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Abstract Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14C-A947 (BRM degrader)—was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. Results Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2–3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. Conclusions Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

BackgroundMental health (MH) and substance use (SU) care supports are often difficult to access for the lesbian, gay, bisexual, transgender, queer, questioning, and 2-spirit (LGBTQ2S+) population. There is little known on how the shift to web-based care has affected and changed the experiences of LGBTQ2S+ youths within the MH care system. ObjectiveThis study sought to examine how web-based care modalities have affected access to care and quality of care for LGBTQ2S+ youths seeking MH and SU services. MethodsResearchers used a web-based co-design method to explore this population’s relationship with MH and SU care supports, focusing on the experiences of 33 LGBTQ2S+ youths and their relationship with MH and SU supports during the COVID-19 pandemic. A participatory design research method was used to gain experiential knowledge of LGBTQ2S+ youths’ lived experience with accessing MH and SU care. Thematic analysis was used to examine the resulting audio-recorded data transcripts and create themes. ResultsThemes related to web-based care included accessibility, web-based communication, provision of choice, and provider relationship and interactions. Barriers to care were identified in particular for disabled youths, rural youths, and other participants with marginalized intersecting identities. Unexpected benefits of web-based care were also found and emphasize the idea that this modality is beneficial for some LGBTQ2S+ youths. ConclusionsDuring the COVID-19 pandemic, a time where MH- and SU-related problems have increased, programs need to reevaluate current measures so that the negative effects of web-based care modalities can be reduced for this population. Implications for practice encourage service providers to be more empathetic and transparent when providing services for LGBTQ2S+ youths. It is suggested that LGBTQ2S+ care should be provided by LGBTQ2S+ folks or organizations or service providers who are trained by LGBTQ2S+ community members. Additionally, hybrid models of care should be established in the future so that LGBTQ2S+ youths have the option to access in-person services, web-based ones, or both as there can be benefits to web-based care once it has been properly developed. Implications for policy also include moving away from a traditional health care team model and developing free and lower-cost services in remote areas.

SMARCA2 has been identified as a synthetic lethal target in SMARCA4 mutated tumors, however, homology between the two has hindered the development of selective SMARCA2 inhibitors. Here, the authors synthesize a proteolysis targeting chimera (PROTAC) capable of SMARCA2 specific degradation and demonstrate its utility in the treatment of SMARCA4 mutated tumors.

Purpose: Among Gleason pattern 4 types, cribriform pattern is associated with the worst outcomes. We hypothesized that larger cribriform patterns would be associated with increased Decipher scores and higher biochemical recurrence (BCR) risk in Gleason 3+4=7 prostatectomy patients. Materials and Methods: The slide from patients who underwent prostatectomy from January 2016 to March 2020 on which Decipher was performed was re-reviewed for Gleason score and cribriform patterns, with large cribriform defined as cribriform acini with greater than 12 lumens and simple cribriform as 12 or fewer lumens. Differences in Decipher score were analyzed in a generalized linear model controlling for pathology stage and tumor margin status. A multivariable Cox proportional hazards model was performed for BCR-free survival. Results: Of 337 cases, 118 were Gleason 3+4=7. The mean Decipher scores in 3+4=7 cases without cribriform, with simple cribriform, and with large cribriform were 0.41, 0.54, and 0.62, respectively. In a multivariable model with pathology stage, margin tumor length, and percentage pattern 4 as covariates, compared to cases without cribriform, simple cribriform was associated with 0.10 increase in Decipher (p=0.03) and 4.7-fold hazard ratio of BCR (95% confidence interval [CI], 0.4–56.5; p=0.22) and large cribriform was associated with 0.17 increase in Decipher (p

Background: Changes in demographics and composition of pharmacy faculty, along with faculty perceived stress, work-life balance and career satisfaction have yet to be fully documented. Objective: To compare recent results from a national survey of work-life balance and career satisfaction of United States (U.S.) pharmacy faculty with results obtained from a similar survey from 2012. Methods: A 46-item anonymous survey administered via Qualtrics (Provo, UT) was sent to members of the American Association of Colleges of Pharmacy (AACP) in 2018. Information regarding demographics, stress, work-life balance, career satisfaction and intent to leave academia was collected. Although not part of the previous survey, participant information related to bullying and abuse in the pharmacy academic work was also gathered. While actual p-values are reported for all comparisons, a more conservative p-value of 0.01 was chosen a priori to indicate significance as multiple comparisons were made. Results: A total of 1090 pharmacy faculty completed the survey, comparable to the number obtained in 2012 (n = 811). Overall response rates were similar for both years. The majority of pharmacy faculty in 2018 were female, white, married or with partner, worked in a pharmacy practice department and for a public institution. Notable differences between surveys included an increase in females, more associate professors and an increase in non-white faculty in 2018, relative to 2012. Stress, as measured by mean Perceived Stress Scale (PSS) scores was also significantly higher in 2018 (16.0 ± 6.6 vs. 13.5 ± 6.7, p < 0.01) relative to 2012. Faculty from 2018 were significantly less likely to report an intention to remain in academia (61.8% vs 86.3%, p < 0.01), relative to 2012. A sizable number of pharmacy faculty surveyed in 2018 also reported observing or experiencing hostility in the workplace, which included either bullying or verbal or physical abuse. Conclusions: The makeup of pharmacy educators has evolved quickly over the last several years to comprise more female and associate professors who work within a pharmacy practice department. Also noteworthy is the significant increase in self-reported stress over the six-year timeframe. The direct implications of these findings are unknown but suggest that pharmacy academia is maturing in rank and changing to reflect the current pharmacy workforce (i.e., more females and additional clinical practice roles). Increases in responsibility likely accompany these maturing roles and may, along with other factors, contribute to the observed changes in the reported stress levels among faculty. Further research is called for regarding the reported hostility in pharmacy academic workplace and dovetails with concurrent work being done on citizenship and organizational citizenship behavior among pharmacy faculty. Findings of the study may aid pharmacy school administrators and stakeholders with plans to recruit, develop and retain faculty.

IntroductionTumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.MethodsWe retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.ResultsAmong 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.ConclusionsIn a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.

Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is a provisional renal cell carcinoma subtype with a growing list of published fusion partners. VCL-ALK gene fusion represents an uncommon fusion partner (only 6 reported cases), almost always associated with sickle cell trait and typically in a pediatric population. Herein, we report only the second case of VCL-ALK gene fusion ALK-RCC from a 31-year-old female without associated sickle cell trait, and also only the third reported case occurring in an adult patient. The tumor (measuring 8.5 cm and confined to the kidney) demonstrated mostly solid growth, pleomorphic nuclei, variably rhabdoid to vacuolated cytoplasm, and showed diffuse strong immunoreactivity for both PAX8 and ALK stains. Gene panel sequencing confirmed VCL-ALK gene fusion in the tumor. This study expands the clinical framework for diagnostic consideration of this rare tumor with potential targeted pharmacotherapy.

Obsessive-compulsive disorder (OCD) generally responds to first-line treatment but patients often relapse. The United Kingdom National OCD Inpatient Service treats patients who have failed to respond to at least two trials of SRI, augmented with a dopamine blocker and two trials of ERP. Despite this, they have profound treatment-refractory OCD and require 24-h nursing care due to severe OCD. We examined patients' Y-BOCS score on admission, discharge and at each follow-up from all patients discharged over 5 years (02/01/2014-31/12/18). Data were analysed using SPSS. Paired student t-tests were used to assess improvement from admission to discharge and each follow-up. Over 5 years, 130 adult patients were treated: 79 male and 51 female with an average age of 42.3 years (20-82; sd14.4). Their ethnic backgrounds were; 115 Caucasian, 11 South Asian, 1 Chinese, and 3 Unspecified. On admission, the average Y-BOCS total score was 36.9 (30-40; sd2.6). At discharge, patients had improved on average by 36% (Y-BOCS reduction to 23.4 = moderate OCD). Similar reduction in Y-BOCS continued throughout the year with an average Y-BOCS of 22.9 at 1 month (n = 69); 23 at 3 months (n = 70); 21.3 at 6 months (n = 78) and 21.9 at 1 year (n = 77). Twenty-seven patients did not attend any follow-up appointment whilst others attended at least one appointment with the majority attending more than 3. Using student t-test, improvements at discharge, 1, 3, 6, and 12 months post-treatment showed a highly significant improvement (p < 0.001). Gains made following inpatient treatment for treatment-refractory OCD were generally maintained until 1 year post-treatment.

Background Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.Methods We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.Results We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).Conclusions The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Summary: Acetylation of histone H3 at lysine 27 is a well-defined marker of enhancer activity. However, the functional impact of this modification at enhancers is poorly understood. Here, we use a chemical genetics approach to acutely block the function of the cAMP response element binding protein (CREB) binding protein (CBP)/P300 bromodomain in models of hematological malignancies and describe a consequent loss of H3K27Ac specifically from enhancers, despite the continued presence of CBP/P300 at chromatin. Using this approach to dissect the role of H3K27Ac at enhancers, we identify a critical role for this modification in the production of enhancer RNAs and transcription of enhancer-regulated gene networks. : Raisner et al. demonstrate that CBP/P300 bromodomain inhibition reduces levels of the H3K27Ac histone modification specifically at enhancers. Known to be correlated with enhancer activity, the authors find this modification to be essential for enhancer activation, associated gene expression, and proliferation of hematological malignancies. Keywords: enhancer, P300, CBP, bromodomain, histone acetylation, H3K27Ac

Summary: Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters and enhancers of pro-tumorigenic target genes. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro. Our findings uncover a role of CBP/EP300-BRD in intratumoral MDSCs that may be targeted therapeutically to boost anti-tumor immunity. : de Almeida Nagata et al. investigate the regulation of intratumoral myeloid-derived suppressor cells (MDSCs) by the CBP/EP300 bromodomain (BRD). By modulating H3K27 acetylation of STAT-associated genes, CBP/EP300-BRD controls MDSC function. Inhibition of the BRD reduces tumor growth in pre-clinical models, suggesting that CBP/EP300-BRD may be targeted to boost anti-tumor immunity. Keywords: CBP, EP300, H3K27ac, bromodomain, myeloid-derived suppressive cells, tumors

Objective. Cognitive impairment is a common symptom of multiple sclerosis (MS), yet treatment is currently limited. The primary goal of this pilot study was to assess the feasibility and acceptability of an at-home, five-week computerized speed of processing (SOP) training intervention for MS patients. In addition, we examined the utility of the intervention to improve speed of information processing, memory, executive function, and health-related quality of life (HRQOL). Method. Fifteen subjects were assigned five weeks of SOP training, two times per week, for a total of ten sessions. Subjects were trained on five computerized SOP tasks that required processing of increasingly complex visual stimuli in successively shorter presentation times. Subjects were given a neuropsychological test battery that included measures of speed of information processing, verbal memory, visual spatial memory, and executive function. Subjects were also administered patient-reported outcome (PRO) measures to assess HRQOL, depression, and work productivity. Neuropsychological and PRO batteries were completed at baseline and after five weeks. Results. Eighty percent of subjects completed the five-week intervention (n = 12). Significant improvements were observed on some, but not all, measures of speed of information processing, verbal memory, and executive function. There were no significant changes in HRQOL. Conclusion. This pilot study supports the feasibility of an at-home SOP training intervention for individuals with MS. SOP training was associated with improvements in several cognitive domains. Larger, randomized controlled trials are warranted.

Children with cerebral palsy frequently experience challenges and barriers to inclusion in early childhood education and care. However, there is limited research exploring the experiences of children with cerebral palsy and their families. Understanding family perspectives on their experience is likely to provide insights for professionals to improve inclusive practices. Using Bronfenbrenner's bioecological theory, this study evaluates online survey responses of factors that parents believed facilitated -- or created barriers towards -- inclusive early childhood education. Ninety-eight parents shared their levels of satisfaction and perspectives regarding the importance of inclusion practices involving their child in Australian settings. Parents reported overall high levels of satisfaction, highlighting the importance of positive educator attitudes, communication between home and settings and partnerships between home, allied health practitioners and early childhood education and care settings. Concerns related to children's psychological wellbeing were raised, particularly regarding children's experiences and challenges with anxiety including separation anxiety.

To compare the timeliness of nongovernmental and governmental communications of infectious disease outbreaks and evaluate trends for each over time, we investigated the time elapsed from the beginning of an outbreak to public reporting of the event. We found that governmental sources improved the timeliness of public reporting of infectious disease outbreaks during the study period.

Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with "good risk" TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%).The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response.In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers.ClinicalTrials.gov NCT00515216.

Tiffany Bogich and colleagues find that breakdown or absence of public health infrastructure is most often the driver in pandemic outbreaks, whose prevention requires mainstream development funding rather than emergency funding.