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"Burger, M"
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The weighty word book
Provides definitions for twenty-six vocabulary words from abasement to zealot with stories containing puns that provide mnemonic devices for remembering the definitions.
Book
Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis
Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.
Although remodelling of the extracellular matrix (ECM) is associated with the establishment of an immunosuppressive tumour microenvironment, whether the ECM can educate tumor-associated macrophage phenotypes is not known. Here, the authors examine this question using decellularized tissue models of omental metastasis from patient biopsies.
Journal Article
Weighty words, too
Provides definitions for twenty-six vocabulary words from \"aggrandizement\" to \"zany\" with stories containing puns that provide mnemonic devices for remembering the definitions.
Book
Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration
The availability of multiple datasets comprising genome-scale RNAi viability screens in hundreds of diverse cancer cell lines presents new opportunities for understanding cancer vulnerabilities. Integrated analyses of these data to assess differential dependency across genes and cell lines are challenging due to confounding factors such as batch effects and variable screen quality, as well as difficulty assessing gene dependency on an absolute scale. To address these issues, we incorporated cell line screen-quality parameters and hierarchical Bayesian inference into DEMETER2, an analytical framework for analyzing RNAi screens (
https://depmap.org/R2-D2
). This model substantially improves estimates of gene dependency across a range of performance measures, including identification of gold-standard essential genes and agreement with CRISPR/Cas9-based viability screens. It also allows us to integrate information across three large RNAi screening datasets, providing a unified resource representing the most extensive compilation of cancer cell line genetic dependencies to date.
Integrated analyses of multiple large-scale screenings can be complicated by batch effects and technical artefacts. McFarland et al. introduce DEMETER2, a hierarchical model coupled with model-based normalization, which allows the assessment of differential dependencies across genes and cell lines.
Journal Article
Strategies against Burnout and Anxiety in Medical Education – Implementation and Evaluation of a New Course on Relaxation Techniques (Relacs) for Medical Students
Burnout and stress-related mental disorders (depression, anxiety) occur in medical students and physicians with a significantly higher prevalence than in the general population. At the same time, the learning of coping mechanisms against stress is still not an integral part of medical education. In this pilot study we developed an elective course for learning relaxation techniques and examined the condition of the students before and after the course. 42 students participated in the semester courses in 2012 and 2013 as well as in a survey at the start and end of each course. The students were instructed in autogenic training (AT) and progressive muscle relaxation according to Jacobsen (PMR) with the goal of independent and regular exercising. At the beginning and the end of the semester/course the students were interviewed using standardized, validated questionnaires on burnout (BOSS-II) and anxiety (STAI-G), depression (BDI), quality of life (SF-12) and sense of coherence (SOC-L9). We compared the results of our students participating in Relacs with results from eight semester medical students (n = 88), assessed with the same questionnaires at similar points of time within their semester. Participating students showed a significant decline in cognitive and emotional burnout stress and in trait anxiety. Furthermore, they showed a reduction in state anxiety and a conspicuous decrease in mean depression. The sense of coherence increased at the same time. A comparative cohort of medical students of 8th semester students, showed lower values for the specified measurement parameters at the beginning, but showed no progressive changes. Our course introducing AT and PMR led to a significant reduction of burnout and anxiety within the participating group of medical students. Even the course attendance for just one semester resulted in significant improvements in the evaluated parameters in contrast to those students who did not attend the course.
Journal Article
Unsuccessful Subjective Well-Being Assimilation Among Immigrants: The Role of Faltering Perceptions of the Host Society
Immigrants in developed countries typically fail to assimilate in terms of their subjective well-being, meaning that their happiness and life satisfaction do not substantially increase with their length of stay or across generations, and therefore their subjective well-being remains lower than that of natives. This finding contrasts with migrants’ own expectations and the predictions of straight-line assimilation theory, along with the general improvement of immigrants’ objective living conditions with their length of stay. Using European Social Survey data, we show that the gradual development of less positive perceptions of the host country’s economic, political, and social conditions is associated with less positive subjective well-being trajectories among first generation immigrants and across migrant generations in developed European countries. This negative association is particularly strong for immigrants whose societal conditions strongly improved by migration and immigrants who arrived after childhood. However, compared with natives, the more positive societal perceptions of first-generation immigrants are associated with a subjective well-being advantage. We attribute these findings to immigrants’ growing aspirations and expectations that follow from their habituation to better conditions in their host country and fewer (more) comparisons to the inferior (better) conditions of the people in their home (host) country. Our findings suggest that delaying or decelerating the process of immigrants’ faltering societal perceptions is a promising pathway to improved subjective well-being assimilation and reduced frustration about their perceived lack of progress.
Journal Article
Treatment of Vulvar Intraepithelial Neoplasia with Topical Imiquimod
The efficacy of local treatment of vulvar intraepithelial neoplasia with imiquimod, an immune-response modifier, was tested in a double-blind, randomized trial. As compared with placebo, imiquimod cream was effective in reducing or eliminating the lesion, relieving symptoms, and clearing the lesion of human papillomavirus.
Imiquimod cream was effective in reducing or eliminating vulvar intraepithelial neoplasia, relieving symptoms, and clearing the lesion of human papillomavirus.
Surgery, the treatment of choice for vulvar intraepithelial neoplasia, removes all visible lesions, with the aim of relieving symptoms and preventing vulvar cancer.
1
However, there are limitations to surgery. The percentage of lesions with positive surgical margins ranges from 24 to 68%.
2
,
3
Recurrences are common, because surgery does not eliminate human papillomavirus (HPV), the cause of most vulvar intraepithelial neoplasia.
4
,
5
Progression is not influenced by radical excision,
4
,
6
and surgery can mutilate the vulva, thereby causing psychosexual distress.
7
–
10
Thus, alternative treatments are needed.
Vulvar intraepithelial neoplasia is caused by HPV,
11
which has prompted the use of imiquimod . . .
Journal Article
Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents
There are currently a number of licensed azole antifungal drugs; however; only 4 (namely, fluconazole, itraconazole, posaconazole, and voriconazole) are used frequently in a clinical setting for prophylaxis or treatment of systemic fungal infections. In this article, we review the pharmacokinetic interactions of these azole antifungal drugs with other coadministered agents. We describe these (2-way) interactions and the extent to which metabolic pathways and/or other supposed mechanisms are involved in these interactions. This article provides an overview of all published drug-drug interactions in humans (either healthy volunteers or patients), and on the basis of these findings, we have developed recommendations for managing the specific interactions.
Journal Article
Outcomes of second opinions in general internal medicine
To date, the outcomes of second opinions in internal medicine in terms of diagnostic yield and patient benefit have not been studied extensively. This retrospective study explores the outcomes of second opinions at a general internal medicine outpatient clinic in an academic hospital. A register of all patients referred to the general internal medicine outpatient clinic of the University Medical Center in Utrecht for a second opinion, was kept. All 173 patients referred between June 2016 and August 2018 were selected. Case records were analyzed for patient characteristics, referring doctor, chief complaint, performed investigations, follow-up time and, established diagnosis, additional diagnoses, initiated treatment and reported benefit. A new diagnosis was established in 13% of all patients. A new treatment was initiated in 56% of all patients: 91% and 51% of patients with and without a new diagnosis respectively (p < 0.001). Of all patients, 19% received an effective treatment (52% vs 14% of patients with vs without a new diagnosis, p < 0.001). Regardless of treatment, resolution or improvement of the chief complaint was achieved in 28% of all patients (52% vs 25% of patients with vs without a new diagnosis, p = 0.006). Regarding diagnostics, 23-33% of radiology, endoscopy and pathology tests performed during second opinion were a repetition of previously conducted investigations. Conventional blood tests were a repetition in 89% of cases. Median time to diagnosis was 64 days (IQR: 25-128 days) and median time to discharge was 75 days (IQR: 31-144 days). Second opinions in general internal medicine lead to the establishment of a new diagnosis in a small proportion of patients. However, the value of second opinions may not be limited to the establishment of diagnoses, as new treatments are often initiated and overall patients report improved symptomatology in 28% of cases.
Journal Article
Prevalence of potential drug–drug interactions in cancer patients treated with oral anticancer drugs
Background:
Potential drug–drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment.
Methods:
A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug–drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports).
Results:
In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42–50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54–1.78,
P
<0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12–0.52,
P
<0001) were risk factors.
Conclusion:
Potential drug–drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions.
Journal Article