Innovation and integration at the Warren Alpert Medical School of Brown University

As Dean of Medicine and Biological Sciences for Brown University from 2008-2013, I oversaw a curriculum that reflects the core of what I believe are the essential components of a medical student’s education. This article describes the philosophy and content of that curriculum.[...

A Cross-Sectional Analysis of Perceptions of Interprofessional Education in Medical Students

Background and Objectives: With the recent paradigm shift in medicine away from traditional hierarchies and patient-physician dyads, there is increased interest in training students to work interprofessionally. A primary focus for improving collaboration in health care is increasing exposure to formalized interprofessional education (IPE) across health professions during training. This study focuses on the effect of formal and informal curricula on medical student attitudes toward IPE. Methods: A cross-sectional survey of all undergraduate medical students was conducted using the Readiness for Interprofessional Learning Scale (RIPLS). Results: Throughout all years of medical school, students agreed with the importance of interprofessional education. Fourth-year medical students had higher total RIPLS scores (64.29 versus 61.0; p=0.007), as well as higher scores on multiple individual RIPLS questions than first-year students. Conclusions: Medical students become more enthusiastic about IPE as their training progresses. Both formal and informal educational opportunities contribute to this effect

The multi-layered nature of the internet-based democratization of brand management

The evolution of the internet, including developments such as Web 2.0, has led to new relationship realities between organizations and their stakeholders. One manifestation of these complex new realities has been the emergence of an internet-based democratization of brand management. Research about this phenomenon has so far mainly focused on investigating just one or more individual themes and thereby disregarded the inherent multi-layered nature of the internet-based democratization of brand management as a holistic, socio-technological phenomenon. The aim of this paper is to address this limitation through an investigation of the various socio-technological democratization developments of the phenomenon. To achieve this aim, a balanced and stakeholder-oriented perspective on brand management has been adopted to conduct an integrative literature review. The review reveals three key developments, which together form the essential parts of the phenomenon: (I) the democratization of internet technology, (II) the democratization of information, and (III) the democratization of social capital. The insights gained help to clarify the basic structures of the multi-layered phenomenon. The findings contribute also to the substantiation of a call for a new brand management paradigm: one that takes not only company-initiated but also stakeholder-initiated brand management activities into accoun

Both base excision repair and O-6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis

Methylating agents are widely distributed environmental carcinogens. Moreover, they are being used in cancer chemotherapy. The primary target of methylating agents is DNA, and therefore, DNA repair is the first-line barrier in defense against their toxic and carcinogenic effects. Methylating agents induce in the DNA O[superscript 6]-methylguanine (O[superscript 6]MeG) and methylations of the ring nitrogens of purines. The lesions are repaired by O[superscript 6]-methylguanine-DNA methyltransferase (Mgmt) and by enzymes of the base excision repair (BER) pathway, respectively. Whereas O[superscript 6]MeG is well established as a pre-carcinogenic lesion, little is known about the carcinogenic potency of base N-alkylation products such as N3-methyladenine and N3-methylguanine. To determine their role in cancer formation and the role of BER in cancer protection, we checked the response of mice with a targeted gene disruption of Mgmt or N-alkylpurine-DNA glycosylase (Aag) or both Mgmt and Aag, to azoxymethane (AOM)-induced colon carcinogenesis, using non-invasive mini-colonoscopy. We demonstrate that both Mgmt- and Aag-null mice show a higher colon cancer frequency than the wild-type. With a single low dose of AOM (3 mg/kg) Aag-null mice showed an even stronger tumor response than Mgmt-null mice. The data provide evidence that both BER initiated by Aag and O[superscript 6]MeG reversal by Mgmt are required for protection against alkylation-induced colon carcinogenesis. Further, the data indicate that non-repaired N-methylpurines are not only pre-toxic but also pre-carcinogenic DNA lesions.Deutsche Forschungsgemeinschaft (DFG) (FOR 527)Deutsche Forschungsgemeinschaft (DFG) (DFG KA 724/13-3)Deutsche Forschungsgemeinschaft (DFG) (WI 3304/1-1

DNA repair modulates the vulnerability of the developing brain to alkylating agents

Neurons of the developing brain are especially vulnerable to environmental agents that damage DNA (i.e., genotoxicants), but the mechanism is poorly understood. The focus of the present study is to demonstrate that DNA damage plays a key role in disrupting neurodevelopment. To examine this hypothesis, we compared the cytotoxic and DNA damaging properties of the methylating agents methylazoxymethanol (MAM) and dimethyl sulfate (DMS) and the mono- and bifunctional alkylating agents chloroethylamine (CEA) and nitrogen mustard (HN2), in granule cell neurons derived from the cerebellum of neonatal wild type mice and three transgenic DNA repair strains. Wild type cerebellar neurons were significantly more sensitive to the alkylating agents DMS and HN2 than neuronal cultures treated with MAM or the half-mustard CEA. Parallel studies with neuronal cultures from mice deficient in alkylguanine DNA glycosylase (Aag[superscript −/−]) or O6-methylguanine methyltransferase (Mgmt[superscript −/−]), revealed significant differences in the sensitivity of neurons to all four genotoxicants. Mgmt−/− neurons were more sensitive to MAM and HN2 than the other genotoxicants and wild type neurons treated with either alkylating agent. In contrast, Aag[superscript −/−] neurons were for the most part significantly less sensitive than wild type or Mgmt[superscript −/−] neurons to MAM and HN2. Aag[superscript −/−] neurons were also significantly less sensitive than wild type neurons treated with either DMS or CEA. Granule cell development and motor function were also more severely disturbed by MAM and HN2 in Mgmt[superscript −/−] mice than in comparably treated wild type mice. In contrast, cerebellar development and motor function were well preserved in MAM-treated Aag[superscript −/−] or MGMT-overexpressing (Mgmt[superscript Tg+]) mice, even as compared with wild type mice suggesting that AAG protein increases MAM toxicity, whereas MGMT protein decreases toxicity. Surprisingly, neuronal development and motor function were severely disturbed in Mgmt[superscript Tg+] mice treated with HN2. Collectively, these in vitro and in vivo studies demonstrate that the type of DNA lesion and the efficiency of DNA repair are two important factors that determine the vulnerability of the developing brain to long-term injury by a genotoxicant.United States. Army Medical Research and Materiel Command (Contract/Grant/Intergovernmental Project Order DAMD 17-98-1-8625)United States. National Institutes of Health (grants CA075576)United States. National Institutes of Health (RO1 C63193)United States. National Institutes of Health (P30 CA043703

Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O6-alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O6-benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG. © 1999 Cancer Research Campaig

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity