PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but its role in PAH is unsettled. Here, we report that: (1) PAI-1 is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared to controls; (2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with up-regulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and (3) pharmacological inhibition of uPA in human PAH PASMCs suppresses pro-proliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that down-regulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent up-regulation of mTOR and TGF-b signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.

Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.

RATIONALE: The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. OBJECTIVE: To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. METHODS AND RESULTS: Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

Extending Arts-Based Interventions in Graduate Medical Education through the Positive Humanities: the Re-FRAME Workshop.

BACKGROUND: Arts-and-humanities-based interventions are commonly implemented in medical education to promote well-being and mitigate the risk of burnout. However, mechanisms for achieving these effects remain uncertain within graduate medical education. The emerging field of the positive humanities offers a lens to examine whether and how arts-based interventions support well-being in internal medicine interns. AIM: Through program evaluation of this visual art workshop, we used a positive humanities framework to elucidate potential mechanisms by which arts-based curricula support well-being in internal medicine interns. SETTING: We launched the re-FRAME workshop at the Philadelphia Museum of Art in winter 2020. PARTICIPANTS: Fifty-six PGY-1 trainees from one internal medicine residency program. PROGRAM DESCRIPTION: The 3-h re-FRAME workshop consisted of an introductory session on emotional processing followed by two previously described arts-based interventions. PROGRAM EVALUATION: Participants completed an immediate post-workshop survey (91% response rate) assessing attitudes towards the session. Analysis of open-ended survey data demonstrated 4 categories for supporting well-being among participants: becoming emotionally aware/expressive through art, pausing for reflection, practicing nonjudgmental observation, and normalizing experiences through socialization. DISCUSSION: Our project substantiated proposed mechanisms from the positive humanities for supporting well-being-including reflectiveness, skill acquisition, socialization, and expressiveness-among medical interns.

Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

The medical humanities at United States medical schools: a mixed method analysis of publicly assessable information on 31 schools.

INTRODUCTION: There have been increasing efforts to integrate the arts and humanities into medical education, particularly during undergraduate medical education (UME). Previous studies, however, have focused on courses and curricular programming without rigorous characterization of the associated paracurricular environment or infrastructure enabling or facilitating these offerings. METHODS: To assess opportunities for students to engage the arts and humanities during their medical education as well as the institutional resources to support those opportunities, we developed the Humanities and Arts Programming Scale (HARPS): an 18-point scale involving eight sub-domains (Infrastructure, Curricular Opportunities, Extracurricular Engagement, Opportunities for Immersion, Faculty Engagement, Staff Support, Student Groups, and Scholarship). This scale was used to evaluate the top-31 ranked United States medical schools as determined by US News and World Report's (USWNR) Medical School Research Rankings using information derived from public-facing, online information. RESULTS: Mean cumulative HARPS score was 11.26, with a median score of 12, a standard deviation of 4.32 and a score range of 3-17. Neither USWNR ranking nor private/public institution status were associated with the cumulative score (p = 0.121, p = 0.739). 52% of institutions surveyed had a humanities-focused center/division with more than 70% of the schools having significant (> 5) faculty engaged in the medical humanities. 65% of schools offered 10 or more paracurricular medical humanities events annually, while 68% of the institutions had more than 5 medical humanities student organizations. While elective, non-credit courses are available, only 3 schools required instruction in the arts and humanities, and comprehensive immersive experiences in the medical humanities were present in only 29% of the schools. CONCLUSIONS: Although there is a significant presence of the medical humanities in UME, there is a need for integration of the arts and humanities into required UME curricula and into immersive pathways for engaging the medical humanities.

Diversity, Equity, and Inclusion: Moving from Performance to Transformation Through the Arts and Humanities.

Effective engagement on issues of diversity, equity, and inclusion (DEI) requires activities that promote deep introspection and group conversations that serve to complement and build upon formal DEI presentations. The arts and humanities by their nature allow for intentional and sustained reflection and have the potential to be transformative of thinking. We therefore propose that the next phase of institutional pro-equity/anti-racism efforts includes arts- and humanities-based initiatives to facilitate reflection and that serve to complement and build upon formal DEI didactic presentations, implicit bias workshops, and anti-racism training.

A Systematic Review and Meta-analysis of Depression, Anxiety, and Sleep Disorders in US Adults with Food Insecurity.

INTRODUCTION: A large number of peer-reviewed studies, with various methodologies and populations, have addressed the effects of food insecurity (FIS) on mental health conditions such as depression, anxiety, and sleep disorders. There are currently, however, no published systematic assessments or meta-analyses of this literature. METHODS: A systematic search of the literature was conducted in PubMed, PsycInfo, Embase, Scopus, and Web of Science. Cross-sectional studies assessing the association between food insecurity and depression, anxiety, or sleep disorders were identified. For each of the three health outcomes, we extracted (or calculated when possible) the following effect sizes: odds ratio (OR), Hedges' g, Pearson correlation coefficients r, or bivariate coefficients. Then, for each mental health-outcome/effect-size pair, the available studies were combined using the random effect model. Heterogeneity, publication bias, and subgroup dependence, for each meta-analysis, were also assessed. RESULTS: Fifty-seven studies provided cross-sectional data on the relationship between FIS and depression (n = 169,433), 13 on anxiety and psychological distress (n = 91,957), and 8 studies provided data on sleep disorders (n = 85,788). Meta-analysis showed that FIS is associated with an increased risk of testing positive for depression OR = 2.74 [95% CI 2.52-2.97, n = 135,500, Q(df = 41) = 69, I2 = 40%], anxiety OR = 2.41 [95% CI 1.81-3.22, n = 51,541, Q(df = 3) = 8, I2 = 63%], and sleep disorders OR = 1.80 [95% CI 1.51-2.15, n = 84,800, Q(df = 5) = 13, I2 = 62%]. The highest risks were found for depression and anxiety which had statistically similar values. The results were robust to covariates and population groups. DISCUSSION: This systematic review and meta-analysis demonstrates a strong association between FIS and depression, anxiety, and sleep disorders, for which more longitudinal studies addressing effect sizes are warranted to further study causation.

A Randomized Controlled Study of Art Observation Training to Improve Medical Student Ophthalmology Skills.

PURPOSE: Observation and description are critical to the practice of medicine, and to ophthalmology in particular. However, medical education does not provide explicit training in these areas, and medical students are often criticized for deficiencies in these skills. We sought to evaluate the effects of formal observation training in the visual arts on the general and ophthalmologic observational skills of medical students. DESIGN: Randomized, single-masked, controlled trial. PARTICIPANTS: Thirty-six first-year medical students, randomized 1:1 into art-training and control groups. METHODS: Students in the art-training group were taught by professional art educators at the Philadelphia Museum of Art, during 6 custom-designed, 1.5-hour art observation sessions over a 3-month period. All subjects completed pre- and posttesting, in which they described works of art, retinal pathology images, and external photographs of eye diseases. MAIN OUTCOME MEASURES: Grading of written descriptions for observational and descriptive abilities by reviewers using an a priori rubric and masked to group assignment and pretesting/posttesting status. RESULTS: Observational skills, as measured by description testing, improved significantly in the training group (mean change +19.1 points) compared with the control group (mean change -13.5 points), P = 0.001. There were significant improvements in the training vs. control group for each of the test subscores. In a poststudy questionnaire, students reported applying the skills they learned in the museum in clinically meaningful ways at medical school. CONCLUSIONS: Art observation training for first-year medical students can improve clinical ophthalmology observational skills. Principles from the field of visual arts, which is reputed to excel in teaching observation and descriptive abilities, can be successfully applied to medical training. Further studies can examine the impact of such training on clinical care.

Defending Racial and Ethnic Diversity in Undergraduate and Medical School Admission Policies.

This Viewpoint argues that reversing or restricting the use of race and ethnicity in academic admission policies could also threaten the diversity of medical schools, both directly by restricting race consciousness in medical school admission practices and indirectly by reducing the overall number of minoritized undergraduate students attending US colleges and universities who could apply to medical school.

HIPPO-Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension.

RATIONALE: Enhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). OBJECTIVES: To determine the role and therapeutic relevance of HIPPO signaling in PAVSMC proliferation/apoptosis imbalance in PAH. METHODS: Primary distal PAVSMCs, lung tissue sections from unused donor (control) and idiopathic PAH lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. MEASUREMENTS AND MAIN RESULTS: Immunohistochemical and immunoblot analyses demonstrated that the HIPPO central component large tumor suppressor 1 (LATS1) is inactivated in small remodeled pulmonary arteries (PAs) and distal PAVSMCs in idiopathic PAH. Molecular- and pharmacology-based analyses revealed that LATS1 inactivation and consequent up-regulation of its reciprocal effector Yes-associated protein (Yap) were required for activation of mammalian target of rapamycin (mTOR)-Akt, accumulation of HIF1α, Notch3 intracellular domain and ß-catenin, deficiency of proapoptotic Bim, increased proliferation, and survival of human PAH PAVSMCs. LATS1 inactivation and up-regulation of Yap increased production and secretion of fibronectin that up-regulated integrin-linked kinase 1 (ILK1). ILK1 supported LATS1 inactivation, and its inhibition reactivated LATS1, down-regulated Yap, suppressed proliferation, and promoted apoptosis in PAH, but not control PAVSMCs. PAVSM in small remodeled PAs from rats and mice with SU5416/hypoxia-induced PH showed down-regulation of LATS1 and overexpression of ILK1. Treatment of mice with selective ILK inhibitor Cpd22 at Days 22-35 of SU5416/hypoxia exposure restored LATS1 signaling and reduced established pulmonary vascular remodeling and PH. CONCLUSIONS: These data report inactivation of HIPPO/LATS1, self-supported via Yap-fibronectin-ILK1 signaling loop, as a novel mechanism of self-sustaining proliferation and apoptosis resistance of PAVSMCs in PAH and suggest a new potential target for therapeutic intervention.

NEU1 sialidase regulates the sialylation state of CD31 and disrupts CD31-driven capillary-like tube formation in human lung microvascular endothelia.

The highly sialylated vascular endothelial surface undergoes changes in sialylation upon adopting the migratory/angiogenic phenotype. We recently established endothelial cell (EC) expression of NEU1 sialidase (Cross, A. S., Hyun, S. W., Miranda-Ribera, A., Feng, C., Liu, A., Nguyen, C., Zhang, L., Luzina, I. G., Atamas, S. P., Twaddell, W. S., Guang, W., Lillehoj, E. P., Puché, A. C., Huang, W., Wang, L. X., Passaniti, A., and Goldblum, S. E. (2012) NEU1 and NEU3 sialidase activity expressed in human lung microvascular endothelia. NEU1 restrains endothelial cell migration whereas NEU3 does not. J. Biol. Chem. 287, 15966-15980). We asked whether NEU1 might regulate EC capillary-like tube formation on a Matrigel substrate. In human pulmonary microvascular ECs (HPMECs), prior silencing of NEU1 did not alter tube formation. Infection of HPMECs with increasing multiplicities of infection of an adenovirus encoding for catalytically active WT NEU1 dose-dependently impaired tube formation, whereas overexpression of either a catalytically dead NEU1 mutant, NEU1-G68V, or another human sialidase, NEU3, did not. NEU1 overexpression also diminished EC adhesion to the Matrigel substrate and restrained EC migration in a wounding assay. In HPMECs, the adhesion molecule, CD31, also known as platelet endothelial cell adhesion molecule-1, was sialylated via α2,6-linkages, as shown by Sambucus nigra agglutinin lectin blotting. NEU1 overexpression increased CD31 binding to Arachis hypogaea or peanut agglutinin lectin, indicating CD31 desialylation. In the postconfluent state, when CD31 ectodomains are homophilically engaged, NEU1 was recruited to and desialylated CD31. In postconfluent ECs, CD31 was desialylated compared with subconfluent cells, and prior NEU1 silencing completely protected against CD31 desialylation. Prior CD31 silencing and the use of CD31-null ECs each abrogated the NEU1 inhibitory effect on EC tube formation. Sialyltransferase 6 GAL-I overexpression increased α2,6-linked CD31 sialylation and dose-dependently counteracted NEU1-mediated inhibition of EC tube formation. These combined data indicate that catalytically active NEU1 inhibits in vitro angiogenesis through desialylation of its substrate, CD31.

Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

BACKGROUND: Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown. METHODS AND RESULTS: Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly upregulated in small remodeled pulmonary arteries and isolated distal PAVSMCs from subjects with idiopathic PAH that have increased ATP levels, proliferation, and survival that depend on glycolytic metabolism. Small interfering RNA- and pharmacology-based analysis showed that although both mTORC1 and mTORC2 contribute to proliferation, only mTORC2 is required for ATP generation and survival of idiopathic PAH PAVSMCs. mTORC2 downregulated the energy sensor AMP-activated protein kinase, which led to activation of mTORC1-S6 and increased proliferation, as well as a deficiency of the proapoptotic protein Bim and idiopathic PAH PAVSMC survival. NADPH oxidase 4 (Nox4) protein levels were increased in idiopathic PAH PAVSMCs, which was necessary for mTORC2 activation, proliferation, and survival. Nox4 levels and mTORC2 signaling were significantly upregulated in small pulmonary arteries from hypoxia-exposed rats at days 2 to 28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15 to 28 suppressed mTORC2 but not Nox4, induced smooth muscle-specific apoptosis in small pulmonary arteries, and reversed hypoxia-induced pulmonary vascular remodeling in rats. CONCLUSIONS: These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via the energy sensor AMP-activated protein kinase to increased proliferation and survival of PAVSMCs in PAH, which suggests a new potential pathway for therapeutic interventions.

A 15-Year Analysis of Supply and Demand for Hematology and Oncology Training in the United States.

PURPOSE: There is a paucity of research on the supply of the hematology and oncology workforce despite projected shortages in the United States Over the past 15 years of the hematology and oncology match (HOM), we hypothesized that there would be more growth in the number of training positions relative to applicants, higher match rates for US allopathic graduates relative to non-US allopathic graduates, and fewer applicants matching at their top fellowship choices. METHODS: This was a national, retrospective cohort study of all applicants in the HOM (2009-2023). Match rates and applicant-to-training position ratios were calculated and compared over time with Pearson tests. RESULTS: Growth in the number of annual training positions (426-708; 66% increase) exceeded growth in the number of interested applicants (706-945; 34% increase; P < .001). Annual applicant-to-training position ratios decreased from 1.7 to 1.3 (r = -0.813; P < .001). Match rates increased over the study period for both US allopathic graduates (79%-88%; r = 0.761; P = .001) and non-US allopathic graduates (45%-63%; r = 0.801; P < .001). During each year, match rates for US allopathic graduates exceeded those for non-US allopathic graduates (P < .001). From 2018 to 2023, US allopathic graduates (83%) had higher match rates than US osteopathic graduates (60%) and international medical graduates (50%; P < .001). The percentage of applicants that matched at one of their top three fellowship choices increased from 53% to 60% (r = 0.480; P = .070). Fewer available annual training positions went unfilled over the study period (3%-0.3%; r = - 0.870; P < .001). CONCLUSION: Match rates have increased in the HOM but remain competitive especially for non-US allopathic graduates. Future investigation is needed to understand disparities in match outcomes by additional applicant and fellowship program characteristics. Ongoing surveillance of HOM outcomes remains critical given the projected shortages in the US hematology and oncology workforce.

Psychological and emotional experiences of participants in a medical school, early assurance admissions program targeting students from groups underrepresented in medicine.

BACKGROUND: There are growing number of pathway programs, with an early assurance of admission, that target undergraduate students from groups underrepresented in medicine (URiM) to enable their competitiveness for and matriculation to medical school, including the Penn Access Summer Scholars (PASS) program. The psychological and emotional experiences of students in these programs, however, have not been previously described. METHODS: Students from the summer 2021 cohort of the PASS program were interviewed using a structured set of questions that explored four specific areas: (i) the application process; (ii) the benefits and value of being in the PASS program; (iii) the emotional and psychological challenges and stresses of being in the PASS program; (iv) feelings and emotions about not taking the MCAT or having to interview at multiple schools. The transcribed, de-identified interviews were then subjected to a qualitative analysis. RESULTS: Students in PASS reported that the program was valuable to them in that it reduced the stress of the pre-medical process; relieved worry and anxiety surrounding the MCAT; enabled development of supportive relationships and provided meaningful exposures to the medical profession and biomedical research. Despite this, students reported feelings of imposterism, guilt, and fear of disappointing, along with varying degrees of regret over not taking the MCAT and not interviewing at more than one medical school. CONCLUSIONS: URiM and other marginalized students participating in early assurance admissions programs likely enter medical school with a range of positive and negative emotions as a result of their participation in these programs. These data can be used to inform the development of programing and other initiatives that further support the transition and success of these students in medical school.

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium.

We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however, a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1), and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule-1 (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1(-/-) lungs compared with lungs from wild-type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1(-/-) PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in WT mice was significantly lowered in PECAM-1(-/-) mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker VEGF compared with untreated (sham) and PECAM-1(-/-) lungs. Thus PECAM-1 (and caveolae) are parts of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal.

Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression.

Most patients who die from cancer succumb to treatment-refractory advanced metastatic progression. Although the early stages of tumor metastasis result in the formation of clinically silent micrometastatic foci, its later stages primarily reflect the progressive, organ-destructive growth of already advanced metastases. Early-stage metastasis is regulated by multiple factors within tumor cells as well as by the tumor microenvironment (TME). In contrast, the molecular determinants that control advanced metastatic progression remain essentially uncharacterized, precluding the development of therapies targeted against it. Here we show that the TME, functioning in part through platelet endothelial cell adhesion molecule 1 (PECAM-1), drives advanced metastatic progression and is essential for progression through its preterminal end stage. PECAM-1-KO and chimeric mice revealed that its metastasis-promoting effects are mediated specifically through vascular endothelial cell (VEC) PECAM-1. Anti-PECAM-1 mAb therapy suppresses both end-stage metastatic progression and tumor-induced cachexia in tumor-bearing mice. It reduces proliferation, but not angiogenesis or apoptosis, within advanced tumor metastases. Because its antimetastatic effects are mediated by binding to VEC rather than to tumor cells, anti-PECAM-1 mAb appears to act independently of tumor type. A modified 3D coculture assay showed that anti-PECAM-1 mAb inhibits the proliferation of PECAM-1-negative tumor cells by altering the concentrations of secreted factors. Our studies indicate that a complex interplay between elements of the TME and advanced tumor metastases directs end-stage metastatic progression. They also suggest that some therapeutic interventions may target late-stage metastases specifically. mAb-based targeting of PECAM-1 represents a TME-targeted therapeutic approach that suppresses the end stages of metastatic progression, until now a refractory clinical entity.

Medical Students' Reflections on Their Experiences in a Trauma Chaplain Shadowing Program.

The importance of spirituality in patient care is well recognized and efforts to develop educational opportunities to improve medical students' competency in spirituality and health are ongoing. In this regard, shadowing of healthcare chaplains has emerged as an experiential approach for providing exposure to and instruction in issues of spirituality in the patient experience and in patient care. Recently published data suggest that a 6-8 hour experience of shadowing a trauma chaplain is effective at introducing first-year medical students to healthcare chaplaincy, difficult spiritual conversations with patients and families, and interprofessional collaboration. As a follow-up to these data, this study provides a qualitative analysis of student reflections written immediately after their shadowing experience with the goal of further characterizing the educational impact of trauma chaplain shadowing. Qualitative analysis of 90 anonymous, student reflections indicated that trauma chaplain shadowing was an experience that provided insights about nature of chaplaincy, enabled opportunities to closely observe the relational skills of chaplains, allowed students to bear witness to suffering, fostered growth toward a professional identity, and facilitated recognition of shortcomings in medical education and clinical medicine. These data therefore provide further evidence of the value of chaplain shadowing in not only enhancing students' understanding of various dimensions of spirituality and medicine but also in promoting their development of a strong physician identity.