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Supplemental Figure S2. Mutational signatures of Merkel cell polyomavirus-positive Merkel cell carcinomas

Supplemental Table S7 A. Selected somatic mutation calls and Sanger validation results

Supplemental Table S3. MCPyV detection in MCC tumors by qPCR, immunohistochemistry, and transcriptome sequencing

Supplemental Figure Legends

We sought to identifying the possible existence of disparities between rural and urban residents of Michigan for the incidence by stage of disease and disease-specific mortality for cutaneous melanoma (CM).Incidence rates for stage of disease and disease-specific mortality of cutaneous melanoma were calculated and controlled for gender, age, and area of residence from January 1, 2014, to December 31, 2018, from data collected form the Michigan Department of Health and Human Services and the Centers for Disease Control and Prevention.The incidence rates for CM were significantly higher in rural Michigan counties, from 2014-2018, for all patients, both age groups, both genders and all stages. Melanoma-specific mortality rates were also significantly higher for all patients, both age groups and both genders in rural Michigan counties. Using logistic regression analysis, while controlling for age and gender, rural Michigan counties continued to have a higher melanoma-specific morality rate during our study period (OR = 1.491; 95% CI, 1.27-1.74; p = .001).We found significant disparities in the incidence rates and disease specific mortality for cutaneous melanoma in rural compared to urban Michigan from 2014-2018.

Introduction Our objective was to study the impact and clinical operation of an integrated model for free specialized dermatology care via collaboration between an academic institution and a nonprofit outpatient clinic through an analysis of patient demographics and care provided. Methods Hope@UMHS is a partnership between the University of Michigan Health System (UMHS) and Hope Clinic (HC) which provides free specialty consultations to uninsured residents of Southeast Michigan. A retrospective chart review was completed for patients referred to the UMHS Dermatology clinic as part of the HOPE@UMHS collaboration from April 2012 through February 2020. Results Of the 294 referred patients, 264 were managed in 30 clinic sessions over 8 years, staffed by 92 unique volunteers. Patients most commonly presented with atopic dermatitis (10.5%), seborrheic dermatitis (7.9%), and actinic keratosis (7.4%). The majority of patients (68.2%) were prescribed at least one new medication. Nine skin cancers, including one melanoma, were diagnosed and treated. There were 102 procedures performed. Eighty-seven percent of patients received conclusive evaluation and treatment at the time of their consultation. Conclusion Our experience illustrates that providing free, comprehensive dermatology care in a university hospital by partnering with a nonprofit clinic is both feasible and beneficial to the greater community.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (

Basal cell carcinoma, squamous cell carcinoma, and melanoma represent the three most common skin cancers that occur on the face. The most common surgical treatments for facial skin cancers are Mohs surgery and standard local excision. The effective utilization of either of these techniques is based on tumor and patient risk stratification incorporating known risk factors for occult invasion and local recurrence, combined with patient comorbidities, expectations, and desires. Best available evidence highlights multiple and consistent risk factors for each specific skin cancer type, and dictate local control rates reported in the literature. Recognizing gaps in the literature, we compare and review surgical treatment guidelines and data for standard local excision versus Mohs surgery for cutaneous nonmelanoma and melanoma skin cancer. This article serves as a resource for optimal therapeutic decision making for surgical management of skin cancer on the face.

Researchers have identified numerous mechanisms that make cooperation in the prisoner's dilemma possible, yet recent research has proposed what ranks among the most basic of mechanisms: the presence of time. When organisms in spatial models can interact at multiple points in time within a generation, cooperation can evolve in a wider range of settings than in spatial models in which interaction occurs at a single moment. Here we further explore this mechanism via an analytic model that studies the effect of time on cooperation when no spatial dimension is present. The model shows that the mere presence of two or more points in time at which social interaction can occur creates an opportunity for mutant cooperators to invade a well-mixed population of defectors playing the one-shot prisoner's dilemma under the replicator dynamics. These invasions lead to a nonequilbrium cycling of strategies in which cooperation consistently reemerges at alternating time points.

Velu and Iyer (1) underscore the need and opportunity to study “near misses” in the COVID-19 era of social science research, thus elaborating on a key aspect of the causal inference challenges we discuss in our Opinion article (2). The literature on causal inference would classify “near misses” and “hypothetical histories” as “counterfactuals”: depictions of what would have happened to an entity, absent some intervention, all else equal (3⇓–5). Counterfactuals provide a baseline for measuring an intervention’s causal effect. Theoretically, the difference between the observed outcome following an intervention and the result occurring had that intervention never happened constitutes the causal effect … [↵][1]1To whom correspondence may be addressed. Email: daltonclarkconley{at}gmail.com or tjohnson{at}willamette.edu. [1]: #xref-corresp-1-1

Scholars have documented the failed randomization in 1969’s inaugural Vietnam Selective Service Lottery, but the story of how statisticians fixed that problem remains untold. Here, as the 50th anni...

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.

Over the last few decades, social scientists have experienced the causal revolution, the replication crisis, and, now in just a matter of months, another epoch: the era of coronavirus disease 2019 (COVID-19) research. According to Google Scholar, approximately 142,000 COVID-19–related articles have appeared since 2020. That amounts to about 389 articles per day, or, roughly, one article every 4 minutes. Many of these articles are in the social sciences—that is, concerned not directly with medical outcomes but rather with COVID-19’s impact on social, behavioral, and economic outcomes. Social scientists investigating COVID-related topics are not the first to use a historical moment to advance general knowledge about human behavior. Other one-time events, from the U.S. Vietnam-era draft lotteries to Hurricane Katrina to the 2008 financial crisis, have spawned important trends in social science research. Image credit: Dave Cutler (artist). Thus far, most of this research has had a direct focus on managing COVID-19, yet a growing number of articles enlist the pandemic to study basic questions about financial investment, education, politics, learning, crime, and other aspects of social life. As COVID-19 research in the social sciences moves toward basic science, we anticipate that it will increasingly intersect with the recent scholarly trends in the social sciences: the “causal revolution,” which shifted social scientists toward research designs that could establish causal relations between study variables instead of mere correlations, and the “replication crisis,” which focused social scientists on ensuring the reproducibility of published findings. Researchers who incorporate the pandemic into causal inference strategies will encounter questions about the generalizability of findings produced by rigorously studying a historically distinct event. And others may question the usefulness of conclusions that rest on analyses that do not appear to be replicable in the traditional sense of rerunning an experiment. Fortunately, past research using “natural experiments” … [↵][1]1To whom correspondence may be addressed. Email: dconley{at}princeton.edu or tjohnson{at}willamette.edu. [1]: #xref-corresp-1-1

We study a spatial, one-shot prisoner’s dilemma (PD) model in which selection operates on both an organism’s behavioral strategy (cooperate or defect) and its decision of when to implement that strategy, which we depict as an organism’s choice of one point in time, out of a set of discrete time slots, at which to carry out its PD strategy. Results indicate selection for cooperators across various time slots and parameter settings, including parameter settings in which cooperation would not evolve in an exclusively spatial model—as in work investigating exogenously imposed temporal networks. Moreover, in the presence of time slots, cooperators’ portion of the population grows even under different combinations of spatial structure, transition rules, and update dynamics, though rates of cooperator fixation decline under pairwise comparison and synchronous updating. These findings indicate that, under certain evolutionary processes, merely existing in time and space promotes the evolution of cooperation., Johnson and Smirnov show that temporal dynamics influence cooperation in the spatial prisoner’s dilemma. Studying simulation models, they find that when evolutionary selection operates on the time at which individuals socially interact, cooperation evolves at a wider range of parameter values than in standard spatial prisoner’s dilemma models.

To reduce transmission of COVID-19, public officials must help their communities resolve a series of novel social dilemmas. For instance, when social distancing becomes widespread, the likelihood of COVID-19 exposure decreases, thus tempting individuals to leave their homes while others stay sheltered. Yet, if all indulge that temptation, then rates of transmission will increase: everyone would have fared better by cooperatively staying at home. Past research has studied such social dilemmas to understand why cooperation occurs despite incentives that conspire against it. In this narrative review, we select relevant insights from this literature to inform COVID-19 response and we structure those insights around the response stages that government officials face. Together, the measures that we identify can ameliorate the social dilemmas born from the COVID-19 pandemic.

According to its designers, the U.S. merit system centered on a “pivotal idea”: The civil service would use “open, fair, honest, impartial, competitive examination” to find the people “best fitted to discharge the duties of the position.” Officials would announce job openings to the widest-possible applicant pool and assess that pool on uniformly applied, job-relevant criteria. Over time, however, alternative hiring mechanisms have increased in popularity as means to improve the speed or flexibility the hiring process, with limited research on their impact on the federal service. To understand their effects, we examine all federal, nondefense employees hired between 1983 and 2013 to assess whether four alternative hiring procedures affect the educational attainment (a proxy for qualifications) and career advancement (a proxy for quality) of new hires. We find that employees hired through competitive examinations possess more education upon entry than employees selected through two of those alternative procedures; however, employees hired through all four alternative procedures advance in their careers at least as rapidly as those selected via competitive examinations.

Background: The diagnosis and management of pediatric melanomas is challenging given the presence of both melanomas and histologically aggressive Spitz tumors of undetermined biological significance (S-UBS) in this age group. Study objectives were to examine: factors leading to diagnostic delays, therapy side effects and patient outcomes in these diagnostic groups. Methods: A retrospective case review was performed using The University of Michigan’s pediatric oncology database over a 13-year timespan. Patients referred to our clinic for consideration of interferon therapy due to a diagnosis of a stage III melanoma or aggressive appearing S-UBS with significant lymph node involvement were included. Results: We found two major causes of diagnosis delay: patients with amelanotic lesions misdiagnosed as having a wart and cases reviewed by non-expert pathologists upfront. The side effects from interferon therapy requiring dose adjustments included neutropenia, thrombocytopenia and mood disturbances. There was wide variability in surveillance scan utilization, therefore leading to variability in patient radiation exposure. Unlike melanoma patients, none of the S-UBS patients experienced disease progression or death. Conclusions: This study highlights the challenges with the initial clinical diagnosis and pathological sub-categorization of the pediatric S-UBS/melanoma spectrum of skin lesions and emphasizes the role of expert pathology review upfront. Further, education at the primary care level could improve accurate and timely diagnoses. Earlier diagnosis could spare patients from more extensive interventions, metastatic spread or adverse outcomes in this patient population. This study is limited due to its retrospective, single-institution perspective.

To measure the effect of veterans’ preference on U.S. federal workforce quality, researchers have assessed whether military veterans advance in their federal careers at a different rate than nonveterans. This research, however, has produced mixed results. In research concerning recent employee cohorts, nonveterans outpace veterans’ advancement, implying that veterans’ preference lessens employee quality. In older cohorts, veterans and nonveterans advance comparably. The latter research, however, controls for employees’ entry positions, whereas research concerning recent cohorts does not do so, thus inhibiting direct comparison of results. To facilitate such comparisons, we controlled for veterans’ and nonveterans’ entry positions in a study of career advancement among all white-collar, U.S. executive branch workers entering employment from 1992 to 2013. In these recent cohorts, we find roughly equivalent rates of career advancement among veterans and nonveterans when controlling for entry positions. This finding holds when using grade or pay increases as measures of advancement.

Centralized sanctioning institutions cultivate cooperation by eradicating the gains from free-riding. Studies show that electing a community member to operate a centralized sanctioning institution further increases support for the public good. These studies have overlooked an all-too-common attribute of non-laboratory elections: political inequality. In this paper, we replicate those studies and, then, introduce novel experimental treatments that examine how political inequality influences the cooperation-enhancing effect of a democratic election to centralized sanctioning institutions. In our novel treatment conditions, participants receive either a random allotment of votes that they can use to elect a centralized sanctioning authority or an allocation of votes proportional to their earnings in a previously-executed public goods game. We find that political inequalities created via the random allocation of votes do not hinder cooperation, whereas political inequalities created via past game play undermine elected authorities and diminish contributions to the public good from individuals advantaged by political inequality.

Background and Objectives Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. Methods Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. Results Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2, and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. Conclusions SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2, and/or with ulceration. Thin melanoma

Previous research has reported correlations between the military service records of parents and their children. Those studies, however, have not determined whether a parent’s military service causally influences an offspring’s participation in the armed forces. To investigate the possibility of a causal relationship, we examined whether lottery numbers issued to draft-eligible men during the U.S. Vietnam-era Selective Service Lotteries influenced the military participation of those men’s children. Our study found higher rates of military participation among children born to fathers whose randomly assigned numbers were called for induction. Furthermore, we perform statistical analyses indicating that the influence of lottery numbers on the subsequent generation’s military participation operated through the military service of draft-eligible men as opposed to mechanisms unrelated to service such as “draft dodging.” These findings provide evidence of a causal link between the military service of parents and their children.

The incidence of melanoma is increasing, with 76 380 new cases of invasive melanoma and 68 480 new cases of melanoma in situ expected in 2016.To review the contemporary management of early-stage melanoma.We searched PubMed, MEDLINE, and the Cochrane Database of Systematic Reviews databases from January 1, 2011, to May 1, 2016, yielding 966 articles. We focused our search on early-stage (melanoma in situ, stage I, and stage II) cutaneous melanoma. After excluding articles, 41 articles were manually reviewed. A review of the bibliographies of selected articles generated additional references.While the majority of recent advances have been in the treatment of advanced melanoma, surgical excision with margins based on the presence and depth of invasion continues to be the cornerstone of management. Sentinel lymph node biopsy plays a central role in the staging and treatment of melanoma.Accurate diagnosis and adequate surgical excision are critical in reducing local recurrences and improving outcomes. Sentinel lymph node biopsy is useful in staging the regional nodal basin and guiding treatment in appropriately selected patients.

Past research shows that ethnic diversity reduces the ability to sanction norm violators, ultimately undermining cooperation. We test this directly by experimentally varying the ethnic composition of groups playing a dictator game with third-party punishment among two ethnic groups along the Kenya–Tanzania border. We also implement a structurally identical game where the endowment division is randomly determined in order to isolate a punishment motivation from the motivation to rectify income inequality. While costly income adjustment in both games is driven primarily by norm violations and inequality aversion, the ethnic composition of groups also influences sharing and sanctioning behavior in Kenya but not Tanzania, consistent with documented differences in the strength of nationalism across the two countries. However, the way in which shared ethnicity affects sanctioning in Kenya—namely, increased punishment of out-group violations against in-group members—is at odds with theories that anticipate that costly sanctioning will primarily target coethnics.

Significance Wartime mobilization shapes state development, since veterans also display high rates of civilian public employment. Such a pattern could result from a treatment effect of military service—likely resulting from government programs that institute veterans hiring preferences. Alternatively, veterans may be temperamentally predisposed to prefer public employment. We rule out this latter self-selection possibility by examining whether birthdates randomly called for induction in the Vietnam-Era Selective Service Lotteries appear disproportionately in the population of nonsensitive personnel records of the civilian US executive branch. We find that birthdates called for induction appear with disproportionately high frequency among draft-eligible employees at risk of induction. Net of selection, military service affects entry into public sector employment, and thus, wartime mobilization continues to influence who works in the administrative state., Since at least T. H. Marshall, scholars have recognized military service as a form of sacrifice that warrants compensation from the state. War-widow pensions, expansion of the franchise, and subsidized higher education are all examples of rights and benefits “bestowed” in return for wartime mobilization. Similarly, in the United States, governments have hired veterans preferentially for civilian public jobs as recompense for active military service. Although oft overlooked, those policies seem influential: the percentage of job holders identifying as veterans in the civilian US executive branch exceeds the proportion in the wider population by several multiples. This century-old pattern suggests another way that wartime mobilization has influenced the state. Yet, efforts to understand it have struggled to rule out the possibility that those who serve in the armed forces are predisposed to work for the state in both military and civilian capacities. Here, we rule out this possibility by examining whether birthdates randomly called for induction in the Vietnam-Era Selective Service Lotteries (VSSL) appear disproportionately in the population of nonsensitive personnel records of the civilian US executive branch. We find that birthdates called for induction appear with unusually high frequency among employees who were draft eligible and at risk for induction but not among other employees. This finding suggests a treatment effect from military service, thus dovetailing with the hypothesis that wartime mobilization has substantially and continually influenced who works in the contemporary administrative state.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.

Primary cutaneous umbilical melanoma is rare. Thorough information regarding its characteristics and treatment, including use of sentinel lymph node biopsy (SLNB) staging, is difficult to obtain. The unique anatomy of the umbilicus adds to the complexity of diagnosing and treating melanoma at this site.To improve understanding of diagnosis and treatment of primary cutaneous umbilical melanoma through presenting 7 new cases and reviewing 39 cases in the literature.The University of Michigan melanoma database query and review of the literature regarding reported cases of primary umbilical melanoma.In 7 new and 39 previously reported cases of primary cutaneous umbilical melanoma, we describe signs and symptoms, histopathologic features, differential diagnosis, relevant anatomical considerations, and definitive treatment including SLNB when applicable.Our series, combined with a thorough literature review and compilation of findings, provides a better understanding and appreciation of melanoma in the unique anatomical site of the umbilicus, with a reminder to carefully examine the umbilicus during a full skin examination in patients at risk of melanoma. Primary umbilical melanoma presents and can be appropriately treated similarly to cutaneous melanoma in other sites, with attention to relevant anatomy.

Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL). Objective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management. Design, Setting, and Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium. Main Outcomes and Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion. Results: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients. Conclusions and Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.

Myriad studies show that politically-salient events influence civic and political engagement. Yet, on the other hand, decades of research indicate that familial factors mold political and civic dispositions early in life, before an individual experiences political events outside the family. Viewing these two lines of research together, we ask if individuals’ political and civic dispositions might be influenced not solely by their own experiences, but, also, by the experiences of those individuals who create their family environment—namely, their parents. Do parents’ life experiences—before the birth of their children—affect their offspring’s public engagement? To answer that question, we examine how the assignment of military service, via the Vietnam-era Selective Service Lotteries, affected rates of public participation among the children of draft-eligible men. Our analysis finds a negative relationship between a father’s probability of draft-induced military service and his offspring’s public participation. In addition to highlighting how parents’ life experiences can influence the social behavior of their children, this finding challenges the prevailing view that the Vietnam conflict did not contribute to declining civic engagement and it shows how experiences within bureaucratic institutions can yield long-standing effects on politically-relevant behaviors.

Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.

Fibroblasts produce collagens and other proteins that form the bulk of the extracellular matrix (ECM) in connective tissues. Emerging data point to functional heterogeneity of fibroblasts. However, the lack of sub-type specific markers hinders our understanding of the different roles of fibroblasts in ECM biology, wound healing, diseases and aging. We have investigated the utility of the cell surface protein CD26 (dipeptidyl peptidase-4) to identify functionally distinct fibroblast subpopulations in human skin. Using flow cytometry and immunohistology, we find that CD26, in combination with the cell surface glycoprotein CD90, identifies a distinct subpopulation of cells which express relatively high levels of type I collagen (COL1A1), a hallmark of fibroblasts. Importantly, the population of CD26(+) fibroblasts is selectively increased following wounding of human skin. These cells account for the majority of COL1A1 expression during the ECM remodeling phase of healing. The proportion of CD26(+) fibroblasts in the skin of young and aged individuals is similar, indicating that loss of collagen production during aging does not involve selective reduction of CD26(+) fibroblasts. In culture, the majority of freshly isolated CD26(−) fibroblasts gain expression of CD26(+). Taken together, these data provide a foundation for targeting CD26(+) fibroblasts to modulate wound healing in human skin.

The oncofetal mRNA binding protein, IMP1 or insulin-like growth factor-2 mRNA-binding protein 1 [IGF2BP1], promotes the overexpression of several oncogenic proteins by binding to and stabilizing their mRNAs. IMP1 is frequently overexpressed in melanoma and is associated with a poor prognosis, but the full spectrum of IMP1 target transcripts remains unknown. Here we report identification of Protein Kinase C alpha (PKCα), as a novel molecular target of IMP1. Overexpression of IMP1 resulted in increased levels of PKCα, while RNAi knockdown of IMP1 resulted in decreased PKCα mRNA stability, PKCα protein levels, and MAPK/ERK activation. In addition to IMP1 acting as a positive regulator of PKCα mRNA, we also report the identification of miR-340 as a negative regulator of PKCα mRNA. In melanoma cancer cells, inhibition of miR-340 led to increased PKCα protein levels. PKCα plays important roles in numerous signaling pathways including the MAPK/ERK signaling pathway. PKCα activates RAF1, which in turn activates MEK1, and activates downstream transcriptional targets of MAPK through activation of JNK signaling. Together, these pathways provide a way to activate MAPK signaling downstream of BRAF and MEK1 inhibitors, which are commonly used to treat melanoma. Analysis of 117 melanoma tumors samples showed that overexpression of PKCα is associated with poorer overall survival. In patients harboring BRAF(V600E) or NRAS mutations, PKCα overexpression is associated with a 11-fold increased risk of death. Thus, PKCα mRNA is a novel target of IMP1, which is commonly overexpressed in melanoma and is linked to poorer overall survival.

Importance Early melanoma detection strategies include skin self-examination (SSE), physician skin examination (PSE), and promotion of patient knowledge about skin cancer. Objective To investigate the association of SSE, PSE, and patient attitudes with the detection of thinner superficial spreading melanoma (SSM) and nodular melanoma (NM), the latter of which tends to elude early detection. Design, Setting, and Participants This cross-sectional, questionnaire-based, multicenter study identified patients with newly diagnosed cutaneous melanoma at 4 referral hospital centers in the United States, Greece, and Hungary. Among 920 patients with a primary invasive melanoma, 685 patients with SSM or NM subtype were included. Interventions A standardized questionnaire was used to record sociodemographic information, SSE and PSE practices, and patient perceptions in the year prior to diagnosis. Main Outcomes and Measures Data were analyzed according to histologic thickness, with a 2-mm cutoff for thinner SSM and NM. Results Of 685 participants (mean [SD] age, 55.6 [15.1] years; 318 [46%] female), thinner melanoma was detected in 437 of 538 SSM (81%) and in 40 of 147 NM (27%). Patients who routinely performed SSE were more likely to be diagnosed with thinner SSM (odds ratio [OR], 2.61; 95% CI, 1.14-5.40) but not thinner NM (OR, 2.39; 95% CI, 0.84-6.80). Self-detected clinical warning signs (eg, elevation and onset of pain) were markers of thicker SSM and NM. Whole-body PSE was associated with a 2-fold increase in detection of thinner SSM (OR, 2.25; 95% CI, 1.16-4.35) and thinner NM (OR, 2.67; 95% CI, 1.05-6.82). Patient attitudes and perceptions focusing on increased interest in skin cancer were associated with the detection of thinner NM. Conclusions and Relevance Our findings underscore the importance of complementary practices by patients and physicians for the early detection of melanoma, including regular whole-body PSE, SSE, and increased patient awareness.

Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma.

To facilitate cooperation, moral externalization requires truthful and meticulous information about others’ moral commitments (Stanford target article, sect. 6). By definition, this information does not exist in the low-information environments where humans display their “hypercooperativeness.” Furthermore, collecting that information – if possible – entails costs that other mechanisms for correlated interaction avoid. Hence, moral externalization is an unlikely mechanism for cooperation, let alone “hypercooperation.”

Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

While SLN biopsy is recommended for melanoma ≥1 mm in depth, its use among the elderly population is more controversial. We reviewed our experience at the University of Michigan with melanoma patients ≥75 years of age. A total of 952 melanoma patients ≥75 years of age from 1996 to 2011 were identified from our institutional review board-approved database. In addition to clinicopathologic features and outcome data, comorbidity data were collected to calculate the Charlson comorbidity index (CCI). Univariate and multivariate Cox regression analysis was performed to characterize predictors of outcome. Kaplan–Meier analysis was used to generate survival curves. Among 553 clinically node-negative patients with melanoma ≥1 mm in Breslow thickness, 213 had wide excision alone, whereas 340 had excision and SLN biopsy, with 83 (24 %) having a positive SLN. SLN biopsy was less likely with older age (p

Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia.To characterize the clinicopathologic features of these rare lesions.Subungual atypical lentiginous melanocytic proliferations from patients20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible.Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome.Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only.Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.