•Sigma 1 Receptor mediates cancer-specific apoptosis induced by combination treatment with p53 plus Rimcazole.•ROS production and ER stress are induced by combination treatment with p53 plus ...Rimcazole.•Calcium mobilization is induced by combination treatment with p53 plus Rimcazole.•p38 MAPK is activated by combination treatment with p53 plus Rimcazole.•p53 plus Rimcazole induces activation of caspase-3 and the upregulation of Bax.
Over the last years, many improvements have been made in the treatment of breast cancer; however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of p53 and Rimcazole, a Sigma 1 Receptor antagonist. Rimcazole and p53 are being evaluated in preclinical and clinical trials, respectively. While p53 is a promising antitumor therapeutic agent, antagonists of Sigma 1 Receptor also inhibit tumor cell survival and induce apoptosis. Our current study demonstrates for the first time the synergistic effect of p53 in combination with the Sigma 1 Receptor antagonist Rimcazole. Furthermore, we show that shRNA knockdown of Sigma 1 Receptor in combination with p53, lead to a similar synergistic effect, and that this synergistic effect, in breast cancer growth suppression occurs independent of p53 status. Furthermore, this combination treatment induced ER stress, p38 MAPK activation, ROS production, and proteins involved in apoptosis (caspases-3, Bax) in breast cancer cells. Combining these therapeutic anti-cancer molecules provides an innovative approach for potentially treating human breast cancer.
•Unsupervised machine learning analysis of continuous body temperature data revealed early signals of aGVHD in allo-HCT mice.•Continuous measurement of body temperature is promising for early ...prediction of aGVHD in human allo-HCT patients.
The highly conserved SNARE protein SEC22B mediates diverse and critical functions, including phagocytosis, cell growth, autophagy, and protein secretion. However, these characterizations have thus ...far been limited to in vitro work. Here, we expand our understanding of the role Sec22b plays in vivo. We utilized Cre-Lox mice to delete Sec22b in three tissue compartments. With a germline deletion of Sec22b, we observed embryonic death at E8.5. Hematopoietic/endothelial cell deletion of Sec22b also resulted in in utero death. Notably, mice with Sec22b deletion in CD11c-expressing cells of the hematopoietic system survive to adulthood. These data demonstrate Sec22b contributes to early embryogenesis through activity both in hematopoietic/endothelial tissues as well as in other tissues yet to be defined.
As of January 1990, 933 persons with human immunodeficiency virus type 1 (HIV-l) infection were clinically evaluated at Wilford Hall US Air Force (USAF) Medical Center. The Walter Reed HIV staging ...system was used in these evaluations to describe disease status and progression. Most persons were diagnosed through mandatory HIV testing in the USAF and were asymptomatic at the time of diagnosis. As of May 1990, 161 HIV-positive seroconverters (estimated overall seroconversion rate of 0.156/1000 person-years between 30 June 1988 and 1 July 1990) had been identified among active-duty USAF personnel, as they had previously tested negative for antibody to HIV. Men constitute 95% of the USAF HIV-positive population. An in vitro T helper cell functional assay was assessed to predict rate of CD4+ T cell decline over the subsequent year (mean, 15 months) in patients with >200 CD4+ T cells/mm3, This assay may prove useful for prognostication and comparisons of patients in clinical trials of anti-HIV interventions.
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