Organizations in science and medicine must hold each other accountable for discriminatory practices.

Many organizations persist in working with others that engage in known, remediable structural discrimination. We name this practice interorganizational structural discrimination (ISD) and argue it is a pivotal contributor to inequities in science and medicine. We urge organizations to leverage their relationships and demand progress from collaborators.

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.

Exploring the Psychological Impact of Childhood-Onset Psoriasis: A Systematic Review.

BACKGROUND: Childhood-onset psoriasis (COP) is often associated with various psychological challenges. While numerous studies have delved into the connection between adult-onset psoriasis and its potential to heighten a patient's susceptibility to various psychological challenges, less has been written about the influence of childhood psoriasis on psychological disorders, particularly anxiety and depression, eating disorders, and substance abuse. In this study, we delve into studies that shed light on these associated risks. METHODS: A systematic literature review was conducted using PubMed, focusing on the psychological impacts of childhood-onset psoriasis. From an initial pool of 313 articles, we utilized Covidence for screening and selection, adhering to strict exclusion criteria such as psoriasis in adulthood and incorrect study designs. This process refined our focus to 12 relevant articles, which were critically analyzed to understand the psychological comorbidities associated with childhood-onset psoriasis. RESULTS: Our review reveals a significant link between childhood-onset psoriasis and increased instances of depression and anxiety. Notably, children with psoriasis demonstrate higher frequencies of suicidal thoughts and behaviors, as well as a marked propensity for substance abuse and addiction. The study also uncovers a strong connection between psoriasis in children and the development of eating disorders like anorexia nervosa and bulimia nervosa. CONCLUSION: COP significantly affects the psychological wellbeing of children, with heightened risks for depression, anxiety, suicidality, substance abuse, and eating disorders. These findings underscore the need for comprehensive management strategies that encompass not only the physical symptoms but also the mental health and psychological support for children with psoriasis. Early intervention and regular screenings are crucial in mitigating these risks and improving the quality of life for pediatric patients with psoriasis.

Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation.

Scratching triggers skin flares in atopic dermatitis. We demonstrate that scratching of human skin and tape stripping of mouse skin cause neutrophil influx. In mice, this influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.

Dermatology and anatomy laboratory: comparing three formats of integration.

BACKGROUND: Medical schools rarely offer exposure to clinical dermatology in the first-year curriculum. OBJECTIVE: We describe and report student satisfaction results of three novel teaching methods for integrating basic dermatology concepts into gross anatomy laboratory. METHODS: During the first year of the intervention, 180 students attended an hour-long anatomy laboratory session during which skin lesions were examined. One attending and three resident dermatologists spent time at all tables of students, then circulated to answer questions. During the second year, 189 students participated in the same teaching session preceded by a 30-minute in-class lecture. During the third year, 172 students were given the option to view a supplemental online video module before or after the teaching session. Each year following the teaching session students were sent an optional online survey regarding the impact of the teaching session on their understanding of skin lesions and their cadaver experience. RESULTS: Overall, students believed the intervention helped them develop a better understanding and appreciation for dermatology. Preceding the laboratory session with a lecture or educational video yielded higher satisfaction scores. CONCLUSIONS: This brief teaching intervention illustrates an approach to introducing dermatologic entities within the foundational science curriculum of the first year of medical school.

Interactive teaching and repeat exposure maximize medical student satisfaction but do not promote long-term retention of dermatologic knowledge.

BACKGROUND: Instructional methods for teaching medical students to recognize common skin lesions vary widely. There is little published data comparing various teaching methods and their impact on medical student retention of dermatologic knowledge. METHODS: Our prospective cohort study analyzed how teaching methods (interactive teaching versus. traditional didactic teaching versus. self-guided review alone) impacted second year medical students' ability to recognize common skin lesions one year after initial exposure to the material. Our study also looked at student satisfaction with different teaching methods. RESULTS: There was no significant difference in long-term retention of knowledge between different teaching methods. However, students preferred the interactive format over the traditional didactic format. Spaced review is important for long-term retention, but an in-class review session two months after content was initially taught provided no added benefit over spaced self-review alone. CONCLUSIONS: Medical students are able to maintain long-term retention of dermatologic knowledge irrespective of in-class teaching method. Repeat exposure to material is important but self-review of dermatology alone is sufficient for long-term retention. Dermatology course directors should incorporate interactive teaching into medical school curricula to increase learner satisfaction.

Dermatology and anatomy laboratory: comparing three formats of integration.

BACKGROUND: Medical schools rarely offer exposure to clinical dermatology in the first-year curriculum. OBJECTIVE: We describe and report student satisfaction results of three novel teaching methods for integrating basic dermatology concepts into gross anatomy laboratory. METHODS: During the first year of the intervention, 180 students attended an hour-long anatomy laboratory session during which skin lesions were examined. One attending and three resident dermatologists spent time at all tables of students, then circulated to answer questions. During the second year, 189 students participated in the same teaching session preceded by a 30-minute in-class lecture. During the third year, 172 students were given the option to view a supplemental online video module before or after the teaching session. Each year following the teaching session, students were sent an optional online survey regarding the impact of the teaching session on their understanding of skin lesions and their cadaver experience. RESULTS: Overall, students felt the intervention helped them develop a better understanding and appreciation for dermatology. Preceding the laboratory session with a lecture or educational video yielded higher satisfaction scores. CONCLUSIONS: This brief teaching intervention illustrates an approach to introducing dermatologic entities within the foundational science curriculum of the first year of medical school.

Histiocytoid autoimmunity-related neutrophilic dermatosis in a patient with rheumatoid arthritis.

Autoimmunity-associated neutrophilic dermatoses are a recently recognized manifestation of connective tissue diseases, in particular, lupus erythematosus. These entities are clinically and sometimes histopathologically distinct from classic neutrophilic dermatoses. We describe a case of an autoimmunity-related neutrophilic dermatosis in a patient with rheumatoid arthritis. In addition to this uncommon association, there was an absence of mature neutrophils and a population of immature histiocytoid granulocytes. This unusual case expands the concept of histiocytoid neutrophilic dermatoses to include those seen in association with autoimmune connective tissue diseases.

Melanoma spheroid formation involves laminin-associated vasculogenic mimicry.

Melanoma is a tumor where virulence is conferred on transition from flat (radial) to three-dimensional (tumorigenic) growth. Virulence of tumorigenic growth is governed by numerous attributes, including presence of self-renewing stem-like cells and related formation of patterned networks associated with the melanoma mitogen, laminin, a phenomenon known as vasculogenic mimicry. Vasculogenic mimicry is posited to contribute to melanoma perfusion and nutrition in vivo; we hypothesized that it may also play a role in stem cell-driven spheroid formation in vitro. Using a model of melanoma in vitro tumorigenesis, laminin-associated networks developed in association with three-dimensional melanoma spheroids. Real-time PCR analysis of laminin subunits showed that spheroids formed from anchorage-independent melanoma cells expressed increased α4 and ß1 laminin chains and α4 laminin expression was confirmed by in situ hybridization. Association of laminin networks with melanoma stem cell-associated nestin and vascular endothelial growth factor receptor-1 also was documented. Moreover, knockdown of nestin gene expression impaired laminin expression and network formation within spheroids. Laminin networks were remarkably similar to those observed in melanoma xenografts in mice and to those seen in patient melanomas. These data indicate that vasculogenic mimicry-like laminin networks, in addition to their genesis in vivo, are integral to the extracellular architecture of melanoma spheroids in vitro, where they may serve as stimulatory scaffolds to support three-dimensional growth.

Duration of symptoms does not correlate with results of T-cell gene rearrangement studies in patients evaluated for cutaneous T-cell lymphoma.

OBJECTIVES: We aimed to determine if clonality on T-cell gene rearrangement studies correlated with duration of cutaneous symptoms in patients with skin disease who are being evaluated for cutaneous T-cell lymphoma (CTCL). Specifically, our goal was to determine if symptom duration could help better optimize sample selection for T-cell gene rearrangement studies. METHODS: Biopsies were reviewed from patients within both general dermatology clinic and CTCL specialty clinic for clonality results in relation to disease duration. RESULTS: We did not find an association between duration and clonality in any group. CONCLUSIONS: The yield of T-cell gene rearrangement studies is similar between shorter and longer duration of disease implying that there is not an optimal duration range in which T-cell gene rearrangement studies are more likely to give a positive result.

Impact of the 2009 AJCC staging guidelines for melanoma on the number of mitotic figures reported by dermatopathologists at one institution.

BACKGROUND: In 2009 the revised seventh staging system for melanoma recommended the use of mitotic count to separate stage T1a from T1b. However, careful scrutiny of cases may lead to an inadvertent selection effect, with consequent increased reporting of mitotic counts. METHODS: We investigated whether there is a significant increase in mitotic counts reported since 2009 for melanomas with a Breslow thickness of 1.0 mm or less. We conducted a retrospective, case-controlled study examining invasive melanoma cases at a large academic center. Mitotic counts were compared between pathology reports before 2009 (n = 61) and after 2009 (n = 125), with a subset of slides re-examined in a blinded fashion. RESULTS: Before the 2009 staging guidelines, 51% of cases had one or more mitosis reported compared to 38% after 2009 (p = 0.113). Blinded re-counting did not yield a significant difference when compared with the original pathology reports in either group. CONCLUSIONS: There was not a significant difference in the number of mitoses reported after the implementation of the new guidelines.

Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts.

Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.

Nestin depletion induces melanoma matrix metalloproteinases and invasion.

Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.

Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors.

DNA methylation is the most well-studied epigenetic modification in cancer biology. 5-hydroxymethylcytosine is an epigenetic mark that can be converted from 5-methylcytosine by the ten-eleven translocation gene family. We recently reported the loss of 5-hydroxymethylcytosine in melanoma compared with benign nevi and suggested that loss of this epigenetic marker is correlated with tumor virulence based on its association with a worse prognosis. In this study, we further characterize the immunoreactivity patterns of 5-hydroxymethylcytosine in the full spectrum of melanocytic lesions to further validate the potential practical application of this epigenetic marker. One hundred and seventy-five cases were evaluated: 18 benign nevi, 20 dysplastic nevi (10 low-grade and 10 high-grade lesions), 10 atypical Spitz nevi, 20 borderline tumors, 5 melanomas arising within nevi, and 102 primary melanomas. Progressive loss of 5-hydroxymethylcytosine from benign dermal nevi to high-grade dysplastic nevi to borderline melanocytic neoplasms to melanoma was observed. In addition, an analysis of the relationship of nuclear diameter with 5-hydroxymethylcytosine staining intensity within lesional cells revealed a significant correlation between larger nuclear diameter and decreased levels of 5-hydroxymethylcytosine. Furthermore, borderline lesions uniquely exhibited a diverse spectrum of staining of each individual case. This study further substantiates the association of 5-hydroxymethylcytosine loss with dysplastic cytomorphologic features and tumor progression and supports the classification of borderline lesions as a biologically distinct category of melanocytic lesions.

Evaluation of stromal HGF immunoreactivity as a biomarker for melanoma response to RAF inhibitors.

Of more than 150 000 published studies evaluating new biomarkers, fewer than 100 biomarkers have been implemented for patient care. One reason for this is lack of rigorous testing by the medical community to validate claims for biomarker clinical relevance, and potential reluctance to publish negative results when confirmation is not obtained. Here we sought to determine the utility and reproducibility of immunohistochemical detection of hepatocyte growth factor (HGF) in melanoma tissue, an approach of potential assistance in defining patients with innate resistance to BRAF inhibitor therapy. To this end, a published and a revised method that retained sensitivity but with greater specificity for HGF detection, were evaluated in cells known to endogenously express HGF, and in models where HGF is upregulated via cytokine induction and via overexpression by gene transfection. Consequent patient evaluation in collaboration with the Melanoma Institute Australia of a cohort of 41 melanoma specimens with extensive clinical annotation failed to validate HGF immunohistochemistry as a predictor of response to BRAF inhibitors. Targeted therapies for advanced melanoma and other cancers show great promise, and rigorous validation studies are thus indicated for approaches that seek to personalize such therapies to maximize therapeutic efficacy.

Systemic lupus erythematosus-associated neutrophilic dermatosis: a review and update.

Neutrophilic dermatoses are a rare manifestation of systemic lupus erythematosus (SLE). In recent years, a growing body of literature describes a pathologic spectrum of neutrophilic infiltrates that may be seen in lupus patients. It is particularly important to recognize that neutrophilic dermatoses can be the initial manifestation of SLE in a third of patients. We were able to identify 47 patients with SLE associated with neutrophilic tissue reactions. In this review, we describe the histologic and clinical features of these cases in the hope that increased awareness of this unusual manifestation of SLE will generate prompt diagnosis and improved patient care.