A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A–E). The QII aimed to increase referrals, genetic counseling (GC), and ...germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC).
QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression.
For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes.
A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.
•A coordinated quality improvement initiative was completed in five community-based health system oncology care centers.•Referral, genetic counseling, and genetic testing improved for patients with ovarian and triple-negative breast cancer.•Average time to completion of genetic testing for patients with ovarian cancer significantly decreased at almost all sites.•The most effective quality improvement interventions standardized genetic counseling referral and delivery processes.
Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that ...the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth
and
Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer.
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The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ...ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC
= 0.02 μM, BRET IC
= 0.41 μM, BRD4(1) IC
= 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.
Erosion, sediment production, and routing on a tectonically active continental margin reflect both tectonic and climatic processes; partitioning the relative importance of these processes remains ...controversial. Gulf of Alaska contains a preserved sedimentary record of the Yakutat Terrane collision with North America. Because tectonic convergence in the coastal St. Elias orogen has been roughly constant for 6 My, variations in its eroded sediments preserved in the offshore Surveyor Fan constrain a budget of tectonic material influx, erosion, and sediment output. Seismically imaged sediment volumes calibrated with chronologies derived from Integrated Ocean Drilling Program boreholes show that erosion accelerated in response to Northern Hemisphere glacial intensification (∼2.7 Ma) and that the 900-km-long Surveyor Channel inception appears to correlate with this event. However, tectonic influx exceeded integrated sediment efflux over the interval 2.8–1.2 Ma. Volumetric erosion accelerated following the onset of quasi-periodic (∼100-ky) glacial cycles in the mid-Pleistocene climate transition (1.2–0.7 Ma). Since then, erosion and transport of material out of the orogen has outpaced tectonic influx by 50–80%. Such a rapid net mass loss explains apparent increases in exhumation rates inferred onshore from exposure dates and mapped out-of-sequence fault patterns. The 1.2-My mass budget imbalance must relax back toward equilibrium in balance with tectonic influx over the timescale of orogenic wedge response (millions of years). The St. Elias Range provides a key example of how active orogenic systems respond to transient mass fluxes, and of the possible influence of climate-driven erosive processes that diverge from equilibrium on the million-year scale.
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for ...the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC
= 0.94 nM, BRET IC
= 6.2 nM; BRD4(1) IC
= 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.
Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). The two current treatments hematopoietic stem cell ...transplantation (HSCT) and enzyme replacement therapy (ERT), are insufficiently effective in addressing neurologic disease, in part due to the inability of lysosomal enzyme to cross the blood brain barrier. With a goal to more effectively treat neurologic disease, we have investigated the effectiveness of AAV-mediated IDUA gene delivery to the brain using several different routes of administration. Animals were treated by either direct intracerebroventricular (ICV) injection, by intrathecal (IT) infusion into the cerebrospinal fluid, or by intranasal (IN) instillation of AAV9-IDUA vector. AAV9-IDUA was administered to IDUA-deficient mice that were either immunosuppressed with cyclophosphamide (CP), or immunotolerized at birth by weekly injections of human iduronidase. In animals treated by ICV or IT administration, levels of IDUA enzyme ranged from 3- to 1000-fold that of wild type levels in all parts of the microdissected brain. In animals administered vector intranasally, enzyme levels were 100-fold that of wild type in the olfactory bulb, but enzyme expression was close to wild type levels in other parts of the brain. Glycosaminoglycan levels were reduced to normal in ICV and IT treated mice, and in IN treated mice they were normalized in the olfactory bulb, or reduced in other parts of the brain. Immunohistochemical analysis showed extensive IDUA expression in all parts of the brain of ICV treated mice, while IT treated animals showed transduction that was primarily restricted to the hind brain with some sporadic labeling seen in the mid- and fore brain. At 6 months of age, animals were tested for spatial navigation, memory, and neurocognitive function in the Barnes maze; all treated animals were indistinguishable from normal heterozygous control animals, while untreated IDUA deficient animals exhibited significant learning and spatial navigation deficits. We conclude that IT and IN routes are acceptable and alternate routes of administration, respectively, of AAV vector delivery to the brain with effective IDUA expression, while all three routes of administration prevent the emergence of neurocognitive deficiency in a mouse MPS I model.
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential ...therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzob1,4diazepin-2-one.
Introduction
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease that negatively impacts overall health, quality of life (QoL), and work productivity. Prior studies on AD ...burden by severity have focused on moderate-to-severe disease. Here, we describe the clinical and humanistic burden of AD in Europe across all severity levels, including milder disease.
Methods
Data were analyzed from the 2017 National Health and Wellness Survey from adult respondents with AD in the EU-5 (France, Germany, Italy, Spain, and the UK). AD disease severity was defined based on self-reported assessments as “mild,” “moderate,” or “severe” and by Dermatology Life Quality Index (DLQI) severity bands. Self-reported outcomes for AD respondents by severity were assessed using propensity score matching. These outcomes included a wide range of selected medical/psychological comorbidities, overall QoL and functional status (EuroQol 5-Dimensions 5-Level and Short Form-36 version 2 questionnaires), and work productivity and activity impairment (Work Productivity and Activity Impairment questionnaire).
Results
In total, 4208 respondents with AD (mild AD, 2862; moderate AD, 1177; severe AD, 169) and 4208 respondents without AD were included in this analysis. Results showed greater burden across severity levels compared with matched non-AD controls. A higher proportion of respondents with mild-to-moderate AD, defined by DLQI severity bands, reported atopic comorbidities (
P
< 0.05) and a wide range of cardiac, vascular, and metabolic comorbidities, including hypertension, high cholesterol, angina, and peripheral vascular disease (
P
< 0.005), compared with non-AD controls. Relative to potential impacts of various medical and psychological burdens, respondents with mild-to-moderate AD reported higher activity impairment than controls (
P
< 0.0001).
Conclusion
Clinical and humanistic burden was observed in European respondents with AD compared with matched non-AD controls across severity levels, with burden evident even in milder disease, highlighting the importance of improving disease management in early stages of AD.
Background
The body mass index (BMI) is the most commonly used anthropometric indicator. However, it does not discern among the different body components. The body fat content, expressed as fat mass ...index (FMI), is an accurate way to estimate adiposity. Since most metabolic diseases are associated with excess fat tissue, our aims were to comparatively analyze the frequency of associated metabolic abnormalities in patients with different obesity degrees based on BMI and FMI and to determine the best cut-off value of both indicators to predict metabolic abnormalities.
Methods
From a cohort of 2007 patients, BMI and FMI were calculated using DXA. Individuals were classified into the different obesity degrees according to the reference ranges from the World Health Organization (WHO) and the National Health and Nutrition Examination Survey (NHANES). A comparative analysis between BMI, FMI, and their correlation to the presence of metabolic alterations was performed.
Results
BMI underestimated the degree of obesity when compared with FMI. Spearman’s rank-order correlation for both indexes resulted in very high coefficients (rho Spearman’s = 0.857;
p
= 0.0001). The prevalence of metabolic alterations increased as BMI and FMI also increased. Despite the high positive statistical correlation between BMI and FMI, it was seen that some comorbidities were more specifically related to one particular index.
Conclusions
There were no significant differences between the BMI and the FMI for predicting the degree of obesity. Likewise, there were no significant differences between them for the prediction of metabolic alterations.
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