MUC16 as a novel target for cancer therapy Aithal, Abhijit; Rauth, Sanchita; Kshirsagar, Prakash ...
Expert opinion on therapeutic targets,
08/2018, Volume:
22, Issue:
8
Journal Article
Peer reviewed
Open access
MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal ...physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.
The aim of this study was to elucidate the relative impact of three phenotypes often used to characterize obesity on perturbation of molecular pathways involved in obesity. The three obesity-related ...phenotypes are (1) body mass index (BMI), (2) amount of subcutaneous adipose tissue (SATa), and (3) amount of retroperitoneal adipose tissue (RPATa). Although it is generally accepted that increasing amount of RPATa is ‘unhealthy’, a direct comparison of the relative impact of the three obesity-related phenotypes on gene expression has, to our knowledge, not been performed previously. We have used multiple linear models to analyze altered gene expression of selected obesity-related genes in tissues collected from 19 female pigs phenotypically characterized with respect to the obesity-related phenotypes. Gene expression was assessed by high-throughput qPCR in RNA from liver, skeletal muscle and abdominal adipose tissue. The stringent statistical approach used in the study has increased the power of the analysis compared to the classical approach of analysis in divergent groups of individuals. Our approach led to the identification of key components of cellular pathways that are modulated in the three tissues in association with changes in the three obesity-relevant phenotypes (BMI, SATa and RPATa). The deregulated pathways are involved in biosynthesis and transcript regulation in adipocytes, in lipid transport, lipolysis and metabolism, and in inflammatory responses. Deregulation seemed more comprehensive in liver (23 genes) compared to abdominal adipose tissue (10 genes) and muscle (3 genes). Notably, the study supports the notion that excess amount of intra-abdominal adipose tissue is associated with a greater metabolic disease risk. Our results provide molecular support for this notion by demonstrating that increasing amount of RPATa has a higher impact on perturbation of cellular pathways influencing obesity and obesity-related metabolic traits compared to increase in BMI and amount of SATa.
In the present study we hypothesized that a higher degree of gut microbiota (GM) transfer and colonization could be reached by rectal inoculation compared to oral inoculation, which is commonly used ...in mouse studies for GM transfer. We treated C57BL/6NTac Specific Pathogen Free (SPF) mice with antibiotics and subsequently we inoculated these with GM from donor mice of the same strain by either the oral or the rectal inoculation method. 16S rRNA gene sequencing of the colon microbiota showed no difference in microbial community on account of inoculation method as determined by unweighted UniFrac distance metrics in C57BL/6NTac SPF mice. In addition, qPCR analysis on colon tissue revealed no difference in mRNA expression between the inoculation methods. Next, the SPF mice were compared to germ-free (GF)-mice to identify differences in inoculation efficacy. Whether the mice were antibiotic treated SPF or GF clearly influenced GM determined by 16S rRNA gene sequencing where the SPF mice experienced up-regulation of S24–7 (p = .0001) and a decrease in Rikenellaceae (p = .016) compared to GF mice. qPCR analysis on colon tissue revealed up-regulation in mRNA gene expression of Il6, Il10, Reg3g and transcription factor RORγt (Rorc) in GF mice compared to SPF mice on a significant level (p < .05). This gene expression profile is consistent with post colonization development of the intestinal barrier in GF mice.
•Rectal and oral inoculation is equally efficient for faecal transplantation in mice•A slightly higher inoculation efficacy can be obtained with GF mice compared to SPF mice.•Bacterial abundances and gene expressions differ between antibiotic treated and germ-free mice after inoculation
Pancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible Kras
; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon ...tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of Kras
in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.
Stimulated Brillouin scattering (BS) in optical fibers is investigated for the generation of millimeter waves (mm-waves) for radio over fiber systems. Predictions of a numerical simulation are ...compared to experimental results, and both are in good agreement with each other. With the numerical simulation, the optimum parameter for the technique is calculated. It will be shown that the optimum length of the fiber for BS depends on the signal rather than on the pump power. This gives us the opportunity to adjust the parameters for any given fiber length. The advantages and limits of the proposed method for mm-wave generation are discussed.
In this article, we aim at theoretical specification and integration of mechanisms proposed within the Social Identity Approach to Health and Well‐being. We differentiate group‐level and ...individual‐level effects of shared social identity by distinguishing three different aspects: individual identification, group identification, and individually perceived group identification. We discuss specific group‐level mechanisms (i.e., mutual social support and collective self‐efficacy) and individual level‐mechanisms (i.e., attribution and appraisal processes regarding stressors and resources) for each of the three aspects. A core conclusion is that the positive effects of shared social identity on health and well‐being crucially depend on its close relationship with social support, and that although social support is an interindividual phenomenon, it is intraindividual mechanisms—attribution and appraisal—that shape the psychological partnership between social identity and social support. Therefore, we put special emphasis on cross‐level interactions between group‐ and individual‐level mechanisms, which have been widely neglected in earlier research.
Because of the overlap between the social roles of women and followers, we predicted that people would show a bias, that is, favor female followers over male followers. To support this hypothesis, we ...conducted two studies: An explicit test of the bias using a scenario design and an implicit association test (IAT)‐based study. Both studies show that the role of an ideal follower is more strongly associated with the female gender role, which seems to be caused partly by a more communal connotation of the follower role. This effect might contribute to the underrepresentation of women in leadership positions as they are perceived to be an ideal fit for followership positions; but it may also push men away from being followers and into leadership positions.
We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of ...tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc β,β-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.
The credibility and transparency of industrial and organisational psychological (IOP) research within South Africa was recently challenged by Efendic and Van Zyl (2019). The authors briefly showed ...inconsistencies in statistical results reported by authors of the South African Journal of Industrial Psychology (SAJIP), that various studies were insufficiently powered, that best-practice guidelines for the reporting of results were mostly only partially followed and that no transparency exists with regard to the research process. They demonstrated that authors of the SAJIP may knowingly or unknowingly be engaging in questionable research practices, which directly affects the credibility of both the discipline and the journal. Furthermore, they suggested practical guidelines for both authors and the SAJIP on how this could be managed. Based on these suggestions, the authors invited prominent members of the IOP scientific community to provide scholarly commentary on their paper in order to aid in the development of 'a clear strategy on how the confidence crisis in IOP could be managed, what the role of SAJIP is in this process and how SAJIP and its contributors could proactively engage to address these issues'. Seven members of the editorial board and two international scholars provided commentaries in an attempt to further the debate about the nature, causes, consequences and management of the credibility crisis within the South African context. The purpose of this final rebuttal article was to summarise and critically reflect on the commentaries of the nine articles to advance the debate on the confidence crisis within the South African IOP discipline.
PDF
