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Biomedical subjects

S Ferrari

Publications and source records attributed to S Ferrari.

At least 127 records · Page 7Linked to original sources
PubMed1997

Phosphorylation and activation of B-Myb by cyclin A-Cdk2.

BACKGROUND: Cyclins and their catalytic partners, the cyclin-dependent kinases (Cdks), function as key regulators of the eukaryotic cell cycle. Specific cyclin-Cdk complexes are active at successive stages during the cell cycle and control cell-cycle progression by phosphorylating specific target proteins, most of which have not yet been identified. B-Myb, a conserved member of the Myb oncoprotein family, is a sequence-specific DNA-binding protein expressed in virtually all proliferating mammalian cells. Increasing evidence suggests that B-Myb plays an important role during the late G1 and early S phases of the cell cycle. In this study, we have examined the regulation of B-Myb activity by cyclin-Cdks. RESULTS: We found that the transcriptional transactivation potential of B-Myb was repressed by a regulatory domain located at the carboxyl terminus of the protein. Coexpression of B-Myb and cyclin A relieved this repression by phosphorylation of B-Myb in its carboxy-terminal region. Tryptic phosphopeptide mapping revealed that endogenous B-Myb was phosphorylated in cells undergoing S phase. CONCLUSIONS: This work provides evidence for a link between the Myb oncoprotein family and the cell-cycle machinery. We have shown that the carboxyl terminus of B-Myb acts as a cell-cycle sensor that regulates the transactivation function of B-Myb. Moreover, our studies have identified B-Myb as a target of cyclin A-Cdk2 and have indicated that B-Myb activity is regulated by phosphorylation mediated by cyclin A-Cdk2.

3T3 Cells↗
PubMed1997

Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial.

High calcium intake during childhood has been suggested to increase bone mass accrual, potentially resulting in a greater peak bone mass. Whether the effects of calcium supplementation on bone mass accrual vary from one skeletal region to another, and to what extent the level of spontaneous calcium intake may affect the magnitude of the response has, however, not yet been clearly established. In a double-blind, placebo-controlled study, 149 healthy prepubertal girls aged 7.9+/-0.1 yr (mean+/-SEM) were either allocated two food products containing 850 mg of calcium (Ca-suppl.) or not (placebo) on a daily basis for 1 yr. Areal bone mineral density (BMD), bone mineral content (BMC), and bone size were determined at six sites by dual-energy x-ray absorptiometry. The difference in BMD gain between calcium-supplemented (Ca-suppl.) and placebo was greater at radial (metaphysis and diaphysis) and femoral (neck, trochanter, and diaphyses) sites (7-12 mg/cm2 per yr) than in the lumbar spine (2 mg/cm2 per yr). The difference in BMD gains between Ca-suppl. and placebo was greatest in girls with a spontaneous calcium intake below the median of 880 mg/d. The increase in mean BMD of the 6 sites in the low-calcium consumers was accompanied by increased gains in mean BMC, bone size, and statural height. These results suggest a possible positive effect of calcium supplementation on skeletal growth at that age. In conclusion, calcium-enriched foods significantly increased bone mass accrual in prepubertal girls, with a preferential effect in the appendicular skeleton, and greater benefit at lower spontaneous calcium intake.

Absorptiometry, Photon↗
PubMed1997

Evidence for different mechanisms of growth inhibition of T-cell lymphoma by phorbol esters and concanavalin A.

Stimuli that are mitogenic for mature T-cells induce cell cycle arrest in some T-cell tumors and T-cell hybridomas. The molecular mechanism of this growth inhibition is poorly understood. In this report, we show that in EL4, a murine T-lymphoma cell line, stimulation with concanavalin A or treatment with phorbol 13-myristate 12-acetate (PMA) inhibit growth, due to cell cycle arrest at both the G1 and the G2/M phases. The block at the G1 phase is accompanied by the appearance of a hypophosphorylated form of the retinoblastoma protein (pRb), due to the inhibition of G1 cyclin-Cdk complexes. However, the molecular mechanisms leading to this G1 cell cycle arrest differ between concanavalin A and PMA: concanavalin A inhibits both cyclin E-Cdk2 and cyclin D-Cdk4 complexes, while PMA inhibits only cyclin E-Cdk2. We demonstrate that concanavalin A inhibits cyclin D-Cdk4 activity by decreasing the amount of cyclin D. The inhibition of cyclin E-Cdk2 by both concanavalin A and PMA is due to increased binding of the Cdk inhibitor p21 to this complex. However, while stimulation of the cells with concanavalin A did not result in an evident increase of the total level of p21, treatment of the cells with PMA increased p21 levels significantly. Our results indicate, furthermore, that the G2/M block results from the inhibition of cyclin A- and cyclin B1-associated kinase activities. As for cyclin E-Cdk2, the inhibition of the cyclin A-Cdk2 complex is due to increased binding of the p21 inhibitor.

Animals↗
PubMed1997

Osteogenic sarcoma of the extremity with detectable lung metastases at presentation. Results of treatment of 23 patients with chemotherapy followed by simultaneous resection of primary and metastatic lesions.

BACKGROUND: In the past 20 years, it has been demonstrated that the combination of surgery and chemotherapy improves the prognosis for patients with osteosarcoma of the extremity without detectable metastases at presentation. By contrast, the efficacy of chemotherapy coupled with aggressive surgery has not yet been well established for patients with metastatic disease at diagnosis. The current study evaluates the efficacy of chemotherapy associated with simultaneous surgery of primary and metastatic lesions in patients presenting with osteosarcoma of the extremity with lung metastases. METHODS: Patients with lung metastases originating from an osteosarcoma of the extremity received chemotherapy (high dose methotrexate, cisplatin, doxorubicin, and ifosfamide) followed by simultaneous resection of primary and metastatic lesions and additional chemotherapy. RESULTS: Between January 1993 and June 1995, 23 patients entered the study. After primary chemotherapy, lung metastases disappeared in three patients, whereas in four patients they remained surgically unresectable. All seven patients received surgical treatment of the primary tumor only. In the remaining 16 patients, a simultaneous resection of the primary and metastatic tumors was performed after chemotherapy. The resection of metastatic lesions resulted in a complete remission in 15 patients and an incomplete remission in 1 patient. All five patients who never achieved tumor free status died within a few months. Of the 18 patients who achieved radiologic remission at a 30-month follow-up (range, 14-50 months), 10 (55.5%) remained continuously free of disease, 7 relapsed with new metastases, and 1 died of toxicity. In 13 of the 18 patients who underwent a complete simultaneous resection of the primary and the metastatic lesions, or whose pulmonary metastases disappeared after chemotherapy, a strong correlation was found between degree of necrosis of the primary tumor and of the metastatic tumor. CONCLUSIONS: In patients presenting with osteosarcoma of the extremity with lung metastases, the combination of aggressive chemotherapy with simultaneous resection of the primary and metastatic lesions improves traditionally negative outcomes. The strong correlation found between the histologic response of the primary and metastatic tumors supports the strategy, largely used currently in the neoadjuvant treatment of osteosarcoma, of tailoring postoperative chemotherapy on the basis of the histologic response of the primary tumor to preoperative chemotherapy.

Adolescent↗
PubMed1997

Antisense inhibition of c-fes proto-oncogene blocks PMA-induced macrophage differentiation in HL60 and in FDC-P1/MAC-11 cells.

To gain some insight into the role of c-fes in macrophage differentiation, we have analyzed the ability of HL60 leukemic promyelocytic cells and FDC-P1/MAC-11 murine myeloid precursor cells to differentiate in response to phorbol esters after inhibition of c-fes function. Fes inactivation has been obtained by using oligodeoxynucleotides (ODN) complementary to the 5' region of c-fes mRNA and to 5' splice junctions of c-fes primary transcript. After 5 days (d) in culture, in several separate experiments performed with different ODN preparations, a complete inhibition of c-fes expression was observed in HL60 and in FDC-P1/MAC-11 cells. No perturbation of cell growth was evident in our experimental conditions in both cell lines after c-fes inhibition. Furthermore, in HL60 cells lacking c-fes product, an almost complete downregulation of the alpha 4 beta 1 fibronectin receptor occurred. However, in both cell lines, the induction of macrophage differentiation by phorbol esters resulted in an almost complete maturation arrest as evaluated by morphological, cytochemical, immunological criteria, and by the cytofluorimetric cell cycle analysis. A loss of the adhesion capacity of both myeloid cell lines, when compared to terminally differentiated macrophages, was also observed. These results suggest that HL60 and FDC-P1/MAC-11 cells, when treated with phorbol 12-myristate 13-acetate, require c-fes protein expression to activate the genetic program underlying macrophage differentiation.

Animals↗
PubMed1997

Calcium homeostasis in ageing: studies on the calcium binding protein calbindin D28K.

Calbindin D28K is a neuronal calcium binding protein which may act as a buffer of neuronal calcium. Evidence suggests that disturbance of calcium homeostasis is important in neurodegeneration, possibly via changes in calbindin D28K. Immunoreactivity of calbindin D28K is compared in Alzheimer's disease and age-matched controls. The size and number of calbindin D28K positive neurons in Alzheimer's disease tissue is reduced. There is also shrinkage of the dendritic tree. Continuing work examines the function of calbindin D28K using transgenic mice.

Aged↗
PubMed1997

Delayed spongiform leukoencephalopathy after heroin abuse.

Here we report the clinical and pathological findings in a 30-year-old drug addict in whom an intravenous injection of heroin led to reversible coma with respiratory depression and heart failure. On regaining consciousness, the patient was found to have rhabdomyolysis with renal failure requiring dialysis and peripheral neuropathy. Three weeks later his neurological condition suddenly deteriorated and delayed encephalopathy developed, leading to death 20 days later. The neuropathological study of the brain disclosed pale, spongy myelin with diffuse reactive astrogliosis and microglial proliferation, without hypoxic necrotic lesions. The cerebral and cerebellar cortices were unchanged. The absence of typical hypoxic lesions and the presence of spongiosis with massive astrocytosis distinguished this case from the previously reported cases of delayed leukoencephalopathy following severe hypoxia. An immunocytochemical study designed to exclude an underlying alteration of the metabolic oxidative pathway detected normal expression of the respiratory chain complexes IV, III and V. Despite the absence of an oxidative chain alteration in our patient, we cannot exclude the possibility that an individual predisposition played a pathogenetic role in this delayed leukoencephalopathy.

Adult↗
PubMed1997

Long-term effects of angiotensin-converting enzyme inhibitors and calcium antagonists on the right and left ventricles in essential hypertension.

To compare the effects of chronic antihypertensive treatment on left and right ventricular structure and function, 24 patients with mild to moderate, never-treated hypertension were randomized to receive fosinopril (20 mg daily) or amlodipine (10 mg daily) for 12 months. At baseline and subsequently at the end of third, sixth, and twelfth months, each patient underwent an integrated echocardiographic study and noninvasive ambulatory blood pressure monitoring. Both drugs significantly reduced blood pressure, casual or monitored (p < 0.01), and left ventricular mass index (from 125 +/- 32 to 100 +/- 12 gm/m2 [p < 0.02] with amlodipine and from 106 +/- 18 to 89 +/- 10 gm/m2 [p < 0.02] with fosinopril). The decrease in left ventricular mass was essentially caused by a reduction of ventricular thickness. Free right ventricular wall thickness was also lowered in both groups, more consistently with amlodipine (from 8.0 +/- 2.1 to 6.4 +/- 0.8 mm; p < 0.01), without an increase in plasma natriuretic peptide and insulin concentrations or heart rate. With both treatments, the decrease in ventricular mass was not associated with impairment of systolic function, whereas a trend toward an improvement of Doppler echocardiographic indexes of biventricular diastolic function was observed. In conclusion, both amlodipine and fosinopril induced similar qualitative effects on anatomy and function of both ventricles. The clinical meaning of these observations must be defined further by means of adequately sized prospective trials.

Adult↗
PubMed1997

Computerized tomography and magnetic resonance guided stereotactic brain biopsy in nonimmunocompromised and AIDS patients.

BACKGROUND: The utility of stereotactic brain biopsy (SBB) in AIDS patients still remains controversial. The authors investigated SBB-related diagnostic accuracy, complications, and postoperative sequelae in nonimmunocompromised (NIC) patients and AIDS patients. The role of bioptic yield in treatment planning was also studied in AIDS patients. METHODS: From 1990-95, 200 computerized tomography (CT) or magnetic resonance imaging (MRI)-guided SBBs were performed in our Department; 172 bioptic procedures were performed in NIC patients (169), and 28 SBBs in AIDS patients (27). The statistical significance was evaluated using the Fisher exact t-test. RESULTS: SBB accuracy was very high in both NIC (94.8%) and AIDS (92.9%) patients. Statistical analysis indicated nonsignificant (NS) differences between the two study groups (P > 0.05). Diagnostic yield resulted higher in contrast-enhancing (CE) brain lesions (98.6% in NIC and 95.0% in AIDS patients; P > 0.05; NS), than in non-CE lesions (74.1% in NIC and 87.5% in AIDS patients; P > 0.05; NS). The overall complication rate was similar in both groups (17.2% in NIC and 14.8% in AIDS patients, P > 0.05, NS). The most frequent complication was hemorrhage, with statistically negligible differences between the two study groups (P > 0.05). The frequency of complications involving minor/major morbidity or mortality was very low in NIC (5.9%, 0.6%, and 2.4%, respectively), and in AIDS (3.7%, 7.4%, and 0.0%, respectively) patients. Regarding the therapeutic impact of bioptic diagnosis for neuro-AIDS patients, the preoperative treatment attitude was modified in 23/27 cases (85.2%), and the empiric anti-toxoplasmosis regimen was changed or withdrawn in 17/21 patients (81.0%). CONCLUSION: Our experience demonstrated SBB to be an accurate, manageable, and reasonably safe diagnostic tool in both NIC and AIDS patients. These results suggest also that timely SBB indication in selected AIDS patients, reaching an early diagnosis, may on one side prevent unnecessary and potentially toxic empiric therapeutic regimens, and on the other address the appropriate treatment, thereby improving length and quality of life in such patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy.

BACKGROUND: Most of the studies of the treatment of non-metastatic osteosarcoma of the extremity have reported results in terms of probability of survival up to five years with a minimum follow-up of less than two to three years. Definition of reliable indicators of prognosis and predictive factors for survival require mature data derived from a long-term survival analysis. PATIENTS AND METHODS: A review of 127 patients with non-metastatic osteosarcoma of the extremity, treated between March 1983 and June 1986, was performed. The treatment protocol consisted of primary chemotherapy with MTX (randomization to high vs. moderate dosages) and CDP followed by surgery. Postoperatively, patients with < 60% tumor necrosis received ADM and BCD; those with tumor necrosis > or = 60% < 90% (Fair Responders FR) were given MTX, CDP and ADM. Up to January 1984, patients with tumor necrosis > 90% received MTX and CDP only, and after then they were given the same treatment as for FR. A multivariate analysis to test predictive factors for survival was performed. RESULTS: With a median follow-up of 134 months (range 114-153), the 12-year DFS was 46%. A good histologic response, an LDH baseline value within the normal range, and the use of high-dose MTX were positive predictive factors for DFS. With a median time of observation for survivors of 130 months, the 12-year overall survival was 53%. None of the patients who relapsed with local or distant recurrences other than lung metastasis are now alive. Patients with a relapse-free interval longer than 24 months had a significantly better post-relapse survival than those with a shorter relapse-free interval (40% vs. 7%; P = 0.0159). All of the patients who were not surgically treated had disease progression and died within 40 months after the first recurrence. The surgically-treated patients had a 30% post-relapse survival probability. CONCLUSIONS: In non-metastatic osteosarcoma of the extremity, chemotherapy-induced tumor necrosis, the baseline LDH serum value and the use of HDMTX are significant predictive factors for DFS. The relapse-free interval and the possibility of metastasectomy are significant factors conditioning the post-relapse survival.

Adolescent↗
PubMed1997

Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is a rare bone tumor usually treated like osteosarcoma. Studies on analogies and differences between the two tumors have seldom been reported. PATIENTS AND METHODS: Between March 1982 and December 1994, 51 patients with high-grade MFH of bone and 390 with high-grade osteosarcoma were treated with the same regimen of neoadjuvant chemotherapy. All of the tumors in both groups were located in the limbs. Preoperative chemotherapy was performed according to three different, successively activated, regimens consisting of MTX/CDP intraarterially, MTX/CDP/ADM, and MTX/CDP/ADM//IFO. RESULTS: The rate of limb salvage was the same in both the MFH (92%) and osteosarcoma (85%) patients. MFH showed a statistically significantly lower rate of good histologic response, 90% or more tumor necrosis (27% vs. 67%, P = 0.00001) for all three regimens. Despite this low chemosensitivity, the disease-free survivals of the two neoplasms were similar (67% vs. 65%). CONCLUSIONS: In terms of histologic response to primary chemotherapy, MFH has a lower chemosensitivity than osteosarcoma. Nevertheless, the two tumors have similar prognoses when treated with chemotherapy regimens based on MTX, CDP, ADM and IFO.

Adolescent↗
PubMed1997

ExGen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo.

Nonviral vectors might represent a safe alternative to adenovirus for gene therapy of lung disorders, in particular cystic fibrosis (CF). Cationic lipids have been shown to correct the CF defect both in vitro and in vivo, but more efficient vectors are needed to improve the low gene transfer efficiency. Here, we show that the cationic polymer ExGen 500, a linear polyethylenimine derivative, is more efficient than cationic lipids in transferring reporter genes to lung epithelial cells in vitro. In vivo ExGen 500 was able to mediate gene transfer into both newborn and adult rabbit lungs with comparable efficiencies. The best levels of transfection were obtained using neutral complexes. Under such conditions, luciferase activities corresponding to about 10(3) RLU/10 s/mg of protein were reproducibly obtained 2 days after transfection throughout the four lung lobes of newborn and adult rabbits. A nlslacZ reporter gene showed transfected cells around the lumen of large and small bronchi. No signs of acute toxicity (inflammation, cellular infiltration etc) were detected by direct histopathological analysis. Within 1 week after instillation, transgene expression decreased by two orders of magnitude.

Animals↗
PubMed1997

Cardiorespiratory changes during gynaecological laparoscopy by abdominal wall elevation: comparison with carbon dioxide pneumoperitoneum.

We have studied the cardiorespiratory changes produced by abdominal wall elevation (AWE) or carbon dioxide pneumoperitoneum (PN) in 20 women undergoing gynaecological laparoscopy. Arterial pressure, heart rate, lung/chest complicance and blood-gas tensions were measured 10 min after induction of general anaesthesia (T0), 10 min after abdominal distension in the supine position (T1) and 10 min after the Trendelenburg position was assumed (T2). Visual analogue scores for pain were recorded 1 and 6 h after the end of surgery. We found that lung/chest compliance was reduced significantly in group PN at T1 and T2 compared with both T0 and group AWE. Diastolic arterial pressure increased significantly in group PN at T1 and T2 compared with both T0 and group AWE, while it remained unchanged in group AWE. Arterial PCO2 increased significantly only in group PN after pneumoperitoneum, while oxygenation was almost unchanged in both groups. AWE patients had greater abdominal pain 1 h after surgery. Six hours after surgery pain was similar in the two groups. These data indicate that abdominal wall elevation reduced pulmonary compliance less than a pneumoperitoneum in patients undergoing gynaecological laparoscopy.

Abdominal Muscles↗
PubMed1997

Neoadjuvant chemotherapy for osseous malignant fibrous histiocytoma of the extremity: results in 18 cases and comparison with 112 contemporary osteosarcoma patients treated with the same chemotherapy regimen.

Eighteen patients with high grade malignant fibrous histiocytoma (MFH) of bone and 112 patients with high grade osteosarcoma (OS) of the extremity were treated with neoadjuvant chemotherapy comprised of methotrexate, cisplatinum, doxorubicin and ifosfamide. For the 18 patients with MFH, surgery involved amputation in 2 cases and limb salvage in 16 (89%); the 112 osteosarcoma patients had amputation in 8 cases and limb salvage procedure in 104 cases (93%). The rate of good histologic response to preoperative chemotherapy (90% or more tumor necrosis) was significantly higher in patients with osteosarcoma than in patients with MFH (74% vs 28%; p < 0.003). However, at a median follow-up of 38 months (range 25-61), the 3-year event-free survival (EFS) did not differ in the two groups (MFH 77.8%, OS 70.5%; p = ns). In patients with MFH, no local recurrences were registered, whereas in the osteosarcoma group there were 6 local relapses (5.%). The effectiveness of neoadjuvant chemotherapy in the treatment of osteosarcoma has been assessed during the last 15 years. The results of the present study seem to indicate that, in spite of a usually poor histologic response to preoperative treatment, neoadjuvant chemotherapy is very effective also in MFH of bone.

Adolescent↗
PubMed1997

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE: This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS: The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS: A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION: The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

Adolescent↗