Three prominent hallmarks of triple-negative/basal-like breast carcinomas, a subtype of breast cancer gene phenotype associated with poor relapse-free and overall survival, are overexpression of the ...epidermal growth factor receptor (EGFR), hyperactivation of the MEK/ERK transduction pathway and high sensitivity to DNA-damaging agents. The cytotoxic interaction between EGFR inhibitors (monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors such as gefitinib) and DNA cross-linking agents (e.g. platinum derivatives) might represent a promising combination for the treatment of triple-negative/basal-like breast tumors that are dependent upon EGFR/MEK/ERK signaling. We evaluated the growth and molecular interactions of the anti-EGFR antibody cetuximab (erbitux) and the DNA cross-linking agent cisplatin (cis-diammedichloroplatinum; CDDP) in the gefitinib-resistant MDA-MB-468 breast cancer cell line, an in vitro model system that shows many of the recurrent basal-like molecular abnormalities including ER-PR-HER2-negative status, TP53 deficiency, EGFR overexpression, PTEN loss and constitutive activation of the MEK/ERK pathway. Unlike other basal-like breast cancer models, MDA-MB-468 cells do not carry mutations of the key DNA repair gene BRCA1. Concurrent treatment with sub-optimal doses of cetuximab significantly enhanced CDDP-induced apoptotic cell death. However, an isobologram-based mathematical assessment of the nature of the interaction revealed a loss of synergism when employing a high-dose of cetuximab. Since BRCA1 depletion has been found to decrease DNA damage repair and cell survival in MDA-MB-468 cells when treated with DNA-damaging drugs, we employed ELISA-based quantitative analyses to measure BRCA1 protein levels in CDDP+/- cetuximab-treated cells. Cetuximab as single agent was as efficient as CDDP at increasing BRCA1 protein expression. Interestingly, cetuximab co-exposure significantly antagonized the ability of CDDP to up-regulate BRCA1 expression. Low-scale phosphor-proteomic approaches i.e. phospho-receptor tyrosine kinase (RTK) and phospho-mitogen-activated protein kinases (MAPKs) Array Proteome Profiler capable of simultaneously identifying the relative levels of phosphorylation of 42 different RTKs and 23 different MAPKs and other serine/threonine kinases, respectively revealed the ability of Cetuximab, as single agent, to paradoxically induce hyper-phosphorylation of EGFR while concomitantly deactivating p42/44 (ERK1/ERK2) MAPK. Unexpectedly, ELISA-based quantitative analyses of EGFR protein content demonstrated that simultaneous exposure to cetuximab and optimal doses of CDDP completely depleted EGFR protein in MDA-MB-468 cells. Although these findings preclinically support, at least in part, ongoing clinical trials for 'triple-negative/basal-like' metastatic breast cancer patients who are receiving either cetuximab alone versus cetuximab plus carboplatin (http://www.clinicaltrials.gov/ct/show/NCT00232505), the unexpected ability of CDDP to promote a complete depletion of the cetuximab target EGFR further suggests that treatment schedules, cetuximab/CDDP doses and BRCA1 status should be carefully considered when combining anti-EGFR antibodies and platinum derivatives in triple-negative/basal-like breast carcinomas.
We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter ...Telescope (BLAST). Compared to the direct Fourier transform method of deconvolution, the L-R operation restores images with better-controlled background noise and increases source detectability. Intermediate iterated images are useful for studying extended diffuse structures, while the later iterations truly enhance point sources to near the designed diffraction limit of the telescope. The L-R method of deconvolution is efficient in resolving compact sources in crowded regions while simultaneously conserving their respective flux densities. We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available high-resolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 45 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the spectral energy distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21 cm radio continuum and 12CO molecular line emission. The restored extended large-scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high-resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting SEDs to multi-wavelength data. All of these compact sources are still quite cold (typical temperature below ~ 16 K) and are above the critical Bonner-Ebert mass. They have associated low-power young stellar objects. Further evidence for starless clumps has also been found in the IC 5146 region.
This study describes how elderly subjects initiate gait, and step from a position of quiet stance. Based on scores from selected standardized tests subjects were placed in either a high (HFL) or low ...functional level (LFL) group and were asked to initiate gait, step onto a 10
cm high, 1.22
m wide curb and step over a 10
cm high, 9
cm wide obstacle at a self paced speed. Stepping conditions affected the velocity of movement. It was clear that all subjects decreased initiation velocity for both curb and obstacle compared to gait initiation. Swing and stance limb acceleration ground reaction forces and EMG amplitude were modulated according to initiation velocity. Toe clearance was greater for obstacle than curb and gait initiation. Swing toe-off was significantly earlier and there was a trend for obstacle clearance to be greater for the HFL group. Those in the LFL group appear to be at a greater risk for falling due to the possible effect of slower rate of toe-off that could influence toe clearance over the obstacle.
Background
This study aimed to evaluate the perioperative outcomes and pathology of patients undergoing laparoscopic splenectomy for splenic masses.
Methods
The records for 174 patients who underwent ...laparoscopic splenectomy from May 1994 to August 2006 were reviewed. Patient demographics, preoperative imaging, American Society of Anesthesiologists (ASA) score, body mass index (BMI), estimated blood loss (EBL), operative time, spleen size, complications, hospital length of stay (LOS), pathology, and mortality were extracted from the records. Data are expressed as means ± standard deviation. Statistical significance (
p
< 0.05) was determined using a two-tailed
t
-test and Fisher’s exact test.
Results
A splenic mass was diagnosed preoperatively for 18 patients (10.3%) (7 males and 11 females). The mean patient age was 51.4 ± 13.7 years. The mean ASA was 2.3 ± 0.8, and the mean BMI was 27.3 ± 5.8 kg/m
2
. Computed tomography scans demonstrated splenic masses in all the patients. The mean mass size was 4.3 ± 3.3 cm (range, 1.0–11.0 cm), and the mean spleen length was 14.6 ± 7.5 cm (range, 5.5–40.2 cm). Total laparoscopic splenectomy was completed for 15 patients, and hand-assisted splenectomy was performed for 3 patients (2 converted). The mean operative time was 128.3 ± 38.5 min, and the mean EBL was 110 ± 137.5 ml. There were no intraoperative complications or 30-day mortalities. The postoperative complication rate was 11.1%, and the mean LOS was 1.9 ± 1.0 days. The pathology for six patients (33.3%) was malignant (5 lymphomas and 1 adenocarcinoma). There were three false-positive positron emission tomography (PET) scans. Compared with 73 patients undergoing laparoscopic splenectomy for idiopathic thrombocytopenic purpura, there was no significant difference in mean EBL, operative time, conversion rate, complication rate, LOS, or 30-day mortality rate (
p
> 0.05).
Conclusions
Laparoscopic splenectomy is appropriate for patients whose indication for surgery is splenic mass. Suspicious splenic masses should be removed due to the relatively high incidence of malignant pathology, most commonly lymphoma.
Background Substantial survival benefits exist for patients with early-stage breast cancer who undergo treatment with single-modality tamoxifen, ovarian ablation or suppression, or chemotherapy. To ...determine whether additional benefits exist with combined treatment, the Adjuvant Breast Cancer (ABC) Trials were undertaken. Methods The ABC Ovarian Ablation or Suppression Trial randomly assigned pre- and perimenopausal patients with early-stage breast cancer who were receiving prolonged (5 years) tamoxifen treatment with or without chemotherapy to ovarian ablation or suppression (by oophorectomy, ovarian irradiation, or treatment with luteinizing hormone–releasing hormone agonist) versus no ovarian ablation or suppression. Trial endpoints included relapse-free and overall survival. Hazard ratios (HRs) were derived from Cox models, and all statistical tests were two-sided. Results Between 1993 and 2000, 2144 (1063 ovarian ablation or suppression, 1081 no ovarian ablation or suppression) patients were randomly assigned. A total of 942 (89%) received ovarian ablation or suppression as allocated. Overall, no evidence of a benefit for ovarian ablation or suppression was observed for relapse-free survival (relapse in the ovarian ablation/suppression versus no ovarian ablation/suppression group, 290 events versus 306 events, HR = 0.95, 95% confidence interval CI = 0.81 to 1.12; P = .56) or overall survival (death from any cause in the ovarian ablation or suppression versus no ovarian ablation/suppression group, 215 events versus 230 events, HR = 0.94, 95% CI = 0.78 to 1.13; P = .44), nor were differences seen after adjustment for age, nodal status, or estrogen receptor (ER) status. Conclusion Overall, no added effect of ovarian ablation or suppression was seen on relapse-free survival or overall survival of premenopausal women who were treated for early-stage breast cancer. However, the role of ovarian ablation or suppression in young (<40 years) women with ER-positive tumors, especially those not receiving chemotherapy, requires further study.
Aims: To describe interactions between risk factors for iron deficiency (ID).
Methods: A random community sample of 316 children 6–23 months old of whom 13% had ID. Risk factors for ID were ...determined using logistic regression. Relative risks (RR) and 95% confidence intervals (95%CIs) were estimated. An additive relationship between risk factors was present if the RR of ID when both factors were present exceeded the sum of individual RRs of ID.
Results: Independent risk factors for ID in a multivariate model were prematurity/low birthweight (RR 4.82, 95%CI 1.57–7.42), increased body mass index (5.57, 1.41–12.18), eating fruit only as a snack (3.48, 1.38–7.28), having no milk formula (4.40, 2.06–7.27), daily cow's milk (4.71, 1.99–8.56) and having only homemade first solids (2.91, 1.01–6.40). Eating fruit only as a snack had an additive relationship with three other dietary risk factors: no milk formula (RR 11.75, 95%CI 4.58–19.46), cow's milk daily (13.48, 1.20–42.37) and only homemade first solids (8.66, 3.43–14.76). Larger body mass had an additive relationship with four dietary factors: no milk formula (RR 14.69, 95%CI 1.95–24.00), fruit only as a snack (10.11, 4.59–16.36), cow's milk daily (12.28, 5.97–21.95) and only homemade first solids (7.05, 1.27–16.27). Prematurity/low birthweight had an additive relationship with two dietary risk factors: no milk formula (RR 9.16, 95%CI 2.42–12.11) and only homemade first solids (7.15, 1.47–9.73).
Conclusions: Risk factors for ID interact to place young children at high risk of ID.
Aims To report the coexistence of inflammatory hepatocellular adenoma (IHCA) and HNF1alpha-inactivated HCA (H-HCA) in cases from a multicentre study. Methods and results We report nine cases with the ...coexistence of IHCA and H-HCA; eight occurred in women, and one in a man. The numbers of nodules and the sizes of the largest and smallest HCAs were variable. In one case, the nodules of the two different subtypes were discovered at different times. In all women, HCAs were histologically typical, regardless of their subtype, whereas H-HCA in the man differed histologically from classic H-HCA. Conclusions These cases suggest that a predisposition to develop multiple adenomas, hypothetically caused by a 'benign tumorigenic field effect', although common to all HCAs, may result in different genotypes and phenotypes. Although this is rare, it is expected that more cases with the coexistence of different genotypes will emerge, owing to progress in the use of specific immunohistochemical approaches. PUBLICATION ABSTRACT
The chaperone Hsp90 plays a key role in the maturation and activation of many ‘client’ proteins in eukaryotic cells. In the oomycete
Achlya ambisexualis two populations of
hsp90 transcripts that ...differ slightly in size (2.8 and 2.9
kb) are present in heat-shocked mycelia. Only the 2.8
kb transcripts are seen in vegetative mycelia and in mycelia undergoing antheridiol-induced differentiation. Two different
hsp90 cDNAs were isolated and characterized. Although nearly identical, an additional eight nucleotide sequence was present at the end of the 3
′UTR of one of the two cDNAs. RT-PCR analyses indicated that
hsp90 transcripts containing the eight nucleotide extension, were present only in heat-shocked mycelia.
Hsp90 transcripts lacking this sequence were present in vegetative mycelia and the levels of these transcripts increased in both heat-shocked and hormone-treated mycelia. Each
hsp90 cDNA encoded a nearly identical Hsp90 protein. However, two Hsp90 proteins (86 and 84
kDa) were observed on immunoblots of mycelial proteins. Only one of these, i.e., the 86
kDa protein was detected by an anti-phosphoserine antibody, suggesting that the difference in mass of the two Hsp90 isoforms, was due at least in part, to different levels of phosphoserine residues.
Index descriptors: Hsp90; Chaperones; Steroid hormone; Antheridiol; Heat shock protein;
Achlya; Oomycete
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