Team effectiveness model for science (TEMS): Using a mutual learning shared mindset to design, develop, and sustain science teams.

In this paper, we introduce the Team Effectiveness Model for Science (TEMS) and describe a multiphase set of interventions for forming a new team or developing an existing team. TEMS uses a shared mutual learning mindset as the model's central and guiding element. It shows how team mindset leads to behavior and to results and how this affects the characteristics of effective team functioning. TEMS addresses two related questions: What are the variables that contribute to effective teams? and How do the variables need to be designed to make their relevant contributions? Team models often answer the first question without fully answering the second. By addressing three gaps, TEMS contributes to enhancing science team effectiveness. Gap 1 is the absence of explicit core values, assumptions, and norms that serve as the foundation for developing and maintaining science team effectiveness. Gap 2 is the absence of a process for integrating the science and relationship aspects of a science team. Gap 3 is the absence of team processes and structures that are derived from the team's values, assumptions, and norms. Using TEMS to design new or intervene with existing teams focuses on shifting mindset, developing behavioral skills, and designing processes and structures congruent with the new mindset.

Changes in the National Cancer Institute's R01 workforce: growth, aging, retention, and policy implications.

Scientific progress and discovery of preventions and cures for life-threatening diseases depend on the vitality of the biomedical research workforce. We analyzed the workforce of cancer researchers applying for and receiving R01 awards from the National Cancer Institute (NCI) from fiscal years 1990 to 2016, the last year prior to implementation of the Next Generation Researchers Initiative. Here we report that the NCI R01 Principal Investigator (PI) workforce expanded 1.4-fold and aged over this time frame. We tracked 9 age groups and found that the number of PIs in the 3 oldest groups increased dramatically, in contrast with the younger groups. Sustained increases in the number of funded older PIs stemmed from increases in the number of older PIs submitting applications, rather than higher funding rates for older PIs. The decline in the number of funded younger PIs was driven in part by (a) a marked increase in time from PhD degree to first R01 application and award, as well as (b) a decrease in retention of PIs in the funded R01 workforce beyond their first R01 award. The NCI is using these and other analyses to inform strategies and policies for attracting, supporting, and retaining meritorious early-career researchers.

Graduate Education for the Future: New Models and Methods for the Clinical and Translational Workforce.

This paper is the third in a five-part series on the clinical and translational science educational pipeline, and it focuses on strategies for enhancing graduate research education to improve skills for interdisciplinary team science. Although some of the most cutting edge science takes place at the borders between disciplines, it is widely perceived that advancements in clinical and translational science are hindered by the "siloed" efforts of researchers who are comfortable working in their separate domains, and reluctant to stray from their own discipline when conducting research. Without appropriate preparation for career success as members and leaders of interdisciplinary teams, talented scientists may choose to remain siloed or to leave careers in clinical and translational science all together, weakening the pipeline and depleting the future biomedical research workforce. To address this threat, it is critical to begin at what is perhaps the most formative moment for academics: graduate training. This paper focuses on designs for graduate education, and contrasts the methods and outcomes from traditional educational approaches with those skills perceived as essential for the workforce of the future, including the capacity for research collaboration that crosses disciplinary boundaries.

The 'Welcome Letter': A Useful Tool for Laboratories and Teams.

The ability to clearly set expectations is an important leadership characteristic. However it is very common for individuals heading up research laboratories or scientific collaborations to struggle with, or not identify the advantages of, explicitly communicating what they expect of the people working in their lab or participating on their team, not to mention what the participants can expect in return. Here we describe a 'Welcome Letter' as a tool that can be used in the scientific setting to effectively create a framework for working relationships and serve as a scaffold for building trust. The 'Welcome Letter' enables the lab leader to articulate expectations prior to incorporating new members into the group. Scientific teams can use the letter in much the same way, crafting it together to develop a shared vision for the functioning of the collaboration and once crafted, sharing it with new team members.

Collaboration and team science: from theory to practice.

Interdisciplinary efforts are becoming more critical for scientific discovery and translational research efforts. Highly integrated and interactive research teams share a number of features that contribute to their success in developing and sustaining their efforts over time. Through analysis of in-depth interviews with members of highly successful research teams and others who did not meet their goals or ended because of conflicts, we identified key elements that are critical for team success and effectiveness. There is no debate that the scientific goal sits at the center of the collaborative effort. However, supporting features need to be in place to avoid the derailment of the team. Among the most important of these is trust: without trust, the team dynamic runs the risk of deteriorating over time. Other critical factors of which both leaders and participants need to be aware include developing a shared vision, strategically identifying team members and purposefully building the team, promoting disagreement while containing conflict, and setting clear expectations for sharing credit and authorship. Self-awareness and strong communication skills contribute greatly to effective leadership and management strategies of scientific teams. While all successful teams share the characteristic of effectively carrying out these activities, there is no single formula for execution with every leader exemplifying different strengths and weaknesses. Successful scientific collaborations have strong leaders who are self-aware and are mindful of the many elements critical for supporting the science at the center of the effort.

Herbal tonic does not inhibit estrogen receptor negative mammary tumor development in a transgenic mouse model.

Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. In this study four experimental groups of female MMTV-Neu mice were left untreated or treated with 3% Flor-Essence® in utero, from birth until 5 weeks of age, or throughout their lifetime. Palpable mammary tumor incidence and body weight was determined weekly for each group. The mice were sacrificed at 28 weeks of age and mammary tumors were enumerated to determine average tumor incidence and multiplicity for each group. Female mice exposed to Flor-Essence® herbal tonic in utero weighed significantly more than the control group (p < 0.001). The average tumor incidence and tumor multiplicity in the experimental mice treated with Flor-Essence® herbal tonic did not differ from the control animals. Flor-Essence® does not inhibit mammary tumor incidence or mammary tumor multiplicity in MMTV-Neu transgenic mice. Flor-Essence® exposure in utero causes increased body weight in experimental animals. This conclusion challenges widely available anecdotal information as well as the hopes of the consumer that this product will inhibit or suppress tumor development.

Cigarette smoking during pregnancy: chromosome translocations and phenotypic susceptibility in mothers and newborns.

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9+/-5.8 (mean+/-S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65+/-5.75 and 1.37+/-3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37+/-0.27 and 0.15+/-0.14 breaks per cell, respectively, a difference that was highly significant (p<0.0001). In newborns there was a positive association between bleomycin sensitivity and the frequencies of aberrations as measured by chromosome painting: p

Distinct effects of calorie restriction and exercise on mammary gland gene expression in C57BL/6 mice.

Energy balance, including diet, weight, adiposity, and physical activity, is associated with carcinogenesis. Epidemiologic studies indicate that obesity and sedentary and/or active behavior are risk factors for breast cancer in postmenopausal women and survival in both premenopausal and postmenopausal breast cancer patients. Thus, understanding the influence of energy balance modulation on changes in gene expression patterns in the normal mammary gland is important for understanding mechanisms linking energy balance and breast cancer. In a 6-week-long study, female C57BL/6 mice (9-week-old) were randomized into four groups: (a) food consumed ad libitum (AL), (b) AL with access to running wheels (AL+EX), (c) 30% calorie restricted (CR), and (d) 30% CR with access to running wheels (CR+EX). CR mice received 70% of calories but 100% of all other nutrients compared with AL mice. Diet and exercise treatments, individually and combined, had significant effects on body composition and physical activity. Affymetrix oligomicroarrays were used to explore changes in gene expression patterns in total RNA samples from excised whole mammary glands. Contrasting AL versus CR resulted in 425 statistically significant expression changes, whereas AL versus AL+EX resulted in 45 changes, with only 3 changes included among the same genes, indicating that CR and EX differentially influence expression patterns in noncancerous mammary tissue. Differential expression was observed in genes related to breast cancer stem cells, the epithelial-mesenchymal transition, and the growth and survival of breast cancer cells. Thus, CR and EX seem to exert their effects on mammary carcinogenesis through distinct pathways.

International study of factors affecting human chromosome translocations.

Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from 16 laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages versus a linear relationship (p<0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR)=1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes.

Spontaneous and irradiation-induced tumor susceptibility in BRCA2 germline mutant mice and cooperative effects with a p53 germline mutation.

Mutations in both p53 and BRCA2 are commonly seen together in human tumors suggesting that the loss of both genes enhances tumor development. To elucidate this interaction in an animal model, mice lacking the carboxy terminal domain of Brca2 were crossed with p53 heterozygous mice. Females from this intercross were then irradiated with an acute dose of 5 Gy ionizing radiation at 5 weeks of age and compared to nonirradiated controls. We found decreased survival and timing of tumor onsets, and significantly higher overall tumor incidences and prevalence of particular tumors, including stomach tumors and squamous cell carcinomas, associated with the homozygous loss of Brca2, independent of p53 status. The addition of a p53 mutation had a further impact on overall survival, incidence of osteosarcomas and stomach tumors, and tumor latency. The spectrum of tumors observed for this Brca2 germline mouse model suggest that it faithfully recapitulates some human disease phenotypes associated with BRCA2 loss. In addition, these findings include extensive in vivo data demonstrating that germline Brca2 and p53 mutations cooperatively affect animal survivals, tumor susceptibilities, and tumor onsets.

Essiac and Flor-Essence herbal tonics stimulate the in vitro growth of human breast cancer cells.

BACKGROUND: People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence and Essiac Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence and Essiac for their effects on the growth of human tumor cells in culture. METHODS: The effect of Flor-Essence and Essiac((R)) herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. RESULTS: Flor-Essence and Essiac herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls in both estrogen receptor positive (MCF-7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-436) cell lines. Exposure to the tonics also produced a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells. A 10(-7) M concentration of ICI 182,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence and Essiac, but did not affect cell proliferation. CONCLUSION: Flor-Essence and Essiac Herbal Tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action.

PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor.

Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

Flor-Essence herbal tonic does not inhibit mammary tumor development in Sprague Dawley rats.

BACKGROUND: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. METHODS: Female Sprague-Dawley rats were given water or exposed to 3 or 6% Flor-Essence beginning at 1 day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethyl-benz[a]anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. RESULTS: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0 and 59.4% for the 3 and 6% Flor-Essence groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0 and 97.3% for rats consuming 3 and 6% Flor-Essence, respectively. Mean mammary tumor multiplicity (+/-SES) for the controls was 2.8 (+/-0.5) and statistically different from the 3 or 6% Flor-Essence groups with 5.2 (+/-0.7), and 4.8 (+/-0.6), respectively (p < or = 0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. CONCLUSIONS: Flor-Essence can promote mammary tumor development in the Sprague-Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

A potent modifier of liver cancer risk on distal mouse chromosome 1: linkage analysis and characterization of congenic lines.

The C3H/HeJ (C3H) and CBA/J (CBA) mouse strains are classical mouse models of cancer susceptibility, exhibiting high risks for both spontaneous and chemically induced liver cancer. By analysis of backcrosses and intercrosses between C3H or CBA and resistant B6 mice, we have mapped a potent modifier of hepatocellular carcinoma development to distal chromosome 1, linked to the marker D1Mit33 with combined LOD(W) scores of approximately 5.9 (C3H) and 6.5 (CBA). We previously identified this region as one of two that modify susceptibility in the more distantly related C57BR/cdJ (BR) strain. Congenic B6.C3H(D1Mit5-D1Mit17) and B6.BR(D1Mit5-D1Mit17) mice developed significantly more liver tumors than B6 mice did (6- to 13-fold, P < 10(-11), in males; 3- to 4-fold, P < 10(-3), in females). Thus, distal chromosome 1 carries one or more genes that are sufficient to confer susceptibility to liver cancer.

Impact of environmental exposures on the mutagenicity/carcinogenicity of heterocyclic amines.

Carcinogenic heterocyclic amines are produced from overcooked foods and are highly mutagenic in most short-term test systems. One of the most abundant of these amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces breast, colon and prostate tumors in rats. Human dietary epidemiology studies suggest a strong correlation between either meat consumption or well-done muscle meat consumption and cancers of the colon, breast, stomach, lung and esophagus. For over 20 years our laboratory has helped define the human exposure to these dietary carcinogens. In this report we describe how various environmental exposures may modulate the risk from exposure to heterocyclic amines, especially PhIP. To assess the impact of foods on PhIP metabolism in humans, we developed an LC/MS/MS method to analyze the four major PhIP urinary metabolites following the consumption of a single portion of grilled chicken. Adding broccoli to the volunteers' diet altered the kinetics of PhIP metabolism. At the cellular level we have found that PhIP itself stimulates a significant estrogenic response in MCF-7 cells, but even more interestingly, co-incubation of the cells with herbal teas appear to enhance the response. Numerous environmental chemicals found in food or the atmosphere can impact the exposure, metabolism, and cell proliferation response of heterocyclic amines.

Linking laboratory and clinical research: the development of molecularly targeted therapeutics inside the national cancer institute center for cancer research.

Understanding the molecular basis of the pathways regulating the cancer cell promises to revolutionize clinical practice. The results of genomic- an proteomic-based studies at the National Cancer Center Institute Center for Cancer Research (NCI CCR) include the indentation of a molecular biomarker for ovarian cancer based on serum proteomic patterns that permits early detection and a new method for the diagnostic and prognostic assessment of subclasses of diffuse large B-cell lymphoma based on molecular criteria. The biological informativeness of molecularly based diagnostic categories confers the additional clinical advantage of identifying molecular pathways that can be selectively targeted for treatment. Molecular profiling of clear cell renal carcinoma, eg, has revealed that it responds to antiangiogenic agents. Moreover, targeted immunomodulatory interventions are proving effective against many cancers. The discovery and development of molecularly based means for detecting, diagnosis, and treating cancer are central priorities of the NCI CCR, which provides an interactive environment encouraging multidisciplinary collaborations, especially among basic and clinical investigators. Its infrastructure supports the iterative flow of information from the bench to the bedside and from the bedside to the bench, expediting the delivery of molecularly based therapeutics to cancer patients.