Biomedical subjects

Denise Li

Publications and source records attributed to Denise Li.

4 recordsLinked to original sources

PubMed2006

Stat5a/b are essential for normal lymphoid development and differentiation.

Cytokines that use the common gamma chain gammac are critical for lymphoid development and function. Mutations of the IL-7 receptor, gammac, or its associated kinase, Jak3, are the major cause of human severe combined immunodeficiency. Although activated by IL-7, Stat5a/b (Stat, signal transducer and activator of transcription) have been thought to play limited roles in lymphoid development. However, we now show that mice completely deficient in Stat5a/b have severely impaired lymphoid development and differentiation. Absence of Stat5 also abrogates T cell receptor gamma rearrangement and survival of peripheral CD8(+) T cells. Thus, deficiency of Stat5 results in severe combined immunodeficiency, similar in many respects to deficiency of IL-7R, gammac, and Jak3.

Animals↗

PubMed2006

Cytohesin binder and regulator (cybr) is not essential for T- and dendritic-cell activation and differentiation.

Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.

Animals↗

PubMed2004

Jak3 and the pathogenesis of severe combined immunodeficiency.

The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal structure data, these patient-derived mutations have aided in the elucidation of the functions of various structural components of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering from immune-mediated diseases.

Animals↗

PubMed2004

What is the current evidence on pain and sedation assessment in nonresponsive patients in the intensive care unit?

Assessing pain and sedation in nonresponsive patients is challenging. A major challenge is the confounding effect of sedation on objective indicators of pain. Clinicians might infer that adequate sedation means different patient states: promotion of amnesia, sleep/rest, patient safety, ventilator synchrony, and hemodynamic stability. Hence, an ideal measure that can adequately address the complexity and individualize the nature of the goals of pain and sedation therapy remains elusive. Furthermore, the behavioral responses to pain and anxiety/agitation (eg, restlessness, ventilator dyssynchrony, and movement) have many similarities. Tolerance to mechanical ventilation has been suggested to have validity in both an ICU pain scale and a sedation scale. Additional research is needed to establish the validity, sensitivity, and specificity of these pain indicators in sedated patients. In the meantime, in circumstances where patients are nonresponsive to external stimuli, clinicians should integrate other information such as actual or potential risks of pain (eg, extensiveness of injury, invasive therapies, intubation) and risks of pain-related functional impairment into their pain assessment in nonresponsive, sedated patients.

Adult↗