PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment. 相似文献
Anemia has a high prevalence in patients with cancer. Its frequency and severity depend on tumor type, tumor stage, duration of disease, and treatment status. The etiology of cancer-related anemia is multifactorial and includes myelotoxicity of treatment, bone marrow infiltration, impaired erythropoietin production, blood loss, and the anemia of chronic disease. Anemia affects health-related quality of life (QOL) and may impact on tolerance or even outcome of anticancer therapy. Despite its high prevalence and impact on QOL, anemia is often under-recognized and under-treated. Treatment should correct etiologic factors, whenever possible. Symptomatic treatments are red blood cell transfusions and administration of erythropoietic growth factors. Transfusions result in rapid improvement of anemia-related symptoms but are usually only given to patients with moderate to severe anemia. Administration of epoetins (epoetin alfa, epoetin beta) or darbepoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and improves QOL in patients with cancer-related anemia. Trials determining the exact association of anemia with both response to chemo(radio)therapy and survival are ongoing. Physicians should be aware of the clinical relevance of and treatment options for anemia in cancer patients. 相似文献
Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction. 相似文献
Background: Liver dysfunction as a result of impaired oxygen availability frequently occurs following hemorrhage and contributes to delayed mortality. Artificial oxygen carriers may improve oxygen supply to vital organs while avoiding the need for allogeneic transfusion.
Methods: Rats were subjected to hemorrhagic hypotension (mean arterial pressure = 35-40 mmHg for 120 min) and were subsequently resuscitated with (1) stored whole rat blood, (2) pentastarch, or (3) pentastarch combined with perflubron emulsion (PFE; 2.7 or 5.4 g/kg body weight), a second-generation artificial oxygen carrier. Recovery of liver adenosine triphosphate, hepatocellular injury, and expression of glutamine synthetase 1, a gene that is induced by exposure of hepatocytes to low partial pressure of oxygen, were studied at 4 h of resuscitation.
Results: Stored whole blood or pentastarch failed to restore liver adenosine triphosphate concentrations after prolonged shock as compared to sham controls and resulted in increased gene expression of glutamine synthetase 1. Addition of 2.7 g PFE/kg restored liver adenosine triphosphate to control, whereas 5.4 g PFE/kg resulted in adenosine triphosphate concentrations significantly above control. Improved hepatocellular oxygen supply was also confirmed by restoration of the physiologic expression pattern of glutamine synthetase 1. Serum enzyme concentrations were highest after resuscitation with stored blood, whereas addition of PFE failed to further decrease enzyme concentrations as compared to pentastarch alone. 相似文献
We investigated the effects of the receptor-coupled protein tyrosine kinase (RTK) v-Fms on the membrane current properties
of NIH3T3 mouse fibroblasts. We found that v-Fms, the oncogenic variant of the macrophage colony-stimulating factor receptor
c-Fms, activates a K+ current that is absent in control cells. The activation of the K+ current was Ca2+-dependent, voltage-independent, and was completely blocked by the K+ channel blockers charybdotoxin, margatoxin and iberiotoxin with IC50 values of 3nM, 18 nM and 76nM, respectively. To identify signalling components that mediate the activation of this K+ current, NIH3T3 cells that express different mutants of the wildtype v-Fms receptor were examined. Mutation of the binding
site for the Ras-GTPase-activating protein led to a complete abolishment of the K+ current. A reduction of 76% and 63%, respectively, was observed upon mutation of either of the two binding sites for the
growth factor receptor binding protein 2. Mutation of the ATP binding lobe, which disrupts the protein tyrosine kinase activity
of v-Fms, led to a 55% reduction of the K+ current. Treatment of wild-type v-Fms cells with Clostridium sordellii lethal toxin or a farnesyl protein transferase inhibitor, both known to inhibit the biological function of Ras, reduced the
K+ current amplitude to 17% and 6% of the control value, respectively. This is the first report showing that an oncogenic RTK
can modulate K+ channel activity. Our results indicate that this effect is dependent on the binding of certain Ras-regulating proteins to
the v-Fms receptor and is not abolished by disruption of its intrinsic protein tyrosine kinase activity. Furthermore, our
data suggest that Ras plays a key role for K+ channel activation by the oncogenic RTK v-Fms.
Received: 19 November 1997 / Accepted: 21 January 1998 相似文献
The September 2002 COM. A 24-year-old female presented with a history of 3 generalized seizures, the first of which had occurred 6 months before admission. Her neurological examination was normal, but upon admission her MRI showed a small cystic lesion in the left parieto-occipital region. The lesion was hyper-intense on T-2 weighted images and did not show contrast enhancment. At surgery, the tumor was found to be deep to the cortex and was a cyst with amber fluid surrounded by gliotic brain. Microscopically, the tumor was well-demarcated from the surrounding tissues, which showed reactive changes, including Rosenthal fibers. The tumor was composed of GFAP-positive glial cells, which were arranged in a pseudopapillary fashion around blood vessels. In between, the tumor cells were positive for neuronal markers. The diagnosis was papillary glioneuronal tumor (PGNT), a relatively recently described lesion that may be a variant of ganglioglioma. The current literature on PGNTs is reviewed. 相似文献
Microdeletion syndromes are commonly transmitted as dominant traits and are frequently associated with variably expressed pleiotropic phenotypes. Nonlethal homozygous microdeletions, on the other hand, are very rare. Here, we delineate the fifth and so far largest homozygous microdeletion in nonmalignancies of approximately 400 kb on chromosome 4q11-q12 in a large consanguineous East-Anatolian family with six affected patients. The deleted region contains the beta-sarcoglycan gene (SGCB), the predicted gene SPATA18 (spermatogenesis associated 18 homolog) and several expressed sequence tags. Patients presented with a severe and progressive Duchenne-like muscular dystrophy phenotype, a combination of hyperlaxity and joint contractures, chest pain, palpitations, and dyspnea. 相似文献