Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice

EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.     

Granulocyte-colony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils

Nd2 is a monoclonal antibody against pancreatic cancer. We have previously reported that human/mouse chimeric antibody Nd2 (c-Nd2) can induce antibody-dependent cell-mediated cytotoxicity (ADCC) with peripheral blood mononuclear cells (PBMs) as effectors. In this study, we investigated whether c-Nd2 can induce ADCC with poly-morphonuclear neutrophils (PMNs) as effector cells and the effects of granulocyte-colony stimulating factor (G-CSF) in enhancing this cytotoxicity. Cytotoxicities for pancreatic cancer cell line, SW1990 were dose-dependently increased by c-Nd2 during co-culture with PMNs and these cytotoxicities were significantly suppressed by the addition of neutralizing antibodies against CD16, which is Fcgamma receptor expressed on PMN membranes. PMNs treated with G-CSF significantly enhanced in vitro ADCC activity against SW1990 induced by c-Nd2. The in vivo growth of subcutaneously transplanted SW1990 tumor in nude mouse was significantly inhibited by i.p. administration of c-Nd2 compared to control (non-specific IgG1). In addition, this inhibitory effect was enhanced by the combination of c-Nd2 and G-CSF. Immunohistochemical study with anti-mouse neutrophil elastase antibody demonstrated strong infiltrations of PMNs into and around the transplanted tumor, treated with c-Nd2 and G-CSF. These results suggest that PMNs play an important role in c-Nd2 inducing ADCC and that combination immunotherapy of c-Nd2 with G-CSF may have clinical applications in the treatment of patients with pancreatic cancer by enhancing ADCC.     

Restoration of transforming growth factor Beta signaling by functional expression of smad4 induces anoikis

Smad proteins transduce signals carried by the transforming growth factor beta (TGF-beta) cytokine superfamily from receptor serine/threonine kinases at the cell surface to the nucleus, thereby affecting cell proliferation, differentiation, as well as pattern formation during early vertebrate development. Smad4/DPC4, located at chromosome 18q21, was identified as a candidate tumor suppressor gene that is inactivated in nearly half of all pancreatic carcinomas. For functional characterization of Smad4, a recombinant adenovirus encoding Smad4 (Ad-Smad4) was generated. When Smad4 was expressed in Smad4-null breast carcinoma cell line MDA-MB-468 using the recombinant adenovirus, TGF-beta signaling was restored as determined by TGF-beta-dependent activity of plasminogen activator inhibitor 1 promoter and p21 expression. Infection with Ad-Smad4 in the presence of TGF-beta1 also resulted in an altered cell morphology that coincided with enhanced beta1 integrin expression and reduced efficiency of colony formation in soft agar. In agreement with increased p21 expression, Smad4-expressing cells showed modest reduction in S phase. However, Smad4 expression did not lead to induction of apoptosis under normal culture conditions. Interestingly, when Smad4-expressing cells were detached and incubated in suspension, they underwent rapid apoptosis in a TGF-beta-dependent manner. Induction of apoptosis caused by loss of anchorage is known as anoikis. Anoikis is believed to prevent colonization elsewhere of detached cells. Additional characterization revealed an increase in the level of focal adhesion kinase 2 (or Pyk2) and activation of caspases 2, 3, 6, and 8 during anoikis because of Smad4 expression and restoration of TGF-beta signaling. Because resistance to anoikis in tumor cells is thought to contribute to metastasis, our data suggest a functional basis for the strong correlation between defects in Smad4 and development of malignancy.     

Temperament and early environmental influences in kleptomania

The purpose of this investigation was to shed light on the temperament and early life experiences of people suffering from kleptomania. Twelve outpatients (five men [41.6%]; seven women [58.3%]; mean age, 39.6 +/- 11.0 years) who met DSM-IV criteria for kleptomania and had no other axis I disorders by Structured Clinical Interview for DSM-IV (SCID) completed the Tridimensional Personality Questionnaire (TPQ) and the Parental Bonding Instrument (PBI). Patients with kleptomania had significantly higher novelty-seeking scores (P =.001), higher harm-avoidance scores (P =.005), and lower reward-dependence scores (P =.023) than normal controls. The kleptomania subjects had significantly lower maternal and paternal care scores, and lower maternal protection scores, than the normative values (P <.05). Neither TPQ nor PBI scores correlated with illness severity. These findings suggest that an understanding of early parenting behavior and a dimensional approach to the personality of kleptomaniacs may offer insight into this disorder and provide clues to treatment strategies.     

Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

OBJECTIVE: The authors reviewed available evidence on neonatal neuroimaging strategies for evaluating both very low birth weight preterm infants and encephalopathic term neonates. IMAGING FOR THE PRETERM NEONATE: Routine screening cranial ultrasonography (US) should be performed on all infants of <30 weeks' gestation once between 7 and 14 days of age and should be optimally repeated between 36 and 40 weeks' postmenstrual age. This strategy detects lesions such as intraventricular hemorrhage, which influences clinical care, and those such as periventricular leukomalacia and low-pressure ventriculomegaly, which provide information about long-term neurodevelopmental outcome. There is insufficient evidence for routine MRI of all very low birth weight preterm infants with abnormal results of cranial US. IMAGING FOR THE TERM INFANT: Noncontrast CT should be performed to detect hemorrhagic lesions in the encephalopathic term infant with a history of birth trauma, low hematocrit, or coagulopathy. If CT findings are inconclusive, MRI should be performed between days 2 and 8 to assess the location and extent of injury. The pattern of injury identified with conventional MRI may provide diagnostic and prognostic information for term infants with evidence of encephalopathy. In particular, basal ganglia and thalamic lesions detected by conventional MRI are associated with poor neurodevelopmental outcome. Diffusion-weighted imaging may allow earlier detection of these cerebral injuries. RECOMMENDATIONS: US plays an established role in the management of preterm neonates of <30 weeks' gestation. US also provides valuable prognostic information when the infant reaches 40 weeks' postmenstrual age. For encephalopathic term infants, early CT should be used to exclude hemorrhage; MRI should be performed later in the first postnatal week to establish the pattern of injury and predict neurologic outcome.     

Antithrombotic effect of tissue factor inhibition by inactivated factor VIIa: an ex vivo human study

FFR-rFVIIa is an inactivated recombinant factor VIIa (rFVIIa) that inhibits the binding of factor VIIa to tissue factor (TF). It has been shown to prevent TF-induced thrombosis in animals. The present study is a substudy of the Active Site Inhibited Seven (ASIS) trial and examines the antithrombotic effect of 3 doses of FFR-rFVIIa in 24 patients undergoing percutaneous coronary intervention (PCI). Group 1 (n=9) received 400 microg/kg FFR-rFVIIa and 40 to 50 U/kg heparin, group 2 (n=7) received 200 microg/kg FFR-rFVIIa and 100 U/kg heparin, and group 3 (n=8) received 50 microg/kg FFR-rFVIIa and 100 U/kg heparin. Blood thrombogenicity was assessed as total thrombus area and fibrin deposition on the perfusion chamber at shear rate conditions typical of mild-moderate coronary stenosis. Baseline blood thrombogenicity was evaluated a day before PCI, after heparin administration. A second perfusion chamber study was performed just before PCI, 15 minutes after the administration of heparin and FFR-rFVIIa. Thrombus formation at a high shear rate was markedly reduced in groups 1 and 2 after drug administration, by 79% to 84% and 76% to 87%, respectively (P<0.004 [group 1], P<0.04 [group 2]). In group 3, moderate thrombus reduction of 46% to 48% was achieved (P<0.04). Fibrin deposition in all 3 groups was nearly eliminated after drug administration. Our data demonstrate that FFR-rFVIIa has a potent antithrombotic effect at different shear rates and severe arterial injury conditions.