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1.  Fluid mechanical consequences of pendular activity, segmentation and pyloric outflow in the proximal duodenum of the rat and the guinea pig 
We conducted numerical experiments to study the influence of non-propagating longitudinal and circular contractions, i.e. pendular activity and segmentation, respectively, on flow and mixing in the proximal duodenum. A lattice-Boltzmann numerical method was developed to simulate the fluid mechanical consequences for each of 22 randomly selected sequences of high-definition video of real longitudinal and radial contractile activity in the isolated proximal duodenum of the rat and guinea pig. During pendular activity in the rat duodenum, the flow was characterized by regions of high shear rate. Mixing was so governed by shearing deformation of the fluid that increased the interface between adjacent domains and accelerated their inter-diffusion (for diffusion coefficients approx. less than 10−8 m² s−1). When pendular activity was associated with a slow gastric outflow characteristic of post-prandial period, the dispersion was also improved, especially near the walls. Mixing was not promoted by isolated segmentative contractions in the guinea pig duodenum and not notably influenced by pylorus outflow. We concluded that pendular activity generates mixing of viscous fluids ‘in situ’ and accelerates the diffusive mass transfer, whereas segmentation may be more important in mixing particulate suspensions with high solid volume ratios.
doi:10.1098/rsif.2013.0027
PMCID: PMC3645412  PMID: 23536539
small intestine; mixing; viscosity; gastrointestinal flow; lattice Boltzmann; diffusion
2.  Characterisation of Mixing in the Proximal Duodenum of the Rat during Longitudinal Contractions and Comparison with a Fluid Mechanical Model Based on Spatiotemporal Motility Data 
PLoS ONE  2014;9(4):e95000.
The understanding of mixing and mass transfers of nutrients and drugs in the small intestine is of prime importance in creating formulations that manipulate absorption and digestibility. We characterised mixing using a dye tracer methodology during spontaneous longitudinal contractions, i.e. pendular activity, in 10 cm segments of living proximal duodenum of the rat maintained ex-vivo. The residence time distribution (RTD) of the tracer was equivalent to that generated by a small number (8) of continuous stirred tank reactors in series. Fluid mechanical modelling, that was based on real sequences of longitudinal contractions, predicted that dispersion should occur mainly in the periphery of the lumen. Comparison with the experimental RTD showed that centriluminal dispersion was accurately simulated whilst peripheral dispersion was underestimated. The results therefore highlighted the potential importance of micro-phenomena such as microfolding of the intestinal mucosa in peripheral mixing. We conclude that macro-scale modeling of intestinal flow is useful in simulating centriluminal mixing, whereas multi-scales strategies must be developed to accurately model mixing and mass transfers at the periphery of the lumen.
doi:10.1371/journal.pone.0095000
PMCID: PMC3991651  PMID: 24747714
3.  The International Cancer Expert Corps: A Unique Approach for Sustainable Cancer Care in Low and Lower-Middle Income Countries 
Frontiers in Oncology  2014;4:333.
The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship–partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally.
doi:10.3389/fonc.2014.00333
PMCID: PMC4237042  PMID: 25478326
health disparities; cancer; global health; underserved; non-communicable diseases
5.  CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer 
SpringerPlus  2013;2:52.
Background
While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results.
Findings
In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case–control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease.
We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control.
Conclusions
This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.
doi:10.1186/2193-1801-2-52
PMCID: PMC3584248  PMID: 23476897
6.  Cytoplasmic Estrogen Receptor in breast cancer 
Clinical Cancer Research  2011;18(1):118-126.
Purpose
In addition to genomic signaling, it is accepted that ERα has non-nuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of non-nuclear ER in clinical specimens.
Experimental Design
A panel of ERα-specific antibodies (SP1, MC20, F10, 60c, 1D5) were validated by western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world.
Results
Four of the antibodies specifically recognized ER by western and QIF, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with pearson’s correlations (r2 values)ranging from 0.87-0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other 4 antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%.
Conclusions
Our data shows ERα present in the cytoplasm in a number of cases using multiple antibodies, while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value.
doi:10.1158/1078-0432.CCR-11-1236
PMCID: PMC3263348  PMID: 21980134
non-nuclear; Estrogen Receptor; cytoplasmic; breast cancer
7.  Breast cancer: a neglected disease for the majority of affected women worldwide 
The breast journal  2011;17(3):289-295.
Recent progress with declines in mortality in some high income countries has obscured the fact that for the majority of women worldwide who are newly diagnosed, breast cancer is a neglected disease in the context of other numerically more frequent health problems. For this growing majority, it is also an orphan disease, in that detailed knowledge about tumor characteristics and relevant host biology necessary to provide even basic care are absent. With the possible exception of nutritional recommendations, current international cancer policy and planning initiatives are irrelevant to breast cancer. The progress that has occurred in high income countries has come at extraordinary fiscal expense and patient toxicity, which of themselves suggest non-relevance to women and health care practitioners in middle and low income countries. The implications of these circumstances seem clear: if the promise of the now 60 year-old Declaration of Human Rights, that the fruits of medical science accrue to all mankind, is to be realized with respect to breast cancer, a basic and translational global research initiative should be launched.
doi:10.1111/j.1524-4741.2011.01067.x
PMCID: PMC3089688  PMID: 21410589
8.  American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer 
Journal of Clinical Oncology  2010;28(16):2784-2795.
Purpose
To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers.
Methods
The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.
Results
Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria.
Recommendations
The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
doi:10.1200/JCO.2009.25.6529
PMCID: PMC2881855  PMID: 20404251
9.  American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer 
Purpose
To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers.
Methods
The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.
Results
Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria.
Recommendations
The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
PMCID: PMC3073033  PMID: 20524868
10.  Adjuvant hormonal therapy in pre-menopausal women with operable breast cancer: not-so peripheral perspectives 
Oncology (Williston Park, N.Y.)  2010;24(4):322-327.
Reviews of issues around adjuvant hormonal therapies for breast cancer in pre-menopausal women often focus on recent and current large clinical trials, and fail to address other subjects that are very germane to evidence-based and investigatory clinical practice. Discussed here, these include: 1.The descriptive epidemiology of breast cancer globally, 2. Critical issues in tumor hormonal receptor testing; 3. Compelling data which demonstrate hormonal receptor positive breast cancer is a chronic disease; 4. Data supportive of combined hormonal therapy with tamoxifen as the standard of care, and the limited justifications for awaiting the SOFT and TEXT trial results; 5. Pharmacogenetic hypotheses with tamoxifen; 6. The ethical issues in ovarian suppression versus ablative treatment; and 7. Emerging data about the importance of primary tumor removal surgery itself and “surgical stress” in solid tumor management.
PMCID: PMC3073037  PMID: 20464842
11.  Breast cancer hormone receptor assay results of core needle biopsy and modified radical mastectomy specimens from the same patients 
Clinical breast cancer  2010;10(2):154-159.
Background
Hormone receptor expression is the most important biomarker and is the cornerstone in the management of breast cancer, hence, the accuracy of its testing is critical in treatment decisions.
Patients and Methods
One hundred sixty consecutive patients accrued to an adjuvant hormonal therapy clinical trial between March 2003 and May 2008 were studied. Estrogen receptor (ER) and progesterone receptor (PR) protein assays of tissues from MRM specimens were compared to their prior CNB ER and PR immunohistochemical assay results.
Results
The tumors of 146 (91.2%) out of the 160 CNB HR positive patients remained HR positive in MRM specimen assays. Estrogen receptor positivity decreased from 95% in the CNB to 81.9% in MRM specimens and PR positivity from 93.8% to 86.9%. The overall agreement between CNB and MRM specimens was 81.9% for ER and 85.6% for PR. The mean Allred scores were significantly higher in CNB than in MRM specimens – ER: 6.6 (SD 2.02) vs 4.71(SD 2.62); PR: 6.68 (SD 2.16) vs 5.99 (SD 2.68); p<0.001 and p=0.001 respectively.
Conclusion
Core needle biopsy specimens are associated with identification of more frequent and higher levels of tumoral hormonal receptor proteins than MRM specimens. Delayed fixation of MRM tissues likely accounted for this finding. Optimal selection of patients for hormonal therapies is dependent on tissue management strategies prior to formal hormonal receptor protein testing procedures.
doi:10.3816/CBC.2010.n.021
PMCID: PMC3052378  PMID: 20299318
breast cancer; hormone receptor assay; core needle biopsy; modified radical mastectomy
12.  Global cancer research initiative 
Cancer is an increasing problem for low- and middle-income countries undergoing an epidemiologic transition from dominantly acute communicable disease to more frequent chronic disease with increased public health successes in the former domain. Progress against cancer in high-income countries has been modest and has come at enormous expense. There are several well-conceived global policy and planning initiatives which, with adequate political will, can favorably impact the growing global cancer challenges. Most financial resources for cancer, however, are spent on diagnosis and management of patients with disease in circumstances where specific knowledge about effective approaches is significantly limited, and the majority of interventions, other than surgery, are not cost-effective in resource-limited countries by global standards. In summary, how to intervene effectively on a global scale for the majority of citizens who develop cancer is poorly defined. In contrast to technology-transfer approaches, markedly increased clinical research activities are more likely to benefit cancer sufferers. In these contexts, a global cancer research initiative is proposed, and mechanisms for realizing such an effort are suggested.
PMCID: PMC3004570  PMID: 21188101
breast cancer; research; global; international; low-income; middle-income
13.  Defining a global research agenda for breast cancer 
Cancer  2008;113(8 Suppl):2366-2371.
In contrast to western high income nations, the incidence and mortality from breast cancer are increasing in most low and middle income countries worldwide. Current approaches to breast cancer control developed for populations of high income societies should not be directly transferred without evaluation. A relevant research agenda includes population differences in tumor biology and metabolization of systemic therapies; cultural and psychosocial issues; and operations in health care systems. Highest priority should be given to assessments of clinical downstaging and basic systemic treatment effectiveness in low and middle income populations. Partnerships of existing organizations in high income nations with those in low and middle income countries are currently the most feasible sources of research support.
doi:10.1002/cncr.23831
PMCID: PMC2603276  PMID: 18837032
breast cancer; research; global; international; developing countries; low and middle income countries, LMC; cost efficacy, technology transfer
14.  FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene 
Cell  2007;129(7):1275-1286.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion, functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression, regardless of the status of HER-2 amplification. In toto, the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
doi:10.1016/j.cell.2007.04.034
PMCID: PMC1974845  PMID: 17570480

Results 1-14 (14)