Proposing the Community Triad Model to action social accountability in medical schools.

This article is the third in a series exploring drivers of social accountability (SA) in medical schools across Canada. Findings from the two previous articles have highlighted a central relationship between community, students, and faculty at medical schools, and led to the emergence of a new social accountability model- the Community Triad Model (CTM). The CTM proposes an interconnectedness between community, students, faculty, and the broader institution, and the pathways through which community-based learning directly and indirectly influences decision-making in medical institutions. This article explores the relationships between the three arms of the CTM by examining the literature on community engagement and SA, as well as by revisiting popular models and foundational SA reports to garner insights into authentic community engagement in health professions education. While there is an abundance of literature demonstrating the impact of community placements on students, there are limited studies describing the influence of communities on faculty and the broader institution either directly, or indirectly via students. The authors recommend that institutions be more intentional in engaging students and faculty, and learn from their experiences with community to shape curriculum, practices, policies, and culture of the broader institution. This study offers an operational model of SA that is easy to adopt and implement. It intends to demonstrate how the components of the triad (students, faculty/leadership, community) function together in the community engagement and social accountability of medical schools.

Little Doctors: Agents of change in Indian rural communities.

The child-to-child approach to health advocacy is one that draws on the strengths and agency of children to make a positive impact within their communities. The approach has been popularly used for health education in low- and middle-income countries. This article describes the 'Little Doctors' program that implemented the child-to-child approach in the towns of KC Patty and Oddanchatram, located in remote hilly regions of Tamil Nadu, India starting in 1986 to train middle- and high school children to respond to diseases prevalent in their communities along with practices for preventative measures. The program involved sessions that used a combination of creative instructional methods to engage students and provided take-home messages for them to act on with their families and community. The program was successful in creating a creative learning environment for children, offering a shift from the traditional methods of classroom instruction. Students who successfully completed the program were awarded certificates as 'Little Doctors' in their communities. Although the program did not conduct formal evaluations of the program effectiveness, students reported successfully recalling complex topics such as early signs of diseases like tuberculosis and leprosy that were prevalent in the community during the time. The program experienced several challenges and had to be discontinued despite its continued benefits to the communities.

Choice of cover crop influences soil fungal and bacterial communities in Prince Edward Island, Canada.

Soil fungal and bacterial communities play various roles in agroecosystems and are significantly influenced by agricultural management practices. Currently, little is known about the effects of selected cover crops on soil fungal and bacterial communities in no-till systems. In this study, eight cover crops, three mixed crops, and an unmanaged fallow control were evaluated over 2 years for their effects on the soil microbiome. Internal transcribed spacer (ITS) and 16S rRNA amplicon sequencing was performed to characterize fungal and bacterial communities in the soil during the cover crop growing season, and in the subsequent year. Fungal and bacterial alpha diversity significantly increased over time and were influenced in the subsequent growing season by choice of cover crops. Some fungal and bacterial trophic and functional groups were also affected by crop choice. Fungal pathotroph abundance was positively associated with oilseed radish, alfalfa, and phacelia, but negatively associated with sorghum-sudangrass. Beneficial symbiotrophic fungi and functional nitrification-related bacterial groups were also associated with sorghum-sudangrass and buckwheat. These findings suggest that choice of cover crops influences the soil microbial community composition and may impact plant health in the subsequent crops.

Twelve tips for using ePosters as an active learning strategy.

ePosters (electronic Posters), a modification of traditional paper-based posters have gained popularity in medical education conferences since 2011. ePoster in educational settings differs from the traditional poster in that it allows the ePoster creator to focus on the learning process rather than reporting scientific outcomes. However, there is limited literature comparing ePosters to traditional paper-based posters and their impact on the student learning experience. ePosters as an assessment tool are well suited for online learning. This article presents twelve tips for using ePosters as an active learning strategy in classrooms and describes how to incorporate ePosters as a formative and summative assessment tool in health professions education, at all levels.

Integrative review of the needs and challenges of indigenous palliative care in rural and remote settings.

AIMS: To appraise and synthesize the empirical literature on the needs and challenges of Indigenous peoples' accessibility to palliative care in rural and remote settings. DESIGN: Whittemore and Knafl's updated approach to integrative reviews, PRISMA guidelines and CASP (2020) checklists for narrative analysis were followed. DATA SOURCES: A systematic search of the published empirical literature from 1 January 2015 to 31 December 2021 was undertaken in five databases. REVIEW METHODS: Twenty-four studies met the research question and the inclusion criteria. RESULTS: Four themes describe the findings: Respect of Indigenous cultural beliefs on death and dying, connection to the land, needs for culturally responsive care and presence of institutional and systemic barriers. These themes indicate a pressing need to increase the accessibility and utilization of palliative care. Most of the studies were qualitative and conducted by teams of Indigenous and non-Indigenous researchers. CONCLUSION: Integrating Indigenous knowledge and providing culturally responsive palliative care are steps towards achieving the decolonization of palliative care and responding to Indigenous people's needs of palliative care services. Institutional and systemic racism affect Indigenous peoples' access and delivery of palliative services in Canada and globally. IMPACT: The review highlights the need for establishing partnerships and building local capacity with Indigenous communities to develop and implement culturally responsive palliative care programmes in remote locations.

Select Cover Crop Residue and Soil Microbiomes Contribute to Suppression of Fusarium Root and Crown Rot in Barley and Soybean.

Fusarium root and crown rot (FRCR) negatively impact several economically important plant species. Cover crops host different soil and residue microbiomes, thereby potentially influencing pathogen load and disease severity. The carryover effect of cover crops on FRCR in barley and soybean was investigated. Field trials were conducted in Prince Edward Island, Canada. Two cover crops from each plant group, including forbs, brassicas, legumes, and grasses, were grown in a randomized complete block design with barley and soybean planted in split plots the following year. Barley and soybean roots were assessed for FRCR through visual disease rating and Fusarium spp. were isolated from diseased tissue. Fungal and bacterial communities in cover crop residues were quantified using amplicon sequencing. The disease-suppressive effects of soil were tested in greenhouse studies. The results indicated that sorghum-sudangrass-associated microbiomes suppress Fusarium spp., leading to reduced FRCR in both barley and soybean. The oilseed radish microbiome had the opposite effect, consequently increasing FRCR incidence in barley and soybean. The results from this study indicate that cover crop residue and the associated soil microbiome influence the incidence and severity of FRCR in subsequent crops. This information can be used to determine cover cropping strategies in barley and soybean production systems.

"Navigating chaos": Urban, Rural, and Remote Patient Experiences in Accessing Healthcare with Indigenous and Non-Indigenous Perspectives of Living with Chronic Low Back Pain.

Background: Healthcare access for chronic low back pain is complex and should consider not only the health system, but patient care seeking experiences as well. People who live in rural and remote communities and/or identify as being Indigenous may often encounter additional barriers to accessing care for chronic low back pain; thus, these contexts must be considered to fully understand barriers and facilitators. Aims: The aim of this study was to understand care-seeking experiences of people living with chronic back pain in Saskatchewan and determine unique experiences facing urban, rural, remote, and/or Indigenous peoples. Methods: Thirty-three participants with chronic low back pain completed a preliminary survey followed by individual semistructured interviews. Participants were categorized as urban, rural, or remote including Indigenous status. A qualitative interpretive research approach with inductive thematic analysis was employed. Results: Three overarching themes were identified with the following subthemes: (1) healthcare access challenges: challenges to accessing care, challenges within the health system, and challenges leading to self-directed management/coping strategies; (2) healthcare access facilitators: funded care, participant education and knowledge, patient-provider communication, and care closer to home; and (3) participant recommendations for improved care provision: coordination of care, integrative and holistic care, and patient-centered care and support. Rural and remote participants highlighted travel as a main barrier. Indigenous participant experiences emphasized communication with healthcare providers and past experiences influencing desire to access care. Conclusion: Participants identified a range of challenges and facilitators as well as recommendations for improving access to care for chronic low back pain, with unique barriers for rural, remote, and Indigenous participants.

Contexte: L'accès aux soins de santé pour la lombalgie chronique est complexe et devrait tenir compte non seulement du système de santé, mais aussi des expériences de recherche de soins des patients. Les personnes vivant dans des communautés rurales et éloignées et/ou qui s'identifient comme autochtones font souvent face à des obstacles supplémentaires pour accéder aux soins pour la lombalgie chronique; il faut donc tenir compte de ces contextes pour bien comprendre les obstacles et les facilitateurs.Objectifs: L'objectif de cette étude était de comprendre les expériences de recherche de soins des personnes vivant avec une lombalgie chronique en Saskatchewan et de déterminer les expériences uniques d'accès aux soins auxquelles sont confrontées les personnes vivant en milieu urbain, rural, éloigné et/ou ayant un statut d'autochtone.Méthodes: Trente-trois participants souffrant de lombalgie chronique ont répondu à un questionnaire préliminaire suivi d'entretiens individuels semi-structurés. Les participants ont été catégorisés comme vivant en milieu urbain, rural, éloigné, incluant ceux ayant un statut d'autochtone. Une approche de recherche qualitative interprétative avec une analyse thématique inductive a été utilisée.Résultats: Trois thèmes principaux ont été répertoriés avec les sous-thèmes suivants : (1) difficultés d'accès aux soins de santé : difficultés pour accéder aux soins, difficultés au sein du système de santé et difficultés conduisant à des stratégies de gestion et d'adaptation autonomes; (2) facilitateurs de l'accès aux soins de santé : financement des soins, éducation et connaissances des participants, communication entre le patient et le prestataire de soins et proximité des soins par rapport au domicile et (3) recommandations des participants pour l'amélioration de la prestation des soins : la coordination des soins, les soins intégrés et holistiques, les soins et le soutien centrés sur le patient. Les participants des régions rurales et éloignées ont souligné que les déplacements constituaient un obstacle majeur. Les expériences des participants autochtones ont mis l'accent sur la communication avec les prestataires de soins de santé et les expériences passées qui influencent le désir d'accéder aux soins.Conclusion: Les participants ont répertorié un ensemble de difficultés, de facilitateurs et de recommandations pour améliorer l'accès aux soins pour les lombalgies chroniques, qui présente des obstacles uniques pour les participants vivant en milieu rural et éloigné et les participants autochtones.

Effect of freeze-dried berries on the development of reflux-induced esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma in humans is increasing more rapidly than any other malignancy in the United States. Animal studies have demonstrated the efficacy of freeze-dried berry supplementation on carcinogen-induced esophageal squamous cell carcinoma in rats; however, no such studies have been done in esophagoduodenal anastomosis (EDA), an animal model for reflux-induced esophageal adenocarcinoma (EAC) development. Eight-week-old male Sprague-Dawley rats were randomized into 3 groups: EDA + control diet (EDA-CD; n = 10); EDA + 2.5% black raspberry diet (EDA-BRB; n = 11) and EDA + 2.5% blueberry diet (EDA-BB; n = 12). After 2 wk of feeding the respective diets, the rats underwent EDA surgery to induce gastroesophageal reflux and then continued the diet. Measurement of feed intake suggested that all EDA-operated animals had lower feed intake starting at 10 wk after surgery and this was significant close to termination at 24 wk. There were no significant differences in either reflux esophagitis (RE), intestinal metaplasia (IM) (70% in CD, 64% in BRB, and 66% in BB; P = 0.1) or EAC incidence (30% for CD, 34% for BRB, and 25% for BB; P = 0.2) with supplementation. Berry diets did not alter COX-2 levels, but BB diet significantly reduced MnSOD levels (1.23 ± 0.2) compared to control diet (2.05 ± 0.14; P < 0.05). We conclude that a dietary supplementation of freeze-dried BRB and BB at 2.5% (w/w) was not effective in the prevention of reflux-induced esophageal adenocarcinoma in this EDA animal model.

Diet composition affects surgery-associated weight loss in rats with a compromised alimentary tract.

BACKGROUND: Esophageal adenocarcinoma (EAC) is the fastest growing cancer in terms of incidence and has a high mortality rate. The animal model to study EAC uses esophagoduodenal anastomosis (EDA) to induce mixed-reflux (bile/acid) causing esophagitis, Barrett's esophagus, and EAC sequence within 6 mo. However, the lack of fully functional stomach in these rats leads to the development of malnutrition. METHODS: We have assessed the ability of a chemically pure, purified ingredient diet (AIN-93M) to reduce surgery-associated malnutrition in rats that have undergone the EDA-surgery. Animals were either sham- (SH) or EDA-operated and fed either a grain-based rodent diet (RD) (SH-RD, n=3; EDA-RD, n=10) or a purified diet (PD) (SH-PD, n=4; EDA-PD, n=11). The animals were weighed periodically for assessment of weight gain and euthanized at the end of 24 wk to measure esophageal tumor incidence. RESULTS: Animals that underwent sham surgery continued to gain weight throughout the study period and no tumors were detected. The EDA-operated animals had significantly lower weight gain compared with sham animals. There was no significant difference in weight gain among EDA animals fed two different types of diets until 9 wk after the surgery. After 9 wk, EDA-RD continued to lose weight significantly, whereas the weight loss leveled in EDA-PD (P<0.001). At termination, neither tissue histopathology nor tumor incidence was significantly different between the groups. CONCLUSION: These results show that compared with a natural ingredient diet, a purified ingredient diet can reduce surgery-associated weight loss in rats with a compromised alimentary tract. This reduction in malnutrition has the potential to reduce the confounding effects of weight loss on future animal studies reported.

The resistance of esophageal adenocarcinoma to bile salt insult is associated with manganese superoxide dismutase expression.

BACKGROUND: Bile acids are implicated as etiologic agents in esophageal cancer. We sought to analyze the impact of bile acid exposure on esophageal epithelial cells, Barrett's metaplastic cells (BE), esophageal adenocarcinoma cells (EAC), and esophageal squamous carcinoma cell (ESC). We sought to determine if cellular resistance is related to manganese superoxide dismutase expression. METHODS: Cells were exposed to sodium choleate (CA), sodium deoxycholate (DCA), sodium glycocholate (GCA), sodium taurocholate (TCA), or a 1:1 mixture (MIX) of reagents at concentrations in the range 0.2-0.8 mM. Cell viability was evaluated by MTT assay. Manganese superoxide dismutase (MnSOD) expression was analyzed by Western blot. Statistical analysis was performed using SPSS ver. 17.0, SPSS Inc., Chicago, IL. RESULTS: Bile salt exposure inhibited cell viability in esophageal squamous cells in time- and growth-dependent manner. There was a 50% decrease in cell viability from 4 to 24 h. BE, EAC, and ESC cell lines were more resistant to bile insult. In untreated cell lines, MnSOD expression was significantly decreased in EAC and ESC cell lines compared with esophageal squamous epithelial cells and BE cells (P=0.002). Exposure of ESC cells to bile salt increased MnSOD expression. CONCLUSION: The confirmation of the role of reactive oxygen species (ROS) and bile acids in esophageal carcinogenesis has interesting implications for chemoprevention in patients with reflux esophagitis and Barrett's esophagus. Further studies are necessary to assess the preventative role of antioxidant supplementation.

Molecular changes in the esophageal epithelium after a subchronic exposure to cigarette smoke in the presence of bile-acid reflux.

BACKGROUND: Gastroesophageal reflux of bile acids plays an important role in the development of Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC). Cigarette smoke has been demonstrated to exacerbate the effects of reflux and thus the initial stages of EAC carcinogenesis. To date, no in vivo studies have been conducted to look at the concomitant effects of cigarette smoke and bile acids on EAC incidence. METHODS: In this pilot study, rats that underwent esophagoduodenal anastomosis (EDA) surgery to induce reflux were exposed to whole-body cigarette smoke 3 weeks after surgery. Smoke exposure (135 mg/m³/day) was done for 4 h/day for 5 consecutive days and animals were euthanized after a 48-h recovery period. RESULTS: Exposure to EDA-smoke accelerated the development of BE when compared to EDA-air. The presence of reflux caused a significant 3.5-fold increase in nuclear factor-κB-inducing kinase (NIK) staining (1.47 ± 0.6; p = 0.01). Animals with both reflux and smoking had the highest (10-fold; 4 ± 0.9) induction of cyclooxygenase-2 (COX-2) expression (p < 0.05). Similarly, there was a 10-fold increase in 4-aminobiphenyl (4-ABP) protein adducts identified in all smoke-exposed animals (p < 0.01). CONCLUSION: Cigarette smoke aggravates reflux-induced BE and potentially accelerates the progression of BE to EAC through the loss of manganese superoxide dismutase (MnSOD), and overexpression of NF-κB- and COX-2-mediated factors.

Prevention of oxidative DNA damage by bioactive berry components.

The hormone 17ss-estradiol (E(2)) causes oxidative DNA damage via redox cycling of its metabolites such as 4-hydroxy estradiol (4E(2)). In this study, ACI rats (8 wk old) were fed either AIN-93M diet or diets supplemented with 0.5% each of mixed berries (strawberry, blueberry, blackberry, and red and black raspberry), blueberry alone (BB; 2.5%), or ellagic acid (EA; 400 ppm) from 2 wk prior to and up to 12 wk of E(2) treatment. The liver DNA was analyzed for the presence of 8-oxo-7,8-dihydroguanine (8-oxodG) and other polar adducts by 32P-postlabeling. Compared to sham treatment, E(2) significantly increased the levels of both 8-oxodG and P-1 subgroup (259% and 214%, respectively; P< 0.05). EA diet significantly reduced E(2)-induced levels of 8-oxodG, P-1, P-2, and PL-1 by 79, 63, 44, and 67%, respectively (P< 0.001). BB diet also significantly reduced the levels of P-1, P-2, and PL-1 subgroups by 77, 43, and 68%, respectively (P< 0.001). Mixed berries were, however, ineffective. In addition, aqueous extracts of berries (2%) and EA (100 microM) were tested for their efficacy in diminishing oxidative DNA adducts induced by redox cycling of 4E(2) catalyzed by copper chloride in vitro. EA was the most efficacious (90%), followed by extracts of red raspberry (70%), blueberry, and strawberry (50% each; P< 0.001).

Dietary berries and ellagic acid prevent oxidative DNA damage and modulate expression of DNA repair genes.

DNA damage is a pre-requisite for the initiation of cancer and agents that reduce this damage are useful in cancer prevention. In this study, we evaluated the ability of whole berries and berry phytochemical, ellagic acid to reduce endogenous oxidative DNA damage. Ellagic acid was selected based on >95% inhibition of 8-oxodeoxyguosine (8-oxodG) and other unidentified oxidative DNA adducts induced by 4-hydroxy-17ss-estradiol and CuCl(2) in vitro. Inhibition of the latter occurred at lower concentrations (10 microM) than that for 8-oxodG (100 microM). In the in vivo study, female CD-1 mice (n=6) were fed either a control diet or diet supplemented with ellagic acid (400 ppm) and dehydrated berries (5% w/w) with varying ellagic acid contents - blueberry (low), strawberry (medium) and red raspberry (high), for 3 weeks. Blueberry and strawberry diets showed moderate reductions in endogenous DNA adducts (25%). However, both red raspberry and ellagic acid diets showed a significant reduction of 59% (p < 0.001) and 48% (p < 0.01), respectively. Both diets also resulted in a 3-8 fold over-expression of genes involved in DNA repair such as xeroderma pigmentosum group A complementing protein (XPA), DNA excision repair protein (ERCC5) and DNA ligase III (DNL3). These results suggest that red raspberry and ellagic acid reduce endogenous oxidative DNA damage by mechanisms which may involve increase in DNA repair.

Cranberry proanthocyanidins modulate reactive oxygen species in Barrett's and esophageal adenocarcinoma cell lines.

BACKGROUND: We recently reported that a cranberry proanthocyanidin rich extract (C-PAC) induces autophagic cell death in apoptotic resistant esophageal adenocarcinoma (EAC) cells and necrosis in autophagy resistant cells. EAC is characterized by high morbidity and mortality rates supporting development of improved preventive interventions. OBJECTIVE: The current investigation sought to investigate the role of reactive oxygen species (ROS) in the context of C-PAC induced cell death. METHODS: A panel of human esophageal cell lines of EAC or BE (Barrett's esophagus) origin were treated with C-PAC and assessed for ROS modulation using CellROX® Green reagent and the Amplex Red assay to specifically measure hydrogen peroxide levels. RESULTS: C-PAC significantly increased ROS levels in EAC cells, but significantly reduced ROS levels in CP-C BE cells. Increased hydrogen peroxide levels were also detected in C-PAC treated EAC cells and supernatant; however, hydrogen peroxide levels were significantly increased in medium alone, without cells, suggesting that C-PAC interferes or directly acts on the substrate. Hydrogen peroxide levels did not change in C-PAC treated CP-C BE cells. CONCLUSION: These experiments provide additional mechanistic insight regarding C-PAC induced cancer cell death through modulation of ROS. Additional research is warranted to identify specific ROS species associated with C-PAC exposure.

Influence of berry polyphenols on receptor signaling and cell-death pathways: implications for breast cancer prevention.

Breast cancer is the most commonly diagnosed cancer among women worldwide. Many women have become more aware of the benefits of increasing fruit consumption, as part of a healthy lifestyle, for the prevention of cancer. The mechanisms by which fruits, including berries, prevent breast cancer can be partially explained by exploring their interactions with pathways known to influence cell proliferation and evasion of cell-death. Two receptor pathways, estrogen receptor (ER) and tyrosine kinase receptors, especially the epidermal growth factor receptor (EGFR) family, are drivers of cell proliferation and play a significant role in the development of both primary and recurrent breast cancer. There is strong evidence to show that several phytochemicals present in berries such as cyanidin, delphinidin, quercetin, kaempferol, ellagic acid, resveratrol, and pterostilbene interact with and alter the effects of these pathways. Furthermore, they also induce cell death (apoptosis and autophagy) via their influence on kinase signaling. This review summarizes in vitro data regarding the interaction of berry polyphenols with the specific receptors and the mechanisms by which they induce cell death. This paper also presents in vivo data of primary breast cancer prevention by individual compounds and whole berries. Finally, a possible role for berries and berry compounds in the prevention of breast cancer and a perspective on the areas that require further research are presented.

Effect on pro-inflammatory and antioxidant genes and bioavailable distribution of whole turmeric vs curcumin: Similar root but different effects.

Curcuma longa is a perennial member of the Zingiberaceae family, and cultivated mainly in India, and Southeast Asia. The hypothesis for this study is that turmeric will have distinctive effects from curcumin due to the presence of other bioactive compounds. Thirty Eight-week old Sprague-Dawley rats were separated into three oral feeding groups. Group 1, standard rat chow, Control diet - AIN 93M, group 2 - Curcumin - 700ppm or 0.7g/kg diet, and group 3 - Turmeric - 14,000ppm or 14g/kg diet for a total of 3weeks. One group of rats were feed all three diets only and another group underwent esophagoduodenal anastomosis to evaluate the effects of bioavailability. Curcumin diet did not increase the transcription of mRNA of TNF-alpha, IL-6, iNOS, and COX-2. The average fold change in the mRNAs level was not significant. Whereas turmeric diet increases the levels of IL-6 (1.9-fold, p=0.05), iNOS (4.39-fold, p=0.02), IL-8 (3.11-fold, p=0.04), and COX-2 (2.02-fold, p=0.05), suggesting that turmeric either was more bioavailable or had more affect on pro-inflammatory genes compare to curcumin diet. We have demonstrated the molecular effects of curcumin and turmeric in the role as an anti-inflammatory therapy. However, significant bioavailable differences do occur and must be considered in further chemopreventative investigative trials the setting of reflux esophagitis, Barrett's esophagus, and other upper gastrointestinal cancers.

Effect of Berry Extracts and Bioactive Compounds on Fulvestrant (ICI 182,780) Sensitive and Resistant Cell Lines.

Fulvestrant (ICI 182,780; ICI) is approved for the treatment of advanced metastatic breast cancer that is unresponsive to other endocrine therapies. Berries are frequently consumed for their antioxidant, anti-inflammatory, and anticancer potential. In this study, we tested the efficacy of two berry extracts (Jamun-EJAE and red raspberry-RRE) and their bioactive compounds (Delphinidin-Del and Ellagic acid-EA) to inhibit cell proliferation with or without a sublethal dose of ICI in various breast cancer cell lines. ICI-sensitive (LCC1, ZR75-1, and BT474) and -resistant (LCC9, ZR75-1R) cells were subjected to treatment with berry extracts alone (0.1-100 µg/mL) or with a sub-lethal dose of ICI ( 1). EA, in doses tested, did not have any significant effects on any of the cell lines. Finally, we found that the extracts were more effective at lower, physiologically relevant concentrations than at higher experimental doses.

Interaction of dietary polyphenols with molecular signaling pathways of antiestrogen resistance: possible role in breast cancer recurrence.

Abstract Breast cancer is the most common cancer diagnosed in women and its global incidence is rising rapidly. Adjuvant hormonal therapy, with antiestrogens (AE) such as tamoxifen and fulvestrant, is highly effective in the treatment of estrogen receptor-positive (ER+) breast cancers and is largely responsible for the increase in survival rates seen in the past four decades. However, nearly 50% of women with ER+ cancer display de novo or acquired resistance to AE therapies. Potential molecular mechanisms driving the resistance phenotype are beginning to be elucidated, allowing further development of more effective therapeutic and preventive strategies to reduce the overall mortality due to breast cancer. Over 70% of breast cancer survivors surveyed report increasing their comsumption of fruits, vegetables, and natural product supplements upon diagnosis. These are rich sources of dietary polyphenols (PPs) that can interact with cell-signaling pathways involved in the development of AE resistance. However, research on mechanisms by which these agents may affect AE resistance and whether PP intake can significantly change breast cancer recurrence is limited. We summarize the available data on the effects of PPs on breast cancer recurrence and the interactions of these compounds with some of the signaling pathways hypothesized to drive cell death and survival involved in the development of AE resistance in breast cancer.

Dietary freeze-dried black raspberry's effect on cellular antioxidant status during reflux-induced esophagitis in rats.

INTRODUCTION: Esophageal cancer consists of two distinct types, esophageal adenocarcinoma (EAC) and squamous cell carcinoma, both of which differ significantly in their etiology. Freeze-dried black raspberry (BRB) has been consistent in its ability to modulate the biomarkers and reduce the incidence of carcinogen-induced squamous cell carcinoma in rats. In our previous studies in the esophagoduodenal anastomosis (EDA) model, we have shown that the early modulation of manganese superoxide dismutase (MnSOD) significantly correlates with the development of reflux-induced EAC in rats. In this study we looked at the short-term effects of a BRB-supplemented diet on the modulation of antioxidant enzymes in reflux-induced esophagitis. METHODS: Male SD rats (8 wk old; n = 3-5) were randomized into three groups--sham-operated, fed control AIN-93M diet (SH-CD), EDA operated and fed either control diet (EDA-CD) or 2.5% (w/w) BRB diet (EDA-BRB). The effect of both reflux and dietary supplementation was analyzed 2 and 4 wk after EDA surgery. RESULTS: Animals in the EDA groups had significantly lower weight gain and diet intake compared to SH-CD (P < 0.05). The sham-operated animals received an average esophagitis score of 0.1 ± 0.1; this increased significantly in EDA-CD animals to 1.8 ± 0.14 (P < 0.001 versus SH-CD) and in EDA-BRB group to 1.7 ± 0.06 (P < 0.001 versus SH-CD), with BE changes also present. However, dietary supplementation of BRB did not alter or ameliorate the grade of esophagitis or the induction of BE. BRB diet caused a 43% increase in MnSOD levels compared to EDA-CD (0.73 ± 0.16; P = 0.09); however, this effect was not statistically significant and at 4 wk, EDA-CD (0.58 ± 0.12) showed an increase in MnSOD expression compared to SH-CD (0.34 ± 0.01). CONCLUSIONS: In conclusion, our data suggest that dietary BRB does not increase the levels of cellular antioxidant enzymes or reduce the levels of lipid peroxidation compared to a control diet, in a short-term study of gastroesophageal reflux induction in the EDA animal model. However, it remains to be tested whether this is indicative of its ineffectiveness to inhibit reflux-induced EAC incidence over the long term.

Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer.

Lack of understanding of endocrine resistance remains one of the major challenges for breast cancer researchers, clinicians, and patients. Current reductionist approaches to understanding the molecular signaling driving resistance have offered mostly incremental progress over the past 10 years. As the field of systems biology has begun to mature, the approaches and network modeling tools being developed and applied therein offer a different way to think about how molecular signaling and the regulation of critical cellular functions are integrated. To gain novel insights, we first describe some of the key challenges facing network modeling of endocrine resistance, many of which arise from the properties of the data spaces being studied. We then use activation of the unfolded protein response (UPR) following induction of endoplasmic reticulum stress in breast cancer cells by antiestrogens, to illustrate our approaches to computational modeling. Activation of UPR is a key determinant of cell fate decision making and regulation of autophagy and apoptosis. These initial studies provide insight into a small subnetwork topology obtained using differential dependency network analysis and focused on the UPR gene XBP1. The XBP1 subnetwork topology incorporates BCAR3, BCL2, BIK, NFκB, and other genes as nodes; the connecting edges represent the dependency structures amongst these nodes. As data from ongoing cellular and molecular studies become available, we will build detailed mathematical models of this XBP1-UPR network.