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PubMed2026

CEBPG demonstrates oncogene functions and modulates the expression of genes involved in cervical cancer related pathways.

BACKGROUND: Cervical cancer is a major cause of female cancer incidence and mortality globally. Targeted therapy shows promise with higher efficacy and fewer side effects, yet effective biomarkers are needed. CEBPG, a bZIP transcription factor, has attracted attention as a potential biomarker and therapeutic target. It promotes tumor growth in various cancers, but its role in cervical cancer is unclear. The aim of this study is to investigate the expression, biological function, and transcriptional regulatory mechanisms of CEBPG in cervical cancer. METHODS: This study analyzed CEBPG expression in cervical cancer using The Cancer Genome Atlas (TCGA) data, overexpressed it in HeLa cells, and conducted proliferation, apoptosis, migration, and invasion experiments. RNA sequencing (RNA-seq) revealed CEBPG's transcriptional regulatory network. RESULTS: Our findings revealed that CEBPG expression was significantly higher in cervical cancer than in normal tissues. Overexpression of CEBPG in HeLa cells significantly enhanced proliferation, migration, and invasion while repressing apoptosis. RNA-seq analysis identified numerous differentially expressed genes (DEGs) enriched in pathways critical for tumorigenesis and progression, such as angiogenesis, cell proliferation, and migration. Bioinformatics analysis identified 27 potential transcriptional targets of CEBPG, several of which were associated with poor prognosis and higher expression in cervical cancer tissues. CONCLUSIONS: CEBPG may contribute to malignant phenotypes in cervical cancer, potentially through the transcriptional regulation of specific target genes. The high expression of CEBPG in cervical cancer and its demonstrated role in promoting malignancy through transcriptional regulation provide novel insights into the molecular mechanisms of cervical carcinogenesis and progression. This offers directions for further exploration of CEBPG as a potential therapeutic target and biomarker.

CEBPG↗
PubMed2006

Social capital and health: civic engagement, community size, and recall of health messages.

OBJECTIVES: We explored the effects of community integration and pluralism on recall of cardiovascular disease health information messages. METHODS: With 1980-1983 data from the Minnesota Heart Health Program, we examined whether ties to community groups were associated with recall of health messages, and whether this relation was modified by size and degree of differentiation of the community. RESULTS: A higher level of civic engagement through ties to community groups was associated with better recall of health messages. Ties to community groups independently contributed to better message recall even after control for gender, education, and other variables. The moderating role of community size was non-significant but intriguing. CONCLUSIONS: Community group membership could increase exposure to health messages, providing a critical pathway for social capital to influence health promotion and, thus, public health outcomes.

Adult↗
PubMed2005

Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function.

Neuroscientific developments have promulgated interest in developing efficacious medications for the treatment of substance dependence. Previous pharmacological strategies that involve the use of relatively specific medications to alter corticomesolimbic dopaminergic neuronal activity--the critical pathway for expression of the reinforcing effects of abused drugs--have yielded modest efficacy in the treatment of alcohol dependence, and no medication has been established as a treatment for cocaine dependence. Since corticomesolimbic dopaminergic neurons interact with other neurotransmitters that modulate the effects of dopamine in the nucleus accumbens, would it not be possible to control these dopaminergic effects more reliably with a medication that acts contemporaneously on more than one neuromodulator of dopaminergic function? Further, since the long-term use of either alcohol or cocaine results in neuronal adaptations as a result of sensitisation, would the chances of effective therapy not be bolstered by administering a medication that was also able to mitigate these chronic effects? Thus, a new conceptual approach is needed. My proposal is that a medication--in this case topiramate--that principally potentiates inhibitory GABA(A) receptor-mediated input and antagonises excitatory glutamatergic afferents to the corticomesolimbic dopaminergic system should have therapeutic potential in treating either alcohol or cocaine dependence or perhaps both. This is because the principal neurochemical effects of topiramate would not only serve to decrease the acute reinforcing effects of alcohol or cocaine, but might also facilitate cessation of their use following a period of long-term use by decreasing neuronal sensitisation. This overview highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence and introduces preliminary evidence to indicate that it might also have utility in treating cocaine dependence. Finally, to place the material on topiramate in context, information has been included on the utility and development of other medications that modulate GABA- or glutamate-mediated neuronal systems for the treatment of alcohol or cocaine dependence.

Alcoholism↗
PubMed2003

Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status.

The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.

Antibodies, Monoclonal↗
PubMed2005

Development of oncology drug response markers using transcription profiling.

Transcriptional profiling of a tumor's entire genomic complement has become a key tool in the analysis of human cancers and identification of novel markers to predict disease state, outcome, and response to therapy. At present, this technology provides the most comprehensive approach for the analysis of somatic changes altering critical pathways during transformation of stable diploid cells into unstable tumor cells. Such analyses are impacting the development of novel anti-cancer drugs through the early detection of cancer, development of targeted therapies, identification of optimal dose and regimens for new drugs, and segmentation of patients to enrich response rates and reduce risk of adverse events.

Antineoplastic Agents↗
PubMed2003

Clinical development of 17-allylamino, 17-demethoxygeldanamycin.

17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate signaling pathways critical to the molecular economy of many types of tumors, including oncogene signaling, cyclin-dependent kinase activation, steroid hormone receptors, and mediators of invasion and metastasis. Thus, Hsp90-directed agents could affect molecules upon which tumors depend for their proliferation and survival. Initial clinical studies have therefore sought to incorporate assessment of these endpoints into initial clinical evaluations. Three schedules of administration have been supported for initial evaluation in Phase I studies sponsored by the National Cancer Institute (NCI) or supported by NCI and sponsored by Cancer Research UK. In the daily times five schedule, a recommended Phase II dose (RPTD) of 40 mg/m(2) has been reached, while once weekly or three of four weekly schedules are defining RPTDs of 295 and 308 mg/m(2). Toxicity is tolerable and appears dominated by hepatic, gastrointestinal, and constitutional symptoms. Concentrations of drug at peak of ~1700-3000 nM are concordant with concentrations predictive of useful outcomes in pre-clinical model systems. Evidence of modulation of Hsp90 partner molecules has been obtained in both surrogate and some tumor compartments. These very early results encourage additional clinical evaluations of 17AAG and related molecules.

Animals↗
PubMed2002

Secretase as a target for Alzheimer's disease.

The amyloid-beta peptide (Abeta) is the major protein component of the characteristic cerebral plaques of Alzheimer s disease (AD), and a large body of evidence supports a pathogenic role for this peptide. Thus, the proteases beta- and gamma-secretase that are responsible for carving Abeta out of its precursor protein are considered prime targets for therapeutic design. beta-Secretase is a membrane-anchored aspartyl protease of the pepsin family, while gamma-secretase is much more complex. gamma-Secretase requires presenilin, a multipass membrane protein that is the site of dozens of missense mutations that alter Abeta formation and cause hereditary AD. Two conserved aspartates in presenilin are required for gamma-secretase activity, and aspartyl protease transition-state analogue inhibitors of gamma-secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. gamma-Secretase appears to be a multi-component complex of integral membrane proteins, and so far presenilin and a single-pass membrane protein called nicastrin have been identified as members of this complex. A closely similar or identical protease activity is essential for a signaling pathway critical for embryogenesis and hematopoiesis, raising concerns about gamma-secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.

Alzheimer Disease↗
PubMed1997

Serotonin reuptake inhibitors and the adequacy of antidepressant treatment.

OBJECTIVE: To determine whether the use of serotonin reuptake inhibitors (SSRIs) improves antidepressant medication prescribing patterns for both psychiatric and non-psychiatric physicians. DATA SOURCES/SETTING: Drug utilization review of 4,103 prescriptions for antidepressant medications with patients diagnosed with depressive disorders over an eighteen-month period from the formulary records of a large insurance company. DESIGN: Using standards developed for clinical guidelines, variation in trial and treatment adequacy between drug types and physician specialty was studied. PRINCIPAL FINDINGS: Thirty-five percent of initial antidepressant trials were not prescribed for an adequate duration or at an adequate dosage level. SSRIs were more likely to be prescribed adequately than any other antidepressant reviewed. Psychiatrists were more likely to prescribe antidepressants at an adequate dosage level, whereas non-psychiatric physicians were more likely to attain adequate duration of treatment. CONCLUSIONS: A greater reliance on SSRIs may increase the likelihood of maintaining adequacy in antidepressant treatments. Although higher in cost than other treatment choices, their lower side effect profile is likely to maximize patient satisfaction and physician and patient adherence to guidelines. In order to ensure effective and efficient antidepressant usage, such patterns must be identified and appropriate performance improvement strategies (e.g., Total Quality Improvement, critical pathways) may be employed.

Antidepressive Agents↗
PubMed2006

Genomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation.

PURPOSE: Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50%, and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation. The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity. Therefore, it is imperative to identify those patients who will benefit from chemoradiation therapy and those who will develop recurrent disease. In this study, we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation. PATIENTS AND METHODS: A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms. RESULTS: A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence. Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables: node status, IL-8, intracellular adhesion molecule-1, transforming growth factor-beta, and fibroblast growth factor receptor 4. CONCLUSION: Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence, and those who are more likely to benefit from chemoradiation therapy. A larger prospective study is needed to validate these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation.

Antineoplastic Agents↗
PubMed2003

The role of transforming growth factor-beta in primary brain tumors.

Dramatic therapeutic benefits of targeting specific signal transduction pathways in some cancers have pushed rational molecular targeting to the forefront of cutting-edge cancer therapy. The identification and targeting of pathways critical to the phenotype of cancers offers new hope in the treatment of many patients. Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that is frequently expressed in multiple types of malignant brain tumors. TGF-beta exerts a complex set of effects in cancers with an early tumor suppressive effect through growth inhibition but later effects in cancer development that are tumorigenic - including increased tumor cell motility and invasion, induction of angiogenesis, and immune suppression. Early preclinical and clinical studies have shown promise of anti-TGF-beta strategies in the treatment of malignant gliomas suggesting TGF-beta may be a potential new therapeutic target in neuro-oncology.

Animals↗
PubMed1995

Metabolic deactivation of the herbicide thiazopyr by animal liver esterases.

1. Thiazopyr was hydrolysed in vitro to its corresponding acid by rabbit and porcine liver esterases. 2. A wide range of thiazopyr esterase activity was observed in extracts from liver acetone powders from 15 animal species with bovine, rabbit and pigeon showing the highest activities. 3. Using soybean tissue culture cells and Arabidopsis seedlings, the acidic metabolite was shown to possess < 1% of the herbicidal activity of thiazopyr. 4. We propose that biotransformation of thiazopyr to the acid is a critical pathway of metabolism in animals and plants.

Animals↗
PubMed2003

Genetic regulation of systemic angiogenesis in the mouse lung.

The work in this study takes advantage of a new experimental model in the mouse that completely isolates the angiogenic process from the direct effects of ischemia. The model also leads to lung angiogenesis that mimics the vascular source of many lung pathologies, and allows investigation of the temporal and spatial factors that can promote or inhibit angiogenesis. This work describes the expression patterns of genes relevant to pro-angiogenic signals and conditions in response to ischemia in the lung. The most notable changes were increases in the expression of genes involved in inflammation and tissue remodeling. In particular, the results confirm a important role of ELR+ CXC chemokines as proangiogenic signals. In addition, the experimental findings in this mouse lung model show that lung ischemia, rather than hypoxia, is the essential trigger for angiogenesis. Results from this model also suggest potential approaches for determining critical pathways and potential therapeutic strategies related to the control of angiogenesis.

Animals↗
PubMedDate not supplied

Hormonal effects on the mammary gland of postmenopausal nonhuman primates.

Macaques are Old World anthropoid primates with a high degree of genetic identity to human beings and striking similarities in breast development, reproductive endocrinology, and menstrual cycle characteristics. These animals share critical pathways of hormone metabolism with humans, to a degree that is distinct from rodent models. Macaques also express estrogen receptors alpha and beta, progesterone receptors, and androgen receptors in the normal breast in patterns similar to those described for women. Spontaneously occurring hormone-dependent breast cancers occur in macaques at a similar prevalence to lower-risk populations of women, and these neoplasms exhibit similar growth patterns and key molecular changes seen in human lesions. These similarities lend support to a biomarker approach for modeling breast cancer risk. Estrogen+progestogen treatment of postmenopausal animals produces a proliferative response in the normal breast epithelium which reflects the breast cancer promoting effects of continuous combined hormone replacement therapy. Studies of novel agents such as tibolone, selective estrogen receptor modulators, and alternative progestogens in macaques have also helped to identify hormonal therapies with a more acceptable balance of benefit to risk. Future studies of novel selective estrogens, androgens, and dietary estrogens in the macaque model will further contribute to our understanding of breast cancer risk and prevention.

Animals↗
PubMed2005

CpG island hypermethylation profiling of lung cancer using restriction landmark genomic scanning (RLGS) analysis.

Lung cancer remains the leading cause of cancer related mortality, accounting for almost one-third of cancer deaths in men and one-fourth of cancer deaths in women; 160,440 lung cancer deaths are expected in 2004. Survival from lung cancer depends mainly upon the stage at presentation. As localized tumors generally do not cause symptoms, the disease is usually diagnosed in symptomatic patients at advanced stages when the prognosis is poor. As a result, the overall 5-year lung cancer survival rate is only 15%. It is well known that epigenetic alterations such as DNA methylation of CpG dinucleotides located in CpG islands within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could identify potential biomarkers for lung cancer risk. Our goal for this study is to identify novel hypermethylated genes in lung cancer. We have investigated the methylation profiles of DNA samples from 14 paired lung tumor and adjacent normal tissues resected from the same individuals using restriction landmark genomic scanning (RLGS). We could assess the DNA methylation status of an average of 2,012 CpG islands for each tumor. We identified 162 differentially methylated loci where CpG islands were hypermethylated in lung tumors but not in adjacent non-cancer tissues. Among 162 sites of differential DNA methylation, detected from at least one tumor/normal pair, 21 hypermethylated genes were identified that were not reported previously as hypermethylated in lung tumor tissue.

Adenocarcinoma↗
PubMed2006

Future trends in patient-reported outcomes assessment for patients with advanced-stage lung cancer receiving targeted therapy.

Recent advances in cancer cell biology have led to the development of therapeutic agents that target pathways critical to the development and progression of disease. These so-called "targeted therapies" might offer patients a more tolerable alternative to traditional systemic chemotherapy that often achieves therapeutic benefit at the cost of debilitating side effects. Several targeted agents have been recently tested in clinical trials of advanced-stage lung cancer. As interest in these therapies grows, an understanding of their impact on the patient's well-being will be important. Patient-reported outcome measures such as formal assessments of health-related quality of life and disease symptoms provide a useful means for addressing the impact of therapy from the perspective of the patient. We summarize the most commonly used measures of health-related quality of life in clinical trials of advanced-stage lung cancer. Although existing measurement systems do provide adequate coverage of many important patient-related outcome issues, the advent of targeted therapies in advanced-stage lung cancer does expose several measurement gaps. We highlight some of these gaps by reviewing a representative sample of recently conducted clinical trials of targeted lung cancer therapy and offer insight as to how these gaps can be filled. We also briefly discuss a set of issues unique to patients receiving targeted therapy (eg, perceptions of treatment efficacy, treatment compliance, patient satisfaction, and treatment convenience) and consider a few methodologic concerns unique to patients with advanced cancer.

Clinical Trials as Topic↗
PubMed1994

Promoting quality mental health care delivery with critical path care plans.

1. Mental Health providers are under increasing pressure to provide objective, individualized care that produces outcomes that may be measured against accepted clinical standards. 2. Clinicians may now track patient responses throughout a continuum of treatment in varying locations by using a customized critical path/treatment plan format. 3. Care delivery is documented by superimposing actual occurrences over desired ones on a critical pathway.

Continuity of Patient Care↗
PubMed2001

Induction of a novel mechanism of accelerated bacterial clearance by lipopolysaccharide in CD14-deficient and Toll-like receptor 4-deficient mice.

Despite the lack of a proinflammatory response to LPS, CD14-deficient mice clear Gram-negative bacteria (Escherichia coli 0111) at least 10 times more efficiently than normal mice. In this study, we show that this is due to an early and intense recruitment of neutrophils following the injection of Gram-negative bacteria or LPS in CD14-deficient mice; in contrast, neutrophil infiltration is delayed by 24 h in normal mice. Similar results of early LPS-induced PMN infiltration and enhanced clearance of E. coli were seen in Toll-like receptor (TLR) 4-deficient mice. Furthermore, the lipid A moiety of LPS induced early neutrophil infiltration not only in CD14-deficient and TLR-4-deficient mice, but also in normal mice. In conclusion, the lipid A component of LPS stimulates a unique and critical pathway of innate immune responses that is independent of CD14 and TLR4 and results in early neutrophil infiltration and enhanced bacterial clearance.

Adjuvants, Immunologic↗
PubMed2007

IL-10 regulation by HIV-Tat in primary human monocytic cells: involvement of calmodulin/calmodulin-dependent protein kinase-activated p38 MAPK and Sp-1 and CREB-1 transcription factors.

The anti-inflammatory cytokine, IL-10 plays an important role in HIV immunopathogenesis. The HIV accessory protein, Tat is not only critical for viral replication, but affects the host immune system by influencing cytokine production including IL-10. During HIV infection, IL-10 production by monocytic cells is up-regulated, representing a critical pathway by which HIV may induce immunodeficiency. Herein, we show that extracellular Tat-induced IL-10 expression in normal human monocytes. To understand the signaling pathways underlying HIV-Tat induced IL-10 transcription, we investigated the involvement of MAPK as well as calcium signaling and the downstream transcription factor(s). Our results suggest that Tat-induced calcium influx regulated IL-10 transcription in monocytic cells. The experiments designed to further understand the molecules involved in the calcium signaling suggested that calmodulin and calmodulin-dependent protein kinase-II (CaMK-II)-activated p38 MAPK played a role in extracellular Tat-induced IL-10 expression in primary human monocytes. Furthermore, Tat-induced IL-10 expression was regulated by p38 MAPK- and CaMK II-activated CREB-1 as well as Sp-1 transcription factors. Taken together, our results suggest that extracellular HIV-Tat induced IL-10 transcription in primary human monocytes is regulated by CREB-1 and Sp-1 transcription factors through the activation of calmodulin/CaMK-II-dependent p38 MAPK.

Calcium↗