Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

Building block libraries and structural considerations in the self-assembly of polyoxometalate and polyoxothiometalate systems

Inorganic metal-oxide clusters form a class of compounds that are unique in their topological and electronic versatility and are becoming increasingly more important in a variety of applications. Namely, Polyoxometalates (POMs) have shown an unmatched range of physical properties and the ability to form structures that can bridge several length scales. The formation of these molecular clusters is often ambiguous and is governed by self-assembly processes that limit our ability to rationally design such molecules. However, recent years have shown that by considering new building block principles the design and discovery of novel complex clusters is aiding our understanding of this process. Now with current progress in thiometalate chemistry, specifically polyoxothiometalates (POTM), the field of inorganic molecular clusters has further diversified allowing for the targeted development of molecules with specific functionality. This chapter discusses the main differences between POM and POTM systems and how this affects synthetic methodologies and reactivities. We will illustrate how careful structural considerations can lead to the generation of novel building blocks and further deepen our understanding of complex systems

Clinical and radiographic evaluations of healing femoral fractures managed with conventional and novel allo-cadaveric bone plates in dogs

Femoral diaphyseal fractures are usually amenable to reduction with the use of orthodox fixation implants, which in most cases are expensive and cause intense stress to the patient, hence the need for safer, new biomaterials. This study assessed the use of allo-cadaveric bone plates (CBP-A) and conventional bone plates in managing femoral fractures in dogs. A total of four 8-12 kg Nigerian indigenous dogs were randomly divided into two groups, with each consisting of a male and female dog. Sterilized osteotome wire was employed to surgically create transverse mid-shaft femoral fractures in all the dogs. The fractures in Group I dogs were managed using Vitallium-alloy bone plates and served as control, while Group II fractures were reduced and fixed using CBP-A. Clinical and radiographic assessments for three months were carried out to compare the fracture healing between the groups. Results showed an early stabilization of vital parameters with a premature attempt to use the operated limb on days 4 and 5 post-reduction in groups I and II, respectively. The radiographs revealed good fracture reduction and fixation in all the dogs with the gradual disappearance of the fracture line, as well as progressive bone remodelling as the fracture healing advanced through the sixth week. At 12 weeks, there was distinct medullary and cortical continuity in all the dogs. Therefore, the novel CBP-A used in this study has effectively provided the needed fixation stability with minimal external immobilization for the repair of dog femoral fractures; hence, it should be recommended for use

Impact of T Helper Cell Subtype on CAR-T Cell Therapy Efficacy

Background and Hypothesis: Chimeric antigen receptors (CARs) are recombinant receptors with high affinity for the target antigen. Used for tumor therapy, CARs are transduced into patient T cells. CAR-T cells specific for CD19 are used to treat B cell acute lymphoblastic leukemia (B-ALL). Cancerous B cells are destroyed by CAR-T cells in an antigen-specific manner. Currently being used in conjunction with radiation and other cancer therapies to prohibit relapse, Dr. Marco Davila of the Moffitt Cancer Center, has shown that CAR-T therapy induces long term remission and B cell aplasia. Experimental Design: In this experiment the CAR vector obtained from Dr. Davila was transduced into T helper cells cultured under varying conditions (Th0, Th9, and ThGranzyme A). B cell killing and longevity of transduced CAR-Th cells were monitored as part of the criteria for determining the most effective Th subtype for the CAR-T therapy. The target cell killing-mechanism was analyzed at the RNA level using quantitative polymerase chain reaction (qPCR) to analyze gene expression of cytotoxic molecules including granzymes A/B, perforins, Fas-FasL, and TNF-α. Th9 cells were expected to be among the most effective of the indicated subtypes due to their longevity and coordination of the immune response. Results: T cells in all conditions were effectively transduced for CAR expression, although Th9 cells demonstrated a greater proportion of cultured cells that were transduced with the CAR. QPCR results suggest that there is specification of cytotoxic programs among the culture conditions. In Th9 cells, qPCR results suggest their use of perforin and TNF-α. Ongoing studies will compare cytotoxic activity. Potential Impact: Further steps after determining the most effective culture conditions include injecting transduced Th cells of the optimized subtype into mice afflicted with BALL to assess cancer killing in vivo as well as the potential harm of the therapy to the patient

The anti-bacterial iron-restriction defence mechanisms of egg white; the potential role of three lipocalin-like proteins in resistance against Salmonella

Salmonella enterica serovar Enteritidis (SE) is the most frequently-detected Salmonella in foodborne outbreaks in the European Union. Among such outbreaks, egg and egg products were identified as the most common vehicles of infection. Possibly, the major antibacterial property of egg white is iron restriction, which results from the presence of the iron-binding protein, ovotransferrin. To circumvent iron restriction, SE synthesise catecholate siderophores (i.e. enterobactin and salmochelin) that can chelate iron from host iron-binding proteins. Here, we highlight the role of lipocalin-like proteins found in egg white that could enhance egg-white iron restriction through sequestration of certain siderophores, including enterobactin. Indeed, it is now apparent that the egg-white lipocalin, Ex-FABP, can inhibit bacterial growth via its siderophore-binding capacity in vitro. However, it remains unclear whether ex-FABP performs such a function in egg white or during bird infection. Regarding the two other lipocalins of egg white (Cal-γ and α-1-glycoprotein), there is currently no evidence to indicate that they sequester siderophores

Consumer trust and confidence in the compliance of Islamic banks

Islamic banks compete with traditional (non-Islamic) banks for customers. This article aims to provide insight into why some Muslims choose to bank with Islamic banks in Pakistan, while others do not. Specifically, it addresses the questions: to what extent are trust and confidence active influencers in the decision-making process, are they differentiated or are they one of the same? Also how does the Pakistani collective cultural context further complicate the application of these concepts? For the purposes of this article trust refers to people and their interpersonal or social relations whereas confidence concerns institutions such as banks. Drawing on interviews with Muslim consumers in Pakistan, this study provides further insight into consumer behaviour within financial services and specifically Islamic banking and contributes to our theoretical understanding of the concepts of trust and confidence

Determination of the antimicrobial susceptibility pattern of extended spectrum beta lactamase (esbl) producing and the non-esbl producing strains of Escherichia coli

Background: The extended spectrum beta lactamases producing bacteria are bacteria of great concern among Gram negative bacilli. Escherichia coli stand out as major carrier of this enzyme. The appropriate control of this resistance pattern depends on using the antimicrobial regimen of best choice. Therefore the value of the susceptibility profile of organism harboring this enzyme cannot be overemphasized.Objectives: To determine the antimicrobial susceptibility of extended spectrum beta lactamases (ESBL) producing and the non-ESBL producing strains of Escherichia coli from clinical isolates of Escherichia coli in University of Maiduguri Teaching Hospital.Methodology: Confirmed variants of Escherichia coli were screened and confirmed for ESBL possession. Subsequently, modified Kirby Bauer method was utilized to test for antibiotic susceptibility using the commercially available Oxoid single disc for some major antibiotics.Results: A total of 172 strains of Escherichia coli were identified during the study period. Out of this number; 131 were identified as ESBL positive while a total of 41 were ESBL negative. The highest sensitivity for both the ESBL positive and ESBL negative strains of Escherichia coli was observed with Imipenem followed closely by Gentamicin.Conclusion: The study reveals narrow choice of antibiotics for the ESBL positive isolates of Escherichia coli although Imipenem antibiotic still retains its sensitivity.Keywords: Cephalosporins, Resistance, Maiduguri, Nigeri

Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

Prevalence and risk factors of cervical cancer among women in an urban community of Kwara State, North Central Nigeria

Background. Cervical cancer is the second most common malig- nancy in women worldwide with a high incidence in under-devel- oped countries and Nigeria is one of these countries. This study aimed at screening for cervical cancer using Papanicolaou smear and to identify risk factors for cervical cancer among women in Olufadi community, Kwara state, North-central Nigeria. Methods. This was a cross-sectional study involving the screening of women aged 25-64 years for cervical cancer using Papanicolaou smear. Respondents were selected through systematic random sam- pling of households. Interviewer- administered questionnaire and clinical report form were also used to collect data. In addition, Pap smear samples were taken. Data was analyzed using SPSS version 15. Results. Only 10 (5.0%) respondents had positive cytology result, while the rest were normal. Of the 10 positive cytology results, 1(10.0%) was high grade squamous intraepithelial lesion (HGSIL) while the remaining 9(90.0%) were low grade squamous intraepithelial lesion (LGSIL) which corresponds to 0.5% and 4.5% of the total respondents respectively. Risk fac- tors for cervical cancer identified included coitarche, tobacco smoking, number of sexual partners and family history of cervi- cal cancer. Conclusion. The findings from this study attest to the increasing burden of cervical cancer. The high number of positive results obtained from the study coupled with the presence of risk factors was an indication of how useful regular screening will be in the early detection of cervical cancer

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe