Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.

Efficacy of laser hair removal in hidradenitis suppurativa: A systematic review and meta-analysis.

OBJECTIVES: Hidradenitis suppurativa (HS) is a chronic inflammatory condition characterized by painful nodules, draining tunnels, and fibrotic scarring in intertriginous, hair-bearing areas. The pathogenesis involves follicular occlusion and subsequent rupture, leading to uncontrolled inflammation. Treatment options for HS are limited and lack universal effectiveness. Laser hair removal (LHR) has been explored as a potential treatment; however, the efficacy and appropriate laser modalities remain unclear. This systematic review examined the efficacy and adverse effects of LHR in HS. METHODS: A comprehensive literature search was conducted from inception to September 2023 in Ovid MEDLINE, Ovid Embase, and The Cochrane Library (Wiley) with predefined inclusion and exclusion criteria, and a meta-analysis was conducted. RESULTS: Ten studies were selected (n = 227 total patients) and included six randomized controlled trials, two nonrandomized experimental studies, and two case series. Various laser modalities, including long-pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) (n = 115), intense pulsed light (n = 18), Alexandrite (n = 54), intralesional 1064 nm diode (n = 20), and combined fractional CO2 and long-pulsed Nd:YAG laser (n = 20), consistently demonstrated significant improvement in HS disease severity, irrespective of the disease scoring method used. Minimal adverse effects (primarily mild pain and erythema) were reported. A meta-analysis of three studies utilizing long-pulsed Nd:YAG laser demonstrated a standardized mean difference in disease severity of -1.68 (95% confidence interval: -2.99; -0.37), favoring treatment with LHR for HS. CONCLUSIONS: Hair follicles are key in HS pathogenesis and all included studies showed a significant improvement in HS disease severity after LHR regardless of the laser device used, likely related to hair follicle unit destruction. HS is a complex and heterogenous condition, and multiple disease scoring methods complicate outcome comparisons across studies. However, LHR, utilizing various techniques, is an effective treatment option for HS with minimal adverse effects.

Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis.

Adenosine is an extracellular signaling molecule that is particularly relevant in times of cellular stress, inflammation and metabolic disturbances when the levels of the purine increase. Adenosine acts on two G-protein-coupled stimulatory and on two G-protein-coupled inhibitory receptors, which have varying expression profiles in different tissues and conditions, and have different affinities for the endogenous ligand. Studies point to significant roles of adenosine and its receptors in metabolic disease and bone health, implicating the receptors as potential therapeutic targets. This review will highlight our current understanding of the dichotomous effects of adenosine and its receptors on adipogenesis versus osteogenesis within the bone marrow to maintain bone health, as well as its relationship to obesity. Therapeutic implications will also be reviewed.

Food Allergy: Searching for the Modern Environmental Culprit.

Food allergy is a modern disease. Its exponential increase in prevalence in the last 70 years cannot be explained by genetic factors alone. In this review we discuss the hypotheses that have been suggested previously, and the evidence that supports them, to explain this rise in prevalence as well as the medical treatments that have developed as a result of basic exploration within these paradigms. We argue that one major area of fruitful exploration that would help generate new ideas may be systematic analyses of the unknown factors of the modern environment that may contribute to the formation of food allergy. Through this lens, we review the current understanding of food allergy pathogenesis and propose novel research directions, with implications for the current strategies for managing food allergy.

An adenosine receptor-Krüppel-like factor 4 protein axis inhibits adipogenesis.

Adipogenesis represents a key process in adipose tissue development and remodeling, including during obesity. Exploring the regulation of adipogenesis by extracellular ligands is fundamental to our understanding of this process. Adenosine, an extracellular nucleoside signaling molecule found in adipose tissue depots, acts on adenosine receptors. Here we report that, among these receptors, the A2b adenosine receptor (A2bAR) is highly expressed in adipocyte progenitors. Activation of the A2bAR potently inhibits differentiation of mouse stromal vascular cells into adipocytes, whereas A2bAR knockdown stimulates adipogenesis. The A2bAR inhibits differentiation through a novel signaling cascade involving sustained expression of Krüppel-like factor 4 (KLF4), a regulator of stem cell maintenance. Knockdown of KLF4 ablates the ability of the A2bAR to inhibit differentiation. A2bAR activation also inhibits adipogenesis in a human primary preadipocyte culture system. We analyzed the A2bARKLF4 axis in adipose tissue of obese subjects and, intriguingly, found a strong correlation between A2bAR and KLF4 expression in both subcutaneous and visceral human fat. Hence, our study implicates the A2bAR as a regulator of adipocyte differentiation and the A2bAR-KLF4 axis as a potentially significant modulator of adipose biology.

The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases.

Modulation of the low affinity adenosine receptor subtype, the A2b adenosine receptor (A2bAR), has gained interest as a therapeutic target in various pathologic areas associated with cardiovascular disease. The actions of the A2bAR are diverse and at times conflicting depending on cell and tissue type and the timing of activation or inhibition of the receptor. The A2bAR is a promising and exciting pharmacologic target, however, a thorough understanding of A2bAR action is necessary to reach the therapeutic potential of this receptor. This review will focus on the role of the A2bAR in various cardiovascular and metabolic pathologies in which the receptor is currently being studied. We will illustrate the complexities of A2bAR signaling and highlight areas of research with potential for therapeutic development.

G protein-coupled receptors and adipogenesis: a focus on adenosine receptors.

G-protein coupled receptors (GPCRs) are a large family of proteins that coordinate extracellular signals to produce physiologic outcomes. Adenosine receptors (AR) are one class of GPCRs that have been shown to regulate functions as diverse as inflammation, blood flow, and cellular differentiation. Adenosine signals through four GPCRs that either inhibit (A1AR and A3AR) or activate (A2aAR and A2bAR) adenylyl cyclase. This review will focus on the role of GPCRs, and in particular, adenosine receptors, in adipogenesis. Preadipocytes differentiate to mature adipocytes as the adipose tissue expands to compensate for the consumption of excess nutrients. These newly generated adipocytes contribute to maintaining metabolic homeostasis. Understanding the key drivers of this differentiation process can aid the development of therapeutics to combat the growing obesity epidemic and associated metabolic consequences. Although much literature has covered the transcriptional events that culminate in the formation of an adipocyte, less focus has been on receptor-mediated extracellular signals that direct this process. This review will highlight GPCRs and their downstream messengers as significant players controlling adipocyte differentiation.

A novel mechanism of control of NFκB activation and inflammation involving A2B adenosine receptors.

The nuclear factor kappa B (NFκB) pathway controls a variety of processes, including inflammation, and thus, the regulation of NFκB has been a continued focus of study. Here, we report a newly identified regulation of this pathway, involving direct binding of the transcription factor NFκB1 (the p105 subunit of NFκB) to the C-terminus of the A(2B) adenosine receptor (A(2B)AR), independent of ligand activation. Intriguingly, binding of A(2B)AR to specific sites on p105 prevents polyubiquitylation and degradation of p105 protein. Ectopic expression of the A(2B)AR increases p105 levels and inhibits NFκB activation, whereas p105 protein levels are reduced in cells from A(2B)AR-knockout mice. In accordance with the known regulation of expression of anti- and pro-inflammatory cytokines by p105, A(2B)AR-null mice generate less interleukin (IL)-10, and more IL-12 and tumor necrosis factor (TNF-α). Taken together, our results show that the A(2B)AR inhibits NFκB activation by physically interacting with p105, thereby blocking its polyubiquitylation and degradation. Our findings unveil a surprising function for the A(2B)AR, and provide a novel mechanistic insight into the control of the NFκB pathway and inflammation.

Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort.

Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer.

Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort.

Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Orebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions.

Quantitative assessment of neuropilin-2 as a simple and sensitive diagnostic assay for spitzoid melanocytic lesions.

There is a significant need for the development of diagnostic tools that can precisely distinguish Spitz nevi and spitzoid melanomas. Here, we report the development of a PCR-based quantitative diagnostic assay for spitzoid melanocytic lesions utilizing the expression ratio of neuropilin-2 and melan-A genes in primary tumor specimens. We find that the expression ratio of neuropilin-2/melan-A is significantly increased in spitzoid melanomas compared with Spitz nevi. The diagnostic potential of this quantitative assay was validated in two independent sets of patient samples as demonstrated in a receiver operating characteristic curve analysis showing an area under the curve value of 91.8%. Furthermore, the assay was found to quantitatively distinguish the clinical nature of atypical spitzoid melanocytic lesions that were diagnostically undetermined using histopathologic criteria alone. Our data indicate that this quantitative assay may be used as a tool in determining the diagnostic classification of histologically challenging spitzoid tumors.

Emerging Biomarkers in Cutaneous Melanoma.

Earlier identification of aggressive melanoma remains a goal in the field of melanoma research. With new targeted and immune therapies that have revolutionized the care of patients with melanoma, the ability to predict progression and monitor or predict response to therapy has become the new focus of research into biomarkers in melanoma. In this review, promising biomarkers are highlighted. These biomarkers have been used to diagnose melanoma as well as predict progression to advanced disease and response to therapy. The biomarkers take various forms, including protein expression at the level of tissue, genetic mutations of cancer cells, and detection of circulating DNA. First, a brief description is provided about the conventional tissue markers used to stage melanoma, including tumor depth. Next, protein biomarkers, which provide both diagnostic and prognostic information, are described. This is followed by a discussion of important genetic mutations, microRNA, and epigenetic modifications that can provide therapeutic and prognostic material. Finally, emerging serologic biomarkers are reviewed, including circulating melanoma cells and exosomes. Overall the goal is to identify biomarkers that aid in the earlier identification and improved treatment of aggressive melanoma.

The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR), an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR null background. Reinstatement of macrophage A2bAR expression in A2bAR null mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice.

Integration of basic science and clinical medicine: the innovative approach of the cadaver biopsy project at the Boston University School of Medicine.

PROBLEM: Curricular integration has emerged as a consistent theme in medical education reform. Vertical integration of topics such as pathology offers the potential to bring basic science content into the clinical arena, but faculty/student acceptance and curricular design pose challenges for such integration. APPROACH: The authors describe the Cadaver Biopsy Project (CBP) at Boston University School of Medicine as a sustainable model of vertical integration. Faculty and select senior medical students obtained biopsies of cadavers during the first-year gross anatomy course (fall 2009) and used these to develop clinical cases for courses in histology (spring 2010), pathology (fall 2010-spring 2011), and radiology (fall 2011 or spring 2012), thereby linking students' first experiences in basic sciences with other basic science courses and later clinical courses. Project goals included engaging medical stu dents in applying basic science princi ples in all aspects of patient care as they acquire skills. The educational intervention used a patient (cadaver)-centered approach and small-group, collaborative, case-based learning. OUTCOMES: Through this project, the authors involved clinical and basic science faculty-plus senior medical students-in a collaborative project to design and implement an integrated curriculum through which students revisited, at several different points, the microscopic structure and pathophysiology of common diseases. NEXT STEPS: Developing appropriate, measurable out comes for medical education initiatives, including the CBP, is challenging. Accumu lation of qualitative feedback from surveys will guide continuous improvement of the CBP. Documenting longer-term impact of the curricular innovation on test scores and other competency-based outcomes is an ultimate goal.

Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival.

PURPOSE: Fatty acid synthase (FASN) regulates de novo lipogenesis, body weight, and tumor growth. We examined whether common germline single nucleotide polymorphisms (SNPs) in the FASN gene affect prostate cancer (PCa) risk or PCa-specific mortality and whether these effects vary by body mass index (BMI). METHODS: In a prospective nested case-control study of 1,331 white patients with PCa and 1,267 age-matched controls, we examined associations of five common SNPs within FASN (and 5 kb upstream/downstream, R(2) > 0.8) with PCa incidence and, among patients, PCa-specific death and tested for an interaction with BMI. Survival analyses were repeated for tumor FASN expression (n = 909). RESULTS: Four of the five SNPs were associated with lethal PCa. SNP rs1127678 was significantly related to higher BMI and interacted with BMI for both PCa risk (P(interaction) = .004) and PCa mortality (P(interaction) = .056). Among overweight men (BMI > or = 25 kg/m(2)), but not leaner men, the homozygous variant allele carried a relative risk of advanced PCa of 2.49 (95% CI, 1.00 to 6.23) compared with lean men with the wild type. Overweight patients carrying the variant allele had a 2.04 (95% CI, 1.31 to 3.17) times higher risk of PCa mortality. Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (P(interaction) = .02). CONCLUSION: FASN germline polymorphisms were significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men.

Gleason score and lethal prostate cancer: does 3 + 4 = 4 + 3?

PURPOSE Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4. These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 + 3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3 cancers, and the predictive ability of GS from a standardized review versus original scoring. PATIENTS AND METHODS Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients diagnosed between 1984 and 2004 from the Physicians' Health Study and Health Professionals Follow-Up Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR) were estimated according to original GS and standardized GS. We compared the discrimination of standardized and original grading with C-statistics from models of 10-year survival. Results For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72). CONCLUSION Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic information. A standardized review of GS can improve prediction of PCa survival.