Options in Hypersensitivity Reactions to Chemotherapeutics

Opinion statement

Purpose of review

Chemotherapeutic drugs still represent a gold standard for the treatment of neoplastic disease. They can induce hypersensitivity reactions and are the third leading cause of fatal drug-induced anaphylaxis in the USA. This article has tried to highlight and summarize the most recent scientific progress concerning risk factors, pathogenesis, diagnosis, and treatment of these reactions.

Recent findings

Identification of patients at high risk of developing hypersensitivity reactions allows risk stratification to guide clinical decision-making. Therefore, the most recent researches evaluated the possibility to perform risk stratification in case of hypersensitivity reactions to platinum compounds and taxanes. In addition, new data are now available regarding the role of in vitro test for the diagnosis of reactions to platins and the role of drug provocation test in case of hypersensitivity to a number of chemotherapeutics. However, actually, the allergological work-up includes a very careful anamnesis of the patient and the characteristics of reaction, whereas skin tests are useful only for few classes of chemotherapy, namely platinum salts and probably taxanes. Premedication, desensitization and, in some cases, skin tests are able to prevent the majority of hypersensitivity reactions, permitting the administration of the most effective therapy.

Summary

Clearly, more studies are needed to better understand, diagnose, treat, and prevent these reactions. To reach this aim, a multidisciplinar approach to the cancer patient with potential allergies is needed.

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How Can We Influence the Performance of Drug Challenge in Future Treatment

Abstract

Drug provocation tests are assumed to be the gold standard of drug allergy workup by ensuring the most objective results in clinical observation irrespective of the underlying mechanism of the reaction. Despite its some disadvantages, it is still one of the cornerstones of the drug allergy diagnosis. In this review, new methods for improving diagnostic accuracy of drug provocation tests will be discussed. In this sense, extended challenges are recently shown to have better outcome especially in diagnosing non-immediate reactions due to antibiotics. In children with non-immediate mild cutaneous reactions, provocation tests are becoming to take place of skin tests with promising results. Furthermore, drug provocation tests have been shown to prevent unnecessary desensitization protocols in newly developed drugs such as biological agents. These new data on diagnostic performance of drug provocation test seem to influence the future treatments in patients with drug hypersensitivity reactions.

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Correction to: Hand Eczema: Treatment Options

Abstract

Unfortunately, the original publication of this article contained mistakes. The publisher introduced an error after proofreading where all occurrences of "topical corticosteroids" were typographically written as "topical corticost-effectivenesseroid".

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Asthma and Cleaning: What’s New?

Abstract

Professional and domestic cleanings are associated with work-related asthma (WRA). Increased risk of asthma has been shown in many epidemiological and surveillance studies, and several case reports describe the relationship between exposure to one or more cleaning agents and WRA. Moreover, exposure to cleaning chemicals could be associated with severe uncontrolled asthma. Cleaning sprays, bleach, ammonia, disinfectants, mixing products, and specific job tasks have been identified as specific causes and/or triggers of asthma or airway respiratory diseases. Their measurements at the workplace could be interesting but hardly feasible. It is still under controversy whether cleaning products are airway irritants or sensitizers. The social consequence of unemployment in this population is one of the most important limitations to the management of occupational in cleaning professionals. The prognosis of the disease depends of removal from exposure, with avoidance of high-risk cleaning products, even at home.

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Anaphylaxis in the Workplace

Abstract

Occupational anaphylaxis (OcAn) main causes comprise food, medications, insect stings/bites, and natural rubber latex (NRL). An in-depth investigation is required, before labeling a reaction as OcAn.

A written emergency management plan, health and safety education, and training and surveillance should be implemented after proper diagnosis. Education on when and how to use the adrenaline auto-injector device should be provided likewise. Moreover, surveillance and advice on risk of allergen exposure and how to minimize their risk of sensitization at the beginning of their employment or training is mandatory. Workers who have developed sensitization to an allergen in the occupational setting may also develop anaphylaxis outside the work environment, from exposure to the same or to cross-reacting allergens. We believe that removal from exposure shall avoid subsequent OcAn episodes; therefore, once OcAn has been diagnosed, this intervention shall be implemented.

This review highlights the different causes of OcAn, their physiopathology, cofactors, diagnosis, and its management, focusing on the medication spectrum. Interested readers may acquire knowledge on this severe, potentially life-threatening systemic hypersensitivity reaction, which generally involves an immunologic IgE mechanism.

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Occupational Asthma, Not a Trivial Disorder and a Source of Fatal and N ear-Fatal Events

Opinion statement

Purpose of review

Asthma is one of our society's heaviest health burdens, which is estimated to be responsible for 250,000 deaths every year. Whenever severe asthma with fatal or near-fatal events is described, occupational asthma is not specifically mentioned, but its importance should not be underestimated.

Recent findings

Occupational asthma (OA) is the most prevalent work-related pulmonary disease. Therefore, it is a very important concern for health prevention and occupational health professionals. Although asthma treatments and earlier diagnosis have improved this condition's control, severe exacerbations with unpredictable consequences still occur. Early diagnosis and allergen avoidance are the two main objectives in our approach to this disease. Obtaining a correct diagnosis and recognizing the responsible allergen is not an easy task to achieve, but it should be the clinician's biggest concern. Severe exacerbations can be caused by many different triggers and their identification usually requires a well-trained expert in the field. Allergen avoidance should be the primary goal to avoid fatal or near-fatal asthma events, but good asthma control also is necessary to decrease OA future risk. The asthmagens involved in severe reactions are heterogeneous, making their identification difficult, but necessary. As these agents are used in very different industries and can be ubiquitous, OA should be considered in every patient with work-related asthma exacerbations or symptoms.

Summary

Severe events have been described with many types of agents and allergenic sources; therefore, every patient should be treated to obtain a good illness control, regardless of the responsible allergenic source.

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Allergic Contact Dermatitis: Therapeutic Management

Abstract

Purpose of Review

Allergic contact dermatitis (ACD) is a common condition and may entail negative impacts on people's quality of life along with a substantial economic burden. Appropriately managing it through patient education, allergen avoidance, and symptomatic treatment is crucial for its resolution. Our review aims to establish a practical approach to ACD management, based on a comprehensive discussion of available therapeutic options for ACD, a review of the latest findings in this field, and personal insights from our clinical practice experience.

Recent Findings

Topical treatments constitute the first-line therapy for ACD. Randomized clinical trials have shown topical corticosteroids to improve clinical and nonclinical outcomes, while tacrolimus has proven effective and safe. Evidence is lacking for oral corticosteroids in ACD sufferers, so recommendations for its use are primarily based on results obtained in dermatitis of other etiologies. In contrast, some studies have assessed azathioprine and phototherapy for ACD.

Summary

Patient education and allergen avoidance are paramount for managing ACD. However, individualized symptomatic treatment is warranted in several clinical situations. Although these treatments are widely used in clinical practice, few studies support their use for ACD. Further research is needed.

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Lessons of Drug Allergy Management Through the World Health Organization’s International Classification of Diseases (ICD)-11

Abstract

Purposes of review

In order to introduce the advances and use of the new sub-section addressed to the drug hypersensitivity reactions (DHRs) in the World Health Organizations' International Classification of Diseases (ICD)-11 revision, we here proposed a used case document and discuss the perspective of this new framework.

Recent findings

We expect that the construction of the new section addressed to DHRs in the ICD-11 will allow the collection of more accurate epidemiological data to support quality management of patients with drug allergies, and better facilitate health care planning to implement public health measures to prevent and reduce the morbidity and mortality attributable to DHRs.

Summary

Allergy and hypersensitivity reactions, including DHRs, have never been well classified in the World Health Organization's (WHO) ICD. The ALLERGY in ICD-11 initiative was launched 6 years ago to have a better representation of these disorders in the ongoing 11th revision of the ICD. It has been supported by six major international allergy academies, and collaboration with the WHO has been established and is ongoing so far. This document intends to present advances and use of the new "Drug hypersensitivity" section of the ICD-11.

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Hypersensitivity Reactions to Iodinated Contrast Media: Is it a True Allergy?

Opinion statement

Classically, hypersensitivity reactions to iodinated contrast media (ICM) have been termed pseudoallergic, allergy-like, or anaphylactoid. The origin of these terms to define ICM hypersensitivity reactions could be in relation to the use of traditional, classic, ionic ICMs. These ionic ICMs have a high osmolality, and the reactions have been considered as secondary to non-specific histamine release. Currently, ionic ICMs have been replaced by non-ionic compounds with low or iso-osmolality, which, although to a lesser extent, can also produce hypersensitivity reactions. In recent years, there has been growing evidence that some of these reactions, especially the more severe, can be triggered by an IgE-dependent mechanism. Also, in recent decades, there has been an increase in non-immediate reactions, especially in the form of maculopapular exanthems occurring up to several days after the administration of ICM. In these non-immediate reactions, the involvement of T lymphocytes has been clearly demonstrated. The finding of positive skin tests and other in vitro studies for ICMs would support a specific immunological mechanism in a percentage of ICM-induced reactions. However, although there is a body of evidence suggesting that ICMs can induce true allergy reactions, the main guidelines for contrast media management, such as those proposed by US (American College of Radiology Manual on Contrast Media) or European (European Society of Urogenital Radiology Guidelines on Contrast Media) societies, continue to consider only immediate reactions and handle them as non-allergic reactions, without any allergy testing. In ICM reactions an allergic evaluation should be mandatory, not only to study the possible mechanisms involved but also to identify the ICM involved in the reaction and to find an alternative one that could be used in future radiological explorations.

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Precision Medicine in the Management of Drug Allergy

Abstract

Purpose of study

The term precision medicine has been developed in the last five or more years to describe the concept of treating patients individually based on a variety of factors. Precision medicine can be applied to the field of drug allergy where phenotypes, endotypes, and biomarkers have been defined.

Recent findings

Phenotypes of drug allergy can be based on (1) the mechanism of the underlying reaction; (2) the clinical presentation of the reaction; and (3) the timing of the reaction in regards to exposure to the drug. Endotypes of drug allergy can be defined based on mechanisms, pharmacologic processes, and human leukocyte antigen haplotypes. Lastly, biomarkers utilized in drug allergy include skin tests, specific IgE tests, basophil activation tests, cellular-based assays, mediator measurement, drug patch tests, and genotyping. The approach to penicillin allergy in recent years highlights the application of precision medicine in drug allergy.

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Results of endoscopic vacuum-assisted closure device for treatment of upper GI leaks

Abstract

Background

Esophageal perforations and postoperative leakage of esophagogastrostomies are considered to be life-threatening conditions due to the potential development of mediastinitis and consecutive sepsis. Vacuum-assisted closure (VAC) techniques, a well-established treatment method for superficial infected wounds, are based on a negative pressure applied to the wound via a vacuum-sealed sponge. Endoluminal VAC (E-VAC) therapy as a treatment for GI leakages in the rectum was introduced in 2008. E-VAC therapy is a novel method, and experience regarding esophageal applications is limited. In this retrospective study, the experience of a high-volume center for upper GI surgery with E-VAC therapy in patients with leaks of the upper GI tract is summarized. To our knowledge, this series presents the largest patient cohort worldwide in a single-center study.

Methods

Between October 2010 and January 2017, 77 patients with defects in the upper gastrointestinal tract were treated using the E-VAC application. Six patients had a spontaneous perforation, 12 patients an iatrogenic injury, and 59 patients a postoperative leakage in the upper gastrointestinal tract.

Results

Complete restoration of the esophageal defect was achieved in 60 of 77 patients. The average duration of application was 11.0 days, and a median of 2.75 E-VAC systems were used. For 21 of the 77 patients, E-VAC therapy was combined with the placement of self-expanding metal stents.

Conclusion

This study demonstrates that E-VAC therapy provides an additional treatment option for esophageal wall defects. Esophageal defects and mediastinal abscesses can be treated with E-VAC therapy where endoscopic stenting may not be possible. A prospective multi-center study has to be directed to bring evidence to the superiority of E-VAC therapy for patients suffering from upper GI defects.

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An endoscopic mucosal grading system is predictive of leak in stapled rectal anastomoses

Abstract

Background

Anastomotic leak is a devastating postoperative complication following rectal anastomoses associated with significant clinical and oncological implications. As a result, there is a need for novel intraoperative methods that will help predict anastomotic leak.

Methods

From 2011 to 2014, patient undergoing rectal anastomoses by colorectal surgeons at our institution underwent prospective application of intraoperative flexible endoscopy with mucosal grading. Retrospective review of patient medical records was performed. After creation of the colorectal anastomosis, application of a three-tier endoscopic mucosal grading system occurred. Grade 1 was defined as circumferentially normal appearing peri-anastomotic mucosa. Grade 2 was defined as ischemia or congestion involving <30% of either the colon or rectal mucosa. Grade 3 was defined as ischemia or congestion involving >30% of the colon or rectal mucosa or ischemia/congestion involving both sides of the staple line.

Results

From 2011 to 2014, a total of 106 patients were reviewed. Grade 1 anastomoses were created in 92 (86.7%) patients and Grade 2 anastomoses were created in 10 (9.4%) patients. All 4 (3.8%) Grade 3 patients underwent immediate intraoperative anastomosis takedown and re-creation, with subsequent re-classification as Grade 1. Demographic and comorbidity data were similar between Grade 1 and Grade 2 patients. Anastomotic leak rate for the entire cohort was 12.2%. Grade 1 patients demonstrated a leak rate of 9.4% (9/96) and Grade 2 patients demonstrated a leak rate of 40% (4/10). Multivariate logistic regression associated Grade 2 classification with an increased risk of anastomotic leak (OR 4.09, 95% CI 1.21–13.63, P = 0.023).

Conclusion

Endoscopic mucosal grading is a feasible intraoperative technique that has a role following creation of a rectal anastomosis. Identification of a Grade 2 or Grade 3 anastomosis should provoke strong consideration for immediate intraoperative revision.

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Probing depth is an independent risk factor for HbA1c levels in diabetic patients under physical training: a cross-sectional pilot-study

Abstract

Background

This cross-sectional study investigates the potential association between active periodontal disease and high HbA1c levels in type-2-diabetes mellitus subjects under physical training.

Methods

Women and men with a diagnosis of non-insulin-dependent diabetes mellitus and ongoing physical and an ongoing exercise program were included. Periodontal conditions were assessed according to the CDC-AAP case definitions. Venous blood samples were collected for the quantitative analysis of HbA1c. Associations between the variables were examined with univariate and multivariate regression models.

Results

Forty-four subjects with a mean age of 63.4 ± 7.0 years were examined. Twenty-nine subjects had no periodontitis, 11 had a moderate and 4 had a severe form of periodontal disease. High fasting serum glucose (p < 0.0001), high BMI scores (p = 0.001), low diastolic blood pressure (p = 0.030) and high probing depth (p = 0.036) were significantly associated with high HbA1c levels.

Conclusions

Within the limitations of this study HbA1c levels are positively associated with high probing pocket depth in patients with non-insulin-dependent diabetes mellitus under physical exercise training. Control and management of active periodontal diseases in non-insulin-dependent patients with diabetes mellitus is reasonable in order to maximize therapeutic outcome of lifestyle interventions.

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Associations of multidimensional health literacy with reported oral health promoting behaviour among Slovak adults: a cross-sectional study

Abstract

Background

Modification of health literacy (HL) is an important factor for improving and maintaining oral health. The aim of the study is to examine the association of HL with oral health-promoting behaviour (OHPB) and assess possible mediating effects of HL on the impact of socioeconomic status on OHPB.

Methods

A cross-sectional questionnaire survey on the Slovak general adult population (N = 360, mean age 39) was conducted in 2014 and 2015. The association of HL (9 domains of the Health Literacy Questionnaire) and OHPB was analysed using logistic regression models adjusted for gender, age and educational level. Testing the mediating effect of HL domains between education attainment and OHPB was performed using the Sobel test.

Results

Women and respondents with higher education reported better OHPB. Regular tooth-brushing is associated with better HL in five domains: Feeling understood and supported by healthcare provider, Having sufficient information to manage my health, Activelymanaging my health, Social support for health, Appraisal of health information (Odds ratios (ORs) from 1.64 to 2.33, p < 0.05). Using interdental tools is in association with better HL in two domains: Feeling understood and supported by a healthcare provider and Having sufficient information to manage my health (ORs 1.71 to 1.80, p < 0.05). Respondents who visited a dentist for prevention score higher in Social support for health (OR 1.79, p < 0.05). Using a tongue scraper and single brush and reporting gums bleeding is notstatistically significantly associated with HL. Mediation was confirmed between the effect of respondents' education on using fluoride toothpaste – mediated respondent's ability to find good health information. Frequency of tooth-brushing and using interdental hygiene aids were both mediated by patient's sufficient information to manage health.

Conclusions

Our results indicate HL to be an important factor related to good oral health, and HL should be considered when planning oral health interventions.

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Putative salivary protein biomarkers for the diagnosis of oral lichen planus: a case-control study

Abstract

Background

Salivary protein biomarkers for screening and diagnosis of oral lichen planus (OLP) are not well-defined. The objective of this study was to identify putative protein biomarkers for OLP using proteomic approaches.

Methods

Pooled unstimulated whole saliva was collected from five OLP patients and five healthy control participants. Saliva samples were then subjected to two-dimensional gel electrophoresis, followed by mass spectrometry to identify putative protein biomarkers. Subsequently, a subset of these putative biomarkers were validated in 24 OLP patients and 24 age-matched healthy control subjects, using an enzyme-linked immunosorbent assay (ELISA). Immunoblotting analyses were then performed in 3 pairs of age- and sex-matched OLP patients and healthy controls to confirm results from the ELISA study.

Results

Thirty-one protein spots were identified, corresponding to 20 unique proteins. Notably, fibrinogen fragment D and complement component C3c exhibited increased expression in OLP patients, while cystatin SA exhibited decreased expression in OLP patients, compared with healthy control subjects. ELISA analyses indicated increased expression of fibrinogen fragment D and complement component C3c, and decreased expression of cystatin SA, in the saliva of OLP patients. Statistical differences in the expression of salivary complement C3c were observed between OLP patients and healthy control subjects. Immunoblotting analyses confirmed the results of our ELISA study.

Conclusion

Complement C3c, fibrinogen fragment D and cystatin SA may serve as salivary biomarkers for screening and/or diagnosis of OLP.

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A cross-sectional study on the association between vitamin D levels and caries in the permanent dentition of Korean children

Abstract

Background

A recent study in Canada reported that vitamin D deficiency is associated with dental caries. Because Koreans have been reported to be deficient in vitamin D, we investigated the relationship between dental caries and reduced serum vitamin D levels in Korean children. The purpose of this study was to analyze the relationships between blood vitamin D [25(OH)D] concentrations and dental caries in the permanent dentition of Korean children.

Methods

Data were collected from the Korea National Health and Nutrition Examination Survey performed in 2008–2013. A total of 1688 children (10–12 years of age) were enrolled. Vitamin D intake was measured through analysis of 25-hydroxy vitamin D [25(OH)D] levels. Caries experience in permanent dentition was assessed using the decay-missing-filled teeth (DMFT) index and decayed-missing-filled (DMF) rate. Statistical analyses included complex samples Chi-square tests, complex samples logistic regression analyses, and Pearson's correlations.

Results

The group with 25(OH) D levels lower than 50 nmol/L had a higher proportion of children with caries in the permanent dentition and permanent first molar than the group with 25(OH)D levels of 50 nmol/L or more. When external factors, such as sex, were controlled, 25(OH)D levels were not significantly correlated with caries, but were significantly correlated with first molar caries. Children with 25(OH)D levels lower than 50 nmol/L were 1.295 times more likely to have first molar caries than those with 25(OH)D levels of 50 nmol/L or more. Additionally, 25(OH)D levels and DMFT were negatively correlated; however, the degree of correlation was not strong.

Conclusions

The association between 25(OH)D and dental caries is still not clear. However, our findings suggested that vitamin D insufficiency may be a risk factor for dental caries.

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Factors associated with seeking preventive dental care: an integrative model exploration of behaviors in Mexican immigrants in Midwest America

Abstract

Background

Mexican immigrants in the United States suffer from poor oral health. The objective of the current study was to explore the utility of applying theory-based factors associated with seeking preventive dental care in a sample of Mexican American adults.

Methods

Data were collected from a cross-sectional survey of a sample of 157 people of Mexican origin (64% female; age 34 ± 11 years) recruited primarily from church congregations and lay community organizations in Central Indiana. Using the Integrative Model of Behavioral Prediction as the guiding framework, structural equation modeling was used to test factors associated with intention to seek preventive dental care.

Results

Attitude towards seeking preventive dental care (estimate = 0.37; p < .0001) and self-efficacy for seeking preventive dental care (estimate = 0.68; p < .0001) were associated with intention to seek preventive dental care. The association between dental beliefs and intention to seek preventive dental care was mediated by attitude and self-efficacy (indirect effect = 0.26, p = .002), and the association between past behavior and intention to seek preventive dental care was mediated by self-efficacy (indirect effect = 0.26, p = .003).

Conclusions

These findings suggest that interventions to increase preventive dental care seeking behavior among Mexican Americans should focus on changing attitudes toward seeking preventive dental care and on increasing self-efficacy to seek preventive dental care. Findings also support the use of interventions to influence dental beliefs.

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Do hypoxia and L-mimosine modulate sclerostin and dickkopf-1 production in human dental pulp-derived cells? Insights from monolayer, spheroid and tooth slice cultures

Abstract

Background

To understand the responses of the dental pulp to hypoxia is of high relevance for regenerative endodontics and dental traumatology. Here, we aimed to reveal the effects of hypoxia and the hypoxia mimetic agent L-mimosine (L-MIM) on the production of sclerostin (SOST) and dickkopf-1 (DKK-1) in human dental pulp-derived cells (DPC).

Methods

DPC in monolayer, spheroid and tooth slice cultures were treated with L-MIM or hypoxia. Resazurin-based toxicity and MTT assays were performed to determine cell viability. mRNA and protein levels of SOST and DKK-1 were measured with quantitative reverse transcription PCR and ELISA, respectively. To validate the hypoxia-like response, SDF-1, VEGF and IL-8 were assessed. In addition Western blots for HIF-1α, HIF-2α and HIF-3α were done.

Results

Cells were vital upon treatment procedures and showed increased levels of HIF-1α, and HIF-2α. In monolayer cultures, mRNA levels of SOST and DKK-1 were downregulated by L-MIM and hypoxia, respectively. A significant downregulation of SOST by hypoxia was found at the protein level compared to untreated cells while the effect on DKK-1 and the impact of L-MIM on SOST and DKK-1 did not reach the level of significance at the protein level. In spheroid cultures, mRNA levels of SOST and DKK-1 were downregulated by L-MIM. A significant downregulation of DKK-1 upon hypoxia treatment was found at the protein level while the impact of hypoxia on SOST and the effect of L-MIM on SOST and DKK-1 did not reach the level of significance. SOST and DKK-1 were also produced in tooth slices, but no pronounced modulation by L-MIM or hypoxia was found. Evaluation of SDF-1, VEGF and IL-8 showed a hypoxia-like response in the culture models.

Conclusions

There is no pronounced influence of hypoxia and L-MIM on DPC viability, SOST and DKK-1 protein production. However, the specific response depends on the culture model and the level of evaluation (mRNA or protein). These results deepen our understanding about the role of hypoxia and the potential impacts of hypoxia-based strategies on dental pulp.

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The Role of the Sucrose-Responsive IR60b Neuron for Drosophila melanogaster: A Hypothesis.

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The Role of the Sucrose-Responsive IR60b Neuron for Drosophila melanogaster: A Hypothesis.

Chem Senses. 2018 Mar 13;:

Authors: Szyszka P, Galizia CG

Abstract
In a recent paper, Joseph and colleagues (Joseph et al., 2017) have characterized an IR60b receptor-expressing neuron in Drosophila. They showed that it responds to sucrose and serves to limit sucrose consumption, and proposed that it may thereby act to prevent overfeeding. Here, we propose an alternative hypothesis for the functional role of sucrose feeding control, and for how this limitation of sucrose uptake is accomplished. Adult fruit flies feed by excreting saliva onto the food, and imbibing the predigested liquefied food, or by filling the crop, where the food is predigested. Enzymes in the saliva hydrolyze starch and disaccharides into absorbable monosaccharides. Premature ingestion into the midgut would not give the enzymes in the saliva enough time to predigest the food. Thus, IR60b neurons might serve as a sensor to monitor the digestive state of external food or crop content: when disaccharides (sucrose) concentration is high, ingestion to the gut is inhibited, keeping a low concentration of starch and disaccharides in the midgut.

PMID: 29546407 [PubMed - as supplied by publisher]

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Characterization of the relationships between sleep duration, quality, architecture and chemosensory function in non-obese females.

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Characterization of the relationships between sleep duration, quality, architecture and chemosensory function in non-obese females.

Chem Senses. 2018 Mar 07;:

Authors: Szczygiel EJ, Cho S, Tucker RM

Abstract
Little is known about the relationship between sleep and chemosensation. The purpose of this study was to characterize the relationship between chemosensory function and sleep duration, quality and architecture. A total of 56 non-obese (BMI<30 kg/m2) female participants who denied having diagnosed sleep disorders completed testing. Sleep was measured for two nights using a single-channel (A1-A2) electroencephalogram-(EEG) (Zmachine). Sweet taste threshold and preference as well as olfactory threshold, recognition ability, and pleasantness ratings were evaluated. Sweet taste preference was correlated with total sleep time (TST) (P=0.0074) as well as with the sum of rapid eye movement (REM) and stage N3/slow wave sleep (SWS) duration (P=0.0008). Participants who slept more than the average TST or more than the average REM+SWS time preferred lower concentrations of sweetness (P=0.041, 0.049, respectively), than those whose sleep times fell below the means. Multiple linear regression revealed that REM and SWS predicted approximately 18% of the variance of sweet taste preference. These findings suggest that scientific and consumer studies related to sweet preference might benefit from screening participants for short sleep duration prior to testing.

PMID: 29522075 [PubMed - as supplied by publisher]

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The Chemical Sensitivity and Electrical Activity of Individual Olfactory Sensory Neurons to a Range of Sex Pheromones and Food Odors in the Goldfish.

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The Chemical Sensitivity and Electrical Activity of Individual Olfactory Sensory Neurons to a Range of Sex Pheromones and Food Odors in the Goldfish.

Chem Senses. 2018 Mar 03;:

Authors: Sato K, Sorensen PW

Abstract
Although it is well established that the olfactory epithelium of teleost fish detects at least 6 classes of biologically-relevant odorants using five types of olfactory sensory neurons (OSNs), little is understood about the specificity of individual OSNs and thus how they encode identity of natural odors. In this study we used in vivo extracellular single-unit recording to examine the odor-responsiveness and physiological characteristics of 109 individual OSNs in mature male goldfish to a broad range of biological odorants including feeding stimuli (amino acids, polyamines, nucleotides), sex pheromones (sex steroids, prostaglandins) and a putative social cue (bile acids). Sixty-one OSNs were chemosensitive, with over half of these (36) responding to amino acids, 7 to polyamines, 7 to nucleotides, 5 to bile acids, 9 to prostaglandins, and 7 to sex steroids. Approximately a quarter of the amino acid-sensitive units also responded to polyamines or nucleotides. Three of 6 amino acid-sensitive units responded to more than one amino acid compound, and 5 sex pheromone-sensitive units detected just one sex pheromone. While pheromone-sensitive OSNs also responded to the adenylyl cyclase activator, forskolin, amino acid-sensitive OSNs responded to either forskolin or a phospholipase C activator, imipramine. Most OSNs responded to odorants and activators with excitation. Our results suggest that pheromone information is encoded by OSNs specifically tuned to single sex pheromones and employ adenylyl cyclase, suggestive of a labeled-line organization, while food information is encoded by a combination of OSNs that use both adenylyl cyclase and phospholipase C and are often less specifically tuned.

PMID: 29514213 [PubMed - as supplied by publisher]

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Tastant-evoked Arc expression in the nucleus of the solitary tract and nodose/petrosal ganglion of the mouse is specific for bitter compounds.

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Tastant-evoked Arc expression in the nucleus of the solitary tract and nodose/petrosal ganglion of the mouse is specific for bitter compounds.

Chem Senses. 2018 Mar 05;:

Authors: Töle J, Stolzenburg A, Tyree SM, Stähler F, Meyerhof W

Abstract
Despite long and intense research, some fundamental questions regarding representation of taste information in the brain still remain unanswered. This might in part be due to shortcomings of the established methods that limit the researcher either to thorough characterization of few elements or analyze the response of the entirety of neurons to only one stimulus. To overcome these restrictions, we evaluate the use of the immediate early gene Arc as a neuronal activity marker in the early neural structures of the taste pathway, the nodose/petrosal ganglion (NPG) and the nucleus of the solitary tract (NTS). Responses of NPG and NTS neurons were limited to substances that taste bitter to humans and are avoided by mice. Arc expressing cells were concentrated in the rostromedial part of the dorsal NTS suggesting a role in gustatory processing. The use of Arc as a neuronal activity marker has several advantages, primarily the possibility to analyze the response of large numbers of neurons while using more than one stimulus makes Arc an interesting new tool for research in the early stages of taste processing.

PMID: 29514200 [PubMed - as supplied by publisher]

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Nicotinic acetylcholine receptor (CHRN) expression and function in cultured human adult fungiform (HBO) taste cells.

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Nicotinic acetylcholine receptor (CHRN) expression and function in cultured human adult fungiform (HBO) taste cells.

PLoS One. 2018;13(3):e0194089

Authors: Qian J, Mummalaneni S, Larsen J, Grider JR, Spielman AI, Özdener MH, Lyall V

Abstract
In rodents, CHRNs are involved in bitter taste transduction of nicotine and ethanol. Currently, it is not clear if CHRNs are expressed in human taste cells and if they play a role in transducing the bitter taste of nicotine and ethanol or in the synthesis and release of neurohumoral peptides. Accordingly, we investigated the expression and functional role of CHRNs in HBO cells. Using molecular techniques, we demonstrate that a subset of HBO cells express CHRNs that also co-express TRPM5, T1R3 or T2R38. Exposing HBO cells to nicotine or ethanol acutely or to nicotine chronically induced a differential increase in the expression of CHRN mRNA and protein in a dose- and time-dependent manner. Acutely exposing HBO cells to a mixture containing nicotine plus ethanol induced a smaller increase in CHRN mRNAs relative to nicotine or ethanol treatment alone. A subset of HBO cells responded to nicotine, acetylcholine and ATP with a transient increase in [Ca2+]i. Nicotine effects on [Ca2+]i were mecamylamine sensitive. Brain-derived neurotrophic factor (BDNF) protein was detected in HBO cells using ELISA. Acute nicotine exposure decreased BDNF in HBO cells and increased BDNF release in the medium. CHRNs were also detected in HEK293 cells by RT-PCR. Unlike HBO cells, CHRNs were localized in most of HEK293 cells and majority of HEK293 cells responded to nicotine and ethanol stimulation with a transient increase in [Ca2+]i. BDNF levels in HEK293 cells were significantly higher than in HBO cells but the nicotine induced release of BDNF in the media was a fraction of the BDNF cellular content. We conclude that CHRNs are expressed in TRPM5 positive HBO cells. CHRN mRNA expression is modulated by exposure to nicotine and ethanol in a dose- and time-dependent manner. Nicotine induces the synthesis and release of BDNF in HBO cells.

PMID: 29513745 [PubMed - in process]

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Stachybotrychromenes A–C: novel cytotoxic meroterpenoids from Stachybotrys sp.

Abstract

In the course of gaining new insights into the secondary metabolite profile of various Stachybotrys strains, in particular concerning triprenyl phenol-like compounds, so far, unknown metabolites with analogous structural features were discovered. Three novel meroterpenoids containing a chromene ring moiety, namely stachybotrychromenes A–C, were isolated from solid culture of the filamentous fungus Stachybotrys chartarum DSMZ 12880 (chemotype S). Their structures were elucidated by means of comprehensive spectroscopic analysis (1D and 2D NMR, ESI-HRMS, and CD) as well as by comparison with spectroscopic data of structural analogues described in literature. Stachybotrychromenes A and B exhibited moderate cytotoxic effects on HepG2 cells after 24 h with corresponding IC₅₀ values of 73.7 and 28.2 μM, respectively. Stachybotrychromene C showed no significant cytotoxic activity up to 100 μM. Moreover, it is noteworthy that stachybotrychromenes A–C are produced not only by S. chartarum chemotype S but also S. chartarum chemotype A and Stachybotrys chlorohalonata.

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Glucosylation of T-2 and HT-2 toxins using biotransformation and chemical synthesis: Preparation, stereochemistry, and stability

Abstract

Plant-derived phase II metabolites of T-2 toxin (T2) and HT-2 toxin (HT2) were first described in 2011 and further characterized in the following years. Since then, some efforts have been made to understand their biosynthesis, occurrence, toxicity, toxicokinetics, and finally relevance for consumers. Thus, the probably most important question is whether and how these metabolites contribute to toxicity upon hydrolysis either during food processing or the gastrointestinal passage. To answer this question, firstly, knowledge on the correct stereochemistry of T2 and HT2 glucosides is important as this affects hydrolysis and chemical behavior. So far, contradictory results have been published concerning the number and anomericity of occurring glucosides. For this reason, we set up different strategies for the synthesis of mg-amounts of T2, HT2, and T2 triol glucosides in both α and ß configuration. All synthesized glucosides were fully characterized by NMR spectroscopy as well as mass spectrometry and used as references for the analysis of naturally contaminated food samples to validate or invalidate their natural occurrence. Generally, 3-O-glucosylation was observed with two anomers of HT2 glucoside being present in contaminated oats. In contrast, only one anomer of T2 glucoside was found. The second aspect of this study addresses the stability of the glucosides during thermal food processing. Oat flour was artificially contaminated with T2 and HT2 glucosides individually and extruded at varying initial moisture content and temperature. All four glucosides appear to be more stable during food extrusion than the parent compounds with the glucosidic bond not being hydrolyzed.

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Reducing production of fumonisin mycotoxins in Fusarium verticillioides by RNA interference

Abstract

The fungus Fusarium verticillioides is a maize pathogen that can produce fumonisin mycotoxins in ears under certain environmental conditions. Because fumonisins pose health risks to humans and livestock, control strategies with minimal risk to the environment are needed to reduce fumonisin contamination. Host-induced gene silencing is a promising technique in which double-stranded RNA expressed in the plant host is absorbed by an invading fungus and down-regulates genes critical for pathogenicity or mycotoxin production in the fungus. A key preliminary step of this technique is identification of DNA segments within the targeted fungal gene that can effectively silence the gene. Here, we used segments of the fumonisin biosynthetic gene FUM1 to generate double-stranded RNA in F. verticillioides. Several of the resulting transformants exhibited reduced FUM1 gene expression and fumonisin production (24- to 3675-fold reduction in fumonisin FB₁). Similar reductions in fumonisin production resulted from double-stranded RNA constructs with segments of FUM8, another fumonisin biosynthetic gene (3.5- to 2240-fold reduction in fumonisin FB₁). FUM1 or FUM8 silencing constructs were transformed into three isolates of F. verticillioides. Whole genome sequence analysis of seven transformants revealed that reductions in fumonisin production were not due to mutation of the fumonisin biosynthetic gene cluster and revealed a complex pattern of plasmid integration. These results suggest the cloned FUM1 or FUM8 gene segments could be expressed in maize for host-induced gene silencing of fumonisin production.

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The mycoestrogen zearalenone in Portuguese flowing waters and its potential environmental impact

Abstract

This study provides the first environmental risk assessment (ERA) for zearalenone (ZEN), the only known mycoestrogen, based on a broad-scale investigation on its occurrence in rivers and creeks from Portugal. Water sample filtration and immunoaffinity columns (IAC) clean-up followed by liquid chromatograph with tandem mass spectrometry (LC/MSⁿ ) provided an analytical method with good analytical performance. ZEN levels were determined for seven Portuguese rivers and one creek, during two different seasons, in a total of 38 samples collected upstream wastewater treatment plants (WWTPs). Overall, 23.7% were contaminated with ZEN at levels ranging between 5.6 and 82.6 ng/L. The highest concentration was observed during spring, although no statistically significant differences were observed between spring and autumn sampling campaigns. The potential ecotoxicological risk from ZEN to different trophic levels of aquatic organisms was evaluated by means of risk quotients (RQs) calculation. Although all the RQs obtained were lower than 1, our results confirm that ZEN is a relatively frequent contaminant in flowing waters in Portugal and might contribute to the overall estrogenic activity in the environment.

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First report of an atypical new Aspergillus parasiticus isolates with nucleotide insertion in aflR gene resembling to A. sojae

Abstract

Aflatoxins are toxic and carcinogenic secondary metabolites produced primarily by the filamentous fungi Aspergillus flavus and Aspergillus parasiticus and cause toxin contamination in food chain worldwide. Aspergillus oryzae and Aspergillus sojae are highly valued as koji molds in the traditional preparation of fermented foods, such as miso, sake, and shoyu. Koji mold species are generally perceived of as being nontoxigenic and are generally recognized as safe (GRAS). Fungal isolates were collected from a California orchard and a few were initially identified to be A. sojae using β-tubulin gene sequences blasted against NCBI data base. These new isolates all produced aflatoxins B₁, B₂, G₁, and G₂ and were named as Pistachio Winter Experiment (PWE) strains. Thus, it is very important to further characterize these strains for food safety purposes. The full length of aflR gene of these new isolates was sequenced. Comparison of aflR DNA sequences of PWE, A. parasiticus and A. sojae, showed that the aflatoxigenic PWE strains had the six base insertion (CTCATG) similar to domesticated A. sojae, but a pre-termination codon TGA at nucleotide positions 1153–1155 was absent due to a nucleotide codon change from T to C. Colony morphology and scanning microscopic imaging of spore surfaces showed similarity of PWE strains to both A. parasiticus and A. sojae. Concordance analysis of multi locus DNA sequences indicated that PWE strains were closely linked between A. parasiticus and A. sojae. The finding documented the first report that such unique strains have been found in North America and in the world.

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Malignant triton tumor of the duodenum: report of a case

Abstract

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

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A cadaveric demonstration of visualization of the urethra using a lighted stent during transanal intersphincteric resection

Abstract

Urethral injury is one of the crucial intraoperative complications during transanal total mesorectal excision (taTME) for male patients with low rectal cancer. Urethral injury can occur during the anterior dissection around the inferior lobe of the prostate and the membranous urethra. A tool to visualize the urethra around this area would be useful to avoid urethral injury. We report a cadaveric demonstration of visualization of the urethra using a lighted stent during transanal intersphincteric resection. The lighted stent (InfraVision Ureteral Kit, Stryker) was placed through the irrigation channel of a clear three-way urinary catheter. After the anterior dissection, the visibility of the lighted stent was investigated under the three laparoscopic light conditions: (1) normal intensity; (2) low intensity; and (3) turned-off. In the proper dissection plane that led to preservation of the urethra, the lighted stent was hardly visible under the normal-intensity condition, but it was clearly visible under the turned-off condition. In the improper dissection plane that led to urethral injury, the lighted stent was clearly visible under both the normal-intensity and the turned-off conditions. Visualization of the urethra using the lighted stent under the turned-off condition of the laparoscopic light can be useful to avoid inadvertent urethral injury during the anterior dissection of male taTME. Clear visibility of the lighted stent under the normal-intensity condition can indicate that the dissection plane is too close to the urethra.

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Laparoscopic transhiatal lymphadenectomy in the lower mediastinum for adenocarcinoma of the esophagogastric junction

Abstract

Laparoscopic transhiatal esophagogastrectomy is difficult because the lower mediastinum is so deeply located that the operative field is narrow and restricted by surrounding organs. Therefore, we performed lymphadenectomy with opening of the bilateral mediastinal pleura to maintain safety and obtain better exposure of lymph nodes and important organs. We will present our technique for laparoscopic lower mediastinal lymphadenectomy and reconstruction for cancer of the esophagogastric junction. Five abdominal ports were used. Retraction of the left lobe of the liver exposed the esophageal hiatus. A long, narrow gastric tube (3 cm wide) was formed, and regional abdominal lymph nodes (No. 1, 2, 3a, 7, 8a, 9, 19, and 20) were resected. The diaphragmatic hiatus was widely split and the opened bilateral mediastinal pleura enabled better exposure for lymph node dissection and reconstruction. The level where the inferior vena cava passed through the diaphragm into the chest was used as a landmark to identify supradiaphragmatic (No. 111) and lower thoracic paraesophageal nodes (No. 110), which were completely retrieved with this procedure. The posterior mediastinal nodes (No. 112pulR, 112pulL, and 112aoA) were also retrieved with bilateral opening of the mediastinal pleura and dissection of the inferior pulmonary ligaments. An esophagogastric tube anastomosis with pseudo-fornix was made with a no-knife linear stapler to prevent postoperative reflux esophagitis. This approach enabled safe and accurate laparoscopic lower mediastinal nodal dissection. With the advantage of a narrow gastric tube, the good working space made tension-free anastomosis possible.

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Correction to: The structural changes of pharyngeal airway contributing to snoring after orthognathic surgery in skeletal class III patients

Abstract

The publication of this article [1] unfortunately contained several mistakes.

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Clinical and molecular characteristics of gliosarcoma and modern prognostic significance relative to conventional glioblastoma

Abstract

Gliosarcoma is a rare histopathologic variant of glioblastoma traditionally associated with a poor prognosis. While gliosarcoma may represent a distinct clinical entity given its unique histologic composition and molecular features, its relative prognostic significance remains uncertain. While treatment of gliosarcoma generally encompasses the same standardized approach used in glioblastoma, supporting evidence is limited given its rarity. Here, we characterized 32 cases of gliosarcoma and retrospectively evaluated survival relative to 451 glioblastoma patients diagnosed during the same era within the same institution. Overall, we identified 22 primary gliosarcomas, representing 4.7% of WHO Grade IV primary glioblastomas, and 10 secondary gliosarcomas. With median age of 62, patients were predominately Caucasian (87.5%) and male (65.6%). Tumors with available molecular profiling were primarily MGMT-unmethylated (87.5%), IDH-1-preserved (100%) and EGFR wild-type (100%). Interestingly, while no significant median survival difference between primary gliosarcoma and glioblastoma was observed across the entire cohort (11.0 vs. 14.8 months, p = 0.269), median survival was worse for gliosarcoma specifically among patients who received modern temozolomide-based (TMZ) chemoradiotherapy (11.0 vs. 17.3 months, p = 0.006). Matched-pair analysis also trended toward worse median survival among gliosarcomas (11.0 vs. 19.6 months, log-rank p = 0.177, Breslow p = 0.010). While adjuvant radiotherapy (HR 0.206, p = 0.035) and TMZ-based chemotherapy (HR 0.531, p = 0.000) appeared protective, gliosarcoma emerged as a significantly poor prognostic factor on multivariate analysis (HR 3.27, p = 0.012). Collectively, our results suggest that gliosarcoma may still portend worse prognosis even with modern trimodality therapy.

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Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients

Abstract

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m² every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125 mg/m² and bevacizumab 10 mg/kg every 2 weeks. The response rate was 37.1% for lom-bev and 30.1% for iri-bev. Median progression-free survival (PFS) was 23 weeks for lom-bev and 21 weeks for iri-bev (p = 0.9). Overall survival (OS) was 37 weeks for lom-bev and 32 weeks for iri-bev (p = 0.5). Lom-bev caused a significantly higher frequency of thrombocytopenia (11.4% grade 3–4) compared to iri-bev (3.5% grade 3–4). Iri-bev patients had more gastrointestinal toxicity with regard to nausea, vomiting, diarrhea, constipation and stomatitis. Within the limitations of the study lom-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision in recurrent GBM therapy as efficacy is equal and no predictive factors for efficacy exist.

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Recursive partitioning analysis is predictive of overall survival for patients undergoing spine stereotactic radiosurgery

Abstract

Spine stereotactic radiosurgery (SRS) offers excellent radiographic and pain control for patients with spine metastases. We created a prognostic index using recursive partitioning analysis (RPA) to allow better patient selection for spine SRS. Patients who underwent single-fraction spine SRS for spine metastases were included. Primary histologies were divided into favorable (breast/prostate), radioresistant (renal cell/sarcoma/melanoma) and other. Cox proportional hazards regression was done to identify factors associated with overall survival (OS). RPA was performed to identify factors to classify patients into distinct risk groups with respect to OS. A total of 444 patients were eligible. Median dose was 16 Gy (range 8–18) in 1 fraction and median follow-up was 11.7 months. At time of analysis, 103 (23.1%) patients were alive. Median OS was 12.9 months. RPA identified three distinct classes. Class 1 was defined as KPS > 70 with controlled systemic disease (n = 142); class 3 was defined as KPS ≤ 70 and age < 54 years or KPS ≤ 70 age ≥ 54 years and presence of visceral metastases (n = 95); all remaining patients comprise class 2 (n = 207). Median overall survival was 26.7 months for class 1, 13.4 months for class 2, and 4.5 months for class 3 (p < 0.01). Our analysis demonstrates that there is considerably variability in survival among patients undergoing spine SRS. We created an objective risk stratification via RPA for spine SRS. Given the safety and efficacy of spine SRS and good survival in class 1 and 2 patients, this RPA can help clinicians identify patients who may benefit from upfront spine SRS.

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To drive or not to drive, that is still the question: current challenges in driving recommendations for patients with brain tumours

Abstract

Driving is a complex task that requires integration of various skills that may be impaired in patients with brain tumours. Determining fitness to drive is a responsibility of all physicians in Canada; however, it is an inconsistent practice based on few objective guidelines. The primary purpose of the study is to determine the consistency of driving recommendations amongst health care professionals in Ontario. Secondary aims include evaluation of physician awareness of driving regulations and determination of whether physicians would benefit from more specific driving guidelines. An 18-item questionnaire was sent to 126 health care professionals who take care of patients with brain tumours in Ontario. Seventy-five health care professionals responded to the survey. Less than 10% said they could reliably determine fitness to drive and almost an equal percentage of respondents indicated that determining fitness to drive should be a shared responsibility. The factors deemed important in determining driving safety were highly variable; 70% indicated that cognitive and emotional deficits were important. Over a third of respondents never heard of the CMA guidelines and of those who were familiar with it, 12.5% felt they were sufficient to inform clinical decisions. 90% of respondents wanted more specific and detailed driving guidelines for patients with brain tumours. The current guidelines for physicians are not specific enough for physicians to confidently determine fitness to drive in this population. These findings suggest the need for more detailed guidelines for driving safety that are based on empirical studies on driving habits and performance in patients with a variety of brain tumours.

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Treatment and outcomes of 28 patients with spinal metastasis from gynecological cancer

Abstract

The aim of this study was to provide some useful information concerning clinical characteristics, surgical treatment, potential contributing factor and prognostic factors for patients with gynecological cancer (GC) spinal metastasis. We reviewed 28 patients with GC spinal metastasis in our spine tumor center between July 2008 and July 2015. Surgeries were performed on 22 of them. Univariate and multivariate analyses were conducted to identify potential prognostic factors affecting spinal metastasis-free survival (SMFS) and overall survival. The operative patients responded favorably according to decrease of VAS score and increase of Frankel grade after surgery. The 1- and 2-year survival rates in all patients were 60.7 and 41.0%, respectively. Univariate analysis suggested that age at diagnosis with GC was the potential contributing factor for spinal metastasis, while Frankel grade, ECOG-PS, visceral metastasis and chemotherapy were the potential prognostic factors affecting survival. Multivariate analysis indicated that the independent prognostic factors came from visceral metastasis and chemotherapy. Surgery played an important role in improving patients' quality of life. Patients over 50 years old had a shorter SMFS after diagnosed with GC. Visceral metastasis was an adverse prognostic factor for patients with GC spinal metastasis, while chemotherapy was a favorable one.

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Transforming growth factor beta induced (TGFBI) is a potential signature gene for mesenchymal subtype high-grade glioma

Abstract

Previous study revealed that higher expression of transforming growth factor beta induced (TGFBI) is correlated to poorer cancer-specific survival and higher proportion of tumor necrosis and Fuhrman grades III and IV in clear cell renal cell carcinomas. However, the relationships between TGFBI expression and malignant phenotypes of gliomas remain unclear. We downloaded and analyzed data from seven GEO datasets (GSE68848, GSE4290, GSE13041, GSE4271, GSE83300, GSE34824 and GSE84010), the TCGA database and the REMBRANDT database to investigate whether TGFBI could be a biomarker of glioma. From microarray data (GSE68848, GSE4290) and RNA-seq data (TCGA), TGFBI expression levels were observed to correlate positively with pathological grade, and TGFBI expression levels were significantly higher in gliomas than in normal brain tissues. Furthermore, in GSE13041, GSE4271 and the TCGA cohort, TGFBI expression in the mesenchymal (Mes) subtype high-grade glioma (HGG) was significantly higher than that in the proneural subtype. Kaplan–Meier survival analysis of GBM patients in the GSE83300 dataset, REMBRANDT and TCGA cohort revealed that patients in the top 50% TGFBI expression group survived for markedly shorter periods than those in the bottom 50%. Analysis of grade III gliomas showed that the median survival time was significantly shorter in the TGFBI high expression group than in the TGFBI low expression group. In addition, we found that TGFBI expression levels might relate to several classical molecular characterizations of glioma, such as, IDH mutation, TP53 mutation, EGFR amplification, etc. These results suggest that TGFBI expression positively correlates with glioma pathological grades and that TGFBI is a potential signature gene for Mes subtype HGG and a potential prognostic molecule.

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Overexpression of aryl hydrocarbon receptor (AHR) signalling pathway in human meningioma

Abstract

Aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor and involved in tumorigenesis of many cancers. However there are no reports on AHR in human meningioma. Therefore we examined the status of the AHR and its signalling molecules in human meningioma by using tumor biopsy samples and autopsy control meninges. We report the up regulation of AHR pathway genes like aryl hydrocarbon receptor nuclear translocator (ARNT), aldehyde dehydrogenase1family memberA3 (ALDH1A3), cytochrome P450, family1, subfamily A polypeptide1 (CYP1A1) and TCCD induced poly ADP ribose polymerase (TIPARP) gene expression in human meningioma. Further, AHR protein expression was found to be up regulated in all grades of human meningioma. We found that AHR localized in the nucleus for high grade anaplastic meningioma through immunohistochemical analysis. Since AHR signalling pathway was known to involve in inhibition of apoptosis in cancer cells, we evaluated the cyclophilin D levels which maintains mitochondrial permeability transition pore a critical event during apoptosis. We report that cyclophilin D levels were upregulated in all grades of human meningioma compared to control meninges. Finally we also evaluated c-Fos protein levels as its levels were regulated by AHR. Here we report that c-Fos protein levels were down regulated in all grades of human meningioma compared to control meninges. To sum-up we found that AHR signalling pathway components were upregulated, as the grade of the meningioma progresses from low to high grade, suggesting an important role of AHR signalling pathway in human meningioma.

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Analysis of immunobiologic markers in primary and recurrent glioblastoma

Abstract

Glioblastoma (GBM) generates a varied immune response and understanding the immune microenvironment may lead to novel immunotherapy treatments modalities. The goal of this study was to evaluate the expression of immunologic markers of potential clinical significance in primary versus recurrent GBM and assess the relationship between these markers and molecular characteristics of GBM. Human GBM samples were evaluated and analyzed with immunohistochemistry for multiple immunobiologic markers (CD3, CD8, FoxP3, CD68, CD163, PD1, PDL1, CTLA4, CD70). Immunoreactivity was analyzed using Aperio software. Degree of strong positive immunoreactivity within the tumor was compared to patient and tumor characteristics including age, gender, MGMT promoter methylation status, and ATRX, p53, and IDH1 mutation status. Additionally, the TCGA database was used to perform similar analysis of these factors in GBM using RNA-seq by expectation–maximization. Using odds ratios, IDH1 mutated GBM had statistically significant decreased expression of CD163 and CD70 and a trend for decreased PD1, CTLA4, and Foxp3. ATRX-mutated GBMs exhibited statistically significant increased CD3 immunoreactivity, while those with p53 mutations were found to have significantly increased CTLA4 immunoreactivity. The odds of having strong CD8 and CD68 reactivity was significantly less in MGMT methylated tumors. No significant difference was identified in any immune marker between the primary and recurrent GBM, nor was a significant change in immunoreactivity identified among age intervals. TCGA analysis corroborated findings related to the differential immune profile of IDH1 mutant, p53 mutant, and MGMT unmethylated tumors. Immunobiologic markers have greater association with the molecular characteristics of the tumor than with primary/recurrent status or age.

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Temporal stability of MGMT promoter methylation in glioblastoma patients undergoing STUPP protocol

Abstract

Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies.

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Necrosis is a consistent factor to recurrence of meningiomas: should it be a stand-alone grading criterion for grade II meningioma?

Abstract

The purpose of this study was to evaluate spontaneous necrosis as a possible isolated factor for progression and recurrence in grade I meningiomas classified according to the current World Health Organization (WHO) classification. Meningiomas are the most frequently reported primary intracranial tumours, accounting for more than 35%. The 2016 WHO classification of central nervous system tumors stratifies meningiomas in grades I (benign), II (atypical), and III (malignant), according to histopathological aspects and the risk of progression or recurrence. Among 110 patients with intracranial meningiomas, 70 were WHO grade I meningiomas with no findings of atypia (G1WON), 15 were WHO grade I with necrosis (G1WN), 21 were WHO grade II (G2), and 4 were WHO grade III (G3). The mean follow-up was 5.9 ± 0.2 years. High performance scale (KPS ≥ 80) was different (p < 0.001) between WHO grade I meningiomas without (81.4%) and with (60%) necrosis. The 5-year mortality rate was 1.4, 6.7 and 5.9% for G1WON, G1WN and G2, respectively, with significant difference (p = 0.011) related to the presence of necrosis. The risk of recurrence was 3.7 times higher in G1WN than in G1WON (p = 0.017), and 4.2 times in G2 (p = 0.010). Progression-free survival (PFS) was clearly higher in patients with G1WON compared to G1WN and G2 (p = 0.002 and p < 0.001, respectively). There was no significant difference in PFS between G1WN and G2 (p = 0.692). Retreatment was also superior in meningioma with necrosis. Our findings provide clear statistical data to consider that patients with benign meningiomas and histologic findings of spontaneous necrosis are at increased risk of progression and recurrence compared to those with benign lesion without atypical features. Statistical analysis curves also suggest that these lesions behave more similarly to those currently classified as WHO grade II meningioma.

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Update on the effect of exogenous hormone use on glioma risk in women: a meta-analysis of case-control and cohort studies

Abstract

Various studies have confirmed the important roles of endogenous hormones in the development of gliomas, while the roles of exogenous hormones remain controversial. Based on case-control studies and cohort studies, a meta-analysis was exerted to explore the effect of two exogenous hormones use (HRT: hormone replacement therapy; OC: oral contraceptives) on glioma risk. 16 eligible studies, including 11 case-control studies and 5 cohort studies, containing 8055027 women, were included in our study. All included studies have reported the relative risks (RRs) or odds ratios (ORs), and 95% confidence intervals (CIs). We use the fixed-effects model to calculate the estimated overall risk. In case-control studies, the risk of glioma was lower in women who had ever been treated with an exogenous hormone than in the control group (HRT: OR 0.91, 95% CI 0.84–0.99; OC: OR 0.99, 95% CI 0.91–1.07). In research of cohort studies, similar results have been obtained (HRT: RR 0.95, 95% CI 0.83–1.08; OC: RR 0.75, 95% CI 0.66–0.84). Our study further confirmed that the use of exogenous hormones has an important impact on the risk of glioma in women. However, more prospective studies are needed to further confirm this conclusion.

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Discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis

Abstract

When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion.

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Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas

Abstract

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m² po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2–67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.

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Clinical and dosimetric study of radiotherapy for glioblastoma: three-dimensional conformal radiotherapy versus intensity-modulated radiotherapy

Abstract

Background and purpose

We aimed to compare three-dimensional conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) for the treatment of glioblastoma.

Materials and methods

Retrospective study of 220 patients with glioblastoma, treated with 3D-CRT or IMRT, with or without surgery. Dosimetric parameters as well as clinical and survival data for the two techniques were analyzed and compared.

Results

The median conformity index was 1.53 (range 0–2.69) for 3D-CRT and 1.25 (range 0.97–2.01) for IMRT, p < 10⁻⁴. The median homogeneity index was 0.10 (range 0.03–0.32) for 3D-CRT and 0.07 (range 0.03–0.18) for IMRT, p < 10⁻⁴. There were significantly fewer acute grade 1 and 2 neurological toxicities in the IMRT group especially for edema (1.3 versus 12.4%, p = 0.017), concentration disorders (6.6 versus 19.9%, p = 0.003) and consciousness disorders (2.6 versus 13.2%, p = 0.002) although IMRT patients had a significantly worse pre-treatment neurological status than 3D-CRT patients. Median survival was 16.0 months (range 11.9–17.8) for IMRT and 13.4 months (range 11.7–15.7) for 3D-CRT patients (p = 0.542).

Conclusion

IMRT improved target conformity and reduced neurological toxicities for patients with glioblastomas.

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Tumor microenvironment after biodegradable BCNU wafer implantation: special consideration of immune system

Abstract

Biomaterials to treat cancers hold therapeutic potential; however, their translation to bedside treatment requires further study. The carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea; BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. However, how this wafer affects the surrounding tumor microenvironment is not well understood to date. We retrospectively reviewed all patients with glioblastoma treated with and without BCNU wafers who underwent repeat resection at tumor recurrence. We investigated radiological imaging; the interval between the two surgeries; and immunohistochemistry of CD3, CD4, CD8, CD20, CD68, FOXP3, and PD1. We implanted BCNU wafers in 41 newly diagnosed glioblastoma patients after approval of the wafer in Japan. Of them, 14 underwent surgery at recurrence and tissue was obtained from around the wafers. The interval between the first and second surgeries ranged from 63 to 421 days. The wafer could be observed on magnetic resonance imaging at up to 226 days, whereas intraoperatively the biodegraded material of the wafer could be found at up to 421 days after the initial surgery. Immunohistochemical analysis demonstrated that CD8+ and CD68+ cells were significantly increased, but FOXP3+ cells did not increase, after wafer implantation compared to tissue from cases without wafer implantation. MRI data and immune cells, as well as interval between surgeries and immune cells, demonstrated positive correlation. These results helped us to understand the bioactivity of bioengineered materials and to establish a new approach for immunotherapy.

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Optimizing intrapleural bevacizumab dosing in non-small-cell lung cancer-mediated malignant pleural effusion: less is more

Future Oncology, Ahead of Print.


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Upper gastrointestinal malignancies in 2017: current perspectives and future approaches

Future Oncology, Ahead of Print.


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Advances in immunotherapy for acute myeloid leukemia

Future Oncology, Ahead of Print.


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Insights into the hepatocellular carcinoma patient journey: results of the first global quality of life survey

Future Oncology, Ahead of Print.


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The role of IDH mutations in acute myeloid leukemia

Future Oncology, Ahead of Print.


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The use of alectinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancer

Future Oncology, Ahead of Print.


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Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma

Future Oncology, Ahead of Print.


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Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations?

Future Oncology, Ahead of Print.


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IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug?

Future Oncology, Ahead of Print.


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Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy

Future Oncology, Ahead of Print.


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Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

Future Oncology, Ahead of Print.


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Triple negative breast cancer: are we scoring a home run?

Future Oncology, Ahead of Print.


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Do checkpoint inhibitors provide new hope for management of metastatic penile carcinoma?

Future Oncology, Ahead of Print.


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CD59: a promising target for tumor immunotherapy

Future Oncology, Ahead of Print.


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Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects

Future Oncology, Ahead of Print.


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MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme

Future Oncology, Ahead of Print.


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miR-181a targets GATA6 to inhibit the progression of human laryngeal squamous cell carcinoma

Future Oncology, Ahead of Print.


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YB-1 promotes laryngeal squamous cell carcinoma progression by inducing miR-155 expression via c-Myb

Future Oncology, Ahead of Print.


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Adolescent Social Isolation Affects Schizophrenia-Like Behavior in the MAM-E17 Model of Schizophrenia

Abstract

Social isolation (SI) during adolescence may induce schizophrenia-like behavior. In the present study, we investigated whether adolescent SI might affect the development of schizophrenia-like behavior in the MAM-E17 neurodevelopmental model of schizophrenia. Rats were socially isolated for 10 days during adolescence (postnatal days (P) 30–40), followed by resocialization until late adolescence (P45–P48) or early adulthood (P70–P75); behavioral and neurochemical studies were performed at these ages. The behavioral studies analyzed locomotor activity, social interaction, recognition memory, and sensorimotor gating; GAD65 and GAD67 protein levels were measured in the prefrontal cortex. The results showed that SI did not affect locomotor activity, but it prevented the social interaction deficits induced by MAM administration at both of the analyzed age points. However, SI induced a deficit in recognition memory in the MAM group during adolescence, which was not observed in the MAM-treated, socially housed rats at this age. In adulthood, impairments in recognition memory were detected in both MAM groups. In contrast, SI did not accelerate the appearance of sensorimotor gating deficits in MAM animals during adolescence, and sensorimotor gating impairments were observed in both MAM groups during adulthood. Adolescent SI rearing did not affect any examined behavioral responses in the VEH-treated groups. SI altered the levels of GAD65 and GAD67 proteins during adolescence in both groups; however, the decrease in the level of GAD65 protein was observed only in the adult MAM-SI group. Thus, SI rearing during a defined period of adolescence might have specific effects on the emergence of schizophrenia-like abnormalities in MAM-treated animals.

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Identification and Quantification of Cocaine and Active Adulterants in Coca-Paste Seized Samples: Useful Scientific Support to Health Care

Abstract

Adulteration is a common practice in the illicit drugs market, but the psychoactive and toxic effects provided by adulterants are clinically underestimated. Coca-paste (CP) is a smokable form of cocaine which has an extremely high abuse liability. CP seized samples are sold adulterated; however, qualitative and quantitative data of CP adulteration in forensic literature is still scarce. Besides, it is unknown if adulterants remain stable when CP is heated. This study was designed to report the chemical content of an extensive series of CP seized samples and to demonstrate the stability (i.e., chemical integrity) of the adulterants heated. To achieve this goal, the following strategies were applied: (1) a CP adulterated sample was heated and its fume was chemically analyzed; (2) the vapor of isolated adulterants were analyzed after heating; (3) plasma levels of animals exposed to CP and adulterants were measured. Ninety percent of CP seized samples were adulterated. Adulteration was dominated by phenacetin and caffeine and much less by other compounds (i.e., aminopyrine, levamisole, benzocaine). In the majority of CP analyzed samples, both cocaine and caffeine content was 30%, phenacetin 20% and the combination of these three components reached 90%. Typical cocaine pyrolysis compounds (i.e., BA, CMCHTs, and AEME) were observed in the volatilized cocaine and CP sample but no pyrolysis compounds were found after isolated adulterants heating. Cocaine, phenacetin, and caffeine were detected in plasma. We provide current forensic data about CP seized samples and demonstrated the chemical integrity of their adulterants heated.

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Combinatorial Preconditioning of Rat Brain Cultures with Subprotective Ethanol and Resveratrol Concentrations Promotes Synergistic Neuroprotection

Abstract

Preconditioning brain cultures with moderate concentrations of ethanol (EtOH) or trans-resveratrol (RES), key red wine constituents, can prevent amyloid-β (Aβ) neurotoxicity. Past studies have indicated that moderate EtOH activates synaptic N-methyl-D-aspartate receptors (NMDAR) that, in part, signal via protein kinase C (PKC) to increase protective antioxidant proteins such as peroxiredoxin-2 (Prx2). RES preconditioning also is reported to involve NMDAR and PKC. However, although moderate, the EtOH and RES concentrations used have been noticeably above circulating levels from two glasses of wine, a daily intake linked to reduced risk of cognitive decline among older social drinkers. Given their mechanistic parallels, we speculated that subprotective EtOH and RES concentrations in a combinatorial preconditioning paradigm might elicit synergistic neuroprotection. To examine this notion, rat cerebellar cultures were pretreated with 10 mM EtOH (circulating concentration after ~ 2 drinks), 5 μM RES, EtOH + RES combinatorially, or media alone (controls). After 3 days, media were removed, and fresh media aliquots containing Aβ_25–35 (25 μM) were added. Assessing apoptosis 24 h later with Hoescht 33342, neurodegeneration did not differ from controls in cultures separately preconditioned with 10 mM EtOH or 5 μM RES. However, apoptosis was prevented in combinatorially preconditioned cultures. Also, immunoblotting revealed elevated Prx2 levels due to combinatorial pretreatment that correlated with subsequent neuroprotection, whereas Prx2 was unchanged in separately pretreated cultures. Although the protective mechanisms require clarification, synergistically upregulated NMDAR-PKC-Prx2 (and other antioxidant proteins) is a reasonable component. These findings imply that EtOH + RES antioxidant synergy could be involved in neurobenefits attributed to low-moderate wine consumption.

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Metabolic Enhancer Piracetam Attenuates the Translocation of Mitochondrion-Specific Proteins of Caspase-Independent Pathway, Poly [ADP-Ribose] Polymerase 1 Up-regulation and Oxidative DNA Fragmentation

Abstract

Piracetam, a nootropic drug, has been clinically used for decades; however, its mechanism of action still remains enigmatic. The present study was undertaken to evaluate the role of mitochondrion-specific factors of caspase-independent pathway like apoptotic-inducing factor (AIF) and endonuclease-G (endo-G) in piracetam-induced neuroprotection. N2A cells treated with lipopolysaccharide (LPS) exhibited significant cytotoxicity, impaired mitochondrial activity, and reactive oxygen species generation which was significantly attenuated with piracetam co-treatment. Cells co-treated with LPS and piracetam exhibited significant uptake of piracetam in comparison to only piracetam-treated cells as estimated by liquid chromatography-mass spectrometry (LC-MSMS). LPS treatment caused significant translocation of AIF and endonuclease-G in neuronal N2A cells which were significantly attenuated with piracetam co-treatment. Significant over-expression of proinflammatory cytokines was also observed after treatment of LPS to cells which was inhibited with piracetam co-treatment demonstrating its anti-inflammatory property. LPS-treated cells exhibited significant oxidative DNA fragmentation and poly [ADP-ribose] polymerase-1 (PARP-1) up-regulation in nucleus, both of which were attenuated with piracetam treatment. Antioxidant melatonin but not z-VAD offered the inhibited LPS-induced DNA fragmentation indicating the involvement of oxidative DNA fragmentation. Further, we did not observe the altered caspase-3 level after LPS treatment initially while at a later time point, significantly augmented level of caspase-3 was observed which was not inhibited with piracetam treatment. In total, our findings indicate the interference of piracetam in mitochondrion-mediated caspase-independent pathway, as well as its anti-inflammatory and antioxidative properties.

Graphical Abstract

Graphical abstract indicating the novel interference of metabolic enhancer piracetam (P) in neuronal death mechanisms

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Association Study Between Metallothionein-3 Protein Polymorphisms and Autism

Abstract

Genetic susceptibility to high mercury body burden has been suggested as an autism risk factor in children. Metallothionein III (MT3) is the brain-specific form of the metallothionein family, which plays a key role in metal metabolism. We therefore looked for genetic variations in the MT3 gene that might increase the predisposition to autism. DNA was extracted from 132 autistic children and 132 age and gender-matched unrelated controls. All the samples were analyzed for nine single nucleotide polymorphisms (SNPs) with minor allele frequency > 10% in the MT3 gene. The mRNA levels of MT3 in white blood cells were evaluated by real-time PCR. We did not detect any association between these MT3 polymorphisms and the mRNA levels of MT3. We did not detect any association between MT3 polymorphisms and autism risk. However, we detected four novel MT3 SNPs that are not in the human SNP database. The clinical importance of these SNPs needs further investigation. Our data suggest that MT3 gene polymorphisms are not associated with autism.

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Anacardic Acids from Cashew Nuts Prevent Behavioral Changes and Oxidative Stress Induced by Rotenone in a Rat Model of Parkinson’s Disease

Abstract

Anacardic acids (AAs) are alkyl phenols mainly presenting in cashew nuts. The antioxidant effects of these compounds have been an area of interest in recent research, with findings suggesting potential therapeutic use for certain diseases. Nevertheless, none of these studies were performed in order to test the hypothesis of whether anacardic acids are capable of preventing behavioral changes and oxidative stress induced by the pesticide rotenone in experimental model of Parkinson's disease. In our research, adult male rats were treated orally with AAs (1, 3, 10, 25, 50, or 100 mg/kg/day) 1 h before rotenone (3 mg/kg; s.c.) for five consecutive days. The behavioral testing strategies, including tests for general locomotor activity (open field), motor coordination (rotarod), and spatial memory performance (elevated T-maze), were carried out. Lipoperoxidation levels and total superoxide dismutase (t-SOD) activity, as well as cytoplasmic and mitochondrial SOD gene expression, were assessed in the substantia nigra (SN), striatum, and cerebral cortex. The results showed that AAs dose-dependently prevented the rotenone-induced learning and motor impairment from 10 mg/kg/day. AAs also precluded rotenone-induced lipoperoxidation in all doses, acting directly on the mitochondria, and improved the t-SOD activity in the doses 25–100 mg/kg/day. AAs per se (100 mg/kg/day) increased SOD gene expression and t-SOD activity. Our findings indicate that the oral administration of AAs prevents rotenone-induced behavioral changes and oxidative stress, in part due to a modulatory action on the mitochondria and SOD gene expression. These data suggest that AAs have promising neuroprotective action against degenerative changes in Parkinson's disease.

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Human Umbilical Cord Matrix Stem Cells Reverse Oxidative Stress-Induced Cell Death and Ameliorate Motor Function and Striatal Atrophy in Rat Model of Huntington Disease

Abstract

Huntington disease (HD) is an inherited disorder hallmarked by progressive deterioration of specific neurons, followed by movement and cognitive anomalies. Cell therapy approaches in neurodegenerative conditions have concentrated on the replenishment of lost/dying neurons with functional ones. Multipotent mesenchymal stem cells (MSCs) have been represented as a potential remedy for HD. In this study, we evaluated the in vitro and in vivo efficacy of umbilical cord matrix stem cells (UCMSCs) and their paracrine effect against oxidative stress with a specific focus on HD. To this end, UCMSCs were isolated, immunophenotypically characterized by the positive expression of MSC markers, and exhibited multilineage potentiality. Besides, synthesis of neurotrophic factors of GDNF and VEGF by UCMSC was confirmed. Initially, PC12 cells were exposed to superoxide in the presence of conditioned media (CM) collected from UCMSC (UCMSC-CM) and cell viability plus neuritogenesis were measured. Next, bilateral striatal transplantation of UCMSC in 3-nitropropionic acid (3-NP) lesioned rat models was conducted, and 1 month later, post-graft analysis was performed. According to our in vitro results, CM of UCMSC protected PC12 cells against oxidative stress and considerably enhanced cell viability and neurite outgrowth. On the other hand, transplanted UCMSC survived, decreased gliosis, and ameliorated motor coordination and muscle activity, along with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. Collectively, our findings imply that UCMSCs provide an enriched platform by largely their paracrine factors, which downgrades the unfavorable effects of oxidative stress.

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Sulforaphane Attenuated the Pro-Inflammatory State Induced by Hydrogen Peroxide in SH-SY5Y Cells Through the Nrf2/HO-1 Signaling Pathway

Abstract

Sulforaphane (SFN), an isothiocyanate obtained from cruciferous vegetables, exerts antioxidant, antiapoptotic, and antitumor activities in different cell types. Moreover, SFN has been viewed as an anti-inflammatory agent. Nonetheless, the mechanism underlying the ability of SFN in modulating the immune response in mammalian cells is not completely understood yet. Therefore, we investigated here whether and how SFN would be effective in preventing inflammation induced by a pro-oxidant agent (hydrogen peroxide, H₂O₂) in the human neuroblastoma SH-SY5Y cells. The cells were treated with SFN at 5 μM for 30 min before a challenge with H₂O₂ for an additional 24 h. Pretreatment with SFN reduced the secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well as decreased the levels of cyclooxygenase-2 (COX-2) in H₂O₂-treated cells. SFN also decreased the activity of the transcription factor nuclear factor-κB (NF-κB) and the immunocontent of the p65 NF-κB subunit in the cell nucleus. The inhibition of heme oxygenase-1 (HO-1) by ZnPP-IX at 10 μM or the silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by small interfering RNA targeting Nrf2 attenuated the anti-inflammatory and cytoprotective effects induced by SFN. Therefore, SFN exerted an anti-inflammatory effect in H₂O₂-challenged SH-SY5Y cells by a mechanism dependent on the Nrf2/HO-1 signaling pathway.

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Transcriptome-Wide Identification of Differentially Expressed Genes and Long Non-coding RNAs in Aluminum-Treated Rat Hippocampus

Abstract

Aluminum (Al) is an environmental neurotoxicant with a wide exposure, but the molecular mechanism underlying its toxicity remains unclear. We used RNA sequencing (RNA-seq) in the hippocampus of Al-treated rats to identify 96 upregulated and 652 downregulated mRNAs, and 37 dysregulated long non-coding (lnc)RNAs. Gene ontology analysis showed that dysregulated genes were involved in glial cell differentiation, neural transmission, and vesicle trafficking. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed clustering of differentially expressed mRNAs and lncRNA target genes in several pathways, including the "adenosine monophosphate-activated protein kinase signaling pathway," "extracellular matrix receptor interaction," "the phosphatidylinositol 3 kinase–protein kinase B signaling pathway," and "focal adhesion" signaling pathway. RNA-seq results were validated by reverse transcription (RT)-PCR. Additionally, Al induced changes to the number and morphology of glial cells in the hippocampus of rats, as shown by glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunochemistry. RT-PCR and western blotting validated the significant increase in expression of glial cell-related genes GFAP and SOX10 following Al exposure compared with control rats, consistent with RNA-seq results. Collectively, these results suggest that aberrant mRNAs and lncRNAs respond to Al neurotoxicity, and that glial cell-related genes play important roles in the Al neurotoxicity mechanism. These findings provide the basis for designing targeted approaches for the treatment or prevention of Al-induced neurotoxicity.

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Peripheral Administration of Tetanus Toxin Hc Fragment Prevents MPP + Toxicity In Vivo

Abstract

Several studies have shown that intrastriatal application of 1-methyl-4-phenylpyridinium (MPP⁺) produces similar biochemical changes in rat to those seen in Parkinson's disease (PD), such as dopaminergic terminal degeneration and consequent appearance of motor deficits, making the MPP⁺ lesion a widely used model of parkinsonism in rodents. Previous results from our group have shown a neuroprotective effect of the carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) under different types of stress. In the present study, pretreatment with the intraperitoneal injection of Hc-TeTx in rats prevents the decrease of tyrosine hydroxylase immunoreactivity in the striatum due to injury with MPP⁺, when applied stereotaxically in the striatum. Similarly, striatal catecholamine contents are restored, as well as the levels of two other dopaminergic markers, the dopamine transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2). Additionally, uptake studies of [³H]-dopamine and [³H]-MPP⁺ reveal that DAT action is not affected by Hc-TeTx, discarding a protective effect due to a reduced entry of MPP⁺ into nerve terminals. Behavioral assessments show that Hc-TeTx pretreatment improves the motor skills (amphetamine-induced rotation, forelimb use, and adjusting steps) of MPP⁺-treated rats. Our results lead us to consider Hc-TeTx as a potential therapeutic tool in pathologies caused by impairment of dopaminergic innervation in the striatum, as is the case of PD.

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