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Importance: Somatic variants in the RAS/MAPK pathway genes are commonly associated with melanocytic nevi and melanoma, whereas germline variants in these genes are associated with RASopathies, syndromes involving multiple organs, including the skin. Nevi counts may be higher in some RASopathies, but studies on features observed through dermoscopy are limited., Objective: To determine the distinguishing dermoscopic features of melanocytic nevi and how the RAS pathway influences them by comparing nevi in patients with cardiofaciocutaneous syndrome (CFC) and Costello syndrome (CS)., Design, Setting, and Participants: In this prospective cohort study, patients with CFC and CS, 2 RASopathies caused by variants in the downstream and upstream components of the RAS/MAPK pathway, were recruited from the international CFC and CS family conferences. Some patients with CFC also elected to participate in a longitudinal follow-up study., Main Outcomes and Measures: The main outcomes were dermoscopic features and, in the longitudinal follow-up study, nevi counts, which were recorded over time., Results: A total of 39 patients, 16 with CFC and 23 with CS, were enrolled (overall cohort: 26 [66.7%] female; median [IQR] age, 13.0 [7.6-22.0] years). The 112 nevi overall frequently displayed an organized dermoscopic pattern (CFC, 61 [84.7%]; CS, 34 [85.0%]) rather than a disorganized pattern (CFC, 6 [8.3%]; CS, 1 [2.5%]). Of the organized nevi, homogenous brown was the most common pattern (CFC, 41 [67.2%]; CS, 22 [64.7%]), followed by reticular (CFC, 11 [18.0%]; CS, 7 [20.6%]) and globular (CFC, 9 [14.8%]; CS, 5 [14.7%]). Pigmented networks occurred in 12 nevi in CFC (16.7%) and 6 nevi in CS (15%; P > .99). Of these, 6 CFC-associated nevi (50%) and no CS-associated nevi had atypical networks (P = .05). Six patients with CFC in the follow-up study developed significantly more nevi within 5 years (median [IQR] increase, 24.5 [10-120] nevi; P = .04)., Conclusions and Relevance: In this cohort study, the findings suggest that nevi in patients with CFC and CS commonly display organized homogenous brown dermoscopic patterns, and the number of nevi may significantly increase over time in those with CFC. A disorganized pattern and atypical networks may be more frequent in patients with CFC. Future studies are needed to determine the risk of melanoma in individuals with CFC or CS.

Competing Interests: Conflicts of Interest: None declared.

Background: S100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME., Objectives: To compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case-control study., Methods: A previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0-4%; 2 = 5-25%; 3 = 26-50%; 4 = 51-75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1-50%; 3 = > 50%). A positive test was defined as > 50% staining., Results: The area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6-52.8%] and 98.2% (95% CI 93.6-99.8%) for S100A8, and 79.8% (95% CI 70.5-87.2%) and 87.3% (95% CI 79.6-92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7-49.7%) and specificity of 99.1% (95% CI 95.0-100.0%)., Conclusions: S100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma., Competing Interests: Conflicts of interest M.K. reports a pending patent application. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tumor necrosis factor (TNF) inhibitors may paradoxically induce pustular eruptions, most of which are classified as pustular psoriasis. Amicrobial pustulosis of the folds (APF) is a much rarer entity that was recently recognized to occur in the setting of chronic anti-TNF therapy and inflammatory bowel disease, with 12 existing cases in the literature. Amicrobial pustulosis of the folds is a neutrophilic dermatosis characterized by aseptic pustules involving the major and minor skin folds, genital regions, and scalp. Herein, we report an additional case of paradoxical APF induced by chronic infliximab therapy in a patient with Crohn disease.

Neurofibromatosis type 1 ( NF1 ) is commonly mutated in melanoma, yet the risk of melanoma in individuals with NF1 is incompletely understood. We performed a systematic review to investigate the risk and characteristics of melanoma and melanocytic nevi in NF1 individuals. PubMed was searched for articles describing NF1 individuals with melanoma, or melanocytic nevi. Those with cutaneous and ocular melanomas were compared to the general population using Surveillance, Epidemiology, and End Results data. Fifty-three articles describing 188 NF1 patients were included (melanoma n  = 82, melanocytic nevi n  = 93, melanocytic nevi, and melanoma n  = 13). Compared to the general population, NF1 patients with cutaneous melanomas had earlier melanoma diagnoses (49.1 vs. 58.6 years, P = 0.012), thicker tumors (3.7 vs. 1.2 mm, P = 0.006), and more frequent disease-specific deaths (27.3% vs. 8.6%, P = 0.005) with shorter survival (12.9 vs. 34.2 months, P = 0.011). Ocular melanomas made up 15.0% of all melanomas in NF1 patients versus 1.5% in the general population ( P < 0.001). In pooling all population-based studies describing melanoma in NF1 populations, NF1 individuals had 2.55 higher odds of having melanoma compared to the general population. A nevus spilus was commonly reported among NF1 individuals with nevi (44.8%, 39/87). Our findings suggest that NF1 individuals may have a higher risk for developing melanomas and tend to have thicker melanomas and worse survival compared to the general population, highlighting the importance of cutaneous and ophthalmologic surveillance in NF1 patients. Our review also supports the association between NF1 and nevus spilus., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: None disclosed.

Frontal fibrosing alopecia (FFA) is a progressive cicatricial alopecia that can affect patients with skin of color (SOC); however, patients with SOC often are underrepresented in clinical trials and scientific publications on FFA. To better understand the management of FFA in patients with SOC, we sought to assess the clinical evidence for the efficacy of FFA treatment modalities specifically in these patients. This systematic review discusses studies on FFA characteristics and treatment outcomes in Black patients.

Introduction: The purpose of this study was to evaluate the effect of collimation on image quality and radiation dose to the eye lenses of the personnel involved in computed radiography of the canine pelvis. Materials and Methods: A retrospective study of canine pelvic radiographs ( N = 54) was undertaken to evaluate the relationship between image quality and the degree of field the collimation used. This was followed by a prospective cadaver study ( N = 18) that assessed the effects on image quality and on scattered radiation dose of different collimation field areas and exposure parameters. All radiographs were analyzed for image quality using a Visual Grading Analysis (VGA) with three observers. Finally, the potential scattered radiation dose to the eye lens of personnel restraining a dog for pelvic radiographs was measured. Results: The retrospective study showed a slightly better (statistically non-significant) VGA score for the radiographs with optimal collimation. Spatial and contrast resolution and image sharpness showed the greatest improvement in response to minimizing the collimation field. The prospective study showed slightly better VGA scores (improved image quality) with the optimal collimation. Increasing the exposure factors especially the tube current and exposure time (mAs) resulted in improved low contrast resolution and less noise in the radiographs. The potential eye lens radiation dose increased by 14, 28, and 40% [default exposures, increased the tube peak potential (kVp), increased mAs, respectively] as a result of reduced collimation (increased beam size). Conclusion: The degree of collimation has no statistically significant on image quality in canine pelvic radiology for the range of collimation used but does have an impact on potential radiation dose to personnel in the x-ray room. With regard to radiation safety, increases in kVp are associated with less potential scatter radiation exposure compared to comparable increases in mAs., 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 © 2021 Bisgaard, McEvoy, Nielsen, Allberg, Müller, Timm, Meyer, Johansen, Pedersen and Precht.)

CtIP is a DNA end resection factor widely implicated in alternative end-joining (A-EJ)-mediated translocations in cell-based reporter systems. To address the physiological role of CtIP, an essential gene, in translocation-mediated lymphomagenesis, we introduced the T855A mutation at murine CtIP to nonhomologous end-joining and Tp53 double-deficient mice that routinely succumbed to lymphomas carrying A-EJ-mediated IgH-Myc translocations. T855 of CtIP is phosphorylated by ATM or ATR kinases upon DNA damage to promote end resection. Here, we reported that the T855A mutation of CtIP compromised the neonatal development of Xrcc4 -/- Tp53 -/- mice and the IgH-Myc translocation-driven lymphomagenesis in DNA-PKcs -/- Tp53 -/- mice. Mechanistically, the T855A mutation limits DNA end resection length without affecting hairpin opening, translocation frequency, or fork stability. Meanwhile, after radiation, CtIP-T855A mutant cells showed a consistent decreased Chk1 phosphorylation and defects in the G2/M cell cycle checkpoint. Consistent with the role of T855A mutation in lymphomagenesis beyond translocation, the CtIP-T855A mutation also delays splenomegaly in λ-Myc mice. Collectively, our study revealed a role of CtIP-T855 phosphorylation in lymphomagenesis beyond A-EJ-mediated chromosomal translocation., Competing Interests: The authors declare no competing interest.

The nicotinamide cofactor specificity of enzymes plays a key role in regulating metabolic processes and attaining cellular homeostasis. Multiple studies have used enzyme engineering tools or a directed evolution approach to switch the cofactor preference of specific oxidoreductases. However, whole-cell adaptation toward the emergence of novel cofactor regeneration routes has not been previously explored. To address this challenge, we used an Escherichia coli NADPH-auxotrophic strain. We continuously cultivated this strain under selective conditions. After 500 to 1,100 generations of adaptive evolution using different carbon sources, we isolated several strains capable of growing without an external NADPH source. Most isolated strains were found to harbor a mutated NAD + -dependent malic enzyme (MaeA). A single mutation in MaeA was found to switch cofactor specificity while lowering enzyme activity. Most mutated MaeA variants also harbored a second mutation that restored the catalytic efficiency of the enzyme. Remarkably, the best MaeA variants identified this way displayed overall superior kinetics relative to the wild-type variant with NAD + . In other evolved strains, the dihydrolipoamide dehydrogenase (Lpd) was mutated to accept NADP + , thus enabling the pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase complexes to regenerate NADPH. Interestingly, no other central metabolism oxidoreductase seems to evolve toward reducing NADP + , which we attribute to several biochemical constraints, including unfavorable thermodynamics. This study demonstrates the potential and biochemical limits of evolving oxidoreductases within the cellular context toward changing cofactor specificity, further showing that long-term adaptive evolution can optimize enzyme activity beyond what is achievable via rational design or directed evolution using small libraries. IMPORTANCE In the cell, NAD(H) and NADP(H) cofactors have different functions. The former mainly accepts electrons from catabolic reactions and carries them to respiration, while the latter provides reducing power for anabolism. Correspondingly, the ratio of the reduced to the oxidized form differs for NAD + (low) and NADP + (high), reflecting their distinct roles. We challenged the flexibility of E. coli 's central metabolism in multiple adaptive evolution experiments using an NADPH-auxotrophic strain. We found several mutations in two enzymes, changing the cofactor preference of malic enzyme and dihydrolipoamide dehydrogenase. Upon deletion of their corresponding genes we performed additional evolution experiments which did not lead to the emergence of any additional mutants. We attribute this restricted number of mutational targets to intrinsic thermodynamic barriers; the high ratio of NADPH to NADP + limits metabolic redox reactions that can regenerate NADPH, mainly by mass action constraints.

Over the last decades, the revolution in DNA sequencing has changed the way we understand the genetics and biology of B-cell lymphomas by uncovering a large number of recurrently mutated genes, whose aberrant function is likely to play an important role in the initiation and/or maintenance of these cancers. Dissecting how the involved genes contribute to the physiology and pathology of germinal center (GC) B cells -the origin of most B-cell lymphomas- will be key to advance our ability to diagnose and treat these patients. Genetically engineered mouse models (GEMM) that faithfully recapitulate lymphoma-associated genetic alterations offer a valuable platform to investigate the pathogenic roles of candidate oncogenes and tumor suppressors in vivo , and to pre-clinically develop new therapeutic principles in the context of an intact tumor immune microenvironment. In this review, we provide a summary of state-of-the art GEMMs obtained by accurately modelling the most common genetic alterations found in human GC B cell malignancies, with a focus on Burkitt lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma, and we discuss how lessons learned from these models can help guide the design of novel therapeutic approaches for this disease., 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 © 2021 Meyer, Koul and Pasqualucci.)

Background: Currently, limited information is available regarding selection of the most successful strategies for recruitment of older adult kidney transplant recipients as research participants., Objective: The aim of this study was to explore multiple modes of recruitment strategies to enroll older kidney transplant recipients in a 1-year longitudinal study., Methods: We used a feasibility design to explore the following recruitment methods: face-to-face contact in the transplant clinic, paper flyers placed in the transplant clinic, Facebook, an online transplant newsletter, and a university website listing of research studies., Results: Enrollment was open for 9 months, during which time websites and the Facebook portal were active, 142 newsletters were e-mailed, and 424 patients were approached in the transplant clinic. Among patients approached in the clinic, 12 did not own a smartphone required for the study. The sample consisted of 60 participants (39 men, 21 women), with a mean age of 64.5 ± 4.7 years. Of the participants who enrolled in the study, the largest number (75%, n = 45) was recruited using the face-to-face method in the transplant clinic. The online transplant newsletter was the second-best recruitment source (18%, n = 11)., Discussion: Recruitment strategies using face-to-face contact and the online newsletter associated with the transplant clinic organization appeared to be more effective than strategies not associated with the transplant clinic (Facebook and university website). Findings suggest that using a familiar organization communication method to recruit older chronic disease population may be the most beneficial.

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tumor buds in colorectal cancer are hypothesized to undergo a (partial) epithelial-mesenchymal transition (EMT). If so, cytokeratin (CK) and vimentin (VIM) co-expression is expected. CK+/VIM+ can also be found in some stromal cells; however, their origin remains unclear. Here, we determine the frequency of CK+/VIM+ tumor cells and characterize the CK+/VIM+ stroma in colorectal cancer. Three cell populations (CK+, VIM+, CK+/VIM+) were sorted using DepArray and fluorescence-activated cell sorting (FACS). Tumor areas were selected to include tumor center, stroma and tumor budding. Fluorescence microscopy was used to visualize co-expressing cells on whole slides. A next-generation tissue microarray (ngTMA) of matched Pan-CK-positive and -negative stroma was constructed and stained for E-cadherin, VIM, Snail1, Twist1, Zeb1 and Zeb2, COL11A1, SPARC, CD90, α-SMA, FAP and WT1. CK+/VIM+ co-expressing tumor cells were detected using all three methods. With DepArray, only tumor budding areas contained CK+/VIM+ cells. The proportion of CK+/VIM+ tumor cells was low (1.5%-22%). CK+ stroma was associated with aggressive tumor features like distant metastasis (P = .0003), lymphatic invasion (P = .0009) and tumor budding (P = .0084). CK+/VIM+ stroma was characterized by positive WT1 (P < .001), ZEB2 (P < .001), TWIST1 (P = .009), and FAP (P = .003). Our data suggest that CK+/VIM+ tumor cells exist, albeit in low numbers and could represent a subgroup of tumor buds in partial EMT. CK+/VIM+ stroma may be of mesothelial origin and shows features of mesenchymal cells and cancer-associated fibroblasts. These results, together with the association with metastasis point to cells in mesothelial-mesenchymal transition (MMT). This atypical stroma may be a potential target for therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)-derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently, Crebbp -deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss of Crebbp was insufficient to initiate malignant transformation, compound Crebbp -haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis. Significance: Loss-of-function mutations of CREBBP are common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation. Cancer Discov; 7(3); 322-37. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 235 ., (©2017 American Association for Cancer Research.)

Developing tissues that contain mutant or compromised cells present risks to animal health. Accordingly, the appearance of a population of suboptimal cells in a tissue elicits cellular interactions that prevent their contribution to the adult. Here we report that this quality control process, cell competition, uses specific components of the evolutionarily ancient and conserved innate immune system to eliminate Drosophila cells perceived as unfit. We find that Toll-related receptors (TRRs) and the cytokine Spätzle (Spz) lead to NFκB-dependent apoptosis. Diverse "loser" cells require different TRRs and NFκB factors and activate distinct pro-death genes, implying that the particular response is stipulated by the competitive context. Our findings demonstrate a functional repurposing of components of TRRs and NFκB signaling modules in the surveillance of cell fitness during development., (Copyright © 2014, American Association for the Advancement of Science.)