Citations

Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.

Abstract Targeting interactions between α4β7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEβ7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. β1 and β7 integrin expression on circulating lymphocytes was similar across groups. TGF-β1 treatment induced expression of αE on both β7+ and β7− T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4β7 can become αEβ7+. ITGAE gene polymorphisms did not alter protein induction following TGF-β1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-β, and increased TGF-β–responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline β7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE− T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4β7−, and α4β7+ T cells may upregulate αEβ7 in response to TGF-β once within the gut mucosa.

Abstract While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological brain age. We here first examine whether radiomics analysis of the texture of brain T2-FLAIR MRI images can be used to predict brain age in stroke patients. We then assess the clinical determinants of accelerated brain aging and, finally, its impact on post-stroke functional outcomes. Leveraging a multisite cohort of 4,163 ischemic stroke patients, we show that older-appearing patients have more hypertension, diabetes mellitus, prior strokes, and smoking history and are more likely to develop worse post-stroke outcomes than their younger-appearing counterparts. Our results strengthen the importance of preventive medicine for maintaining brain health in stroke patients as they age and suggest a novel methodology to capture previously undescribed prognostic information available on commonly acquired MRI sequences during routine stroke care.

AbstractIntroductionActive engagement in research and scholarly output is challenging for pharmacists following residency training.ObjectivesTo determine the current structure of institutional support for pharmacy research, describe barriers to increasing staff research support and scholarly output, and benchmark best practices.MethodsA national survey was developed and distributed to the Vizient Consortium Director of Pharmacy listserv. The survey was conducted between October 2, 2019 and January 31, 2020 and incorporated 23 base questions assessing seven domains: financial support, study design/conduct support, interdisciplinary support, staff incentives, pharmacy research oversight, best practices, and barriers to research support.ResultsThe survey was distributed to 253 directors of pharmacy and 49 (19%) distinct responses were obtained. Most responders (71%) reported less than 25% of clinical staff were involved in research. Responses indicated most departmental research was driven by residents: 43% reported postgraduate year one (PGY1) and postgraduate year two (PGY2) residents were responsible for at least 75% of research projects. The greatest barriers to conducting research included time (72%), funding (33%), and knowledge/experience (32%). Research support included access to statisticians for data analysis (63%) or study design (57%), development of a pharmacy research committee (55%), and financial support or stipends (45%).ConclusionDespite institutional financial and educational support, the most commonly reported barriers to conducting pharmacy research were time, funding, and knowledge or experience of staff pharmacists.

256 Background: Ovarian cancer is the leading cause of gynecologic cancer mortality in the US. Given the high burden of disease and complexities in the provision of quality care, a multidisciplinary team approach is critical to optimal care delivery. In 2019, the Association of Community Cancer Centers (ACCC) launched a multiphase, stakeholder-driven initiative to improve care for this patient population. Results of a national survey of cancer programs to identify the needs of patients are reported here. Methods: A 20 question survey was developed by an expert steering committee including gynecologic oncologists, pathologists, genetic counselors, a nurse navigator, and cancer center administrators. The instrument was designed to collect data about cancer programs, key ovarian cancer patient needs, and barriers to and opportunities for improving ovarian cancer care. The online survey was open for participation for 4 weeks using the Qualtrics platform and distributed via email to ACCC and Society of Gynecologic Oncology members. Results: We received 26 total responses from Comprehensive Community (26%), NCI-Designed Comprehensive (22%), Academic Comprehensive (22%), and Integrated Network (13%) Cancer Programs. Annual ovarian cancer cases ranged from 22 to 190 (median: 50.5). 85% of programs has a multidisciplinary team for ovarian cancer and 61% were part of a referral network. On average, programs has 1.5 phase II and 2 phase III clinical trials currently available for ovarian cancer (all programs had at least 1 trial available). Palliative care and comprehensive symptom management was integrated into the first appointment (15%), integrated at the time of recurrence (4%), and most frequently, available by consult (81%). We assessed genetic testing practices at each program. Aggregated across programs, 79% of patients received germline multipanel testing, 71% germline BRCA only, 50% somatic multigene, and 51% somatic BRCA only. The frequency of consultations included: genetic counseling (75%), nurse navigation (75%), social work (50%), dietetics (40%), financial counseling (25%). Genetic evaluations were typically ordered by Gynecologic Oncology (88%), genetic counseling (4%), or both (8%). When asked what topic they would choose for a quality improvement project, genetic testing and counseling was the most frequent choice (46%), followed by clinical trials enrollment and availability (23%), multidisciplinary team care (19%), education on best practices (15%), palliative care (15%), and ancillary services (15%). Conclusions: Multidisciplinary care for ovarian cancer was common across a range of cancer programs but integration of palliative care, social work, dietetics, and financial counseling could be improved. Expanding clinical trials and genetic testing and counseling were the most frequently identified opportunities to improve ovarian cancer care.

AbstractSince vaccination for SARS‐CoV‐2 coronavirus started, the trajectory of patient numbers infected with the virus has improved once; however, variants of SARS‐CoV‐2 have emerged and more people have been infected; therefore, pandemic status is still far from resolution. Government and social efforts to prevent coronavirus infection continue in most states in the US and globally even after the Centers for Disease Control and Prevention declared some restriction relief for fully vaccinated people in March 2021. Healthcare institutions and various professional organizations have developed guidelines or policies to prevent the spread of these coronaviruses in the setting of apheresis. In this report, the issues that apheresis services may encounter under the current COVID‐19 (SARS‐CoV‐2 coronavirus disease) pandemic will be discussed with potential strategies that can be adapted for efficient and optimum use of apheresis resources.

Abstract Background: Young doctors have made up a substantial part of healthcare forces during the Coronavirus Disease 2019 (COVID-19) pandemic. The aim of this study was to determine the rate and level of psychological distress among young doctors during the COVID-19 outbreak. Methods: This cross-sectional cohort study, dedicated to doctors, at or below the age of 40, was conducted in 62 countries as an online survey between September – November 2020. Survey questions covered the following areas: 1. demographics 2. work environment 3.the ‘Hospital Anxiety and Depression Scale (HADS)’ and the ‘Perceived Stress Scale 10 (PSS-10)’. The primary outcome was the rate and level of anxiety/depression and stress among surveyed population defined according to adopted cut off values (HADS>13, PSS-10>14). Secondary outcomes included risk factors for increased HADS and PSS-10 scores.Results: Among 1186 respondents, median aged 32 [29–36], 675 (44.5%) females, 96% reported a high level of anxiety/depression and 97% reported a high level of stress. Factors associated with significantly higher scores for anxiety/depression were increased work hours [OR 1.61 95%CI (1.12–2.34);p=0.01] and loss of pay [OR 5.53, 95% CI (1.57–19.47);p=0.008], while reduced work hours [OR 0.68 95% CI (0.48 - 0.98);p=0.03], increased salaries [OR 0.54 95% CI (0.35–0.85);p=0.003) and good training [OR 0.99 95%CI (0.99– 1.00);p=0.002] were associated with lower scores. Higher scores for stress were associated with higher professional experience [OR 1.08 95% CI (1.02–1.14);p=0.008], reduced salaries [OR 1.74 95% CI (1.01–2.92);p=0.04] and living with a partner [OR 1.53 95% CI (1.08–2.17);p=0.01]. Conclusions: A high rate of young doctors working clinically during the COVID-19 pandemic reported a persistently high level of psychological distress more than six months after the initial outbreak. Improvements in work organization, including reduced work hours and financial security are essential to prevent further psychological suffering among young doctors worldwide.

Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.