Synthesis of Novel 6-(4-Substituted piperazine-1-yl)-9(b-D-ribofuranosyl) purine Derivatives, Which Lead to Senescence-Induced Cell Death in liver Cancer Cells

Cataloged from PDF version of article.Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N-6 were synthesized and evaluated for their cytotoxicity on Huh7, HepG2, FOCUS, Mahlavu liver, MCF7 breast, and HCT116 colon carcinoma cell lines. The purine nucleoside analogues were analyzed initially by an anticancer drug-screening method based on a sulforhodamine B assay. Two nucleoside derivatives with promising cytotoxic activities (11 and 12) were further analyzed on the hepatoma cells. The N-6-(4-Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC50 values between 5.2 and 9.2 mu M. Similar to previously described nucleoside analogues, compound 11 also interferes with cellular ATP reserves, possibly through influencing cellular kinase activities. Furthermore, the novel nucleoside analogue 11 was shown to induce senescence-associated cell death, as demonstrated by the SA beta-gal assay. The senescence-dependent cytotoxic effect of 11 was also confirmed through phosphorylation of the Rb protein by p15(INK4b) overexpression in the presence of this compound

Animal Models for Limbal Stem Cell Deficiency: A Critical Narrative Literature Review

\ua9 2024, The Author(s). This literature review will provide a critical narrative overview of the highlights and potential pitfalls of the reported animal models for limbal stem cell deficiency (LSCD) and will identify the neglected aspects of this research area. There exists significant heterogeneity in the literature regarding the methodology used to create the model and the predefined duration after the insult when the model is supposedly fully fit for evaluations and/or for testing various therapeutic interventions. The literature is also replete with examples wherein the implementation of a specific model varies significantly across different studies. For example, the concentration of the chemical, as well as its duration and technique of exposure in a chemically induced LSCD model, has a great impact not only on the validity of the model but also on the severity of the complications. Furthermore, while some models induce a full-blown clinical picture of total LSCD, some are hindered by their ability to yield only partial LSCD. Another aspect to consider is the nature of the damage induced by a specific method. As thermal methods cause more stromal scarring, they may be better suited for assessing the anti-fibrotic properties of a particular treatment. On the other hand, since chemical burns cause more neovascularisation, they provide the opportunity to tap into the potential treatments for anti-neovascularisation. The animal species (i.e., rats, mice, rabbits, etc.) is also a crucial factor in the validity of the model and its potential for clinical translation, with each animal having its unique set of advantages and disadvantages. This review will also elaborate on other overlooked aspects, such as the anaesthetic(s) used during experiments, the gender of the animals, care after LSCD induction, and model validation. The review will conclude by providing future perspectives and suggestions for further developments in this rather important area of research

Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines

We synthesized a series of novel amide derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid and assessed their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines) with the sulforhodamine B assay. Compound 4j with 2-chloro-4-pyridinyl group in the amide part exhibited promising cytotoxic activity against all cell lines with IC50values of 1.6 μM, 3.3 μM and 1.1 μM for Huh7, MCF7 and HCT116 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G1 phase as an indicator of apoptotic cell death induction. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-carboxamide derivatives may possess potential in the design of more potent compounds for intervention with cancer cell proliferation. © 2014 Elsevier Masson SAS

Spatial variability of precipitation regimes over Turkey

Turkish annual precipitation regimes are analysed to provide large-scale perspective and redefine precipitation regions. Monthly total precipitation data are employed for 107 stations (1963–2002). Precipitation regime shape (seasonality) and magnitude (size) are classified using a novel multivariate methodology. Six shape and five magnitude classes are identified, which exhibit clear spatial structure. A composite (shape and magnitude) regime classification reveals dominant controls on spatial variability of precipitation. Intra-annual timing and magnitude of precipitation is highly variable due to seasonal shifts in Polar and Subtropical zones and physiographic factors. Nonetheless, the classification methodology is shown to be a powerful tool that identifies physically-interpretable precipitation regions: (1) coastal regimes for Marmara, coastal Aegean, Mediterranean and Black Sea; (2) transitional regimes in continental Aegean and Southeast Anatolia; and (3) inland regimes across central and Eastern Anatolia. This research has practical implications for understanding water resources, which are under ever growing pressure in Turkey

Modeling resilience and sustainability in ancient agricultural systems

The reasons why people adopt unsustainable agricultural practices, and the ultimate environmental implications of those practices, remain incompletely understood in the present world. Archaeology, however, offers unique datasets on coincident cultural and ecological change, and their social and environmental effects. This article applies concepts derived from ecological resilience thinking to assess the sustainability of agricultural practices as a result of long-term interactions between political, economic, and environmental systems. Using the urban center of Gordion, in central Turkey, as a case study, it is possible to identify mismatched social and ecological processes on temporal, spatial, and organizational scales, which help to resolve thresholds of resilience. Results of this analysis implicate temporal and spatial mismatches as a cause for local environmental degradation, and increasing extralocal economic pressures as an ultimate cause for the adoption of unsustainable land-use practices. This analysis suggests that a research approach that integrates environmental archaeology with a resilience perspective has considerable potential for explicating regional patterns of agricultural change and environmental degradation in the past

Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis

Cataloged from PDF version of article.Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism

Full Spectrum Archaeology

Full Spectrum Archaeology (FSA) is an aspiration stemming from the convergence of archaeology’s fundamental principles with international heritage policies and community preferences. FSA encompasses study and stewardship of the full range of heritage resources in accord with the full range of associated values and through the application of treatments selected from the full range of appropriate options. Late modern states, including British Columbia, Canada, nominally embrace de jure heritage policies consonant with international standards yet also resist de facto heritage management practice grounded in professional ethics and local values and preferences. In response, inheritor communities and their allies in archaeology are demonstrating the benefits of FSA and reclaiming control over cultural heritage. Archaeology and heritage management driven by altruistic articulation of communal, educational, scientific and other values further expose shortcomings and vulnerabilities of late modern states as well as public goods in and from FSA

Understanding Change in Romantic Relationship Expectations of International Female Students from Turkey

In the light of grounded theory, the authors explored change in romantic relationship expectations of international students. Twelve female graduate students from Turkey were interviewed and several themes were identified explaining the presence and absence of change in participants’ attitudes toward romantic relationships. The findings are discussed in relation to acculturation and direction for future research is presented