Breastfeeding Practice Before Bottle-Feeding: An Initiative to Increase the Rate of Breastfeeding for Preterm Infants at the Time of Neonatal Intensive Care Unit Discharge.

Preterm babies who received 72 hours of breastfeeding practice before introducing a bottle had significantly higher rates of breastfeeding at the time of neonatal intensive care unit (NICU) discharge than did babies who were introduced to bottle-feeding with or before breastfeeding during the first 72 hours of oral feeding or babies who were primarily bottle-fed. There were no statistical differences in corrected gestational age (CGA) at birth, first oral feeding, or full oral feeds, in days from first to full oral feeds, or in CGA or days of life at NICU discharge.

Serrated Lesion Detection in a Population-based Colon Screening Program.

BACKGROUND: Serrated lesions give rise to 15% to 30% of all colorectal cancers, driven predominantly by the sessile serrated polyp (SSP). Fecal immunochemical test (FIT), has low sensitivity for SSPs. SSP detection rate (SSPDR) is influenced by performance of both endoscopists and pathologists, as diagnosis can be subtle both on endoscopy and histology. GOALS: To evaluate the SSPDR in a population-based screening program, and the influence of subspecialty trained pathologists on provincial reporting practices. STUDY: The colon screening program database was used to identify all FIT-positive patients that received colonoscopy between January 2014 and June 2017. Patient demographics, colonoscopy quality indicators, pathologic diagnoses, and FIT values were collected. This study received IRB approval. RESULTS: A total of 74,605 colonoscopies were included and 26.6% had at least 1 serrated polyp removed. The SSPDR was 7.0%, with 59% of the SSPs detected having a concurrent conventional adenoma. The mean FIT value for colonoscopies with only serrated lesions was less than that for colonoscopies with a conventional adenoma or colorectal cancer (P<0.0001). Centers with a gastrointestinal subspecialty pathologist diagnosed proportionally more SSPs (P<0.0001), and right-sided SSPs than centers without subspecialists. CONCLUSIONS: Serrated lesions often occur in conjunction with conventional adenomas and are associated with lower FIT values. Knowledge of the characteristics of SSPs is essential for pathologists to ensure accurate diagnosis of SSPs.

Population-based Screening for BRAF V600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis.

PURPOSE: BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing. EXPERIMENTAL DESIGN: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAF V600E testing. Outcomes among IHC-detected BRAF V600E mCRC (BRAF IHC) were compared with patients with next-generation sequencing (NGS)-identified BRAF V600E-mutated mCRC from two institutions (BRAF NGS) with patients spanning from 2004 to 2018. RESULTS: All-stage population prevalence of BRAF V600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAF IHC had worse median overall survival (mOS) than BRAF NGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAF V600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line. CONCLUSIONS: Patients with BRAF V600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction.

Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies.

Estudio piloto de preferencia y aceptabilidad de recetas con camote biofortificado: un estudio transversal a nivel comunitario / Pilot Study on Preference and Acceptability of Biofortified Sweet Potatoes Recipes: A Community-based Cross-sectional Study

Resumen Antecedentes: la deficiencia de vitamina A persiste como problema de salud pública en el área campesina e indígena de Panamá. Objetivo: determinar la aceptabilidad y preferencia de las amas de casa por cuatro recetas con camote biofortificado en comunidades indígenas y campesinas. Materiales y métodos: estudio piloto descriptivo y transversal en 50 amas de casas provenientes de Chichica, Comarca indígena Ngäbe-Buglé, y El Copé, comunidad campesina ubicada en la provincia de Coclé, Panamá. Se aplicaron pruebas de aceptabilidad sensorial y de preferencia mediante escala hedónica a cuatro recetas locales de camote (pesada de camote, refresco de camote, tamal de camote y camote asado). Se recolectaron datos sociodemográficos, sobre diversidad dietética y frecuencia de consumo de alimentos fuente de vitamina A. También se realizó un análisis de contenido de vitamina A al camote biofortificado. Resultados: participaron 50 mujeres, 62 % Chichica, 52 % edad 34-49 años. Se observó diferencia en la diversidad de dieta por comunidad para raíces/ tubérculos y vegetales/hortalizas en Chichica (81 % y 48 %, respectivamente) y El Copé (42 % y 11 %, respectivamente) (prueba de proporciones prtest, p<0,05); también en frutas color naranja, vísceras/carnes y lácteos en Chichica (55 %, 42 % y 58 %, respectivamente) y El Copé (84 %, 74 % y 79 %, respectivamente) (prtest, p<0,05). La aceptabilidad fue alta para pesada (94 %), refresco (98 %), tamal (100 %) y camote asado (84 %). La preferencia fue alta para tamal de camote (92 %), sin diferencias por comunidad (prtest, p=0,112). La preferencia fue alta para pesada en El Copé (74 %) y refresco en Chichica (61 %), se observó diferencia significativa (prtest, p=0,0163). El contenido de vitamina A del camote biofortificado fue de 1000 µg/100 g. Conclusiones: las cuatro preparaciones evaluadas son aceptadas. La preferencia es mayor para el tamal en ambas comunidades, la pesada de camote en El Copé y el refresco de camote en Chichica.

Abstract Background: Vitamin A deficiency persists as public health problem in Panamanian rural communities. Objective: To determine acceptability and preference of four recipes using biofortified sweet potatoes by Panamanian women in rural non-indigenous and indigenous communities. Materials and Methods: A descriptive and cross-sectional pilot study with 50 women from rural non-indigenous and indigenous communities of El Cope (Coclé Province) and Chichica (Comarca Ngäbe Buglé), in Panama. Sensory acceptability and preference tests were applied using hedonic scale to evaluate four local recipes (sweet potato pesada, sweet potato drink, sweet potato tamale, and roasted sweet potato). Sociodemographic data, diversity of diet and frequency of vitamin A food sources were collected. Additionally, vitamin A composition analysis were used to evaluate the content in the biofortified sweet potato. Results: A total of 50 women, 62 % in Chichica, 52 % in 34-49 years range. Significant difference was observed in diet diversity for roots/tubers and vegetables groups in Chichica 81 % y 48 %, respectively) and El Copé (42 % y 11 %, respectively) (proportional test (prtest), p<0.05); as well as for orange colored fruits, meats and milk/dairy groups in Chichica (55 %, 42 % y 58 %, respectively) and El Copé (84 %, 74 % y 79 %, respectively) (prtest, p<0.05). High acceptability for all recipes, pesada (94 %), sweet potato drink (98 %), tamale (100 %), and roasted sweet potato (84 %). Preference is high for sweet potato tamale in both communities as a savory recipe; and sweet potato pesada in El Copé (74 %) and sweet potato drink in Chichica (61 %) as sweet recipes (prtest, p=0.0163). Vitamin A content in the biofortified sweet potato is 1000µg/100g. Conclusion: The four recipes are accepted. Preference for tamale in both communities; preference for pesada in El Copé and sweet potato drink in Chichica.

Soluble bone-derived osteopontin promotes migration and stem-like behavior of breast cancer cells.

Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44+CD24- phenotype. In the current study, we tested the hypothesis that these ALDHhiCD44+CD24- breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDHhiCD44+CD24- breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p≤0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p≤0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases.

Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior.

Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused on identifying factors inherent to breast cancer cells that are responsible for this observed metastatic pattern (termed organ tropism), however much less is known about factors present within specific organs that contribute to this process. This is in part because of a lack of in vitro model systems that accurately recapitulate the organ microenvironment. To address this, an ex vivo model system has been established that allows for the study of soluble factors present within different organ microenvironments. This model consists of generating conditioned media from organs (lymph node, bone, lung, and brain) isolated from normal athymic nude mice. The model system has been validated by demonstrating that different breast cancer cell lines display cell-line specific and organ-specific malignant behavior in response to organ-conditioned media that corresponds to their in vivo metastatic potential. This model system can be used to identify and evaluate specific organ-derived soluble factors that may play a role in the metastatic behavior of breast and other types of cancer cells, including influences on growth, migration, stem-like behavior, and gene expression, as well as the identification of potential new therapeutic targets for cancer. This is the first ex vivo model system that can be used to study organ-specific metastatic behavior in detail and evaluate the role of specific organ-derived soluble factors in driving the process of cancer metastasis.

Lung-derived factors mediate breast cancer cell migration through CD44 receptor-ligand interactions in a novel ex vivo system for analysis of organ-specific soluble proteins.

Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231,MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior.

The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the "Seed" and the "Soil"?

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.

Recombinant human erythropoietin in combination with chemotherapy increases breast cancer metastasis in preclinical mouse models.

PURPOSE: Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study. EXPERIMENTAL DESIGN: Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents. RESULTS: A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05). CONCLUSIONS: The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy.

Remembering helpers and hinderers depends on behavioral intentions of the agent and psychopathic characteristics of the observer.

Individual differences in proneness towards granting benefits (i.e., helping) or imposing costs (i.e., hindering) may have led to processes that detect and remember people who are prone to help or hinder. We examined two factors that might influence such memory: the intentionality of the acts and individual differences in psychopathy characteristics. Participants viewed several videos of computer-animated agents that helped or hindered another agent, either intentionally or unintentionally. Afterward, participants had better memory for agents that acted intentionally. Additionally, participants with more psychopathic tendencies had enhanced memory for helpers, suggesting that certain individual characteristics might result in heightened memory for people who are prone to granting benefits.

High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability.

Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDH(low)CD44(low/-) cells, ALDH(hi)CD44(+)CD24(-) (MDA-MB-231) and ALDH(hi)CD44(+)CD133(+) (MDA-MB-468) cells demonstrated increased growth (P < 0.05), colony formation (P < 0.05), adhesion (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2gamma receptor null mice, ALDH(hi)CD44(+)CD24(-) and ALDH(hi)CD44(+)CD133(+) cells showed enhanced tumorigenicity and metastasis relative to ALDH(low)CD44(low/-) cells (P < 0.05). These novel results suggest that stem-like ALDH(hi)CD44(+)CD24(-) and ALDH(hi)CD44(+)CD133(+) cells may be important mediators of breast cancer metastasis.

Jab1 is a target of EGFR signaling in ERalpha-negative breast cancer.

INTRODUCTION: c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERalpha-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERalpha- phenotype. METHODS: MDA-MB-231 and MDA-MB-468 ERalpha-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry. RESULTS: EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERalpha- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004). CONCLUSION: Jab1 is a target of EGFR signaling in ERalpha- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERalpha- breast cancer.