Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. ...1α,25-dihydroxyvitamin D(3) 1α,25(OH)(2)D(3) is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1α,25(OH)(2)D(3) analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D(3 )(MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1α,25(OH)(2)D(3), possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)(2)D(3) in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
We investigated whether Kupffer cell phagocytosis is differentially regulated following hypoxia (by breathing hypoxic gas) and trauma-hemorrhage. We hypothesized that the differences might result ...from a differential activation of hypoxia-inducible factor (HIF)-1alpha and phosphoinositide 3-kinase (PI3K)/Akt pathway under those conditions.
HIF-1alpha is a biologic O2 sensor enabling adaptation to hypoxia. Studies have shown that under hypoxic conditions, HIF-1alpha enhances macrophage phagocytosis. Trauma-hemorrhage also produces a hypoxic insult with HIF-1alpha activation; however, macrophage phagocytosis is suppressed under those conditions. Thus, signaling molecules other than HIF-1alpha should be taken into consideration in the regulation of macrophage phagocytosis following cellular hypoxia or trauma-hemorrhage.
Male C3H/HeN mice were subjected to sham operation, trauma-hemorrhage (laparotomy, 90 minutes hemorrhagic shock, MAP 35 +/- 5 mm Hg followed by resuscitation) or hypoxia (5% O2 for 120 minutes). The trauma-hemorrhage and hypoxia groups received Wortmannin (PI3K inhibitor), YC-1 (HIF-1alpha inhibitor) or vehicle at the time of maximum bleedout in the trauma-hemorrhage group or at a PaO2 of 30 mm Hg during hypoxic air inhalation. Mice were killed 2 hours later and samples/cells collected.
While the systemic and Kupffer cell hypoxic states were similar in the trauma-hemorrhage and hypoxia groups, phagocytic capacity was suppressed following trauma-hemorrhage but enhanced in the hypoxia group. Kupffer cells from both groups showed increased HIF-1alpha activation, which was prevented by Wortmannin or YC-1 treatment. The increase in Kupffer cell phagocytosis following hypoxemia was also prevented by Wortmannin or YC-1 treatment. Akt activation was suppressed in the trauma-hemorrhage group, but enhanced in the hypoxia group. Wortmannin and YC-1 treatment prevented the increase in Akt activation.
These findings indicate that the suppression of Kupffer cell phagocytosis following trauma-hemorrhage is independent of cellular hypoxia and activation of HIF-1alpha, but it is possibly related to suppression of the Akt activation.
Extracellular signal-regulated protein kinase (ERK) is known to be involved in pro-inflammatory and chemotactic events in response to injury. The aim of this study is to elucidate whether ERK plays ...any role in 17beta-estradiol (E2)-mediated attenuation of lung injury and pro-inflammatory mediators after trauma-hemorrhage.
Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure approximately 40 mm Hg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle (cyclodextrin), E2 (1 mg/kg body weight BW), or the ERK inhibitor PD98059 (2 mg/kg BW). At 2 h after sham operation or trauma-hemorrhage, various parameters were measured.
Trauma-hemorrhage led to a significant increase in lung ERK phosphorylation, which was associated with increased lung myeloperoxidase activity, wet-to-dry weight ratio, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein-2 levels. Circulatory IL-6, TNF-alpha, and lactate levels were also increased after trauma-hemorrhage compared with shams. Administration of E2 or ERK inhibitor PD98059 after trauma-hemorrhage attenuated the trauma-hemorrhage-induced increase in lung injury markers, ERK phosphorylation and cytokines/chemokines, ICAM-1 production, as well as circulatory cytokines and lactate levels.
These results collectively suggest that the salutary effects of E2 on the lung after trauma-hemorrhage are mediated via an ERK pathway and subsequent downregulation of pro-inflammatory mediator production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report a study in patients with mucinous and non-mucinous appendiceal adenocarcinoma treated surgically whose records were examined to elucidate their clinicopathologic features and prognostic ...factors for survival.
The medical records of 34 patients with mucinous and non-mucinous appendiceal adenocarcinoma (1991-2005) were retrospectively reviewed.
There was no significant difference between mucinous and non-mucinous tumors in patient demographics, clinicopathologic features, type of operation and outcome. Non-mucinous tumors had a higher incidence of leukocytosis than mucinous ones. The overall 5-year survival rate for 34 patients with appendiceal adenocarcinoma was 35.8%. In the univariate analysis, predictors of survival were the type of operation, resectability, carcinomatosis and tumor stage. Tumor stage significantly influenced patient survival in the multivariate analysis.
Mucinous appendiceal adenocarcinoma had clinicopathologic characteristics and a prognosis similar to non-mucinous, except that there was more leukocytosis in non-mucinous tumors. Tumor stage is an independent predictor for survival among patients with appendiceal adenocarcinoma.
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