RESUMEN
In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.
Asunto(s)
Carcinoma de Células Renales , Daño del ADN , Neoplasias Renales , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/genética , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Daño del ADN/efectos de los fármacos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Línea Celular Tumoral , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , ARN/metabolismo , ARN/genética , Animales , Epigénesis Genética/efectos de los fármacos , Proteómica , Ratones , Reparación del ADN/efectos de los fármacosRESUMEN
OBJECTIVE: The aim of the study was to evaluate the effectiveness of "The Vulva Diaries" podcast as a novel learning tool for vulvovaginal disease education. MATERIALS AND METHODS: Medical students and residents were invited to participate in the study using social media advertisements. Online pretests and posttests, one based on a podcast episode regarding genital herpes and the other on lichen sclerosus, were used to assess changes in knowledge level pre- and post-podcast listening in medical students and residents respectively. A second posttest was sent out 2 weeks after the first to assess knowledge retention. Results were analyzed using paired t tests comparing mean scores before and after podcast. RESULTS: In medical students, the average test score increased by 20% (n = 56, p < .001). Similarly, in residents the average test score increased by 23.1% (n = 22, p < .001). Medical students and residents rated their average preference for using podcasts as compared with other resources at 3.6 and 3.7/5, respectively. Furthermore, in both groups, there was no significant difference between average scores for posttest 1 versus posttest 2 written 2 weeks later suggested excellent knowledge retention. CONCLUSIONS: "The Vulva Diaries" podcast increases knowledge on vulvovaginal disease and is an effective learning tool for health care trainees in women's health. This study emphasizes the role of podcasts as a valuable educational resource within gynecology. The success of such initiatives will hopefully bolster the effort to correct the lack of provider knowledge in treating vulvovaginal diseases.
Asunto(s)
Educación Médica , Ginecología , Internado y Residencia , Femenino , HumanosRESUMEN
OBJECTIVE: The aim of the study was to determine how experts treat vulvar high-grade squamous intraepithelial neoplasia (VHSIL) and differentiated vulvar intraepithelial neoplasia (dVIN). METHOD: A 26-question survey was designed through a literature review, reviewed by the Survey Committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), and distributed to all ISSVD members via e-mail in January 2019. RESULTS: Overall, 90 of 441 physician members consented to participate and 78 of 90 were eligible to complete the survey. Most respondents were gynecologists (77%), followed by dermatologists (12%). Forty-five percent responded that their pathology was being reported using the 2015 ISSVD terminology of vulvar squamous intraepithelial lesions. The most common first-line treatments were as follows: unifocal VHSIL-excision (65%), multifocal VHSIL-imiquimod 5% (45%), VHSIL in a hair-bearing area-excision (69%), and clitoral disease-imiquimod 5% (47%). In the recurrent VHSIL, excision was favored (28%), followed by imiquimod 5% (26%) and laser (19%). Differentiated vulvar intraepithelial neoplasia was most often first treated with excision (82%), and more patients were referred to gynecologic oncology. Most patients were seen in follow-up at 3 months (range: 1 week-6 months). Sixty-seven respondents provided 26 different ways to follow treated patients, which were most commonly every 6 months for 2 years and then yearly (25%), followed by every 6 months indefinitely (18%). CONCLUSIONS: Treatment of VHSIL and dVIN varies among vulvar experts with excision being the most common treatment, except in multifocal VHSIL where imiquimod is commonly used. There is wide variation in how patients are followed after treatment.
Asunto(s)
Carcinoma in Situ/patología , Carcinoma de Células Escamosas/patología , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/terapia , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Sociedades Médicas , Encuestas y Cuestionarios , Vagina/patología , Vulva/patologíaRESUMEN
Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF "state." Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low-specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.