Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing.

New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

The Threshold of Toxicological Concern (TTC) is a pragmatic tool for the safety assessment: Case studies of cosmetic ingredients with low consumer exposure.

The Threshold of Toxicological Concern (TTC) is an internationally accepted pragmatic and conservative tool for the safety assessment of substances, which is used in a wide range of regulatory contexts. The TTC approach produces human exposure threshold values (TTC values) originally derived by Munro from oral toxicity data on cancer and non-cancer toxicity endpoints. This database has been recently substantially enlarged by the COSMOS database, an enhanced oral non-cancer TTC dataset on a larger chemical domain, thereby resulting in a new, transparent and public TTC database also including 552 cosmetics-related chemicals. The 5th percentile point of departure value for each Cramer Class was determined, from which human exposure TTC values have been derived. The combined COSMOS/Munro dataset provided TTC values of 46, 6.2 and 2.3 µg/kg bw/day for Cramer Classes I, II or III, respectively. In order to demonstrate the diverse scope and successful application of the TTC concept to cosmetic ingredients including hair dyes, fragrances and plant-derived ingredients, Cosmetics Europe has prepared several case studies. Overall, the TTC concept is not only useful to replace animal testing but can also successfully be applied to the safety evaluation of cosmetic ingredients in the marketed formulas with low human exposure.

A novel resident-as-teacher training program to improve and evaluate obstetrics and gynecology resident teaching skills.

BACKGROUND: Residents play a significant role in teaching, but formal training, feedback, and evaluation are needed. AIMS: Our aims were to assess resident teaching skills in the resident-as-teacher program, quantify correlations of faculty evaluations with resident self-evaluations, compare resident-as-teacher evaluations with clinical evaluations, and evaluate the resident-as-teacher program. METHOD: The resident-as-teacher training program is a simulated, videotaped teaching encounter with a trained medical student and standardized teaching evaluation tool. Evaluations from the resident-as-teacher training program were compared to evaluations of resident teaching done by faculty, residents, and medical students from the clinical setting. RESULTS: Faculty evaluation of resident teaching skills in the resident-as-teacher program showed a mean total score of 4.5 ± 0.5 with statistically significant correlations between faculty assessment and resident self-evaluations (r = 0.47; p < 0.001). However, resident self-evaluation of teaching skill was lower than faculty evaluation (mean difference: 0.4; 95% CI 0.3-0.6). When compared to the clinical setting, resident-as-teacher evaluations were significantly correlated with faculty and resident evaluations, but not medical student evaluations. Evaluations from both the resident-as-teacher program and the clinical setting improved with duration of residency. CONCLUSIONS: The resident-as-teacher program provides a method to train, give feedback, and evaluate resident teaching.

Does education influence pediatricians' perceptions of physician-specific barriers for maternal depression?

Pediatric residency reforms have increased emphasis on psychosocial issues, but we do not know whether this has changed pediatricians' perceptions of barriers to addressing maternal depression. A survey of 1600 members of the American Academy of Pediatrics investigated whether training in adult mental health issues and perceived barriers to addressing maternal depression differed for current pediatric residents, pediatricians in practice <5 years, and those in practice >or=5 years. Training did not differ for respondents who were currently in training, in practice <5 years, or in practice >or=5 years. Those in practice >or=5 years reported more barriers to addressing maternal depression compared with current residents. Current residents with training in adult mental techniques reported fewer barriers to the care of maternal depression. However, in spite of residency reforms, 81% of current residents reported no training in adult mental health issues.

The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo.

Cross-talk between receptor tyrosine kinases and estrogen receptor is at least partly responsible for the development of acquired resistance to endocrine therapies. Hence, targeting receptor tyrosine kinases and their downstream partners with inhibitors/antagonists may reverse this resistance. Although ras mutations are rare in breast cancer (2%), aberrant function of Ras signal transduction pathways is common. We therefore investigated the efficacy of the farnesyltransferase inhibitor (FTI) R115777 (tipifarnib) in combination with tamoxifen in MCF-7 human breast cancer models both in vitro and in vivo. There was a synergistic antiproliferative interaction between R115777 and 4-hydroxy-tamoxifen in vitro as calculated by median effect analysis. The combination resulted in a significantly greater G(1) arrest than either drug alone and this was associated with marked inhibition of cyclin D1 and induction of the cell cycle inhibitor p27(kip1). Combining R115777 with either tamoxifen or estrogen withdrawal in vivo produced a significantly greater inhibition of tumor growth and lower xenograft cell proliferation than either therapy alone. These results suggest that the combination of this FTI with endocrine therapy may be of therapeutic benefit in the treatment of breast cancer. Enhanced G1 arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen.

Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer.

Improving endocrine responsiveness and preventing the development of resistance is the goal of many current strategies that are looking to combine aromatase inhibitors with novel drugs that target various pathways in estrogen receptor (ER) positive breast cancer. Pre-clinical models of acquired resistance to aromatase inhibitors have suggested an increase in several signaling pathways including peptide growth factor signaling (EGFR, HER2) and activation of the mTOR signaling pathway. These may result in associated 'cross-talk' activation of ER-dependent gene transcription, such that dual blockade of ER together with other signaling pathways has become a logical approach to improve endocrine responsivness. Clinical strategies with aromatase inhibitors are looking to prevent activation of these pathways either through combination with the selective ER downregulator fulvestrant, or with various signal transduction inhibitors (STIs) including monoclonal antibodies (trastuzumab), small molecule tyrosine kinase inhibitors (TKIs) against EGFR or HER2 (lapatinib, gefitinib) and mTOR antagonists (temsirolimus). Early clinical data have emerged this year for some of these approaches with mixed results. This article reviews the rationale for these strategies, and discusses the lessons that need to be learnt if we are to successfully integrate these new drugs with aromatase inhibitors in the clinic.

Clinicians' attitudes to spirituality in old age psychiatry.

BACKGROUND: The aim of this survey is to investigate professional attitudes to the presence and value of spiritual care from Old Age Psychiatrists. METHOD: All registered members of the Faculty of the Psychiatry of Old Age in the United Kingdom were asked to complete a 21-question semi-structured questionnaire. The first mail shot took place in 2002 and the second mail shot to non-respondents in 2003. Quantitative and qualitative analyses were carried out on the answers received. RESULTS: The response rate was 46%. The majority of respondents (92%) recognize the importance of spiritual dimensions of care for older people with mental health needs and about a quarter of respondents appear to consider referring patients to the chaplaincy service. In contrast, integration of spiritual advisors within the assessment and management of individual cases is rare. CONCLUSIONS: Opinions vary as to whether provision of spiritual care should become widely available to older people with mental health needs who are admitted to hospital. Old age psychiatrists recognize that awareness of spiritual dimensions may be important for their patients. They seem less clear about the role of spiritual advisors and how NHS multidisciplinary clinical teams and spiritual and pastoral care services can be best integrated. Much work needs to be done on developing effective training and operational policies in this area.

Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance.

There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.

New targets for therapy in breast cancer: farnesyltransferase inhibitors.

Current systemic therapies for breast cancer are often limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues, and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in development of various signal transduction inhibitor drugs as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines that contain wild-type ras, including breast cancer cells. Additive or synergistic effects were observed when FTIs were combined with cytotoxic agents (in particular the taxanes) or endocrine therapies (tamoxifen). Phase I trials with FTIs have explored different schedules for prolonged administration, and dose-limiting toxicities included myelosuppression, gastrointestinal toxicity and neuropathy. Clinical efficacy against breast cancer was seen for the FTI tipifarnib in a phase II study. Based on promising preclinical data that suggest synergy with taxanes or endocrine therapy, combination clinical studies are now in progress to determine whether FTIs can add further to the efficacy of conventional breast cancer therapies.

Protein farnesyltransferase inhibitors.

Current systemic cytotoxic therapies for cancer are limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in various signal transduction inhibitor drugs being developed as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation (addition of a 15-carbon farnesyl moiety) for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines, many of which contain wild type ras. While understanding the mechanism of action of FTIs remains an important research goal, three different FTIs have entered clinical development. Several Phase I trials with each drug have explored different schedules for prolonged administration, and dose-limiting toxicities (DLTs) have varied from myelosuppression, gastrointestinal toxicity and neuropathy. Evidence for anticancer efficacy has come from a number of Phase II studies, not necessarily in tumour types containing ras mutations, which were the initial target for these drugs. Perhaps the most promising use for FTIs will be in combination with conventional cytotoxic drugs, based on preclinical data suggesting synergy, particularly with the taxanes. Clinical combination studies are in progress, and larger Phase II/III clinical trials are planned to see if FTIs can add to the efficacy of conventional therapies.

25th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 10-14 December 2002 Update on preclinical and translational research.

The Annual San Antonio Breast Cancer Symposium is one of the largest regular conferences devoted to breast cancer research and treatment. In particular, it provides a forum in which to discuss the more translational aspects of current basic research, and the 2002 meeting was no exception. Growth factor pathways and endocrine resistance, cancer genomics and the clinical applications of proteomics were three of the major topics for discussion. Presentations on genetic susceptibility and the development of prognostic and predictive markers also created much interest.

25th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 10-14 December 2002 Update on clinical research.

The Annual San Antonio Breast Cancer Symposium has become a key forum for the presentation and discussion of both translational scientific aspects as well as clinical aspects of breast cancer care. In this report of the 25th Annual Meeting, an update of the salient clinical data is presented. The findings of the CALGB 9741 trial, an updated analysis of the Arimidex, Tamoxifen, Alone or in Combination study, and other significant paper and poster presentations are discussed. Summaries are also given of the clinical plenary lectures and minisymposia on adjuvant therapy and aromatase inhibitors.

Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer.

Recent evidence suggests that common molecular adaptations occur during resistance to both tamoxifen and estrogen deprivation that use various signal transduction pathways, often involving cross-talk with a retained and functional estrogen receptor (ER) protein. There appear to be several different levels at which this cross-talk may occur, including peptide growth factor signaling via the type 1 tyrosine kinase growth factor receptor family [epidermal growth factor receptor (EGFR) and HER2], which may become up-regulated during endocrine treatment, ultimately being harnessed by cells to allow them hormone-independent growth. ER may remain involved in cell growth with ligand-independent phosphorylation and activation via different intracellular mitogen-activated protein kinases. ER may also become involved in non-nuclear estrogen-dependent signaling via interaction with the phosphatidylinositol 3'-kinase/Akt cell survival pathway or may interact with the stress-activated protein kinase/c-Jun-NH(2)-terminal kinase pathway. Understanding these mechanisms will permit the optimal integration of new signal transduction inhibitors (STIs) into breast cancer therapy. Preclinical approaches that have shown promise include the use of EGFR tyrosine kinase inhibitors for hormone-resistant breast cancer cells that are dependent on either EGFR or HER2 signaling. Likewise, farnesyl transferase inhibitors, mitogen-activated protein kinase inhibitors, and cell cycle inhibitors have all shown activity in experimental breast cancer models. Emerging data suggest that STIs may be more effective when given in combination with endocrine therapy either to overcome resistance or to prevent/delay emergence of the resistance phenotype. Clinical trials are in progress to determine the safety and optimal schedule for each of the various STIs, and studies of STIs in combination with aromatase inhibitors have commenced in breast cancer to see whether the therapeutic response to endocrine therapy can be enhanced further.