Showing papers by "Johns Hopkins University published in 1993"

Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity

Abstract: To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

Population-based norms for the mini-mental state examination by age and educational level

Abstract: Objective —To report the distribution of Mini-Mental State Examination (MMSE) scores by age and educational level Design —National Institute of Mental Health Epidemiologic Catchment Area Program surveys conducted between 1980 and 1984 Setting —Community populations in New Haven, Conn; Baltimore, Md; St Louis, Mo; Durham, NC; and Los Angeles, Calif Participants —A total of 18 056 adult participants selected by probability sampling within census tracts and households Main Outcome Measures —Summary scores for the MMSE are given in the form of mean, median, and percentile distributions specific for age and educational level Results —The MMSE scores were related to both age and educational level There was an inverse relationship between MMSE scores and age, ranging from a median of 29 for those 18 to 24 years of age, to 25 for individuals 80 years of age and older The median MMSE score was 29 for individuals with at least 9 years of schooling, 26 for those with 5 to 8 years of schooling, and 22 for those with 0 to 4 years of schooling Conclusions —Cognitive performance as measured by the MMSE varies within the population by age and education The cause of this variation has yet to be determined Mini-Mental State Examination scores should be used to identify current cognitive difficulties and not to make formal diagnoses The results presented should prove to be useful to clinicians who wish to compare an individual patient's MMSE scores with a population reference group and to researchers making plans for new studies in which cognitive status is a variable of interest (JAMA 1993;269:2386-2391)

Clues to the pathogenesis of familial colorectal cancer

Abstract: A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.

Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis

Abstract: Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.

Treatment of Colonic and Rectal Adenomas with Sulindac in Familial Adenomatous Polyposis

Abstract: Background Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. Methods We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. Results A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number...

The new WHO classification of brain tumours.

Abstract: The new edition of the World Health Organization (WHO) book on 'Histological Typing of Tumours of the Central Nervous System' reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar medulloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.

Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53

Abstract: THE tumour-suppressor gene p53 is inactivated in most human malignancies1 either by missense mutations1 or by binding to oncogenic proteins2–4. In human soft tissue sarcomas, inactivation apparently results from MDM2 gene amplification4. MDM2 is an oncogene product5,6 that may function by binding to p53 and inhibiting its ability to activate transcription3. Here we show that, when expressed in Saccharomyces cerevisiae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic activation domain. The isolated p53 activation domain fused to another DNA-binding protein is also inactivated by MDM2, confirming that MDM2 can inhibit p53 function by concealing the activation domain of p53 from the cellular transcription machinery.

Epidemiologic Evidence Showing That Human Papillomavirus Infection Causes Most Cervical Intraepithelial Neoplasia

Abstract: Given improvements in human papillomavirus (HPV) testing that have revealed a strong link between sexual activity history and cervical HPV infection the authors conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. The authors studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente a large prepaid health plan in Portland Oregon. The established epidemiologic risk factors for CIN were assessed by telephone interview. The authors performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. The case subjects demonstrated the typical epidemiologic profile of CIN: they had more sex partners more cigarette smoking earlier ages at first sexual intercourse and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. 76% of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. The data show that the great majority of all grades of CIN can be attributed to HPV infection particularly with the cancer-associated types of HPV. In light of this conclusion the investigation of the natural history of HPV has preventive as well as etiologic importance. (authors)

Fabrication and Magnetic Properties of Arrays of Metallic Nanowires

Abstract: Arrays of ferromagnetic nickel and cobalt nanowires have been fabricated by electrochemical deposition of the metals into templates with nanometer-sized pores prepared by nuclear track etching. These systems display distinctive characteristics because of their one-dimensional microstructure. The preferred magnetization direction is perpendicular to the film plane. Enhanced coercivities as high as 680 oersteds and remnant magnetization up to 90 percent have also been observed.

Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide

Abstract: The promoter region of the mouse gene for macrophage-inducible nitric oxide synthase (mac-NOS; EC 1.14.13.39) has been characterized. A putative TATA box is 30 base pairs upstream of the transcription start site. Computer analysis reveals numerous potential binding sites for transcription factors, many of them associated with stimuli that induce mac-NOS expression. To localize functionally important portions of the regulatory region, we constructed deletion mutants of the mac-NOS 5' flanking region and placed them upstream of a luciferase reporter gene. The macrophage cell line RAW 264.7, when transfected with a minimal promoter construct, expresses little luciferase activity when stimulated by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), or both. Maximal expression depends on two discrete regulatory regions upstream of the putative TATA box. Region I (position -48 to -209) increases luciferase activity approximately 75-fold over the minimal promoter construct. Region I contains LPS-related responsive elements, including a binding site for nuclear factor interleukin 6 (NF-IL6) and the kappa B binding site for NF-kappa B, suggesting that this region regulates LPS-induced expression of the mac-NOS gene. Region II (position -913 to -1029) alone does not increase luciferase expression, but together with region I it causes an additional 10-fold increase in expression. Together the two regions increase expression 750-fold over activity obtained from a minimal promoter construct. Region II contains motifs for binding IFN-related transcription factors and thus probably is responsible for IFN-mediated regulation of LPS-induced mac-NOS. Delineation of these two cooperative regions explains at the level of transcription how IFN-gamma and LPS act in concert to induce maximally the mac-NOS gene and, furthermore, how IFN-gamma augments the inflammatory response to LPS.

Trinucleotide repeat length instability and age of onset in Huntington's disease

Abstract: The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.

The New Economics for Industry, Government, Education

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Genetic Mapping of a Locus Predisposing to Human Colorectal Cancer

Abstract: Genetic linkage analysis was used to determine whether a specific chromosomal locus could be implicated in families with a history of early onset cancer but with no other unique features. Close linkage of disease to anonymous microsatellite markers on chromosome 2 was demonstrated in two large kindreds. The pairwise lod scores for linkage to marker D2S123 in these kindreds were 6.39 and 1.45 at zero recombination, and multipoint linkage with flanking markers resulted in lod scores of 6.47 and 6.01. These results prove the existence of a genetically determined predisposition to colorectal cancer that has important ramifications for understanding and preventing this disease.

Association of Hormone-Replacement Therapy with Various Cardiovascular Risk Factors in Postmenopausal Women

Abstract: Background Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. Methods To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, and nonusers who had never used them. Results Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers, and lower me...

Report of the International Workshop on Screening for Breast Cancer

Abstract: Background Over the past 30 years, eight major randomized controlled trials of breast cancer screening--with mammography and/or clinical breast examination--have been conducted. Results from several trials have been updated during the past year, and initial results of three other trials have been reported. Purpose The National Cancer Institute held an International Workshop on Screening for Breast Cancer in February 1993 to conduct a thorough and objective critical review of the world's most recent clinical trial data on breast cancer screening, consider the new evidence, assess the current state of knowledge, and identify issues needing further research. Methods Investigators representing the eight randomized controlled trials of breast cancer screening in women aged 40-74 presented published and unpublished data. Evidence relating to the effectiveness of breast cancer screening in different age groups, especially women aged 40-49, was presented. Results For women aged 40-49, randomized controlled trials consistently demonstrated no benefit from screening in the first 5-7 years after study entry. A meta-analysis of six trials found a relative risk of 1.08 (95% confidence interval = 0.85-1.39) after 7 years' follow-up. After 10-12 years of follow-up, none of four trials have found a statistically significant benefit in mortality; a combined analysis of Swedish studies showed a statistically insignificant 13% decrease in mortality at 12 years. Only one trial (Health Insurance Plan) has data beyond 12 years of follow-up, and results show a 25% decrease in mortality at 10-18 years. Statistical significance of this result is disputed, however. In women aged 50-69, all studies show mortality reductions; three of four studies show reductions of about 30% at 10-12 years after study entry. Results from two of these trials were statistically significant. Too few women over age 70 have been included in studies for adequate analysis. Conclusions For women aged 40-49, randomized controlled trials of breast cancer screening show no benefit 5-7 years after entry. At 10-12 years, benefit is uncertain and, if present, marginal; thereafter, it is unknown. For women aged 50-69, screening reduces breast cancer mortality by about a third. Currently available data for women age 70 or older are inadequate to judge the effectiveness of screening. Implications Randomized trials have provided stronger scientific evidence regarding the effectiveness of screening for breast cancer than for any other cancer. However, much still needs to be learned. Periodic gatherings of scientists in the field should speed the process.

One hundred and forty-five consecutive pancreaticoduodenectomies without mortality.

Abstract: OBJECTIVE: A review of mortality and morbidity for pancreaticoduodenectomy was performed for 145 consecutive patients who underwent the operative procedure between 1988 and 1991. SUMMARY BACKGROUND DATA: In the past, pancreaticoduodenectomy has carried a high hospital morbidity and mortality. During the 1970s, many considered that the operation should be abandoned. Recent data, however, suggest that a marked drop in both morbidity and mortality have occurred for this operative procedure. METHODS: Among the 145 consecutive patients who underwent pancreaticoduodenectomy, 108 patients were 69 years of age or younger, and 37 were 70 years of age or older. Four patients were 80 years of age or older. One hundred and seven patients had a malignant neoplasm, whereas 38 patients had benign disease. There were no significant differences in preoperative risk factors when the younger and older, and benign disease and malignant disease groups were compared. RESULTS: Mean operative time was 7.3 hours. Median blood loss was 0, indicating that more than one-half of the patients underwent pancreaticoduodenectomies without blood transfusions. There were no significant differences in postoperative complications when the younger and older, and benign disease and malignant disease groups were compared. There was no hospital or 30-day mortality. CONCLUSIONS: With appropriate preoperative selection, virtually any patient in any age group, with benign or malignant disease, can undergo pancreaticoduodenectomy with minimal risk of hospital mortality.

A Weighted Nearest Neighbor Algorithm for Learning with Symbolic Features

Abstract: In the past, nearest neighbor algorithms for learning from examples have worked best in domains in which all features had numeric values. In such domains, the examples can be treated as points and distance metrics can use standard definitions. In symbolic domains, a more sophisticated treatment of the feature space is required. We introduce a nearest neighbor algorithm for learning in domains with symbolic features. Our algorithm calculates distance tables that allow it to produce real-valued distances between instances, and attaches weights to the instances to further modify the structure of feature space. We show that this technique produces excellent classification accuracy on three problems that have been studied by machine learning researchers: predicting protein secondary structure, identifying DNA promoter sequences, and pronouncing English text. Direct experimental comparisons with the other learning algorithms show that our nearest neighbor algorithm is comparable or superior in all three domains. In addition, our algorithm has advantages in training speed, simplicity, and perspicuity. We conclude that experimental evidence favors the use and continued development of nearest neighbor algorithms for domains such as the ones studied here.

Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia

Abstract: The existence of water-selective channels has been postulated to explain the high water permeability of erythrocytes and certain epithelial cells. The aquaporin CHIP (channel-forming integral membrane protein of 28 kDa), a molecular water channel, is abundant in erythrocytes and water-permeable segments of the nephron. To determine whether CHIP may mediate transmembrane water movement in other water-permeable epithelia, membranes of multiple organs were studied by immunoblotting, immunohistochemistry, and immunoelectron microscopy using affinity-purified anti-CHIP IgG. The apical membrane of the choroid plexus epithelium was densely stained, implying a role for CHIP in the secretion of cerebrospinal fluid. In the eye, CHIP was abundant in apical and basolateral domains of ciliary epithelium, the site of aqueous humor secretion, and also in lens epithelium and corneal endothelium. CHIP was detected in membranes of hepatic bile ducts and water-resorptive epithelium of gall bladder, suggesting a role in bile secretion and concentration. CHIP was not detected in glandular epithelium of mammary, salivary, or lacrimal glands, suggesting the existence of other water-channel isoforms. CHIP was also not detected within the epithelium of the gastrointestinal mucosa. CHIP was abundant in membranes of intestinal lacteals and continuous capillaries in diverse tissues, including cardiac and skeletal muscle, thus providing a molecular explanation for the known water permeability of certain lymphatics and capillary beds. These studies underscore the hypothesis that CHIP plays a major role in transcellular water movement throughout the body.

Touched with fire : manic-depressive illness and the artistic temperament

Abstract: The anguished and volatile intensity associated with the artistic temperament was once thought to be a symptom of genius or eccentricity peculiar to artists, writers and musicians. Kay Jamison's work, based on her study as a clinical psychologist and researcher in mood disorders, reveals that many artists subject to exalted highs and despairing lows were in fact engaged in a struggle with clinically identifiable manic-depressive illness. Jamison presents proof of the biological foundations of this disease and applies what is known about the illness to the lives and works of some of the world's greatest artists including Byron, Van Gogh, Schumann and Woolf.

Correlation of pathologic findings with progression after radical retropubic prostatectomy.

Abstract: Background. This study was performed to evaluate the effect of positive margins, Gleason grade, and capsular penetration on progression after radical prostatectomy. Methods. The authors followed 507 men with totally embedded retropubic prostatectomy specimens performed for clinical Stages A and B prostate cancer for a mean of 3.9 years. Results. Fifty-nine percent of the specimens had negative margins, 37% had focally positive margins, and 4% had extensive positive margins. Although some positive margins were the result of extensive and/or high-grade tumor, in many cases, the tumors only focally reached the capsular margin such that positive margins resulted from an inability to remove additional soft tissue surrounding the prostate. Gleason sum 7 tumors had a significantly higher progression rate compared with Gleason sum 5 or 6 ones, although historically Gleason sum 5–7 lesions had been considered together as intermediate-grade tumors. In a multivariate analysis, positive margins and Gleason sum strongly correlated with progression, whereas capsular penetration did not. Only approximately 50% of patients with positive margins experienced disease progression during 5 years of follow-up. The most common single sites of positive margins were distal (22%), posterior (17%), and posterolateral (14%); 22% of positive margins were extensive. Only four patients (0.8% of the total) had positive margins only in the region of the spared neurovascular bundle and experienced progression. Conclusions. The most likely explanation for the discrepancy between margins and progression is that some of these margins represented artifactually positive margins caused by the unique problems with handling and assessing radical prostatectomy specimens. Radical prostatectomy provided excellent local control, with only 8% of patients exhibiting local recurrence. Sixty-one percent of men with progression had an elevated serum prostate-specific antigen level as their only manifestation of progression. The significance of isolated elevated serum prostate-specific antigen levels is uncertain, and long-term morbidity and mortality will depend on whether these patients have local disease or occult distant metastases.

Regression analysis for correlated data.

Abstract: Regression analysis is among the most commonly used methods of statistical analysis in public health research. Its objective is to describe the relationship of a response with explanatory variables. One example of a regression problem is to identify factors associated with the racial difference in the risk of low birthweight (29). Regression includes the following as special cases: linear models for measured responses, logistic models for binary responses, and survival analyses for times to events. A basic assumption of regression analysis is that all observations are statistically independent, or at least uncorrelated with each other. In the low birthweight example, this assumption would mean that knowing one child's birthweight status provides no informa­ tion as to whether another child in the study has a low birthweight. One may argue that the assumption of independence is unlikely to be true if children of the same mother are included in the sample. Due to their common household environment and genes, we would expect a child to have a greater chance of having a low birthweight if his/her sibling had. Data from this hypothetical example can usefully be thought of as being "clustered" into families. Birth­ weights from different families are likely independent; those from the same cluster are not. This dependence among observations from the same cluster must be accounted for in assessing the relationship between risk factors and health outcomes.

beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease

Abstract: Reinvestigation of the chemical structure of beta-amyloid peptide (A beta) deposits in the vascular tissue of Alzheimer disease brains revealed that the 42-residue form A beta-(1-42), rather than the more soluble A beta-(1-40) form, is the predominant peptide. Following removal of the surrounding tissue with SDS and collagenase, A beta was solubilized in formic acid and purified by Superose 12 chromatography. Peptides generated by enzymatic and chemical digestion of the A beta were purified by HPLC and characterized by amino acid analysis, sequence analysis, and mass spectrometry. In the leptomeningeal vessels, the average ratio of A beta-(1-42)/A beta-(1-40) was 58:42, whereas in the parenchymal vessels this ratio was 75:25. Interestingly, vascular A beta contains considerably less isomerized and racemized aspartyl residues than does neuritic plaque A beta, suggesting that the vascular amyloid is "younger." The discrete nature of the bands and spherical deposits of A beta associated with arterioles and capillaries, respectively, suggests that this amyloid arises from the vascular tissue itself. Increasing A beta deposition appears to lead to the distortion and occlusion of capillaries, which may contribute significantly to the pathology of Alzheimer disease.