The present study was undertaken to examine the mechanistic basis for the recent observation that the pyridine nucleotide derivative 6-aminonicotinamide (6AN, NSC 21206) enhances the accumulation and ...resulting cytotoxicity of cisplatin in a variety of tumor cell lines. When A549 lung cancer cells or K562 leukemia cells were treated with 62.5 microM 6AN for 21 h and then pulse-labeled with (35)Smethionine for 1 h, increased labeling of five polypeptides, one of which corresponded to a M(r) approximately 78,000 glucose-regulated protein (GRP78), was observed. Two subsequent observations, however, suggested that up-regulation of these polypeptides was unlikely to explain the interaction between 6AN and cisplatin: 1) the concentration of 6AN required to induce GRP78 was 4-fold higher than the dose required to sensitize cells to cisplatin; and 2) simultaneous treatment of cells with 6AN and cycloheximide prevented the increase in GRP78 but not the sensitizing effect of 6AN. On the contrary, treatment with the protein synthesis inhibitors cycloheximide, anisomycin, or puromycin as well as prolonged exposure to the RNA synthesis inhibitor actinomycin D mimicked the biochemical modulating effects of 6AN on cisplatin action. Conversely, 6AN inhibited protein synthesis, whereas 18 6AN analogs that failed to enhance Pt-DNA adducts and cisplatin cytotoxicity failed to inhibit protein synthesis. These observations are consistent with a model in which 6AN and other inhibitors of protein synthesis act as modulating agents by increasing cisplatin accumulation, thereby enhancing the formation of Pt-DNA adducts and subsequent cisplatin-induced cell death.
This study characterized cases with a negative high-risk Hybrid Capture 2 (HRHC2; Digene, Gaithersburg, MD) test result with concurrent or follow-up biopsy-confirmed high-grade cervical ...intraepithelial neoplasia (CIN 2/3). From 2,306 HRHC2 tests, 10 negative results were identified with CIN 2/3 (false-negative rate, 4.5%). The majority of the patients had abnormal colposcopic findings and high-grade squamous intraepithelial lesion (HSIL) shown by concurrent cytologic examination, although with few abnormal cells. No trend was evident in the location of the dysplastic epithelium or overall lesion size. In 4 tests, the relative light units over cutoff was more than 0.4 but less than 1.0, suggesting that low quantities of human papillomavirus (HPV) DNA were present in the sample. The negative predictive value for HRHC2 testing may be compromised when the copy number of the HPV DNA is low, and a negative HRHC2 test result may be falsely negative in patients with abnormal colposcopic findings or concurrent cytologic findings showing HSIL.
This article comprehensively reviews the clinical trials and considers the future directions of the use of vitamin D and its analogs in the treatment or chemoprevention of breast cancer. ...Chemopreventive treatment strategies strive to delay the onset of certain cancers, prevent the progression of malignant disease after diagnosis, or delay the advent of recurrence after curative treatment. We first summarize the epidemiological evidence that led to the hypothesis that vitamin D may have an anti-cancer activity. Vitamin D shows great potential as a therapy for breast cancer; however, its use in clinical trials has been hindered by the induction of hypercalcemia at a concentration required to suppress cancer cell proliferation. This has led to the development of less calcemic analogs of vitamin D. We review the clinical trials with breast cancer patients using vitamin D analogs.
A probabilistic approach to the classification of fine-needle aspirates (FNAs) of the breast recently was recommended and received endorsement from the National Cancer Institute (NCI). In this ...system, FNAs are classified as benign, indeterminate/atypical, suspicious/probably malignant, and malignant, but to the authors' knowledge the use of these diagnostic categories has not been evaluated on a large scale. Furthermore, this classification scheme has not been applied to FNAs of nonpalpable lesions of the breast obtained under imaging guidance. Thus, the current study focused on whether the diagnostic categories could be applied usefully to ultrasound-guided FNAs (US-FNAs) of nonpalpable breast lesions.
Between 1988-1996, 1885 US-FNAs were performed on 1639 patients. The original FNA diagnoses were reclassified into the NCI-supported recommendations for diagnostic categories of breast FNAs. The cytologic findings were correlated with the tissue specimens, which were available in 851 cases, or with clinical follow-up of a minimum of 2 years in 127 of the 274 patients with benign solid lesions.
The 1885 cases were categorized as follows: 1057 (56.1%) as benign, 86 (4.6%) as atypical, 79 (4.2%) as probably malignant, 502 (26.6%) as malignant, and 161 (8.5%) as unsatisfactory (defined as < 6 epithelial cell groups on all slides). The benign US-FNAs included 480 (45.4%) cysts and 577 (54.6%) solid lesions. Combined clinical and surgical follow-up showed that the frequency of malignancy was 3.7% in US-FNAs classified as benign, 52.9% in those designated as atypical, 75.8% in those designated as suspicious, and 98.9% in those classified as malignant. Based on combined histologic and clinical follow-up, a sensitivity of 97.1% and specificity of 99.1% were found for US-FNAs when definitive benign and malignant diagnoses were considered. A false-negative rate of 3.7% was attributed to sampling error. A false-positive rate of 0.68% was secondary to interpretative error of proliferative lesions.
Application of the NCI-supported diagnostic categories to US-FNA of nonpalpable breast lesions is useful in stratifying aspirates based on the likelihood of underlying malignancy. The subcategories of US-FNAs diagnosed as atypical have similar probabilities of malignancy; this justifies their being grouped as a single category wherein tissue biopsy would be required to exclude carcinoma. Benign and inadequate FNA diagnoses must be correlated with the clinical and imaging findings and in noncorrelative cases the patient should undergo biopsy. US-FNA is a sensitive and specific means with which to diagnose nonpalpable breast lesions.
Integrin Connections Map: To Infinity and beyond Martin, Karen H.; Slack, Jill K.; Boerner, Scott A. ...
Science (American Association for the Advancement of Science),
05/2002, Letnik:
296, Številka:
5573
Journal Article
Recenzirano
Integrins are transmembrane proteins that serve as primary sensors of the extracellular matrix (ECM) environment. In response to interactions with the ECM, integrins initiate signaling pathways that ...regulate cell migration, growth, and survival. Advances in imaging have contributed to the understanding of the dynamic nature of these cell-ECM interactions and the complexes that form at these sites and have provided insights into their regulation and signal organizing functions.
Nine participants with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who were human leukocyte antigen (HLA)-A1, HLA-A2, or HLA-A3, were eligible to enroll in a phase 1 study ...designed to assess the safety and immunogenicity of a peptide-based vaccine. Participants received 5 class I major histocompatibility complex-restricted synthetic peptides derived from multiple ovarian cancer-associated proteins plus a class II major histocompatibility complex-restricted synthetic helper peptide derived from tetanus toxoid protein. The vaccines were administered with granulocyte macrophage-colony stimulating factor in Montanide ISA-51 adjuvant over a 7-week period. All vaccine-related toxicities were grade 1 to 2, the most common being injection site reaction (grade 2, 100%), fatigue (grade 1, 78%), and headache (grade 1, 67%). Lymphocytes from the peripheral blood and a node draining a secondary vaccine site (sentinel immunized node) were harvested during the course of vaccination and T-cell responses to the peptides were evaluated using an enzyme-linked immunosorbent spot assay. CD8 T-cell responses were detected in 1 participant ex vivo and in 8 of 9 participants (89%) after in vitro stimulation. All 4 HLA-A2 and HLA-A3-restricted peptides were immunogenic. This includes 2 peptides, folate binding protein (FBP191-199) and Her-2/neu754-762, which had not previously been evaluated in vaccines in humans. Responding T cells required over 200 nM for half-maximal reactivity. These data support continued investigation of these peptides as immunogens for patients with ovarian cancer but, owing to low potency, also suggest a need for additional immunomodulation in combination with vaccines to increase the magnitude and to improve the quality of the T-cell responses.
To characterize cervicovaginal cytology samples with < 5,000 squamous cells on the initial ThinPrep slide (Cytyc Corp., Boxborough, Massachusetts, U.S.A) and to attempt sample recovery using acetic ...acid.
Cervicovaginal cytology samples with <5,000 squamous cells on the original ThinPrep slide and residuum were reprocessed by adding 3 mL of 3:1 CytoLyt (Cytyc)/glacial acetic acid with production of a second slide. Both slides were reviewed for squamous cell quantitation and the presence of background material and abnormal cells.
From a total of 1,833 cases, 147 (8.0%) were identified for reprocessing; 71 (48.3%) were grossly bloody and 58 (39.4%) grossly cloudy. Reprocessing resulted in a second slide with > 5,000 squamous cells in 116 (78.9%) cases and was most effective on cloudy samples (89.7% recovery) and bloody samples (71.8% recovery). Abnormal cells were identified in 13 (8.9%) reprocessed samples. In all but 2 cases the abnormal cells were present on the initial slide and demonstrated the same degree of abnormality as the reprocessed slide but were fewer in number.
Acetic acid recovery increases squamous cell recovery when initially inadequate, reducing the number of unsatisfactory cases and in rare cases identifying a cytologically significant lesion not apparent on the original slide.
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