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North American paragonimiasis. A case report. | Paragonimiasis is a parasitic infection with a predilection for pulmonary involvement. Paragonimus species occur throughout the world and exist in nature in a snail-crustacean-mammalian life cycle. Human disease is most frequently encountered in cultures that ingest raw or undercooked crustaceans. North American paragonimiasis; caused by an endemic Paragonimus species; Paragonimus kellicotti; predominantly causes disease in carnivorous and omnivorous animals but may cause human disease if the intermediate h | 10667165 | [
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North American paragonimiasis. A case report. | ost; the crayfish; is ingested raw or undercooked.A previously healthy; 21-year-old male was infected with P kellicotti and developed parasitic hemoptysis. The disease was contracted through the ingestion of local; undercooked crayfish. Diagnosis was established through the morphologic examination of eggs in the cytologic preparation of bronchioalveolar lavage fluid. The patient was successfully treated with praziquantel and recovered without incident.Paragonimiasis is a cause of parasitic hemoptysis worldw | 10667165 | [
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North American paragonimiasis. A case report. | ide. Paragonimiasis is infrequently encountered in North America and is usually not considered in the differential diagnosis of hemoptysis unless specific risk factors are known. The cytologist or cytopathologist; therefore; may be the first to encounter the diagnostic eggs and should be familiar with this disease. | 10667165 | [
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Granular cell ameloblastoma of the jaw. A report of two cases with fine needle aspiration cytology. | Fine needle aspiration cytology (FNAC) of jaw tumors has not been studied extensively. Ameloblastomas are jaw tumors that show a wide morphologic spectrum and thus may pose some diagnostic difficulties. Of the many types; granular cell ameloblastoma (GCA) is an uncommon variant that possesses distinctive features. To the best of our knowledge; there have been no previous reports on the cytologic findings of GCA. We present two cases diagnosed by FNAC.Two cases of GCA were diagnosed on cytology and subsequen | 10667166 | [
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Granular cell ameloblastoma of the jaw. A report of two cases with fine needle aspiration cytology. | tly confirmed on histology. Both patients presented with a large; lytic jaw tumor. FNAC smears showed characteristic granular cells along with spindle and basaloid cells.Although GCAs are rare tumors; they possess distinctive features that permit an accurate diagnosis; provided that this entity is kept in mind. This tumor has to be differentiated from cystic odontogenic lesions; epulis and granular cell myoblastoma. An accurate preoperative diagnosis also helps the surgeon to plan more extensive surgery as | 10667166 | [
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Granular cell ameloblastoma of the jaw. A report of two cases with fine needle aspiration cytology. | these tumors show a great propensity for malignant change and metastases. | 10667166 | [
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The making of a germ panic, then and now. | Over the last 2 decades; a heightened interest in germs has been evident in many aspects of American popular culture; including news coverage; advertisements; and entertainment media. Although clearly a response to the AIDS epidemic and other recent disease outbreaks; current obsessions with germs have some striking parallels with a similar period of intense anxiety about disease germs that occurred between 1900 and 1940. A comparison of these 2 periods of germ "panic" suggests some of the long-term cultura | 10667179 | [
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The making of a germ panic, then and now. | l trends that contributed to their making. Both germ panics reflected anxieties about societal incorporation; associated with expanding markets; transportation networks; and mass immigration. They were also shaped by new trends in public health education; journalism; advertising; and entertainment media. In comparison to the first germ panic; the current discourse about the "revenge of the superbugs" is considerably more pessimistic because of increasing worries about the environment; suspicions of governme | 10667179 | [
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The making of a germ panic, then and now. | ntal authority; and distrust of expert knowledge. Yet; as popular anxieties about infectious disease have increased; public health scientists have been attracting favorable coverage in their role as "medical detectives" on the trail of the "killer germ." | 10667179 | [
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Immunization and the American way: 4 childhood vaccines. | Childhood immunization constitutes one of the great success stories of American public health in the 20th century. This essay provides a historical examination of this topic through 4 particularly important examples: diphtheria; pertussis; polio; and measles. Each case study illustrates how new vaccines have posed unique challenges related to basic science; clinical trial methodology; medical ethics; and public acceptance. A brief comparison of each story to the experience of Great Britain; however; suggest | 10667180 | [
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Immunization and the American way: 4 childhood vaccines. | s an underlying unity connecting all 4 examples. Whereas the British led the way in introducing formal clinical trial methodology in the field of immunization development; the Americans excelled in the rapid translation of laboratory knowledge into strategies suitable for mass application. Although this distinction appears to have diminished in recent years; it offers insight into the sources of creativity underlying American vaccine development and the corresponding difficulties sometimes created for utili | 10667180 | [
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Immunization and the American way: 4 childhood vaccines. | zing vaccines fruits rationally. | 10667180 | [
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Violence victimization after HIV infection in a US probability sample of adult patients in primary care. | This study estimated the proportion of HIV-infected adults who have been assaulted by a partner or someone important to them since their HIV diagnosis and the extent to which they reported HIV-seropositive status as a cause of the violence.Study participants were from a nationally representative probability sample of 2864 HIV-infected adults who were receiving medical care and were enrolled in the HIV Costs and Service Utilization Study. All interviews (91% in person; 9% by telephone) were conducted with co | 10667181 | [
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Violence victimization after HIV infection in a US probability sample of adult patients in primary care. | mputer-assisted personal interviewing instruments. Interviews began in January 1996 and ended 15 months later.Overall; 20.5% of the women; 11.5% of the men who reported having sex with men; and 7.5% of the heterosexual men reported physical harm since diagnosis; of whom nearly half reported HIV-seropositive status as a cause of violent episodes.HIV-related care is an appropriate setting for routine assessment of violence. Programs to cross-train staff in antiviolence agencies and HIV care facilities need to | 10667181 | [
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A community-level HIV prevention intervention for inner-city women: results of the women and infants demonstration projects. | This study examined the effects of a multisite community-level HIV prevention intervention on women's condom-use behaviors.The theory-based behavioral intervention was implemented with low-income; primarily African American women in 4 urban communities. It was evaluated with data from pre- and postintervention cross-sectional surveys in matched intervention and comparison communities.At baseline; 68% of the women had no intention of using condoms with their main partners and 70% were not using condoms consi | 10667182 | [
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A community-level HIV prevention intervention for inner-city women: results of the women and infants demonstration projects. | stently with other partners. After 2 years of intervention activities; increases in rates of talking with main partners about condoms were significantly larger in intervention communities than in comparison communities (P = .03). Intervention communities also had significant increases in the proportion of women who had tried to get their main partners to use condoms (P = .01). The trends for condom use with other partners were similar but nonsignificant.Many women at risk for HIV infection are still not usi | 10667182 | [
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Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. | This study examined epidemiologic factors affecting mortality from pneumococcal pneumonia in 1995 through 1997.Persons residing in a surveillance area who had community-acquired pneumonia requiring hospitalization and Streptococcus pneumoniae isolated from a sterile site were included in the analysis. Factors affecting mortality were evaluated in univariate and multivariate analyses. The number of deaths from pneumococcal pneumonia requiring hospitalization in the United States in 1996 was estimated.Of 5837 | 10667183 | [
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Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. | cases; 12% were fatal. Increased mortality was associated with older age; underlying disease. Asian race; and residence in Toronto/Peel; Ontario. When these factors were controlled for; increased mortality was not associated with resistance to penicillin or cefotaxime. However; when deaths during the first 4 hospital days were excluded; mortality was significantly associated with penicillin minimum inhibitory concentrations of 4.0 or higher and cefotaxime minimum inhibitory concentrations of 2.0 or higher. | 10667183 | [
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Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. | In 1996; about 7000 to 12;500 deaths occurred in the United States from pneumococcal pneumonia requiring hospitalization.Older age and underlying disease remain the most important factors influencing death from pneumococcal pneumonia. Mortality was not elevated in most infections with beta-lactam-resistant pneumococci. | 10667183 | [
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"Broken windows" and the risk of gonorrhea. | We examined the relationships between neighborhood conditions and gonorrhea.We assessed 55 block groups by rating housing and street conditions. We mapped all cases of gonorrhea between 1994 and 1996 and calculated aggregated case rates by block group. We obtained public school inspection reports and assigned findings to the block groups served by the neighborhood schools. A "broken windows" index measured housing quality; abandoned cars; graffiti; trash; and public school deterioration. Using data from the | 10667184 | [
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"Broken windows" and the risk of gonorrhea. | 1990 census and 1995 updates; we determined the association between "broken windows;" demographic characteristics; and gonorrhea rates.The broken windows index explained more of the variance in gonorrhea rates than did a poverty index measuring income; unemployment; and low education. In high-poverty neighborhoods; block groups with high broken windows scores had significantly higher gonorrhea rates than block groups with low broken windows scores (46.6 per 1000 vs 25.8 per 1000; P < .001).The robust assoc | 10667184 | [
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"Broken windows" and the risk of gonorrhea. | iation of deteriorated physical conditions of local neighborhoods with gonorrhea rates; independent of poverty; merits an intervention trial to test whether the environment has a causal role in influencing high-risk sexual behaviors. | 10667184 | [
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Effectiveness of an intervention promoting the female condom to patients at sexually transmitted disease clinics. | This study evaluated a behavioral intervention designed to promote female condoms and reduce unprotected sex among women at high risk for acquiring sexually transmitted diseases (STDs).The effect of the intervention on barrier use was evaluated with a pretest-posttest design with 1159 female STD clinic patients.Among participants with follow-up data; 79% used the female condom at least once and often multiple times. More than one third of those who completed the study used female condoms throughout follow-u | 10667185 | [
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Effectiveness of an intervention promoting the female condom to patients at sexually transmitted disease clinics. | p. Use of barrier protection increased significantly after the intervention; and high use was maintained during a 6-month follow-up. To account for attrition; the use of protection by all subjects was projected under 3 conservative assumptions. The initial visit and termination visit projections suggest that use increased sharply after the intervention and declined during follow-up but remained elevated compared with the baseline.Many clients of public STD clinics will try; and some will continue; to use fe | 10667185 | [
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Effectiveness of an intervention promoting the female condom to patients at sexually transmitted disease clinics. | male condoms when they are promoted positively and when women are trained to use them correctly and to promote them to their partners. A behavioral intervention that promotes both female and male condoms can increase barrier use. | 10667185 | [
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Factors associated with tympanostomy tube insertion among preschool-aged children in the United States. | Recurrent and persistent otitis media is often treated by tympanostomy tube insertion to ventilate the middle ear and restore hearing. This study examined the factors that predict which children are most likely to receive tympanostomy tubes through 3 years of age.Multiple logistic regression was conducted on data from a nationally representative sample of children (N = 8285).By 3 years of age; 6.8% of US children had tubes inserted. Logistic regression indicated that after control for number of ear infectio | 10667186 | [
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Factors associated with tympanostomy tube insertion among preschool-aged children in the United States. | ns; children without any gaps in health insurance; who attended a day-care center; who were White; whose birth-weight was less than 1500 g; and who lived in the Midwest or South were significantly more likely to have tympanostomy tubes.These data suggest that differences exist as to who receives tubes. Of particular concern are differences by race/ethnicity and continuity of health insurance coverage. With expansions in health care coverage to larger proportions of uninsured children; it will be important t | 10667186 | [
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Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. | This study sought to test the relationships between relative body weight and clinical depression; suicide ideation; and suicide attempts in an adult US general population sample.Respondents were 40;086 African American and White participants interviewed in a national survey. Outcome measures were past-year major depression; suicide ideation; and suicide attempts diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders; Fourth Edition. The primary predictor was relative body weight; t | 10667187 | [
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Risk factors for homelessness among indigent urban adults with no history of psychotic illness: a case-control study. | This study identified risk factors for homelessness among indigent urban adults without dependent children and with no history of psychotic illness.We conducted a matched case-control study; stratified by sex; of 200 newly homeless men and women and 200 indigent men and women with no history of homelessness. Newly homeless case subjects were recruited from shelter assessment centers in New York City. Never-homeless control subjects; selected from public assistance centers; were single adults applying for ho | 10667188 | [
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Risk factors for homelessness among indigent urban adults with no history of psychotic illness: a case-control study. | me relief. Control subjects were matched with case subjects according to ethnicity; age; and sex. Trained interviewers employed standardized research instruments to probe 3 domains of risk factors: symptom severity and substance use disorder; family support and functioning; and prior use of services.Significant interaction effects by sex were present for symptom severity; heroin use disorder; and prior service use. Greater numbers of the homeless of both sexes lacked a high school diploma and had less incom | 10667188 | [
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Risk factors for homelessness among indigent urban adults with no history of psychotic illness: a case-control study. | e from all sources; including from their families; than of the never homeless.Newly homeless men and women with no history of psychotic illness differed from their never-homeless counterparts in the 3 domains investigated; but socioeconomic factors were also important. | 10667188 | [
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Patterns and correlates of physical activity among US women 40 years and older. | This study describes the patterns of physical activity among minority women by using a variety of definitions and determines sociodemographic and behavioral correlates of physical activity in this population.A cross-sectional study was conducted in 1996 and 1997 among US women 40 years and older (n = 2912) of the following racial/ethnic groups: African American; American Indian/Alaskan Native; Hispanic; and White.Physical activity was lowest among African Americans and American Indians/Alaskan Natives (adju | 10667189 | [
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Patterns and correlates of physical activity among US women 40 years and older. | sted odds ratios [ORs] for no leisure-time activity were 1.35 [95% confidence interval (CI) = 1.08; 1.68] and 1.65 [95% CI = 1.33; 2.06]; respectively). A much higher proportion of women were classified as being physically active when occupational activity rather than more traditional assessments of leisure activity were used to determine level of physical activity. On the basis of a composite definition of physical activity; 72% of respondents reported being physically active. Women living in rural regions | 10667189 | [
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Patterns and correlates of physical activity among US women 40 years and older. | (OR = 1.33; 95% CI = 1.12; 1.58) were more likely than urban inhabitants to be completely inactive during leisure time.Minority women are among the least active subgroups in American society; although not all groups are less active than White women when all domains of physical activity are taken into account. | 10667189 | [
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Prevalence and risk factors of drug-resistant tuberculosis along the Mexico-Texas border. | This study determined factors associated with drug resistance among 3496 patients with tuberculosis who resided in Texas counties along the Mexican border.Univariate and logistic regression analyses were performed to identify risk factors associated with drug resistance.Among patients with a history of previous tuberculosis; being 19 years or younger was the only factor associated with multiple drug resistance. Female sex; being 20 to 39 years of age; and foreign birth were risk factors for resistance among | 10667190 | [
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Prevalence and risk factors of drug-resistant tuberculosis along the Mexico-Texas border. | patients with no history of previous tuberculosis.Factors contributing to drug resistance among Hispanic tuberculosis patients along the Texas-Mexico border may differ from those among other populations in the United States. | 10667190 | [
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Implementation of guidelines for HIV counseling and voluntary HIV testing of pregnant women. | This study assessed HIV counseling and testing among pregnant women.A survey was administered to 9115 women who gave birth at 66 Chicago-area hospitals in 1997 and 1998.Fifty-eight percent of the women received HIV counseling; and 65% were offered testing. Fifty-six percent were tested for HIV. Among the women tested; 88% were given their test result. Women were more likely to be tested if they received HIV counseling and were more likely to be offered testing if they received such counseling.Rates of HIV c | 10667191 | [
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Implementation of guidelines for HIV counseling and voluntary HIV testing of pregnant women. | ounseling for; and offers of testing to; pregnant women need to be increased. | 10667191 | [
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Diminishing educational differences in breast cancer mortality among Finnish women: a register-based 25-year follow-up. | This study examined trends in breast cancer mortality by education; age; and birth cohort.Census records of Finnish women 35 years and older were linked with death records for 1971 through 1995.Excess breast cancer mortality of more-educated women has declined rapidly; mainly because of increasing mortality among less-educated women and stable or decreasing mortality among more-educated 35- to 64-year-old women. During the 1990s; mortality among more-educated 50- to 64-year-old women declined particularly f | 10667192 | [
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Diminishing educational differences in breast cancer mortality among Finnish women: a register-based 25-year follow-up. | ast.The causes of declining differences by education in breast cancer mortality are difficult to verify; but they may be due in part to narrowing differences in reproductive behavior among the younger birth cohorts and to a period effect possibly associated with the introduction of breast cancer screening in the late 1980s. | 10667192 | [
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Increasing trends in the use of breast-conserving surgery in California. | The purpose of this study was to determine temporal trends in breast-conserving surgery in California from 1988 through 1995.Logistic regression was used to analyze data on 104;466 cases of early-stage breast cancer reported to the California Cancer Registry.A monotonically increasing trend in breast-conserving surgery was detected after adjustment for age; race/ethnicity; stage at diagnosis; and neighborhood education level. Breast-conserving surgery increased at similar rates among all racial/ethnic group | 10667193 | [
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Increasing trends in the use of breast-conserving surgery in California. | s. Older age; Asian or Hispanic race/ethnicity; late-stage diagnosis; and residence in an undereducated neighborhood were factors associated with lower use of breast-conserving surgery.Although disparities are evident; use of breast-conserving surgery increased steadily in all groups examined in this study. | 10667193 | [
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Acceptability and feasibility of urine screening for Chlamydia and gonorrhea in community organizations: perspectives from Denver and St Louis. | nan | 10667194 | [
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Need for HIV/AIDS early identification and preventive measures among middle-aged and elderly women. | nan | 10667195 | [
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Telomerase. A target for anticancer therapy. | Telomerase is absent in most normal tissues; but is abnormally reactivated in all major cancer types. Telomerase enables tumor cells to maintain telomere length; allowing indefinite replicative capacity. Albeit not sufficient in itself to induce neoplasia; telomerase is believed to be necessary for cancer cells to grow without limit. The presence of telomerase has been detected in virtually all cancer types including the most prevalent cancers of the prostate; breast; lung; colon; bladder; uterus; ovary; an | 10667198 | [
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Telomerase. A target for anticancer therapy. | d pancreas as well as in lymphomas; leukemias; and melanomas. In addition; data from cancer patients indicate that telomerase levels correlate with clinical outcome in neuroblastomas; leukemias; and prostate; gastric; and breast cancers. Studies using an antisense to the human telomerase RNA component demonstrate that telomerase in human tumor lines can be blocked ex vivo. In these experiments; telomerase inhibition led to telomere shortening and cancer cell death; validating telomerase as a target for anti | 10667198 | [
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Telomerase. A target for anticancer therapy. | cancer therapy. Telomerase is a uniquely appealing target for drug discovery because its dichotomic expression in normal versus cancer cells suggests that no serious side effects would result from a treatment abrogating telomerase activity. A variety of approaches to telomerase inhibition are being investigated and are discussed. | 10667198 | [
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A paradigm for cancer treatment using the retinoblastoma gene in a mouse model. | Discovery of tumor suppressor genes has provided a rational approach to cancer prevention and treatment. Loss of retinoblastoma susceptibility gene (Rb) function is a rate-limiting event in the development of human and mouse cancers. Establishment of animal models of cancer associated with Rb deficiency allowed us to develop and test long-awaited approaches to genetic correction for treating tumors in vivo. Recent studies demonstrated that (1) prevention of carcinogenesis is achieved by correction of gene c | 10667199 | [
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A paradigm for cancer treatment using the retinoblastoma gene in a mouse model. | opy number in Rb+/- mice; and (2) reconstitution of Rb gene functions is sufficient for suppression of neoplasia in immunocompetent mice. These results fulfill a promise of cancer treatment by reconstitution of tumor suppressor function. | 10667199 | [
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Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export. | Trichostatin A (TSA); an inhibitor of the eukaryotic cell cycle and an inducer of morphological reversion of transformed cells; inhibits histone deacetylase (HDAC) at nanomolar concentrations. Recently; trapoxin; oxamflatin; and FR901228; antitumor agents structurally unrelated to TSA; were found to be potent HDAC inhibitors. These inhibitors activate expression of p21Waf1 and 16INK4A in a p53-independent manner. Changes in the expression of these cell cycle regulators by an increase in histone acetylation | 10667200 | [
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Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export. | may be responsible for cell cycle arrest and antitumor activity by HDAC inhibitors. The target molecule of leptomycin B (LMB); a potent antitumor agent; was genetically and biochemically identified as CRM1; a protein reported as being required for chromosome structure control. We showed that CRM1 was a receptor for the nuclear export signal (NES) and that LMB inhibited nuclear export of proteins. Using LMB; we identified a novel NES in fission yeast transcription factor Pap1; the function of which is abolis | 10667200 | [
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The dual role of cytoskeletal anchor proteins in cell adhesion and signal transduction. | beta-Catenin and plakoglobin are homologous proteins having a dual role in cell adhesion and in transactivation together with LEF/TCF transcription factors. Overexpression of plakoglobin suppresses tumorigenicity; whereas increased beta-catenin levels are considered oncogenic. We compared the nuclear translocation and transactivation by beta-catenin and plakoglobin. Overexpression of each protein resulted in nuclear translocation and formation of structures that also contained LEF-1 and vinculin with beta-c | 10667201 | [
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The dual role of cytoskeletal anchor proteins in cell adhesion and signal transduction. | atenin; but not with plakoglobin. Transfection of LEF-1 translocated endogenous beta-catenin; but not plakoglobin into the nucleus. Chimeras of the Gal4 DNA-binding domain and the transactivation domains of either plakoglobin or beta-catenin were equally potent in transactivation; but induction of LEF-1-responsive transcription was higher with beta-catenin. Overexpression of wt plakoglobin or mutant beta-catenin lacking the transactivation domain induced nuclear accumulation of the endogenous beta-catenin a | 10667201 | [
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The dual role of cytoskeletal anchor proteins in cell adhesion and signal transduction. | nd LEF-1-responsive transactivation. The nuclear localization and constitutive beta-catenin-dependent transactivation in SW480 cancer cells were inhibited by overexpressing cadherin or alpha-catenin. Moreover; transfecting the cytoplasmic tail of cadherin inhibited transactivation; by competition with LEF-1 in the nucleus for beta-catenin binding. The results indicate that (1) plakoglobin and beta-catenin differ in nuclear translocation and complexing with LEF-1 and vinculin; (2) LEF-1-dependent transactiva | 10667201 | [
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Cytoskeletal tumor suppressors that block oncogenic RAS signaling. | Several distinct peptides or drugs that block the Rho family GTPases-mediated pathways were found to suppress RAS-induced malignant phenotype. They include (1) C3 enzyme that selectively inactivates Rho; (2) ACK42; a peptide that blocks the interaction of CDC42 with its effectors such as ACKs; (3) PAK18; a peptide that blocks the activation of PAK and membrane ruffling; and (4) actin-binding drugs; chaetoglobosin K (CK) and MKT-077; that block membrane ruffling by capping and bundling actin filaments; respe | 10667202 | [
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Cytoskeletal tumor suppressors that block oncogenic RAS signaling. | ctively. | 10667202 | [
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Antiangiogenic domains shared by thrombospondins and metallospondins, a new family of angiogenic inhibitors. | The growth of solid tumors has been shown to depend on neovascularization. By understanding the mechanisms that control the neovascular response; it may be possible to design therapeutic strategies to selectively prevent or halt pathologic vascular growth and restrain cancer progression. Thrombospondin-1 is an extracellular matrix protein that among several functions suppresses capillary growth in angiogenesis assays. We have demonstrated that within the context of the mammary gland TSP1 can modulate normal | 10667203 | [
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Antiangiogenic domains shared by thrombospondins and metallospondins, a new family of angiogenic inhibitors. | development of blood vessels. Expression of TSP1 in transgenic animals under the control of the MMTV promoter was associated with a 50-72% reduction in capillary growth. In addition; TSP1 reduced tumor size in transgenic overexpressors. The data suggest an important role for TSP1 in modulating vascular growth in both normal and pathologic tissues. The antiangiogenic region of TSP1 has been mapped to the type I (properdin) repeats. To identify novel proteins with such a domain; we have cloned two cDNAs (MET | 10667203 | [
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Antiangiogenic domains shared by thrombospondins and metallospondins, a new family of angiogenic inhibitors. | H-1 and METH-2) which also have antiangiogenic properties. In addition to carboxyterminal thrombospondin-like domains they also contain metalloproteinase and disintegrin sequences. Expression of both proteins is broad but nonoverlapping. Recombinant fragments from these sequences have strong antiangiogenic potential in the CAM and cornea pocket assays. At the same molar ratio; METH-1 and METH-2 are about 20-fold more potent than TSP1. We predict that these proteins are likely endogenous modulators of vascul | 10667203 | [
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Antiangiogenic domains shared by thrombospondins and metallospondins, a new family of angiogenic inhibitors. | ar growth with relevant therapeutic potential in cancer and other disease states. | 10667203 | [
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Immunotherapy of cancer. | The goal of cancer treatment is to develop modalities that specifically target tumor cells; thereby avoiding unnecessary side effects to normal tissue. Vaccine strategies that result in the activation of the immune system specifically against proteins expressed by a cancer have the potential to be effective treatment for this purpose. An early vaccine approach that was developed by our group involves the insertion of the granulocyte-macrophage colony stimulating factor (GM-CSF) gene into cancer cells that a | 10667204 | [
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Immunotherapy of cancer. | re then used to immunize patients. These genetically modified tumor cells produce the immune activating protein GM-CSF in the local environment of the tumor cells; specifically activating the patient's T cells to eradicate cancer at metastatic sites. We have performed many studies that demonstrate that this vaccine can cure mice of cancer. We recently demonstrated that this approach can activate an immune response in patients with renal cell carcinoma. We are currently testing a similar approach in patients | 10667204 | [
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Immunotherapy of cancer. | with pancreatic cancer. Until recently; whole tumor cells were used to produce the vaccine because the proteins expressed by the tumor cells that can be recognized by the immune system were unknown. However; recent advances have allowed the identification of many of the proteins expressed by some cancers. In addition; significant attention has been focused on the mechanisms by which antitumor immunity can be modulated. These active areas of research will undoubtably lead to the development of more specific | 10667204 | [
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Immunotherapy of cancer. | and more potent vaccine strategies in the near future. The first part of this paper focuses on data from two recent clinical trials that evaluated the whole tumor cell approach. The second part of this paper discusses some of the more exciting antigen-specific vaccine approaches that are under development for the treatment of cancer. | 10667204 | [
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Intracellular signaling of the TGF-beta superfamily by Smad proteins. | TGF-beta is a potent inhibitor of cell growth; and accumulating evidence suggests that perturbation of the TGF-beta signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF-beta superfamily. Smads 2 and 3 are phosphorylated by the TGF-beta type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF-beta stimulation. The heteromeric Smad com | 10667205 | [
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Intracellular signaling of the TGF-beta superfamily by Smad proteins. | plexes translocate into the nucleus; where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF-beta. Smads 2 and 3 form homo- as well as hetero-oligomers with Smad4 upon ligand stimulation. Both homo-oligomers and hetero-oligomers directly bind to DNA; suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand-dependent manner; p300 enhances transact | 10667205 | [
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Intracellular signaling of the TGF-beta superfamily by Smad proteins. | ivation by TGF-beta; suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant; Smad3(DE); blocked the activation of wild-type Smad2 and Smad3. Thus; the missense mutation not only disrupts the function of the wild-type Smad but also creates a dominant-negative Smad; which could actively contribute to oncogenesis. | 10667205 | [
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Bacterial toxins inhibiting or activating small GTP-binding proteins. | Amino acids located on the switch 1 or switch 2 domains of small GTPases of the Ras and Rho family are targets of several bacterial toxins. Exoenzyme C3 from Clostridium botulinum ADP-ribosylates specifically Rho at R43 and prevents the recruitment of Rho on the cell membrane. This blocks the downstream effects of the Rho GTPase. However; exoenzyme C3 is not a toxin; and chimeric proteins fusing C3 with the B moiety of either diphtheria toxin or Pseudomonas aeruginosa exotoxin A have been produced to intoxi | 10667206 | [
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Bacterial toxins inhibiting or activating small GTP-binding proteins. | cate cells with low concentration of C3. C. difficile toxin B modifies by glucosylation Rho on T37 and Rac and Cdc42 on T35. Glucosylation of Rho; Rac; and Cdc42 blocks the binding of these GTPases on their downstream effectors. C. sordellii lethal toxin modifies Ras; Rap; and Rac on T35 by glucosylation. Cytotoxic necrotizing factor 1 (CNF1); from uropathogenic Escherichia coli strains; deamidates Q63 of Rho into E63; thereby blocking the intrinsic or GAP-mediated GTPase of Rho. This allows permanent activ | 10667206 | [
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Bacterial toxins inhibiting or activating small GTP-binding proteins. | ation of Rho. Thus; Rho GTPases are targets for three different toxin activities. Molecular mechanisms of these toxins are discussed. | 10667206 | [
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Farnesyltransferase inhibitors. Preclinical development. | The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization; farnesyl-protein transferase (FPTase) | 10667207 | [
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Farnesyltransferase inhibitors. Preclinical development. | ; would be a target for the development of novel anticancer agents. We have developed potent; cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo; these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and; in some cases; cause regression of mammary and salivary tumors in several s | 10667207 | [
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Farnesyltransferase inhibitors. Preclinical development. | trains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers; a hypothesis that is currently being tested in the clinic. | 10667207 | [
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Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease. | A novel fatty acid-based chloromethyl ketone; UM96001; which was designed to be a Ras C-terminal sequence-specific endoprotease inhibitor; at low micromolar concentrations (1-5.0 microM); potently inhibits ras-transformed rat kidney cell growth; whereas the growth of untransformed normal rat kidney cells is not affected under the same conditions. UM96001 almost completely blocks the anchorage-independent clonogenic growth of ras-transformed rat and human cancer cells at low micromolar concentrations. Inhibi | 10667208 | [
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Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease. | tion of ras-transformed rat and human cancer cell growth by UM96001 may occur via the mechanism of selective induction of apoptosis of the cells. Furthermore; TPCK and BFCCMK; the known selective inhibitors of Ras C-terminal sequence-specific endoprotease; also yield similar inhibition results. These results provide the first experimental evidence that the endoproteolysis of Ras oncoproteins may be important for Ras-mediated cell growth and apoptosis. Therefore; the Ras C-terminal sequence-specific endoprot | 10667208 | [
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Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease. | ease may be a potential anticancer target. | 10667208 | [
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Azatyrosine. Mechanism of action for conversion of transformed phenotype to normal. | Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-alanine] has the unique property of converting ras- or c-erbB-2 transformed phenotype to normal. The administration of azatyrosine also inhibits tumor formation in transgenic mice harboring the normal human c-Ha-ras which is mutated during treatment with various chemical carcinogens. To elucidate the molecular mechanism; we investigated how azatyrosine functions and what are its major targets. Azatyrosine functions downstream of ras; azatyrosine does not alter eithe | 10667209 | [
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Azatyrosine. Mechanism of action for conversion of transformed phenotype to normal. | r the level of GTP-bound Ras or the total amount of Ras. Instead; azatyrosine inhibits the activation of c-Raf-1 kinase by oncogenic c-ErbB-2; resulting in inactivation of AP1. It is interesting that azatyrosine also restores the expression of the rhoB gene; the product of which regulates the formation of actin stress fibers. Azatyrosine is incorporated into cellular proteins to replace tyrosine. Several experiments indicate that replacement of tyrosine is likely to be a cause for its conversion of transfor | 10667209 | [
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Azatyrosine. Mechanism of action for conversion of transformed phenotype to normal. | med phenotype to normal. To prove this hypothesis; we are attempting to develop a mutant of tyrosyl-tRNA synthetase that; unlike wild type; can aminoacylate azatyrosine more efficiently than can tyrosine. | 10667209 | [
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SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. | RAS interacts with multiple targets in the cell and controls at least two signaling pathways; one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. These two pathways appear to act synergistically to cause transformation. Human smooth muscle alpha-actin promoter is repressed in RAS-transformed cells and derepressed in revertant cell lines; suggesting that it is a sensitive marker to follow phenotypic changes in fibroblast cells. SCH 5134 | 10667210 | [
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SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. | 4 is a pyrazoloquinoline derivative identified on the basis of its ability to derepress alpha-actin promoter in RAS-transformed cells. Previous studies have shown that SCH 51344 is a potent inhibitor of RAS transformation. However; SCH 51344 had very little effect on the activities of proteins in the ERK pathway; suggesting that it inhibits RAS transformation by a novel mechanism. Recently; we have demonstrated that SCH 51344 specifically blocks membrane ruffling induced by activated forms of H-RAS; K-RAS; | 10667210 | [
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SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. | N-RAS; and RAC. Treatment of fibroblast cells with this compound had very little effect on RAS-mediated activation of ERK and JUN kinase activities. SCH 51344 was effective in inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting this pathway may be an effective approach to inhibiting t | 10667210 | [
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SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. | ransformation by RAS and other oncogenes. | 10667210 | [
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Activation of apoptosis and its inhibition. | The induction of apoptosis; or controlled cell death; by various stimuli has been shown to activate a cascade of endoproteases; called caspases; that cleave numerous cellular proteins necessary for cellular homeostasis. This review discusses this family of proteases together with a variety of mammalian and viral regulatory proteins that act to control this activation. | 10667211 | [
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Strategies to adapt adenoviral vectors for targeted delivery. | The utility of current generation adenoviral vectors for targeted; cell-specific gene delivery is limited by the promiscuous tropism of the parent virus. To address this issue; we have developed both genetic and immunologic methods to alter viral tropism. Immunologic retargeting has been achieved via conjugates comprised of an antifiber knob Fab and a targeting moiety consisting of a ligand or antireceptor antibody. Gene delivery by this approach has been accomplished via a variety of cellular pathways incl | 10667212 | [
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Strategies to adapt adenoviral vectors for targeted delivery. | uding receptors for folate; FGF; and EGF. In addition to cell-specific gene delivery; this strategy has allowed enhanced gene delivery to target cells lacking the native adenoviral receptor; CAR. Of note; this specific and extended gene delivery allowed enhanced survival in murine models of human carcinoma via cancer gene therapy. Genetic strategies to alter adenoviral tropism have included both fiber modification and fiber replacement. In the former; we have identified the HI loop of fiber as a propitious | 10667212 | [
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Strategies to adapt adenoviral vectors for targeted delivery. | locale for introduction of heterologous peptides. Incorporation of an RGDC peptide at this locale allowed gene delivery via cellular integrins with dramatic efficiency augmentations. As a strategy to achieve both new tropism as well as to ablate native tropism; methods have been developed to replace the fiber protein with heterologous motif which preserves the key trimeric quaternary structure of fiber and allows for propagation. Such a fiber-replacement virus has been rescued and has demonstrated capacitie | 10667212 | [
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Homeodomain-derived peptides. In and out of the cells. | The internalization of homeodomains and of homeopeptides derived from the third helix of the homeodomain of Antennapedia; a Drosophila transcription factor; is used by some investigators to target exogenous hydrophilic compounds into live cells. In addition to this very practical aspect of drug delivery; translocation across biologic membranes of peptides subsequently addressed to the cell cytoplasm and nucleus raises several questions. A first series of questions pertains to the mechanism of translocation. | 10667213 | [
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Homeodomain-derived peptides. In and out of the cells. | Thanks to the synthesis of several peptides derived from the third helix of the Antennapedia homeodomain; we began to investigate the mechanism of translocation and we have shown that it is not dependent upon the presence of a chiral receptor and probably involves the formation of inverted micelles. A second series of questions is related to the physiologic significance of the phenomenon. In a first approach; we demonstrated that some full-length homeoproteins are internalized and secreted in vitro. The me | 10667213 | [
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Homeodomain-derived peptides. In and out of the cells. | chanism of internalization is probably similar to that of the homeodomain or of its third helix; but secretion involves a different mechanism which requires an association with specialized intracellular membranous structures. The existence of specific mechanisms for homeoprotein internalization and secretion suggests that this class of transcription factors may have important signaling properties. | 10667213 | [
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