Assessment of eligibility criteria in renal cell carcinoma trials evaluating systemic therapy.

OBJECTIVES: To characterise the restrictiveness of eligibility criteria in contemporary renal cell carcinoma (RCC) trials, using recommendations from the American Society of Clinical Oncology (ASCO)-Friends of Cancer Research (FCR) initiative. METHODS: vPhase I-III trials assessing systemic therapies in patients with RCC starting between 30 June 2012 and 30 June 2022 were identified. Eligibility criteria regarding brain metastases, prior or concurrent malignancies, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, and human immunodeficiency virus (HIV) infection were identified and stratified into three groups: exclusion, conditional inclusion, and not reported. Descriptive statistics were used to determine the frequency of eligibility criteria. Fisher's exact test or chi-square test were used to calculate their associations with certain trial characteristics. RESULTS: A total of 423 RCC trials were initially identified of which 112 (26.5%) had sufficient accessible information. Exclusion of patients with HIV infection, HBV/HCV infection, brain metastases, and prior or concurrent malignancies were reported in 74.1%, 53.6%, 33.0%, and 8.0% of trials, respectively. In the context of HIV and HBV/HCV infection, patients were largely excluded from trials evaluating immunotherapy (94.4% and 77.8%, respectively). In addition, brain metastases were excluded in trials assessing targeted therapy (36.4%), combined therapy (33.3%), and immunotherapy (22.2%). Exclusion of patients with prior or concurrent malignancies was less frequently reported, accounting for 9.1%, 8.3%, and 5.6% targeted therapy, combined therapy and immunotherapy trials, respectively. CONCLUSION: A substantial proportion of RCC trials utilise restrictive eligibility criteria, excluding patients with fairly prevalent comorbidities. Implementing the ASCO-FCR recommendations will ensure resulting data are more inclusive and aligned with patient populations in the real-world.

Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma.

BACKGROUND: Preclinical evidence demonstrating circadian rhythmicity within the immune system provides a rationale for hypothesis that immune checkpoint inhibitor (ICI) infusion time-of-day may serve as an actionable mechanism to improve outcomes. Herein, we explore the association between ICI time of infusion (TOI) and outcomes in metastatic renal cell carcinoma (mRCC). METHODS: Data from patients with mRCC who received nivolumab or nivolumab/ipilimumab, in first- or second-line were retrospectively collected. Patients who received < 20% of infusions after 16:30 were assigned to the early TOI sub-cohort, while the rest were assigned to the late TOI sub-cohort. Clinical outcomes were compared across the 2 groups. RESULTS: Among 135 patients included, 89 (65.9%) and 46 (34.1%) were assigned to early and late TOI sub-cohorts, respectively. Baseline characteristics were comparable across the 2 sub-cohorts. Objective response rate (ORR) was 36.0% with early TOI versus 29.5% with late TOI (P = .157). Median time to treatment failure (TTF) was 9.5 months in the early TOI sub-cohort versus 4.6 months in the late TOI sub-cohort with a hazard ratio (HR) of 1.405 (95% CI, 0.919-2.149; P = .11) in univariate analysis and 1.694 (95% CI, 1.064-2.698; P = .026) in multivariate analysis. Higher cut offs allocating patients into the late TOI sub-cohort yielded an incremental increase in the HR for TTF and overall survival (OS) that reached statistical significance. CONCLUSIONS: In patients with mRCC, early TOI yielded a numerical increase in ORR, TTF and OS, with the TTF difference reaching significance in multivariate analysis. Prospective randomized studies are warranted to examine the impact of chronomodulation on outcomes with ICIs in mRCC.

Examining Exclusion Criteria in Advanced Prostate Cancer Clinical Trials: An Assessment of recommendations From the American Society Of Clinical Oncology and Friends of Cancer Research.

PURPOSE: Eligibility criteria illustrate the characteristics of the study population and promote the safety of participants. However, overreliance on restrictive eligibility criteria may limit the generalizability of outcomes. As a result, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) issued statements to curtail these challenges. In this study, we aimed to assess restrictiveness in eligibility criteria across advanced prostate cancer clinical trials. MATERIALS AND METHODS: We identified all phase I, II, and III advanced prostate cancer clinical trials between June 30, 2012, and June 30, 2022, through Clinicaltrials.gov. We evaluated whether a clinical trial excluded, conditionally included, or did not report 4 common criteria: brain metastases, prior or concurrent malignancies, HIV infection, and hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. Performance status (PS) criteria were recorded based on the Eastern Cooperative Oncology Group (ECOG) scale. RESULTS: Out of 699 clinical trials within our search strategy, 265 (37.9%) trials possessed all the required data and were included in our analysis. The most common excluded condition of our interest was brain metastases (60.8%), followed by HIV positivity (46.4%), HBV/HCV positivity (46.0%), and concurrent malignancies (15.5%). Additionally, 50.9% of clinical trials only included patients with ECOG PS 0 to 1. HIV and HBV/HCV infection were exclusion criteria of 22 (80.8%) and 19 (73.1%) immunotherapy trials, respectively. CONCLUSION: Patients with brain metastases, prior or concurrent malignancies, HIV infection, HBV/HCV infection, or low-functioning PS were overly restricted from participating in advanced prostate clinical trials. Advocating for broader criteria may ameliorate generalizability.

The Gut Microbiome and Metastatic Renal Cell Carcinoma.

The introduction of targeted therapy (TT) and immuno-oncology (IO) agents have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). However, despite the significant improvements in survival and clinical response yielded by these agents, a significant percentage of patients still experience progressive disease. Evidence now suggests that microorganisms living in the gut (i.e., the gut microbiome) could be used as a biomarker for response and may also have utility in increasing response to these treatments. In this review, we present an overview of the role of the gut microbiome in cancer and its potential implications in the treatment of mRCC.

Perceptions of COVID-19 Vaccination in Patients with Genitourinary Cancers: A Survey Study.

Since the approval of the COVID-19 vaccines, their safety and efficacy has been widely demonstrated in patients with cancer. However, there remain patients with reservations regarding vaccination. We aimed to assess genitourinary cancer patients' perceptions of the vaccines as well as barriers and influencers of decision-making through the completion of a questionnaire. While vaccine-associated concerns were observed, most patients with genitourinary cancers were willing to receive the vaccine. Moving forward, differing strategies could be considered to enhance patient education on the utility of vaccination in the setting of cancer and beyond.

Decoupling the role of RORγt in the differentiation and effector function of TH17 cells.

RORγt is known to instruct the differentiation of T helper 17 (TH17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of TH17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-dependent thymocyte development, and TH17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for TH17-mediated EAE. Thus, RORγt regulates the effector function of TH17 cells in addition to TH17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of TH17 cells responsible for autoimmunity.

Outcome for Neoadjuvant Treatment of Parotid Gland Adamantinoma-Like Ewing Sarcoma: Case Report and Review of Literatures.

Adamantinoma-like Ewing sarcoma typically shows t(11;22) EWSR1::FLI1 translocation and complex epithelial differentiation. It poses a diagnostic challenge, especially in the head and neck region, due to its under-recognition and significant histologic overlap with other malignancies. Neoadjuvant and adjuvant treatment information on head and neck Adamantinoma-like Ewing sarcoma is limited. Herein, we report a case of a 78-year-old female with Adamantinoma-like Ewing sarcoma of the parotid gland, including the imaging findings and clinical response to neoadjuvant therapy followed by surgery. The efficacy of neoadjuvant therapy in the treatment of Adamantinoma-like Ewing sarcoma is discussed in the context of a review of pertinent literature. Adamantinoma-like Ewing sarcoma in the head and neck is frequently misdiagnosed as poorly differentiated squamous cell carcinoma or a basaloid salivary gland carcinoma. Adamantinoma-like Ewing sarcoma is a EWS1::FLI1 translocation driven tumor; frequently misdiagnosed on head and neck biopsies as poorly differentiated carcinoma, or squamous cell carcinoma. Ewing sarcoma-specific chemoregimen appears effective for this entity. If diagnosed early, patient may be amenable to neoadjuvant therapy, which may improve surgical and cosmetic outcomes. This is especially important in head and neck regions.

The COVID-19 pandemic and its skin effects.

OBJECTIVE: To review the current literature on cutaneous diseases associated with the global coronavirus disease 2019 (COVID-19) pandemic, and to provide a general overview for family physicians of dermatologic presentations associated with COVID-19. QUALITY OF EVIDENCE: Google Scholar and PubMed searches were conducted using the terms COVID-19, SARS-CoV-2, pandemic, dermatology, livedoid, chilblain, urticaria, maculopapular, Kawasaki's, and related synonyms. Additional terms were personal protective equipment (PPE), hand hygiene, and psychosocial factors affecting skin diseases. Only English-language literature was reviewed. Evidence ranged from levels I to III. MAIN MESSAGE: Coronavirus disease 2019 is associated with a range of cutaneous presentations through direct infection with severe acute respiratory syndrome coronavirus 2, such as maculopapular, vesicular, pseudo-chilblain, livedoid, necrotic, urticarial, and Kawasaki-like rashes. Indirect presentations secondary to behavioural modifications are associated with use of personal protective equipment and sanitization procedures. Furthermore, psychosocial factors and stress associated with the pandemic also exacerbate pre-existing skin conditions. CONCLUSION: The COVID-19 pandemic has increased rates of dermatologic conditions through direct infection, behavioural changes, and association with psychosocial factors. As the incidence of COVID-19 increases, family physicians should be well equipped to diagnose and manage dermatologic presentations as they change within the context of the pandemic.

Certolizumab Pegol in Plaque Psoriasis: Considerations for Pregnancy.

Psoriasis is a chronic, immune-mediated skin condition which commonly affects women of childbearing age. Certolizumab pegol (CZP) is an anti-tumor necrosis factor-alpha (anti-TNFα) agent that has demonstrated long-term safety and efficacy in treating moderate-to-severe plaque psoriasis. Previously, there has been limited safety data surrounding its use in pregnancy. The objective of this article is to review pivotal clinical trial data for CZP and explore safety considerations for this agent in pregnancy. This review demonstrates that CZP offers a safe and effective treatment option for women during childbearing years based on pharmacokinetics and available safety data. The observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.

Diagnosis and Management of Atopic Dermatitis for Primary Care Providers.

OBJECTIVE: To provide primary care providers an up-to-date approach to the diagnosis and management of atopic dermatitis (AD). QUALITY OF EVIDENCE: PubMed, Cochrane, and MEDLINE databases were searched for relevant meta-analyses, randomized controlled trials, systematic reviews, and observational studies about the diagnosis and management of AD. MAIN MESSAGE: AD is a common chronic skin disease characterized by immune dysregulation and skin barrier dysfunction. It has a substantial impact on quality of life across all ages. Despite this, AD is often still undertreated due to inaccurate diagnoses, even by many experienced dermatologists. Many primary care providers may not be aware of its commonly associated medical and psychiatric comorbidities or be familiar with new treatment options. CONCLUSION: In this clinical review, we describe the pathophysiology, epidemiology, diagnosis, and treatment of AD, specifically highlighting commonly used therapies and novel medications.

An Expanded Plasmid-Based Genetic Toolbox Enables Cas9 Genome Editing and Stable Maintenance of Synthetic Pathways in Phaeodactylum tricornutum.

With the completion of the genome sequence, and development of an efficient conjugation-based transformation system allowing the introduction of stable episomes, Phaeodactylum tricornutum has become an ideal platform for the study of diatom biology and synthetic biology applications. The development of plasmid-based genetic tools is the next step to improve manipulation of this species. Here, we report the identification of endogenous P. tricornutum promoters and terminators allowing selective expression of antibiotic resistance markers from stably replicating plasmids in P. tricornutum. Significantly, we developed a protocol for sequential conjugation of plasmids from Escherichia coli to P. tricornutum and demonstrated simultaneous replication of two plasmids in P. tricornutum. We developed a simple and robust conjugative system for Cas9 editing that yielded up to 60% editing efficiency of the urease gene. Finally, we constructed a plasmid encoding eight genes involved in vanillin biosynthesis that was propagated in P. tricornutum over four months with no evidence of rearrangements, with whole-plasmid sequencing indicating that the majority of mutations occurred after plasmid assembly and initial conjugation rather than during long-term propagation. The plasmid-based tools described here will facilitate investigation of the basic biology of P. tricornutum and enable synthetic biology applications.

Electronic approaches to making sense of the text in the adverse event reporting system.

INTRODUCTION: Health care organizations working to eliminate preventable harm and to improve patient safety must have robust programs to collect and to analyze data on adverse events in order to use the information to affect improvement. Such adverse event reporting systems are based on frontline personnel reporting issues that arise in the course of their daily work. Limitations in how existing software systems handle these reports mean that use of this potentially rich information is resource intensive and prone to variable results. AIM: The aim of this study was to develop an electronic approach to processing the text in medical event reports that would be reliable enough to be used to improve patient safety. METHODS: At Connecticut Children's Medical Center, staff manually enter reports of adverse events into a web-based software tool. We evaluated the ability of 2 electronic methods-rule-based query and semi-supervised machine learning-to identify specific types of events ("use cases") versus a reference standard. Rule-based query was tested on 5 use cases and machine learning on a subset of 2 using 9164 events reported from February 2012-January 2014. RESULTS: Machine learning found 93% of the weight-based errors and 92% of the errors in patient-identification. Rule-based query had accuracy of 99% or greater, high precision, and high recall for all use cases. CONCLUSIONS: Electronic approaches to streamlining the use of adverse event reports are feasible to automate and valuable for categorizing this important data for use in improving patient safety.

Current trends in the surgical treatment of pediatric ovarian torsion: we can do better.

INTRODUCTION: Current literature strongly recommends ovarian preservation for pediatric patients with ovarian torsion. The purpose of this study was to evaluate national trends in the surgical management of pediatric ovarian torsion and to compare outcomes between pediatric surgeons (PED) and gynecologists (GYN). METHODS: We queried Pediatric Health Information System (PHIS) data from 2007 to 2011 for patients <18years old with a diagnosis of ovarian torsion who underwent a surgical procedure. Patients with malignant disease were excluded. Outcomes were compared between pediatric surgeons and gynecologists. RESULTS: A total of 1151 patients were identified with a mean age of 10.7±4.1years with a bimodal distribution. Pediatric surgeons performed the majority of procedures (81%) and were more likely to use a laparoscopic approach (PED 27% vs. GYN 17%, p<.05). Pediatric surgeons were more likely to perform an oophorectomy (PED 38% vs. GYN 27%, p<.01), and more likely to administer antibiotics for this clean procedure (PED 61% vs. GYN 29%, p<.001). The overall reoperation rate was 5.1% and did not differ significantly by subspecialty (PED 4.4% vs. GYN 7.8%, p>.05). CONCLUSIONS: These data demonstrate a significant opportunity for pediatric surgeons and gynecologists to improve ovarian salvage rates and to reduce unnecessary antibiotic utilization for children with ovarian torsion.

Exploring the consequences of combining medical students with and without a background in biomedical sciences.

CONTEXT: Medical schools have tended to admit students with strong backgrounds in the biomedical sciences. Previous studies have shown that those with backgrounds in the social sciences can be as successful in medical school as those with science backgrounds. However, the experience of being a 'non-science' student over time has not been well described. METHODS: A mixed-methods study was developed and run with the aim of elucidating the personal experiences of science and non-science students at our institution. Data were generated from a student survey that focused on participants' self-identification as science or non-science students, and on their sense of preparedness and stress, and from a series of student focus groups exploring participants' experiences of science and non-science issues in all aspects of their training. Descriptive statistics were generated for structured survey data. Focus group data and unstructured survey data were analysed to identify common themes. End-of-module and end-of-year examination data for the four class cohorts in the programme were also analysed to compare science and non-science student performance over time. RESULTS: There were clear differences between the experiences and performance of science and non-science students. We found dichotomies in students' self-reported sense of preparedness and stress levels, and marked differences in their examination performance, which diminished over time to converge around the third year of their studies. Combining science and non-science students in the same class affected the students to different extents and in different ways. The potential disruption of mixing science and non-science students diminished as their levels of performance converged. CONCLUSIONS: The psychosocial stress experienced by non-science students and the challenges it posed, in both their academic and their personal lives, have implications for how such students should be supported, and how curricula can be configured to afford quality learning for all medical students.

Lopinavir shows greater specificity than zinc finger ejecting compounds as a potential treatment for human papillomavirus-related lesions.

Non-surgical, antiviral treatment options are desirable for HPV-related lesions within the genitourinary and upper digestive tract. We compared the toxicity of three zinc finger-ejecting (ZFE) compounds (4,4-dithiodimorpholine, azodicarbonamide, and diamide) to the HIV protease inhibitor lopinavir using HPV-positive SiHa, CaSki, HeLa, ME180, and HPV-negative C33A cervical carcinoma cell lines as well as primary human foreskin keratinocytes (PHFKs). Colorimetric growth assays revealed selective toxicity when treated with lopinavir. All carcinoma cell lines, except CaSki, were sensitive to 20 µM lopinavir whereas primary PHFKs were highly resistant. In contrast, 4,4-dithiodimorpholine was uniformly toxic to all cells tested while azodicarbonamide and diamide showed no effect at all. It is concluded that lopinavir may be an attractive candidate to treat pre-cancerous and cancerous HPV-positive lesions.

Vitamin A is systemically bioavailable after intratracheal administration with surfactant in an animal model of newborn respiratory distress.

Chronic lung disease (CLD) is a major cause of long-term morbidity in extremely LBW infants with respiratory distress syndrome. Parenteral vitamin A administration decreases the risk of CLD. We tested the hypothesis that intratracheal vitamin A administration with surfactant is systemically bioavailable without interfering with the functional properties of exogenous surfactant. Newborn piglets were ventilated with 100% FiO2 and sequential saline lavage induced respiratory distress syndrome. During lung injury induction, ventilator changes were allowed, but none were made following treatment allocation. Animals were assigned by chance in a blinded control trial to three groups: I=control; II=surfactant; III=surfactant+vitamin A. Hemodynamics, lung mechanics, and blood gases were measured following instrumentation, pre- and posttreatment for 4 h, at which time the liver was sampled for retinol determination. All parameters improved in animals receiving surfactant. A significant interaction existed between time and group for PaO2 and alveolar-arterial oxygen difference (A-aDO2). Hepatic levels of retinol were higher (p<0.001) in animals receiving retinyl acetate. Intratracheal administration of surfactant+vitamin A did not alter the beneficial effects of surfactant on lung compliance and gas exchange. Intratracheal Vitamin A was associated with rapid hepatic uptake. Further studies are warranted.

Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors.

We discovered a high-level amplicon involving the chr19q13.41 microRNA (miRNA) cluster (C19MC) in 11/45 ( approximately 25%) primary CNS-PNET, which results in striking overexpression of miR-517c and 520g. Constitutive expression of miR-517c or 520g promotes in vitro and in vivo oncogenicity, modulates cell survival, and robustly enhances growth of untransformed human neural stem cells (hNSCs) in part by upregulating WNT pathway signaling and restricting differentiation of hNSCs. Remarkably, the C19MC amplicon, which is very rare in other brain tumors (1/263), identifies an aggressive subgroup of CNS-PNET with distinct gene-expression profiles, characteristic histology, and dismal survival. Our data implicate miR-517c and 520g as oncogenes and promising biological markers for CNS-PNET and provide important insights into oncogenic properties of the C19MC locus.

Paradigms for pharmacological characterization of C. elegans synaptic transmission mutants.

The nematode, Caenorhabditis elegans, has become an expedient model for studying neurotransmission. C. elegans is unique among animal models, as the anatomy and connectivity of its nervous system has been determined from electron micrographs and refined by pharmacological assays. In this video, we describe how two complementary neural stimulants, an acetylcholinesterase inhibitor, called aldicarb, and a gamma-aminobutyric acid (GABA) receptor antagonist, called pentylenetetrazole (PTZ), may be employed to specifically characterize signaling at C. elegans neuromuscular junctions (NMJs) and facilitate our understanding of antagonistic neural circuits. Of 302 C. elegans neurons, nineteen GABAergic D-type motor neurons innervate body wall muscles (BWMs), while four GABAergic neurons, called RMEs, innervate head muscles. Conversely, thirty-nine motor neurons express the excitatory neurotransmitter, acetylcholine (ACh), and antagonize GABA transmission at BWMs to coordinate locomotion. The antagonistic nature of GABAergic and cholinergic motor neurons at body wall NMJs was initially determined by laser ablation and later buttressed by aldicarb exposure. Acute aldicarb exposure results in a time-course or dose-responsive paralysis in wild-type worms. Yet, loss of excitatory ACh transmission confers resistance to aldicarb, as less ACh accumulates at worm NMJs, leading to less stimulation of BWMs. Resistance to aldicarb may be observed with ACh-specific or general synaptic function mutants. Consistent with antagonistic GABA and ACh transmission, loss of GABA transmission, or a failure to negatively regulate ACh release, confers hypersensitivity to aldicarb. Although aldicarb exposure has led to the isolation of numerous worm homologs of neurotransmission genes, aldicarb exposure alone cannot efficiently determine prevailing roles for genes and pathways in specific C. elegans motor neurons. For this purpose, we have introduced a complementary experimental approach, which uses PTZ. Neurotransmission mutants display clear phenotypes, distinct from aldicarb-induced paralysis, in response to PTZ. Wild-type worms, as well as mutants with specific inabilities to release or receive ACh, do not show apparent sensitivity to PTZ. However, GABA mutants, as well as general synaptic function mutants, display anterior convulsions in a time-course or dose-responsive manner. Mutants that cannot negatively regulate general neurotransmitter release and, thus, secrete excessive amounts of ACh onto BWMs, become paralyzed on PTZ. The PTZ-induced phenotypes of discrete mutant classes indicate that a complementary approach with aldicarb and PTZ exposure paradigms in C. elegans may accelerate our understanding of neurotransmission. Moreover, videos demonstrating how we perform pharmacological assays should establish consistent methods for C. elegans research.

Cyproheptadine displays preclinical activity in myeloma and leukemia.

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G(0)/G(1) phase. After D-cyclin suppression, cyproheptadine induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of myeloma and leukemia, cyproheptadine inhibited tumor growth without significant toxicity. Cyproheptadine-induced apoptosis was preceded by activation of the mitochondrial pathway of caspase activation and was independent of the drug's known activity as an H1 histamine and serotonin receptor antagonist. Thus, cyproheptadine represents a lead for a novel therapeutic agent for the treatment of malignancy. Because the drug is well tolerated and already approved in multiple countries for clinical use as an antihistamine and appetite stimulant, it could be moved directly into clinical trials for cancer.

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin.

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.