Development of a Coronavirus Disease 2019 (COVID-19) Application Ontology for the Accrual to Clinical Trials (ACT) network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that are critical to COVID-19 research.

Development of a COVID-19 Application Ontology for the ACT Network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research.

Individual and cumulative health afflictions are associated with greater impairment in physical and mental function in former professional American style football players.

Background: Former American style football players (ASF players) have recognized health concerns associated with prior sport participation. It remains unknown whether categorizations of current health conditions, referred to in this report as afflictions (conceptually framed as neurocognitive, cardiovascular, cardiometabolic, sleep apnea, and chronic pain) are associated with physical and mental function.

Objective: To evaluate the association of afflictions to physical and mental function.

Self-Reported Cognitive Function and Mental Health Diagnoses among Former Professional American-Style Football Players.

Clinical practice strongly relies on patients' self-report. Former professional American-style football players are hesitant to seek help for mental health problems, but may be more willing to report cognitive symptoms. We sought to assess the association between cognitive symptoms and diagnosed mental health problems and quality of life among a cohort of former professional players.

Exposure to American Football and Neuropsychiatric Health in Former National Football League Players: Findings From the Football Players Health Study.

Background: Former American football players have a higher prevalence of cognitive impairment than that of the US general population. It remains unknown what aspects of playing football are associated with neuropsychiatric outcomes.

Hypothesis: It was hypothesized that seasons of professional football, playing position, and experience of concussions were associated with cognition-related quality of life (QOL) and indicators of depression and anxiety.

Association of Concussion Symptoms With Testosterone Levels and Erectile Dysfunction in Former Professional US-Style Football Players.

Importance: Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown.

The Football Players' Health Study at Harvard University: Design and objectives.

The Football Players Health Study at Harvard University (FPHS) is a unique transdisciplinary, strategic initiative addressing the challenges of former players' health after having participated in American style football (ASF). The whole player focused FPHS is designed to deepen understanding of the benefits and risks of participation in ASF, identify risks that are potentially reversible or preventable, and develop interventions or approaches to improve the health and wellbeing of former players. We are recruiting and following a cohort of former professional ASF players who played since 1960 (current n = 3785).

Multisystem afflictions in former National Football League players.

Background: The long-term health consequences of participation in American style football (ASF) are not well understood.

Methods: We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment.

Mortality Among Professional American-Style Football Players and Professional American Baseball Players.

Importance: Studies of American-style football players have suggested lower overall mortality rates compared with general populations, but with possibly increased neurodegenerative mortality. However, comparisons with general populations can introduce bias. This study compared mortality between US National Football League (NFL) and US Major League Baseball (MLB) players, a more appropriate comparison group of professional athletes.

Accrual to Clinical Trials (ACT): A Clinical and Translational Science Award Consortium Network.

The Accrual to Clinical Trials (ACT) network is a federated network of sites from the National Clinical and Translational Science Award (CTSA) Consortium that has been created to significantly increase participant accrual to multi-site clinical trials. The ACT network represents an unprecedented collaboration among diverse CTSA sites. The network has created governance and regulatory frameworks and a common data model to harmonize electronic health record (EHR) data, and deployed a set of Informatics for Integrating Biology and the Bedside (i2b2) data repositories that are linked by the Shared Health Research Information Network (SHRINE) platform.

Relation of Anterior Cruciate Ligament Tears to Potential Chronic Cardiovascular diseases.

We have enrolled a cohort of former National Football League players (n = 3,506) who played since 1960 to assess potential long term health consequences associated with participating in the sport. Each participant has completed a self-administered questionnaire including reporting of physician-diagnosed health conditions. One of the early assessments was to evaluate whether anterior cruciate ligament (ACL) tears were associated with later life co-morbidities, including cardiovascular effects.

Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.

Ex vivo alloanergization with belatacept: a strategy to selectively modulate alloresponses after transplantation.

Ex vivo alloanergization of human immune cells, via allostimulation in the presence of costimulatory blockade with either a combination of anti-B7.1 and anti-B7.2 antibodies or first-generation cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), induces alloantigen-specific hyporesponsiveness and expands alloantigen-specific regulatory T cells (Treg).

Ex vivo expansion of human CD8+ T cells using autologous CD4+ T cell help.

Background: Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model.

IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3-dependent manner in human CD8(+) T cells.

Although both MHC class II/CD8α double-knockout and CD8β null mice show a defect in the development of MHC class I-restricted CD8(+) T cells in the thymus, they possess low numbers of high-avidity peripheral CTL with limited clonality and are able to contain acute and chronic infections. These in vivo data suggest that the CD8 coreceptor is not absolutely necessary for the generation of Ag-specific CTL. Lack of CD8 association causes partial TCR signaling because of the absence of CD8/Lck recruitment to the proximity of the MHC/TCR complex, resulting in suboptimal MAPK activation.

Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell.

Purpose: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups.

Aberrant expression of functional BAFF-system receptors by malignant B-cell precursors impacts leukemia cell survival.

Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies.We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI.

Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells.

Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated.

Induction of alloantigen-specific anergy in human peripheral blood mononuclear cells by alloantigen stimulation with co-stimulatory signal blockade.

Allogeneic hematopoietic stem cell transplantation (AHSCT) offers the best chance of cure for many patients with congenital and acquired hematologic diseases. Unfortunately, transplantation of alloreactive donor T cells which recognize and damage healthy patient tissues can result in Graft-versus-Host Disease (GvHD). One challenge to successful AHSCT is the prevention of GvHD without associated impairment of the beneficial effects of donor T cells, particularly immune reconstitution and prevention of relapse.

Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors.

Objective: Rationally designed therapies aim at the specific disruption of critical signaling pathways activated by malignant transformation or signals from the tumor microenvironment. Because mammalian target of rapamycin (mTOR) is an important signal integrator and a key translational regulator, we evaluated its potential involvement in T-cell acute lymphoblastic leukemia (T-ALL) and whether mTOR blockade synergizes with chemotherapeutic agents or other signaling antagonists to inhibit primary leukemia T cells.

Materials And Methods: mTOR signaling status was assessed using biochemical, immunostaining, and molecular regulation studies and functional assays performed to assess the impact of mTOR blockade on T-ALL proliferation, survival, and cell cycle.

A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254.

Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation.

A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4+ T cells restricted by prevalent HLA-DR alleles.

Many preclinical experiments have attested to the critical role of CD4(+) T cell help in CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. Recent clinical trials have demonstrated that reinfusion of CD4(+) T cells can induce responses in infectious diseases and cancer. However, few standardized and versatile systems exist to expand antigen-specific CD4(+) T(h) for clinical use.

Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies.

Allogeneic hematopoietic stem-cell transplantation can cure some patients with high-risk B-cell malignancies, but disease relapse following transplantation remains a significant problem. One approach that could be used to augment the donor T-cell-mediated antitumor effect is the infusion of allogeneic donor-derived T cells expressing a chimeric antibody receptor (CAR) specific to the B-cell antigen CD19. However, the use of such cells might result in toxicity in the form of graft-versus-host disease mediated by CD19-specific (CD19-CAR) T cells possessing alloreactive endogenous T-cell receptors.