Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma

Abstract

Piwi-like RNA-mediated gene silencing 1 (PIWIL1) has been identified as a novel extremely highly expressed cancer-testis (CT) gene in lung adenocarcinoma. However, the exact function and mechanism of PIWIL1 in lung adenocarcinoma remains unclear. Herein, we sought to investigate the role of PIWIL1 in the occurrence and development of lung adenocarcinoma. We examined the expression pattern of PIWIL1 in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples, and validated it by Real-Time PCR (RT-PCR) in additional 21 paired lung adenocarcinoma tissues and 16 normal tissues. Subsequently, we explored the biological function of PIWIL1 in A549 and H1299 cell lines by gain and loss-of-function analyses. Using TCGA lung adenocarcinoma data, we further performed coexpression and Gene Ontology (GO) analyses, and analyzed the association of DNA methylation levels in PIWIL1 promoter region with its expression. Finally, we evaluated its expression in different mutation status of significantly mutated genes (SMGs) in TCGA lung adenocarcinoma data. We observed that PIWIL1 was expressed in testis and lung adenocarcinoma but not in other normal tissues, and its high expression was associated with shortened survival of lung cancer patients. Overexpression of PIWIL1 could facilitate the proliferation, invasion and migration of lung adenocarcinoma cells and vice versa. GO analysis revealed that PIWIL1 upregulated genes were enriched in embryonic development, cell proliferation and regulation of transcription. Moreover, promoter DNA hypomethylation of PIWIL1 could contribute to its aberrant expression in tumors. Interestingly, PIWIL1 expression was significantly higher in patients without hepatocyte growth factor (HGF) or serine/threonine kinase 11 (STK11) mutation (P = 0.006 and 0.005, respectively). PIWIL1 is an epidriver gene in lung adenocarcinoma, indicating a potential target for further therapy.

PIWIL1 is a novel extremely highly expressed cancer-testis gene in lung adenocarcinoma. PIWIL1 could promote the ability of proliferation, invasion, and migration in lung adenocarcinoma. The expression status of PIWIL1 is regulated by methylation in promoter region.

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Prognostic value of PD-L1 expression in combination with CD8+ TILs density in patients with surgically resected non-small cell lung cancer

Abstract

To investigate the prognostic value of PD-L1 expression combined with CD8⁺ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8⁺ TILs, and oncogenic alterations. PD-L1⁺ was detected in 71 (39.9%) and CD8^high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR⁻ were associated with both PD-L1⁺ and CD8^high TILs. Patients with CD8^high TILs had longer OS (P = 0.012). PD-L1⁻ was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8^high TILs (HR = 0.411; 95% CI, 0.177–0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1⁺/CD8^high and PD-L1⁺/CD8^low, respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8^high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8⁺ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Combination of PD-L1 and CD8⁺ TILs density may suggest impressive prognostic value in NSCLC patients instead of PD-L1 alone. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions, and significance of PD-L1 expression in a single-biopsy specimen in advanced NSCLC may be overestimated in clinical practice.

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Three cases of Nagashima-type palmoplantar keratosis associated with atopic dermatitis: A diagnostic pitfall

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Abrupt generalized pustules in patients with rheumatoid arthritis and interstitial lung disease

Abstract

We report a case of a 30-year-old Chinese woman with rheumatoid arthritis and interstitial lung disease who abruptly developed generalized pustules and a high fever for 10 days. She had been taking oral prednisone, iguratimod and total glucosides of peony regularly for 5 months prior. In addition, she had taken metronidazole for 3 days 20 days prior which she had used before with no adverse reaction. She had no history of similar lesions and psoriasis. A biopsy of a pustule on the back showed spongiform pustule of Kogoj. She was suspected of having generalized pustular psoriasis or acute generalized exanthematous pustulosis. Finally, she was diagnosed with generalized pustular psoriasis (von Zumbusch type) considering the characteristics and clinical course of the rash. In addition to the above three drugs, systemic cyclosporin (5 mg/kg per day) was applied, and the lesions and fever resolved within the proceeding 2 months.

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Unusual subcutaneous invasion of myxoid liposarcoma

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Transverse nasal crease with milia and comedones: Dermoscopic observation

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Successful treatment of hidradenitis suppurativa with rituximab for a patient with idiopathic carpotarsal osteolysis and chronic active antibody-mediated rejection

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Agranulocytosis associated with voriconazole-induced hypersensitivity syndrome

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Non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Abstract

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non-corticosteroid adherence. As such, non-corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non-corticosteroid users and 225 with moderate to severe itch who were defined as non-corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non-corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.

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Three cases of Nagashima-type palmoplantar keratosis associated with atopic dermatitis: A diagnostic pitfall

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Waardenburg syndrome type IIE in a Japanese patient caused by a novel non-frame-shift duplication mutation in the SOX10 gene

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Abrupt generalized pustules in patients with rheumatoid arthritis and interstitial lung disease

Abstract

We report a case of a 30-year-old Chinese woman with rheumatoid arthritis and interstitial lung disease who abruptly developed generalized pustules and a high fever for 10 days. She had been taking oral prednisone, iguratimod and total glucosides of peony regularly for 5 months prior. In addition, she had taken metronidazole for 3 days 20 days prior which she had used before with no adverse reaction. She had no history of similar lesions and psoriasis. A biopsy of a pustule on the back showed spongiform pustule of Kogoj. She was suspected of having generalized pustular psoriasis or acute generalized exanthematous pustulosis. Finally, she was diagnosed with generalized pustular psoriasis (von Zumbusch type) considering the characteristics and clinical course of the rash. In addition to the above three drugs, systemic cyclosporin (5 mg/kg per day) was applied, and the lesions and fever resolved within the proceeding 2 months.

http://ift.tt/2mTDvBE

Economic assessment of actual prescription of drugs for treatment of atopic dermatitis: Differences between dermatology and pediatrics in large-scale receipt data

Abstract

Using large-scale receipt data, we analyzed the differences in the prescription of drugs and their costs between dermatology and pediatrics in the treatment of atopic dermatitis (AD) in children. Between August 2010 and July 2011, 50 706 patients were diagnosed as having AD, and the data of 21 075 (15 257 dermatology, 5818 pediatric) patients aged 0–14 years were included in this study. The use of classes I (strongest), II (very strong), and III (strong) topical corticosteroids and tacrolimus was significantly higher in dermatology than in pediatrics (class I, 2.88% vs 0.76%; class II, 27.68% vs 8.32%; class III, 52.53% vs 39.88%; tacrolimus, 5.05% vs 2.82%; all P < 0.05). Although total drug costs were higher in dermatology than in pediatrics, mean drug costs per person were significantly higher in pediatrics. Moisturizers and protective agents had the highest cost (~ ¥690 million). The introduction rate of generic drugs was low at 8.3% among classes I–V. The introduction rate of moisturizers and protective agents, for which costs were the highest, was approximately 9%. The prescription of generic classes II–V topical corticosteroids and moisturizers and protective agents was also significantly higher in dermatology than in pediatrics (P < 0.05). Among patients younger than 2 years, 4405 received drugs for AD; classes I and II topical corticosteroids and tacrolimus (against the guidelines) were administrated in 35 (0.8%), 474 (10.8%) and 29 patients (0.7%), respectively. The introduction of generic drugs is still low, and the use of generic moisturizers and protective agents should be addressed further.

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Unusual subcutaneous invasion of myxoid liposarcoma

http://ift.tt/2mTDfma

Transverse nasal crease with milia and comedones: Dermoscopic observation

http://ift.tt/2zvpq3j

Successful treatment of hidradenitis suppurativa with rituximab for a patient with idiopathic carpotarsal osteolysis and chronic active antibody-mediated rejection

http://ift.tt/2mTCYzE

Agranulocytosis associated with voriconazole-induced hypersensitivity syndrome

http://ift.tt/2zuATQo

Core outcome research measures in anal cancer (CORMAC): protocol for systematic review, qualitative interviews and Delphi survey to develop a core outcome set in anal cancer

Introduction

The incidence of anal squamous cell carcinoma (ASCC) has increased threefold in the last 30 years. Initial treatment is chemoradiotherapy, associated with short-term and long-term side effects. Future therapy innovations aim to reduce morbidity in treatment of early tumours while maintaining treatment efficacy, and to escalate treatment intensity in locally advanced tumours with acceptable quality of life (QoL). However, all phase III randomised controlled trials to-date have utilised different primary outcomes, which hinders evidence synthesis and presents challenges to the selection of optimal outcomes in future trials. No trial comprehensively assessed long-term side effects and QoL, suggesting outcomes reflecting issues important to patients are under-represented. This project aims to determine the priority outcomes for all stakeholders and reach agreement on a standardised core set of outcomes to be measured and reported on in all future ASCC trials.

Methods and analysis

A systematic review will identify all outcomes reported in trials and observational studies of chemoradiotherapy as primary treatment for ASCC. Outcomes of importance to patients will be identified through patient interviews. The long list of outcomes generated from the systematic review and interviews will be used to create a two-round Delphi process, including key stakeholders (patients and healthcare professionals). The results of the Delphi will be discussed at a face-to-face consensus meeting. Discussion will focus on outcomes that did not achieve consensus through the Delphi process and conclude with anonymous voting to ratify the final core outcome set (COS).

Ethics and dissemination

The final COS will feed directly into the PersonaLising Anal cancer radioTherapy dOse (PLATO) national anal cancer trials and the Association of coloproctologists of Great Britain and Ireland (ACPGBI) supported national anal cancer database. Utilisation of the COS will increase the relevance of research output to all stakeholders and increase the capacity for data synthesis between trials. This study has ethical approval and is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative.

Trial registration number

PROSPERO registration ID: CRD42016036540

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Maternal and neonatal outcomes of vaginal breech delivery for singleton term pregnancies in a carefully selected Cameroonian population: a cohort study

Background and objectives

Vaginal breech delivery (VBD) is known to be associated with more perinatal and maternal complications. Very few studies on the subject have been carried out in poor-resource settings. The aim of this study was to determine maternal and neonatal outcomes in carefully selected cases of VBD for singleton term pregnancies in a tertiary centre in Cameroon.

Design

A retrospective cohort study.

Setting

A tertiary hospital in Yaounde, Cameroon.

Participants

Cases of VBD of newborns weighing 2500–3500 g were matched in a ratio of 1:4 to consecutive vaginal cephalic deliveries (VCDs) of newborns weighing 2500–3500 g over a 5-year period. Both groups were matched for maternal age and parity. We excluded cases of multiple gestations, footling breech, clinically inadequate maternal pelvis, preterm delivery, post-term pregnancies, fetal demise prior to the onset of labour, placenta praevia and fetal anomaly incompatible with vaginal delivery.

Outcome measures

Neonatal and maternal adverse outcomes of VBD observed till 6 weeks after delivery analysed using Bonferroni correction.

Results

Fifty-three (53) VBDs were matched against 212 VCD. Unlike women who had VCD, those who underwent VBD were more likely to have prolonged labour (OR 8.05; 95% CI 3.00 to 11.47; P<0.001), and their newborns were more likely to suffer from birth asphyxia (OR 10.24; 95% CI 4.92 to 21.31; P<0.001).

Conclusion

The study infers a strong association between VBD of singleton term pregnancies and maternofetal morbidity when specific protocols are applied. This, however, failed to translate into higher differences in perinatal mortality. This finding does not discount the role of VBD in low-income countries, but we emphasise the need for specific precautions like close monitoring of labour and adequate anticipation for neonatal resuscitation in order to reduce these complications.

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Impact of multimorbidity on healthcare professional task shifting potential in patients with type 2 diabetes in primary care: a French cross-sectional study

Objectives

To estimate the transferability of processes of care from general practitioners (GPs) to allied healthcare professionals and the determinants of such transferability.

Design

French national cross-sectional multicentre study

Setting

128 family practices providing supervised training for residents in general practice.

Participants

All patients consulting with their GP over a total number of 20 days (ie, 1 day a week from December 2011 to April 2012). Encounters where type 2 diabetes was one of the managed health problems were selected for analysis.

Primary and secondary outcome measures

Processes that were associated with specific health problems were collected by 54 residents. Potential process transferability was the main outcome assessed, as well as the professionals involved in the collaboration and the eventual conditions associated with transfer.

Results

From 8572 processes of care that concerned 1088 encounters of patients with diabetes, 21.9% (95% CI 21.1% to 22.8%) were considered eligible for transfer from GPs to allied healthcare professionals (78.1% to nurses, 36.7% to pharmacists). Processes were transferable with condition(s) for 70.6% (ie, a protocol, shared record or supervision). The most transferable processes concerned health maintenance (32.1%) and cardiovascular risk factors (hypertension (28.7%), dyslipidaemia (25.3%) and diabetes (24.3%)). Multivariate analysis showed that educational processes or a long-term condition status were associated with increased transferability (OR 3.26 and 1.47, respectively), whereas patients with higher intellectual occupations or those with two or more associated health problems were associated with lower transferability (OR 0.33 and 0.81, respectively).

Conclusions

A significant part of GP activity relating to patients with multimorbidity including type 2 diabetes could be transferred to allied healthcare professionals, mainly on prevention and global education to cardiovascular risk factors. The organisational and finance conditions of team work as views of patients and healthcare professionals must be explored before implementation in primary care.

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Authorship, plagiarism and conflict of interest: views and practices from low/middle-income country health researchers

Objectives

To document low/middle-income country (LMIC) health researchers' views about authorship, redundant publication, plagiarism and conflicts of interest and how common poor practice was in their institutions.

Design

We developed a questionnaire based on scenarios about authorship, redundant publication, plagiarism and conflicts of interest. We asked participants whether the described practices were acceptable and whether these behaviours were common at their institutions. We conducted in-depth interviews with respondents who agreed to be interviewed.

Participants

We invited 607 corresponding authors of Cochrane reviews working in LMICs. From the 583 emails delivered, we obtained 199 responses (34%). We carried out in-depth interviews with 15 respondents.

Results

Seventy-seven per cent reported that guest authorship occurred at their institution, 60% reported text recycling. For plagiarism, 12% of respondents reported that this occurred 'occasionally', and 24% 'rarely'. Forty per cent indicated that their colleagues had not declared conflicts of interest in the past. Respondents generally recognised poor practice in scenarios but reported that they occurred at their institutions. Themes identified from in-depth interviews were (1) authorship rules are simple in theory, but not consistently applied; (2) academic status and power underpin behaviours; (3) institutions and culture fuel bad practices and (4) researchers are uncertain about what conflict of interests means and how this may influence research.

Conclusions

LMIC researchers report that guest authorship is widely accepted and common. While respondents report that plagiarism and undeclared conflicts of interest are unacceptable in practice, they appear common. Determinants of poor practice relate to academic status and power, fuelled by institutional norms and culture.

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Midwife or doctor local opinion leader to implement a national guideline in babies on postnatal wards (DesIGN): protocol of a cluster-randomised, blinded, controlled trial

Introduction

Neonatal hypoglycaemia is a common condition that can cause developmental delay. Treatment of neonatal hypoglycaemia with oral dextrose gel has been shown to reverse hypoglycaemia and reduce admissions to neonatal intensive care for hypoglycaemia. An evidence-based clinical practice guideline was written to guide the use of dextrose gel to treat neonatal hypoglycaemia in New Zealand. However, it is unclear what clinical discipline might most effectively lead the implementation of the guideline recommendations.

Objective

To determine if midwife or doctor local opinion leaders are more effective in implementing a clinical practice guideline for use of oral dextrose gel to treat hypoglycaemia in babies on postnatal wards.

Methods and analysis

A cluster-randomised, blinded, controlled trial. New Zealand maternity hospitals that care for babies born at risk of neonatal hypoglycaemia will be randomised to having either a local midwife or doctor lead the guideline implementation at that hospital. The primary outcome will be the change in the proportion of hypoglycaemic babies treated with dextrose gel from before implementation of the guideline to 3 months after implementation.

Ethics and dissemination

Approved by Health and Disability Ethics Committee: 15/NTA/31. Findings will be disseminated to peer-reviewed journals, guideline developers and the public.

Trial registration number

ISRCTN61154098.

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The effect of nut consumption on markers of inflammation and endothelial function: a systematic review and meta-analysis of randomised controlled trials

Objectives

To examine the effect of nut consumption on inflammatory biomarkers and endothelial function.

Design

A systematic review and meta-analysis.

Data sources

MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health Literature and Cochrane Central Register of Controlled Trials (all years to 13 January 2017).

Eligibility criteria

Randomised controlled trials (with a duration of 3 weeks or more) or prospective cohort designs conducted in adults; studies assessing the effect of consumption of tree nuts or peanuts on C-reactive protein (CRP), adiponectin, tumour necrosis factor alpha, interleukin-6, intercellular adhesion molecule 1, vascular cell adhesion protein 1 and flow-mediated dilation (FMD).

Data extraction and analysis

Relevant data were extracted for summary tables and analyses by two independent researchers. Random effects meta-analyses were conducted to explore weighted mean differences (WMD) in change or final mean values for each outcome.

Results

A total of 32 studies (all randomised controlled trials) were included in the review. The effect of nut consumption on FMD was explored in nine strata from eight studies (involving 652 participants), with consumption of nuts resulting in significant improvements in FMD (WMD: 0.79%(95% CI 0.35 to 1.23)). Nut consumption resulted in small, non-significant differences in CRP (WMD: –0.01 mg/L (95% CI –0.06 to 0.03)) (26 strata from 25 studies), although sensitivity analyses suggest results for CRP may have been influenced by two individual studies. Small, non-significant differences were also found for other biomarkers of inflammation.

Conclusions

This systematic review and meta-analysis of the effects of nut consumption on inflammation and endothelial function found evidence for favourable effects on FMD, a measure of endothelial function. Non-significant changes in other biomarkers indicate a lack of consistent evidence for effects of nut consumption on inflammation. The findings of this analysis suggest a need for more research in this area, with a particular focus on randomised controlled trials.

PROSPERO registration number

CRD42016045424.

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Cerebrospinal fluid biomarkers for the diagnosis and prognosis of Parkinsons disease: protocol for a systematic review and individual participant data meta-analysis

Introduction

Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder related to α-synuclein misfolding and aggregation. For this reason, it belongs to the family of 'synucleinopathies', which also includes some other neurological diseases. Although imaging and ancillary investigations may be helpful in the diagnostic workup, the diagnosis of PD mostly relies on the clinician's expertise. Furthermore, there is a need today for markers that can track the disease progression in PD that might improve the evaluation of novel disease-modifying therapies. The cerebrospinal fluid (CSF) has been widely investigated with the purpose of finding useful diagnostic and prognostic biomarkers for PD.

Methods and analysis

This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol 2015 statement and was registered on the PROSPERO international prospective register of systematic reviews. An international collaboration will be established. We will search the Cochrane Library, Web of Science, Medline and Embase from inception, using appropriate search strategies. Individual participant data from all included studies will be merged into a single database. We will include any study assessing the diagnostic and prognostic role of CSF biomarkers in PD. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use Quality Assessment of Diagnostic Accuracy Studies-2 and Quality in Prognostic Studies. We will use standard meta-analytic procedures. We will first explore the utility of each CSF biomarker in turn. For each biomarker, we will assess its diagnostic and prognostic utility by means of receiver operating characteristic analysis and regression models. We will then move towards a multivariate approach considering different panels of biomarkers.

Ethics and dissemination

Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.

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Local anaesthetics combined with vasoconstrictors in patients with cardiovascular disease undergoing dental procedures: systematic review and meta-analysis protocol

Introduction

The use of vasoconstrictors combined with local anaesthetics (LAs) in dentistry for patients with cardiovascular disease (CVD) is still controversial in the scientific literature. It raises concerns regarding the possibility of transient episodes, triggering negative cardiovascular outcomes.

Method/design

Trials eligible for our systematic review will enrol patients with CVD who have undergone dental treatments carried out with the use of LAs by comparing two arms: LAs with vasoconstrictors and LAs without vasoconstrictors. The research will be conducted in the electronic databases, namely Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Healthstar (via Ovid), Cumulative Index to Nursing and Allied Health Literature and Web of Science, from their inception to December 2017, without any restrictions in terms of language and status of publication. A team of reviewers will independently assess titles, abstracts and complete text to determine eligibility. For eligible studies, the same reviewers will perform data extraction and evaluate the risk of bias in the selected articles. The selected outcomes comprise death, mortality by a specific cause, stroke, acute myocardial infarction, hospitalisation, pain, bleeding, arrhythmias, ischaemic episodes, anxiety, adverse effects, changes in blood pressure, changes in heart rate, anxiety and results obtained via oximetry. Whenever possible, we will conduct a meta-analysis to establish the effects of LAs with and without vasoconstrictors in the patients with CVD, and the overall quality of evidence for each outcome will be determined using the Grading of Recommendations Assessment, Development and Evaluation classification system.

Ethics and dissemination

Ethics committee approval was not necessary because this is a protocol of systematic review. This systematic review will be submitted for presentation at conferences and for publication in a peer-reviewed journal. Our review will assess the risks of cardiovascular events when using LAs with and without vasoconstrictors in patients with CVD, focusing on important clinical outcomes.

PROSPERO registration number

CRD42016045421.

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Identifying clinical features in primary care electronic health record studies: methods for codelist development

Objective

Analysis of routinely collected electronic health record (EHR) data from primary care is reliant on the creation of codelists to define clinical features of interest. To improve scientific rigour, transparency and replicability, we describe and demonstrate a standardised reproducible methodology for clinical codelist development.

Design

We describe a three-stage process for developing clinical codelists. First, the clear definition a priori of the clinical feature of interest using reliable clinical resources. Second, development of a list of potential codes using statistical software to comprehensively search all available codes. Third, a modified Delphi process to reach consensus between primary care practitioners on the most relevant codes, including the generation of an 'uncertainty' variable to allow sensitivity analysis.

Setting

These methods are illustrated by developing a codelist for shortness of breath in a primary care EHR sample, including modifiable syntax for commonly used statistical software.

Participants

The codelist was used to estimate the frequency of shortness of breath in a cohort of 28 216 patients aged over 18 years who received an incident diagnosis of lung cancer between 1 January 2000 and 30 November 2016 in the Clinical Practice Research Datalink (CPRD).

Results

Of 78 candidate codes, 29 were excluded as inappropriate. Complete agreement was reached for 44 (90%) of the remaining codes, with partial disagreement over 5 (10%). 13 091 episodes of shortness of breath were identified in the cohort of 28 216 patients. Sensitivity analysis demonstrates that codes with the greatest uncertainty tend to be rarely used in clinical practice.

Conclusions

Although initially time consuming, using a rigorous and reproducible method for codelist generation 'future-proofs' findings and an auditable, modifiable syntax for codelist generation enables sharing and replication of EHR studies. Published codelists should be badged by quality and report the methods of codelist generation including: definitions and justifications associated with each codelist; the syntax or search method; the number of candidate codes identified; and the categorisation of codes after Delphi review.

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Effectiveness of Gastrostomy for Improving Nutritional Status and Quality of Life in Patients with Epidermolysis Bullosa: A Systematic Review

Abstract

Inherited epidermolysis bullosa (EB) is a group of rare genetic disorders clinically characterized by a wide range of skin and mucosal blistering after minor trauma¹. This condition is caused by mutations on genes coding for structural proteins of the skin and affects both genders from all ethnic groups, and its estimated prevalence is about 500,000 cases worldwide².

This article is protected by copyright. All rights reserved.

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Effectiveness of Gastrostomy for Improving Nutritional Status and Quality of Life in Patients with Epidermolysis Bullosa: A Systematic Review

Abstract

Inherited epidermolysis bullosa (EB) is a group of rare genetic disorders clinically characterized by a wide range of skin and mucosal blistering after minor trauma¹. This condition is caused by mutations on genes coding for structural proteins of the skin and affects both genders from all ethnic groups, and its estimated prevalence is about 500,000 cases worldwide².

This article is protected by copyright. All rights reserved.

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Phytochemical and pharmacological evaluation of ethanolic extract of Lepisanthes rubiginosa L. leaves

The current study was conducted to evaluate the antioxidant, analgesic, antihyperglycemic, neuropharmacological and antidiarrheal activities of ethanolic extract of Lepisanthes rubiginosa L. leaves in different e...

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In vitro cytotoxic activity of medicinal plants from Nigeria ethnomedicine on Rhabdomyosarcoma cancer cell line and HPLC analysis of active extracts

Cancer is a leading cause of death world-wide, with approximately 17.5 million new cases and 8.7 million cancer related deaths in 2015. The problems of poor selectivity and severe side effects of the available...

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A putative Chondroprotective role for IL-1β and MPO in herbal treatment of experimental osteoarthritis

Herbal treatment may have a chondroprotective and therapeutic effect on Osteoarthritis (OA). We investigated the mechanism of action of ginger and curcumin rhizomes cultivated in Egypt in treatment of OA in ra...

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Acknowledgements to Reviewers

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Author Guidelines

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Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

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Acknowledgements to Reviewers

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Nasal Cytology: a Precision Medicine tool in clinical practice

Abstract

The BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis represents a precise and accurate document in defining the different sub-groups of patients suffering from allergic rhinitis (AR) and non-allergic rhinitis (NAR). We would like to stimulate the debate about this matter, mainly concerning the definition and classification of NAR. In particular, we would convince the readers that there are different phenotypes/endotypes of NAR in addition to non-allergic rhinitis with eosinophils (NARES). This concept is clinically relevant as deserves an adequate work-up and constitutes the background for the Precision Medicine (PM) approach.

This article is protected by copyright. All rights reserved.

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The COL5A3 and MMP9 genes interact in eczema susceptibility

Abstract

Background

Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored Gene–Gene (G-G) interactions.

Objective

Our aim was to detect new interacting genes involved in eczema.

Methods

The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second-step, an interaction analysis of the selected genes. Analyses were carried out at both SNP and gene levels in three asthma-ascertained family samples: the discovery dataset of 388 EGEA (Epidemiological study on the Genetics and Environment of Asthma) families and the two replication datasets of 253 SLSJ (Saguenay-Lac-Saint-Jean) families and 207 MRCA (Medical Research Council) families.

Results

One pair of SNPs, rs2287807 in COL5A3 and rs17576 in MMP9, that were detected in EGEA at P ≤ 10^-5 showed significant interaction by meta-analysis of EGEA, SLSJ and MRCA samples (P=1.1x10^-8 under the significant threshold of 10^-7). Gene-based analysis confirmed strong interaction between COL5A3 and MMP9 (P=4x10^-8 under the significant threshold of 4x10^-6) by meta-analysis of the three datasets. When stratifying the data on asthma, this interaction remained in both groups of asthmatic and non-asthmatic subjects.

Conclusion

This study identified significant interaction between two new genes, COL5A3 and MMP9, which may be accounted for by a degradation of COL5A3 by MMP9 influencing eczema susceptibility.

Further confirmation of this interaction as well as functional studies are needed to better understand the role of these genes in eczema.

This article is protected by copyright. All rights reserved.

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Novel STRA6 null mutations in the original family described with Matthew–Wood syndrome

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Single suture craniosynostosis: Identification of rare variants in genes associated with syndromic forms

We report RNA-Sequencing results on a cohort of patients with single suture craniosynostosis and demonstrate significant enrichment of heterozygous, rare, and damaging variants among key craniosynostosis-related genes. Genetic burden analysis identified a significant increase in damaging variants in ATR, EFNA4, ERF, MEGF8, SCARF2, and TGFBR2. Of 391 participants, 15% were found to have damaging and potentially causal variants in 29 genes. We observed transmission in 96% of the affected individuals, and thus penetrance, epigenetics, and oligogenic factors need to be considered when recommending genetic testing in patients with nonsyndromic craniosynostosis.

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Congenital limb deficiencies and major associated anomalies in Alberta for the years 1980–2012

There is a wide range of the proportion of congenital anomalies associated with limb deficiencies reported in the literature. This variation is primarily attributed to methodology and classification differences. The distribution of associated anomalies among cases with congenital limb deficiencies in Alberta born between January 1, 1980 and December 31, 2012 is described. Of the 170 cases identified, most were live born (75.3%), male (61.8%), had longitudinal limb deficiencies (78.8%), and had associated anomalies outside the musculoskeletal system (77.6%). Significant associations between the preaxial longitudinal group and the central nervous, gastrointestinal, and cardiovascular systems are reported as well as between the postaxial longitudinal group and congenital hip and foot anomalies. Probable and possible syndrome diagnoses are described for cases with recognized malformation patterns.

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Nasal Cytology: a Precision Medicine tool in clinical practice

Abstract

The BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis represents a precise and accurate document in defining the different sub-groups of patients suffering from allergic rhinitis (AR) and non-allergic rhinitis (NAR). We would like to stimulate the debate about this matter, mainly concerning the definition and classification of NAR. In particular, we would convince the readers that there are different phenotypes/endotypes of NAR in addition to non-allergic rhinitis with eosinophils (NARES). This concept is clinically relevant as deserves an adequate work-up and constitutes the background for the Precision Medicine (PM) approach.

This article is protected by copyright. All rights reserved.

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Brain-derived neurotrophic factor (BDNF) determines a sex difference in cue-conditioned alcohol seeking in rats

Publication date: 26 February 2018
Source:Behavioural Brain Research, Volume 339
Author(s): Samuel J. Hogarth, Emily J. Jaehne, Maarten van den Buuse, Elvan Djouma
Alcohol use disorder is a detrimental addictive disease that develops through prolonged ethanol exposure and regular intoxication. However, the changes in the underlying neurobiology leading to alcohol addiction remain unclear. Brain-Derived Neurotrophic Factor (BDNF) is implicated in substance abuse disorders including alcoholism. As the vast majority of previous animal model studies have concentrated on males only, the aim of this study was to determine whether endogenous BDNF mediates alcohol seeking in a sex-specific manner.We used an operant self-administration paradigm where the animals were trained in operant chambers to self-administer a 10% ethanol solution, and compared male and female BDNF heterozygous (HET) and wildtype (WT) rats. Over several weeks, the animals progressed through acquisition, progressive ratio, extinction, and reinstatement phases.There were no significant sex or genotype differences in the number of alcohol-paired lever presses during acquisition, progressive ratio and extinction. However, a significant difference between male and female WT rats following alcohol-primed reinstatement was completely absent in BDNF HET rats suggesting a role of BDNF in sex differences in alcohol seeking after abstinence. Female BDNF HET rats showed significantly higher number of alcohol-paired lever presses during reinstatement than female WT controls.These findings suggest that BDNF regulatory pathways are involved in sex differences in reinstatement of alcohol intake and emphasize the need to include both male and female animals to explore sex-specific interactions in addiction neurocircuitry.



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Relevance-dependent modulation of tactile suppression during active, passive and pantomime reach-to-grasp movements

Publication date: 26 February 2018
Source:Behavioural Brain Research, Volume 339
Author(s): Damian M. Manzone, J. Timothy Inglis, Ian M. Franks, Romeo Chua
When we move, our ability to detect tactile events on the moving limb is reduced (e.g., movement-related tactile suppression). This process prevents unimportant sensory information from bombarding our central nervous system. This study investigated whether movement-related suppression can be modulated according to task relevance, while introducing a novel motor-driven complex upper limb movement. In three experiments, participants performed volitional self-driven and passive motor-driven reaching and grasping movements. Over the course of the movement, weak electrical stimulation was presented at task-relevant (i.e., index finger) and irrelevant sites (i.e., forearm) on the moving limb. In Experiment 1, participants displayed reduced detectability during movement (90% resting detection). This was true for all locations on the moving limb irrespective of task-relevance and during both self and motor-driven movements. In Experiments 2 and 3 a range of stimulus amplitudes were presented to one task-relevant location during both self and motor-driven movements (Experiment 2A), to a task-relevant and irrelevant site (Experiment 2B) and during a targeted and pantomime/no target reach (Experiment 3). This allowed us to estimate perceptual thresholds and assess the magnitude of movement-related suppression. During both self and motor-driven movements participants exhibited movement-related suppression. Suppression was greater at the irrelevant site (forearm) than at the relevant site (index finger) of the limb. Further, the magnitude of suppression varied with task relevance such that pantomime movements elicited more suppression than targeted movements. Collectively, these experiments suggest that although tactile suppression may be a general consequence of movement, suppression can be modulated in a relevance-dependent manner.



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The development of neuromotor skills and hand preference during infancy

Abstract

Assessing infant handedness has been controversial. Different assessment techniques and theoretical approaches produce different results. Evidence from a dynamic systems perspective showed that the development of postural control during infancy affects the expression of an infant's handedness. However, others found that developmental changes in postural control influenced the amount of symmetrical (bimanual) reaching during infancy, but not hand preference. Since most studies of infant handedness use age to assess development, perhaps measures of an infant's developing neuromotor control, irrespective of age, would better predict changes in an infant's hand preference. To assess neuromotor development, items from [Touwen's (1976) Neurological development in infancy. Lavenham, Suffolk: The Lavenham Press, LTD]. "Group III" indices were used. These items assess developmental changes in neuromotor abilities throughout the 6–14-month age period. Hand preference for acquiring objects was measured during these same months. Group Based Trajectory Models (GBTM) of 380 infants identified four different groups of infants according to the trajectory of the development of their hand preferences (32% Early Right, 12% Early Left, 25% Late Right, 30% No Preference). A multilevel model was used to compare these four developmental trajectories according to age and neuromotor development. Age, not neuromotor development, is a better predictor of differences in developmental trajectories of the four hand preference groups. However, Late Right infants are significantly less developed at 6 months than No Preference, Early Right and Left infants and both Early Right and Left infants are most advanced at 6 months. All groups exhibit similar rates of neuromotor development indicating no "catch-up" by the Late Right infants. Thus, any assessment of infant handedness will incorporate necessarily four groups of infants with differently developing hand preferences and neuromotor abilities.

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Leaf saponins of Quillaja brasiliensis enhance long-term specific immune responses and promote dose-sparing effect in BVDV experimental vaccines

Publication date: Available online 23 November 2017
Source:Vaccine
Author(s): Samuel Cibulski, Mariana Rivera-Patron, Norma Suárez, Macarena Pirez, Silvina Rossi, Anna Carolina Yendo, Fernanda de Costa, Grace Gosmann, Arthur Fett-Neto, Paulo Michel Roehe, Fernando Silveira
Saponin-based adjuvants are promising adjuvants that enhance both humoral and T-cell-mediated immunity. One of the most used natural products as vaccine adjuvants are Quillaja saponaria bark saponins and its fraction named Quil A®. Despite that, its use has been restricted for human use due to safety issues. As an alternative, our group has been studying the congener species Quillaja brasiliensis saponins and its performance as vaccine adjuvants, which have shown to trigger humoral and cellular immune responses comparable to Quil A® but with milder side effects. Here, we studied a semi purified aqueous extract (AE) and a previously little characterized saponin-enriched fraction (QB-80) from Q. brasiliensis as vaccine adjuvants and an inactivated virus (bovine viral diarrhea virus, BVDV) antigen co-formulated in experimental vaccines in mice model. For the first time, we show the spectra pattern of the Q. brasiliensis saponins by MALDI-TOF, a novel and cost-effective method that could be used to characterize different batches during saponins production. Both AE and QB-80 exhibited noteworthy chemical similarities to Quil A®. In addition, the haemolytic activity and toxicity were assessed, showing that both AE and QB-80 were less toxic than Quil A®. When subcutaneously inoculated in mice, both fractions promoted long-term strong antibody responses encompassing specific IgG1 and IgG2a, enhanced the avidity of IgG antibodies, induced a robust DTH reaction and significantly increased IFN-ɣ production in T CD4⁺ and T CD8⁺ cells. Furthermore, we have proven herein that AE has the potential to promote dose-sparing, substantially reducing the dose of antigen required for the BVDV vaccines and still eliciting a mixed Th1/Th2 strong immune response. Based on these results, and considering that AE is a raw extract, easier and cheaper to produce than commercially available saponins, this product can be considered as candidate to be escalated from experimental to industrial uses.



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Molecular epidemiology of influenza B virus and implications in immunization strategy, Southern Brazil

Publication date: Available online 23 November 2017
Source:Vaccine
Author(s): Bruna Lapinscki, Luciane A. Pereira, Meri B. Nogueira, Luine R. Vidal, Irina Riediger, Maria C. Debur, Mayra Presibella, Sonia M. Raboni
Epidemiological indicators have shown the substantial impact of influenza B (Flu B) on the development of severe acute respiratory infection (SARI) and on mortality rates. In Brazil, the trivalent vaccine, composed of only one Flu B lineage is available. We investigated Flu B infections in clinical samples collected by the epidemiological surveillance service of Paraná State, Brazil, from 2013 to 2016. The Flu B lineages Yamagata- (B/Yam) and Victoria-like (B/Vic) were identified using the qRT-PCR assay, and notification forms were reviewed. Among 379 Flu B positive samples evaluated, 370 (98%) were characterized as B/Yam or B/Vic lineages. Both co-circulated with a frequency of 47% and 53%, respectively. B/Yam infected equally both genders, while B/Vic was more frequent in females (71%). The median age of patients infected by B/Vic (23y; 11–35) was lower than that of patients infected by B/Yam (32y; 12–50). Mismatch between the vaccine and the circulating strain was observed in the 2013 season, with a high number of SARI cases. B/Vic lineage was associated with a larger number of SARI cases (62%), while B/Yam with influenza-like illness (ILI) (61%). Differences were observed in the strains circulating in separate regions of Paraná State. B/Vic was prevalent in the northwestern (67%) and B/Yam in the southeastern region (60%). The unpredictability of Flu B lineage circulation causes a substantial increase in severe disease during epidemics in a vaccine mismatch season. In addition, the differences in the epidemiological profile of the target population of Flu B infections in relation to other respiratory viruses, as well as among the B/Vic and B/Yam lineages may also be associated to an increase in disease burden. These findings have direct consequences on vaccination strategies. Therefore, further molecular epidemiology studies of Flu B in Brazil are required to corroborate these primary results.



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Knowledge, attitudes, and practices of private sector immunization service providers in Gujarat, India

Publication date: Available online 23 November 2017
Source:Vaccine
Author(s): José E. Hagan, Narayan Gaonkar, Vikas Doshi, Anas Patni, Shailee Vyas, Vihang Mazumdar, J.K. Kosambiya, Satish Gupta, Margaret Watkins
BackgroundIndia is responsible for 30% of the annual global cohort of unvaccinated children worldwide. Private practitioners provide an estimated 21% of vaccinations in urban centers of India, and are important partners in achieving high vaccination coverage.MethodsWe used an in-person questionnaire and on-site observation to assess knowledge, attitudes, and practices of private immunization service providers regarding delivery of immunization services in the urban settings of Surat and Baroda, in Gujarat, India. We constructed a comprehensive sampling frame of all private physician providers of immunization services in Surat and Baroda cities, by consulting vaccine distributors, local branches of physician associations, and published lists of private medical practitioners. All providers were contacted and asked to participate in the study if they provided immunization services. Data were collected using an in-person structured questionnaire and directly observing practices; one provider in each practice setting was interviewed.ResultsThe response rate was 82% (121/147) in Surat, and 91% (137/151) in Baroda. Of 258 participants 195 (76%) were pediatricians, and 63 (24%) were general practitioners. Practices that were potential missed opportunities for vaccination (MOV) included not strictly following vaccination schedules if there were concerns about ability to pay (45% of practitioners), and not administering more than two injections in the same visit (60%). Only 22% of respondents used a vaccination register to record vaccine doses, and 31% reported vaccine doses administered to the government. Of 237 randomly selected vaccine vials, 18% had expired vaccine vial monitors.ConclusionsQuality of immunization services in Gujarat can be strengthened by providing training and support to private immunization service providers to reduce MOVs and improve quality and safety; other more context specific strategies that should be evaluated may involve giving feedback to providers on quality of services delivered and working through professional societies to adopt standards of practice.



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Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm

Abstract

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

Aromatase inhibitor-related arthralgias (AIA) are common and may lead to therapy noncompliance. Whereas traditional gene studies to identify arthralgia risk have been limited in scope, we employed a novel analytic algorithm to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

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Synergistic inhibition of cell proliferation by combined targeting with kinase inhibitors and dietary xanthone is a promising strategy for melanoma treatment

Summary

α-Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single-agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)-3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α-mangostin, by screening from a kinase inhibitor library for melanogenesis in SK-MEL-2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis-related proteins. We also explored the molecular mechanisms for the apoptosis-inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α-mangostin, which we verified through apoptosis-related methods. These data provide a strong rationale for the use of α-mangostin as an adjunct to GSK-3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α-mangostin might be inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.

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Synergistic inhibition of cell proliferation by combined targeting with kinase inhibitors and dietary xanthone is a promising strategy for melanoma treatment

Summary

α-Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single-agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)-3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α-mangostin, by screening from a kinase inhibitor library for melanogenesis in SK-MEL-2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis-related proteins. We also explored the molecular mechanisms for the apoptosis-inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α-mangostin, which we verified through apoptosis-related methods. These data provide a strong rationale for the use of α-mangostin as an adjunct to GSK-3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α-mangostin might be inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.

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Dose warping uncertainties for the accumulated rectal wall dose in cervical cancer brachytherapy

Publication date: Available online 22 November 2017
Source:Brachytherapy
Author(s): Laura E. van Heerden, Niek van Wieringen, Kees Koedooder, Coen R.N. Rasch, Bradley R. Pieters, Arjan Bel
PurposeStructure-based deformable image registration (DIR) can be used to calculate accumulated dose volume histogram parameters for cervical cancer brachytherapy (BT). The purpose of this study is to investigate dose warping uncertainties for the accumulated dose to the 2 cm³ receiving the highest dose (D2cm3) in the rectal wall, using a physically realistic model (PRM) describing rectal wall deformation.Methods and materialsFor 10 patients, treated with MRI-guided pulsed dose rate BT (two times 24 × 0.75 Gy, given in two applications BT1 and BT2), the planning images were registered with structure-based DIR. The resulting transformation vectors were used to accumulate the total rectum dose from BT. To investigate the dose warping uncertainty, a PRM describing rectal deformation was used. For point pairs on rectumBT1 and rectumBT2 that were at the same location according to the PRM, the dose for BT1 and BT2 was added (DPRM) and compared to the DIR-accumulated dose (DDIR) in the BT2 point. The remaining distance after DIR between corresponding point pairs, defined as the residual distance, was calculated.ResultsFor points within the D2cm3 volume, more than 75% was part of the D2cm3 volume according to both PRM and DIR. The absolute dose difference was <7.3 GyEQD2, and the median (95th percentile) of the residual distance was 8.7 (22) mm.ConclusionsDIR corresponded with the PRM for on average 75% of the D2cm3 volume. Local absolute dose differences and residual distances were large. Care should therefore be taken with DIR for dose-warping purposes in BT.



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Reduction of MRI signal distortion from titanium intracavitary brachytherapy applicator by optimizing pulse sequence parameters

Publication date: Available online 22 November 2017
Source:Brachytherapy
Author(s): Thomas P. Sullivan, Matthew M. Harkenrider, Murat Surucu, Abbie M. Wood, Joseph H. Yacoub, Steven M. Shea
PurposeTo demonstrate that optimized pulse sequence parameters for a T2-weighted (T2w) fast spin echo acquisition reduced artifacts from a titanium brachytherapy applicator compared to conventional sequence parameters.Methods and materialsFollowing Institutional Review Board approval and informed consent, seven patients were successfully imaged with both standard sagittal T2w fast spin echo parameters (voxel size of 0.98 × 0.78 × 4.0 mm³; readout bandwidth of 200 Hz/px; repetition time of 2800 ms; echo time of 91 ms; echo train length of 15; 36 slices; and imaging time of 3:16 min) and an additional optimized T2w sequence (voxel size of 0.98 × 0.98 × 4.0 mm³; readout bandwidth of 500 Hz/px; repetition time of 3610 ms; echo time of 91 ms; echo train length of 25; 18–36 slices; and imaging time of 1:15–2:30 min), which had demonstrated artifact reduction in prior phantom work. Visualized intracavitary tandem was hand-segmented by two of the authors. Three body imaging radiologists assessed image quality and intraobserver agreement scores were analyzed.ResultsThe average segmented volume of the intracavitary applicator significantly (p < 0.05) decreased with the experimental pulse sequence parameters as compared to the standard pulse sequence. Comparison of experimental and standard T2w sequence qualitative scores for each reviewer showed no significant differences between the two techniques.ConclusionsThis study demonstrated that pulse sequence parameter optimization can significantly reduce distortion artifact from titanium applicators while maintaining image quality and reasonable imaging times.



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Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus

Abstract

The retrotrapezoid nucleus, RTN, regulates breathing in a CO₂ and state-dependent manner. RTN neurons are glutamatergic and innervate principally the respiratory pattern generator; they regulate multiple aspects of breathing, including active expiration, and maintain breathing automaticity during non-REM sleep. RTN neurons encode arterial PCO₂ /pH via cell-autonomous and paracrine mechanisms, and via input from other CO₂-responsive neurons. In short, RTN neurons are a pivotal structure for breathing automaticity and arterial PCO₂ homeostasis.

The carotid bodies stimulate the respiratory pattern generator directly and, indirectly, by activating RTN via a neuronal projection originating within the solitary tract nucleus. The indirect pathway operates under normo- or hypercapnic conditions; under respiratory alkalosis (e.g. hypoxia) RTN neurons are silent and the excitatory input from the carotid bodies is suppressed. Also, silencing RTN neurons optogenetically quickly triggers a compensatory increase in carotid body activity. Thus, in conscious mammals, breathing is subject to a dual and interdependent feedback regulation by chemoreceptors. Depending on the circumstance, the activity of the carotid bodies and that of RTN vary in the same or the opposite direction, producing additive or countervailing effects on breathing. These interactions are mediated either via changes in blood gases or by brainstem neuronal connections but their ultimate effect is invariably to minimize arterial PCO₂ fluctuations.

We discuss the potential relevance of this dual chemoreceptor feedback to cardiorespiratory abnormalities present in diseases in which the carotid bodies are hyperactive at rest, e.g. essential hypertension, obstructive sleep apnea and heart failure.

This article is protected by copyright. All rights reserved

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Direct Testing for Allele-Specific Expression Differences Between Conditions

Allelic imbalance (AI) indicates the presence of functional variation in cis regulatory regions. Detecting cis regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (GxE) interactions and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a Drosophila melanogaster population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies and we show that AI*genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1's was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of GxE and GxG and reaffirms a previous finding, that cis regulation is robust between environments.

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Reference Assembly and Annotation of the Pyrenophora teres f. teres Isolate 0-1

Pyrenophora teres f. teres, the causal agent of net form net blotch (NFNB) of barley, is a destructive pathogen in barley growing regions throughout the world. Typical yield losses due to NFNB range from 10-40%, however, complete loss has been observed on highly susceptible barley lines where environmental conditions favor the pathogen. Currently, genomic resources for this economically important pathogen are limited to a fragmented draft genome assembly and annotation with limited RNA support of the P. teres f. teres isolate 0-1. This research presents an updated 0-1 reference assembly facilitated by long read sequencing and scaffolding with the assistance of genetic linkage maps. Additionally, genome annotation was mediated by RNAseq analysis using three infection time points and a pure culture sample resulting in 11,541 high-confidence gene models. The 0-1 genome assembly and annotation presented here now contains the majority of the repetitive content of the genome. Analysis of the 0-1 genome revealed classic characteristics of a 'two-speed' genome, being compartmentalized into GC-equilibrated and AT-rich compartments. The assembly of repetitive AT-rich regions will be important for future investigation of genes known as effectors which often reside in close proximity to repetitive regions. These effectors are responsible for manipulation of the host defense during infection. This updated P. teres f. teres isolate 0-1 reference genome assembly and annotation provides a robust resource for the examination of the barley-P. teres f. teres host-pathogen co-evolution.

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Restorer-of-Fertility Mutations Recovered in Transposon-Active Lines of S Male-Sterile Maize

Mitochondria execute key pathways of central metabolism and serve as cellular sensing and signaling entities - functions that depend upon interactions between mitochondrial and nuclear genetic systems. This is exemplified in cytoplasmic male sterility type S (CMS-S) of Zea mays, where novel mitochondrial open reading frames are associated with a pollen collapse phenotype, but nuclear restorer-of-fertility (restorer) mutations rescue pollen function. To better understand these genetic interactions, we screened Activator-Dissociation (Ac-Ds), Enhancer/Suppressor-mutator (En/Spm) and Mutator (Mu) transposon-active CMS-S stocks to recover new restorer mutants. The frequency of restorer mutations increased in transposon-active stocks compared to transposon-inactive stocks, but most mutants recovered from Ac-Ds and En/Spm stocks were unstable, reverting upon backcrossing to CMS-S inbred lines. Ten independent restorer mutations recovered from CMS-S Mu transposon stocks were, however, stable upon back crossing. Many restorer mutations condition seed-lethal phenotypes that provide a convenient test for allelism. Eight such mutants recovered in this study included one pair of allelic mutations that were also allelic to the previously described rfl2-1 mutant. Targeted analysis of mitochondrial proteins by immunoblot identified two features that consistently distinguished restored CMS-S pollen from comparably staged, normal-cytoplasm, non-mutant pollen - increased abundance of nuclear-encoded alternative oxidase relative to mitochondria-encoded cytochrome oxidase and decreased abundance of mitochondria-encoded ATP synthase subunit 1 compared to nuclear-encoded ATP synthase subunit 2. CMS-S restorer mutants thus revealed a metabolic plasticity in maize pollen, and further study of these mutants will provide new insights into mitochondrial functions critical to pollen and seed development.

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Wnt/{beta}-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer

One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant CRC cell lines through activating the cytoplasmic tyrosine kinase FAK (focal adhesion kinase). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR (Epidermal Growth Factor Receptor) or ERK1/2 (extracellular-signal-regulated kinases1/2) activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant CRC including cell line xenograft model and a PDX (patient-derived xenograft) model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that while complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant CRC, co-targeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential.

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A Novel YAP1 Inhibitor targets CSCs-enriched Radiation Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma

Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo. Remarkably, radiation resistant cells acquire strong CSC properties and aggressive phenotype, while CA3 can effectively suppresses these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Further, CA3 combined with 5-FU, synergistically inhibits EAC cell growth especially in YAP1 high EAC cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy resistant EC cells endowed with CSCs properties.

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Mechanism informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis

Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations.

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Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated Bid

Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA). Using various small molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib (BTZ). CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O-GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole (KCZ), and verified that it exerts similar sensitizing effect on BTZ-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that BTZ and KCZ act in concert to cause the accumulation of truncated Bid (tBid). Not only does KCZ potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, KCZ strongly enhances BTZ-induced apoptosis in de novo BTZ-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of BTZ and KCZ or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL.

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The administration of surfactant decreased oxidative stress in lungs of mice exposed to cigarette smoke

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Dafne Fernandes Machado, Keila Karine Duarte Campos, Natália Pereira da Silva, Camila de Oliveira Ramos, Sílvia Dantas Cangussú, Guilherme de Paula Costa, André Talvani, Frank Silva Bezerra
The alveolar surfactant, which composition consists of a unique and complex mixture of lipids and proteins, has immunomodulatory action. This study aimed to evaluate the effects of exogenous surfactant on pulmonary inflammatory response in mice exposed to cigarette smoke (CS). Twenty-four mice C57BL/6 were divided into four groups: control group exposed to ambient air (CG); surfactant treated group (SG); CS exposed group (CSG) and CS exposed group treated with surfactant (CSSG). For five days, CSG and CSSG were exposed to 12 commercial cigarettes/day and SG and CSSG received the surfactant by intranasal instillation. At the end of the experiment, the animals were euthanatized for the collection of bronchoalveolar lavage fluid (BALF) and lungs. The total number of leukocytes in BALF increased in CSG compared to CG, however, there was a decrease in CSSG compared to CSG. There was an increase in lipid peroxidation in SG and CSG compared to CG while there was a decrease in CSSG compared to CSG. Regarding the antioxidant enzymes, the catalase (CAT) activity increased in all groups compared to CG and the superoxide dismutase (SOD) activity decreased in CSG compared to the CG and SG. There was an increase in TNF in SG, CSG and CSSG compared to CG. There was an increase in IL-17 in CSSG compared to CG. There was an increase in CCL5 in SG and CSSG compared to CG. Therefore, our results demonstrated that the administration of exogenous surfactant was able to decrease the oxidative processes in the lungs of mice induced by short-term exposure to CS.



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Protocol for a systematic review and meta-analysis on the clinical outcomes and cost of deep inferior epigastric perforator (DIEP) flap versus implants for breast reconstruction

Mastectomy in the context of breast malignancy can have a profoundly negative impact on a woman's self-image, impairing personal, sexual and social relationships. The deep inferior epigastric perforator (DIEP)...

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Toxins, Vol. 9, Pages 378: A Supercluster of Neutralizing Epitopes at the Interface of Ricin’s Enzymatic (RTA) and Binding (RTB) Subunits

Toxins, Vol. 9, Pages 378: A Supercluster of Neutralizing Epitopes at the Interface of Ricin's Enzymatic (RTA) and Binding (RTB) Subunits

Toxins doi: 10.3390/toxins9120378

Authors: Amanda Poon David Vance Yinghui Rong Dylan Ehrbar Nicholas Mantis

As part of an effort to engineer ricin antitoxins and immunotherapies, we previously produced and characterized a collection of phage-displayed, heavy chain-only antibodies (VHHs) from alpacas that had been immunized with ricin antigens. In our initial screens, we identified nine VHHs directed against ricin toxin's binding subunit (RTB), but only one, JIZ-B7, had toxin-neutralizing activity. Linking JIZ-B7 to different VHHs against ricin's enzymatic subunit (RTA) resulted in several bispecific antibodies with potent toxin-neutralizing activity in vitro and in vivo. JIZ-B7 may therefore be an integral component of a future VHH-based neutralizing agent (VNA) for ricin toxin. In this study, we now localize, using competitive ELISA, JIZ-B7's epitope to a region of RTB's domain 2 sandwiched between the high-affinity galactose/N-acetylgalactosamine (Gal/GalNAc)-binding site and the boundary of a neutralizing hotspot on RTA known as cluster II. Analysis of additional RTB (n = 8)- and holotoxin (n = 4)-specific VHHs from a recent series of screens identified a "supercluster" of neutralizing epitopes at the RTA-RTB interface. Among the VHHs tested, toxin-neutralizing activity was most closely associated with epitope proximity to RTA, and not interference with RTB's ability to engage Gal/GalNAc receptors. We conclude that JIZ-B7 is representative of a larger group of potent toxin-neutralizing antibodies, possibly including many described in the literature dating back several decades, that recognize tertiary and possibly quaternary epitopes located at the RTA-RTB interface and that target a region of vulnerability on ricin toxin.

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Response Regarding Surgical Techniques for Retrograde Parotidectomy

Publication date: Available online 22 November 2017
Source:American Journal of Otolaryngology
Author(s): Maxwell Kligerman, Uchechukwu Megwalu, Davud Sirjani




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Feruloyl esterase from Alternaria tenuissima that hydrolyses lignocellulosic material to release hydroxycinnamic acids

Abstract

An extracellular feruloyl esterase from the culture filtrates of the isolated fungus Alternaria tenuissima was successfully purified to apparent homogeneity by anion-exchange and size-exclusion chromatography. Peptide fragments of purified enzyme (designated as AltFAE; molecular weight of 30.3 kDa determined by SDS-PAGE) were identified by mass spectrometry using a NanoLC-ESI-MS/MS system. Michaelis-Menten constants (K _M) and catalytic efficiencies (k _cat/K _M) were determined for typical substrates of feruloyl esterase, and the lowest K _M of 50.6 μM (i.e., the highest affinity) and the highest k _cat/K _M (3.1 × 10⁵ s^—1 M^–1) were observed for methyl ^p-coumarate and methyl ferulate, respectively. Not least, AltFAE catalyzed conversion of lignocellulosic material (e.g. wood meal) to release hydroxycinnamic products, i.e. ferulic- and ^p-coumaric acids.

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Chemical leaching of copper-zinc concentrate with ferric iron biosolution

Abstract

The process of leaching of copper-zinc concentrate with a solution containing biogenic iron, which is a product of the metabolism of iron-oxidizing microorganisms, was studied. The dependence of leaching rate of metals on temperature and pH was determined. It was shown that up to 98% of zinc and 70% of iron could be removed from the concentrate, while up to 7 and 4 g/L of zinc and copper, respectively, were accumulated in the liquid phase, which was sufficient for metal recovery. It was established that a copper concentrate with copper content up to 16% and only 0.5% of zinc could be obtained after chemical leaching for 340 min at 80°C.

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Oxylipins and oxylipin synthesis pathways in fungi

Abstract

Oxylipins are a family of oxygenated fatty acids that are very diverse with regard to origin, structure, and functions. These compounds are found in almost all living beings and serve both as autoregulators of the development of organisms and as communication molecules. The autoregulatory role of oxylipins in fungi is to control the development, reproduction, synthesis of secondary metabolites (including mycotoxins), and adaptive responses. The role of oxylipins in the regulation of pathogenesis accounts for an important aspect of research on the biological activity of these compounds. The synthetic pathways and functions of oxylipins of fungi, the differences between fungal oxylipins and oxylipins from bacteria, higher plants, and mammals, and the role of oxylipins in the interaction of fungi with other organisms are considered in the present review.

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Expression of the zebrafish β-defensin 3 mature peptide in Pichia pastoris and its purification and antibacterial activity

Abstract

Defensins are abundant in cells and tissues that are involved in host defense against microbial infections. zfDB3 (zebrafish β-defensin 3) is one of 3 copies of defensin β-like genes from zebrafish (Danio rerio). Here we focus on mzfDB3, which is the gene encoding for the zebrafish β-defensin 3 mature peptide. A codon-optimized mzfDB3 gene with a 6×His-tag at the 3′-end was inserted into the pPICZαA expression vector and transformed into Pichia pastoris X-33 cells. The recombinant zebrafish β-defensin 3 mature peptide (rmzfDB3) was induced with 1.0% methanol at 29°C for 72 h and purified by immobilized metal affinity chromatography. MALDI-TOF/TOF analysis confirmed the expected purified product (rmzfDB3, 5.9 kDa). Fermentation supernatant, which contained rmzfDB3, showed antibacterial activity against Grampositive (i.e., Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus) and Gram-negative (i.e., Escherchia coli BL21, Vibrio parahaemolyticus, Salmonella lignieres, and Pseudomonas aeruginosa) bacteria.

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Antimicrobial potential of alkalophilic micromycetes Emericellopsis alkalina

Abstract

The ability of alkalophilic micromycetes of the Emericellopsis alkalinа to produce antimicrobial peptides has been studied. Evaluation of the spectrum and the yield of antibiotic compounds has allowed us to choose a promising producer of peptide antimycotics, Emericellopsis аlkalinа А118. The producer exhibits antifungal activity against conditionally pathogenic yeast and mold fungi, i.e., Candida аlbicans, Aspergillus niger, and A. fumigatus. The group of homologous active compounds isolated by the set of identified structural features (molecular weight, the ratio of the absorption at certain wavelengths, and the absence of initiation of Edman sequencing) may be attributed to peptaibols, which are a group of nonribosomal membrane-active antimicrobial peptides with a specificity of action primarily against fungi-micromycetes.

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Creation of thermostable polypeptide cassettes for amino acid balancing in farm animal rations

Abstract

The study of the poultry needs in basic nutrients allowed the development of a scheme for obtaining feed polypeptides ("polypeptide cassettes") enriched with L-amino acids, which are necessary for the metabolism of birds. The amino acid and nucleotide profiles of about 500 bioinformation sequences of thermostable plant proteins and archaea were studied, on the basis of which candidate sequences were selected. In silico, the amino acid and domain composition of the thermostable polypeptides has been optimized. A library of genetically engineered constructs encoding optimized polypeptides with the necessary composition of L-amino acids irreplaceable for poultry has been created. Primary E. coli producer strains were obtained, and the expression and thermostability of the target polypeptides were studied.

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Effect of potassium sorbate, sodium benzoate, and sodium nitrite on biosynthesis of cyclopiazonic and mycophenolic acids and citrinin by fungi of the Penicillium genus

Abstract

The effect of potassium sorbate, sodium benzoate, and sodium nitrite used as preservatives in the food industry in the production of such mytotoxins as citrinin cyclopiazonic and mycophenolic acids by the contaminating fungi Penicillium citrinum, P. commune, and P. brevicompactum, respectively, was investigated. It was shown that the effect of preservatives used at concentrations relevant to the food industry on the synthesis of mycotoxins depended on the species-specific biochemical and physiological features of the cultures. The growth of P. brevicompactum was inhibited to the highest degree by sodium nitrite and potassium sorbate, and the growth of P. commune was so inhibited by sodium benzoate. It was established that the introduction of 0.015% sodium nitrite into the medium resulted in 1.3- and 1.4-fold reductions of the production of citrinin and mycophenolic acid, respectively, while the production of cyclopiazonic acid did not change in comparison with the control. The introduction of 0.015% sodium benzoate caused a more than 1.5-fold increase of the concentration of citrinin, cyclopiazonic, and mycophenolic acids, and the addition of 0.02% potassium sorbate increased the production of cyclopiazonic and mycophenolic acids by 1.7 and 2.6 times, respectively.

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Hydrogen peroxide-induced salt tolerance in the Arabidopsis salicylate-deficient transformants NahG

Abstract

The effect of hydrogen peroxide treatment on the salt tolerance of wild-type Arabidopsis thaliana L. plants (Col-0) and plants transformed with the bacterial salicylate hydroxylase gene (NahG) was studied. The base tolerance to salt stress caused by 200 mM of NaCl in solution culture was higher in plants with the NahG genotype in comparison with the wild-type plants. Growth inhibition was observed for wild-type plants under the action of exogenous hydrogen peroxide, which was not observed for the NahG transformants; salt tolerance increased in the both types of plants after treatment, which was assessed based on the growth indicators and the ability to preserve the chlorophyll pool following NaCl treatment. The content of endogenous Н2О2 in the leaves of wild-type plants increased significantly following exogenous hydrogen peroxide treatment and salt stress, while it practically did not change in the leaves of the NahG genotype. The SOD activity increased in both genotypes after treatment with exogenous hydrogen peroxide, and remained at an elevated level after salt stress in comparison with the nontreated plants. Furthermore, the catalase activity increased in leaves of the salicylate-deficient genotype but not in the Col-0 genotype. The guaiacol peroxidase activity increased in plants of both genotypes under the action of hydrogen peroxide and salt stress, with the NahG plants demonstrating a higher degree of increase. The Н₂О₂ treatment facilitated the increase of the proline content in leaves of the plants of both genotypes under conditions of salt stress. It was concluded that there were hydrogen peroxide signal transduction pathways in Arabidopsis plants that were salicylic acid independent and that the antioxidant system functioned more effectively in salicylate-deficient Arabidopsis plants.

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Activity of Na + /K + -ATPase and the content of phospholipids in the blue mussel Mytilus edulis L. during environmental temperature changes

Abstract

Changes in the activity of Na⁺/K⁺-ATPase and content of membrane lipids (phospholipids) in the gills and hepatopancreas of the blue mussel Mytilus edulis L. have been studied during a sharp temperature increase under aquarian managed conditions. The most pronounced changes were recorded in mollusk gills. A correlation of changes in the activity of membrane-bound Na⁺/K⁺-ATPase and phospholipid content (mainly phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and lysophosphatidylcholine) was revealed; this correlation evidences their mutual involvement in compensation for the temperature effect to help mussels adapt to sharp temperature changes.

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Rational design of enzyme compositions for the production of functional hydrolysates of cow milk whey proteins

Abstract

The design of enzyme compositions for the preparation of functional hydrolysates of whey proteins is studied. Analysis of the protein profiles of the whey from hard, semihard, and soft cheeses showed that the whey contains 50–63% β-lactoglobulin, 19–20% α-lactalbumin, and up to 11% κ-casein. According to the protein profile, the whey from Circassian cheese contains 76% casein (α-, β-, and κ-casein), 12% β-lactoglobulin, and 12% α-lactalbumin. Based on the in silico analysis, the rational design of a multienzyme composition was carried out for the hydrolysis of whey with a known protein composition taking into account the content of amino acid descriptors of biological activity and bitter taste. For the hydrolysis of whey from hard (Montazio), soft (Mozzarella and Gorgonzola), and semihard (Caciotta) cheeses, the determined optimum ratio of the Protamex and Alcalase enzymes was 3.0: 1.0% (90 min, 50°С). For soft pickled unripened cheese (Circassian), the optimum ratio of the Thermolysin and Alcalase enzymes was 2.0: 1.0% (60°С, 120 min). The use of the bioinformatics approach made it possible to obtain hydrolysates with acceptable organoleptic properties and predetermined antioxidant (400–500 μM TE/g protein) and antihypertensive (IC₅₀ 537–2500 mg protein/L) activities.

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Specific features of chitosan depolymerization by chitinases, chitosanases, and nonspecific enzymes in the production of bioactive chitooligosaccharides (Review)

Abstract

The data on features of the hydrolytic cleavage of chitosan by different groups of specific and nonspecific enzymes are summarized. Alternative approaches to the production of chitooligomers and their derivatives are also briefly considered.

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Cultivation of the microalga Neochloris oleoabundans for biofuels production and other industrial applications (a review)

Abstract

Microalgae cultivation for biofuels production and other applications has gained considerable interest recently. Despite their simple structures, microalgae can accumulate significant amounts of neutral lipids per dry cell weight compared to other energy crops. Neochloris oleoabundans is a promising microalga known for its high lipid content and biomass growth rate compared to other species cultivated for biofuels synthesis; therefore, it is considered as a suitable candidate for biodiesel synthesis. This review paper covers several key aspects associated with the cultivation and applications of the microalga N. oleoabundans. Biomass composition, factors affecting the growth, and biomass and lipid productivities of this species were addressed. In addition, different growth conditions as well as alternative readily available nutrient media to support the growth of N. oleoabundans were presented in this review.

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Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging

Purpose: Isocitrate dehydrogenase (<IDH) mutations in glioma patients confer longer survival and may guide treatment decision-making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to pre-operative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 pre-contrast, and T1 post-contrast) and built a predictive model from the outputs. To increase the size of training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to non-invasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional dataset.

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