Biomedical subjects

J J Densmore

Publications and source records attributed to J J Densmore.

4 recordsLinked to original sources

PubMed2000

Mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma that is incurable with current chemotherapeutic approaches. Despite response rates of 50% to 70% to many regimens, all patients have disease progression after chemotherapy, and median survival is approximately 3 years. There is no clear standard of care for MCL, which increases the importance of enrolling patients in clinical trials. Off protocol, chemotherapy with chlorambucil or combination regimens can be used in patients who are not candidates for high-dose therapy. Autologous stem cell transplant as initial therapy has high response rates and prolongs time to progression but has not been shown to improve survival. For young patients with matched donors, allogeneic transplant appears promising in the limited numbers of patients treated to date. Other agents, including rituximab, fludarabine, and cladribine, have demonstrated activity but do not appear to offer survival advantages over combination chemotherapy.

Antibodies, Monoclonal↗

PubMed1998

Calmodulin regulation of Ca2+ entry in Jurkat T cells.

We have previously proposed a role for calmodulin (CaM) in the regulation of initiation of Ca2+ entry in Jurkat T cells, as well as in the regulation of the current that mediates Ca2+ entry, IT. In this report, we provide evidence for the mechanism of CaM action. We have previously shown that activation-induced Ca2+ entry into Jurkat T cells is mediated by a current we have called IT. In the whole cell variation, but not the perforated patch variation, of the patch clamp technique, this current is short-lived (under 6 min) suggesting that the current is under the control of a diffusible component of the cytosol. Addition of CaM to the whole cell recording pipette solution maintained IT for up to 20 min, suggesting that CaM may be this diffusible component. Pharmacological inhibitors of CaM blocked the augmentation of IT normally induced by an activating stimulus. Cells electroporated in the presence of anti-CaM antibodies had reduced influx of extracellular Ca2+, with no change in release of Ca2+ from the internal stores. These observations suggest that T cell receptor engagement initiates Ca2+ influx by a pathway that likely includes CaM, which may in turn regulate IT. Influx of extracellular Ca2+ is required for cellular proliferation, and inhibition of CaM by pharmacological inhibitors reduced cellular proliferation. This same inhibition of proliferation was seen in cells electroporated with anti-CaM antibodies. This suggests that inhibition of CaM and/or IT may be a target for therapeutic inhibition of inappropriate T cell proliferation.

Calcium↗

PubMed1996

A voltage-operable current is involved in Ca2+ entry in human lymphocytes whereas ICRAC has no apparent role.

Presently, it is thought that a non-voltage-gated current is responsible for activation-induced Ca2+ entry in nonelectrically excitable cells such as lymphocytes. However, it has also been proposed that the pathway instead involves a second messenger-regulated Ca2+ channel that is voltage operable, where "voltage operable" is defined as an intrinsic property of the channel protein(s) rather than a requirement of normal gating. To evaluate the contribution of these currents to activation-induced Ca2+ influx, each was examined with respect to its ability to account for Ca2+ influx as reported by Ca(2+)-sensitive dyes. We identified a set of reagents, nordihydroguaiaretic acid and various calmodulin inhibitors, that inhibits Ca2+ entry and blocks the voltage-operable current but leaves the non-voltage-gated current unaltered. Further-more, nordihydroguaiaretic acid inhibited Ca(2+)-dependent proliferation of mitogen-activated human peripheral blood mononuclear cells or Jurkat T cells and specifically blocked Ca(2+)-dependent interleukin 2 production by Jurkat T cells to a degree similar to the immunosuppressant drug cyclosporin A. We also identified compounds, amiloride and Mn2+, that block the non-voltage-gated current but have no effect on either the voltage-operable current or Ca2+ entry. Correspondingly, amiloride had no effect on Ca(2+)-dependent proliferation of Jurkat cells. These observations imply that blockade of the non-voltage-gated current does not block either Ca2+ entry or Ca(2+)-dependent lymphocyte proliferation, whereas blockade of the voltage-operable current does. The data suggest that the voltage-operable current may be a mediator of activation-induced Ca2+ entry in lymphocytes.

Amiloride↗

PubMed1992

A voltage-gated calcium channel is linked to the antigen receptor in Jurkat T lymphocytes.

Activation of T lymphocytes results in an increase in intracellular Ca2+ due in large part to influx of extracellular Ca2+. Using the patch clamp technique, an inward current in Jurkat T lymphocytes was observed upon depolarization from a holding potential of -90 mV but not from -60 mV. This whole-cell current was insensitive to tetrodotoxin, carried by Ba2+, and blocked by Ni2+. Occupancy of the T lymphocyte antigen receptor increased the current's magnitude. These data suggest that antigen receptor-induced Ca2+ entry in T lymphocytes may be mediated by a voltage-regulated Ca channel.

Calcium Channels↗