Differential scanning calorimetry differences in micronized and unmicronized nimesulide uptake processes in biomembrane models.

Nimesulide release from micronized and unmicronized drug particles was tested at pH 7.4 by measuring the transfer to dimyristoylphosphatidylcholine liposomes (multilamellar and unilamellar vesicles), chosen as a biomembrane model. The perturbing effect of increasing molar fractions of pure nimesulide on the thermotropic behaviour of dimyristoylphosphatidylcholine liposomes was investigated by differential scanning calorimetry. In order to study the drug dissolution process by its uptake into void liposomes, measurements were carried out on suspensions of blank liposomes added to weighed amounts of free powdered nimesulide (micronized and unmicronized). The amount of drug transferred was quantified by comparing the effect caused by the dissolved and released drug to that caused by the free drug that had been previously molecularly dissolved in the liposomes. The calorimetric results show that the dissolution rate depends on the nimesulide form (micronized or unmicronized), and that the transfer to the void liposomes is quicker when the drug is in a micronized form. The uptake was faster when unilamellar vesicles were used instead of multilamellar vesicles because of the greater lipid surface. The calorimetric technique could represent an alternative 'in vitro' method that can be applied to the study of the dissolution kinetics directly at the site of drug uptake, mimicking a biological system.     

Stroma cells: a novel target of herceptin activity.

PURPOSE: Stroma cells play a relevant role in tumor development and progression. We investigated the activity of herceptin (HER), a humanized monoclonal antibody widely used for the treatment of HER2-overexpressing epithelial cancer, toward stroma cell lines L87/4 and L88/5. EXPERIMENTAL DESIGN: We studied the antiproliferative potential of HER and role of human serum in HER activity. We also investigated the ability of HER to alter ancillary functions of L87/4 and L88/5, such as support to long-term hematopoiesis, growth factor production, breast cancer cell adhesion, and proliferation. RESULTS: Flow cytometry showed that HER2 membrane expression in L87/4 and L88/5 stroma cells was intermediate between the expression in HER2-negative/dim MCF-7 breast cancer cells and HER2-bright SK-BC3 breast cancer cells. HER2 gene amplification was not detected by fluorescence in situ hybridization in either stromal cell lines. HER significantly inhibited L87/4 and L88/5 proliferation. Mean ID(50)s were found to be 2000 and 1700 micro g/ml for L87/4 and L88/5, respectively, after 3-day exposure and 800 micro g/ml for both cell lines after 9-day exposure. The presence of 10% human serum in the culture increased HER inhibitory activity. IC(50) of stroma cells was found to be intermediate between HER2-bright breast cancer cells (SK-BC3) and HER2-negative/dim breast cancer cells (MCF-7). The drug did not significantly affect the ability of stroma cells to support long-term hematopoiesis in the cobblestone area forming cell assay. In contrast, in coculture assay, MCF7 cells demonstrated a worse adhesion and growth capability on HER-treated stroma layers when compared with untreated stroma. Moreover, HER significantly reduced vascular endothelial growth factor production by L88/5 cells. CONCLUSIONS: Our data support the novel finding that HER may have a relevant activity against stroma cells.     

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27(Kip1) in estrogen-related Endometrial adenocarcinomas.

PURPOSE: p27(Kip1) is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Low levels of p27 are associated with poor prognosis in a variety of gynecological tumors, including breast, ovarian, and cervical carcinomas. The role of p27 in endometrial cancer remains controversial. EXPERIMENTAL DESIGN: In the present study, p27 protein expression was investigated by immunohistochemistry in a series of 217 endometrial adenocarcinomas and, where present, in synchronous normal endometrium, simple and complex hyperplasia (with or without atypia), and cystic atrophy. The relationship between p27 expression and clinical outcome was also evaluated. RESULTS: Immunohistochemical analysis revealed a significant loss of p27 expression from normal (33%) through hyperplastic endometrium (50%) to endometrial adenocarcinomas (71%; P 相似文献   

Significance of low birthweight for gestational age among very preterm infants

Objective To estimate the risk of specific adverse neonatal events resulting from the combined effects of prematurity and low birthweight in very preterm infants (delivered at 24–31 weeks of gestation)
Design A cohort study of specific adverse neonatal events in preterm infants born at between 24 and 31 weeks of gestation.
Setting Pavia, Italy.
Population Two hundred and thirty singleton infants with sonographically confirmed gestational age, delivered at 24 to 31 weeks of gestation.
Methods To evaluate the impact of a lower than expected birthweight on selected neonatal events independently of gestational age, we calculated birthweight standard deviation scores (differences between actual birthweight and fitted birthweight divided by fitted standard deviation) for each week of gestation.
Results After adjustment for gestational age and other confounders, there was a significant linear trend relating a decreasing birthweight SDS to an increased likelihood of neonatal death, intraventricular haemorrhage, severe respiratory distress syndrome, and acidosis. Compared with infants with SDS 0 ( 50th centile of birthweight), infants with birthweight SDS < −1 (< 16th centile) had increased odds for neonatal death [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.42–9.6], grade III-IV intraventricular haemorrhage (OR 17.5, 95% CI 4.04–75.9), and neonatal acidosis (OR 3.22, 95% CI 1.41–7.4). The significance of birthweight SDS as a predictor of neonatal outcome, however, was lower than that of gestational age.
Conclusions A lower than expected birthweight affects the likelihood of several adverse neonatal events in very preterm infants. However, a decreasing birthweight SDS affects neonatal outcome less than decreasing gestation does.     

Perioperative complications in acoustic neuroma (vestibular schwannoma) surgery.

OBJECTIVE: Retrospective study and review of the complications other than those related to the facial nerve and hearing, encountered in acoustic neuroma surgery. Also, an evaluation of hospital stay and its relation with various factors. STUDY DESIGN: Retrospective case review. SETTING: Tertiary neurotologic and skull base referral center. PATIENTS: A series of 707 patients who underwent surgical removal of acoustic neuroma from April 1987 to December 2001. INTERVENTIONS: The surgical approaches used were the enlarged translabyrinthine approach, the enlarged middle fossa approach, and the retrosigmoid approach. In a small number of cases, the operations were performed through other approaches. MAIN OUTCOME MEASURES: The duration of hospital stay and appearance of complications in the perioperative period along with their management. Results related to the facial nerve and hearing were not considered in this study. RESULTS: The most frequent complication was abdominal subcutaneous hematoma (site of fat harvest), which occurred in 23 patients (3.2%). Cerebrospinal fluid leak was present in 20 patients (2.8%), 15 of whom needed revision surgery. Other complications included VIth cranial nerve dysfunction in 12 cases (1.68%), subdural hematoma in 3 cases (0.4%), cerebellopontine angle hematoma in 4 cases (0.6%), cerebellar edema in 2 cases (0.28%), brainstem hematoma in 1 case (0.14%), transitory aphasia in 1 case (0.14%), and lower cranial nerve dysfunction in 1 case (0.14%). Mortality occurred in only one case (0.14%). Medical complications seldom occurred. The postoperative hospital stay ranged from 2 to 36 days, with an average of 6.4 days. The overall hospital stay diminished over time from 10.2 days in 1987 to 1990, to 4.9 days in 2001. There was a significant relation between hospital stay and tumor size, approach used, and presence/absence of complications. CONCLUSIONS: Perioperative complications in acoustic neuroma surgery do exist, but this study demonstrated how low the incidence is. The authors believe that the low percentage of complications is mainly attributable to the majority of operations being carried out in specialized clinics, where they are considered routine operations. They believe that following individualized approaches, depending on tumor size and on the preoperative function of the cranial nerves, is the proper way to reach a significant reduction in complications while maintaining a high percentage of total tumor removal. The results of this study, considered as a basis of comparison with other studies, will certainly be useful in preoperative patient counseling.     

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.     

Dapsone hydroxylamine-mediated alterations in human red blood cells from endometriotic patients

Endometriosis, an estrogen-dependent chronic gynecological disease in women of reproductive age, is characterized by a systemic inflammation status involving also red blood cells (RBCs). In this study, we evaluated how the protein oxidative status could be involved in the worsening of RBC conditions due to dapsone intake in endometriotic women in potential treatment for skin or infection diseases. Blood samples from two groups of volunteers, control group (CG) and endometriosis patient group (PG), were analyzed for their content of band 3 tyrosine phosphorylation (Tyr-P) and high molecular weight aggregate (HMWA) in membranes, and glutathione (GSH) content and carbonic anhydrase (CA) activity in cytosol. In endometriotic patients, RBC showed the highest level of oxidative-related alterations both in membrane and cytosol. More interestingly, the addition of dapsone hydroxylamine (DDS-NHOH) could induce further increase of both membranes and cytosol markers, with an enhancement of CA activity reaching about 66% of the total cell enzyme amount. In conclusion, in PG the systemic inflammatory status leads to the inability of counteracting adjunctive oxidative stress, with a potential involvement of CA-related pathologies, such as glaucoma. Hence, the importance of the evaluation of therapeutic approaches worsening oxidative imbalance present in PG RBC is underlined.