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Biomedical subjects

J B Rubins

Publications and source records attributed to J B Rubins.

At least 19 recordsLinked to original sources
PubMed2001

Mechanisms of G1 checkpoint loss in resected early stage non-small cell lung cancer.

Loss of the G1 checkpoint appears to be extremely common among virtually all neoplasms. A variety of genetic and epigenetic mechanisms have been demonstrated to play significant roles in this process. In a consecutive series of early stage non-small cell lung cancer (NSCLC), we have established the loss of expression of the G1 Cdk inhibitors p15INK4b) and p16INK4a by DNA methylation is very common (37%), and methylation of p16INK4a is tightly correlated with loss of expression of p16INK4a protein (P = 0.0018). Furthermore, methylation of p15INK4b and p16INK4a appear inversely correlated, although methylation of p15INK4b is an infrequent event in this cohort (4%). Methylation was detected in all stages of NSCLC equally, and did not correlate with survival in these patients. Evidence for methylation was more frequent in squamous cell carcinomas in comparison to other tumor histologies (P = 0.0156). In addition, over-expression of cyclin D1 was found to be tightly restricted (P = 0.0032) to those tumors that had retained wild-type expression of pRB, and did not correlate with methylation or expression of p16INK4a gene product. Although loss of p16INK4a function remains tightly correlated with pRB expression, loss of other regulatory elements in NSCLC such as p53 mutation and cyclin D1 over-expression appear independent of loss of the p16INK4a gene product.

Aged↗
PubMed2001

Inhibition of mesothelioma cell growth in vitro by doxycycline.

Malignant mesothelioma causes profound morbidity and nearly universal mortality that is often refractory to conventional treatment modalities of aggressive surgery, radiotherapy, or chemotherapy. Doxycycline, a commonly used antibiotic, has anti-tumor activity against several malignancies, but its anti-tumor effects on malignant mesothelioma have not been evaluated. We report here that concentrations of doxycycline achievable in serum with typical oral doses had cytostatic effects to varying extent on all eight of the mesothelioma cell lines studied but did not affect normal lung fibroblasts. Doxycycline inhibited the production of mitochondrial cytochrome c oxidase, especially in mesothelioma cells more sensitive to its cytostatic effects, and directly inhibited gelatinase A activity; both of these activities are putative mechanisms for the cytostatic activity of doxycycline in other tumor cells. Thus doxycycline may have a role as adjuvant therapy for malignant mesothelioma.

Anti-Bacterial Agents↗
PubMed2001

Pneumococcal disease in the elderly: what is preventing vaccine efficacy?

The effective prevention of Streptococcus pneumoniae infection has a renewed priority in an era in which the emergence of antibacterial-resistant strains has the potential to further compromise efforts to reduce early mortality from invasive pneumococcal infection. Although the 23-valent pneumococcal polysaccharide (PPS) vaccine was approved in the US to prevent respiratory and invasive infection in the elderly and other high-risk populations, the protective efficacy of this vaccine for the growing population of adults aged >65 years remains controversial. The apparent effectiveness of pneumococcal immunisation in clinical studies of elderly adults has varied depending upon whether a reduction in pneumococcal colonisation, pneumonia, bacteraemia or death was used as an outcome. Clinical studies of vaccine efficacy to date suggest that the current pneumococcal vaccine is 56 to 81% effective at preventing invasive pneumococcal infection, and may have additive benefit to influenza vaccine in preventing community-acquired pneumonia, particularly in elderly adults with an increased risk of serious pneumonia requiring hospitalisation. Possible reasons for incomplete protection from pneumococcal infection after immunisation include infection with non-vaccine serotypes, inadequate or ineffective antibody responses, waning of antibody responses, or compromised nonhumoral host defences. Further studies are needed to determine whether: (i) elderly adults who respond poorly to the 23-valent pneumococcal vaccine can be identified prior to immunisation and targeted for study with improved pneumococcal vaccines; (ii) specific nutrient deficiencies can be identified and corrected to improve the immune responsiveness of elderly adults to the PPS vaccine; (iii) newer protein-conjugate or DNA pneumococcal vaccines may be more uniformly immunogenic for elderly adults; and (iv) whether smoking cessation reduces the risk of invasive pneumococcal infection in elderly adults.

Aged↗
PubMed2000

Translational control of the antiapoptotic function of Ras.

Activated Ras has been shown to provide powerful antiapoptotic signals to cells through well defined transcriptional and post- translational pathways, whereas translational control as a mechanism of Ras survival signaling remains unexplored. Here we show a direct relationship between assembly of the cap-dependent translation initiation apparatus and suppression of apoptosis by oncogenic Ras in vitro and in vivo. Decreasing protein synthesis with rapamycin, which is known to inhibit cap-dependent translation, increases the susceptibility of Ras-transformed fibroblasts to cytostatic drug-induced apoptosis. In contrast, suppressing global protein synthesis with equipotent concentrations of cycloheximide actually prevents apoptosis. Enforced expression of the cap-dependent translational repressor, the eukaryotic translation initiation factor (eIF) 4E-binding protein (4E-BPI), sensitizes fibroblasts to apoptosis in a manner strictly dependent on its ability to sequester eIF4E from a translationally active complex with eIF4GI and the co-expression of oncogenic Ras. Ectopic expression of 4E-BP1 also promotes apoptosis of Ras-transformed cells injected into immunodeficient mice and markedly diminishes their tumorigenicity. These results establish that eIF4E-dependent protein synthesis is essential for survival of fibroblasts bearing oncogenic Ras and support the concept that activation of cap-dependent translation by extracellular ligands or intrinsic survival signaling molecules suppresses apoptosis, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Temporal trends in survival after surgical resection of localized non-small cell lung cancer.

To test whether modern preoperative staging modalities and perioperative care improve survival after resection of localized non-small cell lung cancer (NSCLC), we retrospectively reviewed outcomes of 454 patients with NSCLC resected from 1947 through 1969 (designated pre-1970 cases), and 540 patients with cancers resected from 1981 through 1994 (designated post-1980 cases). Mean ages, histological subtypes, surgical stages, and types of surgical procedures differed significantly between the two groups. Compared with pre-1970 cases, post-1980 cases were older, had more adenocarcinoma and less squamous cell carcinoma, and had lesser proportions of advanced stage disease. Postoperative (day 30) mortality was significantly higher for resections of localized (stages 1 and 2) NSCLC prior to 1970. For patients surviving at least 30 days after surgery, subsequent survival after resection of localized NSCLC differed minimally between pre-1970 and post-1980 groups. We conclude that perioperative mortality after resection of localized NSCLC improved, but subsequent postoperative survival for these patients did not significantly improve over the 45-year period studied.

Aged↗
PubMed2000

Gene therapy of established mesothelioma xenografts with recombinant p16INK4a adenovirus.

The absence of expression of the p16INK4a gene product is observed in virtually all mesothelioma tumors and cell lines, whereas wild-type pRB expression is maintained. We have examined the potential therapeutic role of re-expressing the p16INK4a gene product in mice with established human mesothelioma xenografts. Experiments using Adp16 treatments in mesothelioma xenografts demonstrated prolonged survival and potential cure following treatment with p16INK4a-based gene therapy. These results demonstrate that p16INK4a gene transfer may play a therapeutic role in the treatment of mesothelioma.

Adenoviridae↗
PubMed2000

Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.

The benefits of chronic systemic corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are not well established. To determine whether chronic corticosteroid treatment can be safely withdrawn in "steroid-dependent""COPD patients, we performed a double-blind, placebo-controlled study of 38 patients with steroid-dependent COPD. Patients were randomly assigned to receive their usual maintenance prednisone dose for 6 mo (continuous group) or to be withdrawn from prednisone at a rate of 5 mg per week (demand group). The number of COPD exacerbations per patient (primary outcome) was 2.5 +/- 2.7 (mean +/- SD) in the continuous group and 2.7 +/- 2.5 in the demand group (p = 0.60, 95% confidence interval for the difference: -1.1 to 1.7). Spirometric results, dyspnea, and health-related quality of life did not differ significantly in the two groups. The average daily corticosteroid dose was 10.7 +/- 5.2 mg in the continuous group and 6.3 +/- 6.4 mg in the demand group (p = 0.003). Weight decreased in the demand group by 4.8 +/- 2.0 kg, compared with an increase in the continuous group of 0.5 +/- 3.5 kg (p = 0.007). Discontinuation of chronic systemic corticosteroid treatment in steroid-dependent COPD patients did not cause a significant increase in COPD exacerbations, but did reduce total systemic corticosteroid use and body weight. Larger studies may be warranted to establish the relative risks and benefits of chronic corticosteroid treatment of patients with COPD.

Aged↗
PubMed2000

Diagnosis of venous thromboembolism. Step-by-step approach to a still lethal disease.

Rapid diagnosis of VTE is vital in reducing the significant morbidity and mortality rates associated with this disease. Although angiographic studies remain the "gold standard" for diagnosis, many noninvasive diagnostic procedures are available and are appropriate for evaluation in clinically stable patients. The algorithm presented in this article facilitates the practical and efficient use of available resources in diagnosing and treating VTE.

Algorithms↗
PubMed2000

Effect of anesthetics on pathogenesis of experimentally induced murine pneumococcal pneumonia.

BACKGROUND AND PURPOSE: To define the effects of three commonly used anesthetic agents--sodium pentobarbital given intraperitoneally, and inhaled halothane and methoxyflurane--on the pathogenesis of pneumococcal pneumonia and bacteremia in an experimental murine model. METHODS: Swiss outbred mice were anesthetized with either sodium pentobarbital, halothane, or methoxyflurane before intranasal infection with Streptococcus pneumonia. At defined times after infection, bacterial numbers in lungs and blood, markers of acute lung injury, and lung cytokine levels were compared. RESULTS: Mice anesthetized with inhaled halothane or methoxyflurane prior to intranasal inoculation with type-2 Streptococcus pneumoniae developed pneumonia and bacteremia distinctly different from that in mice anesthetized by intraperitoneal (IP) administration of sodium pentobarbital. Mice having brief exposure to inhaled halothane or methoxyflurane had significantly greater numbers of bacteria in lungs and blood 48 hours after inoculation, compared with mice anesthetized by IP administration of pentobarbital. Also, mice inhaling halothane had significantly decreased activities of pro-inflammatory cytokines interleukin 6 and tumor necrosis factor-alpha in lung homogenates at 24 hours after inoculation, compared with those given pentobarbital IP. CONCLUSION: Effects of anesthesia on murine models of pneumonia should be considered in the design and interpretation of studies of pneumococcal pathogenesis.

Administration, Inhalation↗
PubMed1999

Immune activation and virologic response to immunization in recent HIV type 1 seroconverters.

Antigenic stimulation from invasive bacterial infections, and the vaccines designed to prevent them, may promote T cell activation and enhancement of HIV-1 replication. Changes in viral load have been correlated with antigen-specific responses. We prospectively determined the impact of immunization with 23-valent pneumococcal vaccine (PVAX) and Haemophilus influenzae type b (Hib)-modified diphtheria toxoid CRM197 (DT) vaccine on HIV-1 replication in recent HIV-1 seroconverters (n = 14; median, 5.5 months from infection; median CD4+ T cells, 535 microl), and correlated results with vaccine-related immune activation. Specific antibody responses, markers of CD4+ T cell activation (transferrin and interleukin 2 receptors), and viral burden were measured at weeks -2 (pre), 0, 1, 2, 6, and 12 after immunization. By week 2, levels of IgG had increased significantly over baseline in both HIV-1-infected patients and HIV-1-seronegative control subjects (n = 9) for each antigen (geometric mean fold rise: PVAX, 10.1 versus 5.3; Hib, 16.0 versus 11.7; and DT, 26.2 versus 24.5, respectively). Despite these vigorous responses to both polysaccharide and protein antigens, HIV-1-infected patients showed limited evidence of CD4+ T cell activation at 1 week, no consistent rise in HIV-1 burden at any point, and no decline in CD4+ T cell number over time. We conclude that recent HIV-1 seroconverters show vigorous humoral responses to vaccine antigens and limited early evidence of T cell activation, but no substantial or sustained increase in viral replication or decline in CD4+ T cell number. Thus, respiratory bacterial vaccines appear immunogenic and safe early in HIV-1 infection.

Adult↗
PubMed1999

Evaluating pleural effusions. How should you go about finding the cause?

Although many pulmonary and systemic diseases are known to cause pleural effusions, analysis of the pleural fluid pinpoints the cause in most cases. Distinguishing pleural transudates from exudates is an important step. Transudate effusions are caused by a small, well-defined group of illnesses (e.g., cirrhosis, congestive heart failure). Exudative effusions, on the other hand, are associated with a wide variety of causes, including pneumonia, malignancy, TB, drug-induced reactions, and many others. Some effusions remain unexplained despite extensive tests. Surgical approaches may be appropriate for some of these patients, but the risks must be carefully weighed against the benefits.

Diagnosis, Differential↗
PubMed1999

Identification of clinical risk factors for nosocomial pneumococcal bacteremia.

Clinical risks for nosocomial pneumococcal bacteremia (NPB) have been analyzed previously in case series, a study design inadequate for this purpose. Therefore, we performed a case-control study of NPB, pairing each of 37 cases identified retrospectively at the Minneapolis Veterans Affairs Medical Center from the period of 1984-1994 with four or five hospitalized controls. Comorbidities identified at the time of admission that were significantly associated with NPB on univariate and multivariate analysis included respiratory or hematologic malignancy, anemia, chronic obstructive pulmonary disease, and coronary artery disease. All characteristic symptoms and signs of pneumococcal infection were significantly more common in cases than in controls. NPB was strongly associated with death within 7 days of the index blood culture date, and the mortality rate among cases was 40.5%, compared with 1.2% among nonbacteremic controls (P < .00001). We conclude that NPB is a highly lethal infection that is associated with distinct but identifiable clinical risks, symptoms, and signs.

Aged↗
PubMed1999

Determination of antibody responses of elderly adults to all 23 capsular polysaccharides after pneumococcal vaccination.

The 23-valent pneumococcal polysaccharide vaccine was formulated to prevent invasive infection in the elderly and other high-risk populations from the most prevalent Streptococcus pneumoniae serotypes. However, the immunogenicity of all 23 vaccine polysaccharides has not been fully characterized in elderly adults. We previously reported that whereas the majority of elderly subjects had vigorous immune responses to selected pneumococcal vaccine polysaccharides, a subset of elderly individuals responded to fewer than two of seven vaccine serotypes after immunization. To determine whether these elderly low responders have a general inability to respond to pneumococcal vaccine and to determine whether elderly low responders might be identified by their responses to a few polysaccharides, we measured antibody responses of elderly adults to all 23 vaccine polysaccharides after pneumococcal immunization. As a group, elderly subjects showed a significant rise after immunization in geometric mean antibody levels to all 23 vaccine serotypes. However, when individual rather than group immune responses were assessed, the 23-valent vaccine did not appear to be uniformly immunogenic in these elderly subjects. Eleven elderly subjects (20%) had twofold increases in specific antibody after vaccination to only 5 or fewer of the 23 vaccine polysaccharides, and they did not respond to the most prevalent serotypes causing invasive disease. Antibody responses to serotype 9N were found to reliably distinguish low vaccine responders from other elderly subjects. However, no particular group of vaccine polysaccharides could be used as a marker for adequate immune responses if only postvaccination sera were analyzed.

Aged↗
PubMed1999

Killing of Streptococcus pneumoniae by capsular polysaccharide-specific polymeric IgA, complement, and phagocytes.

The role of IgA in the control of invasive mucosal pathogens such as Streptococcus pneumoniae is poorly understood. We demonstrate that human pneumococcal capsular polysaccharide-specific IgA initiated dose-dependent killing of S. pneumoniae with complement and phagocytes. The majority of specific IgA in serum was of the polymeric form (pIgA), and the efficiency of pIgA-initiated killing exceeded that of monomeric IgA-initiated killing. In the absence of complement, specific IgA induced minimal bacterial adherence, uptake, and killing. Killing of S. pneumoniae by resting phagocytes with immune IgA required complement, predominantly via the C2-independent alternative pathway, which requires factor B, but not calcium. Both S. pneumoniae-bound IgA and complement were involved, as demonstrated by a 50% decrease in killing with blocking of Fcalpha receptor (CD89) and CR1/CR3 (CD35/CD11b). However, IgA-mediated killing by phagocytes could be reproduced in the absence of opsonic complement by pre-activating phagocytes with the inflammatory products C5a and TNF-alpha. Thus, S. pneumoniae capsule-specific IgA may show distinct roles in effecting clearance of S. pneumoniae in the presence or absence of inflammation. These data suggest mechanisms whereby pIgA may serve to control pneumococcal infections locally and upon the pathogen's entry into the bloodstream.

Adult↗
PubMed1999

Practical management of pleural effusions. When and how should fluid accumulations be drained?

Management of pleural effusions requires recognition of the cause and initiation of disease-specific therapy. However, it is important to be forewarned that breathing problems do not always improve in these patients, since other disease processes may be contributing to dyspnea. Many options are available for draining effusions and preventing recurrence, but decisions often need to be made quickly so the process does not progress to the point at which intervention becomes much more difficult.

Drainage↗
PubMed1998

Amino acid changes affecting the activity of pneumolysin alter the behaviour of pneumococci in pneumonia.

Pneumolysin is a multi-functional toxin produced by Streptococcus pneumoniae. The toxin has distinct cytotoxic activity and complement-activating activity mediated by different parts of the toxin molecule. Mice challenged intranasally with a type 2 pneumococcal strain contract bronchopneumonia and bacteremia [1]. Mice were infected intranasally with isogenic mutants of this strain in which the chromosomal pneumolysin gene carried point mutations affecting either or both properties of pneumolysin. Reduction in either cytotoxic activity or complement activation by pneumolysin decreased the virulence of the mutant pneumococci. However, it was the ability to activate complement that most affected the behaviour of pneumococci in the lungs and associated bacteremia in the first 24 h following infection.

Amino Acids↗
PubMed1998

Pneumolysin in pneumococcal adherence and colonization.

The universal and highly conserved production of pneumolysin, the major pneumococcal cytolysin, among clinical isolates of Streptococcus pneumoniae and the previously reported association of pneumolysin production with increased pneumococcal adherence to respiratory epithelium in organ cultures suggest that this toxin might be important for nasopharyngeal colonization. We confirmed that pneumolysin-deficient mutant pneumococcal strains had decreased adherence to respiratory epithelial cells in vitro compared with their isogeneic wild-type strains. However, neither early nor sustained colonization by type 14 S. pneumoniae in an established murine model was dependent on bacterial production of pneumolysin. We conclude that pneumolysin production is not a major determinant of successful nasopharyngeal colonization by pneumococci.

Animals↗