The midlife crisis has become a cliché in modern society. Since the mid-twentieth century, the term has been used to explain infidelity in middle-aged men, disillusionment with personal achievements, ...the pain and sadness associated with separation and divorce, and the fear of approaching death. This book provides a meticulously researched account of the social and cultural conditions in which middle-aged men and women began to reevaluate their hopes and dreams, reassess their relationships, and seek new forms of identity and fresh pathways to self-satisfaction. Drawing on a rich seam of literary, medical, media, and cinematic sources, as well as personal accounts, Broken Dreams explores how the crises of middle-aged men and women were shaped by increased life expectancy, changing family structures, shifting patterns of work, and the rise of individualism.
HER2-positive breast cancer (HER2+ BC) is an aggressive subtype with a poor prognosis. Although the antibody trastuzumab, which targets the HER2 growth factor receptor, has improved survival rates, ...patients often present with de novo resistance or acquire resistance after an initial response. Identifying new ways to target HER2 signaling will be critical for overcoming trastuzumab resistance. FAM83A is a novel oncogene identified by its ability to confer resistance to EGFR therapies, a receptor closely related to HER2. Moreover, a prior study identified hyper-tyrosine phosphorylated FAM83A in trastuzumab-resistant HER2+ BC. Here, we find that FAM83A expression is elevated in 36% of HER2+ BC tumors. In a panel of HER2+ BC cell lines, FAM83A expression is significantly increased in the trastuzumab-resistant derivatives relative to parental controls. shRNA-mediated ablation of FAM83A in the panel of HER2+ BC cell lines suppresses HER2+ BC cell growth in both 2D and 3D cell cultures, elevates apoptosis markers, and suppresses PI3K signaling. Growth inhibition following FAM83A knock-down, however, was independent of trastuzumab sensitivity, suggesting that FAM83A is a key signaling component in HER2+ BCs that could serve as a novel therapeutic target in both trastuzumab-resistant and trastuzumab-sensitive cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • We provide a comprehensive description of methodology for studying cellular mechanisms of tDCS. • In vivo and in vitro tDCS animal studies are contextualized by examining experimental ...methodology. • We discuss clinical tDCS at single cell, synaptic, and network levels from studies of animal tDCS.
The perennial leguminous herb
(butterfly pea) has attracted significant interest based on its agricultural and medical applications, which range from use as a fodder and nitrogen fixing crop, to ...applications in food coloring and cosmetics, traditional medicine and as a source of an eco-friendly insecticide. In this article we provide a broad multidisciplinary review that includes descriptions of the physical appearance, distribution, taxonomy, habitat, growth and propagation, phytochemical composition and applications of this plant. Notable amongst its repertoire of chemical components are anthocyanins which give
flowers their characteristic blue color, and cyclotides, ultra-stable macrocyclic peptides that are present in all tissues of this plant. The latter are potent insecticidal molecules and are implicated as the bioactive agents in a plant extract used commercially as an insecticide. We include a description of the genetic origin of these peptides, which interestingly involve the co-option of an ancestral albumin gene to produce the cyclotide precursor protein. The biosynthesis step in which the cyclic peptide backbone is formed involves an asparaginyl endopeptidase, of which in
is known as butelase-1. This enzyme is highly efficient in peptide ligation and has been the focus of many recent studies on peptide ligation and cyclization for biotechnological applications. The article concludes with some suggestions for future studies on this plant, including the need to explore possible synergies between the various peptidic and non-peptidic phytochemicals.
Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which ...inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.
Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In ...addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that harbor mesenchymal/CSC properties following OSM exposure resulted in enhanced tumorigenicity, increased metastasis, and resistance to gemcitabine. OSM induced the expression of
, Snail (
), and OSM receptor (
), engaging a positive feedback loop to potentiate the mesenchymal/CSC program. Suppression of JAK1/2 by ruxolitinib prevented STAT3-mediated transcription of
and
, as well as the emergence of a mesenchymal/CSC phenotype. Likewise, ZEB1 silencing, by shRNA-mediated knockdown, in OSM-driven mesenchymal/CSC reverted the phenotype back to an epithelial/non-CSC state. Importantly, the generation of cells with mesenchymal/CSC properties was unique to OSM, and not observed following IL6 exposure, implicating OSMR and downstream effector signaling as a distinct target in PDAC. Overall, these data demonstrate the capacity of OSM to regulate an epithelial-mesenchymal transition (EMT)/CSC plasticity program that promotes tumorigenic properties.
Therapeutic targeting the OSM/OSMR axis within the TME may prevent or reverse the aggressive mesenchymal and CSC phenotypes associated with poor outcomes in patients with PDAC.
.
The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic ...recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.
ABSTRACT
Prior studies suggest that large book-tax differences (BTDs) are associated with future earnings changes or earnings persistence. The literature has explored a number of potential ...explanations for this relation, without a clear answer emerging. To integrate the various assertions I divide total BTDs into temporary and permanent categories and hypothesize that temporary BTDs (reflected in deferred taxes) predict future changes in pretax earnings, whereas permanent BTDs predict future changes in tax expense. The results are consistent with these hypotheses. Prior studies also suggest that both types of BTDs are associated with earnings management and tax avoidance. I find evidence that tax avoidance firms have a more positive association between their BTDs and both pretax earnings changes and tax expense changes. However, I find only inconsistent evidence on the influence of earnings management on the association of the components of BTDs and future earnings changes, with results dependent on the research design. Overall, the evidence suggests that while tax avoidance and earnings management may contribute to the association between BTDs and future earnings changes, there are also more fundamental drivers of this association.
Objective The Covered vs Balloon Expandable Stent Trial (COBEST) is the first multicenter trial to investigate the patency of covered stents (CSs) and bare-metal stents (BMSs) in the treatment of ...aortoiliac arterial disease. The short-term results demonstrated that CSs were superior to BMSs in maintaining patency for TransAtlantic Inter-Society Consensus (TASC) C and D lesions at 18 months and were equivalent to BMSs for TASC B lesions. The current study was conducted to determine if the initial patency advantage of CSs over BMSs was sustained at the 5-year follow-up. Methods A retrospective post hoc analysis of COBEST was performed. Originally, 125 patients with 168 iliac arteries were prospectively enrolled and randomly assigned to receive a CS or BMS. In this study, 77 of the 125 patients (61.6%; 119 limbs) were assessed at 60 months for the primary and secondary end points, with particular attention paid to the outcomes stratified according to TASC lesion severity. The primary end point was the rate of binary stenosis or freedom from stent occlusion of the treated area, as determined by ultrasound imaging or quantitative visual angiography. Results The 5-year results of the COBEST showed that the CS had a significantly higher patency rate than the BMS at 18, 24, 48, and 60 months (95.1%, 82.1%, 79.9%, 74.7% for CS vs 73.9%, 70.9%, 63% and 62.5% for BMS; log-rank test, P = .01). On multivariate analysis, the type of stent used (hazard ratio HR, 2.797; 95% confidence interval CI, 1.471-5.318; P = .002) and the Rutherford classification (HR, 2.019; 95% CI, 1.278-3.191; P = .026) significantly affected the adjusted primary patency. On subgroup analysis, the CS showed significantly higher patency and a survival benefit compared with the BMS in TASC C and D lesions (HR, 8.639; 95% CI, 54.253-75.753; P = .003). Moreover, fewer patients received target limb revascularization in the CS group than in the BMS group (odds ratio, 2.32; 95% CI, 1.47-3.36; P = .02); however, there was no statistically significant difference in the rate of amputations between the groups. Conclusions The 5-year results of the COBEST demonstrated that the CS has an enduring patency advantage over the BMS in both the short and long terms. Furthermore, the CS showed acceptable patency rates for the treatment of more severe TASC C and D lesions, and patients who received a CS required fewer revascularization procedures. However, the choice of stent did not affect the rate of major limb amputations.
The Oxford Handbook of the History of Medicine celebrates the richness and variety of medical history around the world. In recent decades, the history of medicine has emerged as a rich and mature ...sub-discipline within history, but the strength of the field has not precluded vigorous debates about methods, themes, and sources. Bringing together over thirty international scholars, this book provides a constructive overview of the current state of these debates, and offers new directions for future scholarship. There are three sections: the first explores the methodological challenges and historiographical debates generated by working in particular historical ages; the second explores the history of medicine in specific regions of the world and their medical traditions, and includes discussion of the ‘global history of medicine’; the final section analyses, from broad chronological and geographical perspectives, both established and emerging historical themes and methodological debates in the history of medicine.
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