the SIRT1 inhibitor EX-527 confirmed SIRT1's role in the regulation of pre-rRNA synthesis and processing. Specifically, proteins involved in pre-rRNA transcription, including subunits of the Pol 1 and SL1 complexes and the RNA polymerase I specific transcription initiation factor RRN3 were up-regulated after SIRT1 inhibition. Moreover, many protein effectors and regulators of pre-rRNA processing needed for rRNA maturation were also up-regulated after EX-527 treatment, with the outcome that pre-rRNA and 28S rRNA levels also increased. More generally, we found that SIRT1 inhibition down-regulates metabolic pathways including glycolysis and pyruvate metabolism. Together, these results provide the largest dataset thus far of lysine acetylation stoichiometry (available via ProteomeXchange with identifier PXD005903) and set the stage for further biological investigations of this central PTM.

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Estrogen receptor {beta}-dependent Notch1 activation protects vascular endothelium against tumor necrosis factor {alpha} (TNF{alpha})-induced apoptosis [Molecular Bases of Disease]

Unlike age-matched men, premenopausal women benefit from cardiovascular protection. Estrogens protect against apoptosis of endothelial cells (ECs), one of the hallmarks of endothelial dysfunction leading to cardiovascular disorders, but the underlying molecular mechanisms remain poorly understood. The inflammatory cytokine TNFα causes EC apoptosis while dysregulating the Notch pathway, a major contributor to EC survival. We have previously reported that 17β-estradiol (E2) treatment activates Notch signaling in ECs. Here, we sought to assess whether in TNFα-induced inflammation Notch is involved in E2-mediated protection of the endothelium. We treated human umbilical vein endothelial cells (HUVECs) with E2, TNFα, or both and found that E2 counteracts TNFα-induced apoptosis. When Notch1 was inhibited, this E2-mediated protection was not observed, whereas ectopic overexpression of Notch1 diminished TNFα-induced apoptosis. Moreover, TNFα reduced the levels of active Notch1 protein, which were partially restored by E2 treatment. Moreover, siRNA-mediated knockdown of estrogen receptor β (ERβ), but not ERα, abolished E2's effect on apoptosis. Additionally, the E2-mediated regulation of the levels of active Notch1 was abrogated after silencing ERβ. In summary, our results indicate that E2 requires active Notch1 through a mechanism involving ERβ to protect the endothelium in TNFα-induced inflammation. These findings could be relevant for assessing the efficacy and applicability of menopausal hormone treatment, since they may indicate that in women with impaired Notch signaling, hormone therapy might not effectively protect the endothelium.

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Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation [Microbiology]

Anthrax is a life threatening disease caused by infection with Bacillus anthracis, which expresses lethal factor and the receptor-binding protective antigen. These two proteins combine to form anthrax lethal toxin (LT), whose proximal targets are mitogen activated kinase kinases (MKKs). However, the downstream mediators of LT toxicity remain elusive. We herein report that LT exposure rapidly reduces the levels of cJun, a key regulator of cell proliferation and survival. Blockade of proteasome dependent protein degradation with the 26S proteasome inhibitor MG132 largely restored cJun protein levels, suggesting that LT promotes degradation of cJun protein. Using the MKK1/2 inhibitor U0126, we further show that MKK1/2/Erk1/2 pathway inactivation similarly reduces cJun protein, also restored by MG132 pre-exposure. Interestingly, cJun protein rebounded to normal levels 4 hours following U0126 exposure, but not after LT exposure. The restoration of cJun in U0126 exposed cells was associated with increased cJun mRNA levels and was blocked by inactivation of the JNK1/2 signaling pathway. These results indicate that LT reduces cJun both by promoting cJun protein degradation via inactivation of MKK1/2/Erk1/2 signaling and by blocking cJun gene transcription via inactivation of MKK4/JNK1/2 signaling. In line with cJuns known functions, LT also inhibited cell proliferation. Ectopic expression of LT resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT exposed cells, enabling the cells to maintain relatively normal cJun protein levels and cell proliferation. Taken together, these findings indicate that LT reduces cJun protein levels via two distinct mechanisms, thereby inhibiting critical cell functions, including cellular proliferation.

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The cytosolic domain of T-cell receptor {zeta} associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer [Signal Transduction]

Interactions between lipid bilayers and the membrane-proximal regions of membrane-associated proteins play important roles in regulat-ing membrane protein structure and function. The T-cell antigen receptor (TCR) is an assembly of eight single-pass membrane-spanning subunits on the surface of T-lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its ζ subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs (ITAMs) involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events. Interactions of the cytosolic domain of ζ (ζcyt) with acidic lipids have been implicated in the initiation and regulation of transmembrane signaling. ζcyt is unstructured in solution. Interaction with acidic phospholipids induces structure, but its disposition when bound to lipid bilayers is controversial. Here, using surface plasmon resonance and neutron reflection, we characterized the inter-action of ζcyt with planar lipid bilayers containing mixtures of acidic and neutral lipids. We observed two binding modes of ζcyt to the bilayers in dynamic equilibrium: one in which ζcyt is peripherally associated with lipid headgroups and one in which it penetrates deeply into the bilayer. Such an equilibrium between the peripherally bound and embedded forms of ζcyt apparently control accessibility of the ITAMs to tyrosine kinases and may regulate the TCR signal transduction pathway. Our results reconcile conflicting findings of the ζ structure reported in previous studies and provide a framework for understanding how lipid interac-tions regulate biological activities for this cell-surface receptor system.

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Molecular and functional characterization of the endothelial ATP-sensitive potassium channel [Molecular Bases of Disease]

ATP-sensitive potassium (KATP) channels are widely expressed in the cardiovascular system where they regulate a range of biological activities by linking cellular metabolism with membrane excitability. KATP channels in vascular smooth muscle have a well-defined role in regulating vascular tone. KATP channels are also thought to be expressed in vascular endothelial cells (ECs), but their presence and function in this context is less clear. As a result, we aimed to investigate the molecular composition and physiological role of endothelial KATP channels. We first generated mice with an endothelial specific deletion of the channel subunit Kir6.1 (eKO) using cre-loxP technology. Data from qRT-PCR, patch-clamp, ex-vivo coronary perfusion Langendorff heart experiments and endothelial cell Ca2+ imaging comparing eKO and wild type mice show that Kir6.1-containing KATP channels are indeed present in vascular endothelium. An increase in intracellular [Ca2+], which is central to changes in endothelial function such as mediator release, at least partly contributes to the endothelium-dependent vasorelaxation induced by the KATP channel opener pinacidil. The absence of Kir6.1 did not elevate basal coronary perfusion pressure in eKO mice. However, vasorelaxation was impaired during hypoxia in the coronary circulation and this resulted in greater cardiac injury during ischaemia-reperfusion. The response to adenosine receptor stimulation was impaired in eKO mice in single cells in patch-clamp recordings and in the intact coronary circulation. Our data support the existence of an endothelial KATP channel that contains Kir6.1, is involved in vascular reactivity in the coronary circulation and has a protective role in ischaemia reperfusion.

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High Quantum Yield Blue Emission from Lead-Free Inorganic Antimony Halide Perovskite Colloidal Quantum Dots

ACS Nano

DOI: 10.1021/acsnano.7b04683

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Psychological effects of a disastrous hydrogen fluoride spillage on the local community

On September 27, 2012, at 3:43 pm, a hydrogen fluoride spill occurred in a manufacturing plant located at the 4th complex of the Gumi National Industrial Complex in Gumi City, South Korea. The present study ai...

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Inside front cover (Editorial Board)

Publication date: September 2017
Source:Journal of Fluency Disorders, Volume 53





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IFA News

Publication date: September 2017
Source:Journal of Fluency Disorders, Volume 53





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Israel rake retractor modification to improve exposure during oropharyngeal surgery on patients with larger body habitus

Abstract

Purpose

Elective oropharyngeal surgery including tonsillectomy and uvulopalatopharyngoplasty performed for obstructive sleep apnea is increasingly performed on patients of larger body habitus. The use of the Crowe-Davis retractor in such patients may be complicated by a large barrel-chest making it difficult to anchor the retractor to the Mayo stand for suspension limiting oropharyngeal exposure. Here, we present a simple modification using the Israel Retractor to facilitate suspension of the Crowe-Davis mouth gag.

Methods

Operational instructions were followed for Israel retractor modification in oropharyngeal surgery.

Results

The Crowe-Davis retractor is able to anchor to the Israel retractor, whose prongs articulate on the Mayo Stand for suspension. This extension allows suspension of patients with larger body habitus in oropharyngeal surgery.

Conclusions

Use of the Israel retractor as an extension of the Crowe-Davis retractor handle provides an easy, quick, safe, and reliable method for placing patients of larger body habitus into suspension.

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