Effect of high intensity focused ultrasound (HIFU) in conjunction with a nanomedicines-microbubble complex for enhanced drug delivery

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): Hyounkoo Han, Hohyeon Lee, Kwangmeyung Kim, Hyuncheol Kim
Although nanomedicines have been intensively investigated for cancer therapy in the past, poor accumulation of nanomedicines in tumor sites remains a serious problem. Therefore, a novel drug delivery system is required to enhance accumulation and penetration of nanomedicines at the tumor site. Recently, high-intensity focused ultrasound (HIFU) has been highlighted as a non-invasive therapeutic modality, and showed enhanced therapeutic efficacy in combination with nanomedicines. Cavitation effect induced by the combination of HIFU and microbubbles results in transiently enhanced cell membrane permeability, facilitating improved drug delivery efficiency into tumor sites. Therefore, we introduce the acoustic cavitation and thermal/mechanical effects of HIFU in conjunction with microbubble to overcome the limitation of conventional drug delivery. The cavitation effect maximized by the strong acoustic energy of HIFU induced the preferential accumulation of nanomedicine locally released from the nanomedicines-microbubble complex in the tumor. In addition, the mechanical effect of HIFU allowed the accumulated nanomedicines to penetrate into deeper tumor region. The preferential accumulation and deeper penetration of nanomedicines by HIFU showed enhanced therapeutic efficacy, compared to low frequency ultrasound (US). These overall results demonstrate that the strategy combined nanomedicines-microbubble complex with HIFU is a promising tools for cancer therapy.

Graphical abstract

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Adjuvant therapy in renal cell carcinoma

Publication date: Available online 23 September 2017
Source:Cancer Treatment Reviews
Author(s): Francesco Massari, Vincenzo Di Nunno, Chiara Ciccarese, Jeffrey Graham, Camillo Porta, Francesca Comito, Marta Cubelli, Roberto Iacovelli, Daniel Y.C. Heng
Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.



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Personal exposure and health risk assessment of carbonyls in family cars and public transports—a comparative study in Nanjing, China

Abstract

To evaluate passenger health risks associated with inhalation exposure to carbonyl compounds mainly emitted from decoration materials of vehicles, we tested the carbonyl concentrations in interior air of 20 family cars, 6 metro lines, and 5 buses in the city of Nanjing. To assess non-carcinogenic health risks, we compared the data to the health guidelines of China, US Environmental Protection Agency (EPA), and Office of Environmental Health Hazard Assessment (OEHHA), respectively. To assess carcinogenic risks, we followed a standard approach proposed by the OEHHA to calculate lifetime cancer risks (LCR) of formaldehyde and acetaldehyde for various age groups. The results showed that there are formaldehyde, acetaldehyde, and acrolein concentrations in 40, 35, and 50% of family car samples exceeded the reference concentrations (RfCs) provided by Chinese guidelines (GB/T 27630-2011 and GB/T 18883-2002). Whereas, in the tested public transports, concentrations of the three carbonyls were all below the Chinese RfCs. Fifty and 90% of family cars had formaldehyde and acrolein concentrations exceeding the guidelines of OEHHA. Only one public transport sample (one bus) possesses formaldehyde and acetaldehyde concentrations above the chronic inhalation reference exposure limits (RELs). Furthermore, the assessments of carcinogenic risk of formaldehyde and acetaldehyde showed that lifetime cancer risks were higher than the limits of EPA for some family cars and public transports. In the study, buses and metros appear to be relatively clean environments, with total carbonyl concentrations that do not exceed 126 μg/m³. In family cars, carbonyl levels showed significant variations from 6.1 to 811 μg/m³ that was greatly influenced by direct emissions from materials inside the vehicles. Public transports seemed to be the first choice for resident trips as compared to family cars.

Graphical abstract

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Campylobacteriosis

Campylobacteriosis: Disease caused by Campylobacter jejuni, now the leading cause of bacterial food poisoning, most often spread by contact with raw or undercooked poultry. A single drop of juice from a contaminated chicken is enough to make someone sick with Campylobacteriosis.

Campylobacteriosis usually strikes only one person or a few people at a time. A common way to become infected is to cut poultry meat on a cutting board, and then use the unwashed cutting board or utensil to prepare vegetables or other raw or lightly cooked foods. The Campylobacter organisms from the raw meat can then spread to the other foods. The organism is not usually spread from person to person, but this can happen if the infected person is a small child or is producing a large volume of diarrhea.

Many chicken flocks are silently infected with Campylobacter; that is, the chickens are infected with the organism but show no signs of illness. When an infected bird is slaughtered, Campylobacter can be transferred from the intestines to the meat. More than half of the raw chicken in the US market has Campylobacter on it. Campylobacter is also present in the giblets, especially the liver.

Larger outbreaks of Campylobacteriosis are not usually associated with raw poultry but with drinking unpasteurized milk or contaminated water. Unpasteurized milk can become contaminated if the cow has an infection with Campylobacter in her udder or if the milk is contaminated with manure. Surface water and mountain streams can become contaminated from infected feces from cows or wild birds. This infection is common in the developing world, and travelers to foreign countries are also at risk for becoming infected with Campylobacter.

Animals can also be infected, and some people are known to have acquired their infection from contact with the infected stool of an ill dog or cat.

Symptoms tend to start 2 to 5 days after exposure and typically last a week. They resemble viral gastroenteritis -- diarrhea, fever, abdominal pain, cramping, nausea and vomiting -- but with campylobacter, fever is typical and the diarrhea is often bloody.

Most people get better within 2 to 5 days after the onset of symptoms without specific treatment, although sometimes recovery can take up to 10 days. People with immune deficiencies may benefit from two weeks of antibiotics such as erythromycin or a fluoroquinolone. And, as all types of diarrhea, one should maintain a high intake of fluids for as long as the diarrhea persists.

To prevent campylobacteriosis,

• Cook all poultry products thoroughly. Make sure that the meat is cooked throughout (no longer pink), any juices run clear, and the inside is cooked to 170oF (77oC) for breast meat, and 180oF (82oC) for thigh meat.
• If you are served undercooked poultry in a restaurant, send it back for further cooking.
• Wash hands with soap before handling raw foods of animal origin. Wash hands with soap after handling raw foods of animal origin and before touching anything else.
• Prevent cross-contamination in the kitchen:
  • Use separate cutting boards for foods of animal origin and other foods.
  • Carefully clean all cutting boards, countertops and utensils with soap and hot water after preparing raw food of animal origin.
• Avoid consuming unpasteurized milk and untreated surface water.
• Make sure that persons with diarrhea, especially children, wash their hands carefully and frequently with soap to reduce the risk of spreading the infection.
• Wash hands with soap after having contact with pet feces.

Most people who have campylobacteriosis recover completely. However, some suffer long-term consequences. One is arthritis. Another is a condition called Guillain-Barre syndrome. Both are thought to occur when a person's immune system is "triggered" by the Campylobacter to attack the person's own body. In arthritis, the attack is mounted against joints, while in Guillain-Barre syndrome the attack is against nerves leading to ascending paralysis that typically lasts several weeks and usually requires intensive care. It is estimated that approximately one in every 1000 campylobacteriosis cases leads to Guillain-Barre syndrome. As many as 40% of Guillain-Barre syndrome cases may be triggered by campylobacteriosis.

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Controversy and Debate on Clinical Genomics Sequencing - Paper 4: Clinical Genome-Wide Sequencing: Response to Wilson, Miller and Rousseau’s Response

Publication date: Available online 23 September 2017
Source:Journal of Clinical Epidemiology
Author(s): Shelin Adam, Jan M. Friedman




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A Chinese Robot Has Performed the World's First Automated Dental Implant

In China, a robot dentist installed two dental implants for a woman last Saturday, in what could be the world's first fully automated dental implant surgery, reports the South China Morning Post . Human doctors supervised the whole procedure but did not actively intervene.

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Thermodynamic modeling of the Ta–Mo–C ternary system

Publication date: December 2017
Source:Calphad, Volume 59
Author(s): Cong Zhang, Haiqing Yin, Yong Du, Yafei Pan, Peng Deng
The Ta–Mo–C system was assessed by means of the CALPHAD approach. All of the phase diagram and thermodynamic information available from the literature were critically reviewed. The liquid was modeled as substitutional solution phase, while the carbides including fcc-(Mo,Ta)C1-x, bcc-(Mo,Ta), hcp-(Mo,Ta)2C and η-MoC were described by using corresponding sublattice models. The ζ-Ta4C3-x was considered as a linear compound with carbon content fixed, while shp-MoC was treated to be a binary stoichiometric phase. There was no ternary compound reported in this system. The modeling of Ta–Mo–C ternary system covers the entire composition and temperature ranges, and a set of self-consistent thermodynamic parameters for the Ta–Mo–C system was systematically optimized. Comprehensive comparisons between the calculated and reported phase diagram and thermodynamic data show that the reliable information is satisfactorily accounted for by the present modeling. The liquidus projection and reaction scheme of the Ta–Mo–C system were also generated by using the present thermodynamic parameters.



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Patterns and the Occurrence of KRAS Mutations in Metastatic Colorectal Cancers—a Study from Indian Regional Cancer Centre

Abstract

Mutation analysis of the KRAS oncogene is established as a predictive biomarker in Colorectal cancer (CRC). Many prospective clinical trials have shown that only CRCs with wild-type KRAS respond to anti-epidermal growth factor receptor (EGFR) treatment. Hence, mutation analysis is mandatory before treatment of metastatic CRCs. There are very few studies on the KRAS mutation status in the Indian setting. Hence, this study was done to document the patterns of KRAS mutations in CRCs reporting to a regional cancer centre in South India. Among 150 cases of metastatic colorectal cancer reporting over a period of 20 months, 48 random cases were analyzed for the KRAS mutational status of codons 12 and 13 of the KRAS gene by genomic sequencing. KRAS mutations in codons 12 and 13 were present in 9/48 (18.75%) of all analyzed CRCs. The common types of mutations were glycine to aspartate on codon 12 (p.G12D), glycine to valine on codon 12 (p.G12 V), and glycine to aspartate on codon 13 (p.G13D).

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An atypical presentation of cardiac tamponade and periorbital swelling in a patient with eosinophilic granulomatosis with polyangiitis: a case report

Eosinophilic granulomatosis with polyangiitis is a rare, necrotizing systemic vasculitis associated with asthma and hypereosinophilia. Its cause and pathophysiology are still being elucidated.

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Impact of ankle foot orthosis stiffness on Achilles tendon and gastrocnemius function during unimpaired gait

Publication date: Available online 23 September 2017
Source:Journal of Biomechanics
Author(s): Hwan Choi, Keshia M. Peters, Michael MacConnell, Katie Ly, Eric Eckert, Katherine M. Steele
Ankle foot orthoses (AFOs) are designed to improve gait for individuals with neuromuscular conditions and have also been used to reduce energy costs of walking for unimpaired individuals. AFOs influence joint motion and metabolic cost, but how they impact muscle function remains unclear. This study investigated the impact of different stiffness ankle foot orthoses (AFOs) on medial gastrocnemius muscle (MG) and Achilles tendon (AT) function during two different walking speeds. We performed gait analyses for eight unimpaired individuals. Each individual walked at slow and very slow speeds with a 3D printed AFO with no resistance (free hinge condition) and four levels of ankle dorsiflexion stiffness: 0.25 Nm / °, 1 Nm / °, 2 Nm / °, and 3.7 Nm / °. Motion capture, ultrasound, and musculoskeletal modeling were used to quantify MG and AT lengths with each AFO condition. Increasing AFO stiffness increased peak AFO dorsiflexion moment with decreased peak knee extension and peak ankle dorsiflexion angles. Overall musculotendon length and peak AT length decreased, while peak MG length increased with increasing AFO stiffness. Peak MG activity, length, and velocity significantly decreased with slower walking speed. This study provides experimental evidence of the impact of AFO stiffness and walking speed on joint kinematics and musculotendon function. These methods can provide insight to improve AFO designs and optimize musculotendon function for rehabilitation, performance, or other goals.



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Contrasting roles of phenol and pyrocatechol on the degradation of 4-chlorophenol in a photocatalytic–biological reactor

Abstract

Intimate coupling of photocatalysis and biodegradation (ICPB) provides superior treatment for the degradation of bio-recalcitrant compounds, such as chlorophenol. Photocatalytically generated intermediates can be promptly used by the enclosed biofilms. Chlorophenol degradation can theoretically be accelerated by a co-substrate or be compromised by the competition for photocatalytic reactive oxygen species (ROS); however, studies to examine the comparison are limited in number. Non-chlorinated phenols commonly co-exist in real wastewater; thus, we evaluated the influence of phenol (hard to photo-oxidize) and pyrocatechol (easy to photo-oxidize) on the degradation of 4-chlorophenol (4CP). The removal efficiency of 4CP was 51%, which increased to 62% after phenol addition. Meanwhile, the dechlorination efficiency of 4CP increased from 47 to 63%; similarly, the living/dead cell ratio increased from 49/51 to 79/21. However, pyrocatechol addition led to a decrease in 4CP removal efficiency to 32% and a reduction in living/dead cell ratio to 35/65. The differences in the results were attributed to the extra electron donors provided by the photodegraded products of phenol to bacteria, which enhanced 4CP degradation; meanwhile, pyrocatechol competed with 4CP for ROS, thus inhibiting its degradation. Competition for ROS and co-substrate properties should be considered in the treatment of phenolic wastewater by ICPB.

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Characteristics and trends on global environmental monitoring research: a bibliometric analysis based on Science Citation Index Expanded

Abstract

A bibliometric analysis based on the Science Citation Index Expanded from Web of Science was carried out to provide insights into research activities and trends of the environmental monitoring from 1993 to 2012. Study emphases covered publication outputs, language, categories, journals, countries/territories, institutions, words, and hot issues. The results indicated that the annual output of environmental monitoring publications increased steadily. The environmental sciences and analytical chemistry were the two most common categories. Environmental Monitoring and Assessment published the most articles. The USA and the UK ranked in the top two in terms of all five indicators. The U.S. Environmental Protection Agency took the leading position of the institutions in terms of publication output. The synthesized analysis by words in title, author keywords, and KeyWords Plus provided important clues for hot issues. Researchers paid more attention on water environment monitoring than other environmental factors. The contaminants including organic contaminants, heavy metal, and radiation were most common research focuses, and the organic contaminants and heavy metal of the degree of concern were gradually rising. Sensor and biosensor played an important role in the field of environmental monitoring devices. In addition to conventional device detection method, the remote sensing, GIS, and wireless sensor networks were the mainstream environmental monitoring methods. The international organization, social awareness, and the countries' positive and effective political and policies promoted the published articles.

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Seasonal water chemistry variability in the Pangani River basin, Tanzania

Abstract

The stable isotopes of δ¹⁸O, δ²H, and ⁸⁷Sr/⁸⁶Sr and dissolved major ions were used to assess spatial and seasonal water chemistry variability, chemical weathering, and hydrological cycle in the Pangani River Basin (PRB), Tanzania. Water in PRB was NaHCO₃ type dominated by carbonate weathering with moderate total dissolved solids. Major ions varied greatly, increasing from upstream to downstream. In some stations, content of fluoride and sodium was higher than the recommended drinking water standards. Natural and anthropogenic factors contributed to the lowering rate of chemical weathering; the rate was lower than most of tropical rivers. The rate of weathering was higher in Precambrian than volcanic rocks. ⁸⁷Sr/⁸⁶Sr was lower than global average whereas concentration of strontium was higher than global average with mean annual flux of 0.13 × 10⁶ mol year⁻¹. Evaporation and altitude effects have caused enrichment of δ¹⁸O and δ²H in dry season and downstream of the river. Higher d-excess value than global average suggests that most of the stations were supplied by recycled moisture. Rainfall and groundwater were the major sources of surface flowing water in PRB; nevertheless, glacier from Mt. Kilimanjaro has insignificant contribution to the surface water. We recommend measures to be taken to reduce the level of fluoride and sodium before domestic use.

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Genomic signatures as predictive biomarkers of homologous recombination deficiency in ovarian cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Adriaan Vanderstichele, Pieter Busschaert, Siel Olbrecht, Diether Lambrechts, Ignace Vergote
DNA repair deficiency is a common hallmark of many cancers and is increasingly recognised as a target for cancer therapeutics. Selecting patients for these treatments requires a functional assessment of multiple redundant DNA repair pathways. With the advent of whole-genome sequencing of cancer genomes, it is increasingly recognised that multiple signatures of mutational and chromosomal alterations can be correlated with specific DNA repair defects. The clinical relevance of this approach is underlined by the use of poly-(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination (HR) deficient high-grade serous ovarian cancers. Beyond deleterious mutations in HR-related genes such as BRCA1/2, it is recognised that HR deficiency endows ovarian cancers with specific signatures of base substitutions and structural chromosomal variation. Multiple metrics quantifying loss-of-heterozygosity (LOH) events were proposed and implemented in trials with PARPi. However, it was shown that some of the HR-deficient cases, i.e. CDK12–mutated tumours, were not associated with high LOH-based scores, but with distinct patterns of genomic alterations such as tandem duplication. Therefore, more complex signatures of structural genomic variation were identified and quantified. Ultimately, optimal prediction models for treatments targeting DNA repair will need to integrate multiples of these genomic signatures and will also need to assess multiple resistance mechanisms such as genomic reversion events that partially or fully re-activate DNA repair.



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PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Mathilde Guerin, Keyvan Rezai, Nicolas Isambert, Mario Campone, Aurélie Autret, Jihane Pakradouni, Magali Provansal, Jacques Camerlo, Renaud Sabatier, François Bertucci, Emmanuelle Charafe-Jauffret, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher, Anthony Gonçalves
BackgroundPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.Patients and methodsPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.ResultsA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]).ConclusionCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.Trial registration IDNCT01589861.



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Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Tomonari Kinoshita, Chie Kudo-Saito, Reiko Muramatsu, Tomonobu Fujita, Miyuki Saito, Haruna Nagumo, Toshiharu Sakurai, Shinobu Noji, Emi Takahata, Tomonori Yaguchi, Nobuo Tsukamoto, Yuichiro Hayashi, Kaoru Kaseda, Ikuo Kamiyama, Takashi Ohtsuka, Kenji Tomizawa, Masaki Shimoji, Tetsuya Mitsudomi, Hisao Asamura, Yutaka Kawakami
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8⁺ T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8⁺ T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8⁺ T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8⁺ T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8⁺ T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8⁺ FOXP3⁺ T cells and immunodysfunctional CD8⁺ GATA3⁺ T cells were increased in adenocarcinoma of non-smokers. CD4⁺ FOXP3⁺ regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163⁺ M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.



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Comparison of the accuracy of maxillary position between conventional model surgery and virtual surgical planning

The aim of this study was to determine whether virtual surgical planning (VSP) is an accurate method for positioning the maxilla when compared to conventional articulator model surgery (CMS), through the superimposition of computed tomography (CT) images. This retrospective study included the records of 30 adult patients submitted to bimaxillary orthognathic surgery. Two groups were created according to the treatment planning performed: CMS and VSP. The treatment planning protocol was the same for all patients. (Source: International Journal of Oral and Maxillofacial Surgery)

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Cancer as an ecomolecular disease and a neoplastic consortium

Publication date: Available online 23 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Santiago Ramón y Cajal, Claudia Capdevila, Javier Hernandez-Losa, Leticia de Mattos, Abhishek Ghosh, Julie Lorent, Ola Larsson, Trond Aasen, Lynne-Marie Postovit, Ivan Topisirovic
Current anticancer paradigms largely target driver mutations considered integral for cancer cell survival and tumor progression. Although initially successful, many of these strategies are unable to overcome the tremendous heterogeneity that characterizes advanced tumors, resulting in the emergence of resistant disease. Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in wide phenotypic and molecular heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells and the tumor microenvironment. In this context, cancer may be perceived as an "ecomolecular" disease that involves cooperation between several neoplastic clones and their interactions with immune cells, stromal fibroblasts, and other cell types present in the microenvironment. This collaboration is mediated by a variety of secreted factors. Cancer is therefore analogous to complex ecosystems such as microbial consortia.In the present article, we comment on the current paradigms and perspectives guiding the development of cancer diagnostics and therapeutics and the potential application of systems biology to untangle the complexity of neoplasia. In our opinion, conceptualization of neoplasia as an ecomolecular disease is warranted. Advances in knowledge pertinent to the complexity and dynamics of interactions within the cancer ecosystem are likely to improve understanding of tumor etiology, pathogenesis, and progression. This knowledge is anticipated to facilitate the design of new and more effective therapeutic approaches that target the tumor ecosystem in its entirety.



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Effects of co-composting of farm manure and biochar on plant growth and carbon mineralization in an alkaline soil

Abstract

In the present study, the effects of co-composts of biochar (BC) and farm manure (FM) on the growth of wheat (Triticum aestivum L.) and carbon mineralization in an alkaline soil were investigated. The co-composts of FM and BC were prepared at various ratios (FM₁₀₀:BC₀, FM₇₅:BC₂₅, FM₅₀:BC₅₀, FM₂₅:BC₇₅, FM₀:BC₁₀₀) using aboveground piles and were used in two separate experiments conducted simultaneously. In the plant growth trial, prepared co-composts were applied at a rate of 2% w/w and wheat was grown at two fertilizer levels (half and full) until maturity. In the incubation experiment, same treatments were used and carbon mineralization was studied over a period of 79 days. The priming effect and net CO₂ efflux were calculated using CO₂ release data. Analysis of postincubation soil showed no significant effect of treatments on the pH of soil. However, electrical conductivity and organic matter were significantly influenced by all treatments. The increasing BC ratio in the compost reduced the carbon mineralization in soil in a dose-additive manner. Increase in BC proportion in composts (FM₅₀:BC₅₀, FM₂₅:BC₇₅, FM₀:BC₁₀₀) stabilized the native carbon of the soil and caused negative priming effect (−1.9, −5.6, and −8.48%, respectively). Regarding plant growth, the results showed an enhancement in the grain yield with the application of compost than control. Total nitrogen (N), phosphorus, and potassium (K) contents of the soil were also increased by the application of compost than control (un-amended soil). Significantly higher N and K concentrations in wheat plants were also examined when soil was treated with compost than control. The use of compost with half fertilizer was better in increasing grain yield, especially with higher BC proportion in the compost than FM.

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Activation of peroxymonosulfate by surfactants as the metal-free catalysts for organic contaminant removal

Abstract

The present work described that tertiary ammonium surfactants containing bromide ion as novel metal-free catalysts were innovatively coupled with peroxymonosulfate (PMS) to build a simple catalytic oxidation system, possessing outstanding catalytic ability with organic dye Reactive Red M-3BE (RR M-3BE) as the target pollutant. Furthermore, cetyltrimethylammonium bromide (CTAB), a representative of cationic surfactant, was selected to further investigate the catalytic oxidation performance. It is found that at the critical micelle concentration (CMC) of CTAB, the oxidation efficiency of the CTAB/PMS system was optimal due to the strong electrostatic attraction between the CTA⁺ micelle and reactive anions (Br⁻ and HSO₅⁻), concentrating HSO₅⁻ and Br⁻ at the micellar surface, which accelerated the catalytic oxidation reaction between Br⁻ and HSO₅⁻, generating a mass of highly active reactive species. A hybrid method that combined radical scavenger (methanol) with electron paramagnetic resonance (EPR) technology was adopted for the investigation of reactive species, and the results indicated that hydroxyl radical (•OH) was generated and had a major role in the process. The findings from this work provide a practicable pathway for highly efficient PMS activation in wastewater treatment, and also initiate a promising research area of surfactants in the field of environmental catalysis.

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Erratum to “Impact of Yoga and Meditation on Cellular Aging in Apparently Healthy Individuals: A Prospective, Open-Label Single-Arm Exploratory Study”

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Corrigendum to “Supervised and Unsupervised Subband Adaptive Denoising Frameworks with Polynomial Threshold Function”

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Predictability of Extreme Waves in the Lorenz-96 Model Near Intermittency and Quasi-Periodicity

We introduce a method for quantifying the predictability of the event that the evolution of a deterministic dynamical system enters a specific subset of state space at a given lead time. The main idea is to study the distribution of finite-time growth rates of errors in initial conditions along the attractor of the system. The predictability of an event is measured by comparing error growth rates for initial conditions leading to that event with all possible growth rates. We illustrate the method by studying the predictability of extreme amplitudes of traveling waves in the Lorenz-96 model. Our numerical experiments show that the predictability of extremes is affected by several routes to chaos in a different way. In a scenario involving intermittency due to a periodic attractor disappearing through a saddle-node bifurcation we find that extremes become better predictable as the intensity of the event increases. However, in a similar intermittency scenario involving the disappearance of a 2-torus attractor we find that extremes are just as predictable as nonextremes. Finally, we study a scenario which involves a 3-torus attractor in which case the predictability of extremes depends nonmonotonically on the prediction lead time.

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Quality Control of Mutton by Using Volatile Compound Fingerprinting Techniques and Chemometric Methods

A method for chromatographic fingerprinting of flavor was established for the quality control of mutton. Twenty-five mutton samples that were chosen from twelve batches were investigated by gas chromatography-mass spectroscopy (GC-MS) and gas chromatography-olfactometry (GC-O). Spectral correlative chromatograms combined with GC-O assessment were employed, and 32 common odor-active compounds that characterize mutton flavor fingerprint were obtained. Based on the flavor chromatographic fingerprint data, principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were designed and employed as chromatographic fingerprint methods. Defined categories were perfectly discriminated after PLS-DA was conducted on the fused matrix, demonstrating a 100% accurate classification. Fourteen constituents were further screened with PLS-DA to be the main chemical markers, and they were used to develop similar approaches for the determination of mutton quality and traceability. The flavor fingerprint of mutton established using SPME-GC-MS/O coupled with PLS-DA is appropriate for differentiating and identifying samples, and the procedure would be used in quality control.

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Erratum to “Is p53 Involved in Tissue-Specific Insulin Resistance Formation?”

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Erratum to “Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis”

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An EEG Tool for Monitoring Patient Engagement during Stroke Rehabilitation: A Feasibility Study

Objective. Patient engagement is of major significance in neural rehabilitation. We developed a real-time EEG marker for attention, the Brain Engagement Index (BEI). In this work we investigate the relation between the BEI and temporary functional change during a rehabilitation session. Methods. First part: 13 unimpaired controls underwent BEI monitoring during motor exercise of varying levels of difficulty. Second part: 18 subacute stroke patients underwent standard motor rehabilitation with and without use of real-time BEI feedback regarding their level of engagement. Single-session temporary functional changes were evaluated based on videos taken before and after training on a given task. Two assessors, blinded to feedback use, assessed the change following single-session treatments. Results. First part: a relation between difficulty of exercise and BEI was identified. Second part: temporary functional change was associated with BEI level regardless of the use of feedback. Conclusions. This study provides preliminary evidence that when BEI is higher, the temporary functional change induced by the treatment session is better. Further work is required to expand this preliminary study and to evaluate whether such temporary functional change can be harnessed to improve clinical outcome. Clinical Trial Registration. Registered with clinicaltrials.gov, unique identifier: NCT02603718 (retrospectively registered 10/14/2015).

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Experimental and Analytical Study of Slender Reinforced Concrete Shear Wall under Cyclic In-Plane Lateral Load

This study describes a slender reinforced concrete shear wall experimental test under in-plane cyclic lateral load, and the development of an analytical model which uses the fiber method approach to consider hysteretic nonlinear constitutive material models behavior. The shear wall tested had bending behavior, since the amount of longitudinal reinforcing bars produced weak bending capacity compared to the shear strength. The analytical model tries to represent global and local behavior of the wall, and its calibration is based on reaching experimental parameters like area enclosed and secant stiffness on every loop. After the analytical model was calibrated, the relation between some performance points and damage states observed during the test is studied.

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Antibiotic Resistant Bacterial Isolates from Captive Green Turtles and In Vitro Sensitivity to Bacteriophages

This study aimed to test multidrug resistant isolates from hospitalised green turtles (Chelonia mydas) and their environment in North Queensland, Australia, for in vitro susceptibility to bacteriophages. Seventy-one Gram-negative bacteria were isolated from green turtle eye swabs and water samples. Broth microdilution tests were used to determine antibiotic susceptibility. All isolates were resistant to at least two antibiotics, with 24% being resistant to seven of the eight antibiotics. Highest resistance rates were detected to enrofloxacin (77%) and ampicillin (69.2%). More than 50% resistance was also found to amoxicillin/clavulanic acid (62.5%), ceftiofur (53.8%), and erythromycin (53.3%). All the enriched phage filtrate mixtures resulted in the lysis of one or more of the multidrug resistant bacteria, including Vibrio harveyi and V. parahaemolyticus. These results indicate that antibiotic resistance is common in Gram-negative bacteria isolated from hospitalised sea turtles and their marine environment in North Queensland, supporting global concern over the rapid evolution of multidrug resistant genes in the environment. Using virulent bacteriophages as antibiotic alternatives would not only be beneficial to turtle health but also prevent further addition of multidrug resistant genes to coastal waters.

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Sympathetic Denervation Accelerates Wound Contraction but Inhibits Reepithelialization and Pericyte Proliferation in Diabetic Mice

Previous studies focused on the effects of sympathetic denervation with 6-hydroxydopamine (6-OHDA) on nondiabetic wounds, but the effects of 6-OHDA on diabetic wounds have not been previously reported. In this study, treated mice received intraperitoneal 6-OHDA, and control mice received intraperitoneal injections of normal saline. Full-thickness wounds were established on the backs of mice. The wounds were sectioned (four mice per group) for analysis at 2, 5, 7, 10, 14, 17, and 21 days after injury. The wound areas in the control group were larger than those in the treatment group. Histological scores for epidermal and dermal regeneration were reduced in the 6-OHDA-treated group on day 21. The mast cells (MCs) in each field decreased after sympathectomy on days 17 and 21. The expression levels of norepinephrine, epidermal growth factor (EGF), interleukin-1 beta, NG2 proteoglycan, and desmin in the treatment group were less than those in the control group. In conclusion, 6-OHDA delays reepithelialization during wound healing in diabetic mice by decreasing EGF, but increases wound contraction by reducing IL-1β levels and the number of MCs. Besides, 6-OHDA led to reduced pericyte proliferation in diabetic wounds, which might explain the vascular dysfunction after sympathetic nerve loss in diabetic wounds.

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Erratum to “Nutritional and Lifestyle Interventions for Age-Related Macular Degeneration: A Review”

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Antimicrobial Resistance Profiles of Bacteria Isolated from the Nasal Cavity of Camels in Samburu, Nakuru, and Isiolo Counties of Kenya

This study was designed to determine antimicrobial resistance profiles of bacteria isolated from the nasal cavity of healthy camels. A total of 255 nasal samples (swabs) were collected in Isiolo, Samburu, and Nakuru counties, Kenya, from which 404 bacterial isolates belonging to various genera and species were recovered. The bacterial isolates included Bacillus (39.60%), coagulase-negative Staphylococcus (29.95%), Streptococcus species other than Streptococcus agalactiae (25.74%), coagulase-positive Staphylococcus (3.96%), and Streptococcus agalactiae (0.74%). Isolates were most susceptible to Gentamicin (95.8%), followed by Tetracycline (90.5%), Kanamycin and Chloramphenicol (each at 85.3%), Sulphamethoxazole (84.2%), Co-trimoxazole (82.1%), Ampicillin (78.9%), and finally Streptomycin (76.8%). This translated to low resistance levels. Multidrug resistance was also reported in 30.5% of the isolates tested. Even though the antibiotic resistance demonstrated in this study is low, the observation is significant, since the few resistant normal flora could be harboring resistance genes which can be transferred to pathogenic bacteria within the animal, to other animals' bacteria and, most seriously, to human pathogens.

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Novel MARG-Sensor Orientation Estimation Algorithm Using Fast Kalman Filter

Orientation estimation from magnetic, angular rate, and gravity (MARG) sensor array is a key problem in mechatronic-related applications. This paper proposes a new method in which a quaternion-based Kalman filter scheme is designed. The quaternion kinematic equation is employed as the process model. With our previous contributions, we establish the measurement model of attitude quaternion from accelerometer and magnetometer, which is later proved to be the fastest (computationally) one among representative attitude determination algorithms of such sensor combination. Variance analysis is later given enabling the optimal updating of the proposed filter. The algorithm is implemented on real-world hardware where experiments are carried out to reveal the advantages of the proposed method with respect to conventional ones. The proposed approach is also validated on an unmanned aerial vehicle during a real flight. Results show that the proposed one is faster than any other Kalman-based ones and even faster than some complementary ones while the attitude estimation accuracy is maintained.

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A Case of Ruptured Pulmonary Hydatid Cyst of the Liver and Review of the Literature

Background. Hydatid cyst is an endemic disease frequently localized to the liver. It is frequently observed in Southeast Europe, Middle East, and Turkey. Although the cyst rupture can occur spontaneously, it can also occur upon albendazole treatment. Its surgical treatment includes cystotomy, capitonnage, and wedge resection. Material-Method. A 56-year-old male immigrant was admitted with fever, pain, and cough. Albendazole treatment was initiated and elective surgery was planned. Upon his admission to emergency service, he was diagnosed with pneumonia, and a spontaneous cyst rupture was detected. Result. Thoracotomy and cystotomy were performed. Bile leakage aspiration and lung wedge resection were also performed. Conclusion. Different surgical methods are used in the treatment of hydatid cysts depending on the localization and complications. Follow-up with antihelminthic drugs such as albendazole and mebendazole is recommended in medical treatment.

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Intra-osseous Hemangioma of the Frontal Bone. Report of a Case and review of the literature

Publication date: Available online 23 September 2017
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Joshua S. Brandner, Yeshwant B. Rawal, Louis J. Kim, Jasjit K. Dillon
Intra-osseous hemangiomas of the maxillofacial region are rare lesions that comprise less than 1% of all osseous tumors¹. A review of the literature on intra-osseous hemangiomas of the skull and facial bones revealed a limited number of publications, much of which was largely limited to case reports. This case report summarizes the workup and surgical treatment of a 39-year-old female with an intra-osseous hemangioma of the left frontal bone. The histology, treatment, and literature are reviewed.



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Iron deficiency anemia and hearing loss

We read with great interest the article published in your prestigious journal entitled: "Protein energy malnutrition associates with different types of hearing impairments in toddlers: Anemia increases cochlear dysfunction" by Kamel TB et al. [1]. The authors describe their experience on the early detection of hearing impairment in toddlers with protein energy malnutrition (PEM) and neuro-cognitive effect of PEM in relation to hemoglobin blood level.

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Audio-visual speech perception in prelingually deafened Japanese children following sequential bilateral cochlear implantation

An effect of audio-visual (AV) integration is observed when the auditory and visual stimuli are incongruent (the McGurk effect). In general, AV integration is helpful especially in subjects wearing hearing aids or cochlear implants (CIs). However, the influence of AV integration on spoken word recognition in individuals with bilateral CIs (Bi-CIs) has not been fully investigated so far. In this study, we investigated AV integration in children with Bi-CIs.

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Whole exome sequencing in inborn errors of immunity: use the power but mind the limits.

Purpose of review: Next-generation sequencing, especially whole exome sequencing (WES), has revolutionized the molecular diagnosis of inborn errors of immunity. This review summarizes the generation and analysis of next-generation sequencing data. Recent findings: The focus is on prioritizing strategies for unveiling the potential disease-causing variant. We also highlighted oversights and imperfections of WES and targeted panel sequencing, as well as the need for functional validation. Summary: The information is crucial for a judicious use of WES by researchers, but even more so by the clinical immunologist. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Between-User Reliability of Tier 1 Exposure Assessment Tools Used Under REACH

Abstract

When applying simple screening (Tier 1) tools to estimate exposure to chemicals in a given exposure situation under the Registration, Evaluation, Authorisation and restriction of CHemicals Regulation 2006 (REACH), users must select from several possible input parameters. Previous studies have suggested that results from exposure assessments using expert judgement and from the use of modelling tools can vary considerably between assessors. This study aimed to investigate the between-user reliability of Tier 1 tools. A remote-completion exercise and in person workshop were used to identify and evaluate tool parameters and factors such as user demographics that may be potentially associated with between-user variability. Participants (N = 146) generated dermal and inhalation exposure estimates (N = 4066) from specified workplace descriptions ('exposure situations') and Tier 1 tool combinations (N = 20). Interactions between users, tools, and situations were investigated and described. Systematic variation associated with individual users was minor compared with random between-user variation. Although variation was observed between choices made for the majority of input parameters, differing choices of Process Category ('PROC') code/activity descriptor and dustiness level impacted most on the resultant exposure estimates. Exposure estimates ranging over several orders of magnitude were generated for the same exposure situation by different tool users. Such unpredictable between-user variation will reduce consistency within REACH processes and could result in under-estimation or overestimation of exposure, risking worker ill-health or the implementation of unnecessary risk controls, respectively. Implementation of additional support and quality control systems for all tool users is needed to reduce between-assessor variation and so ensure both the protection of worker health and avoidance of unnecessary business risk management expenditure.

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Evaluation of Tier One Exposure Assessment Models (ETEAM): Project Overview and Methods

Within the European Union, the Registration, Evaluation, Authorisation and restriction of Chemicals (REACH) Regulation (European Parliament, 2006) requires the registration of chemical substances which are manufactured or imported in amounts of 1 tonne or more per year. If the substance being registered is manufactured or imported in quantities of 10 tonnes or more per year, registrants must undertake a chemical safety assessment (CSA) and complete a chemical safety report (CSR). For classified substances, the CSA has to include an exposure assessment for all identified uses. Several computer-based tools are mentioned in the European Chemicals Agency (ECHA) REACH guidance (ECHA, 2012, 2016) as being suitable for assessing worker exposure within the substance registration process. These tools vary in area of application, level of detail and outputs, from simple screening tier 1 tools, which are designed to easily and quickly differentiate those situations that may pose a risk to health from those which do not, to more advanced, higher level tools that should give a more refined and accurate estimate of exposure (for example, Advanced REACH Tool, 2013). Tool predictions are used to identify, iterate, and verify the risk management measures (RMMs) required to control exposure in workplaces, with this information distributed to substance users via the supply chain.

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A Pilot Study: The UNC Passive Aerosol Sampler in a Working Environment

Abstract

Objectives

Dust is generally sampled on a filter using air pumps, but passive sampling could be a cost-effective alternative. One promising passive sampler is the University of North Carolina passive aerosol sampler (UNC sampler). The aim of this study is to characterize and compare the UNC sampler's performance with PM₁₀ and PM_2.5 impactors in a working environment.

Methods

Area sampling was carried out at different mining locations using UNC samplers in parallel with PM_2.5 and PM₁₀ impactors. Two different collection surfaces, polycarbonate (PC) and carbon tabs (CT), were employed for the UNC sampling. Sampling was carried out for 4–25 hours.

Results

The UNC samplers underestimated the concentrations compared to PM₁₀ and PM_2.5 impactor data. At the location with the highest aerosol concentration, the time-averaged mean of PC showed 24% and CT 35% of the impactor result for PM_2.5. For PM₁₀, it was 39% with PC and 58% with CT. Sample blank values differed between PC and CT. For PM_2.5, PC blank values were ~7 times higher than those of CT, but only 1.8 times higher for PM₁₀. The blank variations were larger for PC than for CT.

Conclusions

Particle mass concentrations appear to be underestimated by the UNC sampler compared to impactors, more so for PM_2.5 than for PM₁₀. CT may be preferred as a collection surface because the blank values were lower and less variable than for PC. Future validations in the working environment should include respirable dust sampling.

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How Accurate and Reliable Are Exposure Models?

In this issue of the Annals of Work Exposures and Health, several authors report on the validation of exposure assessment models. Since the introduction of the European regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH; European Parliament, 2006), various risk/exposure assessment tools have been developed and are currently widely used for chemical safety assessments. Between the start of the REACH Registration period in 2008 and September 2014, around 40000 substance dossiers had been submitted to ECHA. As noted by George Box in 1987 'essentially, all models are wrong, but some are useful' (Box et al., 1987), and more recently it has been stated that models cannot and should not replace the collection of good quality exposure measurements (Kromhout, 2016). Nevertheless, the European occupational hygiene community will not be able to collect a sufficient number of exposure measurements to obtain exposure estimates for all relevant existing and new exposure scenarios. The risk assessments under REACH hence follow a tiered approach in which the first tier should provide a conservative (i.e. protective) system that can discriminate between substances in scenarios of some concern and those which are considered safe, and higher tier models should provide a higher degree of accuracy, even if at a cost of less conservative results.

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Wipe Sampling Method and Evaluation of Environmental Variables for Assessing Surface Contamination of 10 Antineoplastic Drugs by Liquid Chromatography/Tandem Mass Spectrometry

Abstract

This paper describes a novel wipe sampling and high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method capable of simultaneously detecting 10 antineoplastic drugs (5-fluorouracil, oxaliplatin, methotrexate, vindesine, ifosfamide, cyclophosphamide, vincristine, vinblastine, docetaxel, and paclitaxel). The good overall recoveries and sensitivity values of this method along with the comparatively short run time (8 min) allows for its use in routine monitoring in health care facilities. The long-term behavior of the studied drugs on contaminated surfaces and the effect of surface roughness on drug recoveries were studied to gain insights about how these environmental variables influence the detection, cleaning, and occupational exposure of these drugs. Surfaces with higher roughness parameter (R_a) values (rougher) had the lowest recoveries while those with lower R_a (smoother) presented the highest recoveries. Long-term assessments evidence distinctive drug behaviors with oxaliplatin, vindesine, vincristine, and vinblastine being the less persistent drugs (~20% was recovered after 24 h) and docetaxel and paclitaxel the most persistent drugs with recoveries of 40% and 80% after 1 month. This information indicates the importance of collecting ancillary information about drug usage (throughput, timing, cleaning procedures, etc.) to interpret the results in the context of potential exposure. Finally, the method was successfully applied to evaluate trace surface contamination down to the single picogram per square centimeter in multiple work areas within three local health care centers on Vancouver Island, Canada.

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Comparing the Advanced REACH Tool’s (ART) Estimates With Switzerland’s Occupational Exposure Data

Abstract

The Advanced REACH Tool (ART) is the most sophisticated tool used for evaluating exposure levels under the European Union's Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) regulations. ART provides estimates at different percentiles of exposure and within different confidence intervals (CIs). However, its performance has only been tested on a limited number of exposure data. The present study compares ART's estimates with exposure measurements collected over many years in Switzerland. Measurements from 584 cases of exposure to vapours, mists, powders, and abrasive dusts (wood/stone and metal) were extracted from a Swiss database. The corresponding exposures at the 50^th and 90^th percentiles were calculated in ART. To characterize the model's performance, the 90% CI of the estimates was considered. ART's performance at the 50^th percentile was only found to be insufficiently conservative with regard to exposure to wood/stone dusts, whereas the 90^th percentile showed sufficient conservatism for all the types of exposure processed. However, a trend was observed with the residuals, where ART overestimated lower exposures and underestimated higher ones. The median was more precise, however, and the majority (≥60%) of real-world measurements were within a factor of 10 from ART's estimates. We provide recommendations based on the results and suggest further, more comprehensive, investigations.

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Surveillance and Analysis of Occupational Carbon Monoxide Poisoning in the Paris Region

Abstract

Objectives

Acute carbon monoxide poisoning is common and often severe. Domestic causes have been extensively documented, while occupational exposures have been reported less frequently. We analyse occupational carbon monoxide poisonings from the available data of the carbon monoxide poisoning surveillance network for Paris and its region, and identify predictive factors of severity for occupational poisoning in order to identify priority prevention actions.

Methods

We retrospectively reviewed all events of acute accidental carbon monoxide exposures which occurred in the Paris region, at the work place, and notified to the surveillance network from 1 January 2005 to 31 December 2011.

Results

Over the 7-year study period, 362 exposed workers were identified, representing 8.15% of all cases of carbon monoxide exposures. The largest number of events occurred in the building sector and most commonly affected occupations were craft and related trades workers. The most common sources of exposure were internal combustion engine equipment that was involved in almost half of cases. Minor severity was observed in 86% of cases, and 13% were moderate or more. We identify that the use of internal combustion engine equipment was significantly associated with increased severity.

Conclusions

Occupational carbon monoxide poisoning is reported less frequently than domestic poisoning and has different and more numerous causes. It can be potentially severe, especially when it is caused by internal combustion engine equipment. Information about risks, compliance with instructions and cleaning rules, and establishment of collective and individual protective equipment would significantly reduce the frequency and severity of carbon monoxide poisoning.

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Monitoring Surface Contamination by Antineoplastic Drugs in Italian Hospitals: Performance-Based Hygienic Guidance Values (HGVs) Project

Abstract

Antineoplastic drugs (ADs) will continue to represent a potential risk for personnel involved in the handling of these compounds and great concerns have been raised by the presence of ADs in many surveyed workplaces. Eight hospitals were investigated by means of wipe sampling for surface residue determination. Each wipe sample was tested for five ADs considered suitable exposure markers. Cyclophosphamide (CP), gemcitabine (GEM), 5-fluorouracil (5-FU), platinum-containing drugs (Pt), and epi-doxorubicin (EPI) contamination levels were measured in 85 per cent of the studied pharmacies and 93 per cent of outpatient care units (OpCUs). This study showed that 83 out of 349 samples were positive in Pharmacies, this proportion being statistically significant (χ² = 42.9, p < 0.001). The positive samples provided evidence of at least one substance with levels greater than the limit of detection (LOD). The two most frequently detected substances were Pt (42%) and CP (30%). These accounted for 72 per cent of the whole dataset, followed by 5-FU and GEM. Based on the 90^th percentile of wipe sampling data distribution, we suggest hygienic guidance values (HGVs) of 3.6, 1.0, 0.9, and 0.5 ng cm⁻² for CP, 5-FU, GEM and Pt, respectively, as the best target levels of the surface contamination load in Italian pharmacies. The approach of proposing guidance values at the 90^th percentile of results obtained from workplaces with good hygiene practice was found to be a simple and practical way of controlling occupational exposure. HGVs were challenged in this study as technical threshold limits to benchmark AD residual surface contamination at workplaces.

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Comprehensive Biological Monitoring to Assess Isocyanates and Solvents Exposure in the NSW Australia Motor Vehicle Repair Industry

Abstract

Urethane products that contain isocyanates are extensively used in the motor vehicle repair (MVR) industry and other industries such as furniture and cabinet-making as two-pack spray paints, clears, and adhesives. Attention has recently been refocussed on isocyanate-containing chemicals, particularly in paints. The spray painters in the MVR industry had a propensity to develop industrial asthma at a rate 80 times higher than the general public, which was previously reported in the UK. To track workers exposure to isocyanates, urine samples were collected from 196 spray painters who worked mainly in 78 MVR shops across 54 New South Wales (NSW) towns and suburbs. The biological monitoring also covered exposure testing to a wide variety of solvents including aromatic hydrocarbons, ketones, and alcohols. The main finding of the study was that 2.6% of the spray painters surveyed in the MVR industry in NSW that handled isocyanate-containing paints showed exposure to isocyanates; with 1.0% being moderately exposed, which is more than twice the current UK's Health and Safety Executive (HSE) Biological Monitoring Guidance Value (BMGV) of 1 µmol mol⁻¹ creatinine. Potential exposures to toluene (a solvent often found in paint thinners) was monitored via hippuric acid (HA) urine levels and showed 2.6% of the spray painters surveyed to be over the US' American Conference of Government Industrial Hygienists (ACGIH) Biological Exposure Index (BEI) of 1010 mmol/mole creatinine for HA. The other solvents or their metabolites were all below their respective BEI; these comprised benzene, xylene, ethyl benzene, methyl ethyl ketone, acetone, methanol, and ethanol. These findings indicate that isocyanates and certain solvents exposure were occurring in the NSW Australia vehicle repair industry, albeit at lower levels than previous occupational biological monitoring studies that showed higher exposure levels, particularly for isocyanates. One reason for this could be the increasing use of water-based paints in the industry, resulting in lower than expected isocyanate and solvent metabolite levels detected in this more recent study. Further, the completion of sample context form, along with spot urine collection in relation to the isocyanate exposure monitoring work details will provide crucial information to interpret the biological analysis results. The development of new biomarkers of isocyanate oligomer-derived triamines should be incorporated in the assessment of isocyanate exposure in the MVR industry to provide a more complete picture of isocyanate exposure.

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A Method to Quantitatively Assess Dermal Exposure to Volatile Organic Compounds

Abstract

Assessing dermal exposure of workers to noxious chemicals becomes increasingly important in industrial settings. Among various chemicals, volatile organic compounds (VOCs) are widely used in industrialized countries, but still there are no validated methodologies able to accurately quantify skin exposure. In this study, we developed a sensitive methodology based on activated charcoal cloth (ACC) to quantitatively assess skin exposure to 181 VOCs. The majority of the VOCs (156) showed a constant desorption efficiency (DE) of ~100% over the studied concentration range. Seven VOCs showed a concentration dependency for the DEs, which we described by a Dubinin–Raduskevich desorption isotherm. For 18 compounds, the DEs were situated below 80% but showed to be constant over the concentration range. All tested VOCs showed a good storage stability on ACC, especially at −80°C storage. Only for n-pentane there was a decrease of ~40% when it was stored for a month. In a controlled environment test, ACC has shown to reflect well the increasing concentrations of VOCs in the air with a high linearity (R² ≥ 0.812, except for gamma-butyrolactone where R² = 0.570). In this study, we show that ACC is a suitable sampling material for quantitatively assessing dermal exposure to 181 VOCs in terms of sensitivity and DE. This method will allow more studies that are detailed on dermal exposure, which will lead to a better assessment of skin exposure in occupational settings.

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Blue-Light Hazard From Gas Metal Arc Welding of Aluminum Alloys

Abstract

Objectives

The objective was to quantify the blue-light hazard from gas metal arc welding (GMAW) of aluminum alloys. The exposure level is expected to depend on the welding conditions. Therefore, it is important to identify the blue-light hazard under various welding conditions.

Methods

We experimentally conducted GMAW of aluminum alloys under various welding conditions and measured the spectral radiance of the arcs. The effective blue-light radiance, which the American Conference of Governmental Industrial Hygienists has defined to quantify the exposure level of blue light, was calculated from the measured spectral radiance. The maximum acceptable exposure duration per 10000 s for this effective blue-light radiance was calculated.

Results

The effective blue-light radiance measured in this study was in the range of 2.9–20.0 W cm⁻²·sr. The corresponding maximum acceptable exposure duration per 10000 s was only 5.0–34 s, so it is hazardous to view the welding arc. The effective blue-light radiance was higher at higher welding currents than at lower welding currents, when pulsed welding currents were used rather than steady welding currents, and when magnesium was included in the welding materials.

Conclusions

It is very hazardous to view the arcs in GMAW of aluminum alloys. Welders and their helpers should use appropriate eye protection in arc-welding operations. They should also avoid direct light exposure when starting an arc-welding operation.

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Atopy as a Modifier of the Relationships Between Endotoxin Exposure and Symptoms Among Laboratory Animal Workers

Abstract

Background

Exposure to endotoxin is known to trigger airway inflammation and symptoms, and atopy may modify the relationship between endotoxin exposure and symptom development.

Objective

To test the a priori hypothesis that atopic status modifies the relationship between endotoxin exposure and respiratory symptom development.

Methods

A prospective study of laboratory workers at The Jackson Laboratories was conducted. Allergy skin testing was performed and population demographic and clinical information was obtained at baseline. Personal exposure assessments for airborne endotoxin and surveys of self-reported symptoms were performed every 6 months. Cox proportional hazards models were used to examine the relationship between endotoxin exposure and development of mouse-associated symptoms and multivariate regression was used to test for interaction.

Results

Overall, 16 (9%) of 174 worker-participants developed mouse-associated rhinoconjunctivitis symptoms by 24 months and 8 (5%) developed mouse-associated lower respiratory symptoms by 24 months. Among workers with endotoxin exposure above the median (≥2.4 EU m⁻³), 5 (6% of 80) atopics reported mouse-associated rhinoconjunctivitis symptoms at 24 months as compared to 3 (3% of 94) non-atopics. Among workers below the median endotoxin exposure (<2.4 EU m⁻³), 1 (1% of 80) atopic reported mouse-associated rhinoconjunctivitis symptoms at 24 months as compared to 7 (7% of 94) non-atopics. For the combination of symptoms, the adjusted hazard ratio was 6.8 (95% confidence interval: 0.7–67.2) for atopics and 0.07 (95% confidence interval: 0.01–0.5) for non-atopics.

Conclusion

In this occupational cohort, atopic workers may be more susceptible to, and non-atopic workers protected from, endotoxin-associated upper and lower respiratory symptoms.

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Validation of Lower Tier Exposure Tools Used for REACH: Comparison of Tools Estimates With Available Exposure Measurements

Abstract

Background

Tier 1 exposure tools recommended for use under REACH are designed to easily identify situations that may pose a risk to health through conservative exposure predictions. However, no comprehensive evaluation of the performance of the lower tier tools has previously been carried out. The ETEAM project aimed to evaluate several lower tier exposure tools (ECETOC TRA, MEASE, and EMKG-EXPO-TOOL) as well as one higher tier tool (STOFFENMANAGER^®). This paper describes the results of the external validation of tool estimates using measurement data.

Methods

Measurement data were collected from a range of providers, both in Europe and United States, together with contextual information. Individual measurement and aggregated measurement data were obtained. The contextual information was coded into the tools to obtain exposure estimates. Results were expressed as percentage of measurements exceeding the tool estimates and presented by exposure category (non-volatile liquid, volatile liquid, metal abrasion, metal processing, and powder handling). We also explored tool performance for different process activities as well as different scenario conditions and exposure levels.

Results

In total, results from nearly 4000 measurements were obtained, with the majority for the use of volatile liquids and powder handling. The comparisons of measurement results with tool estimates suggest that the tools are generally conservative. However, the tools were more conservative when estimating exposure from powder handling compared to volatile liquids and other exposure categories. In addition, results suggested that tool performance varies between process activities and scenario conditions. For example, tools were less conservative when estimating exposure during activities involving tabletting, compression, extrusion, pelletisation, granulation (common process activity PROC14) and transfer of substance or mixture (charging and discharging) at non-dedicated facilities (PROC8a; powder handling only). With the exception of STOFFENMANAGER^® (for estimating exposure during powder handling), the tools were less conservative for scenarios with lower estimated exposure levels.

Conclusions

This is the most comprehensive evaluation of the performance of REACH exposure tools carried out to date. The results show that, although generally conservative, the tools may not always achieve the performance specified in the REACH guidance, i.e. using the 75^th or 90^th percentile of the exposure distribution for the risk characterisation. Ongoing development, adjustment, and recalibration of the tools with new measurement data are essential to ensure adequate characterisation and control of worker exposure to hazardous substances.

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Bilateral Breast and Axillary Lymph Nodes Metastases of an Ovarian Serous Cystadenocarcinoma

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Beloved Northern Ontario dentist dies in plane crash over Lake Huron

Beloved Northern Ontario dentist Dr. Edward Grodecki passed away after his plane crashed into Lake Huron on Wednesday. Image Supplied On Friday, after almost 39 hours of searching, OPP said they found the body of Dr. Edward Grodecki at the bottom of Lake Huron still inside the 'heavily damaged' two-seat Cessna 150 J plane that he was travelling in.

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Iron deficiency anemia and hearing loss

We read with great interest the article published in your prestigious journal entitled: "Protein energy malnutrition associates with different types of hearing impairments in toddlers: Anemia increases cochlear dysfunction" by Kamel TB et al. [1]. The authors describe their experience on the early detection of hearing impairment in toddlers with protein energy malnutrition (PEM) and neuro-cognitive effect of PEM in relation to hemoglobin blood level.

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Audio-visual speech perception in prelingually deafened Japanese children following sequential bilateral cochlear implantation

An effect of audio-visual (AV) integration is observed when the auditory and visual stimuli are incongruent (the McGurk effect). In general, AV integration is helpful especially in subjects wearing hearing aids or cochlear implants (CIs). However, the influence of AV integration on spoken word recognition in individuals with bilateral CIs (Bi-CIs) has not been fully investigated so far. In this study, we investigated AV integration in children with Bi-CIs.

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NEMO Peptide Inhibits the Growth of Pancreatic Ductal Adenocarcinoma by Blocking NF-κB Activation

NF-κB essential modulator (NEMO) binds and regulates IκB kinase (IKK) and is required for NF-κB activation. The NEMO-binding domain peptide (NBDP) of IKK was found to inhibit NF-κB activation and promote apoptosis in cancer cells. Studies have shown that constitutive NF-κB activation, one of the signature molecular alterations in pancreatic ductal adenocarcinoma (PDAC), is a potential therapeutic target. However, preclinical and therapeutic evidence that supports direct targeting of IKK activation in therapy is lacking.

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Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth

Despite its documented role in cell cycle regulation, over-expression of the cyclin-dependent kinase activator CDC25A does not consistently correlate with worse cancer patient outcomes or predict successful clinical response to CDC25A inhibition. The current study was undertaken to investigate CDC25A in skin cancer and understand predictors of positive response to CDC25A targeting. CDC25A was increased in human squamous cell carcinoma (SCC) associated with a shift from a primarily nuclear localization in skin to a strong cytoplasmic localization in SCC, a pattern that was reproduced in skin cancer cell lines.

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Ras Inhibitors Display an Anti-Metastatic Effect by Downregulation of Lysyl Oxidase through Inhibition of the Ras-PI3K-Akt-HIF-1α Pathway

Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-rasG12Vgene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or an siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis.

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Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells

Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis.

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Natural variation of the zygomaticomaxillary complex symmetry in normal individuals

The most frequently encountered midfacial fractures are zygomaticomaxillary complex (ZMC) fractures (Gupta et al., 2009; van Hout et al., 2013; Arangio et al., 2014). In ZMC fracture cases, the restoration of facial symmetry is the main treatment goal after functional recovery (Ellis, 2013; Ellis and Perez, 2014) because symmetry plays an important role in the visual perception of faces (Grammer and Thornhill, 1994; Perrett et al., 1998; Rhodes, 2006). Furthermore, a symmetrical face is correlated with perceived healthiness and attractiveness (Rhodes et al., 1998; Jones et al., 2001; Fink et al., 2006).

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Comparison of the accuracy of maxillary position between conventional model surgery and virtual surgical planning

The aim of this study was to determine whether virtual surgical planning (VSP) is an accurate method for positioning the maxilla when compared to conventional articulator model surgery (CMS), through the superimposition of computed tomography (CT) images. This retrospective study included the records of 30 adult patients submitted to bimaxillary orthognathic surgery. Two groups were created according to the treatment planning performed: CMS and VSP. The treatment planning protocol was the same for all patients.

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Natural variation of the zygomaticomaxillary complex symmetry in normal individuals

The most frequently encountered midfacial fractures are zygomaticomaxillary complex (ZMC) fractures (Gupta et al., 2009; van Hout et al., 2013; Arangio et al., 2014). In ZMC fracture cases, the restoration of facial symmetry is the main treatment goal after functional recovery (Ellis, 2013; Ellis and Perez, 2014) because symmetry plays an important role in the visual perception of faces (Grammer and Thornhill, 1994; Perrett et al., 1998; Rhodes, 2006). Furthermore, a symmetrical face is correlated with perceived healthiness and attractiveness (Rhodes et al., 1998; Jones et al., 2001; Fink et al., 2006).

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Adjuvant therapy in renal cell carcinoma

There are an estimated 62700 new diagnoses of renal cell carcinoma (RCC) every year. For localized and locally advanced tumours, surgery remains the only potentially curative approach. Despite surgical resection, the overall recurrence rate is still estimated to be 35% [1].

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A two-phase algorithm for point-feature cartographic label placement

Abstract

Point-feature cartographic label placement (PFCLP) involves placing labels adjacent to their corresponding point features on a map. A widely accepted goal of PFCLP is to maximize the number of conflict-free labels. This paper presents an algorithm for PFCLP based on the four-slider (4S) model. The algorithm is composed of two phases: an initialization phase during which an initial solution is constructed by an exact algorithm and a heuristic method to maximize the probability of conflict-free labels. The initialization phase is followed by an improvement phase that adopts a backtracking greedy search. The exact algorithm can find a portion of the conflict-free labels in an optimal solution and an extension of the exact algorithm is provided that can find additional conflict-free labels. Computational tests were performed for instances based on standard sets. The two-phase algorithm generated better solutions relative to all methods previously reported in the literature. It also executes at a reasonable speed and is more stable than most other methods.

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Reply

We are very thankful to Russo et al. for their useful comments.1 We hope that these comments and our answers may further clarify which factors may affect different frequency of the left ventricular dysfunction observed in different series of patients with myotonic dystrophy type 1 (DM1).

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Adjuvant therapy in renal cell carcinoma

There are an estimated 62700 new diagnoses of renal cell carcinoma (RCC) every year. For localized and locally advanced tumours, surgery remains the only potentially curative approach. Despite surgical resection, the overall recurrence rate is still estimated to be 35% [1].

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Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth

Despite its documented role in cell cycle regulation, over-expression of the cyclin-dependent kinase activator CDC25A does not consistently correlate with worse cancer patient outcomes or predict successful clinical response to CDC25A inhibition. The current study was undertaken to investigate CDC25A in skin cancer and understand predictors of positive response to CDC25A targeting. CDC25A was increased in human squamous cell carcinoma (SCC) associated with a shift from a primarily nuclear localization in skin to a strong cytoplasmic localization in SCC, a pattern that was reproduced in skin cancer cell lines.

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NEMO Peptide Inhibits the Growth of Pancreatic Ductal Adenocarcinoma by Blocking NF-κB Activation

NF-κB essential modulator (NEMO) binds and regulates IκB kinase (IKK) and is required for NF-κB activation. The NEMO-binding domain peptide (NBDP) of IKK was found to inhibit NF-κB activation and promote apoptosis in cancer cells. Studies have shown that constitutive NF-κB activation, one of the signature molecular alterations in pancreatic ductal adenocarcinoma (PDAC), is a potential therapeutic target. However, preclinical and therapeutic evidence that supports direct targeting of IKK activation in therapy is lacking.

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Ras Inhibitors Display an Anti-Metastatic Effect by Downregulation of Lysyl Oxidase through Inhibition of the Ras-PI3K-Akt-HIF-1α Pathway

Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-rasG12Vgene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or an siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis.

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Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells

Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis.

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Antifungal Effects of Synthetic Human Beta-defensin-3-C15 Peptide on Candida albicans–infected Root Dentin

The aim of this study was to assess the antifungal efficacy of a synthetic human beta-defensin-3-C15 peptide (HBD3-C15) in Candida albicans–infected human root dentin.

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Bacterial Contamination of Endodontic Materials before and after Clinical Storage

The aim of this study was to evaluate the bacterial contamination in endodontic consumables (gutta-percha points, rubber dams, paper mixing pads, caulking agents, and endodontic instrument sponges [EISs]) before and after clinical use and storage.

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Determination of the Influence of Chronic Periodontitis on Pulp Sensibility by Means of Electric and Thermal Cold Testing

Communication between pulp and periodontal tissue has been well established. However, it is unknown when periodontal disease begins to affect the clinical response of pulp tissue. The aim of this study was to assess the influence of periodontal severity on pulp sensibility by means of electric and thermal cold testing.

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Mechanical Properties of Various Heat-treated Nickel-Titanium Rotary Instruments

The purpose of this study was to compare the bending stiffness, cyclic fatigue, and torsional fracture resistances of heat-treated and conventional nickel-titanium rotary instruments.

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Antibiofilm Effect of D-enantiomeric Peptide Alone and Combined with EDTA In Vitro

The aim of this study was to evaluate the effect of DJK-5, a newly developed cationic antimicrobial peptide, on oral multispecies and Enterococcus faecalis biofilms alone or combined with the endodontic chelating agent EDTA in vitro.

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Temperature Rise on the Plugger Surface of 2 Commercially Available Gutta-percha Heating Devices

The objective of this study was to examine the temperature rise on the plugger surface of 2 commercially available gutta-percha heating devices: the System B (Kerr Dental, Amersfoort, The Netherlands) and the System B Cordless Pack Unit (Kerr Dental).

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Fatigue Resistance of Nickel-titanium Instruments Exposed to High-concentration Hypochlorite

The purpose of this study was to introduce a new fatigue test model that simulates the clinical situation for evaluating the corrosion effect of 5.25% sodium hypochlorite (NaOCl) on nickel-titanium (NiTi) files and to evaluate the effect of 3 different temperatures (22°C, 37°C, and 60°C) on the cyclic fatigue of these files.

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Cleaning and Shaping Oval Canals with 3 Instrumentation Systems: A Correlative Micro–computed Tomographic and Histologic Study

The present study evaluated the cleaning and shaping ability of 3 instrumentation systems in oval canals of extracted vital teeth using a correlative analytic approach.

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Dentin-like versus Rigid Endodontic Post: Eleven-year Randomized Controlled Pilot Trial on No-wall to Two-wall Defects

This is the first long-term randomized controlled trial to evaluate dentin-like glass fiber posts (GFPs) compared with rather rigid titanium posts (TPs) for post-endodontic restoration of severely damaged endodontically treated teeth with 2 or fewer remaining cavity walls.

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AIPL1: A specialized chaperone for the phototransduction effector

Publication date: December 2017
Source:Cellular Signalling, Volume 40
Author(s): Ravi P. Yadav, Nikolai O. Artemyev
Molecular chaperones play pivotal roles in protein folding, quality control, assembly of multimeric protein complexes, protein trafficking, stress responses, and other essential cellular processes. Retinal photoreceptor rod and cone cells have an unusually high demand for production, quality control, and trafficking of key phototransduction components, and thus, require a robust and specialized chaperone machinery to ensure the fidelity of sensing and transmission of visual signals. Misfolding and/or mistrafficking of photoreceptor proteins are known causes for debilitating blinding diseases. Phosphodiesterase 6, the effector enzyme of the phototransduction cascade, relies on a unique chaperone aryl hydrocarbon receptor (AhR)-interacting protein-like 1 (AIPL1) for its stability and function. The structure of AIPL1 and its relationship with the client remained obscure until recently. This review summarizes important recent advances in understanding the mechanisms underlying normal function of AIPL1 and the protein perturbations caused by pathogenic mutations.



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Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of the oncogenic protein AEG-1 and activation of AMP-activated protein kinase (AMPK)

Publication date: December 2017
Source:Cellular Signalling, Volume 40
Author(s): Hossam Draz, Alexander A. Goldberg, Vladimir I. Titorenko, Emma S. Tomlinson Guns, Stephen H. Safe, J. Thomas Sanderson
3,3′-Diindolylmethane (DIM) and its synthetic halogenated derivatives 4,4′-Br2- and 7,7′-Cl2DIM (ring-DIMs) have recently been shown to induce protective autophagy in human prostate cancer cells. The mechanisms by which DIM and ring-DIMs induce autophagy have not been elucidated. As DIM is a mitochondrial ATP-synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of intracellular AMP/ATP ratios and activation of AMP-activated protein kinase (AMPK) signaling in prostate cancer cells. We found that DIM and ring-DIMs induced autophagy was accompanied by increased autophagic vacuole formation and conversion of LC3BI to LC3BII in LNCaP and C42B human prostate cancer cells. DIM and ring-DIMs also induced AMPK, ULK-1 (unc-51-like autophagy activating kinase 1; Atg1) and acetyl-CoA carboxylase (ACC) phosphorylation in a time-dependent manner. DIM and the ring-DIMs time-dependently induced the oncogenic protein astrocyte-elevated gene 1 (AEG-1) in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting either AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with overtly cytotoxic concentrations of DIM or ring-DIMs and inhibited the onset of apoptosis in response to these compounds. In summary, we have identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and subsequent activation of AMPK. Our findings could facilitate the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants.



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Interleukin 1 β-induced SMAD2/3 linker modifications are TAK1 dependent and delay TGFβ signaling in primary human mesenchymal stem cells

Publication date: December 2017
Source:Cellular Signalling, Volume 40
Author(s): Guus G. van den Akker, Henk M. van Beuningen, Elly L. Vitters, Marije I. Koenders, Fons A. van de Loo, Peter L. van Lent, Esmeralda N. Blaney Davidson, Peter M. van der Kraan
BackgroundChondrogenic differentiation of mesenchymal stem cells (MSC) requires transforming growth factor beta (TGFβ) signaling. TGFβ binds to the type I receptor activin-like kinase (ALK)5 and results in C-terminal SMAD2/3 phosphorylation (pSMAD2/3C). In turn pSMAD2/3C translocates to the nucleus and regulates target gene expression. Inflammatory mediators are known to exert an inhibitory effect on MSC differentiation. In this study we investigated the effect of interleukin 1 β (IL1β) on SMAD2/3 signaling dynamics and post-translational modifications.ResultsCo-stimulation of MSC with TGFβ and IL1β did not affect peak pSMAD2C levels at 1h post-stimulation. Surprisingly, SMAD3 transcriptional activity, as determined by the CAGA12-luciferase reporter construct, was enhanced by co-stimulation of TGFβ and IL1β compared to TGFβ alone. Furthermore, IL1β stimulation induced CAGA12-luciferase activity in a SMAD dependent way. As SMAD function can be modulated independent of canonical TGFβ signaling through the SMAD linker domain, we studied SMAD2 linker phosphorylation at specific threonine and serine residues. SMAD2 linker threonine and serine modifications were observed within 1h following TGFβ, IL1β or TGFβ and IL1β stimulation. Upon co-stimulation linker modified SMAD2 accumulated in the cytoplasm and SMAD2/3 target gene transcription (ID1, JUNB) at 2–4h was inhibited. A detailed time course analysis of IL1β-induced SMAD2 linker modifications revealed a distinct temperospatial pattern compared to TGFβ. Co-stimulation with both factors resulted in a similar kinetic profile as TGFβ alone. Nevertheless, IL1β did subtly alter TGFβ-induced pSMAD2C levels between 8 and 24h post-stimulation, which was reflected by TGFβ target gene expression (PAI1, JUNB). Direct evidence for the importance of SMAD3 linker modifications for the effect of IL1β on TGFβ signaling was obtained by over-expression of SMAD3 or a SMAD3 linker phospho-mutant. Finally, an inhibitor screening was performed to identify kinases involved in SMAD2/3 linker modifications. We identified TAK1 kinase activity as crucial for IL1β-induced SMAD2 linker modifications and CAGA12-luciferase activity.ConclusionsTGFβ and IL1β signaling interact at the SMAD2/3 level in human primary MSC. Down-stream TGFβ target genes were repressed by IL1β independent of C-terminal SMAD2 phosphorylation. We demonstrate that SMAD2/3 linker modifications are required for this interplay and identified TAK1 as a crucial mediator of IL1β-induced TGFβ signal modulation.

Graphical abstract

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