PURPOSE: PS-341 is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces mechanisms of apoptosis by unknown mechanisms. EXPERIMENTAL DESIGN: Human non-small cell lung cancer cell lines were used to investigate effects PS-341 on cell proliferation, cell cycle progression, and the induction of apoptosis. RESULTS: PS-341 was 38-360-fold more cytotoxic against H460 cells when compared with the proteasome inhibitors MG-132 and PSI. Differential PS-341 cytotoxic effects were found with respect to P53 function: H322 cells (p53 mutant) were 6-fold less sensitive as compared with H460 cells (p53 wild type); and H358 cells (p53 null) were 1.6-fold more sensitive as compared with H460 cells (p53 wild type). A concentration- and time-dependent cell cycle blockade at G(2)-M phase was seen for H460 cells without any direct effects on microtubule polymerization or depolymerization. PS-341 exposure in H460 cells led to stabilization of p53, induction of p21(cip/waf-1) and MDM2 expression, an increase in cyclin B and cyclin A, and the activation of cyclin B and cyclin A kinases. MDM2 induction was found only in H460 cells, whereas in H322 and H358 cells, G(2)-M-phase arrest, p21(cip/waf-1) induction, and an increase in cyclin B1 were found. The commitment of G(2)-M-phase cells to apoptosis was verified by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in drug-free medium. CONCLUSIONS: Our data suggest that the PS-341-induced G(2)-M-phase arrest may be associated with the inhibition of degradation of cell cycle regulators and that the up-regulation of p21(cip/waf-1) expression may be via p53-dependent and/or -independent pathways. The resulting disturbance of cell cycle progression leads either to growth inhibition or to the initiation of apoptotic pathways. 相似文献
: The aim of this work is to invetigate an unusually high rate of late rectal complications in a group of 43 patients treated with concomitant irradiation and chemotherapy for carcinoma of the cervix between December 1988 and April 1991, with a view to identifying predictive factors.
: The biologically effective dose received by each patient to the rectal reference point defined by the International Commission of Radiation Units and Measurements, Report 38, were calculated. Radiotherapy consisted of 46 Gy external beam irradiation plus three dose-rate intracavitary treatments of 10 Gy each prescribed to point A. Cisplatin 30 mg/m2 was given weekly throughout the duration of the irradiation. The results have been compared to data from 119 patients treated with irradiation alone to assess the cofounding effect of the cisplatin.
: The relationship between the biologically effective dose delivered to the rectal reference point and the development of late complications shows a strong dose-response with a threshold for complications occurring at aproximately the same biologically effective dose threshold as that found for external beam irradiation in the head and neck region. The date from the group of patients treated wihout cisplatin is comparable to the date from the first group of patients in the lower dose ranges; the higher doses were not used and thus are not available for comparison.
: Using the linear quadratic model applied to our clinical results, we have established a threshold for late rectal complications for patients treated with external beam irradiation and high dose-rate brachytherapy for carcinoma of the cervix. This threshold is consistent with similar data for external irradiation in the head and neck region. 相似文献
OBJECTIVE: Currently, physicians manage preterm premature rupture of membranes (PPROM) by expectant management or termination of the gestation. A therapy aimed at sealing membranes would be optimal to maintain the pregnancy and achieve a normal neonate. Our objective was to compare an endoscopic technique for intrauterine closure of fetal membrane defects after both iatrogenic and spontaneous rupture of membranes. METHODS: Our technique was performed on four patients experiencing PPROM spontaneously and four patients after genetic amniocentesis. Intrauterine endoscopy allowed direct visualization of membrane defects. Rapid sequential injections of platelets, fibrin glue and powdered collagen slurry were administered at the site of the defect and of trocar placement. Sonography for amniotic fluid index, nitrazine and fern testing and pad count were performed after each procedure at three intervals: immediately post-procedure, and after 24 and 48 h. RESULTS: Eight patients underwent endoscopic intrauterine sealing of ruptured membranes between 16 and 24 weeks of gestation: four were spontaneous ruptures and four were ruptures post-amniocentesis. In the post-amniocentesis group, three patients delivered viable infants at 26, 32 and 34 weeks. In one patient, the membranes ruptured again 12 h after the sealing procedure and she decided to undergo termination of pregnancy. Of the four spontaneous rupture patients, two experienced preterm labor and delivery within 2 days of the procedure. One patient was diagnosed with fetal demise 12 h post-procedure, and one patient delivered a neonate at 31 weeks of gestation with severe respiratory distress syndrome. CONCLUSIONS: This technique for sealing ruptured membranes is effective after amniocentesis, but may not be of benefit with spontaneous rupture. 相似文献
Withdrawal is the main method used amongst couples in Turkey to prevent pregnancy. Discontinuation of use is most likely to be due to the desire to become pregnant or failure of the method. Withdrawal users are less likely to switch to another contraceptive method; however, among users who do switch, they will most likely switch to a modem method. The strongest three determinants that predict withdrawal use are using withdrawal as one's first method, the woman's age, and the husband's education. The woman's work status and the couple's ethnicity are also important predictors of withdrawal use. Family planning programs should target different segments of the population and focus on correct knowledge of all methods. Results indicate that men and women need to learn about family planning options earlier in their lives or prior to marriage. 相似文献
We report a case of postoperative Richter’s hernia presenting through a 5-mm sheath incision. A 58-year-old woman having undergone laparoscopic hysterectomy 8 days before presented with severe left abdominal pain, nausea and light-headedness. The hypothesis of a sigmoid volvulus was suggested based on peroperative rectum and sigmoid release, the X-ray finding, and pain evolution. A secondary laparoscopic procedure allowed both diagnosis of a Richter’s hernia through a 5-mm sheath incision and surgical repair of the hernia. The use of this sheath during the laparoscopic vagina suture caused extension of the wound. Large 5-mm sheath defect sufficient for a Richter’s hernia can be created by multiple passes with small instruments and require surgical closure at the end of laparoscopy. Laparoscopy is useful in cases of postoperative complications, particularly when other complementary examinations are less informative. 相似文献
We report two cases of successful emergency ligation of anomalous left coronary artery arising from the pulmonary artery (ALCAPA) in patients with previous cardiac arrest. Both patients had regained marginal cardiac output after cardiopulmonary resuscitation and had maximal doses of inotropic support. The ALCAPA ligation was then performed as a life-saving procedure in the absence of any kind of mechanical circulatory support. 相似文献
Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) µM for a 48 h exposure with a range of 64–358 µM. Cell killing was schedule-dependent, favoring exposure times ≥48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations ≤200 µM for 48 h. When concentrations were increased to 300 µM for ≥48 h, the MiaPaCa-2 cells arrested in G2 phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of ≥400 µM were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards. The levels of imexon that are cytotoxic in human PCC’s are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G2 arrest, accumulation of ROS, and the induction of apoptosis. 相似文献
Neuronal nitric oxide synthase (NOS I) is a Ca(2+)/calmodulin-binding enzyme that generates nitric oxide (NO*) and L-citrulline from the oxidation of L-arginine, and superoxide (O(2)*(-)) from the one-electron reduction of oxygen (O(2)). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca(2+), which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca(2+) binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca(2+), we demonstrate that Ni(2+), Ba(2+), and Mn(2+) can activate NOS I to metabolize L-arginine to L-citrulline and NO*, and afford O(2)*(-) in the absence of L-arginine. In contrast, Cd(2+) did not activate NOS I to produce either NO* or O(2)*(-), and the combination of Ca(2+) and either Cd(2+), Ni(2+), or Mn(2+) inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO*, O(2)*(-) and products derived from these free radicals. 相似文献
The platinum compounds cisplatin and carboplatin are commonly used in cancer chemotherapy. However, tumors frequently develop resistance to these compounds, significantly decreasing their usefulness in the clinic. In the past few years, basic research has unraveled novel and unexpected mechanisms for the development of platinum resistance. For example, it has been reported that MUC1 expression and particularly the localization of its C-terminal subunit to the mitochondria may affect cisplatin resistance. Another recent finding suggests that cisplatin damage may activate DNA-dependent protein kinase (DNA-PK) to initiate a death signal that can be transmitted to neighboring cells through gap junctions, adding to a growing belief that the interactions of cancer cells with their surroundings may be important to the outcome of chemotherapy. While most clinical efforts have focused on identifying alternative regimens for drug-resistant cancer, it might be possible to exploit our knowledge of the mechanism of platinum resistance to specifically reverse resistance and increase platinum efficacy. The strategy of drug resistance reversal therapy (DRRT) may have significant impact on our approaches to the treatment and management of drug-resistant tumors. 相似文献
Open in a separate windowOBJECTIVESTo evaluate outcomes after thoracic endovascular aortic repair in young patients sustaining traumatic blunt aortic injury (BAI) using iliac extension stent-grafts because of small aortic diameters measuring <24 mm.METHODSRetrospective analysis regarding clinical presentation, trauma management, endovascular techniques and outcome of patients with a small descending aorta involving an iliac extension stent-graft to treat traumatic BAI.RESULTSAmong 48 patients who suffered a BAI and underwent thoracic endovascular aortic repair, 7 received iliac extension stent-grafts. They were 27.4/[standard deviation (SD): −13.1] years old and 6 out of 7 were male. The iliac extension stent-graft was used as distal stent-graft, and a thoracic stent-graft was used in most patients as proximal extension. We achieved overall technical success in all patients during a procedure lasting 92.6 (SD: 54.9) min. One patient died 2 days after the endovascular procedure of hypoxic brain injury, and another died after 17 days of liver failure. That patient had also suffered a spinal cord injury following the procedure, as the stent-graft had been deployed in Ishimaru Zone 2, and the carotid to subclavian bypass had to be omitted because of his critical condition. Control computed tomographic angiographs was available in 6 patients after 7.7 (SD: 5.1) days and showed no endoleak. The surviving patients were discharged after 18.4 (SD: 13.4) days.CONCLUSIONSTreating traumatic BAI using iliac extension stent-grafts in young patients with small aortic diameters is feasible. We observed no mortality caused by the BAI or related to endovascular therapy within this small patient cohort. 相似文献