Rethinking strategies for blood transfusion in hip fracture patients.

OBJECTIVES: Most patients can tolerate a hemoglobin (Hgb) > 8 g per deciliter. In some cases, however, transfusion will delay physical therapy and hospital discharge. This study aims to review Hgb and transfusion data for a large volume of recent hip fracture patients in order to identify new opportunities for decreasing the length of hospital stay. Our hypotheses are that in some cases, earlier transfusion of more blood will be associated with shorter hospital stays, and that Hgb levels consistently decrease for more than 3 days postoperatively. DESIGN: Retrospective chart review. SETTING: Two academic medical centers with Geriatric Fracture Programs. PATIENTS: Data was collected from patients 50 years and older with hip fractures April 2015 and October 2017. INTERVENTION: Operative stabilization of the hip fractures according to standard of care for the fracture type and patient characteristics. Transfusion according to established standards. MAIN OUTCOME MEASUREMENTS: Electronic records were retrospectively reviewed for demographic information, Hgb levels, and transfusion events. RESULTS: One thousand fifteen patients with femoral neck or intertrochanteric hip fractures were identified. Eight hundred sixty met the inclusion criteria. The average length of hospital stay was 6.7 days. The mean patient age was 82 years. The average American Society of Anesthesiologists score was 2.9. The average Hgb level consistently decreased for 5 days postoperatively before beginning to increase on day 6. There was poor consistency between intraoperative Hgb levels and preoperative or postoperative Hgb levels. Three hundred sixty-eight (42.8%) patients were transfused an average of 1.9 (range 1-6) units. One hundred five patients required a transfusion on postoperative day (POD) 1: 72 received only 1 unit of blood: 36 (50%) of the 72 required a second transfusion in the following days, compared to 9 of 33 (27%) who received 2 units on POD 1 (χ2 = 3.8898; P < .05). Patients who received transfusions on POD 3 or later had an average length of stay >2.5 days longer than those who received a transfusion earlier (P = 0.005). CONCLUSIONS: Our findings do not support earlier transfusion of more blood. Although in some cases, there is an association between earlier transfusion of more blood and shorter hospital stay, routine transfusion of more blood would incur higher transfusion risks in some patients who would not otherwise meet criteria for transfusion. After hip fracture surgery, the Hgb usually decreases for 5 days and does not begin to increase until POD 6. This information will provide utility in the population health management of hip fracture patients. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Study

Cheaters allow cooperators to prosper

Cooperation based on the production of costly common goods is observed throughout nature. This is puzzling, as cooperation is vulnerable to exploitation by defectors which enjoy a fitness advantage by consuming the common good without contributing fairly. Depletion of the common good can lead to population collapse and the destruction of cooperation. However, population collapse implies small population size, which, in a structured population, is known to favor cooperation. This happens because small population size increases variability in cooperator frequency across different locations. Since individuals in cooperator-dominated locations (which are most likely cooperators) will grow more than those in defector-dominated locations (which are most likely defectors), cooperators can outgrow defectors globally despite defectors outgrowing cooperators in each location. This raises the possibility that defectors can lead to conditions that sometimes rescue cooperation from defector-induced destruction. We demonstrate multiple mechanisms through which this can occur, using an individual-based approach to model stochastic birth, death, migration, and mutation events. First, during defector-induced population collapse, defectors occasionally go extinct before cooperators by chance, which allows cooperators to grow. Second, empty locations, either preexisting or created by defector-induced population extinction, can favor cooperation because they allow cooperator but not defector migrants to grow. These factors lead to the counterintuitive result that the initial presence of defectors sometimes allows better survival of cooperation compared to when defectors are initially absent. Finally, we find that resource limitation, inducible by defectors, can select for mutations adaptive to resource limitation. When these mutations are initially present at low levels or continuously generated at a moderate rate, they can favor cooperation by further reducing local population size. We predict that in a structured population, small population sizes precipitated by defectors provide a "built-in" mechanism for the persistence of cooperation

HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model

Context specific effects of HER-2 overexpression on the biological responses and transcription program induced by transforming growth factor (TGF)-β in breast cancer cells

<p><b>Copyright information:</b></p><p>Taken from "HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells"</p><p>Breast Cancer Research 2005;7(6):R1058-R1079.</p><p>Published online 8 Nov 2005</p><p>PMCID:PMC1410754.</p><p>Copyright © 2005 Wilson et al.; licensee BioMed Central Ltd.</p> Phenotypes of the luminal MCF-7 and mesenchymal MDA-MB-231 cells with and without engineered HER-2 overexpression. The epithelial growth pattern of MCF-7 cells is characteristically altered by HER-2 overexpression, which promotes an elongated morphology and increased proliferation rates as well as faster growing tumor xenografts [12,13]. The MDA-MB-231 cells are heterogeneous with the majority of cells, having a spindle shaped morphology. The effect of HER-2 overexpression on the morphological appearance was not dramatic except that significantly more (approximately three times) of the large, flattened round cells were observed. The MDA-MB-231 H2 cells have also been shown to be more metastatic than the MDA-MB-231 CN or parental lines (data not shown). Summary of the TGF-β transcriptional program obtained by Affymetrix microarray profiling of cells treated with recombinant TGF-β1. The number of elements significantly affected (p < 0.01 and fold change greater than ± 1.7 using Rosetta Resolver) are graphed. Light and dark red indicate genes upregulated after 6 h and 24 h, respectively, and light and dark green represent genes downregulated after 6 and 24 h, respectively. Highlighted genes from the dominant functional gene signatures as determined by the gene ontology information found in Source [105] and GeneCards [106]. Red and green indicate TGF-β stimulated and repressed genes, respectively. ECM, extracellular matrix

HER-2 overexpression modulates transforming growth factor (TGF)-β responses in a cell context dependent manner

<p><b>Copyright information:</b></p><p>Taken from "HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells"</p><p>Breast Cancer Research 2005;7(6):R1058-R1079.</p><p>Published online 8 Nov 2005</p><p>PMCID:PMC1410754.</p><p>Copyright © 2005 Wilson et al.; licensee BioMed Central Ltd.</p> HER-2 overexpression in MCF-7 breast cancer cells blocks TGF-β mediated growth arrest. CN and H2 cells were treated with diluent control (diamonds) or TGF-β1 (0.2 ng/ml (black circles); 0.4 ng/ml (white circles); or 0.8 ng/ml (triangles)) and counted on the indicated days after treatment. Each point is the average of triplicate wells (± standard deviation for error bars). The growth of MCF-7 CN cells is severely inhibited by TGF-β1. MCF-7 H2 cells are resistant to growth inhibition by TGF-β1. MCF-7 CN (diamonds) versus MCF-7 H2 (white circles) cells treated with 0.2 ng/ml TGF-β1. ZR-75-1 cells are resistant to growth inhibition by TGF-β1 without HER-2 overexpression (ZR-75-1/CN (diamonds) versus ZR-75-1/H2 (white circles)) treated with 0.2 ng/ml TGF-β1. TGF-β1 stimulates the growth of MDA-MB-231 H2 cells. MDA MB-231 CN (diamonds) and H2 cells (white cirlcles) were grown for 6 days in the presence of TGF-β1, β2 or β3 (0.01 to 100 ng/ml) or a diluent control. Cells were pulsed with [H] thymidine for the final 24 h of assay and thymidine incorporation was measured. The average counts of triplicate wells for each data point are represented as % of diluent control. TGF-β induces a 'piling' phenotype in MDA-MB-231 that is dependent on HER-2 overexpression. MDA-MB-231 CN and H2 cells were grown for 5 days in the presence of 10 ng/ml TGF-β1 or diluent control. Cells were stained with crystal violet dye and photographed with a 20× (top four panels) or a 60× (bottom two panels) objective