Showing papers by "Memorial Sloan Kettering Cancer Center published in 1993"
TL;DR: The results of the National Polyp Study support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent coloreCTal cancer.
Abstract: Background The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. Methods The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. Results Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned...
4,310 citations
TL;DR: The existence of numerous SNARE-related proteins, each apparently specific for a single kind of vesicles or target membrane, indicates that NSF and SNAPs may be universal components of a vesicle fusion apparatus common to both constitutive and regulated fusion (including neurotransmitter release), in which the SNAREs may help to ensure vesICLE-to-target specificity.
Abstract: The N-ethylmaleimide-sensitive fusion protein (NSF) and the soluble NSF attachment proteins (SNAPs) appear to be essential components of the intracellular membrane fusion apparatus. An affinity purification procedure based on the natural binding of these proteins to their targets was used to isolate SNAP receptors (SNAREs) from bovine brain. Remarkably, the four principal proteins isolated were all proteins associated with the synapse, with one type located in the synaptic vesicle and another in the plasma membrane, suggesting a simple mechanism for vesicle docking. The existence of numerous SNARE-related proteins, each apparently specific for a single kind of vesicle or target membrane, indicates that NSF and SNAPs may be universal components of a vesicle fusion apparatus common to both constitutive and regulated fusion (including neurotransmitter release), in which the SNAREs may help to ensure vesicle-to-target specificity.
3,190 citations
TL;DR: It is reported that in the absence of SNAP and NSF, these three SNAREs form a stable complex that can also bind synaptotagmin, suggesting that synapttagmin operates as a "clamp" to prevent fusion from proceeding in the absent of a signal.
1,873 citations
TL;DR: The three-dimensional structure of an HNF-3/fork head DNA-recognition motif complexed with DNA has been determined by X-ray crystallography at 2.5 Å resolution and the transcription factor fold is very similar to the structure of histone H5.
Abstract: The three-dimensional structure of an HNF-3/fork head DNA-recognition motif complexed with DNA has been determined by X-ray crystallography at 2.5 A resolution. This alpha/beta protein binds B-DNA as a monomer, through interactions with the DNA backbone and through both direct and water-mediated major and minor groove base contacts, inducing a 13 degrees bend. The transcription factor fold is very similar to the structure of histone H5. In its amino-terminal half, three alpha-helices adopt a compact structure that presents the third helix to the major groove. The remainder of the protein includes a twisted, antiparallel beta-structure and random coil that interacts with the minor groove.
1,238 citations
TL;DR: The availability of the d[AG3(T2AG3)3] solution structure containing four AG3 human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops.
1,217 citations
TL;DR: Colonoscopy performed three years after colonoscopic removal of adenomatous polyps detects important colonic lesions as effectively as follow-up colonoscopy after both one and three years.
Abstract: Background The identification and removal of adenomatous polyps and post-polypectomy surveillance are considered to be important for the control of colorectal cancer. In current practice, the intervals between colonoscopies after polypectomy are variable, often a year long, and not based on data from randomized clinical trials. We sought to determine whether follow-up colonoscopy at three years would detect important colonic lesions as well as follow-up colonoscopy at both one and three years. Methods Patients were eligible if they had one or more adenomas, no previous polypectomy, and a complete colonoscopy and if all their polyps had been removed. They were randomly assigned to have follow-up colonoscopy at one and three years or at three years only. The two study end points were the detection of any adenoma, and the detection of adenomas with advanced pathological features (defined as those >1 cm in diameter and those with high-grade dysplasia or invasive cancer). Results Of 2632 eligible patients, 141...
933 citations
TL;DR: The insights into transformation and leukemogenesis gained in acute promyelocytic leukemia may be a harbinger of further clinical applications and offer a glimpse into the next generation of cancer therapy.
Abstract: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), identified by the French-American-British (FAB) classification as AML-M3. It accounts for approx 10–15% of all AML cases in most reports (1) but can be as high as 32% in some areas of China (2) and 46% among AML patients of American-Mexican descent (3). Clinically, APL is associated with a high incidence of coagulopathy, either disseminated intravascular coagulation (DIC) or hyperfibrinolysis, which are often aggravated during chemotherapy and result in death at an early stage of treatment. Cytogenetically, APL is characterized in 95% of the cases by a balanced reciprocal translocation between chromosomes 15 and 17, t(15;17)(q22;q21), which leads to the formation of two fusion genes, promyelocytic leukemia—retinoic acid receptor α(PML-RARα) or RARα-PML, the former being considered to play a crucial role in leukemogenesis (4).
919 citations
TL;DR: Transforming growth factor β signals through a heteromeric protein kinase receptor that has a limited ability to bind ligand is overcome by the action of betaglycan (TGFβ type III receptor), a separate TGFβ-binding membrane protein of previously unknown function.
888 citations
Memorial Sloan Kettering Cancer Center1, University of Minnesota2, Medical College of Wisconsin3, University of Utah4, University of Texas at Austin5, University of California, Los Angeles6, Fred Hutchinson Cancer Research Center7, University of Kentucky8, Gulf Coast Regional Blood Center9, University of British Columbia10, Stanford University11
TL;DR: The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.
Abstract: Background and Methods Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. Results During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at...
833 citations
TL;DR: In this article, a prospective database of 799 patients with the diagnosis of pancreatic adenocarcinoma were admitted to the Memorial Sloan-Kettering Cancer Center, and their records were entered into the prospective database, and a curative resection was possible in 146 patients with a 30-day operative mortality of 3.4%.
Abstract: From October 1983 to October 1990, 799 patients with the diagnosis of pancreatic adenocarcinoma were admitted to Memorial Sloan-Kettering Cancer Center, and their records were entered into a prospective database. Curative resection was possible in 146 patients (18%), with a 30-day operative mortality of 3.4%. Median follow-up of survivors in the resection group was 28 months. Actuarial 5-year survival in patients who did not undergo resection was 0% (n=653), compared with 24% in the patients who had resection (p
690 citations
TL;DR: The objective was to establish a database of known Membrane Growth Factors as Receptors and to evaluate the role of these factors in the development of Membranes Anchored Growth Factor Cleavage.
Abstract: STRUCTURE AND BIOLOGY OF MEMBRANE-ANCHORED GROWTH FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 6 The EGF Family . . . . . . . . . . . . . . . ... .. . . . ... ... . .. . ... . . . . 5 1 8 Colony-Stimulating Factor-] . . . . . .... . . . .... . . . . . . . . . . . .. . . . . 524 Kit Ligand . . . .. . .. . . . .. . . .. . . ... . . . . . . .. . . . . . . . . .. . . . . 525 Tumor Necrosis Factor-a. ... . . . ... ... .. . . . . . . ... . . . .... . . . .. 525 The Bride oj Sevenless Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 UNIQUE BIOLOGICAL ROLES OF MEMBRANE-ANCHORED GROWTH FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 Cell-Cell Contacts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528 Juxracrine Stimulation .... . . ... . . . . . . .. .. . ... . . . ... . . . . . ... 528 Soluble Forms May Not SubstituteJor Membrane-Anchored Forms. . . . . . . . . . 529 Membrane Growth Factors as Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . 529 Endocytosis of a Membrane-Anchored Ligand. . . . . . . . . . . . . . . . . . . . . . . 530 RELEASE OF MEMBRANE-ANCHORED GROWTH FACTORS . . . . . . . . . . . . 530 Cellular Location and Specificity of the Cleavage Process .. . . . .. . . . . ... 531 Alternative Splicing of Cleavage Regions. . . . . . . . . . . . . . . . . . . . . . . . . . 533 Regulation of Cleavage . . . . .. ... ... . . . ... . . . .. . . .. .... . . . . . 534 Determinants of Membrane Growth Factor Cleavage . . ... . . . .... ... . . . 536
TL;DR: The results indicate that type I receptors are transmembrane protein kinases that associate with type II receptors to generate diverse heteromeric serine/threonine kinase complexes of different signaling capacities.
TL;DR: A gene was cloned from chromosomal translocations affecting band 3q27 that codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors and may be a proto-oncogene specifically involved in the pathogenesis of diffuse large-cell lymphoma.
Abstract: The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.
TL;DR: Activity of these regions in vivo requires an erythroid-specific nuclear factor that binds AP-1-like recognition sites and its tissue-specific component has been characterized by complementary DNA cloning as a new basic region–leucine zipper protein which dimerizes with a ubiquitous partner to form native NF-E2.
Abstract: Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions. Activity of these regions in vivo requires an erythroid-specific nuclear factor (NF-E2) that binds AP-1-like recognition sites. Its tissue-specific component (p45 NF-E2) has been characterized by complementary DNA cloning as a new basic region-leucine zipper protein which dimerizes with a ubiquitous partner to form native NF-E2.
TL;DR: The effects of TGF-beta, which correlated with the inhibition of retinoblastoma protein phosphorylation, suggest that mammalian G1 cyclin-dependent kinases, like their counterparts in yeast, are targets for negative regulators of the cell cycle.
Abstract: Transforming growth factor-beta (TGF-beta) is a naturally occurring growth inhibitory polypeptide that arrests the cell cycle in middle to late G1 phase. Cells treated with TGF-beta contained normal amounts of cyclin E and cyclin-dependent protein kinase 2 (Cdk2) but failed to stably assemble cyclin E-Cdk2 complexes or accumulate cyclin E-associated kinase activity. Moreover, G1 phase extracts from TGF-beta-treated cells did not support activation of endogenous cyclin-dependent protein kinases by exogenous cyclins. These effects of TGF-beta, which correlated with the inhibition of retinoblastoma protein phosphorylation, suggest that mammalian G1 cyclin-dependent kinases, like their counterparts in yeast, are targets for negative regulators of the cell cycle.
TL;DR: This endoscopic protocol accurately detects and differentiates high-grade dysplasia from early adenocarcinoma in Barrett's esophagus and does not necessarily require surgical resection to rule out an undiagnosed adenOCarcinomas.
Journal Article•
TL;DR: The molecular cloning of a full-length 2.65-kilobase complementary DNA encoding the PSM antigen from a human LNCaP complementary DNA library is reported by polymerase chain reaction using degenerate oligonucleotide primers.
Abstract: Recently, a novel M(r) 100,000 prostate-specific membrane glycoprotein (PSM) has been detected by the prostate-specific monoclonal antibody 7E11-C5, raised against the human prostatic carcinoma cell line LNCaP. The PSM antigen is expressed exclusively by normal and neoplastic prostate cells and metastases. We now report the molecular cloning of a full-length 2.65-kilobase complementary DNA encoding the PSM antigen from a human LNCaP complementary DNA library by polymerase chain reaction using degenerate oligonucleotide primers. Analysis of the complementary DNA sequence has revealed that a portion of the coding region, from nucleotide 1250 to 1700, has 54% homology to the human transferrin receptor mRNA. The deduced polypeptide has a putative transmembrane domain enabling the delineation of intra- and extracellular portions of this antigen. In contrast to prostate-specific antigen and prostatic acid phosphatase which are secreted proteins, PSM as an integral membrane protein may prove to be effective as a target for imaging and cytotoxic targeting modalities.
TL;DR: The relief of pain involves the complex interaction of at least six receptor systems, and the implications of opiate receptor multiplicity on the control of pain are discussed.
Abstract: The description of multiple classes of opioid receptors has had a major impact on our understanding of the mechanisms of analgesia. Three major classes of opioid receptors have been defined: mu, kappa, and delta. The mu receptors have been further subclassified into two distinct subtypes (mu 1 and mu 2), as have the delta receptors (delta 1 and delta 2). Kappa receptors have been subdivided into kappa 1, kappa 2, or kappa 3 subtypes. All of these subtypes modulate pain perception, with the exception of the kappa 2 receptor, which has not been adequately examined. Supraspinal systems have been described for mu 1, kappa 3, and delta 2 receptors while mu 2, kappa 1, and delta 1 receptors modulate pain at the spinal level. In addition to their ability to act independently, the various systems also interact synergistically with each other. Thus, the relief of pain involves the complex interaction of at least six receptor systems. This review discusses the implications of opiate receptor multiplicity on the control of pain.
TL;DR: Data from 1972 patients who had undergone pancreaticoduodenectomy or total pancreatectomy for malignancy in New York State between 1984 and 1991 support a defined minimum hospital experience for elective pancreatic resection for maligne to minimize perioperative deaths.
Abstract: OBJECTIVE: The authors examined the effect of hospital and surgeon volume on perioperative mortality rates after pancreatic resection for the treatment of pancreatic cancer. METHODS: Discharge abstracts from 1972 patients who had undergone pancreaticoduodenectomy or total pancreatectomy for malignancy in New York State between 1984 and 1991 were obtained from the Statewide Planning and Research Cooperative System. Logistic regression analysis was used to determine the relationship between hospital and surgeon experience to perioperative outcome. RESULTS: More than 75% of patients underwent resection at minimal-volume (fewer than 10 cases) or low-volume (10-50 cases) centers (defined as hospitals in which a minimal number of resections were performed in a given year), and these hospitals represented 98% of the institutions treating peripancreatic cancer. The two high-volume hospitals (more than 81 cases) demonstrated a significantly lower perioperative mortality rate (4.0%) compared with the minimal- (21.8%) and low-volume (12.3%) hospitals (p < 0.001). The perioperative mortality rate was 15.5% for low-volume (fewer than 9 cases) surgeons (defined as surgeons who had performed a minimal number of resections in any hospital in a given year) (n = 687) compared with 4.7% for high-volume (more than 41 cases) pancreatic surgeons (n = 4) (p < 0.001). Logistic regression analysis demonstrated that perioperative death is significantly (p < 0.05) related to hospital volume, but the surgeon's experience is not significantly related to perioperative deaths when hospital volume is controlled. CONCLUSIONS: These data support a defined minimum hospital experience for elective pancreatectomy for malignancy to minimize perioperative deaths.
TL;DR: The results suggest that T1 bladder cancers exhibiting nuclear overexpression of p53 protein have a higher probability of disease progression and suggests that p53 overeexpression is an important prognostic factor in these patients and may be useful in selecting appropriate therapy.
Abstract: BACKGROUND Approximately one third of the patients with superficially infiltrative transitional cell (T1-TNM pathological staging system) bladder carcinoma who are treated with transurethral resection alone have disease progression. Despite precise pathologic staging and grading, clinical outcome in these patients is not predictable. Recent reports reveal that mutations of the p53 tumor suppressor gene (also known as TP53) occur commonly in bladder cancers. PURPOSE The aim of this study was to investigate the hypothesis that altered patterns of expression of the protein product(s) of the mutated p53 tumor suppressor gene are associated with tumor progression in patients with T1 bladder cancer. METHODS We examined deparaffinized tumor tissue specimens from transurethral resection in 43 patients with T1 bladder cancer who had not received adjuvant therapy. Nuclear overexpression of p53 protein was detected by immunohistochemical analysis using the mouse monoclonal antibody PAb1801, which stains both wild-type and mutant p53 proteins. The data were then correlated with the following conventional prognostic variables: age, sex, histologic presence of associated carcinoma in situ, and vascular invasion of tumor. Disease progression rates per 100 person-years were calculated. RESULTS Median follow-up was 119 months. None of the urothelial and stromal cells from normal bladder specimens showed nuclear overexpression of p53 protein, but patients with T1 bladder tumors could be stratified into two groups with different patterns of staining for p53 protein. Eighteen patients (42%) had no more than 20% tumor cells with positive nuclear staining (group A), while the remaining 25 patients (58%) had 20% or more tumor cells with nuclear immunoreactivity (group B). Patients in group B had a significantly lower progression-free interval (P < .001). Disease progression rates were 20.5% per year for group B and 2.5% for group A. CONCLUSION These results suggest that T1 bladder cancers exhibiting nuclear overexpression of p53 protein have a higher probability of disease progression. This study also suggests that p53 overexpression is an important prognostic factor in these patients and may be useful in selecting appropriate therapy. IMPLICATIONS Large prospective studies are needed to confirm these results and to evaluate nuclear overexpression of p53 protein as a prognostic marker in bladder cancer.
Journal Article•
TL;DR: Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology, indicating that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops.
Abstract: The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor alpha (TGF-alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.
TL;DR: In this article, a nonparametric maximum likelihood estimation of the probability of failing from a particular cause by time t in the presence of other acting causes (i.e., the cause-specific failure probability) is discussed.
Abstract: Nonparametric maximum likelihood estimation of the probability of failing from a particular cause by time t in the presence of other acting causes (i.e., the cause-specific failure probability) is discussed. A commonly used incorrect approach is to take 1 minus the Kaplan-Meier (KM) estimator (1 – KM), whereby patients who fail of extraneous causes are treated as censored observations. Examples showing the extent of bias in using the 1-KM approach are presented using clinical oncology data. This bias can be quite large if the data are uncensored or if a large percentage of patients fail from extraneous causes prior to the occurrence of failures from the cause of interest. Each cause-specific failure probability is mathematically defined as a function of all of the cause-specific hazards. Therefore, nonparametric estimates of the cause-specific failure probabilities may not be able to identify categorized covariate effects on the cause-specific hazards. These effects would be correctly identified ...
TL;DR: It is concluded that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes, and radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.
Abstract: To examine the natural history of lymph node metastasis from sarcomas and the utility of therapeutic lymphadenectomy, clinical histories of all adult patients identified by a prospective sarcoma database for the 10-year period July 1982 to July 1991 were examined. Of the 1772 sarcoma patients, 46 (2.6%) were identified with lymph node metastasis. Median follow-up of all patients from diagnosis of lymph node metastasis was 12.9 months (range, 0 to 100 months). Median survival for nonsurvivors was 12.7 months (range, 0 to 40.7). The tumor types with the highest incidence of lymph node metastasis are angiosarcoma (5/37 total cases; 13.5%), embryonal rhabdomyosarcoma (ERMS) (12/88 total cases; 13.6%), and epithelioid sarcoma (2/12 total cases; 16.7%). Lymph node metastasis from visceral primary (p = 0.004) and malignant fibrous histiocytomas (p = 0.006) were associated with particularly poor prognosis. Thirty-one patients underwent radical, therapeutic lymphadenectomy with curative intent, whereas 15 patients had less than curative procedures, in most cases biopsy only. Patients not treated with radical lymphadenectomy had a median survival of 4.3 months (range, 1 to 32) whereas radical lymphadenectomy was associated with a 16.3 month median survival and the only long-term survivors (46% 5-year survival by Kaplan-Meier). The authors conclude that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes. Radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.
TL;DR: Observations indicate that mammalian facilitative hexose transporters are a physiologically significant pathway for the uptake and accumulation of vitamin C by cells, and suggest a mechanism for the accumulation of ascorbic acid against a concentration gradient.
Abstract: ALTHOUGH vitamin C is critical to human physiology1–5, it is not clear how it is taken up into cells. The kinetics of cell and tissue accumulation of ascorbic acid in vitro indicate that the process is mediated by specific transporters at the cell membrane6. Some experimental observations have linked the transport of ascorbic acid with hexose transport systems in mammalian cells, although no clear information is available regarding the specific role(s) of these transporters, if any, in this process7–16. Here we use the Xenopus laevis oocyte expression system to show that the mammalian facilitative hexose transporters are efficient transporters of the oxidized form of vitamin C (dehydroascorbic acid). Two transport pathways, one with low affinity and one with high affinity for dehydroascorbic acid, were found in oocytes expressing the mammalian transporters, and these oocytes accumulated vitamin C against a concentration gradient when supplied with dehydroascorbic acid. We obtained similar results in experiments using normal human neutrophils. These observations indicate that mammalian facilitative hexose transporters are a physiologically significant pathway for the uptake and accumulation of vitamin C by cells, and suggest a mechanism for the accumulation of ascorbic acid against a concentration gradient.
Book•
Memorial Sloan Kettering Cancer Center1, Stanford University2, Ohio State University3, Roswell Park Cancer Institute4, Washington University in St. Louis5, University of Alabama at Birmingham6, University of Utah7, Duke University8, Harvard University9, Brigham and Women's Hospital10, City of Hope National Medical Center11, Fred Hutchinson Cancer Research Center12, Fox Chase Cancer Center13, Vanderbilt University14, University of South Florida15, University of Nebraska–Lincoln16
TL;DR: In this article, different subtypes of non-Hodgkin's lymphoma (NHL) were compared using histological and immunohistochemical methods, including the normal lymph node structure and function.
Abstract: Part 1 Lymphomagenesis: Lymphocyte differentiation Adult T-cell leukaemia/Lymphoma - a model of retrovirus-induced lymphomagenesis Burkitt's lymphoma and Epstein-Barr virus-associated lymphoid malignancies - models for lymphomagenesis T(14 18) translocation. Part 2 Methods: Histological and immunohistochemical methods Genotype. Part 3 Nodal Non-Hodgkin's Lymphomas: The normal lymph node - structure and function Histological classification Staging of NHLs Analytical study of the different subtypes of NHLs - clinical, histological and immunohistochemical aspects NHLs in childhood NHLs associated with HIV infection. Part 4 Extra-Nodal Non-Hodgkin's lymphomas: Malignant lymphomas of mucosa-associated lymphoid tissues Primary gastrointestinal NHLs Pathology of gastro-intestinal NHLs Cutaneous lymphomas NHLs of the Mediastinum NHLs of the lung Bone marrow involvement Blood involvement in chronic (mature) B & T lymphoproliferative syndromes Liver involvement Spleen involvement Extra-cranial head-and-neck NHLs Central nervous system involvement NHLs of bone Urogenital localizations. Part 5 Treatment of Non-Hodgkin's Lymphomas: Methodology and problems in the comparison of results Treatment of lowgrade NHLs The role of radiation therapy Treatment of aggressive lymphomas (intermediate and highgrade) Intensive chemoradiotherapy and bone-marrow transplantation Salvage therapy after failure Treatment of NHLs in childhood.
TL;DR: The results suggest that anti-EGF receptor MAbs substantially enhance the effects of doxorubicin against well-established xenografts of tumor cells expressing high levels of EGF receptors.
Abstract: Background A variety of human tumors frequently express high levels of epidermal growth factor (EGF) receptor and its ligand, transforming growth factor alpha (TGF-alpha), which in some tumors is associated with poor prognosis. Monoclonal antibodies (MAbs) that block the binding of TGF-alpha or EGF to the receptor can inhibit proliferation of tumor cells that express the receptor. Studies suggest that these MAbs may enhance the antitumor effects of chemotherapy. Purpose Our purpose was to study, in vitro and in vivo, the antitumor effects of doxorubicin in combination with anti-EGF receptor MAbs against tumor cells expressing high levels of EGF receptor. Our goal was to achieve maximum initial cytoreduction with high-dose doxorubicin in association with prolonged blockade of EGF receptor with MAbs. Methods Anti-EGF receptor MAbs 528 (isotype IgG2a) and 225 (isotype IgG1) were used in combination with doxorubicin against cells from human A431 squamous cell carcinoma and human MDA-468 breast adenocarcinoma. Both A431 and MDA-468 cells express high levels of EGF receptors and TGF-alpha. Cultured cells were treated with doxorubicin (range, 0-10 nM) in the presence or absence of MAb 528 or 225 (range, 0-30 nM). At 48 hours, doxorubicin-containing medium was removed, and treatment with antibody was continued for 5 days, when cell proliferation assays were performed. The activity of the agents and the combinations against well-established xenografts in BALB/c nude mice was also studied. In nude mice, doxorubicin was given at doses of 50-100 micrograms/20 g body weight on 2 successive days, and MAbs 528 and 225 were given at a dose range of 0-2 mg intraperitoneally twice a week. Results MAbs 528 and 225 both enhanced the antitumor effects of doxorubicin against A431 and MDA-468 tumor cells, producing additive growth suppression in cell cultures. MAb 528 increased the antitumor effects of doxorubicin by 32%-42%, and similar results were obtained with MAb 225. In BALB/c athymic mice, the treatment of well-established xenografts with either doxorubicin or anti-EGF receptor MAb alone temporarily inhibited growth, but the combination of both agents substantially enhanced antitumor activity over that of doxorubicin alone in A431 and MDA-468 cell xenografts. The combination treatment of mice bearing A431 xenografts resulted in tumor eradication of 40%-100% in the surviving mice in several independent experiments. The enhanced antitumor activity was dose dependent. Conclusions Our results suggest that anti-EGF receptor MAbs substantially enhance the effects of doxorubicin against well-established xenografts of tumor cells expressing high levels of EGF receptors. Implications Clinical trials with anti-EGF receptor MAbs are being conducted, and trials with anti-EGF receptor MAbs combined with doxorubicin are planned.
Journal Article•
TL;DR: The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.
Abstract: We have explored the therapeutic effects of anti-epidermal growth factor receptor monoclonal antibodies (MAbs) 225 and 528 on well established A431 epidermoid carcinoma xenografts, approximately 400 mm3 (1 cm in diameter) at the start of treatment. In previous reports we demonstrated that MAbs 225 and 528 prevented the growth of A431 cell xenografts in nude mice when treatment was begun on the day of tumor cell inoculation. Since anti-epidermal growth factor receptor MAb therapy of well established tumors was unable to retard growth, we explored combination therapy with MAb plus the chemotherapeutic agent cis-diamminedichloroplatinum (cis-DDP). Additive and concentration-dependent growth-inhibitory effects of MAb with cis-DDP were observed in cultures of A431 cells. Neither intensive treatment with 225 MAb (1 mg/mouse, i.p. on day 8 after tumor inoculation, and twice weekly for 4 weeks) nor a maximally tolerated single dose of cis-DDP [150 micrograms/25 g (6 mg/kg) mouse weight, i.p. on day 8] had significant effects on tumor growth. However, the two treatments in combination resulted in substantial xenograft growth inhibition, compared with both an untreated control group and animals treated with a single modality. When a second dose of cis-DDP (150 micrograms/25 g) was added after 10 days, combination therapy with 225 MAb produced striking antitumor effects. At the end of 1 month tumor xenografts had disappeared in all but one mouse, and no tumor relapses occurred during 6 months of observation. Identical results were obtained with anti-epidermal growth factor receptor MAb 528 in combination with cis-DDP. The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.
TL;DR: In intact EL4 thymoma cells, IL-1 beta stimulated a rapid decrease of sphingomyelin and an elevation of ceramide, and enhanced ceramide-activated protein kinase activity, demonstrating tight coupling to the receptor.
Abstract: The mechanism of interleukin-1 (IL-1) signaling is unknown. Tumor necrosis factor-alpha uses a signal transduction pathway that involves sphingomyelin hydrolysis to ceramide and stimulation of a ceramide-activated protein kinase. In intact EL4 thymoma cells, IL-1 beta similarly stimulated a rapid decrease of sphingomyelin and an elevation of ceramide, and enhanced ceramide-activated protein kinase activity. This cascade was also activated by IL-1 beta in a cell-free system, demonstrating tight coupling to the receptor. Exogenous sphingomyelinase, but not phospholipases A2, C, or D, in combination with phorbol ester replaced IL-1 beta to stimulate IL-2 secretion. Thus, IL-1 beta signals through the sphingomyelin pathway.
TL;DR: It is reported that ARF is also required for the binding of the AP-1 adaptor protein of clathrin-coated vesicles to Golgi membranes, suggesting that a mechanistic similarity underlies diverse types of vesicle coats.
TL;DR: Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade.
Abstract: PURPOSETo evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy.PATIENTS AND METHODSThirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response.RESULTSConsidering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or =...