Oxidative stress may be an important determinant of the severity of acute pancreatitis. One-electron reduction of oxidants generates reactive oxygen species (ROS) via redox cycling, whereas ...two-electron detoxification, e.g. by NAD(P)H:quinone oxidoreductase, does not. The actions of menadione on ROS production and cell fate were compared with those of a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy of isolated perfused murine pancreatic acinar cells. Menadione generated ROS with a concomitant decrease of NAD(P)H, consistent with redox cycling. The elevation of ROS was prevented by the antioxidant N-acetyl-l-cysteine but not by the NADPH oxidase inhibitor diphenyliodonium. DMN produced no change in reactive oxygen species per se but significantly potentiated menadione-induced effects, probably via enhancement of one-electron reduction, since DMN was found to inhibit NAD(P)H:quinone oxidoreductase detoxification. Menadione caused apoptosis of pancreatic acinar cells that was significantly potentiated by DMN, whereas DMN alone had no effect. Furthermore, bile acid (taurolithocholic acid 3-sulfate)-induced caspase activation was also greatly increased by DMN, whereas DMN had no effect per se. These results suggest that acute generation of ROS by menadione occurs via redox cycling, the net effect of which is induction of apoptotic pancreatic acinar cell death. Two-electron detoxifying enzymes such as NAD(P)H:quinone oxidoreductase, which are elevated in pancreatitis, may provide protection against excessive ROS and exert an important role in determining acinar cell fate.
Abstract Purpose The aim of this study was to test a novel dual-modality imaging system that combines full-field digital mammography (FFDM) and automated breast ultrasound (ABUS) in a single ...platform. Our Aceso system, named after the Greek goddess of healing, was specifically designed for the early detection of cancer in women with dense breast tissue. Materials and Methods Aceso was first tested using two industry standards: a CDMAM phantom as endorsed by EUREF was used to assess the FFDM images; and the CIRS 040GSE ultrasound phantom was imaged to evaluate the quality of the ABUS images. In addition, 58 women participated in a clinical trial: 51 were healthy volunteers aged between 40 and 65, while 7 were patients referred by the breast clinic, 6 of whom had biopsy-proven breast cancer. Results The CDMAM tests showed that the FFDM results were “acceptable” but fell short of “achievable” which was attributed to the low dose used. The ABUS images had good depth penetration (80 mm) and adequate axial resolution (0.5 mm) but the lateral resolution of 2 mm was judged to be too coarse. In a 42-year old volunteer with extremely dense breast tissue, the ABUS modality detected a lesion (a benign cyst) that was mammographically occult in the FFDM image. For a 73-year old patient with fatty breasts, a malignant lesion was successfully detected and co-registered in the FFDM and ABUS images. On average, each woman spent less than 11 minutes in the acquisition room. Conclusions While there is room for improvement in the quality of both the FFDM and ABUS images, Aceso has demonstrated its ability to acquire clinically meaningful images for a range of women with varying breast densities and therefore has potential as a screening device.
We tested the hypothesis that stimulation of adiponectin receptors with the synthetic agonist AdipoRon suppresses proliferation and induces apoptotic death in human high grade serous ovarian tumor ...cell lines and in ex vivo primary tumors, mediated by activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR). We determined the effect of AdipoRon on high grade serous ovarian tumor cells lines (OVCAR3, OVCAR4, A2780) and ex vivo primary tumor tissue. Western blotting analysis was performed to examine changes in activation of AMPK and mTOR signaling and flow cytometry was utilized to examine changes in cell cycle progression. Immunofluorescence of cleaved caspase-3 positive cells and flow cytometry of annexin V positive cells were used to determine changes in apoptotic response. The CyQUANT proliferation assay was used to assess cell proliferation. AdipoRon treatment increased AMPK phosphorylation (OVCAR3
P
= 0.01; A2780
P
= 0.02) but did not significantly alter mTOR activity. AdipoRon induced G1 cell cycle arrest in OVCAR3 (+ 12.1%,
P
= 0.03) and A2780 (+ 12.0%,
P
= 0.002) cells. OVCAR3 and OVCAR4 cells treated with AdipoRon underwent apoptosis based on cleaved caspase-3 and annexin V staining. AdipoRon treatment resulted in a dose dependent decrease in cell number versus vehicle treatment in OVCAR3 (−61.2%,
P
< 0.001), OVCAR4 (−79%,
P
< 0.001), and A2780 (−56.9%,
P
< 0.001). Ex vivo culture of primary tumors treated with AdipoRon resulted in an increase in apoptosis measured with cleaved caspase-3 immunohistochemistry. AdipoRon induces activation of AMPK and exhibits an anti-tumor effect in ovarian cancer cell lines and primary tumor via a mTOR-independent pathway.
Epithelial ovarian cancer (EOC) has one of the highest death to incidence ratios among all cancers. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype due to ...the lack of therapeutic options following debulking surgery and platinum/taxane‐based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)‐ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair‐deficient (HRD) HGSOCs, recent studies have observed a significant benefit in non‐HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance. Therefore, there is an urgent clinical need to understand PARPi resistance and to introduce novel combinatorial therapies to manage PARPi resistance and extend HGSOC disease‐free intervals. In a panel of HGSOC cell lines, we established matched olaparib sensitive and resistant cells. Transcriptome analysis of the matched olaparib‐sensitive vs ‐resistant cells revealed activation of the Wnt signaling pathway and consequently increased TCF transcriptional activity in PARPi‐resistant cells. Forced activation of canonical Wnt signaling in several PARPi‐sensitive cells via WNT3A reduced olaparib and rucaparib sensitivity. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA‐approved compound, pyrvinium pamoate, which has been shown to promote downregulation of β‐catenin. In both an HGSOC cell line and a patient‐derived xenograft model, we observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARP and Wnt inhibitors.
Felt understanding is a key determinant of positive inter-personal relations, but its role and potential benefits in intergroup relations have been neglected. In the first multi-study, pre-registered ...test of its intergroup effects, we manipulated intergroup felt understanding (understood vs. misunderstood by an outgroup) in six studies (N = 1195) and meta-analyzed its effects. The results in most intergroup contexts supported the prediction that feeling understood (vs. misunderstood) would lead to more positive intergroup orientations (r = 0.25) and action intentions (r = 0.12). These effects were distinct from the effects of feeling liked by an outgroup, which was also manipulated in each study. An important caveat was that the felt understanding manipulation's effect reversed when the outgroup was stereotypically low in competence, but high in warmth (older adults). Overall, the findings indicate the value of incorporating felt understanding into models of intergroup relations and how those relations can be improved.
•Does feeling understood by an outgroup affect intergroup relations?•Six studies tested the effect of intergroup felt understanding.•Felt understanding led to more positive intergroup orientations and action intentions in most contexts.•These effects were distinct from the effects of simply feeling liked by an outgroup.•The findings indicate the value of incorporating felt understanding into models of intergroup relations.
Student difficulties with the transition to writing in higher education are well documented whether from a 'study skills', an 'academic socialisation' or an 'academic literacies' perspective. In ...order to more closely examine the challenges faced by students from widening participation backgrounds and diverse routes into undergraduate study, this project focuses on first-year undergraduate experiences of developing academic literacies on an Education Studies programme at one university in England. It highlights the impact of different support and guidance within and beyond their degree programme where attempts to embed academic literacy development are part of subject modules. The paper reports the findings generated using a mixed methods interpretive approach. Questionnaires were collected at the beginning (n = 48) and end of the students' first year (n = 44), and interviews and visual data collection methods (n =19) were used at the mid-point of the academic year. Key findings highlight students' expectations of achievement on entry to university and the influence of the emotional journey of students as they begin to make progress as academic writers. Identifying, selecting and applying academic reading were an enduring concern whilst some students struggled with the digital literacy implicit in undergraduate work. Importantly, some strategies developed to support student transition to academic writing in higher education may have unintended consequences as they progress through the first year.
Accessible summary
In this article, the formative childhood and adolescent experiences of two young adults with learning disabilities, leading to their transitions from high school to university, are ...chronicled.
Their university studies, as auditing students,1 and the Campus Life program2 through which their studies were supported, also are described.
Finally, their recommendations to other young people with learning disabilities who aspire to higher education are detailed.
Benefits to people with Learning Disabilities:
It is always important to hear, and help others hear, the voices, thoughts and perspectives of people with learning disabilities, especially with respect to what they think contributes to a good life. This is the story of two young adults with learning disabilities, Heidi and Philip, studying at an advanced level, deciding on real careers and, in the process, helping the university to redefine its role in the community.
Summary
Building a meaningful and valued life for individuals with learning disabilities requires the sustained, diligent and coordinated efforts of family members, supporters, educators and the individuals themselves. In this article, the formative childhood and adolescent experiences of two young adults with learning disabilities, leading to their transitions from high school to university, are chronicled. As co‐authors with three of their university supporters, they describe their formative experiences in elementary and secondary school and the transition years that preceded university entry. Their university studies, as auditing students, and the Campus Life program, through which their studies were supported, also are described. Finally, their recommendations to other young people with learning disabilities who aspire to higher education are detailed.
Describes the Multiple Intelligence search (used by the author with 6th and 9th graders) based on Ken Macrorie's "I-Search" and Howard Gardner's theory of multiple intelligences. Describes the ...process as students conducted a search using library resources and technology; became experts on topics they are passionate about; created a professional presentation; and explored topics through multiple intelligences. (SR)
This thesis examines the consistencies of the betrothal scenes in Jane Austen's novels: Pride and Prejudice, Mansfield Park, and Emma. In each, Austen contests the expectations placed on young women ...in the late eighteenth and early nineteenth-centuries by creating independent heroines whose choices and conduct upset the family and the patriarchal society in which she lives. Austen's heroines all decline at least one undesirable marriage proposal prior to accepting one that is intellectually and emotionally satisfying. Additionally, Austen reveals every detail of the declined proposal scenes, while protecting the privacy of the successful marital matches by concealing the intimacy shared between her heroine and their heroes. Finally, this study examines the place of each betrothal, for Austen's heroines all decline proposals that are offered in confined indoor spaces and accept those that take place outdoors. Through close textual analysis and a feminist veil, Austen's ideal reality is revealed.
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