Consumerist views have increased in English higher education. At the same time, the wellbeing of university students is of growing concern. Some research suggests that consumerist views amongst ...students link to lower wellbeing and achievement. This prompted the current paper which speculates that the concept of autonomy (as depicted in self-determination theory) might provide a useful lens through which to analyse consumerist attitudes in UK higher education and their possible effects on students. Self-determination theory posits that people are fulfilled and have optimal motivation when their basic needs for competence, relatedness and autonomy are met. These three basic needs are complementary. Each could provide a lens for examining the facilitators or barriers to optimal motivation within higher education. This paper focuses on autonomy and explores possible links between a consumerist orientation and student wellbeing and achievement in English universities. Using self-determination theory, autonomy-enhancing ways of framing policy and managing the student experience and teaching and learning are outlined. The concept of autonomy offers a useful framework for potential enhancement of student motivation and wellbeing at policy, institutional and programme levels. Further empirical work could usefully explore and refine the hypotheses advanced.
Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of ...suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
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•CD276/B7-H3 is broadly overexpressed in both cancer cells and tumor vasculature•Both angiogenic and non-angiogenic tumor vasculature express CD276•Anti-CD276-drug conjugates display potent anti-tumor and anti-metastatic activity•Pyrrolobenzodiazepine dimers are optimal warheads for targeting tumor vasculature
Seaman et al. show that CD276 is broadly overexpressed in cancer cells and tumor vascular cells and demonstrate anti-CD276-drug conjugates as promising anti-cancer reagents. The drug selected for conjugation is important because tumor vascular cells can be resistant to a drug to which tumor cells are sensitive.
Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are ...inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.
Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and "virtual" biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed ...circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment.
Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined.
CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM.
Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.
Although nonmalignant stromal cells facilitate tumor growth and can occupy up to 90% of a solid tumor mass, better strategies to exploit these cells for improved cancer therapy are needed. Here, we ...describe a potent MMAE-linked antibody-drug conjugate (ADC) targeting tumor endothelial marker 8 (TEM8, also known as ANTXR1), a highly conserved transmembrane receptor broadly overexpressed on cancer-associated fibroblasts, endothelium, and pericytes. Anti-TEM8 ADC elicited potent anticancer activity through an unexpected killing mechanism we term DAaRTS (drug activation and release through stroma), whereby the tumor microenvironment localizes active drug at the tumor site. Following capture of ADC prodrug from the circulation, tumor-associated stromal cells release active MMAE free drug, killing nearby proliferating tumor cells in a target-independent manner. In preclinical studies, ADC treatment was well tolerated and induced regression and often eradication of multiple solid tumor types, blocked metastatic growth, and prolonged overall survival. By exploiting TEM8+ tumor stroma for targeted drug activation, these studies reveal a drug delivery strategy with potential to augment therapies against multiple cancer types.
Summary Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with ...adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine on days 1 and 8 every 21 days, for up to eight cycles) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00939848 , and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 37% vs 13 21%; p=0·05), diarrhoea (eight 13% vs two 3%; p=0·05); platelet count decreased (ten 16% vs four 6%; p=0·09), white blood cell decreased (15 24% vs seven 11%; p=0·06) and fatigue (16 24% vs seven 11%; p=0·04). Interpretation Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Funding Cancer Research UK and AstraZeneca Pharmaceuticals.
While an increasing awareness of the economic, legal, emotional, social, and physical precarity of LGBTQ+ people has sparked new laws, policies, and medical and social services, their epistemic needs ...are just as urgent. For many decades, young people growing up in the United States have been systematically denied access to LGBTQ+ histories, knowledges, and older adults through homophobic and transphobic gatekeeping within education, community, and family networks. As a result, LGBTQ+ folks come of age in relative social isolation, lacking tools to understand their experiences within broader sociohistorical contexts and recognition from others as valuable sources of knowledge. In this article, we explore the complexities of epistemic care as relational work designed to counter legacies of injustice through The LGBTQ+ Intergenerational Dialogue Project. The project—a partnership between an LGBTQ+ community center, an art and design college, and a public research university—brings together racially, socioeconomically, and gender-diverse cohorts of LGBTQ+ younger (eighteen to twenty-nine years old) and older adults (sixty-two to eighty-four years old) for dialogue, art making, and shared meals. Over time, it has evolved as a collaborative hybrid pedagogical/research experiment in which participants become partners in education, community formation, and knowledge production. Interweaving ethnographic narrative from dialogues with theoretical discussion, we connect our work to earlier feminist and gay liberation consciousness-raising practices (1960s–80s) and feminist and queer scholarship on care ethics in both education and research methodologies to think about epistemic justice work as a form of collective self-care.
The health of the majority of South Africa's population is seriously threatened by hunger and micronutrient deficiency, with impaired immune response a real threat, which the current SARSCoV-2 virus ...pandemic has highlighted. Traditional household food-processing techniques can, amongst other advantages, increase nutrient bioavailability in affordable staple foods and hence provide a way, in part, to alleviate malnutrition for food-insecure communities. In this way, immune defence and pathogen resilience of the food insecure could be enhanced so that they can better survive both COVID-19 and future threats.
The Advanced Placement Teacher Investment Program in Indiana (AP-TIP IN) program trains teachers to prepare students for college with rigorous math, science, and English coursework using the College ...Board Advanced Placement Program®. The program's goals are to increase enrollment in math, science, and English Advanced Placement® courses, and increase the number of qualifying scores on AP® exams; subsequently, improved performance in these exams should lead to better postsecondary outcomes. We use comparative interrupted time series models to compare program schools and matched comparison schools and find that AP-TIP IN schools increased the proportion of students taking and passing AP exams, while post-secondary outcomes were similar to matched comparison schools.
Purpose
Our aims are to determine levels of circulating cellular and protein biomarkers in hepatocellular carcinoma (HCC) patients and to analyse any relationships with clinical parameters.
Methods
...Fifty-four consenting patients were recruited. Circulating tumour cells (CTCs) were enumerated (by CellSearch) and characterised via filtration by isolation by size of epithelial tumour cells (ISET) with downstream immunohistochemistry (IHC). Glypican-3 (GPC3) expression in tumour biopsies and CTCs (by IHC) was compared, and levels of circulating caspase-cleaved and full-length cytokeratin 18 (CK18, measured using M30 and M65 ELISAs) were examined as a putative prognostic factor and marker of tumour burden.
Results
CTCs were identified in 14 out of 50 (28 %) patients by CellSearch and in 19 out of 19 (100 %) patients by ISET. The presence of GPC3-positive CTCs by ISET was 100 % concordant with the presence of GPC3-positive cells in the original tumour (
n
= 5). No statistically significant correlations were observed between CTC number and clinical characteristics, although trends were noted between CTC subtypes, Child–Pugh score and tumour node metastasis stage. Serum M30 and M65 levels (as continuous variables) significantly correlated with overall survival (OS) in a univariate analysis (
p
= 0.003 and
p
< 0.001, respectively); M65 levels remained statistically significant in a multivariate analysis (
p
= 0.029).
Conclusions
This is the first study to detect GPC3-positive CTCs in HCC, important for drug development with this target. The significant association of circulating CK18 with OS in HCC further exemplifies the utility of circulating biomarkers in cancer.
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