Characterisation of novel lung cancer cell lines for immuno-inhibitory markers

The present study investigates the expression of immune biomarkers, PD-L1 and HLA-1 on novel lung cancer cell lines (H838, H838-EGFR, A549, A549-ALK, HCC 827, NCI 1650, TWIT, Jacket). PD-L1 and HLA-1 characterisation were initially performed and analysed via flow cytometry. These results showed that the expression of PD-L1 and HLA-1 varies across the cell lines from high percent to low. The effect of IFNy on biomarkers expression was also investigated following a 48 hour incubation period. of the cell lines analysed the expression of PD-L1 increases with IFNy stimulation whilst HLA-1 remains relatively unchanged. Trypan blue assays for cell viability were performed, showing that when stimulated, cells were 100% viable whereas viability decreases upon IFNy exposure

Flow cytometric phenotyping of diverse human cancer cell lines for immunological biomarkers expression

The tumour microenvironment contains a variety of distinct factors that inhibit the immune system and can cause drug resistance. Some of these factors include the expression of cell surface markers which interact directly with immune cells. Cancer cells express programmed death ligand 1 (PD-L1) and reduce the expression of major-histocompatibility complex class I, death-receptors 4/5 and Fas, limiting immune-mediated cancer cell killing. Targeting these immune markers alone or in combination could potentially increase cancer cell death and improve drug efficacy. Utilising flow cytometric analysis on breast, prostate and colorectal cancer cell lines, we have found differential expression of these markers depending on the cancer type. These findings provide a platform for future work that will entail siRNA knockdown of PD-L1 to determine the tumour-intrinsic role of this ligand, in addition to combination therapies in 2D and 3D cell culture

Methoxy-phenyl groups reduce the cytotoxicity and increase the aqueous solubility of phosphonium zwitterions and salts

The ability of phosphonium cations to act as intracellular transport vectors is well-established. Previous research has demonstrated that phosphonioalkylthiosulfate zwitterions, and -thioacetylalkylphosphonium salts are useful precursors for the formation of phosphonium-functionalised gold nanoparticles and enable the nanoparticles to be transported into cells for diagnostic and therapeutic purposes. In this report we describe the synthesis and characterisation of a series of phosphonioalkylthiosulfate zwitterions, and-thioacetylalkylphosphonium salts derived from the methoxy-phenylphosphines tris(2,4,6-trimethoxyphenyl)phosphine, tris(2,6-dimethoxyphenyl)phosphine and tri(4-methoxyphenyl)phosphine. The methoxyphenyl-substituted phosphonium compounds show greater solubility in aqueous systems than the corresponding phenyl derivatives and cytotoxicity studies reveal that the compounds are significantly less toxic than the related triphenylphosphonium derivatives. The solid-state structures of the tris(2,4,6-trimethoxyphenyl)- and tris(2,6-dimethoxyphenyl)-phosphoniopropylthiosulfate zwitterions have been investigated by single crystal X-ray crystallography. The differences in the molecular packing of the compounds may account for greater solubility of these zwitterions in aqueous solutions

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

Programmed death-ligand 1 (PD-L1) is an immune checkpoint inhibitor that binds to its receptor PD-1 expressed by T cells and other immune cells to regulate immune responses; ultimately preventing exacerbated activation and autoimmunity. Many tumors exploit this mechanism by overexpressing PD-L1 which often correlates with poor prognosis. Some tumors have also recently been shown to express PD-1. On tumors, PD-L1 binding to PD-1 on immune cells promotes immune evasion and tumor progression, primarily by inhibition of cytotoxic T lymphocyte effector function. PD-1/PD-L1-targeted therapy has revolutionized the cancer therapy landscape and has become the first-line treatment for some cancers, due to their ability to promote durable anti-tumor immune responses in select patients with advanced cancers. Despite this clinical success, some patients have shown to be unresponsive, hyperprogressive or develop resistance to PD-1/PD-L1-targeted therapy. The exact mechanisms for this are still unclear. This review will discuss the current status of PD-1/PD-L1-targeted therapy, oncogenic expression of PD-L1, the new and emerging tumor-intrinisic roles of PD-L1 and its receptor PD-1 and how they may contribute to tumor progression and immunotherapy responses as shown in different oncology models

Differential interactions of Falcarinol combined with anti-tumour agents on cellular proliferation and apoptosis in human lymphoid leukaemia cell lines

Leukaemia is the most common childhood cancer, and whilst recent advances in therapy have improved survival, current treatments are still limited by their side effects. Thus, new therapies are urgently needed, this study investigated the effects of Falcarinol, a polyacetylene isolated from carrots (Daucus carota) in combination with chemotherapy agents, anti-cancer agents and other apoptosis inducers. Inhibition of cellular proliferation and induction of apoptosis were investigated in three human lymphoid Leukaemia cell lines. Cellular proliferation was determined via ATP quantification using the Cell Titer Glo assay. Induction of apoptosis was investigated using caspase 3 activity assay and confirmed by nuclear morphology using Hoechst 33342. The study demonstrated that CCRF-CEM cells failed to induce synergistic response with any of the investigated chemotherapies, but importantly no inhibition was observed either. Jurkat cells showed a significant synergistic induction of apoptosis following joint treatment with Falcarinol and a Death Receptor 5 agonist (DR5), whereas CCRF-CEM cells showed only an additive response. Conversely within MOLT-3 cells Falcarinol partially inhibited the induction of apoptosis by DR5 agonist although this failed to reach significance. However MOLT-3 cells demonstrated synergistic induction of apoptosis when Falcarinol was combined with either Bortezomib (proteosome inhibitor), or Sulforaphane (histone deacetylase inhibitor). Identification of interactions between natural bioactive compounds with anti-cancer drugs may provide new pathways to target cancerous cells. Furthermore, since some combinations enhance apoptosis but some inhibit apoptosis it may be important to consider these interactions for dietary advice during therapy

Phenotypic Plasticity in Uveal Melanoma Is Not Restricted to a Tumor Subpopulation and Is Unrelated to Cancer Stem Cell Characteristics

Purpose: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and approximately half of those diagnosed will die of metastasis. This study investigates whether UM progression is driven by a subpopulation of stem-like cells, termed “cancer stem cells” (CSCs). Methods: Expression of postulated stem cell markers aldehyde dehydrogenase (ALDH), CD44, and CD133 was analyzed in UM cell lines and primary UM short-term cultures (STCs) established from tumor samples. Additionally, the notion of a “cellular hierarchy” within UM was investigated. Finally, the phenomenon of phenotypic plasticity in response to environmental factors was explored. Results: We demonstrate that expression of ALDH, CD44, and CD133 does not select for a subpopulation of stem-like cells in either UM cell lines or UM STCs. Furthermore, there is an absence of a cellular hierarchy in cell lines and all cells in culture are able to drive tumor progression. Last, we show that established UM cell lines and UM STCs are plastic in nature and switch their phenotype in response to environmental stimuli. Conclusions: We hypothesize that this capacity to undergo phenotypic plasticity may be a consequence of neural crest lineage and renders the exploration of the CSC hypothesis extremely challenging in UM

Limitations on Civil Liability Under Rule 10b-5

In this bachelor science thesis we are going to study the salary system in the real estate agent market by comparing with other businesses and by interviewing people working in the real estate agent-business. The reason why we wanted to study the real estate business is because we thought it was strange that it is almost the sole business where you do not have any guarantee or safety despite an university education. Furthermore, we were interested in knowing why the salary system in the real estate business had not been discussed until the last couple of years. What we found out was that the present salary system is one of the most optimal for both the real estate agent and the consumer, and by comparing it to the international standard, the consumer will profit from the Swedish system. In average, an American real estate agent takes about 7% commission, and this is only for marketing the object and finding a buyer. Subsequently, a legal expert does the paperwork, and the buyer also has his or her own broker. Comparing with other businesses in Sweden, the real estate business terms of salary is bad in comparison to the degree of education. Despite that brokers mainly makes good money, the terms of salary is inferior. But with the present legislation and the interview answers we think that the present salary system is the best for broker as well as for the consumer.　 I  denna  uppsats  granskas  fastighetsmäklarens  avlöningssystem  genom  att  titta  på  andra branscher och genom att intervjua folk i branschen. Anledningen till varför vi ville granska avlöningssystemet i branschen är för att vi tyckte att det var underligt att det nästan är den enda branschen där man inte har någon sorts garanti eller säkerhet trots en eftergymnasial utbildning. Dessutom   var   vi   intresserade   av   att   veta   varför   det   inte   har   kommit   på   tal   om fastighetsmäklarbranschens lönesystem förrän på senare år. Det vi kom fram till var att det systemet som finns idag är bland de mest optimala för både mäklare och konsument och jämför man det med internationella mäklare så tjänar konsumenten på det svenska systemet, i snitt så tar en amerikansk mäklare 7% i provision och detta är enbart för att marknadsföra objektet och hitta en köpare. Sedan är det en jurist som skriver ihop alla papper och dessutom har köparen en egen mäklare också. Jämför man  med  andra branscher i  Sverige så har mäklare  också överlag  dåliga lönevilkor i jämförelse med utbildningsgrad. Trots att mäklare överlag tjänar bra pengar så har man dåliga villkor i övrigt. Men med den lagstiftning vi har idag och i och med att de intervjuer vi har gjort så tycker vi nog att det lönesystem vi har idag är det bästa för såväl mäklare som konsument

Inequalities in access to health and social care among adults with multiple sclerosis: A scoping review of the literature

Variations in access to health care are known to contribute to differences in life expectancy, morbidity and health-related quality-of-life across population subgroups. We undertook a scoping review to identify what is known about in-country variations in access to services for adults with multiple sclerosis and to identify gaps in the literature to inform future research and national policies. We searched MEDLINE, CINAHL, EMBASE, PSYCHINFO, SocINDEX and Social Science Abstracts from inception to end of December 2016 for quantitative studies which had investigated differences in access to prevention services, healthcare services, treatments and social care between inequality groups, defined using the PROGRESS-PLUS framework. A total of 4959 unique abstracts yielded 36 papers which met our eligibility criteria. Only 3 studies were cohort studies and only 4 were population-based; most were from the United States (n = 27). There were 6 studies on access to MS focused care and 6 on access to Disease Modifying drugs. There were 3 studies on access to prevention/lifestyle programmes and none on access to welfare services or information support. There were no papers examining inequalities in access for 'vulnerable' groups, such as, those with learning disability. In the available studies, there was evidence of inequalities in access to services with a trend for worse access among men, older age groups, those from lower socio-economic groups or the least educated, non-caucasians, those with mental health problems and those from rural areas. In the studies on access to disease modifying treatments, older age and lower socioeconomic status were consistently associated with a lower rate of uptake, while race and gender were not. Inequalities or disparities in access to all levels of services and treatments will need to be addressed through a strategic research agenda with an emphasis on population-based studies and development and evaluation of interventions to reduce inequality. [Abstract copyright: Copyright © 2019 Elsevier B.V. All rights reserved.