ABSTRACT
Hydrocarbon-stapled peptides that display key residues of the p53 transactivation domain have emerged as bona fide clinical candidates for reactivating the tumor suppression function of p53 in cancer by dual targeting of the negative regulators HDM2 and HDMX. A recent study questioned the mechanistic specificity of such stapled peptides based on interrogating their capacity to disrupt p53/HDM2 and p53/HDMX complexes in living cells using a new recombinase enhanced bimolecular luciferase complementation platform (ReBiL). Here, we directly evaluate the cellular uptake, intracellular targeting selectivity and p53-dependent cytotoxicity of the clinical prototype ATSP-7041. We find that under standard serum-containing tissue culture conditions, ATSP-7041 achieves intracellular access without membrane disruption, dose-dependently dissociates both p53/HDM2 and p53/HDMX complexes but not an unrelated protein complex in long-term ReBiL experiments, and is selectively cytotoxic to cancer cells bearing wild-type p53 by inducing a surge in p53 protein level. These studies underscore the importance of a thorough stepwise approach, including consideration of the time-dependence of cellular uptake and intracellular distribution, in evaluating and advancing stapled peptides for clinical translation.
Subject(s)
Nuclear Proteins/metabolism , Peptides, Cyclic/pharmacology , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bone Neoplasms/drug therapy , Bone Neoplasms/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Humans , Osteosarcoma/drug therapy , Osteosarcoma/metabolism , Peptides, Cyclic/pharmacokinetics , Protein Binding/drug effectsABSTRACT
In May 2007, the Consorcio Hospital General Universitario de Valencia created the position of "Liaison Oncologist". The holder of this position is responsible for coordinating specialised and primary hospital care in the geographic area of Valencia known as Health Care Department 9 to reduce the waiting time between cancer diagnosis and treatment. In this article we describe the implementation of the innovative proposal of the Liaison Oncologist's Consultation Clinic, which, apart from speeding up and directing diagnostic processes, facilitates access to treatment, prevents duplication of consultations and exploratory procedures by establishing therapeutic plans (preferential channels), gives continuity to diagnostic and therapeutic mechanisms, and permits active follow-up of patients who have finished treatment. An analysis of the results obtained shows that the clinic has allowed us to integrate the various aspects of medical oncology into one system and make it available to patients and primary and specialised care professionals. This system provides the patient with the highest quality of integrated health care, ensures the availability of continued health care to long-term survivors and establishes preferential channels between primary care and specialised cancer care to achieve a quick diagnosis (AU)
Subject(s)
Humans , Male , Female , Outpatients/statistics & numerical data , Ambulatory Care/organization & administration , Ambulatory Care Facilities/organization & administration , Ambulatory Care Facilities/standards , Delivery of Health Care/organization & administration , Delivery of Health Care/standards , Delivery of Health Care , Survivors/statistics & numerical data , Medical Oncology/organization & administration , Medical Oncology/methods , Medical Oncology/standards , Medical Oncology/trendsABSTRACT
INTRODUCTION: Maternal body mass index has an impact on maternal and fetal pregnancy outcome. An increased maternal BMI is known to be associated with admission of the newborn to a neonatal care unit. The reasons and impact of this admission on fetal outcome, however, are unknown so far. OBJECTIVE: The aim of our study was to investigate the impact of maternal BMI on maternal and fetal pregnancy outcome with special focus on the children admitted to a neonatal care unit. METHODS: A cohort of 2049 non-diabetic mothers giving birth in the Charite university hospital was prospectively studied. The impact of maternal BMI on maternal and fetal outcome parameters was tested using multivariate regression analysis. Outcome of children admitted to a neonatal ward (n = 505) was analysed. RESULTS: Increased maternal BMI was associated with an increased risk for hypertensive complications, peripheral edema, caesarean section, fetal macrosomia and admission of the newborn to a neonatal care unit, whereas decreased BMI was associated with preterm birth and lower birthweight. In the neonatal ward children from obese mothers are characterized by hypoglycaemia. They need less oxygen, and exhibit a shorter stay on the neonatal ward compared to children from normal weight mothers, whereas children from underweight mothers are characterized by lower umbilical blood pH and increased incidence of death corresponding to increased prevalence of preterm birth. CONCLUSION: Pregnancy outcome is worst in babies from mothers with low body mass index as compared to healthy weight mothers with respect to increased incidence of preterm birth, lower birth weight and increased neonate mortality on the neonatal ward. We demonstrate that the increased risk for neonatal admission in children from obese mothers does not necessarily indicate severe fetal impairment.
Subject(s)
Body Mass Index , Infant, Newborn, Diseases/etiology , Maternal Welfare , Obesity/complications , Pregnancy Complications , Adult , Birth Weight , Cohort Studies , Female , Germany/epidemiology , Humans , Infant, Newborn , Intensive Care, Neonatal , Obstetric Labor Complications/etiology , Patient Admission , Pregnancy , Pregnancy Outcome , Premature Birth/epidemiology , Prospective Studies , Thinness/complications , Young AdultABSTRACT
INTRODUCTION: Activation of the endothelin (ET) system promotes inflammation and fibrosis in various tissues including the kidney. Male ET-1 transgenic mice are characterized by chronic kidney inflammation and renal scarring. We hypothesized that this renal phenotype might be modulated by androgens. Thus the aim of our study was to elucidate the impact of gonadectomy in ET-1 transgenic mice on kidney function and morphology. - METHODS: Male ET-1 transgenic mice at the age of 10 weeks were randomly allocated to the following groups: normal ET transgenic mice (ET; n = 17) and ET transgenic mice that underwent castration (ET + cas; n = 12). Study duration was 9 months. Creatinine clearance and protein excretion was monitored. At study end animals were sacrificed and kidneys were harvested for histology/immunhistochemistry. RESULTS: Castration significantly ameliorated glomerulosclerosis in ET-1 transgenic mice (ET glomerulosclerosis-score: 3.0 +/- 0.17 vs ET+cas: 2.4 +/- 0.17; p < 0.05) as well as renal perivascular fibrosis (ET fibrosis-score: 3.0 +/- 0.14 vs ET + cas: 2.2 +/- 0.14; p < 0.05). However, interstitial fibrosis and media/lumen-ratio of renal arteries remained unaffected by castration. Regarding inflammation, castration significantly reduced the number of CD4-positive cells in renal tissue of ET-1 transgenic mice (ET CD4-positive cells/10000 cells: 355 +/- 72 vs ET + cas: 147 +/- 28; p < 0.05). Renal tissue contents of CD8 positive cells as well as of macrophages were not affected by castration. Regarding kidney function castration significantly reduced proteinuria in ET-1 transgenic mice whereas creatinine clearance did not differ between study groups. CONCLUSION: Our study demonstrates that the renal histopathological phenotype in male ET-1 transgenic mice with regard to glomerulosclerosis, proteinuria, perivascular fibrosis and immune cell immigration is ameliorated by castration. We thus conclude that the effects of ET-1 overexpression on renal tissue injury are modulated by androgens.
Subject(s)
Androgens/physiology , Endothelin-1/genetics , Kidney Diseases/etiology , Kidney/physiopathology , Androgens/deficiency , Animals , Kidney/pathology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Male , Mice , Mice, Transgenic , Orchiectomy , PhenotypeABSTRACT
The endothelin system has been implicated in the pathogenesis of acute liver failure. However, it has not yet been assessed in a tissue specific manner. - Acute liver failure was induced in rats by two intraperitoneal injections of galactosamine (1.3 g/kg, interval of 12 hours, n = 20). The animals were sacrificed after 48 hours. - Plasma measurements demonstrated that animals receiving galactosamine had a laboratory constellation of severe liver injury and they histologically presented with hepatic necrosis and inflammation. Plasma concentrations of endothelin-1 were elevated 60-fold in the animals receiving galactosamine (p = 0.005). In contrast endothelin-1 tissue contents were decreased in the kidneys and unchanged in the liver. Western blot analysis showed that animals receiving galactosamine had a significantly lower endothelin B receptor concentration in liver and kidney tissue, whereas no differences were detected for endothelin A receptors. - This study demonstrates that the local endothelin system of liver and kidneys is not responsible for the increase of plasma endothelin-1 concentrations in acute liver failure. Since it is well established that the endothelin B receptor acts as a clearance receptor, its decreased density might contribute to the strongly elevated plasma endothelin-1 concentrations seen in this model of acute liver injury.
Subject(s)
Endothelins/metabolism , Liver Failure/metabolism , Animals , Endothelins/blood , Galactosamine , Inflammation , Kidney/metabolism , Liver/metabolism , Liver Failure/chemically induced , Liver Failure/diagnosis , Male , Models, Biological , Necrosis , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
A genetic association study was conducted to assess whether genetically determined alterations of the nitric oxide system are associated with clinical markers of pre-eclampsia. A large number of Caucasian women were consecutively included after delivery and genotyped for the endothelial nitric oxide synthase gene (NOS3) polymorphisms G894T, T789C (n=1502) and intron 4a/b (n=2186). There are no significant differences in mean blood pressure (BP), protein excretion or new-onset peripheral oedema between any of the genotypes over the course of pregnancy. Neither particular haplotypes nor the combined presence of any two alleles is associated with those markers of pre-eclampsia. The maternal polymorphisms do not seem to influence fetal growth, birth weight or the incidence of congenital malformations. We demonstrate in a large Caucasian population that maternal polymorphisms of the NOS3 gene are not related to clinical markers of pre-eclampsia. The functional relevance of the NOS3 variants alone does not seem to be strong enough to affect BP regulation during pregnancy.
Subject(s)
Blood Pressure/physiology , Nitric Oxide Synthase Type III/genetics , Polymorphism, Genetic , Pre-Eclampsia/genetics , Pregnancy Outcome , Proteinuria/urine , Adult , Female , Humans , PregnancyABSTRACT
BACKGROUND AND PURPOSE: Myocardial fibrosis is an unwanted effect associated with chronic renal failure. The adenosine system is involved in cardiac and renal function. Therefore, we investigated the novel selective adenosine A(1) receptor antagonist SLV320 focusing on its potential in preventing cardiomyopathy in rats with 5/6 nephrectomy. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were allocated to 4 groups of 12 rats each: 5/6 nephrectomy (5/6 NX), 5/6 NX plus SLV320 (10 mg kg(-1) d(-1) mixed with food), sham and sham plus SLV320. Study duration was 12 weeks, blood pressure was assessed repeatedly. At study end kidney function was assessed, blood samples and hearts were taken for histology/immunohistochemistry. Pharmacological properties of SLV320 were assessed using receptor binding and enzyme assays and in vivo. KEY RESULTS: SLV320 is a selective and potent adenosine A(1) antagonist in vitro (Ki=1 nM) with a selectivity factor of at least 200 versus other adenosine receptor subtypes. Functional A(1) antagonism was demonstrated in vivo. In rats with 5/6 NX SLV320 significantly decreased albuminuria by about 50%, but did not alter glomerular filtration rate (GFR). SLV320 normalized cardiac collagen I+III contents in 5/6 NX rats. SLV320 prevented nephrectomy-dependent rise in plasma levels of creatinine kinase (CK), ALT and AST. Blood pressure did not differ between study groups. CONCLUSION: SLV320 suppresses cardiac fibrosis and attenuates albuminuria without affecting blood pressure in rats with 5/6 nephrectomy, indicating that selective A(1) receptor antagonists may be beneficial in uraemic cardiomyopathy.
Subject(s)
Adenosine A1 Receptor Antagonists , Blood Pressure/drug effects , Cyclohexanes/pharmacology , Endomyocardial Fibrosis/prevention & control , Heterocyclic Compounds, 2-Ring/pharmacology , Adenosine/pharmacology , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Cell Line , Collagen Type I/metabolism , Collagen Type III/metabolism , Creatine Kinase/metabolism , Cyclohexanes/chemistry , Cyclohexanes/metabolism , Endomyocardial Fibrosis/physiopathology , Fibronectins/metabolism , Glomerular Filtration Rate/drug effects , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/metabolism , Humans , Male , Molecular Structure , Myocardium/metabolism , Myocardium/pathology , Nephrectomy/methods , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A1/physiology , Rolipram/pharmacology , U937 Cells , Xanthines/pharmacologyABSTRACT
Maternal low-protein diet during pregnancy is a risk factor for cardiovascular disease of the offspring in later life. The impact of high-protein diet during pregnancy on the cardiovascular phenotype of the offspring, however, is still unknown. We examined the influence of a high-protein diet during pregnancy and lactation on the renal, hemodynamic, and metabolic phenotype of the F1 generation. Female Wistar rats were either fed a normal protein diet (20% protein: NP) or an isocaloric high-protein diet (40% protein: HP) throughout pregnancy and lactation. At weaning, the offspring were fed with standard diet, and they were allocated according to sex and maternal diet to four groups: normal-protein male (NPm, n = 25), normal-protein female (NPf, n = 19), high-protein male (HPm, n = 24), high-protein female (HPf, n = 29). During the experiment (22 wk), the animals were characterized by repeated measurement of body weight, food intake, blood pressure, glucose tolerance, energy expenditure, and kidney function. At the end of the study period histomorphological analyses of the kidneys and weight measurement of reproductive fat pads were conducted. There were no differences in birth weight between the study groups. No influence of maternal diet on energy expenditure, glucose tolerance, and plasma lipid levels was detected. Blood pressure and glomerulosclerosis were elevated in male offspring only, whereas female offspring were characterized by an increased food efficiency, higher body weight, and increased fat pads. Our study demonstrates that a high-protein diet during pregnancy and lactation in rats programs blood pressure, food efficiency, and body weight of the offspring in a sex-dependent manner.
Subject(s)
Adaptation, Physiological/physiology , Blood Pressure/physiology , Body Weight/physiology , Dietary Proteins/pharmacology , Sex Characteristics , Animals , Animals, Suckling , Birth Weight/physiology , Eating/physiology , Electrolytes/blood , Energy Metabolism/physiology , Female , Heart Rate/physiology , Kidney/anatomy & histology , Kidney/physiology , Lactation/physiology , Male , Organ Size/physiology , Phenotype , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, WistarABSTRACT
BACKGROUND: The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. PATIENTS AND METHODS: Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). RESULTS: Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. CONCLUSIONS: Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.
Subject(s)
Carboplatin/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Palliative Care , Adult , Aged , Carboplatin/adverse effects , Chemotherapy, Adjuvant , Confidence Intervals , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Ovariectomy/methods , Paclitaxel/adverse effects , Probability , Prognosis , Quality of Life , Risk Assessment , Spain , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: To evaluate the efficacy and the toxicity profile of the sequential administration of doxorubicin and docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Eighty-one patients received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m2) and 200 of docetaxel (100 mg/m2 every 21 days). The first 35 patients received doxorubicin every 14 days with G-CSF support, and in the other 46 cases doxorubicin was administered every 21 days without G-CSF. RESULTS: After entire treatment the overall response rate was 65% (18 complete responses). With a median follow-up of 19 months (range, 1-48 months), the median time to progression was 11.3 months and the median survival time was 31 months. As expected, febrile neutropenia was the most important toxicity and it appeared in 26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin every 14 days, the febrile neutropenia incidence was higher during docetaxel treatment, especially after its first administration. CONCLUSIONS: The dose and schedule of doxorubicin and docetaxel used in this trial seems to be active in first-line treatment of patients with MBC. The toxicity profile appears to be better than observed with concomitant schedules.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/administration & dosage , Paclitaxel/analogs & derivatives , Paclitaxel/administration & dosage , Taxoids , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Docetaxel , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Infusions, Intravenous , Middle Aged , Neoplasm Metastasis , Palliative Care , Prospective Studies , Spain , Survival Analysis , Treatment OutcomeABSTRACT
We present a case of a patient with non-resected epidermoid carcinoma of the anal canal, treated with a combination of radiotherapy regional and chemotherapy according to MMC-Ufelos protocol. After the application of the fourth chemotherapy cycle, the patient presented microangiopathic hemolytic anemia associated to Mitomycin-C, which was treated with the application of recurrent plasmapheresis and restricted transfusions of red corpuscles concentrate. The physiopathology of this disorder and its therapeutical implications are review.
Subject(s)
Acute Kidney Injury/chemically induced , Anemia, Hemolytic/chemically induced , Mitomycin/adverse effects , Humans , Male , Middle AgedSubject(s)
Foot Dermatoses/chemically induced , Tegafur/adverse effects , Female , Humans , Middle Aged , SyndromeABSTRACT
4 more cases of cardiotoxicity associated to 5-FU or oral fluoropirimidine (Ptorafur, UFT) in patients without previous heart disease (except in one case) are presented. The toxicity found was myocardial ischemia and EKG changes (in 3 patients) in patients whose enzymes were measured. The etiopathogenesis and features of this toxicity are discussed.
Subject(s)
Fluorouracil/adverse effects , Heart Diseases/chemically induced , Tegafur/adverse effects , Administration, Oral , Aged , Fluorouracil/administration & dosage , Humans , Male , Middle AgedABSTRACT
Certain evidence suggests that buspirone, a novel nonbenzodiazepine anxiolytic, may be a 5-HT1A serotonergic agonist and may antagonize postsynaptic dopaminergic receptors. The latter property raises questions regarding a dyskinesia- or extrapyramidal symptom-inducing potential. We monitored serum prolactin and growth hormone in 10 subjects with generalized anxiety disorder and 10 matched controls before and after 4 weeks of pharmacotherapy. A drug effect upon serotonin-modulated prolactin release or on the tubero-infundibular dopamine axis (prolactin; growth hormone) was negligible at clinically effective dosages of buspirone. Concomitant buspirone levels also failed to demonstrate any significant relationships.
Subject(s)
Anxiety/blood , Buspirone/adverse effects , Growth Hormone/blood , Prolactin/blood , Adult , Anxiety/drug therapy , Anxiety/psychology , Buspirone/blood , Buspirone/therapeutic use , Female , Humans , Male , Middle Aged , Psychiatric Status Rating ScalesABSTRACT
The central nervous and immune systems share a number of common properties, e.g. neurotransmitter receptors. In contrast to age matched healthy and/or hypertensive controls, the total lymphocyte count in 25 carefully diagnosed and staged patients with primary degenerative dementia were significantly reduced and also correlated with the severity of their dementia. Subjects' age, age of dementia onset, or duration of illness were unrelated. Total leukocyte counts were similar between groups. Nutritional status, ACTH, or plasma cortisol in dementia cohort were also not explanatory of their lymphopenia. These results are potentially significant in light of an immune hypothesis for primary degenerative dementia: Alzheimer's type and/or that population's high concomitant risk of infection.
Subject(s)
Alzheimer Disease/immunology , Lymphopenia/immunology , Adrenocorticotropic Hormone/blood , Aged , Alzheimer Disease/diagnosis , Alzheimer Disease/psychology , Female , Humans , Hydrocortisone/blood , Hypertension/immunology , Leukocyte Count , Male , Neuropsychological TestsABSTRACT
Eighteen patients with seasonal affective disorder were compared to 13 patients with recurrent nonseasonal depressions. Seasonal depressions were associated with hypersomnia and carbohydrate craving, and there was a trend for a younger age at onset of seasonal affective disorder.
Subject(s)
Depressive Disorder/diagnosis , Seasons , Adult , Age Factors , Depressive Disorder/etiology , Depressive Disorder/psychology , Diagnosis, Differential , Dietary Carbohydrates , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/psychology , Feeding and Eating Disorders/diagnosis , Feeding and Eating Disorders/psychology , Female , Humans , Male , Middle Aged , Psychiatric Status Rating ScalesABSTRACT
The authors analyzed the dexamethasone suppression test (DST) results of 54 patients with major depressive disorder in relation to their pre-DST levels of cholesterol, sodium, potassium, and blood glucose, which are thought to have adrenocorticotrophic links. Discriminant analysis revealed that sodium alone was a significant predictor of nonsuppression. Validation of the predictive power of sodium could minimize the need for DST administration.