Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Dynamic altruistic cooperation within breast tumors.

BACKGROUND: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance. METHODS: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells. RESULTS: Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKß. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit. CONCLUSIONS: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.

Use of tongue base palpation among oral healthcare providers: Cross-sectional survey.

OBJECTIVES: To assess the use of tongue base palpation during cancer screening exams by Oral Healthcare Providers (OHPs) and explore attitudes about (1) the usefulness of oral cancer screening (OCS) in detecting early, asymptomatic lesions and (2) routine OCS of the general population. STUDY DESIGN: Survey study. SETTING: Private and hospital-based clinical practices of OHPs located in Massachusetts and Connecticut, United States. METHODS: An anonymous, online 9-item survey assessing beliefs and practice patterns about cancer screening exams was distributed to OHPs with practices in Massachusetts and Connecticut from August 2020 to June 2021. Data were analyzed using chi-square tests and Pearson correlations. Statistically significant levels were established at P < .050. RESULTS: One hundred seventy-one responses were analyzed (response rate 17 %). Tongue base palpation was performed as part of a routine cancer screening exam by 55 % of otolaryngologists, 34 % of dentists and 29 % of OMFS (P = .030). Providers who palpated the tongue base were also more likely to use palpation as an exam technique in the tonsils (r = 0.52 [95 % CI 0.40-0.62]; P < .001) among other intra-and extra-oral anatomical subsites. Almost all dentists (92 %) and OMFS (98 %) but only 58 % of otolaryngologists considered OCS useful for detection of early, asymptomatic malignant lesions in the oral cavity (P < .001). CONCLUSIONS: While tongue base palpation can detect oropharyngeal cancers in a pre-symptomatic stage, it is underutilized during routine cancer screening exams. Considering the rising incidence of oropharyngeal cancer, tongue base palpation should be established as a routine part of cancer screening by OHPs.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

The path towards herd immunity: Predicting COVID-19 vaccination uptake through results from a stated choice study across six continents.

Despite unprecedented progress in developing COVID-19 vaccines, global vaccination levels needed to reach herd immunity remain a distant target, while new variants keep emerging. Obtaining near universal vaccine uptake relies on understanding and addressing vaccine resistance. Simple questions about vaccine acceptance however ignore that the vaccines being offered vary across countries and even population subgroups, and differ in terms of efficacy and side effects. By using advanced discrete choice models estimated on stated choice data collected in 18 countries/territories across six continents, we show a substantial influence of vaccine characteristics. Uptake increases if more efficacious vaccines (95% vs 60%) are offered (mean across study areas = 3.9%, range of 0.6%-8.1%) or if vaccines offer at least 12 months of protection (mean across study areas = 2.4%, range of 0.2%-5.8%), while an increase in severe side effects (from 0.001% to 0.01%) leads to reduced uptake (mean = -1.3%, range of -0.2% to -3.9%). Additionally, a large share of individuals (mean = 55.2%, range of 28%-75.8%) would delay vaccination by 3 months to obtain a more efficacious (95% vs 60%) vaccine, where this increases further if the low efficacy vaccine has a higher risk (0.01% instead of 0.001%) of severe side effects (mean = 65.9%, range of 41.4%-86.5%). Our work highlights that careful consideration of which vaccines to offer can be beneficial. In support of this, we provide an interactive tool to predict uptake in a country as a function of the vaccines being deployed, and also depending on the levels of infectiousness and severity of circulating variants of COVID-19.

The role of Popeye domain-containing protein 1 (POPDC1) in the progression of the malignant phenotype.

The Popeye domain-containing protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition and metastasis. However, POPDC1 expression is down-regulated in many types of cancer, thereby reducing its tumour-suppressive actions. This review discusses the role of POPDC1 in the progression of the malignant phenotype and highlights the broad range of benefits POPDC1 stabilisation may achieve therapeutically. Cancer stem cells (CSCs) are a key hallmark of malignancies and commonly promote treatment resistance. This article provides a comprehensive overview of CSC signalling mechanisms, many of which have been shown to be regulated by POPDC1 in other cell types, thus suggesting an additional therapeutic benefit for POPDC1-stabilising anti-cancer drugs. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

Developing a new undergraduate pharmacology core curriculum: The British Pharmacological Society Delphi Method.

The British Pharmacological Society (BPS) developed a new core curriculum for undergraduate pharmacology degrees. To do this, a modification of the Delphi Process was used. Initially, a pharmacology educator workshop was hosted to explore the core attributes expected of pharmacology graduates. We then developed these discussions into knowledge, skills, and attitudes statements and sent them, in the form of a questionnaire, to our Expert Group, which included pharmacology professionals from across academia and industry. In an iterative process, the Expert Group were asked to rank each statement according to how much they agreed it was a core graduate attribute. Where there was disagreement, statements were modified according to feedback. After three rounds of questionnaires, we had a draft core curriculum which was then finalized through a discussion workshop with the education community. In this workshop, practical aspects of curriculum implementation were discussed and the potential for the Society to develop resources to support it considered. The revised core curriculum is freely available on the Society website: https://www.bps.ac.uk/media-library-assets/library/undergraduate-pharmacology-core-curriculum. Several examples exist of the curriculum making an impact within and beyond the United Kingdom, where it has been utilized in a quality assurance context, as a tool for curriculum review and also to guide building new programs. Through a series of further expert workshops, the BPS Education and Training committee is currently developing more granular learning outcomes to accompany the core curriculum alongside recommended resources to enable delivery. In addition, this expanded curriculum is also being reviewed and updated to ensure it is fully inclusive and represents the diversity of pharmacology educators and learners worldwide.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Dysregulation of POPDC1 promotes breast cancer cell migration and proliferation.

Breast cancer subtypes such as triple-negative that lack the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2), remain poorly clinically managed due to a lack of therapeutic targets. This necessitates identification and validation of novel targets. Suppression of Popeye domain-containing protein 1 (POPDC1) is known to promote tumorigenesis and correlate to poor clinical outcomes in various cancers, and also promotes cardiac and skeletal muscle pathologies. It remains to be established whether POPDC1 is dysregulated in breast cancer, and whether overcoming the dysregulation of POPDC1 could present a potential therapeutic strategy to inhibit breast tumorigenesis. We assessed the potential of POPDC1 as a novel target for inhibiting breast cancer cell migration and proliferation. POPDC1 was significantly suppressed with reduced cell membrane localization in breast cancer cells. Furthermore, functional suppression of POPDC1 promoted breast cancer cell migration and proliferation, which were inhibited by POPDC1 overexpression. Finally, cAMP interacts with POPDC1 and up-regulates its expression in breast cancer cells. These findings suggest that POPDC1 plays a role in breast tumorigenesis and represents a potential therapeutic target or biomarker in breast cancer medicine.

POPDC1 is suppressed in human breast cancer tissues and is negatively regulated by EGFR in breast cancer cell lines.

Breast cancer molecular heterogeneity has resulted in disparities in therapeutic response and targeting of molecular subtypes of breast cancer. This necessitates identification and validation of novel therapeutic targets for breast cancer treatment. Suppression of Popeye domain-containing (POPDC) proteins is hypothesized to promote malignant cell behaviour and poor clinical outcomes in various cancers. We aimed to determine whether POPDC proteins are suppressed in human ductal carcinoma tissues and if this correlates to clinical progression and Her2 status. We further assessed if the EGFR regulated POPDC1 in breast cancer. Here we show significant suppression of POPDC1 in malignant breast cancer tissues without correlation to clinical progression. Interestingly, POPDC2 and POPDC3 were highly expressed in malignant breast tissues. Furthermore, HER2+ status significantly correlated with high POPDC2 and POPDC3, but not POPDC1 expression. We further show for the first time that low POPDC1 correlates to high EGFR expression in breast cancer tissues and that EGFR negatively regulates POPDC1 expression in MCF7, MDA231 and SKBR3 breast cancer cells. Furthermore, overexpression of POPDC1 in MCF7, MDA231 and SKBR3 cells attenuated EGF-mediated cell migration and proliferation. These findings show that POPDC1 is suppressed in breast cancer and can potentially be targeted to inhibit EGFR-mediated cell migration and proliferation.

New fossil remains of Homo naledi from the Lesedi Chamber, South Africa.

The Rising Star cave system has produced abundant fossil hominin remains within the Dinaledi Chamber, representing a minimum of 15 individuals attributed to Homo naledi. Further exploration led to the discovery of hominin material, now comprising 131 hominin specimens, within a second chamber, the Lesedi Chamber. The Lesedi Chamber is far separated from the Dinaledi Chamber within the Rising Star cave system, and represents a second depositional context for hominin remains. In each of three collection areas within the Lesedi Chamber, diagnostic skeletal material allows a clear attribution to H. naledi. Both adult and immature material is present. The hominin remains represent at least three individuals based upon duplication of elements, but more individuals are likely present based upon the spatial context. The most significant specimen is the near-complete cranium of a large individual, designated LES1, with an endocranial volume of approximately 610 ml and associated postcranial remains. The Lesedi Chamber skeletal sample extends our knowledge of the morphology and variation of H. naledi, and evidence of H. naledi from both recovery localities shows a consistent pattern of differentiation from other hominin species.

Paper-Based MicroRNA Expression Profiling from Plasma and Circulating Tumor Cells.

BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) holds great promise for monitoring metastatic progression and characterizing metastatic disease. However, leukocyte and red blood cell contamination of routinely isolated CTCs makes CTC-specific molecular characterization extremely challenging. METHODS: Here we report the use of a paper-based medium for efficient extraction of microRNAs (miRNAs) from limited amounts of biological samples such as rare CTCs harvested from cancer patient blood. Specifically, we devised a workflow involving the use of Flinders Technology Associates (FTA)® Elute Card with a digital PCR-inspired "partitioning" method to extract and purify miRNAs from plasma and CTCs. RESULTS: We demonstrated the sensitivity of this method to detect miRNA expression from as few as 3 cancer cells spiked into human blood. Using this method, background miRNA expression was excluded from contaminating blood cells, and CTC-specific miRNA expression profiles were derived from breast and colorectal cancer patients. Plasma separated out during purification of CTCs could likewise be processed using the same paper-based method for miRNA detection, thereby maximizing the amount of patient-specific information that can be derived from a single blood draw. CONCLUSIONS: Overall, this paper-based extraction method enables an efficient, cost-effective workflow for maximized recovery of small RNAs from limited biological samples for downstream molecular analyses.

Ring-Shaped Leiomyoma of the Ciliary Body.

PURPOSE: Ciliary body mesectodermal leiomyoma is a rare, benign smooth muscle tumor that typically presents in women in the second to fourth decade of life. The diagnosis is typically based on clinical color, funduscopic appearance, transillumination properties, and B-scan ultrasonography. METHODS: We present a patient with a 360° ciliary body mass with transillumination and ultrasonographic properties consistent with a ring melanoma. RESULTS: This case emphasizes the difficulty in differentiating the benign leiomyoma from similar appearing malignant tumors such as melanoma. CONCLUSION: The eye was enucleated and the diagnosis was ring-shaped leiomyoma.

POPDC proteins as potential novel therapeutic targets in cancer.

Popeye domain-containing (POPDC) proteins are a novel class of cAMP-binding molecules that affect cancer cell behaviour and correlate with poor clinical outcomes. They are encoded by the POPDC genes POPDC1, POPDC2, and POPDC3. The deletion of POPDC genes and the suppression of POPDC proteins correlate with enhanced cancer cell proliferation, migration, invasion, metastasis, drug resistance, and poor patient survival in various human cancers. Overexpression of POPDC proteins inhibits cancer cell migration and invasion in vitro. POPDC proteins present promising anticancer therapeutic targets and here we review their roles in promoting cancer progression and highlight their potential as anticancer therapeutic targets.

Practice patterns of cataract surgeons at academic medical centers for the management of inadequate capsule support for intracapsular or sulcus intraocular lens placement during cataract surgery.

PURPOSE: To determine practice patterns with regard to intraocular lens (IOL) placement during cataract surgery when there is inadequate capsule support for intracapsular or sulcus IOL placement. SETTING: Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA. DESIGN: Cross-sectional study of anonymous survey results. METHODS: An online survey was e-mailed to the coordinators of all Accreditation Council for Graduate Medical Education-accredited ophthalmology residency programs with a request to forward to all faculty who perform cataract surgery. RESULTS: Sixty-seven (57.2%) of 117 confirmed survey recipients participated. Thirty-six (62.1%) said they felt comfortable placing scleral-fixated posterior chamber IOLs (PC IOLs) independently. Faced with inadequate capsule support, 58.6% would place a primary anterior chamber IOL (AC IOL), 29.3% would place a primary scleral-fixated PC IOL, and 5.3% would leave the patient aphakic for secondary scleral-fixated PC IOL placement. Surgeons not comfortable placing scleral-fixated PC IOLs were most likely to choose primary AC IOLs (77.3%). Surgeons comfortable placing scleral-fixated PC IOLs were more evenly divided between primary AC IOLs (47.2%) and scleral-fixated PC IOLs (41.7%). Among surgeons who favored primary scleral-fixated PC IOLs, 63.7% cited a decreased risk for long-term complications as their reason for IOL choice; 50.0% of surgeons who favored primary AC IOLs cited avoidance of a second surgery. CONCLUSIONS: In general, primary AC IOL placement was preferred in the setting of inadequate capsule support, although less so among surgeons who were comfortable placing scleral-fixated PC IOLs. Lack of comfort with scleral-fixated PC IOL placement suggests a potential unmet training need in residency and fellowship programs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.