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Biomedical subjects

Richard J Epstein

Publications and source records attributed to Richard J Epstein.

14 recordsLinked to original sources
PubMed2005

Primary prevention of human papillomavirus-dependent neoplasia: no condom, no sex.

Cervix cancer is one of several neoplastic disorders that arise following transfer of human papillomavirus (HPV) during unprotected sexual intercourse, and like most other sexually transmitted diseases (STDs), is largely preventable by consistent condom use. This primary prevention strategy has received little support, however, when compared with massive secondary prevention initiatives involving cervical screening. The reasons for this anomalous situation are complex, and include: (i) the asymptomatic nature of most primary HPV infections; (ii) widespread ignorance concerning the venereal aetiology of HPV-related cancers; (iii) the common but incorrect belief that condom use does not reduce HPV transmission; (iv) the perceived irrelevance of safe sex campaigns based on reducing transmission of human immunodeficiency virus (HIV) in high-HPV but low-HIV countries such as the Philippines; (v) the promotion of oral contraception by the medical and pharmaceutical sectors as the sexual prophylaxis of choice; and (vi) the assumption that HPV vaccines will solve the problem. Here it is proposed that the high prevalence of non-HIV STDs, including distressing disorders such as genital warts and herpes simplex, can be exploited with greater efficacy as a public health deterrent to unsafe sex and HPV transmission. Targeting a "mutually assured infection" campaign at vulnerable subgroups such as teenagers and oral contraceptive users could help reverse the global expansion of HPV-related cancers.

Condoms↗
PubMed2005

Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment.

The palliative efficacy of cytotoxic drugs is routinely assessed using tumor shrinkage (response) rates shown in clinical trials. Although adjuvant drug therapy has a goal distinct from that of palliative therapy (i.e., to prolong survival by inhibiting progression of micrometastatic disease), it is widely assumed that the adjuvant efficacy of a drug will parallel its response rate ("activity") in advanced stages of the disease. Reconsideration of this assumption seems timely in view of recent developments: the realization that many predictors of short-term tumor response correlate inversely with long-term survival outcomes; the characterization of tumor progression as a discontinuous process that may include dormant phases; the understanding that micrometastasis is therapeutically suppressible by a variety of mechanisms including direct tumor cell kill, cytotoxic disruption of paracrine growth signals from normal tissues, and targeted inhibition of prometastatic pathways; the recognition that tumor dormancy not only blocks the antimetastatic efficacy of cytotoxic drugs but also represents a therapeutic end point for metastasis-suppressive noncytotoxic drugs such as hormone inhibitors; and the insight that optimal adjuvant drug therapy is likely to include both induction and maintenance components. The traditional view of cytoreductive response as a prerequisite for adjuvant drug efficacy thus merits reappraisal, with a view to accelerating incorporation of novel noncytotoxic maintenance therapies into controlled studies.

Animals↗
PubMed2004

Upregulated Akt signaling adjacent to gastric cancers: implications for screening and chemoprevention.

Most gastric adenocarcinomas arise as a longterm complication of Helicobacter pylori infection of the stomach, but the high prevalence of this infection limits the cost-effectiveness of antibiotic eradication as a cancer prevention strategy. Here we have used phosphorylation-specific antibodies against the Akt kinase consensus sequence to detect downstream substrates of this oncogenic signaling pathway in normal and malignant gastric tissues. In vitro studies confirm that phosphorylation of Akt and its substrates is inducible by epithelial mitogens such as epidermal growth factor (EGF), which is implicated in the pathogenesis of H. pylori gastritis. Control clinical studies confirm far stronger Akt substrate phosphorylation in primary human breast cancers than in matched adjacent normal breast tissues; unexpectedly, however, increased Akt signaling is apparent in both primary stomach cancers and adjacent normal gastric tissues. These findings raise the possibility of a preneoplastic field defect induced in morphologically normal tissues, and suggest that immunoassays of mucosal Akt activity could guide preventive surveillance and/or intervention in patients at risk of gastric cancer. Moreover, since recent reports confirm Akt inhibition by COX-2 inhibitors, these data support the chemopreventive efficacy of such drugs for at-risk individuals.

Adenocarcinoma↗
PubMed2004

Selective tyrosine hyperphosphorylation of cytoskeletal and stress proteins in primary human breast cancers: implications for adjuvant use of kinase-inhibitory drugs.

PURPOSE: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors. EXPERIMENTAL DESIGN: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells. RESULTS: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exhibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-gamma, and phosphatidylinositol 3'-kinase). CONCLUSIONS: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.

Animals↗
PubMed2004

Learning from the problems of problem-based learning.

BACKGROUND: The last decade has witnessed a rapid expansion of biomedical knowledge. Despite this, fashions in medical education over the same period have shifted away from factual (didactic) teaching and towards contextual, or problem-based, learning (PBL). This paradigm shift has been justified by studies showing that PBL improves reasoning and communication while being associated with few if any detectable knowledge deficits. DISCUSSION: Analysis of the literature indicates that the recent rapid rise of PBL has closely paralleled the timing of the information explosion. The growing dominance of PBL could thus worsen the problems of information management in medical education via several mechanisms: first, by creating the impression that a defined spectrum of core factual knowledge suffices for clinical competence despite ongoing knowledge expansion (quality cost); second, by dissuading teachers from refining the educational utility of didactic modalities (improvement cost); and third, by reducing faculty time for developing reusable resources to impart factual knowledge more efficiently (opportunity cost). SUMMARY: These costs of PBL imply a need for strengthening the knowledge base of 21st-century medical graduates. New initiatives towards this end could include the development of more integrated cognitive techniques for facilitating the comprehension of complex data; the design of differentiated medical curricula for producing graduates with defined high-priority skill sets; and the encouragement of more cost-effective faculty teaching activities focused on the prototyping and testing of innovative commercializable educational tools.

Education, Medical↗
PubMed2004

The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies.

Dose-dense adjuvant breast cancer chemotherapy is a new treatment strategy that aims to improve tumour control by using more frequent cytotoxic dosing together with continuous granulocyte colony-stimulating factor (G-CSF) to minimize neutropaenia. In addition to stimulating neutrophil proliferation, G-CSF mobilizes neutrophils from the bone marrow through proteolytic disruption of the chemokine receptor CXCR4 and its chemotactic ligand CXCL12. As breast cancers also express CXCR4 and oestrogen induces CXCL12, the success of dose-dense treatment could partly reflect inhibition of CXCR4-dependent micrometastatic homing and/or paracrine survival, and suggests a benefit of adjuvant oestrogen suppression for patients with oestrogen-receptor-negative, CXCR4-positive disease.

Breast Neoplasms↗
PubMed2004

Journal impact factors do not equitably reflect academic staff performance in different medical subspecialties.

BACKGROUND: The simplest variables to quantify on an academic curriculum vitae are the impact factors (IFs) of journals in which articles have been published. As a result, these measures are increasingly used as part of academic staff assessment. The present study tests the hypotheses that IFs exhibit patterns that are consistent between journals of different specialties and that these IFs reflect the quality of staff academic performance. METHODS: The IFs of a sample of journals from each of four medical specialties-medicine, oncology, genetics, and public and occupational health-were downloaded from the Science Citation Index and compared. Overall and specialty-specific journal IF frequencies were analyzed with respect to distribution patterns, averages, and skew. RESULTS: Approximately 91% of journal IFs fell within the 0 to 5 range, with 97% being less than 10. The overall IF distribution featured a positive skew and a mean of 2.5. Separate analysis of the journal specialty subsets revealed significant differences in IF means (genetics 3.4 > oncology 3.1 > medicine 2.0 > public health 1.6; p < .006), all of which well exceeded the respective IF medians. Journals from the general medicine category exhibited both the lowest IF median (0.7) and the most positively skewed distribution. CONCLUSION: The distribution of IFs exhibits degrees of skew, numeric average, and spread that differ significantly between journal specialty subsets. This suggests that factors other than random variations underlie much of the IF variation between specialty journals and reduces the plausibility of a reliable correlation between IFs and the quality of academic staff performance. It is concluded that a dominant emphasis on IFs in academic recruitment and promotion may select for long-term faculty characteristics other than academic quality alone.

Academic Medical Centers↗
PubMed2003

Quick-FLIC--a short questionnaire for assessing quality of life of cancer patients.

Health-related quality of life instruments tend to include a great many items. This imposes a burden on the respondents as well as undermining response rate and data quality. In this study we developed a shortened version of the Functional Living Index-Cancer (FLIC), now called Quick-FLIC, and examined its measurement properties. A questionnaire package, self-administered by 140 patients, included the FLIC and the Functional Assessment of Cancer Therapy-General. A factor analysis and clinical judgement were used to shorten the FLIC, which included 22 items. Each subscale of FLIC was shortened to include two or three items only. The Quick-FLIC included a total of only 11 items. Nevertheless, the measurement properties of the Quick-FLIC and its subscales were comparable to those of the original FLIC. It is concluded that the shortening of established health-related quality of life instruments is viable in oncology research.

Adult↗
PubMed2003

Phosphoproteomic fingerprinting of epidermal growth factor signaling and anticancer drug action in human tumor cells.

Many proteins regulating cancer cell growth are tyrosine phosphorylated. Using antiphosphotyrosine affinity chromatography, thiourea protein solubilization, two-dimensional PAGE, and mass spectrometry, we report here the characterization of the epidermal growth factor (EGF)-induced phosphoproteome in A431 human epidermoid carcinoma cells. Using this approach, more than 50 distinct tyrosine phosphoproteins are identifiable within five main clusters-cytoskeletal proteins, signaling enzymes, SH2-containing adaptors, chaperones, and focal adhesion proteins. Comparison of the phosphoproteomes induced in vitro by transforming growth factor-alpha and platelet-derived growth factor demonstrates the pathway- and cell-specific nature of the phosphoproteomes induced. Elimination of both basal and ligand-dependent phosphoproteins by cell exposure to the EGF receptor catalytic inhibitor gefitinib (Iressa, ZD1839) suggests either an autocrine growth loop or the presence of a second inhibited kinase in A431 cells. By identifying distinct patterns of phosphorylation involving novel signaling substrates, and by clarifying the mechanism of action of anticancer drugs, these findings illustrate the potential of immunoaffinity-based phosphoproteomics for guiding the discovery of new drug targets and the rational utilization of pathway-specific chemotherapies.

Antineoplastic Agents↗
PubMed2002

Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera.

Estrogen receptor alpha (ERalpha) is a transcription factor that regulates expression of target genes in a ligand-dependent manner. Activation of gene expression is mediated by two transcription activation functions AF-1 and AF-2, which act in a promoter- and cell-specific manner. Whilst AF-2 activity is regulated by estrogen (E2) binding, the activity of AF-1 is additionally modulated by phosphorylation at several sites. One of these phosphorylation sites, serine 118 (S118) is of particular interest as its mutation significantly reduces ERalpha activity. Previous studies have shown that S118 can be phosphorylated by the ERK1/2 mitogen activated protein kinases (MAPK) and by the cyclin-dependent protein kinase Cdk7. In this study we use antisera that specifically recognize ERalpha phosphorylated at S118 to demonstrate that MAPK phosphorylates S118 in a ligand-independent manner, whereas Cdk7 mediates E2-induced phosphorylation of S118. E2 stimulation of S118 phosphorylation was observed within 10 min of its addition and was maximal at 10(-7) M E2. S118 phosphorylation was maximal at 30 min but then declined, such that by 180 min following E2 addition little S118 phosphorylation was evident. S118 phosphorylation was also induced by the partial estrogen antagonist 4-hydroxytamoxifen, but not by the complete antagonist ICI 182, 780. S118 phosphorylation upon addition of the MAPK inducers EGF or PMA followed the expected time courses. Finally, we show that ERalpha is phosphorylated at S118 in vivo using immunoblotting of extracts prepared from a series of ERalpha-positive breast tumours.

Amino Acid Sequence↗