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Rationale: Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator with unique tautomerase enzymatic activity; the precise function has not been clearly defined. We previously demonstrated that individual patients with cystic fibrosis (CF) who are genetically predisposed to be high MIF producers develop accelerated end-organ injury.Objectives: To characterize the effects of the MIF-CATT polymorphism in patients with CF ex vivo. To investigate the role of MIF's tautomerase activity in a murine model of Pseudomonas aeruginosa infection.Methods: MIF and tumor necrosis factor (TNF)-α protein levels were assessed in plasma or peripheral blood mononuclear cell (PBMC) supernatants by ELISA. A murine pulmonary model of chronic Pseudomonas infection was used in MIF wild-type mice (mif(+/+)) and in tautomerase-null, MIF gene knockin mice (mif (P1G/P1G)).Measurements and Main Results: MIF protein was measured in plasma and PBMCs from 5- and 6-CATT patients with CF; LPS-induced TNF-α production from PBMCs was also assessed. The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load, and intraacinar airspace/tissue volume were measured. MIF and TNF-α levels were increased in 6-CATT compared with 5-CATT patients with CF. LPS-induced TNF-α production from PBMCs was attenuated in the presence of ISO-1. In a murine model of Pseudomonas infection, significantly less pulmonary inflammation and bacterial load was observed in mif(P1G/P1G) compared with mif(+/+) mice.Conclusions: MIF-tautomerase activity may provide a novel therapeutic target in patients with chronic inflammatory diseases such as CF, particularly those patients who are genetically predisposed to produce increased levels of this cytokine. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation.Objectives: To identify transcription factor pathways uniquely activated in the lung in response to hypoxia.Methods: After exposure to environmental hypoxia (10% O(2)) for varying periods (3 h to 2 wk), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes the expression of which changed in the hypoxic lung (assessed using microarray analysis) identified potential lung-selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro.Measurements and Main Results: Bioinformatic analysis identified cAMP response element binding (CREB) family members as candidate lung-selective hypoxia-responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and activating transcription factor (ATF)1 and up-regulation of CREB family-responsive genes in the hypoxic lung, but not in other organs. Hypoxia-dependent CREB activation and CREB-responsive gene expression was observed in human primary lung, but not cardiac microvascular endothelial cells.Conclusions: These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia, and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia. [ABSTRACT FROM AUTHOR]

Background: Combination immune checkpoint blockade targeting PD-1 and CTLA-4 leads to high response rates and improved survival in advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM)., Objectives: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a real-world, diverse population of ALM., Methods: This multi-institutional retrospective study analyzed patients with histologically confirmed ALM treated with the combination of PD-1 and CTLA-4 inhibitors between 2010-2022. The primary objective of the study was objective response rate (ORR) per RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS)., Results: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n=81, 74.2%). The ORR for the entire cohort was 18.3% (95% CI 11.6-26.9%), with 9 (8.3%) complete responses (CR) and 11 (10.1%) partial responses (PR). An additional 22 patients (20.2%) had stable disease (SD), and the disease control rate (DCR) was 38.5%. The median PFS was 4.2 months [95% CI 3.25-5.62], while the median OS was 17 months [95% CI 12.4%-23.1%]. A total of 95 patients (87.2%) had a treatment-related adverse event, with 40.4% (n=44/109) experiencing at least one grade 3 or 4 toxicity. Elevated LDH (p=.04), 2+ lines of prior therapy (p=.03), and Asian race/ethnicity (p=.04) were associated with worse OS, while Hispanic/Latino race/ethnicity was associated with better OS (p=.02)., Conclusions: Combination of PD-1 and CTLA-4 blockade is less effective for ALM, as compared to CM, despite similar toxicity. Asian patients, in particular, appear to derive lower benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Dermatology is a competitive field for applicants pursuing a residency, and many applicants turn to dedicated research years to try and increase their competitiveness. Our study aimed to determine the financial costs of a research year and uncover how the costs of a research year vary for different demographic groups. We administered an anonymous survey through various dermatology listservs and social media platforms to prior, current, and future dermatology applicants who had completed a research fellowship during or after medical school. We found the median total fellowship cost ($26,443.20) was higher than the median fellowship income ($23,625.00). Furthermore, we found minority respondents had significantly lower total income, lower fellowship income, and higher net fellowship cost (p<0.05). Ninety participants completed surveys, and over half reported their research year as financially stressful. The majority did state that if given the opportunity, they would choose to do their research year again. Given the overall high costs of research years and the disparity in funding of these years, steps should be taken to address the disparities in fellowship funding or de-emphasize the importance of research fellowships in the dermatology residency selection process., (© 2023. W. Montague Cobb-NMA Health Institute.)

Many conservation actions must be implemented with limited data. This is especially true when planning recovery efforts for extirpated populations, such as grizzly bears (Ursus arctos) within the Bitterroot Ecosystem (BE), where strategies for reestablishing a resident population are being evaluated. Here, we applied individual-based movement models developed for a nearby grizzly bear population to predict habitat use in and near the BE, under scenarios of natural recolonization, reintroduction, and a combination. All simulations predicted that habitat use by grizzly bears would be higher in the northern half of the study area. Under the natural recolonization scenario, use was concentrated in Montana, but became more uniform across the northern BE in Idaho over time. Use was more concentrated in east-central Idaho under the reintroduction scenario. Assuming that natural recolonization continues even if bears are reintroduced, use remained widespread across the northern half of the BE and surrounding areas. Predicted habitat maps for the natural recolonization scenario aligned well with outlier and GPS collar data available for grizzly bears in the study area, with Spearman rank correlations of ≥0.93 and mean class values of ≥9.1 (where class 10 was the highest relative predicted use; each class 1-10 represented 10% of the landscape). In total, 52.4% of outlier locations and 79% of GPS collar locations were in class 10 in our predicted habitat maps for natural recolonization. Simulated grizzly bears selected habitats over a much larger landscape than the BE itself under all scenarios, including multiple-use and private lands, similar to existing populations that have expanded beyond recovery zones. This highlights the importance of recognizing and planning for the role of private lands in recovery efforts, including understanding resources needed to prevent and respond to human-grizzly bear conflict and maintain public acceptance of grizzly bears over a large landscape., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Immunotherapies have changed the landscape of late-stage melanoma; however, data evaluating timely access to immunotherapy are lacking., Methods: A retrospective cohort study utilizing the National Cancer Database was conducted. Stage III and IV melanoma cases diagnosed between 2011 and 2018 that received systemic treatment with either immunotherapy or chemotherapy were included. Chemotherapy included BRAF/MEK inhibitors. Multivariable logistic regression models were utilized to evaluate factors associated with the likelihood of receiving immunotherapy as primary systemic treatment relative to chemotherapy; additionally, Cox proportional hazards models were utilized to incorporate time from diagnosis to primary systemic therapy into the analysis., Results: The study population was comprised of 14,446 cases. The cohort included 12,053 (83.4%) immunotherapy and 2393 (16.6%) chemotherapy cases. In multivariable logistic regression analysis, factors significantly associated with immunotherapy receipt included population density, circle distance, year of diagnosis, Breslow thickness, and cancer stage. Immunotherapy timing was evaluated using multivariable Cox regression analysis. Minorities were less likely to receive timely immunotherapy than non-Hispanic Whites (HR 0.83, CI 0.74-0.93, p = 0.001). Patients at circle distances of 10-49 miles (HR 0.94, CI 0.89-0.99, p = 0.02) and ≥50 miles (HR 0.83, CI 0.77-0.90, p < 0.001) were less likely to receive timely immunotherapy., Conclusion: Patients traveling ≥10 miles and minorities have a decreased likelihood of receiving timely immunotherapy administration for primary systemic treatment. Future research is needed to identify what barriers and approaches can be leveraged to address these inequities., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Conflicts of interest Collin Costello, MD, has grant support from the Melanoma Research Alliance to support melanoma educational programs and research support from DeepX Health for melanoma imaging technology. Both were paid to the institution. Allan Halpern, MD, is an advisor to Canfield Scientific Inc and Scibase Inc.

Competing Interests: Author Costello has no relevant disclosures; unrelated to this study, he is an investigator for DeepX Health. Author Mangold has no relevant disclosures; he has consulted for Kyowa, Eli Lilly, Momenta, UCB, and Regeneron in the past, greater than 24 months ago; he has consulted for PHELEC in the past, greater than 12 months; he has consulted for Incyte, Soligenix, Clarivate, and Bristol Myers Squibb in the past, less than 12 months ago; he consults for Argenyx, Boehringer, Janssen, and Ingelheim currently; he consults for Regeneron and Pfizer currently with payments to the institution; he has grant support from Kyowa, Miragen, Regeneron, Corbus, Pfizer, Incyte, Eli Lilly, Aregenx, Palbella, Abbvie, Priovant, Merck in the last 24 months; beyond 24 months, grant support has come from Sun Pharma, Elorac, Novartis, and Janssen; and his current patents include Methods and Materials for assessing and treating cutaneous squamous cell carcinoma (provisional 63-423254), use of oral JAKi in Lichen Planus (provisional 63/453,065), and Topical Ruxolitinib in Lichen Planus (WO2022072814A1). Author Leachman has received unrestricted educational grant 18 months ago from Caste Biosciences and has been compensated for Orlucent MSAB within 24 months, and Merk MSAB co within 18 months; she has also served as the Co-I on Veriskin: clinical protocol uncompensated, Palvella: MSAB, Local CO-I for Pachyonychia congenita therapeutic uncompensated, and currently is working on Pathology Watch: MSAB research project support uncompensated. All other authors have no conflicts of interest and no financial disclosures.

Competing Interests: None disclosed.

Understanding the density-dependent processes that drive population demography in a changing world is critical in ecology, yet measuring performance-density relationships in long-lived mammalian species demands long-term data, limiting scientists' ability to observe such mechanisms. We tested performance-density relationships for an opportunistic omnivore, grizzly bears (Ursus arctos, Linnaeus, 1758) in the Greater Yellowstone Ecosystem, with estimates of body composition (lean body mass and percent body fat) serving as indicators of individual performance over two decades (2000-2020) during which time pronounced environmental changes have occurred. Several high-calorie foods for grizzly bears have mostly declined in recent decades (e.g., whitebark pine [Pinus albicaulis, Engelm, 1863]), while increasing human impacts from recreation, development, and long-term shifts in temperatures and precipitation are altering the ecosystem. We hypothesized that individual lean body mass declines as population density increases (H1), and that this effect would be more pronounced among growing individuals (H2). We also hypothesized that omnivory helps grizzly bears buffer energy intake from changing foods, with body fat levels being independent from population density and environmental changes (H3). Our analyses showed that individual lean body mass was negatively related to population density, particularly among growing-age females, supporting H1 and partially H2. In contrast, population density or sex had little effect on body fat levels and rate of accumulation, indicating that sufficient food resources were available on the landscape to accommodate successful use of shifting food sources, supporting H3. Our results offer important insights into ecological feedback mechanisms driving individual performances within a population undergoing demographic and ecosystem-level changes. However, synergistic effects of continued climate change and increased human impacts could lead to more extreme changes in food availability and affect observed population resilience mechanisms. Our findings underscore the importance of long-term studies in protected areas when investigating complex ecological relationships in an increasingly anthropogenic world., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Hispanics are more likely to be diagnosed with skin cancer at a later stage and experience worse overall survival than Whites. The objective of this cross-sectional study was to assess the skin cancer knowledge, attitudes, perceived risk, and sun protection practices among an underserved population in the Phoenix area. We recruited participants from the greater Phoenix area to undergo skin examination and complete a questionnaire. 208 participants were included. The majority were Hispanic (64.9%). Of this Hispanic group, most were from Mexico (87.9%). The Hispanic cohort had an overall mean skin cancer knowledge score of 3.68/6, the lowest of any other racial/ethnic group, but had the highest desire to learn more about skin cancer (64.6%, "strongly agree"). They were the most concerned about developing skin cancer (50.4%, "very concerned") but had relatively lower rates of sun protection practices (7.9% "always use" sunscreen, 22.0% "always use" sun-protective clothing). Limitations of this study include a small sample size, lack of validation for the skin cancer knowledge score, lack of season as a covariate in the multivariate analysis, lack of follow-up, and lack of robust skin cancer risk assessment. In conclusion, despite poorer skin cancer knowledge and sun protection practices, the Hispanic population had the highest concern for developing skin cancer and desire to learn more about skin cancer. Targeted and culturally relevant skin cancer and sun protection education for this group is needed., (© 2022. W. Montague Cobb-NMA Health Institute.)

Uric acid disequilibrium is implicated in chronic hyperuricemia-related diseases. Long-term monitoring and lowering of serum uric acid levels may be crucial for diagnosis and effective management of these conditions. However, current strategies are not sufficient for accurate diagnosis and successful long-term management of hyperuricemia. Moreover, drug-based therapeutics can cause side effects in patients. The intestinal tract plays an important role in maintaining healthy serum acid levels. Hence, we investigated the engineered human commensal Escherichia coli as a novel method for diagnosis and long-term management of hyperuricemia. To monitor changes in uric acid concentration in the intestinal lumen, we developed a bioreporter using the uric acid responsive synthetic promoter, pucpro , and uric acid binding Bacillus subtilis PucR protein. Results demonstrated that the bioreporter module in commensal E. coli can detect changes in uric acid concentration in a dose-dependent manner. To eliminate the excess uric acid, we designed a uric acid degradation module, which overexpresses an E. coli uric acid transporter and a B. subtilis urate oxidase. Strains engineered with this module degraded all the uric acid (250 µM) found in the environment within 24 h, which is significantly lower ( p < 0.001) compared to wild type E. coli . Finally, we designed an in vitro model using human intestinal cell line, Caco-2, which provided a versatile tool to study the uric acid transport and degradation in an environment mimicking the human intestinal tract. Results showed that engineered commensal E. coli reduced ( p < 0.01) the apical uric acid concentration by 40.35% compared to wild type E. coli . This study shows that reprogramming E. coli holds promise as a valid alternative synthetic biology therapy to monitor and maintain healthy serum uric acid levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gencer, Mancuso, Chua, Ling, Costello, Chang and March.)

Polyphenon E (Poly E) is a standardized, caffeine-free green tea extract with defined polyphenol content. Poly E is reported to confer chemoprotective activity against prostate cancer (PCa) progression in the TRAMP model of human PCa, and has shown limited activity against human PCa in human trials. The molecular mechanisms of the observed Poly E chemopreventive activity against PCa are not fully understood. We hypothesized that Poly E treatment of PCa cells induces gene expression changes, which could underpin the molecular mechanisms of the limited Poly E chemoprevention activity against PCa. PC-3 cells were cultured in complete growth media supplemented with varied Poly E concentrations for 24 h, then RNA was isolated for comparative DNA microarray (0 vs. 200 mg/L Poly E) and subsequent TaqMan qRT-PCR analyses. Microarray data for 54,613 genes were filtered for >2-fold expression level changes, with 8319 genes increased and 6176 genes decreased. Eight genes involved in key signaling or regulatory pathways were selected for qRT-PCR. Two genes increased expression significantly, MXD1 (13.98-fold; p = 0.0003) and RGS4 (21.98-fold; p = 0.0011), by qRT-PCR. MXD1 and RGS4 significantly increased gene expression in Poly E-treated PC-3 cells, and the MXD1 gene expression increases were Poly E dose-dependent.

Secretory IgA (SIgA) is the most abundant antibody type in intestinal secretions where it contributes to safeguarding the epithelium from invasive pathogens like the Gram-negative bacterium, Salmonella enterica serovar Typhimurium (STm). For example, we recently reported that passive oral administration of the recombinant monoclonal SIgA antibody, Sal4, to mice promotes STm agglutination in the intestinal lumen and restricts bacterial invasion of Peyer's patch tissues. In this report, we sought to recapitulate Sal4-mediated protection against STm in human Enteroids and human intestinal organoids (HIOs) as models to decipher the molecular mechanisms by which antibodies function in mucosal immunity in the human gastrointestinal tract. We confirm that Enteroids and HIO-derived monolayers are permissive to STm infection, dependent on HilD, the master transcriptional regulator of the SPI-I type three secretion system (T3SS). Stimulation of M-like cells in both Enteroids and HIOs by the addition of RANKL further enhanced STm invasion. The apical addition of Sal4 mouse IgA, as well as recombinant human Sal4 dimeric IgA (dIgA) and SIgA resulted a dose-dependent reduction in bacterial invasion. Moreover, basolateral application of Sal4 dIgA to Enteroid and HIO monolayers gave rise to SIgA in the apical compartment via a pathway dependent on expression of the polymeric immunoglobulin receptor (pIgR). The resulting Sal4 SIgA was sufficient to reduce STm invasion of Enteroid and HIO epithelial cell monolayers by ~20-fold. Recombinant Sal4 IgG was also transported in the Enteroid and HIOs, but to a lesser degree and via a pathway dependent on the neonatal Fc receptor (FCGRT). The models described lay the foundation for future studies into detailed mechanisms of IgA and IgG protection against STm and other pathogens.

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest Dr Mangold reports personal fees from Kirin and grants from Elorac, MiRagen, Solagenix, DUSA/Sun Pharma, and Acetilion, outside the submitted work. Drs Costello, DiCaudo, Comfere, Sluzevich, Rule, Craig, Rosenthal, and Pittelkow and authors Besch-Stokes, Severson, Bhullar, Montoya, and Butterfield have no conflicts of interest to declare.

Background: A new trend includes taking a dedicated year away from medical school to complete a research fellowship. There is minimal data on the benefit of a gap year. We aimed to identify if a gap year makes a dermatology applicant more successful in The Match., Methods: Dermatology applicants who applied to Mayo Clinic Arizona for the 2018-2019 application cycle and Mayo Clinic Rochester, Arizona, and Florida for the 2019-2020 application cycle were surveyed., Results: In total, 291 dermatology applicants completed the initial survey, and 236 completed the follow-up survey. Ninety applicants took a gap year, 198 applicants did not. There was no significant difference in match rates. When comparing match rates at top dermatology residency programs, 40.6% of gap-year applicants matched to these residencies versus 19.0% of no gap-year applicants (P < 0.01)., Conclusion: Applicants should weigh the opportunity costs before pursuing research gap years as they may not be universally helpful. Applicants who want to match at a top dermatology program may benefit from a research gap year. This data may have limited generalizability outside of the United States., (© 2021 the International Society of Dermatology.)

Background: Cutaneous squamous cell carcinomas (cSCC) have upstage rates of approximately 10.3% to 11.1%. Data are currently limited on the rate of upstaging for metastatic cSCC., Objective: The aim of this study was to determine the rates of upstaging, between diagnosis and surgery, and differences in management for metastatic and non-metastatic high-risk cSCC., Materials and Methods: This was a retrospective, case-control, single institution, multi-center study. Univariate analysis was used., Results: Sixty-eight subjects (34 metastatic & 34 non-metastatic) with 69 tumors were included. The overall rate of upstaging was 46.4%. The most common reasons for upstage were undocumented tumor size and under-diagnosis of poor differentiation. There were no differences in rates of upstaging. Preoperative imaging was performed in 43.6% of wide local excisions (WLE) versus 3.3% of Mohs micrographic surgery (MMS; p < .001). The median days from surgery to sentinel lymph node biopsy (SLNB), or nodal dissection was shorter for WLE versus MMS (0 vs 221 days, p < .001)., Conclusion: Improved clinical documentation, including documenting tumor size, and the identification of pathologic risk factors, including poor differentiation and depth of invasion, are needed for proper staging. Preoperative imaging and discussion of SLNB may be beneficial for high-risk T2b and T3 tumors., (Copyright © 2021 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The field of dermatology is one of the least racially diverse specialties. We aimed to identify ways in which minorities become underrepresented within dermatology., Methods: We surveyed dermatology applicants who applied to Mayo Clinic in Scottsdale, AZ during the 2018-2019 application cycle and Mayo Clinic in Rochester, Scottsdale, and Jacksonville during the 2019-2020 application cycles. Underrepresented minorities (URM) were defined as Latino/Latina, African American, American Indian/Alaska Native, or Native Hawaiian/Pacific Islander., Results: In total, 149 and 142 dermatology applicants completed the initial 2019 and 2020 surveys, 112 and 124 completed the follow-up surveys. The racial breakdown was 69.9% Caucasian, 23.7% Asian, 5.4% African American, 0.4% American Indian/Alaska Native, and 0.7% Native Hawaiian/Pacific Islander. Eight percent identified as Hispanic/Latino. Median Step 1 scores were lower for URM (p<0.01). URM had more publications (p=0.01). There were no observed differences in away rotations or interviews attended. URM were less likely to match (76.7%) vs. Whites (88.4%) and Asians (96.0%; p=0.03)., Conclusion: URM are taking out more loans, pursuing research fellowships more often than their White counterparts, publishing more, completing the same number of away rotations and interviews, yet have lower match rates leading to underrepresentation in the field. It is important to realize how Step scores might reflect and reproduce disparities between different racial/ethnic backgrounds, in turn influencing the racial composition of dermatology residency programs., Competing Interests: Declaration of Competing Interest No authors have a conflict of interest., (Copyright © 2021 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Cutaneous B cell pseudolymphoma (CBPL), or cutaneous lymphoid hyperplasia, is the most common pseudolymphoma. It typically responds well to local treatment and follows a benign course. Herein, we describe the unique case of a patient with CBPL that was refractory to a variety of treatments, with subsequent response to rituximab followed by methotrexate. This case explores the complex interplay of T and B lymphocytes, and the potential role of perifollicular T cells in treatment resistant CBPL. Further, it describes the additive therapeutic effect of rituximab and methotrexate to target both B cell and T cell populations in CBPL, a strategy already employed in a number of other conditions.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation., Methods: Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival., Results: The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4-7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune-related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI-induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow-up period of 4.6 months (interquartile range, 1.5-13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death., Conclusions: ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further., (© 2020 American Cancer Society.)

Introduction: Access to dermatologic care is a major issue in the United States, especially within the un- and underinsured populations; technology, including teledermatology, will pay a role in improving access to care. Methods: We performed a prospective study between November 2016 and September 2017. We leveraged a partnership between Mayo Clinic and Mountain Park Health Clinic, a community clinic that primarily serves un- and underinsured populations. We implemented a mobile phone-based store and forward (SAF) teledermatology service, which integrated an external community health clinic to an existing electronic health record (EHR) using standardized data capture forms, real-time support, and simple workflows. Results: Thirty-seven patients were enrolled in the study, 65% female and 35% male with an average age of 47.9 (SD = 15.9). The ethnic breakdown was: 81.1% Hispanic, 13.5% Caucasian, and 5.4% African American. The majority, 62.2%, did not have a high school education, 45.9% were unemployed, and 51.4% were uninsured. 64.9% earned less than $25,000 for annual household income. Teledermatology consultation increased the absolute diagnostic and management concordance by 36.6% (p  = 0.01, 95% CI 12.2%-61.0%) and 34.2% ( p < 0.01, 95% CI 11%-57%), respectively. Primary care providers had a significant increase in mean confidence in the diagnosis and management of dermatology conditions pre and poststudy (3.60 vs. 3.70 and 3.21 vs. 3.60, respectively; p < 0.01). Ninety-six percent of the primary care providers agreed (52.0%) and strongly agreed (44.0%) that they would send another patient for teleconsultation. Conclusion: We successfully implemented a SAF teledermatology consultative service in a community health clinic outside our EHR. A similar approach can be used by other large health care organizations to provide integrated, high-quality consultation to clinics with rural, un- and underinsured populations.

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease., Objective: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease., Methods: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome., Results: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113)., Limitations: This is a multicenter but single institution study of a white population., Conclusion: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Little research has been done in teledermatology to examine the effects of standardized templates and subject-specific learning modules., Methods: We performed a prospective study examining the effects of standardized templates and standardized cutaneous oncology learning modules on teledermatology referrals at Mayo Clinic. This data was then compared to previous teledermatology referrals before standardized templates were adopted., Results: A total of 42 teledermatology consultations were performed during the 4-month study period. The use of standardized templates resulted in an absolute reduction in face-to-face referrals. Teledermatology consultation increased the absolute diagnostic and management concordance by 26.2% (P = 0.02) and 33.3% (P < 0.01), respectively, and decreased the absolute diagnostic and management discordance by 19.1% (P = 0.03) and 31.0% (P < 0.01), respectively. The largest knowledge gaps were identified in cutaneous oncology. Educational intervention improved theoretical referral rates and confidence in diagnosis and management overall., Conclusion: The implementation of standardized intake templates reduces the rate of face-to-face referrals. Teledermatology improves primary care-based dermatological care and reduces theoretical referral rates., (© 2019 The International Society of Dermatology.)

Dermatologic diagnosis and monitoring have been dependent largely on visual grading. A skin biopsy is performed in case of diagnostic uncertainty, but can be traumatic, and results are delayed due to time for specimen transport and processing. Biopsies also destroy specimens, prohibiting lesion evolution monitoring. In vivo reflectance confocal microscopy (RCM) offers a diagnostic alternative to skin biopsy. RCM captures real-time, high-resolution images, and has been piloted for the evaluation of various dermatologic conditions. Identification of unique RCM features may distinguish dermatoses with similar clinical morphologies. Allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) are diagnosed by patch testing that currently uses a subjective scoring system. RCM has increasingly been studied for early detection and severity grading of CD. Common RCM features shared by ACD and ICD are stratum corneum disruption, vesicle formation, exocytosis, spongiosis, and parakeratosis. Features unique to ACD are vasodilation, increased epidermal thickness, intercellular edema, and acanthosis. Features unique to ICD are detached corneocytes and targetoid keratinocytes. This review summarizes the use of RCM in evaluating contact eccematous conditions and aims to spark future research and interest in this promising tool., (Copyright © 2019 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Impact Statement: This study is significant because it demonstrates an attempt to design a scaffold specifically for small intestine using a novel fabrication method, resulting in an architecture that resembles intestinal villi. In addition, we use the versatile polymer poly(glycerol sebacate) (PGS) for artificial intestine, which has tunable mechanical and degradation properties that can be harnessed for further fine-tuning of scaffold design. Moreover, the utilization of PGS allows for future development of growth factor and drug delivery from the scaffolds to promote artificial intestine formation.

Background: The development of procedural skills is necessary for medical students. Computer-based video instruction (CBVI) increases knowledge and procedural skills., Objective: This pilot study's aim was to investigate the usefulness of CBVI in dermatologic procedure training for medical students and secondarily assess students' overall perception of the field of dermatology., Methods: Twenty-nine first- and second-year medical students were randomly assigned to the CVBI group or control group, in addition to in-person instructor demonstration of shave and punch biopsies using fresh cadaver tissue. Blinded evaluators graded student performances using a five-point Likert scale immediately after demonstration, and 1 week later to assess knowledge retention., Results: In overall performance, the CBVI group demonstrated higher scores both in shave (3.54 vs 2.59, p = .01) and punch biopsies (3.63 vs 2.88, p = .01) at immediate recall and knowledge retention (3.68 vs 2.67, p = .01; 4.00 vs 2.99, p < .001, respectively). Approximately 33.3% of the students stated that the experience increased their interest in the field of dermatology., Conclusion: Incorporation of CBVI into the dermatology curriculum augments medical students' procedural skills. The CBVI group performed significantly better in all 7 grading categories for shave biopsy and in 5 of 7 categories for punch biopsy. Integration of procedural laboratory tests raises students' interest in dermatology.

Background: Inositol polyphosphate 5-phosphatase (INPP5A) has been shown to play a role in development and progression of cutaneous squamous cell carcinoma (cSCC). The goal of the current study was to explore the prognostic value of INPP5A expression in cSCC., Methods: A total of 189 cases of actinic keratosis and SCC in 174 patients were identified; clinical and outcome data were abstracted, histopathology was rereviewed, and immunohistochemical staining and interpretation was performed for INPP5A., Results: The majority of tumors (89.4%) had an INPP5A score of 2 or 3. No patients had complete loss of INPP5A. Tumors with an INPP5A score of 1 were more likely to be intermediate- to high-risk tumors (Brigham and Women's Hospital stage ≥T2a 85.0% vs 23.7% [P < .0001]) characterized by a larger diameter (2.4 cm vs 1.3 cm [P = .0004]), moderate-to-poor differentiation (86.7% vs 17.6% [P < .0001]), and perineural invasion (37.5% vs 5.3%, [P < .0001]). An INPP5A score of 1 was associated with a worse 3-year survival (a rate of 42.3% [hazard ratio, 2.81, P = .0006]) and a local metastasis rate of 48.0% (hazard ratio, 4.71; P < .0001)., Conclusions: Low INPP5A scores are predictive of aggressive tumors and may be a useful adjunct to guide clinical management of cSCC., (Copyright © 2018. Published by Elsevier Inc.)

Background: Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy., Objective: To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA., Methods: Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment., Results: Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved., Limitations: Single-institution, retrospective review with a small sample size., Conclusion: Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The benign and malignant patterns of acral melanocytic naevi (AMN) and acral melanomas (AM) have been defined in a series of retrospective studies. A three-step algorithm was developed to determine when to biopsy acral melanocytic lesions. This algorithm has only been applied to a Japanese population., Objectives: Our study aimed to review the current management strategy of acral melanocytic lesions and to investigate the utility of the three-step algorithm in a predominately Caucasian cohort., Methods: A retrospective search of the pathology and image databases at Mayo Clinic was performed between the years 2006 and 2016. Only cases located on a volar surface with dermoscopic images were included. Two dermatologists reviewed all dermoscopic images and assigned a global dermoscopic pattern. Clinical and follow-up data were gathered by chart review. All lesions with known diameter and pathological diagnosis were used for the three-step algorithm., Results: Regular fibrillar and ridge patterns were more likely to be biopsied (P = 0.01). The majority of AMN (58.1%) and AM (60%) biopsied were due to physician-deemed concerning dermoscopic patterns. 39.2% of these cases were parallel furrow, lattice-like or regular fibrillar. When patients were asked to follow-up within a 3- to 6-month period, only 16.7% of the patients returned within that interval. The three-step algorithm would have correctly identified four of five AM for biopsy, missing a 6 mm, multicomponent, invasive melanoma., Conclusion: We found one major educational gap in the recognition of low-risk lesions with high rates of biopsy of the fibrillary pattern. Recognizing low-risk dermoscopic patterns could reduce the rate of biopsy of AMN by 23.3%. We identified two major practice gaps, poor patient compliance with follow-up and the potential insensitivity of the three-step algorithm to small multicomponent acral melanocytic lesions., (© 2017 European Academy of Dermatology and Venereology.)