In situ quantitative bioanalysis of monomethyl auristatin E-conjugated antibody-drug conjugates by flow cytometry

Publication date: 30 July 2018
Source:European Journal of Pharmaceutical Sciences, Volume 120
Author(s): Wen-Bin Zhao, Chi-Xiao Qiu, Ying Shen, Wen-Hui Liu, Jie Zhou, Ying-Chun Xu, Zhan Zhou, Shu-Qing Chen
Antibody-drug conjugates (ADCs) consist of cytotoxic agents covalently conjugated to monoclonal antibodies that substantially improve antitumour activity and reduce systemic toxicity. With the growing number of ADCs in clinical applications, more accurate bioanalysis data are urgently needed to facilitate the development and rational use of ADCs. Herein, we used antigen-positive cells as antigen carriers and ofatumumab (OFA-HL) and ofatumumab-based ADC (OFA-HL-MMAE) as examples to establish a new ligand-binding assay (LBA) method based on flow cytometry. We proved that the new method met the required analytical performance criteria and the lower limit of quantitation (LOQ) was 0.2 μg/mL. In addition, the LOQ of the quantitative OFA-HL flow cytometry method was reduced to 0.025 μg/mL by choosing an optimized fluorescent antibody, which indicated that the LOQ of the new method can be improved. What's more, the new method showed good stability and specificity when we used it to determine the concentrations of OFA-HL and OFA-HL-MMAE in mouse serum. During the bioanalysis of ADCs, various factors should be considered. Therefore, choosing optimal methods for ADC bioanalysis is necessary. This new method using in situ antigens not only extends the scope of application of the conventional LBA methods by avoiding the need for soluble antigens, but also improves the authenticity of ADC bioanalysis as a supplementary approach, which is valuable for developing accurate ADC assays.

Graphical abstract

https://ift.tt/2FDETwk

Solid lipid nanoparticles: Reversal of tamoxifen resistance in breast cancer

Publication date: 30 July 2018
Source:European Journal of Pharmaceutical Sciences, Volume 120
Author(s): Gamze Guney Eskiler, Gulsah Cecener, Gokhan Dikmen, Unal Egeli, Berrin Tunca
The objective of the present study was to investigate the effect of tamoxifen (Tam) loaded solid lipid nanoparticles (SLNs) on MCF7 Tam-resistant breast cancer cells (MCF7-TamR). Tam-SLNs were produced by the hot homogenization method. The characterization studies of Tam-SLNs demonstrated good physical stability with small particle size. The in vitro cytotoxicity results showed that Tam-SLNs enhanced the efficacy of Tam and reversed the acquired Tam resistance by inducing apoptosis, altering the expression levels of specific miRNA and the related apoptosis-associated target-genes in both MCF7 and MCF7-TamR cells without damaging the MCF10A control cells (p < 0.05). In conclusion, we demonstrated a molecular mechanism of the induction of apoptosis by Tam-SLNs in MCF7 and MCF7-TamR cells, and thus, we demonstrated that Tam-SLNs were more effective than Tam. The present study suggests that the use SLNs may be a potential therapeutic strategy to overcome Tam-resistance in breast cancer for clinical use.

Graphical abstract

https://ift.tt/2Kwjrgi

Low-level laser irradiation modifies the effect of hyperglycemia on adhesion molecule levels

Abstract

Endothelium plays a key role in maintaining vascular homeostasis by secreting active factors involved in many biological processes such as hemostasis, angiogenesis, and inflammation. Hyperglycemia in diabetic patients causes dysfunction of endothelial cells. Soluble fractions of adhesion molecules like sE-selectin and vascular cell adhesion molecule (sVCAM) are considered as markers of endothelial damage. The low-level laser therapy (LLLT) effectively supports the conventional treatment of vascular complications in diabetes, for example hard-to-heal wounds in patients with diabetic foot syndrome. The aim of our study was to evaluate the effect of low-energy laser at the wavelength of 635 nm (visible light) and 830 nm (infrared) on the concentration of adhesion molecules: sE-selectin and sVCAM in the supernatant of endothelial cell culture of HUVEC line. Cells were cultured under high-glucose conditions of 30 mM/L. We have found an increase in sE-selectin and sVCAM levels in the supernatant of cells cultured under hyperglycemic conditions. This fact confirms detrimental influence of hyperglycemia on vascular endothelial cell cultures. LLLT can modulate the inflammation process. It leads to a decrease in sE-selectin and sVCAM concentration in the supernatant and an increase in the number of endothelial cells cultured under hyperglycemic conditions. The influence of LLLT is greater at the wavelength of 830 nm.

https://ift.tt/2HPg3PO

The hippocampus in depth: a sublayer-specific perspective of entorhinal–hippocampal function

Publication date: October 2018
Source:Current Opinion in Neurobiology, Volume 52
Author(s): Manuel Valero, Liset Menendez de la Prida
Understanding how the brain represents events is a fundamental question in neuroscience. The entorhinal–hippocampal system is central to such representations, which are severely compromised in some neurological diseases. In spite of much progress, a comprehensive, integrated view of spatial, temporal and other aspects of episodic representation remains elusive. Here, we review recent data on the role of cell-type specific entorhinal inputs which excite deep and superficial CA1 pyramidal cells by direct and indirect pathways. We discuss how an entorhinal dialogue with deep-superficial CA1 cells can multiplex neuronal activity along theta phases and how their reactivation may be segregated during sharp-wave ripples. Thus, deep and superficial CA1 sublayers provide substrate for general hippocampal function.

Graphical abstract

https://ift.tt/2JQN7DM

Association of Circulating Tumor Cells With Radiotherapy Benefit and Survival in Early-Stage Breast Cancer

This cohort study determines whether circulating tumor cell status is associated with radiotherapeutic benefit in terms of overall, local recurrence-free, and disease-free survival in patients with early-stage breast cancer.

https://ift.tt/2rjzwhr

Disseminated Lesions in a Patient With a Medical History of Myelodysplastic Syndrome

A man in his 50s with a medical history of myelodysplastic syndrome refractory anemia with excess blasts presented with a 2-month history of nonpruritic infiltrative skin lesions on the left upper chest. What is your diagnosis?

https://ift.tt/2JQoHdx

Testing Ashkenazi Jewish Women for Breast Cancer Mutations in Genes Other Than BRCA1 and BRCA2

To the Editor Walsh et al present data on 1007 Jewish women with breast cancer who were sequenced for 23 candidate genes. There were 111 carriers of a BRCA1 or BRCA2 mutation identified, 29 carriers of a CHEK2 mutation, 1 carrier of an NBN mutation, and 1 carrier of a BRIP1 mutation. The authors use these data to support their position that use of a 23-gene panel is preferable to testing for BRCA1 and BRCA2 alone. We look at the same data and conclude that testing should be limited to BRCA1 and BRCA2.

https://ift.tt/2rj1rOt

Circulating Tumors Cells as a Biomarker of Radiation Benefit

Based on the findings of multiple prospective, randomized, phase 3 clinical trials showing improved local control and disease-free survival and the Early Breast Cancer Trialist's Collaborative Group (EBCTCG) meta-analysis showing overall survival benefit, adjuvant radiation therapy has become the standard of care after breast-conserving surgery (BCS) for patients with early-stage breast cancer. In addition, similar randomized clinical trial data and meta-analyses demonstrate the benefit of postmastectomy radiation therapy for women with axillary node–positive disease. Despite evidence of a benefit from radiation therapy in these unselected populations, no accepted biomarkers are available to predict the benefit from adjuvant radiation therapy for individual patients. In contrast, the development and proven utility of molecularly based gene expression signatures to guide decisions on the use of adjuvant systemic chemotherapy suggest that a risk-adapted, personalized biomarker strategy might also be feasible to predict benefit from radiation. OncotypeDx (Genomic Health), Prosigna (NanoString), MammaPrint (Agendia), EndoPredict (Myriad Genetics), Mammostrat (Clarient Diagnostic Services), and the Breast Cancer Index are examples of gene-expression signatures in early-stage breast cancer; several tests are used in clinical practice to predict the additional benefit of adding chemotherapy to adjuvant endocrine therapy. Studies from multiple groups developing gene expression signatures for a response to radiation therapy have been published, but none are ready for clinical adoption.

https://ift.tt/2JQpgnO

Targetable Genomic Alterations in Adult Patients With Soft-Tissue Sarcomas

This study examines the use of next-generation sequencing for identification of potentially actionable alterations in patients with soft-tissue sarcoma.

https://ift.tt/2I9fXCa

Breast Cancer With a Poor Prognosis Diagnosed After Negative Mammography Results

This study of data from the PROSPR consortium assesses the incidence of and risk factors associated with breast cancer with a poor prognosis after undergoing screening mammography with negative results.

https://ift.tt/2JS3qjH

Testing Ashkenazi Jewish Women for Breast Cancer Mutations in Genes Other Than BRCA1 and BRCA2 —Reply

In Reply Narod et al raise several concerns about our recent suggestion that women of Ashkenazi Jewish (AJ) ancestry consider comprehensive sequencing for inherited predisposition to breast and ovarian cancer. Our data led us to suggest that, given recent advances in sequencing technology and reductions in price, AJ women consider the same complete sequencing for all known breast cancer genes as women of other ancestries.

https://ift.tt/2Ifubla

Quantification of Long-term Survival Benefit in a Comparative Oncology Clinical Study

This study compares conventional hazard ratios and an alternative, clinically interpretable approach to quantify the long-term survival benefit in patients receiving chemotherapy with immunotherapy.

https://ift.tt/2JPlGdn

Neoadjuvant FOLFIRINOX and Chemoradiotherapy for Resectable Pancreatic Adenocarcinoma

This single-arm, phase 2 clinical trial evaluates the margin-negative resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy.

https://ift.tt/2rhBaQz

Blue Infusion

It was not love that endedin a conception, but a rebelcourse of the self, grown outof control into a universeof its own—new arterioles, sleekknots of veins to feed what is, in essence,more of me, transfixed beneath a bowlmy bones make of my neck, an angrylung fugitive.The treatment room todayappears a darker shade of gray, and the wallsfeel plump with picture frames of riverbeds—an unwanted reminder of a smootherpassing, the endlessness of water bodieslike itinerant souls; being, in a way, a tougher distractionfrom my body's reckless arithmetic.

https://ift.tt/2JQFwoS

Mechanochemical treatment of fly ash and de novo testing of milled fly ash

Abstract

Mechanochemical (MC) treatment has been widely proposed to degrade chlorinated organics in various matrix materials. In this study, fly ash from municipal solid waste incineration was grinded without any addition, using an all-dimensional planetary ball mill. The treated fly ash samples were characterised using X-ray diffraction, Raman spectra, scanning electron microscopy and X-ray energy-dispersive spectroscopy. The residual content of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) was monitored, as well as polycyclic aromatic hydrocarbons (PAH), a potential precursor of PCDD/F and amorphous carbon or graphite. Finally, de novo formation experiments were performed to test the chemical reactivity of the treated fly ash. The PCDD/F in milled samples was compared to those resulting from de novo tests on these same samples. The results suggest that both milling as well as de novo tests significantly alter the PCDD/F signature, suggesting substantial differences in the mechanisms of formation and destruction.

https://ift.tt/2HLTnjD

Aloysia citrodora Paláu (Lemon verbena): A review of phytochemistry and pharmacology

Publication date: 10 August 2018
Source:Journal of Ethnopharmacology, Volume 222
Author(s): Roodabeh Bahramsoltani, Pourouchista Rostamiasrabadi, Zahra Shahpiri, André M. Marques, Roja Rahimi, Mohammad Hosein Farzaei
Ethnopharmacological relevanceAloysia citrodora Paláu (Lippia citriodora Kunth), commonly known as "lemon verbena" is a medicinal plant native to South America, North Africa, and South of Europe which is used by native people for several indications such as diarrhea, flatulence, insomnia, and rheumatism.Aim of the reviewDespite the wide biological activities of lemon verbena, there is no current review summarizing medicinal properties of the plant; thus, this paper aims to discuss current state of the art regarding the phytochemistry, pharmacology, and therapeutic applications of A. citrodora considering in vitro, in vivo, and clinical studies.Materials and methodsElectronic databases including PubMed, Scifinder, Cochrane library, Scopus, and Science direct were searched with the scientific name of the plant and its synonyms, as well as the common name. All studies on the ethnobotany, phytochemistry, pharmacology, and clinical application of the plant until October 2017 were included in this review.ResultsDespite the few number of studies on the ethnopharmacology of the plant, A. citrodora is widely assessed regarding its phytochemistry and biological activities. Neral and geranial are the main ingredients of the essential oil; whereas verbascoside is the most significant component of the extract. Biological activities such as antioxidant, anxiolytic, neuroprotective, anticancer, anesthetic, antimicrobial, and sedative effects are proved in cell cultures, as well as animal studies.ConclusionsSeveral pharmacological activities have been reported for A. citrodora; however, the plant is not fully assessed regarding its safety and efficacy in human. Future well-designed human studies are essential to confirm the therapeutic benefits of this plant in clinical settings.

Graphical abstract

https://ift.tt/2FGChO6

Ethnobotany, phytochemistry and pharmacology of Arctotis arctotoides (L.f.) O. Hoffm.: A review

Publication date: 28 June 2018
Source:Journal of Ethnopharmacology, Volume 220
Author(s): Md. Moshfekus Saleh-e-In, Johannes Van Staden
Ethnopharmacological relevanceArctotis arctotoides (Asteraceae) is part of the genus Arctotis. Arctotis is an African genus of approximately 70 species that occur widely in the African continent with diverse medicinal values. This plant is used for the treatment of indigestion and catarrh of the stomach, epilepsy, topical wounds and skin disorders among the ethnic groups in South Africa and reported to have a wide spectrum of pharmacological properties.Aim of the reviewThe aim of the present review is to appraise the botany, traditional uses, phytochemistry, pharmacological potential, analytical methods and safety issues of A. arctotoides. Additionally, this review will help to fill the existing gaps in knowledge and highlight further research prospects in the field of phytochemistry and pharmacology.Materials and methodsInformation on A. arctotoides was collected from various resources, including books on African medicinal herbs and Zulu medicinal plants, theses, reports and the internet databases such as SciFinder, Google Scholar, Pubmed, Scopus, Web of Science, and Mendeley by using a combination of various meaningful keywords. This review surveys the available literature of the species from 1962 to April 2017.ResultsIn vitro and in vivo studies of the medicinal properties of A. arctotoides were reviewed. The main isolated and identified compounds were reported as sesquiterpenes, farnesol derivatives, germacranolide, guaianolides and some steroids, of which, nine were reported as antimicrobial. Monoterpenoids and sesquiterpenoids were the predominant essential oil compound classes of the leaves, flowers, stems and roots. The present review revealed potential pharmacological properties such as anti-oxidant, antibacterial, antifungal and anticancer activities of plant extracts as well as isolated compounds. Moreover, the review reports the safety profile (toxicity) of the crude extracts that had been screened on brine shrimps, rats and human cell lines.ConclusionsThe present review has focused on the phytochemistry, botany, ethnopharmacology, biological activities and toxicological information of A. arctotoides. On the basis of reported data, A. arctotoides has emerged as a good source of natural medicine for the treatment of microbial infections, skin diseases, anti-inflammatory and anticancer agents and also provides new insights for further isolation of new bioactive compounds, especially the discovery of antimicrobial, anti-inflammatory and anticancer novel therapeutic lead drug molecules. Additionally, intensive investigations regarding pharmacological properties, safety assessment and efficacy with their mechanism of action could be future research interests before starting clinical trials for medicinal practices.

Graphical abstract

https://ift.tt/2jrRA4J

Dioscorea zingiberensis C. H. Wright: An overview on its traditional use, phytochemistry, pharmacology, clinical applications, quality control, and toxicity

Publication date: 28 June 2018
Source:Journal of Ethnopharmacology, Volume 220
Author(s): Xinxin Zhang, Ming Jin, Nigatu Tadesse, Jun Dang, Tao Zhou, Hui Zhang, Sicen Wang, Zengjun Guo, Yoichiro Ito
Ethnopharmacological relevanceDioscorea zingiberensis C. H. Wright (D. zingiberensis), Dioscoreaceae, is used extensively in traditional Chinese medicines. The aim of the current review paper is to give a comprehensive overview of the traditional usage and phytochemistry of the plant. Clinical studies performed and products prepared from the plant and active principles will be mentioned. In addition a review of the taxonomy of the genus Dioscorea is given.Materials and methodsA systematic search on literature has been performed in databases like Google Scholar, Science Direct, Scifinder, Web of Science, and in Chinese databases (China Knowledge Resource Integrated, i.e., CNKI and Wanfang) including Ph.D. and M.Sc. dissertations. These from the period 1983–2016 have been searched.ResultsD. zingiberensis is an endemic plant in China widely distributed in some provinces, especially Hubei and Shaanxi. The rhizomes are the medicinal part in Dun-Ye-Guan-Xin-Ning tablets and are used for isolation of diosgenin. Steroidal saponins are believed to be the active principles. More than 70 compounds have been identified. Several of these have been tested in preclinical assays and clinical trials. A wide spectrum of biological effects including cardiovascular, anti-thrombosis, hyperlipidemia, neuroprotection, anti-inflammatory, and anthelmintic effect has been verified.ConclusionsBecause of the promising results from the investigations on the plant material of D. zingiberensis, further in depth analyses ought to be performed to evaluate its potential as either a traditional drug or a source of bioactive principle. The presently performed studies do not explain mechanism of action, pharmacokinetics (ADME properties), or toxicity. All of these topics need more elaborate investigations.

Graphical abstract

https://ift.tt/2FCF3Ed

Network pharmacology-based prediction of active compounds and molecular targets in Yijin-Tang acting on hyperlipidaemia and atherosclerosis

Publication date: 15 July 2018
Source:Journal of Ethnopharmacology, Volume 221
Author(s): A. Yeong Lee, Won Park, Tae-Wook Kang, Min Ho Cha, Jin Mi Chun
Ethnopharmacological relevanceYijin-Tang (YJT) is a traditional prescription for the treatment of hyperlipidaemia, atherosclerosis and other ailments related to dampness phlegm, a typical pathological symptom of abnormal body fluid metabolism in Traditional Korean Medicine. However, a holistic network pharmacology approach to understanding the therapeutic mechanisms underlying hyperlipidaemia and atherosclerosis has not been pursued.Aim of the studyTo examine the network pharmacological potential effects of YJT on hyperlipidaemia and atherosclerosis, we analysed components, performed target prediction and network analysis, and investigated interacting pathways using a network pharmacology approach.Materials and MethodsInformation on compounds in herbal medicines was obtained from public databases, and oral bioavailability and drug-likeness was screened using absorption, distribution, metabolism, and excretion (ADME) criteria. Correlations between compounds and genes were linked using the STITCH database, and genes related to hyperlipidaemia and atherosclerosis were gathered using the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.ResultsNetwork analysis identified 447 compounds in five herbal medicines that were subjected to ADME screening, and 21 compounds and 57 genes formed the main pathways linked to hyperlipidaemia and atherosclerosis. Among them, 10 compounds (naringenin, nobiletin, hesperidin, galangin, glycyrrhizin, homogentisic acid, stigmasterol, 6-gingerol, quercetin and glabridin) were linked to more than four genes, and are bioactive compounds and key chemicals. Core genes in this network were CASP3, CYP1A1, CYP1A2, MMP2 and MMP9. The compound-target gene network revealed close interactions between multiple components and multiple targets, and facilitates a better understanding of the potential therapeutic effects of YJT.ConclusionsPharmacological network analysis can help to explain the potential effects of YJT for treating dampness phlegm-related diseases such as hyperlipidaemia and atherosclerosis.

Graphical abstract

https://ift.tt/2joPLW9

Editorial Board

Publication date: 28 June 2018
Source:Journal of Ethnopharmacology, Volume 220





https://ift.tt/2HRx08o