Biomedical subjects

D Carvajal

Publications and source records attributed to D Carvajal.

9 recordsLinked to original sources

PubMed2006

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1.

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53-/- cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73alpha and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

Animals↗

PubMed2005

Breathing type and body position effects on sternocleidomastoid and suprahyoid EMG activity.

The objective of this study was to determine the effects of breathing type and body position on sternocleidomastoid and suprahyoid electromyographic (EMG) activity. The sample included 18 subjects with upper costal breathing type (study group) and 15 subjects with costo-diaphragmatic breathing type (control group). All individuals had natural dentition and bilateral molar support. EMG recordings at rest and while swallowing saliva were carried out by placing surface electrodes on the left sternocleidomastoid and left suprahyoid muscles. EMG activity was recorded while standing, seated upright, and in the lateral decubitus position. Upper costal breathing type subjects showed a significantly higher suprahyoid EMG activity at rest than costo-diaphragmatic subjects in all body positions studied (mixed model with unstructured covariance matrix). In the lateral decubitus position, both breathing types showed a significantly higher sternocleidomastoid EMG activity at rest and while swallowing saliva. The suprahyoid muscles demonstrated a significantly higher EMG activity at rest as well as in the lateral decubitus position (mixed model with unstructured covariance matrix). These results are relevant because sternocleidomastoid and suprahyoid muscles play an important role in controlling the head posture and mandible dynamics. The neurophysiological mechanisms involved are discussed.

Adult↗

PubMed1996

IL-12-deficient mice are defective but not devoid of type 1 cytokine responses.

Interleukin-12 (IL-12) has been described as a pivotal molecule in the immune response based in part on its ability to influence the differentiation of T helper (Th) cells into a type 1 (Th1) phenotype. This event is crucial in that appropriate differentiation of naive T cells can determine susceptibility or resistance to given pathogens by influencing the balance between cellular and humoral immunity. In order to further delineate the role of IL-12 in the immune response, we generated mice deficient for this cytokine. IL-12 knockout mice were viable, fully fertile, and displayed no obvious developmental abnormalities. Upon immunological analysis, these mice demonstrated an impaired ability to effect a Th1 response as well as an impaired ability to produce interferon-gamma in response to endotoxin in vivo. These data establish an essential role for IL-12 in the generation of optimal Th1 responses in vivo, but weak responses can occur independently of IL-12.

Animals↗

PubMed1995

Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist.

Interleukin-12 (IL-12) is a cytokine that has regulatory effects on T and natural killer (NK) cells and is composed of two disulfide-bonded subunits, p40 and p35. It was recently reported that supernatants from cultures of mouse IL-12 (moIL-12) p40-transfected COS cells could inhibit IL-12-dependent responses in vitro (Mattner, F., et al., Eur. J. Immunol. 1993. 23: 2202). We have further characterized the nature of the inhibitory substance. Purified mouse p40 produced in a baculovirus expression system was found to consist of two species: the p40 monomer and a disulfide-linked p40 dimer [(p40)2]. The (p40)2 was 25- to 50-fold more active than the p40 monomer in causing specific, dose-dependent inhibition of IL-12-induced mouse concanavalin A (Con A) blast proliferation and could also inhibit IL-12-induced interferon-gamma (IFN-gamma) secretion by mouse splenocytes and IL-12-dependent activation of mouse NK cells. Competitive binding studies on mouse Con A blasts showed that (p40)2 was equally effective as moIL-12 in competing with 125I-labeled moIL-12 ([125I]moIL-12) for binding to mouse Con A blasts. However, in contrast to moIL-12, mouse (p40)2 displayed little ability to compete with 125I-labeled human IL-12 (huIL-12) for binding to high-affinity IL-12 receptors (IL-12R) on human phytohemagglutinin (PHA) blasts and caused little or no inhibition of huIL-12-induced human PHA blast proliferation. Nonetheless, mouse (p40)2 was equally effective as moIL-12 in competing with [125I] huIL-12 for binding to COS cells transfected with the human IL-12R beta subunit and expressing low-affinity IL-12 binding sites. These results suggest that (i) the majority of the structural determinants required for binding of IL-12 to its receptor are contained within the p40 subunit, but p35 is required for signaling, (ii) the p40 subunit of IL-12 interacts with the beta subunit of IL-12R, and (iii) (p40)2 may be a suitable IL-12 antagonist for studying the role of IL-12 in various immune responses in vivo as well as in vitro. Further studies are required to determine whether or not (p40)2 is produced by normal lymphoid cells and is a physiologic regulator of IL-12 activity.

Animals↗

PubMed1991

Diabetes-induced rat hyposensitivity to compound 48/80.

Rat mortality and contractile responses of isolated tracheas to compound 48/80 from rats made diabetic 4 days before by a single intravenous injection of alloxan and from diabetic rats that had been treated with insulin 6 h before were compared with control animals. Diabetic animals and tracheal segments from diabetic rats were significantly less responsive to compound 48/80 than control and insulin-treated diabetic animals. On the other hand, diabetic animals have a lower quantity of peritoneal mast cells than control rats, and insulin restored the normal quantity of cells in diabetic animals. These data indicate that diabetes elicits an hyposensitivity to compound 48/80, possibly related to a diabetes-induced decrease in the mast cell count.

Animals↗

PubMed1990

Interference of levamisole with Forssman shock.

The anti-helminthic drug levamisole has been used as an adjunct in the treatment of some immunologic defects including cancer. Recently, it has been shown that this drug inhibits thromboxane synthetase as well. Since Forssman shock in guinea pig is used as a model for pulmonary thromboembolism involving thromboxane A2, we studied the interference of levamisole with bronchoconstriction, thrombocytopenia, endothelial cells and pulmonary damage induced by Forssman antiserum. Levamisole inhibited dose-dependently the pathological changes produced by Forssman antiserum raising the possibility that levamisole may be effective for the treatment of pulmonary thromboembolism in man.

Animals↗

PubMed1990

Interference of levamisole with cerebral edema.

The anthelmintic and immunomodulator drug levamisole is also a thromboxane synthetase inhibitor. The effect of levamisole on cerebral edema in Mongolian gerbils and in rat models of stroke was evaluated. Cerebral ischemia was produced in gerbils by right carotid ligation and in rats by right carotid ligation and anoxia. Mortality and right hemisphere edema were evaluated 24 hours after induction of cerebral anoxia in levamisole treated animals. Levamisole failed to protect gerbils from death or cerebral edema but decreased dose-dependently the cerebral edema in rats. The fact that levamisole inhibits thromboxane synthetase and decrease cerebral swelling in rats supports further tests against human stroke.

Animals↗

PubMed1990

Kerosene-induced asthma.

Clinical evaluation of 286 asthmatic women showed 15.5% of those who improved clinically had contact with kerosene, while 43.9% of those who failed to improve used kerosene as fuel for cooking. In 16 women the onset of asthma occurred soon after they began to use kerosene. Kerosene can cause and aggravate asthma.

Asthma↗

PubMedDate not supplied

Effects of kerosene on airway sensitization to egg albumin in guinea pig.

We undertook a study to determine if pre-exposure to kerosene smoke enhances airway sensitization to egg albumin in the guinea pig. Kerosene vapor inhalation for 15 days, 1 hour daily, in similar conditions to which some housewives who use kerosene as cooking fuel are exposed elicited tracheal damage characterized by signs of dysplasia and inflammatory infiltrate. When these animals were exposed to egg albumin aerosol there was an increase in the antialbumin antibody blood titer and an increased response to egg albumin in the isolated tracheal preparation (Schultz-Dale reaction), We conclude that the airway damage elicited by inhalation of kerosene vapor increase antigen absorption and thereby antibody formation.

Aerosols↗