Search Results (17)

A principal strategic goal of the RCMI Coordinating Center (RCMI-CC) is to improve the health of minority populations and to reduce ethnic and geographic disparities in health by coordinating the development and facilitating the implementation of clinical research across the RCMI Consortium. To more effectively spur inter-institutional collaborative research, the RCMI-CC supports a Clinical Research Pilot Projects Program for hypothesis-driven clinical research projects proposed by postdoctoral fellows, early-career faculty and/or early-stage investigators from two or more RCMI U54 Centers. The purpose of this brief report is to summarize the Science Speed Dating sessions to facilitate cross-site collaboration at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the 2024 RCMI Consortium National Conference. RCMI investigators and IDC Directors from 20 RCMI U54 Centers participated in two rounds of highly interactive small-group presentations of research ideas and resource needs in search of new collaborative and mentoring partnerships. Workshop participants expressed a high level of satisfaction with the speed-networking format and strongly agreed that the workshop was beneficial to their professional-development goals. Full article

The Reverse Chimeric Antigen Receptor (RevCAR) system is an adapter CAR T cell technology that allows the precise tuning of T cell activity and, thus, improved safety management. RevCAR T cells recognize and eradicate tumor cells via a bispecific adapter molecule, termed the RevCAR Target Module (RevTM). To further reduce the risk of on-target off-tumor toxicities, Dual-RevCAR T cells can be employed. These cells harbor two different RevCAR constructs, with the signaling domain of either CD3zeta or CD28. Therefore, Dual-RevCAR T cells only exert their full function when both RevCAR constructs are triggered simultaneously upon recognition of two different tumor antigens via RevTMs, enabling a precise AND-gate targeting approach and rendering them highly interesting for clinical application. For this purpose, standardized and reproducible clinical-grade cell manufacturing is required, for which the CliniMACS Prodigy can be used. Here, we present that automated processing of RevCAR and Dual-RevCAR T cells via the CliniMACS Prodigy results in potent expansion, strong transduction, and a favorable phenotype for clinical application. Moreover, obtained cell products were highly functional in a strict RevTM-dependent manner for both monospecific and AND-gate targeting, clearly underlining their high potential for clinical application against various tumor entities. Full article

Although Chimeric Antigen Receptor (CAR) T-cells have shown high efficacy in hematologic malignancies, they can cause severe to life-threatening side effects. To address these safety concerns, we have developed adaptor CAR platforms, like the UniCAR system. The redirection of UniCAR T-cells to target cells relies on a Target Module (TM), containing the E5B9 epitope and a tumor-specific binding moiety. Appropriate UniCAR-T activation thus involves two interactions: between the TM and the CAR T-cell, and the TM and the target cell. Here, we investigate if and how alterations of the amino acid sequence of the E5B9 UniCAR epitope impact the interaction between TMs and the UniCAR. We identify the new epitope E5B9L, for which the monoclonal antibody 5B9 has the greatest affinity. We then integrate the E5B9L peptide in previously established TMs directed to Fibroblast Activation Protein (FAP) and assess if such changes in the UniCAR epitope of the TMs affect UniCAR T-cell potency. Binding properties of the newly generated anti-FAP-E5B9L TMs to UniCAR and their ability to redirect UniCAR T-cells were compared side-by-side with the ones of anti-FAP-E5B9 TMs. Despite a substantial variation in the affinity of the different TMs to the UniCAR, no significant differences were observed in the cytotoxic and cytokine-release profiles of the redirected T-cells. Overall, our work indicates that increasing affinity of the UniCAR to the TM does not play a crucial role in such adaptor CAR system, as it does not significantly impact the potency of the UniCAR T-cells. Full article

Women of Color faculty continue to experience many challenges in their careers, especially in the science, technology, engineering, and mathematics (STEM) fields. As such, more research is needed that considers structural issues inhibiting their success. Using structuration theory and critical race feminism as a conceptual framework, we conducted semi-structured interviews with 19 faculty and administrators in STEM departments at higher education institutions to investigate their perceptions of structural impediments impacting early-career Women of Color STEM faculty careers. Our findings revealed the need to establish policies that are clear, documented, and transparent. Additionally, incremental approaches to tenure and promotion evaluations should be reconsidered, especially when this approach may position Women of Color faculty to appear as if they are underperforming, when the opposite may be true. Furthermore, as higher education institutions endeavor to diversify the professoriate, this study is significant in enabling institutions and STEM departments to be aware of systemic issues confronting them to make significant inroads in retaining and advancing Women of Color faculty in these disciplines. Full article

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP₂A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations. Full article

Curricular changes in architecture can support to meet the increased demand for sustainability in higher education (HE). Identifying their associated factors is necessary to understand ongoing and future transitions in architecture education. Transition management (TM) frameworks have been frequently used to analyze structural changes in various institutions but have received little attention in architecture education. This study explores the Swiss Federal Institute of Technology (ETH Zurich) as a case study, focusing on its architecture curricula within 32 years from 1990 to 2022, corresponding to multiple generations of academic careers. A multiple-level perspective (MLP) document analysis on curricular changes is conducted in three steps, drawing on a specific perspective on sustainability in architecture. First, generic characteristics that may influence curricular changes are identified from the literature. Second, shifts in the undergraduate curriculum of ETH Zurich are systematically mapped. Third, a classification of implemented curricular shifts results in seven nuanced variations in generic factors. These socio-technical factors involve the development and dissemination of new disciplinary (1) and interdisciplinary (2) approaches to a sustainable built environment (SBE), a relocation of the viewpoint on sustainability from physiology/hygiene to building physics (3), experimentation with inquiry-based learning in niches (4), extended spheres of influence in teaching (5), early committed intra-faculty opinion leaders (6), and the formation of educational networks (7). The proposed approach based on longitudinal curriculum mapping offers a way to locate structural curricular changes, identify hidden educational trends, and inform institutional changes. Full article

Profound health disparities are widespread among Native Hawaiians, other Pacific Islanders, and Filipinos in Hawai‘i. Efforts to reduce and eliminate health disparities are limited by a shortage of investigators trained in addressing the genetic, socio economic, and environmental factors that contribute to disparities. In this conference proceedings report from the 2022 RCMI Consortium National Conference, we describe our mentoring program, with an emphasis on community-engaged research. Elements include our encouragement of a team-science, customized Pilot Projects Program (PPP), a Mentoring Bootcamp, and a mentoring support network. During 2017–2022, we received 102 PPP preproposals. Of these, 45 (48%) were invited to submit full proposals, and 22 (19%) were awarded (8 basic biomedical, 7 clinical, 7 behavioral). Eighty-three percent of awards were made to early-career faculty (31% ethnic minority, 72% women). These 22 awards generated 77 related publications; 84 new grants were submitted, of which 31 were awarded with a resultant return on investment of 5.9. From 5 to 11 investigators were supported by PPP awards each year. A robust usage of core services was observed. Our descriptive report (as part of a scientific conference session on RCMI specialized centers) focuses on a mentoring vehicle and shows how it can support early-stage investigators in pursuing careers in health disparities research. Full article

The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. Full article

This article is concerned with the tenure track (TT) model, which has become increasingly used to extend the period of early career academics’ probation from one to five years across the EU. This article focuses on the TT in Trinity College Dublin (TCD), the oldest and most prestigious university in Ireland, one where gender equality has been embedded more consistently and where the pace of change has been faster than in other Irish universities. Drawing on interviews with thirteen men and women in three faculties, all but one of whom had successfully achieved tenure, this article explores their acceptance of the TT model and the perceived relevance of gender. Men were more likely to accept the model and less likely to see it as gendered. Even those women who identified a lack of clarity around maternity leave and/or gender differences in negotiating ‘fixed’ starting salaries did not identify a systemic gender issue but blamed themselves. Women who were ‘outsiders’ to TCD and in the arts, humanities and social science faculty were most likely to be critical of the model. The findings suggest the importance of a cautionary appraisal of TT, even in institutions that have actively sought to enhance gender equality. Full article

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies. Full article

Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with ⁶⁴Cu²⁺, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with ²²⁵Ac³⁺ and applied for targeted alpha therapy. A single injection of the ²²⁵Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy. Full article

Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients. Full article

Clinical translation of novel immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML) is still at an early stage. Major challenges include immune escape and disease relapse demanding for further improvements in CAR design. To overcome such hurdles, we have invented the switchable, flexible and programmable adaptor Reverse (Rev) CAR platform. This consists of T-cells engineered with RevCARs that are primarily inactive as they express an extracellular short peptide epitope incapable of recognizing surface antigens. RevCAR T-cells can be redirected to tumor antigens and controlled by bispecific antibodies cross-linking RevCAR T- and tumor cells resulting in tumor lysis. Remarkably, the RevCAR platform enables combinatorial tumor targeting following Boolean logic gates. We herein show for the first time the applicability of the RevCAR platform to target myeloid malignancies like AML. Applying in vitro and in vivo models, we have proven that AML cell lines as well as patient-derived AML blasts were efficiently killed by redirected RevCAR T-cells targeting CD33 and CD123 in a flexible manner. Furthermore, by targeting both antigens, a Boolean AND gate logic targeting could be achieved using the RevCAR platform. These accomplishments pave the way towards an improved and personalized immunotherapy for AML patients. Full article

Mentoring to develop research skills is an important strategy for facilitating faculty success. The purpose of this study was to conduct an integrative literature review to examine the barriers and facilitators to mentoring in health-related research, particularly for three categories: new investigators (NI), early-stage investigators (ESI) and underrepresented minority faculty (UMF). PsychINFO, CINAHL and PubMed were searched for papers published in English from 2010 to 2020, and 46 papers were reviewed. Most papers recommended having multiple mentors and many recommended assessing baseline research skills. Barriers and facilitators were both individual and institutional. Individual barriers mentioned most frequently were a lack of time and finding work–life balance. UMF mentioned barriers related to bias, discrimination and isolation. Institutional barriers included lack of mentors, lack of access to resources, and heavy teaching and service loads. UMF experienced institutional barriers such as devaluation of experience or expertise. Individual facilitators were subdivided and included writing and synthesis as technical skills, networking and collaborating as interpersonal skills, and accountability, leadership, time management, and resilience/grit as personal skills. Institutional facilitators included access to mentoring, professional development opportunities, and workload assigned to research. Advocacy for diversity and cultural humility were included as unique interpersonal and institutional facilitators for UMF. Several overlapping and unique barriers and facilitators to mentoring for research success for NI, ESI and UMF in the health-related disciplines are presented. Full article

Burnout syndrome (BOS) in academic physicians is a psychological state resulting from prolonged exposure to job stressors. It leads to a decline in overall job performance, which could result in misjudgment and serious clinical errors. The current study identifies the prevalence, as well as the potential demographic and workload variables that contribute significantly to BOS in academic clinicians. We distributed a modified version of the Maslach Burnout Inventory (MBI) scale to the academic clinicians in our institution; 326/900 responded, with 56.21% male and 43.46% female. The MBI scale comprised of three dimensions of burnout: emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA). Higher scores in EE and DP and lower scores in PA were associated with a higher risk for burnout. In considering the work-life of academic clinicians, this study used a modified version of the MBI to reflect three hypothesized sources of burnout: interactions with students/trainees, interactions with patients, and interactions with administration, as reflected in these three dimensions. Along both the EE and DP dimensions of the MBI, burnout was highest for interactions with administration (51% and 44.8%), moderate for interactions with patients (26.4% and 34.5%), and lowest for interactions with students (11.7% and 9.8%). The highest scores along the personal accomplishment component was found for interactions with students and patients (33.7% and 33.4%). Regression analyses identified several factors associated with higher scores on the EE and DP scales: younger age, surgical specialty, low academic rank, academic main practice, female gender, numerous night shifts, and living alone. Furthermore, higher patient volume contributed significantly to the increasing PA. This study suggests that administrative interaction contributes significantly to burnout amongst physicians, followed by patient care and trainees. Furthermore, surgeons, females, single, early career, and younger faculty staff members are at higher risk of suffering from burnout. Further studies are needed to characterize the nature of administrative interactions that contribute to burnout and to solidify other contributing variables. Full article