The novel role of pyrvinium in cancer therapy

Abstract

Pyrvinium pamoate (PP) is a quinoline-derived cyanine dye which was officially approved by FDA for its anthelmintic properties and therapeutic function against animal-like protists such as Cryp-tosporidium parvum and Plasmodium falciparum in the 1950 s. In the last 10 years, several studies have shown the novel activity of pyrvinium in tumor therapy. Some investigations have indicated that pyrvinium could delay or inhibit tumor cell proliferation in cancer models including colon, breast, lung and prostate cancer and some hematological malignancies. In this review, we discuss multiple critical signaling pathways and mechanisms underlying the anticancer effects of PP. In details, pyrvinium acts through the following main mechanisms: i) energy and autophagy depletion, and ii) inhibition of Akt and Wnt-β-catenin-dependent pathways. Interestingly, pyrvinium has also shown potent anti-cancer stem cell activity. The overwhelming insights into the mechanism of anticancer properties of PP can help establishing novel and future anti-tumor treatment strategies. This article is protected by copyright. All rights reserved

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E2F is Involved in Radioresistance of Carbon Ion Induced Apoptosis via Bax/caspase 3 Signal Pathway in Human Hepatoma Cell

ABSTRACT

Deletion of p53, most common genetic alteration, is observed in human tumors and reported to lead to improve in cell radioresistance. Heavy-ion irradiation (IR) could induce p53-/- cancer cells apoptosis. However, little is known regarding the molecular mechanism in this type of cell apoptosis. The present studies have focused on mechanisms state of signaling pathways as an activator of the cell fate decisions induced by heavy ion IR without p53. Carbon ion IR could induce up-regulation of E2F1 expression in cancer cells. This phenomenon was not observed in X-ray IR group. Up-regulation of E2F1 could cause a higher reduction in clonogenic survival, low level of cellular activity, G2/M phase arrest, promotion of apoptosis rate, up-regulation of phosphor-Rb, Bax, and cleaved-caspase 3 proteins expressions without p53. Changes of E2F1 expressions could partly alter radioresistance in cancer cells. The results were suggested that heavy ion IR could induce p53-/- cancer cells apoptosis via E2F1 signal pathway. Our study provides a scientific rationale for the clinical use of heavy ion as radiotherapy in patients with p53-deficient tumors, which are often resistant to radiotherapy. This article is protected by copyright. All rights reserved

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Application of a novel bioreactor for in vivo engineering of pancreas tissue

Abstract

Type 1 diabetes is characterized by autoimmune destruction of pancreatic cells. Organ transplantation is an acceptable treatment for native organ failure. However, it is associated with several problems due to a number of reasons, such as the lack of appropriate donors and immunosuppression. In our present study, a novel model is presented for in vivo recellularization of acellular pancreas by implanting between the host pancreas and the adjacent omental flap. In this study, the pancreases were harvested and cannulated via the common bile duct and then, the scaffolds were acellularized by a detergent-based protocol. Afterthat, the abdomens of thirty-five rats were opened and the spleen was extracted with the adjacent omentum and placed outside the abdomen. The acellularized scaffold was stretched over the host pancreas and the omentum was wrapped around it to make a sandwich-like structure, which was then fixed with Chromic Sutures 6-0 and marked with Prolene 4-0 on four sides. All samples were biopsied at 14, 30, 60, 90, and 120 days post-transplantation. The result showed marked recellularization of acellularized pancreas with visible neovascularization and neoβ-cells with minimal inflammatory response. This study provides a new approach to produces a normal-like pancreas by allograft transplantation for pancreas tissue engineering. We observed that in vivo transplantation of acellularized pancreas can promote recellularization, proliferation, and differentiation by blood circulation. These findings support that in vivo studies can contribute to finding faster solutions for the treatment of diabetes. This article is protected by copyright. All rights reserved

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The relationship between job satisfaction, work stress, work-family conflict, and turnover intention among physicians in Guangdong, China: a cross-sectional study

Objective

To investigate the relationship between job satisfaction, work stress, work–family conflict and turnover intention, and explore factors associated with turnover intention, among physicians in Guangdong Province, China.

Methods

From August to October 2013, physicians completed questionnaires and scales with regard to their job satisfaction, work stress, work–family conflict, and turnover intention. Binary logistic regression and structural equation modelling (SEM) were used in data analysis.

Results

A total of 3963 physicians were approached, with 3563 completing the questionnaire. The mean score of the overall perception of turnover intention of physicians who worked in Guangdong was 2.71 on a scale ranging from 1 to 6. Hours worked per week, working in an urban/rural area, type of institution, and age significantly impacted on turnover intention. Turnover intention was directly and negatively related to job satisfaction, and it was directly, indirectly and positively related to work stress and work–family conflict.

Conclusion

Job satisfaction, work stress, work–family conflict, hours worked per week, working in an urban/rural area, types of institution and age are influencing factors of turnover intention. Reducing working hours, raising salary, providing more opportunities for career development and training, supporting and encouraging physicians by senior managers could potentially contribute to the reduction in turnover intention.

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Integrating culturally informed approaches into the physiotherapy assessment and treatment of chronic pain: protocol for a pilot randomised controlled trial

Introduction

There is strong evidence that biopsychosocial approaches are efficacious in the management of chronic pain. However, implementation of these approaches in clinical practice is known not to account for the beliefs and values of culturally and linguistically diverse (CALD) patients. This limitation in translation of research contributes to the disparities in outcomes for CALD patients with chronic pain adding to the socioeconomic burden of this prevalent condition. Cultural adaptation of chronic pain assessment and management is urgently required. Thus, the aim of this pilot randomised controlled trial (RCT) is to determine the feasibility, participant acceptance with and clinical effectiveness of a culturally adapted physiotherapy assessment and treatment approach when contrasted with ‘usual evidence based physiotherapy care’ for three CALD communities.

Methods and analysis

Using a participant-blinded and assessor-blinded randomised controlled pilot design, patients with chronic pain who self-identify as Assyrian, Mandaean or Vietnamese will be randomised to either 'culturally adapted physiotherapy assessment and treatment' or ‘evidence informed usual physiotherapy care'. We will recruit 16 participants from each ethnocultural community that will give a total of 24 participants in each treatment arm. Both groups will receive physiotherapy treatment for up to 10 sessions over 3 months. Outcomes including feasibility data, acceptance with the culturally adapted intervention, functional and pain-related measures will be collected at baseline and 3 months by a blinded assessor. Analysis will be descriptive for feasibility outcomes, while measures for clinical effectiveness will be explored using independent samples t-tests and repeated measures analysis of variance. This analysis will inform sample size estimates while also allowing for identification of revisions in the protocol or intervention prior to a larger scale RCT.

Ethics and dissemination

This trial has full ethical approval (HREC/16/LPOOL/194). The results from this pilot RCT will be presented at scientific meetings and published in peer-reviewed journals.

Trial registration number

ACTRN12616000857404

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A scoping review protocol on social participation of indigenous elders, intergenerational solidarity and their influence on individual and community wellness

Introduction

Indigenous elders have traditionally played an important role in maintaining social cohesion within their communities. Today, part of this role has been taken over by government social and healthcare services, but they are having limited success in addressing social challenges. Increasing elders’ social participation and intergenerational solidarity might foster community development and benefit young people, families, communities and the elders themselves. However, knowledge of the contribution of elders’ social participation and intergenerational solidarity to wellness is scattered and needs to be synthesised. This protocol presents a scoping review on the social participation of indigenous elders, intergenerational solidarity and their influence on individual and community wellness.

Methods and analysis

This scoping review protocol is based on an innovative methodological framework designed to gather information from the scientific and grey literature and from indigenous sources. It was developed by an interdisciplinary team including indigenous scholars/researchers, knowledge users and key informants. In addition to searching information databases in fields such as public health and indigenous studies, an advisory committee will ensure that information is gathered from grey literature and indigenous sources.

Ethics

The protocol was approved by the Ethics Review Board of the Université du Québec en Abitibi-Témiscamingue and the First Nations of Quebec and Labrador Health and Social Services Commission.

Discussion

The comprehensive synthesis of the scientific and grey literature and indigenous sources proposed in this protocol will not only raise awareness within indigenous communities and among healthcare professionals and community organisations, but will also enable decision-makers to better meet the needs of indigenous people.

Conclusion

The innovative methodological framework proposed in this scoping review protocol will yield richer information on the contribution of elders to community wellness. This work is an essential preliminary step towards developing research involving indigenous communities, drawing on the social participation of elders and intergenerational solidarity.

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Haemodynamic analysis for recanalisation of intracranial aneurysms after endovascular treatment: an observational registry study in China

Introduction

Recanalisation of intracranial aneurysms following endovascular treatment is a major issue. Many factors, including aneurysm morphology, the method of treatment, and haemodynamics, are considered to be associated with recanalisation. However, the underlying haemodynamic mechanisms are not completely understood.

Methods and analysis

This is a prospective, observational, registry study for patients with intracranial aneurysms who are treated endovascularly. It will enrol 200 eligible patients. Data on morphological, haemodynamic, and treatment factors will be collected prospectively. The advanced virtual stenting technique and porous media method will be used in haemodynamic simulations. The clinical and angiographic outcomes at 6 months will be measured and analysed. This observational study will determine the haemodynamic factors that affect the recanalisation of aneurysms.

Ethics and dissemination

Both the study protocol and written informed consent were reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital (KY2016-023-01). The results of study will be disseminated in professional printed media.

Trial registration number

NCT02812108; Pre-results.

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Guidelines for Contributing Authors

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Table of Contents

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Editorial Board

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Subscriptions Page

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Cover

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Editorial Board

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Table of Contents

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Bioethics and Transhumanism

Abstract

Transhumanism is a “technoprogressive” socio-political and intellectual movement that advocates for the use of technology in order to transform the human organism radically, with the ultimate goal of becoming “posthuman.” To this end, transhumanists focus on and encourage the use of new and emerging technologies, such as genetic engineering and brain-machine interfaces. In support of their vision for humanity, and as a way of reassuring those “bioconservatives” who may balk at the radical nature of that vision, transhumanists claim common ground with a number of esteemed thinkers and traditions, from the ancient philosophy of Plato and Aristotle to the postmodern philosophy of Nietzsche. It is crucially important to give proper scholarly attention to transhumanism now, not only because of its recent and ongoing rise as a cultural and political force (and the concomitant potential ramifications for bioethical discourse and public policy), but because of the imminence of major breakthroughs in the kinds of technologies that transhumanism focuses on. Thus, the articles in this issue of The Journal of Medicine and Philosophy are either explicitly about transhumanism or are on topics, such as the ethics of germline engineering and criteria for personhood, that are directly relevant to the debate between transhumanists (and technoprogressives more broadly) and bioconservatives.

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Antiquity’s Missive to Transhumanism 1

Abstract

To reassure those concerned about wholesale discontinuity between human existence and posthumanity, transhumanists assert shared ground with antiquity on vital challenges and aspirations. Because their claims reflect key misconceptions, there is no shared vision for transhumanists to invoke. Having exposed their misuses of Prometheus, Plato, and Aristotle, I show that not only do transhumanists and antiquity crucially diverge on our relation to ideals, contrast-dependent aspiration, and worthy endeavors but that illumining this divide exposes central weaknesses in transhumanist argumentation. What is more, antiquity’s handling of these topics suggests a way through the impasse in current enhancement debates about human “nature” and helps to resolve a tension within transhumanists’ accounts of what our best moments signify about the ontological requirements for real flourishing.

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Personhood and Natural Kinds: Why Cognitive Status Need Not Affect Moral Status

Abstract

Lockean accounts of personhood propose that an individual is a person just in case that individual is characterized by some advanced cognitive capacity. On these accounts, human beings with severe cognitive impairment are not persons. Some accept this result—I do not. In this paper, I therefore advance and defend an account of personhood that secures personhood for human beings who are cognitively impaired. On the account for which I argue, an individual is a person just in case that individual belongs to a natural kind that is normally characterized by advanced cognitive capacities. Since “human being” is just such a natural kind, individual human beings can be persons even when they do not themselves have advanced cognitive capacities. I argue, furthermore, that we have good reason to accept this account of personhood over rival accounts since it is uniquely able to accommodate the intuitive concept of an impaired person.

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The Posthuman as Hollow Idol: A Nietzschean Critique of Human Enhancement

Abstract

In this paper, the author aims to show that transhumanists are confused about their own conception of the posthuman: transhumanists anticipate radical transformation of the human through technology and at the same time assume that the criteria to determine what is “normal” and what is “enhanced” are univocal, both in our present time and in the future. Inspired by Nietzsche’s notion of the Overhuman, the author argues that the slightest “historical and phenomenological sense” discloses copious variations of criteria, both diachronic and synchronic, for what can be considered “normal” and “enhanced.” Radical transformation through technology does not simply enable us to become “stronger,” “smarter,” or “healthier,” but it can and often will also change the very standard or yardstick with which we measure what counts as “stronger,” “smarter,” or “healthier.” Put yet differently: new and emerging technologies are not neutral means but often bring about different and, from our current perspective, foreign standards for determining what are “normal” and “enhanced” capacities. Since the qualitative meanings of these terms are themselves not fixed, it is unintelligible and too reassuring to simply predict that new technologies will enhance human beings.

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Future Generations and the Justifiability of Germline Engineering

Abstract

The possibility of performing germline modifications on currently living individuals targets future generations’ health and well-being by reducing the diversity of the human gene pool. This can have two negative repercussions: (1) reduction of heterozygosity, the latter being associated with a health or performance advantage; (2) uniformization of the genes involved in reproductive recombination, which may lead to the health risks involved in asexual reproduction. I argue that germline interventions aimed at modifying the genomes of future people cannot be ethically justifiable if there is no possibility of controlling the intervention either by reversing or altering it, whenever need demands it. This argument is challenged on six different grounds: safety, population versus individual focus, spontaneous mutations, exceptionalism, the intentional pursuit of genetic diversity through germline interventions, and harm reduction potential.

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Ear bones

Ear bones: Also know as the ossicles, these are the three tiny bones in the middle ear that carry the sound wave from the ear drum into the cochlea.

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

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Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells

Publication date: August 2017
Source:Cellular Signalling, Volume 36
Author(s): Kalpita Banerjee, Matt P. Keasey, Vladislav Razskazovskiy, Nishant P. Visavadiya, Cuihong Jia, Theo Hagg
Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.

Graphical abstract

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The zinc finger E-box-binding homeobox 1 (Zeb1) promotes the conversion of mouse fibroblasts into functional neurons [Neurobiology]

The zinc finger E-box binding transcription factor Zeb1 plays a pivotal role in the epithelial-mesenchymal transition (EMT). Numerous studies have focused on the molecular mechanisms by which Zeb1 contributes to this process. However, the functions of Zeb1 beyond EMT remain largely elusive. Using a transdifferentiation system to convert mouse embryonic fibroblasts (MEFs) into functional neurons via the neuronal transcription factors Achaete-scute family bHLH transcription factor1 (Ascl1), POU class 3 homeobox 2 (POU3F2/Brn2) and Neurogenin 2 (Neurog2, Ngn2) (ABN), we found that Zeb1 was up-regulated during the early stages of transdifferentiation. Knocking down Zeb1 dramatically attenuated the transdifferentiation efficiency, whereas Zeb1 overexpression obviously increased the efficiency of transdifferentiation from MEFs to neurons. Interestingly, Zeb1 improved the transdifferentiation efficiency induced by even a single transcription factor (e.g., Asc1 or Ngn2). Zeb1 also rapidly promoted the maturation of induced neuron (iN) cells to functional neurons and improved the formation of neuronal patterns and electrophysiological characteristics. iN cells could form functional synapse in vivo after transplantation. Genome-wide RNA arrays showed that Zeb1 overexpression up-regulated the expression of neuron-specific genes and down-regulated the expression of epithelial-specific genes during conversion. Taken together, our results reveal a new role for Zeb1 in the transdifferentiation of MEFs into neurons.

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E3 Ubiquitin Ligase WWP2 Facilitates RUNX2 Transactivation Through A Mono-ubiquitination Manner During Osteogenic Differentiation [Protein Synthesis and Degradation]

Poly-ubiquitination-mediated RUNX2 degradation is an important cause of age and inflammation-related bone loss. NEDD4 family E3 ubiquitin protein ligases are thought to be the major regulators of RUNX2 poly-ubiquitination. However, we observed a mono-ubiquitination of RUNX2 that was catalyzed by WWP2, the member of NEDD4 family E3 ubiquitin ligases. WWP2 has been reported to catalyze mono-ubiquitination of Gooseicoid in chondrocytes, thus facilitating craniofacial skeleton development. In the current studies, we found that osteogenic differentiation of mesenchymal stem cells promoted WWP2 expression and nuclear accumulation. Knockdown of Wwp2 in mesenchymal stem cells and osteoblasts led to significant deficiencies of osteogenesis, including decreased mineral deposition and down-regulation of osteogenic marker genes. Co-immunoprecipitation experiments showed the interaction of WWP2 with RUNX2 in vitro and in vivo. The mono-ubiquitination by WWP2 leads to RUNX2 transactivation, as evidenced by the wide-type of WWP2 but not its ubiquitin ligase-dead mutant augmenting RUNX2-reponsive reporter activity. Moreover, the deletion of WWP2-dependent mono-ubiquitination resulted in striking defects of RUNX2 osteoblastic activity. In addition, ectopic expression of constitutively active type 1A BMP receptor enhanced WWP2-dependent RUNX2 ubiquitination and transactivation, thus demonstrating a regulatory role of BMP signaling in WWP2-RUNX2 axis. Taken together, our results provide evidence that WWP2 serves as a positive regulator of osteogenesis by augmenting RUNX2 transactivation in a non-proteolytic mono-ubiquitination manner.

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The Heme Regulatory Motif of Nuclear Receptor Rev-erb{beta} is a Key Mediator of Heme and Redox Signaling in Circadian Rhythm Maintenance and Metabolism [Gene Regulation]

Rev-erbβ is a heme-responsive transcription factor that regulates genes involved in circadian rhythm maintenance and metabolism, effectively bridging these critical cellular processes. Heme binding to Rev-erbβ indirectly facilitates its interaction with nuclear receptor corepressor (NCoR1), resulting in repression of Rev-erbβ target genes. Fe3+-heme binds as a 6-coordinate complex with axial His and Cys ligands, the latter provided by a heme regulatory motif (HRM). Rev-erbβ was thought to be a heme sensor based on a weak Kd for the Rev-erbβ-heme complex of 2 μM determined with isothermal titration calorimetry. However, our group demonstrated with UV-visible difference titrations that the Kd value is in the low nanomolar range, and the Fe3+-heme off-rate is on the order of 10-6 s-1 making Rev-erbβ ineffective as a sensor of Fe3+-heme. In this study, we dissected the kinetics of heme binding to Rev-erbβ and provide a Kd for Fe3+-heme of ~0.1 nM. Loss of the HRM axial thiolate via redox processes, including oxidation to a disulfide with a neighboring cysteine or dissociation upon reduction of Fe3+- to Fe2+-heme, decreased binding affinity by >20-fold. Furthermore, as measured in a co-immunoprecipitation assay, substitution of the His or Cys heme ligands in Rev-erbβ is accompanied by a significant loss of NCoR1 binding. These results demonstrate the importance of the Rev-erbβ HRM in regulating interactions with heme and NCoR1 and advance our understanding of how signaling through HRMs impacts the major cellular processes of circadian rhythm maintenance and metabolism.

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Degradation of phospholipids under different types of irradiation and varying oxygen saturation

Abstract

The effects of different types of radiation on the formation of peroxide forms of 2-dioleoyl-sn-glycero-3-phosphocholine were studied under various conditions. For the irradiation, an aqueous solution of small unilamellar vesicles was prepared. Variations in parameters such as the dose rate and molecular oxygen saturation levels were evaluated. Our study suggests that the mechanism of the peroxides formation process remains unchanged under irradiation by accelerated electrons, gamma and accelerated protons. The values of radiation chemical yields of the peroxidic form depend on the type of radiation, dose rate, and the saturation of molecular oxygen. The level of oxygen saturation strongly affects the values of radiation chemical yields as well, as the dissolved oxygen is an important agent participating in peroxidation and it is a source of free radicals during the radiolysis. The values of radiation chemical yields strongly suggest that the mechanism of radiation-induced peroxidation of phosphatidylcholines does not proceed via chain reaction.

Graphical Abstract

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Improved Yield of High Molecular Weight Hyaluronic Acid Production in a Stable Strain of Streptococcus zooepidemicus via the Elimination of the Hyaluronidase-Encoding Gene

Abstract

Despite the significant potential of Streptococcus zooepidemicus for hyaluronic acid (HA) production with high molecular weight (MW), the HA degrading properties of hyaluronidase prevents the bacteria to achieve enhanced HA yield with high MW. In the present study, we aim to knockout the hyaluronidase enzyme and assess its effects on the yield and MW of the produced HA. The kanamycin resistance gene between the left and right arms of hyaluronidase gene was inserted into pUC18 plasmid to construct pUC18-L-kana^r-R as a recombinant suicide plasmid. The construct was then transferred into S. zooepidemicus to induce the homologous recombination between the hyaluronidase gene and the kanamycin resistance gene. Gene deletion was confirmed by PCR and enzyme assay. The product was cultured on selectable medium in which the MW of HA was increased from 1.5 to 3.8 MDa. The yield of HA production using the mutant strain was higher in all different concentrations of glucose from 40 to 120 g/l. Moreover, glucose increase results in higher HA production within both wild-type and recombinant strains. However, the growth rate of HA concentration (the slope of the plot), as a consequence of increased glucose concentration, is always higher for the recombinant strain. Unlike the wild-type strain, there was no sharp HA production drop approaching the 6 g/l HA concentration. In conclusion, hyaluronidase activity and HA concentration and MW exhibited a mutual control on each other. Based on our results, deletion of the hyaluronidase gene positively affects the yield and MW of HA.

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Well-Differentiated Laryngeal/Hypopharyngeal Liposarcoma in the MDM2 Era Report of Three Cases and Literature Review

Abstract

Laryngeal/hypopharyngeal liposarcomas are very rare, fewer than 40 cases have been reported. These tumors are polypoid, with a male predisposition, and usually cause hoarseness and difficulty breathing. Their clinical course is characterized by multiple local recurrences. No distant metastasis has been reported, and dedifferentiation is extremely rare. In sum, the prognosis of these tumors is excellent; the 5-year survival rate is essentially 100 %. Pathologic diagnosis of these well-differentiated liposarcomas can be challenging. Many of them were initially diagnosed as benign lipoma, fibrovascular polyp, or "inflammatory polyp". The correct diagnosis is usually made after multiple recurrences. On the other hand, the literature bears out that these incorrect diagnoses do not impact disease-specific survival. Here, we report three patients with laryngeal/hypopharyngeal well-differentiated liposarcomas; this is the first documentation of MDM2 amplification in liposarcomas at this site.

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Orthokeratinized Odontogenic Cyst with an Associated Keratocystic Odontogenic Tumor Component and Ghost Cell Keratinization and Calcifications in a Patient with Gardner Syndrome

Abstract

Gardner syndrome (GS) is caused by mutations in the APC and besides adenomatous colorectal polyps includes such manifestations as osteomas, epidermoid cysts (ECs) and occasionally multiple pilomatricomas. More than 50 % of ECs in patients with GS exhibit pilomatricoma-like ghost cell keratinization. The latter may be explained by the fact that the development of both GS and pilomatricoma is driven by activation of the Wnt/β-catenin signaling pathway. A 62-year-old, Caucasian male with history of GS presented with a unilocular, mixed radiopaque/radiolucent mandibular lesion causing divergence and external root resorption of involved teeth. Histopathologically, the lesion was composed of two cystic components, an orthokeratinized odontogenic cyst (OOC) and a smaller one with characteristics of keratocystic odontogenic tumor (KCOT) featuring, focally, ghost cells and an epithelial morule-like structure. Dystrophic calcifications essentially similar to those seen in pilomatricomas were observed in the fibrous connective tissue wall. The KCOT and OOC epithelia revealed strong and diffuse cytokeratin (AE1/AE3) and β-catenin immunoreactivity. CD10 positive immunostaining was seen in the keratin and superficial spinous cell layers in both OOC and KCOT. The intraepithelial and mural ghost cells showed a cytokeratin (+), β-catenin and CD10 (−) immunophenotype. The diagnosis of OOC with ghost cell calcifications in association with KCOT was rendered. The patient was lost to follow-up. Although a coincidental co-existence cannot be excluded, ghost cell calcifications mimicking pilomatricoma-like changes in an unusual odontogenic cyst combining OOC and KCOT features as seen in this patient with GS may be explained by the common molecular mechanisms underlying the pathogenesis of cutaneous pilomatricomas and GS.

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Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

Abstract

Most nasopharyngeal carcinomas (NPCs) in a high-incidence population are driven by Epstein–Barr virus (EBV) infection. EBV-associated malignancies have increased expression of the programmed death-ligand 1 (PD-L1). Immunotherapy agents targeting the PD-1/PD-L1 pathway have achieved durable treatment effects in patients with various cancer types including EBV-associated malignancies. In this study, we sought to investigate PD-L1 expression in a cohort of patients with NPCs from the Philippines. Fifty-six NPCs were studied for PD-L1, p16, and DNA mismatch repair (MMR) deficiency by immunohistochemistry. One case with MMR deficiency was also assessed for microsatellite instability (MSI) by polymerase chain reaction. EBV and human papillomavirus (HPV) status were tested by in situ hybridization. All NPCs were p16 negative. Three of the 56 NPCs (5%) were EBV negative (EBV−) and HPV negative, while one NPC (1/56, 2%) was EBV positive and showed MSI (EBV+/MSI). Positive PD-L1 expression (PD-L1+), defined as membranous staining in ≥1% tumor cells, was seen in 64% (36/56) of NPCs. All three EBV− NPCs were PD-L1+ as was the EBV+/MSI NPC. PD-L1+ was seen significantly more often in NPCs from non-smokers than those from smokers (23/28, 82% vs 9/18, 50%; P = 0.047). PD-L1+ was not associated with pT, pN, distant metastasis, or clinical stage (P > 0.05). PD-L1+ was not associated with overall survival (P = 0.473). In summary, our results show frequent PD-L1 expression in NPCs regardless of EBV status and a preferential PD-L1 expression in non-smokers. MSI and HPV positivity are exceedingly rare in NPCs.

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Anaplastic Transformation of Papillary Thyroid Carcinoma Only Seen in Pleural Metastasis: A Case Report with Review of the Literature

Abstract

Anaplastic transformation of papillary thyroid carcinoma (PTC) at distant metastatic sites is extremely rare, and there have been fewer than 20 reported cases in the literature. A 61-year-old woman presented with 1-week history of dyspnea. Her past medical history was remarkable because, 19 years ago, she underwent nearly total thyroidectomy and radical neck dissection due to PTC. Computed tomography of the chest revealed a 1.7 cm nodule in the lung and diffuse pleural thickening. Gun biopsy of the lung nodule revealed metastatic PTC with typical histology. However, the pleural biopsy predominantly showed anaplastic pleomorphic and spindle sarcomatoid carcinoma with microscopic focus of PTC. Immunohistochemical results showed both anaplastic sarcomatoid and PTC components positive for TTF-1, galectin-3 and PAX-8, thus supporting anaplastic transformation of PTC at the metastatic site. Subsequently the patient received 1 cycle of cisplatin-based chemotherapy but died from the disease 4 months after diagnosis. Although it is rare, anaplastic transformation of PTC should be considered during differential diagnosis of patients who present with exclusive sarcomatoid morphology at metastatic sites and have a history of PTC. We report another case of anaplastic transformation of PTC, found at pleural metastasis, together with the immunohistochemical profile and a literature review.

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Mucinous Carcinoma with Neuroendocrine Differentiation of Salivary Gland Origin

Abstract

Primary mucinous adenocarcinomas of the salivary gland are rare malignancies defined by aggregates of epithelial cells suspended in large pools of extracellular mucin. We report a case of a giant mucinous adenocarcinoma of salivary gland origin, with low-grade cytoarchitectural features and neuroendocrine differentiation arising in the submental region. Grossly, the tumor measured 12.5 × 13.4 × 8.2 cm and replaced the bone and soft tissues of the anterior oral cavity. Microscopically, the neoplasm was composed of large extracellular pools of mucin, which contained papillary and acinar aggregates, and small nodules of ductal type epithelium with minimal nuclear enlargement, powdery chromatin and little pleomorphism. The nodules comprised 20 % of the tumor and showed morphologic and immunohistochemical evidence of neuroendocrine differentiation. Examination revealed histologic features comparable to mammary gland analogues in mucin predominance, ductal type morphology, expression of estrogen and progesterone receptors, and GATA-3 positivity. This is the first case reported of mucin-rich carcinoma of salivary gland origin exhibiting neuroendocrine differentiation.

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Oral Lichen Sclerosus: A Rare Case Report and Review of the Literature

Abstract

Lichen sclerosus (LS) is a chronic inflammatory mucocutaneous disease that often affects the anogenital area and causes significant discomfort and morbidity. Oral mucosal lesions in LS are extremely rare and might be associated with genital and/or skin manifestations. As a unique manifestation of LS, oral lesions are even more rare, with only 20 cases reported in English-language literature. In reviewing that literature in this paper, we present the case of a 44-year-old white man who sought dental assistance with a complaint of a white spot on his upper lip. Extraoral clinical examination revealed a slight white macule on the left upper lip vermilion next to the labial commissure. Intraoral examination revealed that the macule was approximately 3.5 × 2.0 cm, extended to the upper left labial mucosa, and presented an ivory-white color. Following an incisional biopsy and microscopy, the lesion was shown to be covered by a stratified squamous epithelium showing hyperkeratosis and atrophy. The superficial lamina propria revealed a well-marked band of subepithelial hyalinization and, below it, a band-like mononuclear inflammatory infiltrate. Sections stained by Verhoeff's technique revealed a scantiness of elastic fibers in the superficial lamina propria. The diagnosis of LS was then established. The patient was referred for dermatologic evaluation, which identified no skin or genital lesions, and no treatment was employed. After 6 years, no significant changes in clinical features were observed. Altogether, this rare case makes an important contribution to knowledge on this uncommon condition.

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The New Opt-Out Dutch National Breast Implant Registry – Lessons learnt from the road to implementation

An estimated 1-3% of all women in the Netherlands carry breast implants. Since the introduction five decades ago, problems with a variety of breast implants have emerged with direct consequences for the patients’ health. Plastic surgeons worldwide reacted through campaigning for auditing on long-term implant quality surgeon performance and institutional outcomes in implant registries. Especially the PIP implant scandal of 2010 demonstrated the paucity of epidemiological data and uncovered a weakness in our ability to even ‘track and trace’ patients.

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Domains of quality of life freely expressed by cancer patients and their caregivers: contribution of the SEIQoL

The purposes of this study, performed on a large sample of cancer patient-caregiver dyads, were: i) to simultaneously investigate, using an individualized quality of life (QoL) measure (Schedule for the Evalua...

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Guidelines for allergen immunotherapy in India: 2017-An update

SN Gaur

Indian Journal of Allergy, Asthma and Immunology 2017 31(1):1-2



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Guidelines for practice of allergen immunotherapy in India: 2017-An update

SN Gaur, Raj Kumar, AB Singh, MK Agarwal, Naveen Arora

Indian Journal of Allergy, Asthma and Immunology 2017 31(1):3-33

The practice of Allergy and Immunotherapy is not streamlined in our country and there were no guidelines till we published in 2009 in IJAAI. The guidelines are updated now incorporating the additional information after 2009. The purpose of bringing out these guidelines was to maintain the uniformity in the methods of diagnosis and management i.e. Immunotherapy in the country. Because of different soil conditions, temperature, different allergens, different seasonal variations etc, it was the felt the need to have separate guidelines for India, although such guidelines are available from other organisations. These guidelines are based on available guidelines with modifications/alterations at appropriate places keeping in mind the situation in our country.

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The microscope and the endoscope

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T-helper type 1‐T-helper type 2 shift and nasal remodeling after fine particulate matter exposure in a rat model of allergic rhinitis

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Specific immunoglobulin E and immunoglobulin G4 toward major allergens of house-dust mite during allergen-specific immunotherapy

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Association of pediatric allergic rhinitis with the ratings of attention-deficit/hyperactivity disorder

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Immunopathologic characteristics of nasal polyps in adult Koreans: A single-center study

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International Frontal Sinus Anatomy Classification and anatomic predictors of low-lying anterior ethmoidal arteries

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Effects of changes in nasal volume on voice in patients after endoscopic endonasal transsphenoidal surgery

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Causes of dacryocystorhinostomy failure: External versus endoscopic approach

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Utility of early postoperative imaging after combined endoscopic and open ventral skull base surgery

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Closure of nasal septal perforations with a polydioxanone plate and temporoparietal fascia in a closed approach

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The application of a free nasal floor mucoperiosteal graft in endoscopic sinus surgery

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Endoscopic resection of sinonasal mucosal melanoma has comparable outcomes to open approaches

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Endoscopic-guided coblation treatment of nasal telangiectasias in hereditary hemorrhagic telangiectasia: “How I do it”

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Recurrence of Sinonasal Inverted Papilloma Following Surgical Approach: A Meta-Analysis

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Evidence of Spontaneous Post-transplant HCV Eradication in Two Failed DAA Treatments Awaiting Liver Transplantation

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Sun Should Not Rise and Set on a Case of Acute Intestinal Obstruction

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Insights into the Pathogenesis of Pancreatic Cystic Neoplasms

Abstract

With the current epidemic of diagnosed pancreatic cystic neoplasms on the rise, a substantial amount of work has been done to unravel their biology, thus leading to implications on clinical decision making. Recent genetic profiling of resected human specimens has identified alterations in signaling pathways involving KRAS and GNAS signaling as early events in the pathogenesis of intraductal pancreatic mucinous neoplasms. Progressively, mutations in genes such as TP53, SMAD4, RNF43, and others are thought to characterize invasive and advanced lesions. The role of inflammation in fueling the growth and transformation of these cysts has also begun to be studied with greater interest. A number of promising clinical studies have attempted to integrate these genetic insights into classifying these cysts and treating patients. We have reviewed existing literature on similar lines besides commenting on some useful animal models that recapitulate molecular and phenotypic progression of these cysts.

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Prospective Analysis of Minor Adverse Events After Colon Polypectomy

Abstract

Background

The risks of minor adverse events (MAEs) such as abdominal pain and bloating after colon polypectomy (CP) are less clearly documented than major adverse events. However, these complications may cause significant discomfort during the performance of normal activities. We aimed to estimate the incidence of MAE, associated risk factors, and healthcare resource utilization after CP.

Methods

Patients who underwent CP were prospectively enrolled in this study. Trained nurses contacted patients by telephone at 7 and 30 days after the CP and administered a standardized questionnaire to obtain information regarding the development of complications. MAEs were defined as any discomfort the patient experienced after CP excluding major bleeding, perforation, and post-polypectomy coagulation syndrome.

Results

Among a total of 2716 patients, 2253 patients completed the interview at 7 and 30 days. MAEs occurred in 263 patients (11.7%) before day 7, among which the most common were abdominal pain (4.5%), rectal bleeding (2.8%), and bloating (2.6%). Cumulative incidence of MAEs was in 267 patients (11.9%) at 30 days. On multivariate analysis, female sex (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.58–3.18) and use of meperidine (OR 1.54, 95% CI 1.04–2.27) were risk factors for the occurrence of MAEs. Two patients (0.7%) required hospital admission, 117 patients (43.8%) were treated medically in the outpatient clinic, and the majority at 148 patients (55.4%) experienced resolution of symptoms after observation.

Conclusions

The post-CP MAE rate was as low as 11.8%. The MAEs occurred mainly in the first seven postoperative days and resulted in little use of healthcare resources.

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Identification of potential Campylobacter jejuni genes involved in biofilm formation by EZ-Tn5 Transposome mutagenesis

Biofilm formation has been suggested to play a role in the survival of Campylobacter jejuni in the environment and contribute to the high incidence of human campylobacteriosis. Molecular studies of biofilm format...

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SAR1a promoter polymorphisms are not associated with fetal hemoglobin in patients with sickle cell disease from Cameroon

Reactivation of adult hemoglobin (HbF) is currently a dominant therapeutic approach to sickle cell disease (SCD). In this study, we have investigated among SCD patients from Cameroon, the association of HbF le...

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Combustion-related organic species in temporally resolved urban airborne particulate matter

Abstract

Accurate characterization of the chemical composition of particulate matter (PM) is essential for improved understanding of source attribution and resultant health impacts. To explore this, we conducted ambient monitoring of a suite of 15 combustion-related organic species in temporally resolved PM_2.5 samples during an ongoing animal exposure study in a near source environment in Detroit, MI. All of the 15 species detected were above the method detection limit in 8 h samples. This study focused on two molecular classes: polycyclic aromatic hydrocarbons (PAHs) and hopanes measured in samples. Of the 12 PAHs studied, benzo[b]fluoranthene (169 pg m⁻³), benzo[g,h,i]perylene (124 pg m⁻³), and benzo[e]pyrene (118 pg m⁻³) exhibited the three highest mean concentrations while 17α(H),21β(H)-hopane (189 pg m⁻³) and 17α(H),21β(H)-30-norhopane (145 pg m⁻³) had the highest mean concentrations of the three hopanes analyzed in samples. Ratios of individual compound concentrations to total compound concentrations (∑15 compounds) showed the greatest daily variation for 17α(H),21β(H)-hopane (11–28%) and 17α(H),21β(H)-30-norhopane (8–20%). Diagnostic PAH concentration ratios ([IP]/[IP + BP] (range 0.30–0.45), [BaP]/[BaP + BeP] (range 0.26–0.44), [BaP]/[BP] (range 0.41–0.82), [Bb]/[Bk] (range 2.07–2.66)) in samples reflected impacts from a mixture of combustion sources consistent with greater prevalence of petroleum combustion source emissions (gasoline, diesel, kerosene, and crude oil) compared to coal or wood combustion emissions impacts at this urban site. Results from this study demonstrate that short-duration sampling for organic speciation provides temporally relevant exposure information.

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Tooth Coronal Index and Pulp/Tooth Ratio in Dental Age Estimation on Digital Panoramic Radiographs − A Comparative Study

Assessment of age through teeth is an important aspect of a new emerging science Forensic Odontology. Accurate estimation of age is required for pediatric issues, orthodontic treatments to legal matters [1]. Although skeletal methods could be used for age estimation, but variability of bone maturation is influenced by several environmental factors. Tooth development shows less variability than other developmental features and shows low variability in relation to chronological age [2]. Moreover, dental tissues are more resistant to thermal, chemical and mechanical stimuli and are less affected by endocrine diseases or nutritional variations than other tissues.

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Forensic Age Estimation by Morphometric Analysis of the Manubrium from 3D MR Images

Forensic age estimation is an important tool in anthropology for identification of human remains  [1], however, recently it has gained a lot of interest especially for age estimation of living adolescents and young adults to verify chronological age (CA) in legal proceedings  [2–4] or sports applications  [5,6]. For this purpose, skeletal, sexual and dental maturity indicators are the most frequently used biological features for estimating CA  [7], with skeletal and dental development predominantly being investigated by radiographic imaging methods  [8–10].

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Inflammatory Marker Analysis in Psoriatic Skin Under topical Phospodiesterase 4 Inhibitor Treatment

Topical formulations of the two PDE4i roflumilast and TAK-084 lead to a reduction of inflammatory markers and infiltrating cells in psoriatic lesional skin.

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ImmunoCAP cellulose displays cross-reactive carbohydrate (CCD) epitopes and can cause false-positive test results in patients with high anti-CCD IgE antibody levels

Cellulose-based IgE assays may deliver false-positive test results of up to 2 kUa/L with recombinant allergens in strongly CCD-positive patient sera due to the presence of glycoproteins in the cellulose matrix.

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Expression of Semaphorin 3E Is Suppressed in Severe Asthma

The level of a previously unknown mediator, Semaphorin 3E, is diminished in the airways of severe allergic asthmatic patients. This study suggests a potential role of Semaphorin3E in the pathogenesis of asthma severity.

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Phase 2 to Phase 3 Clinical Trial Transitions: Reasons for Success and Failure in Immunologic Diseases

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A short course of gamma-tocopherol mitigates LPS-induced inflammatory responses in humans ex vivo

Vitamin E, gamma-tocopherol (γT), possesses unique anti-inflammatory activities. A short course of γT supplementation in healthy adults reduced inflammatory cytokine production and gene expression following ex vivo LPS challenge of PBMCs.

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Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells

Follicular helper T cells (Tfh cells) are a CD4 T cell subset essential for germinal center formation and B cell responses, although their role in allergy and allergen-specific immunotherapy (AIT) is unclear. Here, we show that AIT-treated patients have a higher ratio of regulatory Tfh cells (Tfr) to follicular T cells (Tfh) and hypothesize an IL-2 dependent mechanism.

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Pulmonary Inflammation in COPD Patients with Higher Blood Eosinophil Counts

The different nature of airway inflammation in COPD patients with higher blood eosinophil counts supports the concept of eosinophilic COPD being a subgroup of patients with distinct characteristics.

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Utility of a multidisciplinary approach to pediatric hearing loss

Because management of hearing loss (HL) often requires multiple specialists, a multidisciplinary clinic, Pediatric Hearing Management Clinic, (PHMC) was established to coordinate care for children with newly diagnosed HL.

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Chronic obstructive pulmonary disease in Scottish military veterans

Introduction

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Serving military personnel have previously been shown to be more likely to smoke, and to smoke more heavily, than civilians, but there is no clear consensus as to whether in later life, as veterans, they experience a higher prevalence and mortality from COPD than do non-veterans. We examined the risk of COPD in Scottish veterans and assessed the impact of changes in military smoking.

Methods

Retrospective 30-year cohort study of 56 205 veterans born 1945–1985, and 172 741 people with no record of military service, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of COPD resulting in hospitalisation or death.

Results

There were 1966 (3.52%) cases of COPD meeting the definition in veterans, compared with 5434 (3.19%) in non-veterans. The difference was statistically significant (p=0.001) in the unadjusted model although it became non-significant after adjusting for deprivation. The highest risk was seen in the oldest (1945–1949) birth cohort and in veterans with the shortest service (Early Service Leavers). The risk was significantly reduced in veterans born from 1960, and in those with over 12 years' service.

Conclusions

Our findings are consistent with falling rates of military smoking since the 1960s, and with the reduction in smoking with longer service. The oldest veterans, and those with the shortest service, are least likely to have benefited from this, as reflected in their higher risk for COPD.

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Rehydration improves the ductility of dry bone allografts

Abstract

Processing of bone allografts improves infectious safety and allows storing bone substitutes at room temperature. The aim of this study was to compare mechanical properties of the processed Osteopure™ bone with fresh frozen bone. All the samples were pieces from femoral heads retrieved during hip arthroplasty operations. The processing includes chemical decellularization, drying and irradiation with 25 kGy. Three types of samples were tested:

1. fresh frozen thawed wet,

2. dry non-rehydrated graft

3. dry rehydrated graft.

In the 3-point bending test Young's modulus and stress at break yielded no significant difference among the 3 different sample groups. Rehydrating of the dry graft showed increased ductility in strain at break test compared with the other 2 groups (p = 0.003). In compression tests dry grafts had significantly higher maximum effective stress and apparent maximum deformation compared with the grafts of other groups (p < 0.05). Processed bone has almost similar mechanical properties compared with fresh frozen bone. However, rehydration of processed dry graft increases its ductility. These grafts may tolerate bending forces better before breakage.

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Retraction

The article, “Laryngeal Function After Radiation Therapy,” by Mauricio Gamez, Kenneth Hu, and Louis B. Harrison, originally published in the August 2015 issue of Otolaryngologic Clinics (Volume 48, Issue 4, pp. 585–599), has been retracted. Please see the Elsevier Policy on Article Withdrawal (http://ift.tt/1poHqya).

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Technological Advances in Sinus and Skull Base Surgery

Technological advances have always played a major role in the field of Rhinology and Skull Base Surgery. As minimally invasive approaches to the sinuses, orbit, and skull base were developed, pioneering surgeons relied heavily on specialized tools to access and target different anatomic reaches of the head. Since then, technology has continued to evolve in pace with our techniques and areas of focus, with a major emphasis being on multifunctional design and ergonomics. There has been a refinement in foundational tools such as microdebriders that now permit more effective drilling and are cautery enabled; enhancement in our surgical navigation systems that are providing “multimodal” information; and an explosion of bioabsorbable packing materials, including the first ever drug-eluting stent for use in the sinuses.

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Forthcoming Issues

Multidisciplinary Approach to Head and Neck Cancer

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Harnessing Technology at the Edges of Otolaryngology

The first frontal sinus surgery was described in 1750 by Runge, who performed an obliteration procedure. An external and intracranial drainage procedure for a frontal sinus mucocele was described in 1870, and in 1884, the era of trephination was born (Ogston-Luc procedure), but abandoned due to the high rate of nasofrontal duct stenosis and surgical failure. Radical ablation procedures with removal of the anterior table and mucosal stripping were introduced in 1895, but because of the significant cosmetic deformity and high failure rates, conservative procedures became de rigeur from 1905 onward.

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Contributors

SUJANA S. CHANDRASEKHAR, MD

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CME Accreditation Page

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The Operating Room of the Future Versus the Future of the Operating Room

Technological advancement in the operating room is evolving into a dynamic system mirroring that of the aeronautics industry. Through data visualization, information is continuously being captured, collected, and stored on a scalable informatics platform for rapid, intuitive, iterative learning. The authors believe this philosophy (paradigm) will feed into an intelligent informatics domain fully accessible to all and geared toward precision, cell-based therapy in which tissue can be targeted and interrogated in situ. In the future, the operating room will be a venue that facilitates this real-time tissue interrogation, which will guide in situ therapeutics to restore the state of health.

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Technological Advances in Sinus and Skull Base Surgery

OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA

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Contents

Retractionxv

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Copyright

Elsevier

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Index

Note: Page numbers of article titles are in boldface type.

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Isolation and Structure Characterization of Cytotoxic Phorbol Esters from the Seeds of Croton tiglium

Planta Med
DOI: 10.1055/s-0043-110227

Nine new and eleven known phorbol esters were isolated from an acetone extract of the seeds of Croton tiglium. Their structures were determined by extensive analysis of spectroscopic data. Eleven of these compounds were evaluated for their inhibition activity on human tumor cell lines HL-60 and lung carcinoma A549. 12-O-Tiglylphorbol-13-acetate (11), 12-O-(2-methyl)-butyrylphorbol-13-aetate (12), and 12-O-tiglylphorbol-13-isobutyrate (13) exhibited strong inhibition activity against both HL-60 and A549 cell lines with IC50 values ≤ 0.02 and ≤ 0.1 µg/mL, respectively. Compound 18 showed strong inhibition activity against the HL-60 cell line with an IC50 value of 0.02 µg/mL.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Aristolic Acid Derivatives from the Bark of Antidesma ghaesembilla

Planta Med
DOI: 10.1055/s-0043-110141

Antidesma ghaesembilla is an important medicinal and food plant in many Asian countries. Ten substances could be isolated from the dichloromethane and methanol extract: sitostenone (3), daucosterol (4), chavibetol (5), asperphenamate (6), protocatechuic acid (7), vanillic acid-4-O-β-D-glucoside (8), 1-O-β-D-glucopyranosyl-3-O-methyl-phloroglucinol (9), and aristolic acid II-8-O-β-D-glucoside (10), and two new aristolic acid derivatives, 10-amino-5,7-dimethoxy-aristolic acid II (= 6-amino-9,11-dimethoxyphenanthro[3,4-d]-1,3-dioxole-5-carboxylic acid; 1) and 5,7-dimethoxy-aristolochic acid II (= 9,11-dimethoxy-6-nitrophenantro[3,4-d]-1,3-dioxole-5-carboxylic acid; 2). Exposure to humans of some of these compounds is associated with a severe disease today known as aristolochic acid nephropathy. Therefore, the traditional usage of this plant has to be reconsidered carefully.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Examination of the superoxide/hydrogen peroxide forming and quenching potential of mouse liver mitochondria

Publication date: Available online 12 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Liam Slade, Julia Chalker, Nidhi Kuksal, Adrian Young, Danielle Gardiner, Ryan J. Mailloux
Pyruvate dehydrogenase (PDHC) and α-ketoglutarate dehydrogenase complex (KGDHC) are important sources of reactive oxygen species (ROS). In addition, it has been found that mitochondria can also serve as sinks for cellular hydrogen peroxide (H2O2). However, the ROS forming and quenching capacity of liver mitochondria has never been thoroughly examined. Here, we show that mouse liver mitochondria use catalase, glutathione (GSH), and peroxiredoxin (PRX) systems to quench ROS. Incubation of mitochondria with catalase inhibitor 3-amino-1,2,4-triazole (triazole) induced a significant increase in pyruvate or α-ketoglutarate driven O2^●−/H2O2 formation. 1-choro-2,4-dinitrobenzene (CDNB), which depletes glutathione (GSH), elicited a similar effect. Auranofin (AF), a thioredoxin reductase-2 (TR2) inhibitor which disables the PRX system, did not significantly change O2^●−/H2O2 formation. By contrast catalase, GSH, and PRX were all required to scavenging extramitochondrial H2O2. In this study, the ROS forming potential of PDHC, KGDHC, Complex I, and Complex III was also profiled. Titration of mitochondria with 3-methyl-2-oxovaleric acid (KMV), a specific inhibitor for O2^●−/H2O2 production by KGDHC, induced a~86% and ~84% decrease in ROS production during α-ketoglutarate and pyruvate oxidation. Titration of myxothiazol, a Complex III inhibitor, decreased O2^●−/H2O2 formation by ~45%. Rotenone also lowered ROS production in mitochondria metabolizing pyruvate or α-ketoglutarate indicating Complex I does not contribute to ROS production during forward electron transfer from NADH. Taken together, our results indicate that KGDHC and Complex III are high capacity sites for O2^●−/H2O2 production in mouse liver mitochondria. We also confirm that catalase plays a role in quenching either exogenous or intramitochondrial H2O2.



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Assessment of the horizontal transfer of functional genes as a suitable approach for evaluation of the bioremediation potential of petroleum-contaminated sites: a mini-review

Abstract

Petroleum sludge contains recalcitrant residuals. These compounds because of being toxic to humans and other organism are of the major concerns. Therefore, petroleum sludge should be safely disposed. Physicochemical methods which are used by this sector are mostly expensive and need complex devices. Bioremediation methods because of being eco-friendly and cost-effective overcome most of the limitations of physicochemical treatments. Microbial strains capable to degrade petroleum hydrocarbons are practically present in all soils and sediments and their population density increases in contact with contaminants. Bacterial strains cannot degrade alone all kinds of petroleum hydrocarbons, rather microbial consortium should collaborate with each other for degradation of petroleum hydrocarbon mixtures. Horizontal transfer of functional genes between bacteria plays an important role in increasing the metabolic potential of the microbial community. Therefore, selecting a suitable degrading gene and tracking its horizontal transfer would be a useful approach to evaluate the bioremediation process and to assess the bioremediation potential of contaminated sites.

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Thermodynamics of enzyme-catalyzed esterifications: I. Succinic acid esterification with ethanol

Abstract

Succinic acid (SA) was esterified with ethanol using Candida antarctica lipase B immobilized on acrylic resin at 40 and 50 °C. Enzyme activity in the reaction medium was assured prior to reaction experiments. Reaction-equilibrium experiments were performed for varying initial molalities of SA and water in the reaction mixtures. This allowed calculating the molality-based apparent equilibrium constant K _m as function of concentration and temperature. K _m was shown to depend strongly on the molality of water and SA as well as on temperature. It could be concluded that increasing the molality of SA shifted the reaction equilibrium towards the products. Water had a strong effect on the activity of the enzyme and on K _m . The concentration dependence of K _m values was explained by the activity coefficients of the reacting agents. These were predicted with the thermodynamic models Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), NRTL, and Universal Quasichemical Functional Group Activity Coefficients (UNIFAC), yielding the ratio of activity coefficients of products and reactants K _γ . All model parameters were taken from literature. The models yielded K _γ values between 25 and 115. Thus, activity coefficients have a huge impact on the consistent determination of the thermodynamic equilibrium constants K _th. Combining K _m and PC-SAFT-predicted K _γ allowed determining K _th and the standard Gibbs energy of reaction as function of temperature. This value was shown to be in very good agreement with results obtained from group contribution methods for Gibbs energy of formation. In contrast, inconsistencies were observed for K _th using K _γ values from the classical g^E-models UNIFAC and NRTL. The importance of activity coefficients opens the door for an optimized reaction setup for enzymatic esterifications.

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The efficacy of a multimodal analgesia protocol in preventing heterotopic ossification after acetabular fractures surgery

Abstract

Background Heterotopic ossification (HO) after joint surgery is always a disturbing problem for patients and surgeons. Prophylaxis is the most effective therapy. Objective To assess the efficacy and safety of a multimodal analgesia protocol that included parecoxib and celecoxib in preventing HO after acetabular fracture surgery. Setting Selecting patients from trauma registry of our hospital. Method We identified 259 patients who had acetabular fracture surgery between January 2008 and December 2014. Hundredsixty-three patients received parecoxib and celecoxib (Group A) and 96 patients received no prophylaxis (Group B). The presence of HO was assessed according to the classification of Brooker et al. at the 12 month postoperative visit. Main outcome measure The differences in HO incidence and severity between the two groups. Results 49 patients (30.0%) developed HO in the Group A and 44(45.8%) in Group B. The difference in total HO incidence between the two groups was significant (P = 0.011 < 0.05, χ² = 6.530, OR 0.508, 95% CI (0.301–0.857). Severe HO (Brooker grade III or IV) developed in 15 patients (9.2%) in Group A and 17 patients (17.7%) in Group B. Brooker grade I + II was 34(20.9%) and 27(28.1%) in each group. The difference in the severity of HO between the two Groups was significant (P = 0.008 < 0.05). Conclusion A short-term administration of parecoxib and celecoxib aids in the prevention of HO after acetabular fractures surgery.

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An evaluation of the translation of continuing education into diabetes public health care by pharmacists

Abstract

Background Pharmacists are assuming greater public health roles and partaking in continuing education to advance knowledge and skills necessary for the provision of this patient care. Objective We sought to determine what conditions in a Middle East context influence how community pharmacists actually incorporate new information into practice. Setting Community pharmacies in Qatar. Methods A continuing professional development (CPD) program regarding the management of fasting diabetes patients during Ramadan was developed and delivered. Participants then maintained a record of their patient encounters when attempting to screen fasting diabetes patients for risk and offer medication, lifestyle, and monitoring advice. Diary entries were coded using inductive methods and follow-up focus group discussion was conducted to further corroborate the thematic analysis. Main outcome measure Facilitators and barriers to care. Results Forty-one pharmacists attended the CPD program and 35 subsequently made at least one diary entry during the 3-weeks preceding and during Ramadan. One-hundred and forty-eight submitted records and the transcript of one focus group (n = 6) were analyzed. Three main factors were found to influence pharmacists' ability to engage use new knowledge and skills: situational, patient, and pharmacist. Patient reception was the overwhelming influence whereby positive interactions encouraged pharmacists to continue screening and counseling attempts, but difficult encounters were negative reinforcing stimuli in almost equal measure. Conclusion In this Middle East setting, environmental factors play a considerable role in the pharmacists' ability to engage in public health care and reinforce that continuing education for health professionals must be closely aligned with the realities of practice and purposefully considered as part of its evaluation.

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Targeted Metagenome Based Analyses Show Gut Microbial Diversity of Inflammatory Bowel Disease patients

Abstract

Inflammatory bowel disease (IBD) is a multifactorial disease including both genetic and environmental factors. We compared the diversity of intestinal microbesamong a cohort of IBD patients to study the microbial ecological effects on IBD. Fecal samples from patients were sequenced with next generation sequence technology at 16S rDNA region. With statistical tools, microbial community was investigated at different level. The gut microbial diversity of Crohn's disease (CD) patients and colonic polyp (CP) patients significantly different from each other. However, the character of ulcerative colitis (UC) patients has of both CD and CP features. The microbial community from IBD patients can be very different (CD patient) or somewhat similar (UC patients) to non-IBD patients. Microbial diversity can be an important etiological factor for IBD clinical phenotype.

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Low-temperature Synthesis of Heterostructures of Transition Metal Dichalcogenide Alloys (WxMo1–xS2) and Graphene with Superior Catalytic Performance for Hydrogen Evolution

ACS Nano

DOI: 10.1021/acsnano.7b02060

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The PTPN22 R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves’ disease in a Mexican population

Abstract

Objective

The functional PTPN22 R620W polymorphism (rs2476601) is clearly associated with susceptibility to several autoimmune diseases (ADs). However, the PTPN22 R263Q polymorphism (rs33996649) has been scarcely explored in different ADs. Here we aimed to examine the associations of the PTPN22 R620W and R263Q polymorphisms with susceptibility to or protection against rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves' disease (GD) among Mexican patients.

Methods

We conducted a case–control study including 876 patients (405 with SLE, 388 with RA, and 83 with GD) and 336 healthy control individuals. PTPN22 genotypes were determined using the TaqMan 5′ allele discrimination assay.

Results

PTPN22 R620W was associated with GD susceptibility (OR 4.3, p = 0.004), but was not associated with SLE (OR 1.8, p = 0.19). We previously demonstrated that this polymorphism is associated with RA susceptibility (OR 4.17, p = 0.00036). Moreover, PTPN22 R263Q was associated with protection against SLE (OR 0.09, p = 004) and RA (OR 0.28, p = 0.045), but was not associated with GD.

Conclusions

Our data provide the first demonstration that PTPN22 R620W confers GD susceptibility among Latin-American patients. Moreover, this is the second report documenting the association of PTPN22 R263Q with protection against SLE and RA.

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Impaired Interpretation of Others’ Behavior is Associated with Difficulties in Recognizing Pragmatic Language in Patients with Schizophrenia

Abstract

Much attention has been paid to the pragmatic language function in schizophrenia. This study of Japanese patients with schizophrenia examined the relationship between impaired interpretation of the behaviors of other people in social contexts and the ability to recognize metaphor and irony. We assessed 34 patients with schizophrenia and 34 normal subjects using first- and second-order theory of mind tasks, the Metaphor and Sarcasm Scenario Test, and the Dewey Story Test (which tests the ability to judge others' social behaviors). We compared the performance between the groups and analyzed correlations between the tasks. All tasks revealed significant deficits in the patients compared with the controls. In the patient group, metaphor comprehension was correlated with the ability to judge normal behaviors, and irony comprehension was correlated with the ability to judge abnormal behaviors, suggesting that deficits of social cognition in schizophrenia include these two types of factors associated with pragmatic language.

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A Portuguese rapid-onset dystonia-parkinsonism case with atypical features

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Expert’s comment concerning Grand Rounds case entitled “Thoracic osteotomy for Gorham-Stout disease of the spine: a case report and literature review” by C. Maillot et al., Eur Spine J: doi 10.1007/s00586-014-3613-3

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Intestinal differentiated mucinous adenocarcinoma of the endometrium with sporadic MSI high status: a case report

Abstract

Background

Intestinal differentiation of primary mucinous adenocarcinoma of the uterine corpus is exceedingly rare in comparison to the approximately 25% rate in endocervical and ovarian mucinous carcinoma. Additionally, little is known about the related genetic and epigenetic alterations, even though large-scale molecular characterisation of the different types of endometrial cancer took place in the TCGA project along the entities defined by the recent WHO classification.

Case presentation

We present a 62-year-old patient harbouring a primary mucinous carcinoma of the uterine corpus with a morphological resemblance to mucinous colorectal adenocarcinoma. The intestinal differentiation was substantiated by CDX2 and CK20 positivity in the absence of PAX8, p16, WT1, p53, ER, PgR, AFP, SALL4 and Glypican3. A high MSI status with MLH1 hypermethylation was revealed by molecular testing.

Conclusion

Intestinal differentiation of mucinous adenocarcinoma of the endometrium is a unique observation. Besides morphology, it obviously can share molecular features of sporadic MSI colorectal cancers. It can be speculated that either CDX2 positive morula formation or intestinal metaplasia of the endometrium as rare conditions might be the origin of carcinogenesis for this type II endometrial cancer. Both conditions were not detectable in this case. Of note, categorising endometrial cancers in genetic subgroups like MSI high cancers alone might lead to the integration of likewise morphologically different tumours like the case presented here with intestinal differentiation. Hence, careful genotype-phenotype correlations are warranted for studies of mucinous adenocarcinoma of the endometrium.

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Staff-line detection and removal using a convolutional neural network

Abstract

Staff-line removal is an important preprocessing stage for most optical music recognition systems. Common procedures to solve this task involve image processing techniques. In contrast to these traditional methods based on hand-engineered transformations, the problem can also be approached as a classification task in which each pixel is labeled as either staff or symbol, so that only those that belong to symbols are kept in the image. In order to perform this classification, we propose the use of convolutional neural networks, which have demonstrated an outstanding performance in image retrieval tasks. The initial features of each pixel consist of a square patch from the input image centered at that pixel. The proposed network is trained by using a dataset which contains pairs of scores with and without the staff lines. Our results in both binary and grayscale images show that the proposed technique is very accurate, outperforming both other classifiers and the state-of-the-art strategies considered. In addition, several advantages of the presented methodology with respect to traditional procedures proposed so far are discussed.

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DTNI: a novel toxicogenomics data analysis tool for identifying the molecular mechanisms underlying the adverse effects of toxic compounds

Abstract

Unravelling gene regulatory networks (GRNs) influenced by chemicals is a major challenge in systems toxicology. Because toxicant-induced GRNs evolve over time and dose, the analysis of global gene expression data measured at multiple time points and doses will provide insight in the adverse effects of compounds. Therefore, there is a need for mathematical methods for GRN identification from time-over-dose-dependent data. One of the current approaches for GRN inference is Time Series Network Identification (TSNI). TSNI is based on ordinary differential equations (ODE), describing the time evolution of the expression of each gene, which is assumed to be dependent on the expression of other genes and an external perturbation (i.e. chemical exposure). Here, we present Dose-Time Network Identification (DTNI), a method extending TSNI by including ODE describing how the expression of each gene evolves with dose, which is supposed to depend on the expression of other genes and the exposure time. We also adapted TSNI in order to enable inclusion of time-over-dose-dependent data from multiple compounds. Here, we show that DTNI outperforms TSNI in inferring a toxicant-induced GRN. Moreover, we show that DTNI is a suitable method to infer a GRN dose- and time-dependently induced by a group of compounds influencing a common biological process. Applying DTNI on experimental data from TG-GATEs, we demonstrate that DTNI provides in-depth information on the mode of action of compounds, in particular key events and potential molecular initiating events. Furthermore, DTNI also discloses several unknown interactions which have to be verified experimentally.

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The role of epigenetic modifiers in extended cultures of functional hepatocyte-like cells derived from human neonatal mesenchymal stem cells

Abstract

The development of predictive in vitro stem cell-derived hepatic models for toxicological drug screening is an increasingly important topic. Herein, umbilical cord tissue-derived mesenchymal stem cells (hnMSCs) underwent hepatic differentiation using an optimized three-step core protocol of 24 days that mimicked liver embryogenesis with further exposure to epigenetic markers, namely the histone deacetylase inhibitor trichostatin A (TSA), the cytidine analogue 5-azacytidine (5-AZA) and dimethyl sulfoxide (DMSO). FGF-2 and FGF-4 were also tested to improve endoderm commitment and foregut induction during Step 1 of the differentiation protocol, being HHEX expression increased with FGF-2 (4 ng/mL). DMSO (1%, v/v) when added at day 10 enhanced cell morphology, glycogen storage ability, enzymatic activity and induction capacity. Moreover, the stability of the hepatic phenotype under the optimized differentiation conditions was examined up to day 34. Our findings showed that hepatocyte-like cells (HLCs) acquired the ability to metabolize glucose, produce albumin and detoxify ammonia. Global transcriptional analysis of the HLCs showed a partial hepatic differentiation degree. Global analysis of gene expression in the different cells revealed shared expression of gene groups between HLCs and human primary hepatocytes (hpHeps) that were not observed between HepG2 and hpHeps. In addition, bioinformatics analysis of gene expression data placed HLCs between the HepG2 cell line and hpHeps and distant from hnMSCs. The enhanced hepatic differentiation observed was supported by the presence of the hepatic drug transporters OATP-C and MRP-2 and gene expression of the hepatic markers CK18, TAT, AFP, ALB, HNF4A and CEBPA; and by their ability to display stable UGT-, EROD-, ECOD-, CYP1A1-, CYP2C9- and CYP3A4-dependent activities at levels either comparable with or even higher than those observed in primary hepatocytes and HepG2 cells. Overall, an improvement of the hepatocyte-like phenotype was achieved for an extended culture time suggesting a role of the epigenetic modifiers in hepatic differentiation and maturation and presenting hnMSC-HLCs as an advantageous alternative for drug discovery and in vitro toxicology testing.

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Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid

Abstract

Perfluorocarboxylic acids (PFCAs) including perfluorooctanoic acid (PFOA) are environmental pollutants showing high accumulation, thermochemical stability and hepatocarcinogenicity. Peroxisome proliferator-activated receptor α is suggested to mediate their toxicities, but the precise mechanism remains unclear. Previous reports also imply a possible role of constitutive androstane receptor (CAR), a key transcription factor for the xenobiotic-induced expression of various genes involved in drug metabolism and disposition as well as hepatocarcinogenesis. Therefore, we have investigated whether PFCAs activate CAR. In wild-type but not Car-null mice, mRNA levels of Cyp2b10, a CAR target gene, were increased by PFOA treatment. PFCA treatment induced the nuclear translocation of CAR in mouse livers. Since CAR activators are divided into two types, ligand-type activators and phenobarbital-like indirect activators, we investigated whether PFCAs are CAR ligands or not using the cell-based reporter gene assay that can detect CAR ligands but not indirect activators. As results, neither PFCAs nor phenobarbital increased reporter activities. Interestingly, in mouse hepatocytes, pretreatment with the protein phosphatase inhibitor okadaic acid prevented an increase in Cyp2b10 mRNA levels induced by phenobarbital as reported, but not that by PFOA. Finally, in human hepatocyte-like HepaRG cells, PFOA treatment increased mRNA levels of CYP2B6, a CAR target gene, as did phenobarbital. Taken together, our present results suggest that PFCAs including PFOA are indirect activators of mouse and human CAR and that the mechanism might be different from that for phenobarbital. The results imply a role of CAR in the hepatotoxicity of PFCAs.

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Comments regarding “Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature”

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Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells

Abstract

Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1. The extent of triclosan metabolism by each CYP was assessed by reversed-phase high-performance liquid chromatography with online radiochemical detection. Seven isoforms were capable of metabolizing triclosan, with the order of activity being CYP1A2 > CYP2B6 > CYP2C19 > CYP2D6 ≈ CYP1B1 > CYP2C18 ≈ CYP1A1. The remaining 11 isoforms (CYP2A6, CYP2A7, CYP2A13, CYP2C8, CYP2C9, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1) had little or no activity toward triclosan. Three metabolites were detected: 2,4-dichlorophenol, 4-chlorocatechol, and 5′-hydroxytriclosan. Consistent with the in vitro screening data, triclosan was extensively metabolized in HepG2 cells overexpressing CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP2C18, and these cells were much more resistant to triclosan-induced cytotoxicity compared to vector cells, suggesting that CYP-mediated metabolism of triclosan attenuated its cytotoxicity. In addition, 2,4-dichlorophenol and 4-chlorocatechol were less toxic than triclosan to HepG2/vector cells. Conjugation of triclosan, catalyzed by human glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also occurred in HepG2/CYP-overexpressing cells and primary human hepatocytes, with a greater extent of conjugation being associated with higher cell viability. Co-administration of triclosan with UGT or SULT inhibitors led to greater cytotoxicity in HepG2 cells and primary human hepatocytes, indicating that glucuronidation and sulfonation of triclosan are detoxification pathways. Among the 18 CYP-overexpressing cell lines, an inverse correlation was observed between cell viability and the level of triclosan in the culture medium. In conclusion, human CYP isoforms that metabolize triclosan were identified, and the metabolism of triclosan by CYPs, UGTs, and SULTs decreased its cytotoxicity in hepatic cells.

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Polychlorinated biphenyls exposure-induced insulin resistance is mediated by lipid droplet enlargement through Fsp27

Abstract

Although epidemiological and experimental studies demonstrated that polychlorinated biphenyls (PCBs) lead to insulin resistance, the mechanism underlying PCBs-induced insulin resistance has remained unsolved. In this study, we examined in vitro and in vivo effects of PCB-118 (dioxin-like PCB) and PCB-138 (non-dioxin-like PCB) on adipocyte differentiation, lipid droplet growth, and insulin action. 3T3-L1 adipocytes were incubated with PCB-118 or PCB-138 during adipocyte differentiation. For in vivo studies, C57BL/6 mice were administered PCB-118 or PCB-138 (37.5 mg/kg) by intraperitoneal injection and we examined adiposity and whole-body insulin action. PCB-118 and PCB-138 significantly promoted adipocyte differentiation and increased the lipid droplet (LD) size in 3T3-L1 adipocytes. In mice, both PCBs increased adipose mass and adipocyte size. Furthermore, both PCBs induced insulin resistance in vitro and in vivo. Expression of fat-specific protein 27 (Fsp27), which is localized to LD contact sites, was increased in PCB-treated 3T3-L1 adipocytes and mice. Depletion of Fsp27 by siRNA resulted in the inhibition of LD enlargement and attenuation of insulin resistance in PCB-treated 3T3-L1 adipocytes. An anti-diabetic drug, metformin, attenuated insulin resistance in PCB-treated 3T3-L1 adipocytes through the reduced expression of Fsp27 protein and LD size. This study suggests that PCB exposure-induced insulin resistance is mediated by LD enlargement through Fsp27.

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Hepatic glucuronidation of 4- tert -octylphenol in humans: inter-individual variability and responsible UDP-glucuronosyltransferase isoforms

Abstract

4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. The purpose of this study was to assess inter-individual variability in and the possible roles of UGT isoforms in hepatic 4-tOP glucuronidation in the humans. 4-tOP glucuronidation activities in the liver microsomes and recombinant UGTs of humans were assessed at broad substrate concentrations, and kinetics were analyzed. Correlation analyses between 4-tOP and diclofenac or 4-hydroxybiphenyl activities in pooled and individual human liver microsomes were also performed. Typical CL_int values were 17.8 mL/min/mg protein for the low type, 25.2 mL/min/mg protein for the medium type, and 47.7 mL/min/mg protein for the high type. Among the recombinant UGTs (13 isoforms) examined, UGT2B7 and UGT2B15 were the most active of catalyzing 4-tOP glucuronidation. Although the K _m values of UGT2B7 and UGT2B15 were similar (0.36 and 0.42 µM, respectively), the CL_int value of UGT2B7 (6.83 mL/min/mg protein) >UGT2B15 (2.35 mL/min/mg protein). Strong correlations were observed between the glucuronidation activities of 4-tOP and diclofenac (a probe for UGT2B7) or 4-hydroxybiphenyl (a probe for UGT2B15) with 0.79–0.88 of Spearman correlation coefficient (r _s) values. These findings demonstrate that 4-tOP glucuronidation in humans is mainly catalyzed by hepatic UGT2B7 and UGT2B15, and suggest that these UGT isoforms play important and characteristic roles in the detoxification of 4-tOP.

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Systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome

Veno-venous extracorporeal membrane oxygenation (ECMO) for refractory acute respiratory distress syndrome (ARDS) is a rapidly expanding technique. We performed a systematic review and meta-analysis of the most...

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A controlled comparison of the BacT/ALERT® 3D and VIRTUO™ microbial detection systems

Abstract

The performance of the next-generation BacT/ALERT® VIRTUO™ Microbial Detection System (VIRTUO™, bioMérieux Inc., Hazelwood, MO) was compared to the BacT/ALERT® 3D Microbial Detection System (3D, bioMérieux Inc., Durham, NC) using BacT/ALERT® FA Plus (FA Plus), BacT/ALERT® PF Plus (PF Plus), BacT/ALERT® FN Plus (FN Plus), BacT/ALERT® Standard Aerobic (SA), and BacT/ALERT® Standard Anaerobic (SN) blood culture bottles (bioMérieux Inc., Durham, NC). A seeded limit of detection (LoD) study was performed for each bottle type in both systems. The LoD studies demonstrated that both systems were capable of detecting organisms at nearly identical levels [<10 colony-forming units (CFU) per bottle], with no significant difference. Following LoD determination, a seeded study was performed to compare the time to detection (TTD) between the systems using a panel of clinically relevant microorganisms inoculated at or near the LoD with 0, 4, or 10 mL of healthy human blood. VIRTUO™ exhibited a faster TTD by an average of 3.5 h, as well as demonstrated a significantly improved detection rate of 99.9% compared to 98.8% with 3D (p-value <0.05).

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Dual-responsive semi-IPN copolymer nanogels based on poly (itaconic acid) and hydroxypropyl cellulose as a carrier for controlled drug release

Abstract

Dual-responsive nanogels were prepared by polymerization of itaconic acid (IA) and copolymerization with methacrylic acid (MA) in aqueous solution of hydroxypropyl cellulose (HPC) and cross-linking with N, N′-methylenebisacrylamide (MBAm) through an easy and green process. FTIR spectroscopy, TEM, AFM, DLS and zeta potential studies confirmed the semi-interpenetrating (semi-IPN) polymer network structure of nanogels. The LCST of HPC was increased to a higher temperature than HPC's intrinsic LCST, while the presence of the MA comonomer improved the hydrophobicity of the copolymer and reduced LCST to about body temperature and suppressed the excessive nanogel aggregation. It was found that the concentration of reactants impacted the process of nanogel formation. Additionally, an increasing of cross-linker concentration led to a reduced size of HPC nanogels. Besides, the diameter of nanogels was changed with the temperature and pH. TEM and AFM photographs of copolymer nanogels illustrated that the nanoparticles with small diameters (<100 nm) were prepared. With loading the doxorubicin into the copolymer nanogels, the particle size became larger (about 150 nm) and due to the electrostatic interaction of the cationic drug with anionic particles, the zeta potential was increased. Drug release processes were followed at pH = 5.0 and 7.4 and with 37- and 41-°C temperatures, respectively. The maximum in-vitro release studies of drug-loaded nanogels, which is 91% for the pH 5.0 buffer solution at 41 °C, demonstrated the temperature- and pH-sensitivity of prepared copolymer nanogels.

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MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor

Abstract

Purpose

Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.

Methods

MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.

Results

Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.

Conclusions

MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.

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