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An Assessment of the Clinical Trials Pathology Lab’s Research Administration Infrastructure at Fred Hutchinson Cancer Center
Get PDFSuccess in a research enterprise depends on a robust research administration infrastructure. Optimally, it facilitates smooth operations and advances scientific, financial, and strategic goals. Suboptimally, research enterprises risk inefficiencies, financial mismanagement, regulatory violations, and diminished research output. Using a quality improvement framework, this project assessed the research administration infrastructure of the Clinical Trials Pathology Lab at Fred Hutchinson Cancer Center, a CLIA-certified clinical histopathology lab. Observations revealed an underdeveloped research administration infrastructure, spanning pre- and post- award processes and communication. Results offer actionable recommendations focusing on budgeting projects consistently, assessing personnel capacity regularly, instituting a streamlined billing system, standardizing effort tracking, reporting, and certification practices, and hiring a project manager. Recommendations also underscore enhancing communication through clearer meeting structures and centralized project tracking. The assessment stresses that a strong research administration infrastructure translates into more efficient operations, greater financial sustainability, and increased regulatory compliance. This assessment may help other research enterprises use its framework to identify root causes of problems in their own research administration infrastructures, thereby helping them improve inefficiencies and
enhancing overall performance
Oral History of Warren C. Hayman
No full textWarren C. Hayman is an African American educator who spent the last decades of his long career at Morgan State University, where he served as Assistant Dean of Education and Program Coordinator for the Doctoral Program in Urban Educational Leadership. From 1985 to 1997, Hayman worked in the Johns Hopkins University (JHU) School of Continuing Studies as the coordinator for the JHU-Dunbar High School Health Professions Program. The JHU-Dunbar program was a cooperative effort between Johns Hopkins University, the Johns Hopkins Medical Institutions, and Dunbar High School to prepare students for access to higher education and consideration of careers in the health and science professions.
While the oral history primarily focuses on Hayman’s role as program coordinator, Hayman also speaks about his educational background and professional development from the 1960s to the 1980s, during an era of civil rights activism, the rise of Black Studies, and increasing calls for multicultural education. Hayman goes on to discuss the development of the JHU-Dunbar Health Professions Program, which had support from JHU President Steven Muller, Johns Hopkins Hospital President Robert Heyssel, and Dunbar High School Principal Elzee Gladden. Hayman discusses the opportunities created for students in different components of the program, such as the summer bridge program, “A” Course, summer scholars program, and participation in Biomedical Symposiums organized by the Association of Minority Health Professions Schools (AMPHS). The summer scholars program gave students the opportunity for a paid, six-week internship experience with a Johns Hopkins professional in their area of interest, such as pediatrics, veterinary medicine, or ophthalmology. Students worked with faculty and medical professionals associated with Johns Hopkins Hospital, JHU School of Medicine, JHU Bloomberg School of Public Health, and Johns Hopkins Hospital School of Nursing. The interview provides important insight into the history of the JHU-Dunbar program, its impact on student success, and the ongoing relationship between Johns Hopkins, Dunbar High School, and the East Baltimore community. This oral history was conducted as part of the Reexamining Hopkins History Initiative.
In addition to those mentioned above, Dr. Hayman mentions the following Johns Hopkins affiliates who were connected with the program in different capacities: Kerwyn Barbour; Deidra Bishop; Lee Bone; Benjamin Carson; James Coleman; Colene Daniel; Ralph Fessler; Susan Flora; Stanley C. Gabor; Margaret “Peggi” Graves; Joseph S. Hall; Yariela Kerr-Donovan; Dwight Lassiter; James M. McPartland; David G. Nichols; Michael Preston; Mark C. Rogers; Edgar Roulhac; Joseph L. Smith; Roland Smoot; Levi Watkins, Jr
Oral History Interview with Bradford H. Gray
No full textThis interview with Brad Gray, Ph.D. is part of Moral Histories: Voices and Stories from the Founding Figures of Bioethics, an oral history project of the Johns Hopkins Berman Institute of Bioethics. Gray is author of more than 100 articles and two books, Human Subjects in Medical Experimentation (1975) and The Profit Motive and Patient Care (1991). He also edited or coedited two special issues of journals and two books, The New Health Care for Profit (1983) and The Ethics of Hospital Trustees (2004), which grew out of collaborative project between the New York Academy of Medicine and The Hastings Center. His areas of expertise include empirical research in bioethics, human subject research ethics, civil rights in healthcare, data and confidentiality, and for-profit and non-profit healthcare systems.
Brad Gray shares his upbringing on a ranch in the Oklahoma panhandle and his education at Oklahoma State University and Yale University. He describes his role in early bioethics topics such as human subjects research, informed consent, coercion in prisoner research, and the significance of empirical research in bioethics. Gray discusses his career transition from the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to being a study director at the Institute of Medicine (IOM) in the early 1980s. His work at IOM included reports on medical peer review data, civil rights and access to healthcare, prescription drug package inserts, utilization management, and implications of for-profit healthcare, among others. Gray highlights the variability in IRB operations and the challenges in creating a human subjects protection accreditation program. He discusses his collaboration with Mark Schlesinger at Yale when they worked on studies about nonprofit and for-profit healthcare systems. He describes his thirteen years as editor of The Milbank Quarterly, his insights into the likelihood of universal healthcare in the United States, and projects he has worked on with scholars and physicians. The interview ends with a discussion of how he came to be a collector of rare books, most of which are now at the Beineke Rare Book Library at Yale University
ROBOT-ASSISTED PROBE POSITIONING FOR INTRAOPERATIVE ULTRASOUND IMAGING USING FORCE CONTROL AND REINFORCEMENT LEARNING
Get PDFThis thesis explores the enhancement of ultrasound diagnostics through the integration of a robotic system with machine learning techniques. A customized, 3D-printed probe holder was designed to fit various probes and facilitate robotic manipulation for ultrasound imaging. Spatial calibration of the probe using an optical tracker and the fCal phantom ensures accurate probe positioning based on ultrasound image inputs. Hand-tool calibration enables the correct synchronization of the robotic end-effector with the probe. For motion planning, a deep reinforcement learning model was trained on ultrasound images synthesized from CT scans to automate probe positioning, thus minimizing the need for human intervention. The developed approach is expected to improve diagnostic precision, reduce operator dependency, and expand the clinical utility of ultrasound technology
Workplace Challenge: Creating a Patient Safety Program within Field Medical Facilities
No full textWithin field medical facilities there is concerted effort to address patient safety. The program created as a result of this research measured baseline Culture of Safety, trained field medical facility leadership on the science of safety and established Mission readiness for clinical adverse event reporting and root cause analysis. An organizational assessment found [redacted] can strengthen patient safety through implementation of specific actions in the WHO Global Patient Safety Action Plan.
Critical to patient safety is a culture of identifying and learning from errors and implementation of non-punitive systems for reporting and analyzing errors within organizations. To further the newly promulgated Healthcare Quality and Patient Safety standards and support patient safety, a clinical adverse event reporting system is planned for 2024. However, without knowledge of the current culture and team training on the science of safety, even the most technologically sophisticated and well-planned adverse event reporting system will not be meaningful. AHRQ’s Hospital Survey on Patient Safety Culture (HSOPS) was administered in medical hospitals representing over 1,133 personnel. Overall, positive responses were higher than US national averages, and regression showed statistically significant associations from Mission, Level and Country of the medical staff with safety culture domains. Using the TRIP framework, elements of CUSP and TeamSTEPPS were used to train nineteen field medical facility leadership officers on the science of safety and root cause analysis. Training was evaluated using the Kirkpatrick framework through a satisfaction survey and a pre- and post-intervention AHRQ TeamSTEPPS Teamwork Attitudes Questionnaire (T-TAQ) survey. After the training, there were increases in mean response in all five constructs of the T-TAQ but only the changes in Team Structure and Mutual Support were statistically significant. Satisfaction surveys indicated participants found the training to be meaningful. The T-TAQ results combined with the satisfaction survey responses suggest the training was useful to participants and effective. As a result of this research, the science of safety and root cause analysis training will be made available to all field medical personnel through an online training module
CRISPR SCREENS IDENTIFY DHX36 G-QUADRUPLEX RESOLVASE AS EFFECTOR OF HOMOLOGOUS RECOMBINATION REPAIR AND PARPi RESISTANCE
Get PDFHomologous Recombination (HR) is a vital mechanism that repairs DNA double-strand breaks (DSBs) accurately using the undamaged sister chromatid as a template. Deficiencies in HR (HR-D) result in impaired DSB repair, causing cell death or harmful diseases such as cancer. Notably, HR-D cells are sensitive to Poly (ADP-ribose) polymerase inhibitors (PARPis), which trap the repair effector PARP1 on damaged DNA, creating replication obstacles that require HR to be resolved. Despite clinical success, patients undergoing prolonged treatment develop PARPi resistance, highlighting the need to understand the molecular basis of HR and the pathways that help overcome PARPi resistance. Emerging evidence suggests RNA and RNA metabolism-related genes can contribute to DNA repair. Our study aimed to investigate the impact of these factors on HR and PARPi sensitivity. Using CRISPR screening in a cell-based HR reporter, we identified the RNA/DNA G-quadruplex (G4) helicase DHX36 as a strong negative effector of HR. A parallel screen to identify effectors of micro-homology-mediated end joining (MMEJ), an HR-compensatory repair pathway implicated in PARPi resistance, did not reveal a significant role for DHX36, suggesting an HR pathway-specific function. In collaborative work with Dr. Pedro Batista (NCI), we further identified DHX36 as a suppressor of PARPi-induced cell death, consistent with its inhibitory role in HR. Mechanistically, we observed that loss of DHX36 does not increase recruitment of the HR pathway choice effector BRCA1 to DNA breaks, suggesting that early steps in HR are unaffected. Recent studies indicate that DNA G4s can stabilize RNA:DNA hybrids by preventing re-annealing of the displaced ssDNA, which facilitates strand invasion and subsequent recombination events in HR. Supporting a role for DHX36 in this process, we observed a robust accumulation of both DNA G4s and R loops upon DHX36 depletion. Moreover, the depletion of
DHX36 also partially restored HR in BRCA1-deficient cells. Together, these findings suggest that DHX36 suppresses a BRCA1-independent aspect of HR-associated strand invasion, consistent with the increase in PARPi resistance in DHX36-depleted BRCA1-deficient cells. Altogether, our findings highlight DHX36 loss and G4 stabilization as novel modulators of HR and as potential biomarkers for PARPi resistance in HR-D cancers
ENTERICALLY TRIGGERED MICROINJECTOR CAPSULE FOR ORAL DELIVERY OF MACROMOLECULES
No full textOral administration is the most common method of drug delivery in our daily lives. Compared to other drug delivery methods, such as injection administration, it shows better patient compliance, convenience, and reduced cost. However, the bioavailability of oral delivery of macromolecular drugs is extremely low because of the complex gastrointestinal environment and epithelial barrier. To address this problem, we propose to develop an oral delivery platform for macromolecular drugs using cutting-edge micro-scale robotics technologies and targeted drug delivery mechanisms. The drug delivery platform comprises three components: the microinjectors, the enterically triggered capsule, and the mucoadhesive micro discs. We expect the capsule to deploy the microinjectors and mucoadhesive micro discs onto the intestinal mucosa. Next, the microinjectors penetrate the intestinal mucosa, and the micro discs release the macromolecular drugs around the incisions made by the microinjectors. This way, the macromolecular medicines can enter the vast amounts of capillary vessels in the gastrointestinal tract. Consequently, it can enhance the bioavailability of macromolecular drugs
COMMERCIAL VIABILITY OF “GREEN CEMENT” INNOVATIONS IN LATIN AMERICA AND SUB-SAHARAN AFRICA
Get PDFGlobal production of cement is a major contributor to global greenhouse gas emissions. Cement and downstream concrete products are critical to economic growth and development in every country around the world. The unique geographic and economic characteristics of the industry make it “hard to abate.”
Many different commercial approaches have been proposed for reducing or eliminating greenhouse gas emissions from cement production, by both incumbent as well as startup firms. Although these approaches are becoming more commercially viable in the U.S. and Europe, this paper seeks to explore the extent to which these innovative approaches are suitable for applications in emerging markets in Latin America and Sub-Saharan Africa.
Efforts undertaken by CEMEX, a major cement producer, will be reviewed and compared to efforts and approaches being taken by dozens of new startup companies. Industry trends and the outlook over the next few years will be analyzed and discussed
The Roles of the Human ER Aminopeptidases in Shaping Non-Classical MHC-I Antigen Presentation
No full textT cells recognize peptide antigens presented on MHC molecules to identify infected or otherwise abnormal target cells. A critical step in the antigen processing pathway is peptide trimming in the endoplasmic reticulum by ER aminopeptidases (ERAAP in mice) prior to being loaded onto and displayed by MHC Class I molecules. In mouse models, loss of ERAAP function results in defective antigen processing and the presentation of an immunodominant peptide (FYAEATPML or FL9) by non-classical MHC-E (Qa-1 in mice, HLA-E in humans). A unique CD8+ T cell surveils for defective antigen processing and eliminates cells displaying this FL9:Qa-1b complex. In humans, there are two homologous aminopeptidases, ERAP1 and ERAP2, yet it is unknown whether the loss of function of one or both proteins similarly results in antigen processing defects or altered peptide repertoires on non-classical MHC-E.
In this study, we assessed whether human ERAP1 or ERAP2 could independently rescue cells with defective antigen processing from T cell recognition using CRISPR-Cas9 modified cell line models and an FL9:Qa-1b specific T cell reporter. Eliminating functional ERAAP increased FL9:Qa-1b presentation in murine L-cells. The expression of either human ERAP1 or ERAP2 significantly reduced FL9:Qa-1b presentation back to wild-type levels. Our results demonstrate a linkage between the expression of human ERAP1 and ERAP2 and the elimination of immunogenic and immunodominant peptide- MHC-E repertoires. The implications of these findings are that human ERAP1 and ERAP2 act redundantly to promote proper antigen presentation, so functional loss of both proteins would be needed to induce an altered non-classical peptide-MHC-E repertoire. Future studies will determine if human T cells can also identify target cells with defective antigen processing due to independent or combined loss of ERAP1 and ERAP2 function, which may be relevant to immune responses to infectious agents and tumor immunosurveillance
THE DEVELOPMENT OF PHOSPHATIDYLSERINE DECORATED MULTIFUNCTIONAL BLOCK COPOLYMERS AS mRNA DELIVERY PLATFORM TO TREAT AUTOIMMUNE DISEASE
Get PDFAutoimmunity is defined as a loss of self-tolerance leading to tissue destruction and loss of function. There are approximately 8% of the population suffered from autoimmune diseases in the US and 78% of them are women, making it as the third most common type of diseases behind cancer and heart disease. Dendritic cells (DCs) play an important role in regulating immune responses towards either immunity or tolerance. Programming antigen-specific tolerogenic DCs provides a powerful immunotherapy to treat autoimmune disease that have been tested in clinical trials. The nanoparticles encapsulated autoantigens, tolerogenic agents, and DC targeting molecules have shown promise in polarizing DCs towards a tolerogenic phenotype. Here, we develop a phosphatidylserine decorated multifunctional block copolymers to co-deliver the autoantigen-encoding mRNA and tolerogenic agents into DCs to treat autoimmune diseases. Phosphatidylserine was used to targeting DCs and induce the immunosuppressive response. The phosphatidylserine-terminated RAFT agent was synthesized to construct tri-block and di-block copolymers that were composed of pH-responsive endosomal escape block to enhance intracellular delivery, mRNA binding block via electrostatic interaction, nanoparticle stabilization block via PEGylation, and tolerogenic DCs prodrugs. These multifunction block copolymers were synthesized successfully, and the monomer composition was characterized by 1H NMR spectrum. The agarose gel electrophoresis indicated that both of di-block and tri-block copolymer showed a strong mRNA binding ability. mCherry mRNA loaded polyplexes was then treated with DC2.4 dendritic cell line to test in vitro mRNA transfection and cell cytotoxicity. The results showed that although both two copolymers displayed successful mRNA transfection, the triblock copolymers were extremely toxic to DC2.4 cells while the cytotoxicity of di-block copolymers would rise with the increase of loaded mRNA. We synthesized an acidic-cleavable linkage monomer that might dampen the cytotoxicity of the polymers to improve the novel mRNA delivery platform design