Peritumoral administration of immunomodulatory antibodies as a triple combination suppresses skin tumor growth without systemic toxicity.

BACKGROUND: Skin cancers, particularly keratinocyte cancers, are the most commonly diagnosed tumors. Although surgery is often effective in early-stage disease, skin tumors are not always easily accessible, can reoccur and have the ability to metastasize. More recently, immunotherapies, including intravenously administered checkpoint inhibitors, have been shown to control some skin cancers, but with off-target toxicities when used in combination. Our study investigated whether peritumoral administration of an antibody combination targeting PD-1, 4-1BB (CD137) and VISTA might control skin tumors and lead to circulating antitumor immunity without off-target toxicity. METHODS: The efficacy of combination immunotherapy administered peritumorally or intravenously was tested using transplantable tumor models injected into mouse ears (primary tumors) or subcutaneously in flank skin (secondary tumors). Changes to the tumor microenvironment were tracked using flow cytometry while tumor-specific, CD8 T cells were identified through enzyme-linked immunospot (ELISPOT) assays. Off-target toxicity of the combination immunotherapy was assessed via serum alanine aminotransferase ELISA and histological analysis of liver sections. RESULTS: The data showed that local administration of antibody therapy eliminated syngeneic murine tumors transplanted in the ear skin at a lower dose than required intravenously, and without measured hepatic toxicity. Tumor elimination was dependent on CD8 T cells and was associated with an increased percentage of CD8 T cells expressing granzyme B, KLRG1 and Eomes, and a decreased population of CD4 T cells including CD4+FoxP3+ cells in the treated tumor microenvironment. Importantly, untreated, distal tumors regressed following antibody treatment of a primary tumor, and immune memory prevented growth of subcutaneous flank tumors administered 50 days after regression of a primary tumor. CONCLUSIONS: Together, these data suggest that peritumoral immunotherapy for skin tumors offers advantages over conventional intravenous delivery, allowing antibody dose sparing, improved safety and inducing long-term systemic memory. Future clinical trials of immunotherapy for primary skin cancer should focus on peritumoral delivery of combinations of immune checkpoint antibodies.

Object recognition ability predicts category learning with medical images.

We investigated the relationship between category learning and domain-general object recognition ability (o). We assessed this relationship in a radiological context, using a category learning test in which participants judged whether white blood cells were cancerous. In study 1, Bayesian evidence negated a relationship between o and category learning. This lack of correlation occurred despite high reliability in all measurements. However, participants only received feedback on the first 10 of 60 trials. In study 2, we assigned participants to one of two conditions: feedback on only the first 10 trials, or on all 60 trials of the category learning test. We found strong Bayesian evidence for a correlation between o and categorisation accuracy in the full-feedback condition, but not when feedback was limited to early trials. Moderate Bayesian evidence supported a difference between these correlations. Without feedback, participants may stick to simple rules they formulate at the start of category learning, when trials are easier. Feedback may encourage participants to abandon less effective rules and switch to exemplar learning. This work provides the first evidence relating o to a specific learning mechanism, suggesting this ability is more dependent upon exemplar learning mechanisms than rule abstraction. Object-recognition ability could complement other sources of individual differences when predicting accuracy of medical image interpretation.

Global health education in high-income countries: confronting coloniality and power asymmetry.

Contemporary global health education is overwhelmingly skewed towards high-income countries (HICs). HIC-based global health curricula largely ignore colonial origins of global health to the detriment of all stakeholders, including trainees and affected community members of low- and middle-income countries. Using the Consortium of Universities for Global Health's Global Health Education Competencies Tool-Kit, we analyse the current structure and content of global health curricula in HICs. We identify two major areas in global health education that demand attention: (1) the use of a competency-based education framework and (2) the shortcomings of curricular content. We propose actionable changes that challenge current power asymmetries in global health education.

COVID-19 and the impact on blood availability and transfusion practices in low- and middle-income countries.

BACKGROUND/CASE STUDIES: The coronavirus disease 2019 (COVID-19) pandemic disrupted the global blood supply. Low- and middle-income countries (LMICs) already experienced blood supply deficits that preceded the pandemic. We sought to characterize the challenges experienced during the pandemic, and adaptations, such as COVID-19 convalescent plasma (CCP). STUDY DESIGN/METHODS: A cross-sectional survey explored blood availability, challenges, and adaptations. The survey contained 31 questions, e-mailed in English, French, or Spanish, to selected LMIC blood transfusion practitioners. Data acquisition occurred between October 28 and December 28, 2020. A mixed methods analysis followed. RESULTS/FINDINGS: A total of 31 responses from 111 invitations represented 26 LMIC countries. Languages included English (22, 71%), Spanish (7, 22.6%), and French (2, 6.4%). Most respondents (29/31, 93.5%) collected blood; 58% also transfused blood (18/31). The supply of blood came from hospital-based blood donations (61%, 11/18); blood suppliers (17%, 3/18); and both sources (22%, 4/18). Collectively, 77.4% (24/31) of respondents experienced a decline in blood availability, ranging from 10% to 50%. Contributing factors included public fear of COVID-19 (21/24); stay-at-home measures (18/24); logistics (14/24); and canceled blood drives (16/24). Adaptations included increased collaboration within and between institutions (17/27), donor eligibility changes (21/31); social media or phone promotion (22/39); and replacement donation (3/27). Fifteen of 31 responses reported CCP donation (48.4%); CCP transfusion occurred in 6 (19.4%). The primary barrier was engaging recovered patients for donation (7/15). CONCLUSION: Our survey describes challenges experienced by LMIC blood systems during the COVID-19 pandemic. While the decline in blood supplies was severe, adaptive measures included collaboration, outreach, and CCP programs.

Decolonizing Global Health Education: Rethinking Institutional Partnerships and Approaches.

Global health often entails partnerships between institutions in low- and middle-income countries (LMICs) that were previously colonized and high-income countries (HICs) that were colonizers. Little attention has been paid to the legacy of former colonial relationships and the influence they have on global health initiatives. There have been recent calls for the decolonization of global health education and the reexamination of assumptions and practices under pinning global health partnerships. Medicine's role in colonialism cannot be ignored and requires critical review. There is a growing awareness of how knowledge generated in HICs defines practices and informs thinking to the detriment of knowledge systems in LMICs. Additionally, research partnerships often benefit the better-resourced partner. In this article, the authors offer a brief analysis of the intersections between colonialism, medicine, and global health education and explore the lingering impact of colonialist legacies on current global health programs and partnerships. They describe how "decolonized" perspectives have not gained sufficient traction and how inequitable power dynamics and neocolonialist assumptions continue to dominate. They discuss 5 approaches, and highlight resources, that challenge colonial paradigms in the global health arena. Furthermore, they argue for the inclusion of more transfor mative learning approaches to promote change in attitudes and practice. They call for critical reflection and concomitant action to shift colonial paradigms toward more equitable partnerships in global education.

Global survey of transfusion medicine curricula in medical schools: Challenges and opportunities.

BACKGROUND: Physician's knowledge in transfusion medicine (TM) is critical for patient safety. Therefore, ensuring that medical schools provide adequate education in TM is important. The aim of this study was to assess the status of TM education at a global level. STUDY DESIGN AND METHODS: A comprehensive anonymous survey to assess TM education in existing medical school curricula was developed. The survey was distributed to deans and educational leads of medical schools in a range of low-, medium-, high-, and very high-human development index (HDI) countries. It included 20 questions designed to assess specific domains including structure of TM curriculum and teaching faculty. RESULTS: The response rate was 53%. The majority of responding schools from very-high-HDI countries offered a 6-year curriculum after high school or a 4-year curriculum after college education, whereas most schools from medium-HDI countries offered a 5-year medical curriculum. A formal teaching program was available in only 42% of these schools in contrast to 94% of medical schools from very high-HDI. Overall, 25% of all medical schools did not offer structured TM teaching. When offered, most TM teaching was mandatory (95%) and integrated within the third and fourth year of medical school. Formal assessment of TM knowledge was done in 72% of all responding medical schools. More than half of the deans considered the TM education in their medical schools as inadequate. CONCLUSION: Despite its limitations, the current survey highlights significant gaps and opportunities of TM education at a global scale.

Development of a Geogenic Radon Hazard Index-Concept, History, Experiences.

Exposure to indoor radon at home and in workplaces constitutes a serious public health risk and is the second most prevalent cause of lung cancer after tobacco smoking. Indoor radon concentration is to a large extent controlled by so-called geogenic radon, which is radon generated in the ground. While indoor radon has been mapped in many parts of Europe, this is not the case for its geogenic control, which has been surveyed exhaustively in only a few countries or regions. Since geogenic radon is an important predictor of indoor radon, knowing the local potential of geogenic radon can assist radon mitigation policy in allocating resources and tuning regulations to focus on where it needs to be prioritized. The contribution of geogenic to indoor radon can be quantified in different ways: the geogenic radon potential (GRP) and the geogenic radon hazard index (GRHI). Both are constructed from geogenic quantities, with their differences tending to be, but not always, their type of geographical support and optimality as indoor radon predictors. An important feature of the GRHI is consistency across borders between regions with different data availability and Rn survey policies, which has so far impeded the creation of a European map of geogenic radon. The GRHI can be understood as a generalization or extension of the GRP. In this paper, the concepts of GRP and GRHI are discussed and a review of previous GRHI approaches is presented, including methods of GRHI estimation and some preliminary results. A methodology to create GRHI maps that cover most of Europe appears at hand and appropriate; however, further fine tuning and validation remains on the agenda.

New Test of Lorentz Invariance Using the MICROSCOPE Space Mission.

We use data from the T-SAGE instrument on board the MICROSCOPE space mission to search for Lorentz violation in matter-gravity couplings as described by the Lorentz violating standard model extension (SME) coefficients (a[over ¯]_{eff})_{µ}^{w}, where (µ=T, X, Y, Z) and (w=e, p, n) for the electron, proton, and neutron. One of the phenomenological consequences of a nonzero value of those coefficients is that test bodies of different composition fall differently in an external gravitational field. This is similar to "standard" tests of the universality of free fall, but with a specific signature that depends on the orbital velocity and rotation of Earth. We analyze data from five measurement sessions of MICROSCOPE spread over a year finding no evidence for such a signature, but setting constraints on linear combinations of the SME coefficients that improve on best previous results by 1 to 2 orders of magnitude. Additionally, our independent linear combinations are different from previous ones, which increases the diversity of available constraints, paving the way towards a full decorrelation of the individual coefficients.

Inhibition of FAK kinase activity preferentially targets cancer stem cells.

Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo. Oral administration of VS-4718 or VS-6063 to mice bearing xenograft models of triple-negative breast cancer (TNBC) significantly reduced the proportion of CSCs in the tumors, as evidenced by a reduced tumor-initiating capability upon re-implantation in limiting dilutions of cells prepared from these tumors. In contrast, the cytotoxic chemotherapeutic agents, paclitaxel and carboplatin, enriched for CSCs, consistent with previous reports that these cytotoxic agents preferentially target non-CSCs. Importantly, VS-4718 and VS-6063 attenuated the chemotherapy-induced enrichment of CSCs in vitro and delayed tumor regrowth following cessation of chemotherapy. An intriguing crosstalk between FAK and the Wnt/ß-catenin pathway was revealed wherein FAK inhibition blocks ß-catenin activation by reducing tyrosine 654 phosphorylation of ß-catenin. Furthermore, a constitutively active mutant form of ß-catenin reversed the preferential targeting of CSCs by FAK inhibition, suggesting that this targeting is mediated, at least in part, through attenuating ß-catenin activation. The preferential targeting of cancer stem cells by FAK inhibitors provides a rationale for the clinical development of FAK inhibitors aimed to increase durable responses for cancer patients.

Multi-scale crystallographic ordering in the cold-water coral Lophelia pertusa.

Lophelia pertusa is a widespread colonial cold-water coral which can form large three-dimensional habitats for benthic communities. Although it is known to construct an aragonite skeleton with optically opaque and translucent bands, details of its biomineralized structure are unclear. New crystallographic data obtained from Lophelia pertusa using electron backscatter diffraction (EBSD) reveal a remarkably high degree of multiscale self-ordering and provide unprecedented detail on crystallographic orientations within the coral skeleton. The EBSD data unequivocally demonstrate a self-regulated architecture across a range of spatial scales, resulting in a specific structure which contributes to the physical robustness of its skeleton and an evolutionary advantage in such habitats.

Combined Search for Lorentz Violation in Short-Range Gravity.

Short-range experiments testing the gravitational inverse-square law at the submillimeter scale offer uniquely sensitive probes of Lorentz invariance. A combined analysis of results from the short-range gravity experiments HUST-2015, HUST-2011, IU-2012, and IU-2002 permits the first independent measurements of the 14 nonrelativistic coefficients for Lorentz violation in the pure-gravity sector at the level of 10^{-9} m^{2}, improving by an order of magnitude the sensitivity to numerous types of Lorentz violation involving quadratic curvature derivatives and curvature couplings.

PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells.

Cancer stem cells (CSC) have been implicated in disease recurrence, metastasis, and therapeutic resistance, but effective targeting strategies for these cells are still wanting. VS-5584 is a potent and selective dual inhibitor of mTORC1/2 and class I PI 3-kinases. Here, we report that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSC compared with non-CSC in solid tumor cell populations. VS-5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Likewise, VS-5584 treatment ex vivo preferentially reduced CSC in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel and cisplatin were less effective in targeting CSC than bulk tumor cells. Mechanistic investigations revealed that preferential targeting of CSC required inhibition of multiple components of the PI3K-mTOR pathway: coordinate RNAi-mediated silencing of PI3Kα, PI3Kß, and mTOR phenocopied the effect of VS-5584, exhibiting the strongest preferential targeting of CSC, while silencing of individual PI3K isoforms or mTOR failed to replicate the effect of VS-5584. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small-cell lung cancer. Taken together, the preferential targeting of CSC prompts a new paradigm for clinical testing of VS-5584: clinical trials designed with CSC-directed endpoints may facilitate demonstration of the therapeutic benefit of VS-5584. We suggest that combining VS-5584 with classic chemotherapy that debulks tumors may engender a more effective strategy to achieve durable remissions in patients with cancer.

Thinking about thinking and emotion: the metacognitive approach to the medical humanities that integrates the humanities with the basic and clinical sciences.

Medical knowledge in recent decades has grown prodigiously and has outstripped the capacity of the human brain to absorb and understand it all. This burgeoning of knowledge has created a dilemma for medical educators. We can no longer expect students to continue memorizing this large body of increasingly complex knowledge. Instead, our efforts should be redirected at developing in students a competency as flexible thinkers and agile learners so they can adeptly deal with new knowledge, complexity, and uncertainty in a rapidly changing world. Such a competency would entail not only cognitive but also emotional skills essential for the holistic development of their professional identity. This article will argue that metacognition--"thinking about thinking (and emotion)"--offers the most viable path toward developing this competency. The overwhelming volume of medical knowledge has driven some medical schools to reduce the time allocated in their curricula to the "soft-option" humanities as they tend to consider them an expendable "luxury." Vanderbilt University School of Medicine, Nashville, TN, has moved away from the traditional conception of the medical humanities as "the arts," composed of art, music, and literature, toward an approach that integrates the humanities with the basic and clinical sciences, based on metacognition. This metacognitive approach to the humanities, described in this article, has three goals: 1) to develop students as flexible thinkers and agile learners and to provide them with essential cognitive and emotional skills for navigating medical complexity and uncertainty; 2) to elicit in students empathy and tolerance by making them aware of the immense diversity in human cognition (and emotion); and 3) to integrate the humanities with the basic and clinical sciences. Through this metacognitive approach, students come to understand their patterns of cognition and emotions, and in the group setting, they learn to mindfully calibrate their thinking and emotions. They gain a humbling appreciation of the fallibility of the human mind/brain and how cognitive biases and misperception can lead to medical error. They come to appreciate the complex interplay between cognition and emotion, and the importance of cognitive monitoring and emotional regulation. In the group setting, students also gain a sense of perspective of their thinking patterns and emotions in relation to those of their peers. Perspective taking and mindfulness engender tolerance and empathy, which ultimately serves as a platform for working collaboratively in teams as medical professionals. Students become aware of the social context in which thinking and learning occur, and this further shapes their professional identity. Thinking, learning, and interacting in the group setting ultimately induces a shift from self-preoccupation and an individualistic approach to knowledge toward an appreciation of collective cognition and empathy towards others. In this article, I describe the metacognitive approach to the medical humanities at Vanderbilt University School of Medicine and how it is designed to develop students as agile learners and flexible thinkers with the mindful capacity for cognitive and emotional monitoring and regulation. Thinking and learning in the group setting of the colloquium ultimately also fosters the student's professional identity.

Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.

In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.

Determination of methylamines and trimethylamine-N-oxide in particulate matter by non-suppressed ion chromatography.

An ion chromatography method with non-suppressed conductivity detection was developed for the simultaneous determination of methylamines (methylamine, dimethylamine, trimethylamine) and trimethylamine-N-oxide in particulate matter air samples. The analytes were well separated by means of cation-exchange chromatography using a 3 mM nitric acid/3.5% acetonitrile (v/v) eluent solution and a Metrosep C 2 250 (250 mm x 4 mm i.d.) separation column. The effects of the different chromatographic parameters on the separation were also investigated. Detection limits of methylamine, dimethylamine, trimethylamine, and trimethylamine-N-oxide were 43, 46, 76 and 72 microg/L, respectively. The relative standard deviations of the retention times were between 0.42% and 1.14% while the recoveries were between 78.8% and 88.3%. The method is suitable for determining if methylamines and trimethylamine-N-oxide are a significant component of organic nitrogen aerosol in areas with high concentration of these species.

Trimethylamine as precursor to secondary organic aerosol formation via nitrate radical reaction in the atmosphere.

Amines in fine particulate matter have been detected and quantified during ambient studies of winter inversions in Logan, UT, using aerosol mass spectrometry. Amine-related compounds account for 0.5-6 microg m(-3) of fine particulate mass during some wintertime periods. The amine contributions sometimes show a clear diurnal pattern, reaching peak concentrations during the middle of the nightwhile decreasing during the morning and afternoon. Smog chamber reactions show that the reaction of tertiary amines with nitrate radical can account for this behavior in the atmosphere. The lower bound reaction rate of trimethylamine and nitrate radical is estimated at 4.4 x 10(-16) cm3/molecules/s with a conversion rate to the aerosol phase of approximately 65%. This suggests that amines could be a contributor to secondary organic aerosol formation in areas where nitrate radical is a significant player in oxidation chemistry.