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Jean-Pierre P.,Harper Cancer Research Institute | Jean-Pierre P.,University of Notre Dame | Winters P.C.,University of Rochester | Clark J.A.,Boston University | And 6 more authors.
Journal of Cancer Education | Year: 2013

Patient navigation has emerged as a promising strategy for addressing racial-ethnic and socioeconomic disparities in cancer-related care. However, little is known about the impact of patients' perception of the quality of navigation on patient outcomes. We examined the impact of better-rated navigators on patients' satisfaction with cancer-related care. The sample included 1,593 adults (85.8%with abnormal cancer screening and 14.2 % with confirmed cancer diagnosis) who received patient navigation. We defined better-rated navigators as those scoring above the first quartile of mean scores on the Patient Satisfaction with Interpersonal Relationship with Navigator scale.We defined patient satisfaction based on scores above or below the median of the Patient Satisfaction with Cancer-Related Care (PSCC) scale. We controlled for patient and site characteristics using backward selection logistic regression analyses. Among patients with abnormal screening, having a better-rated navigator was associated with high r score on the PSCC (p<0.05). After controlling for other bivariate predictors of satisfaction (e.g., age, race, income, and household size), navigation by better-rated navigators was associated with a greater likelihood of having higher patient satisfaction [odds ratio (OR), 1.38; 95 % confidence interval (CI), 1.05-1.82]. Similar findings between better-rated navigators and score on the PSCC were found for participants with diagnosed cancer (OR, 3.06; 95 % CI, 1.56-6.0). Patients navigated by better-rated navigators reported higher satisfaction with their cancer-related care. © Springer Science+Business Media New York 2013.


Mitra A.K.,Indiana University | Davis D.A.,University of Illinois at Chicago | Tomar S.,Indiana University | Roy L.,Indiana University | And 22 more authors.
Gynecologic Oncology | Year: 2015

Objective Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. Methods To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH-OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119 and UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. Results Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. Conclusions Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community. © 2015 Elsevier Inc. All rights reserved.


Roy L.,Harper Cancer Research Institute | Roy L.,Indiana University | Bikorimana E.,Harper Cancer Research Institute | Bikorimana E.,Indiana University | And 7 more authors.
PLoS Genetics | Year: 2015

Overexpression of miRNA, miR-24, in mouse hematopoietic progenitors increases monocytic/ granulocytic differentiation and inhibits B cell development. To determine if endogenous miR-24 is required for hematopoiesis, we antagonized miR-24 in mouse embryonic stem cells (ESCs) and performed in vitro differentiations. Suppression of miR-24 resulted in an inability to produce blood and hematopoietic progenitors (HPCs) from ESCs. The phenotype is not a general defect in mesoderm production since we observe production of nascent mesoderm as well as mesoderm derived cardiac muscle and endothelial cells. Results from blast colony forming cell (BL-CFC) assays demonstrate that miR-24 is not required for generation of the hemangioblast, the mesoderm progenitor that gives rise to blood and endothelial cells. However, expression of the transcription factors Runx1 and Scl is greatly reduced, suggesting an impaired ability of the hemangioblast to differentiate. Lastly, we observed that known miR-24 target, Trib3, is upregulated in the miR-24 antagonized embryoid bodies (EBs). Overexpression of Trib3 alone in ESCs was able to decrease HPC production, though not as great as seen with miR-24 knockdown. These results demonstrate an essential role for miR-24 in the hematopoietic differentiation of ESCs. Although many miRNAs have been implicated in regulation of hematopoiesis, this is the first miRNA observed to be required for the specification of mammalian blood progenitors from early mesoderm. © 2015 Roy et al.


News Article | February 15, 2017
Site: www.cemag.us

Scientists are one step closer to mimicking the way biological systems interact and process information in the body — a vital step toward developing new forms of biorobotics and novel treatment approaches for several muscle-related health problems such as muscular degenerative disorders, arrhythmia, and limb loss. Using cardiac muscle cells and cardiac fibroblasts — cells found in connective heart tissue – researchers at the University of Notre Dame have created a “living diode,” which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or “computational tissues” that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells’ electrical activity. Zorlutuna’s research was funded by the National Science Foundation. “Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally,” says Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. “The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system — and creating functional control units for biomedical engineering applications such as bioactuators or biosensors.” The team’s work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they rely on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University’s Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute.


News Article | February 15, 2017
Site: phys.org

Using cardiac muscle cells and cardiac fibroblasts - cells found in connective heart tissue - researchers at the University of Notre Dame have created a "living diode," which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or "computational tissues" that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells' electrical activity. Zorlutuna's research was funded by the National Science Foundation. "Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally," said Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. "The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system - and creating functional control units for biomedical engineering applications such as bioactuators or biosensors." The team's work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they relay on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University's Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute. Explore further: Researchers use stem cells to regenerate the external layer of a human heart More information: Uryan Isik Can et al. Muscle-Cell-Based "Living Diodes", Advanced Biosystems (2017). DOI: 10.1002/adbi.201600035


News Article | February 15, 2017
Site: www.eurekalert.org

Scientists are one step closer to mimicking the way biological systems interact and process information in the body - a vital step toward developing new forms of biorobotics and novel treatment approaches for several muscle-related health problems such as muscular degenerative disorders, arrhythmia and limb loss. Using cardiac muscle cells and cardiac fibroblasts - cells found in connective heart tissue - researchers at the University of Notre Dame have created a "living diode," which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or "computational tissues" that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells' electrical activity. Zorlutuna's research was funded by the National Science Foundation. "Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally," said Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. "The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system - and creating functional control units for biomedical engineering applications such as bioactuators or biosensors." The team's work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they relay on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University's Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute.


News Article | November 11, 2016
Site: www.eurekalert.org

The American Cancer Society has reported that lung cancer, which kills more Americans than any other type of cancer, is expected result in an estimated 158,080 deaths in 2016. Although drugs are currently available to fight lung cancer, drug discovery challenges persist because treatment options are limited. Not only is lung cancer often drug resistant, but radiation treatment and surgery can be quite difficult depending on the location of the tumor(s) within the lungs. Rob Stahelin, Adjunct Associate Professor, Chemistry & Biochemistry at the University of Notre Dame, Interim Senior Associate Director at the Harper Cancer Research Institute (HCRI) and Associate Professor of Biochemistry & Molecular Biology at the Indiana University School of Medicine-South Bend, is working to better understand lung cancer at a cellular level and is investigating drugs that could inhibit lung cancer growth and prevent it from spreading. "I'm looking at signals within the lung cancer cells that cause them to grow quickly, move and divide," he said. "With cancers, a primary tumor may metastasize and attack another organ in the body. Lung cancer often metastasizes -- or spreads -- to other organs such as the liver. Once the liver is infected, the cancer causes increased health problems and patients are more likely to succumb to the disease." Stahelin's laboratory aims to advance understanding of how the mechanisms of lipid signaling are controlled in lung and other types of cancers. Membranes, composed mainly of lipids, hold the keys to cell division, growth and metabolism necessary for cancer cell growth and metastasis. That understanding could ultimately help to determine the causes of lung cancer and identify viable targets, lipids or proteins for drug development and treatment.


News Article | November 11, 2016
Site: www.eurekalert.org

Pancreatic cancer, the third leading cause of cancer-related deaths, is projected to be the second by the year 2030, according to a study in the journal of Cancer Research. The five-year survival rate is only 8 percent, making it the only major cancer with a survival rate in the single digits. Despite rising mortality rates, pancreatic cancer is under-researched and underfunded, and there are few Food and Drug Administration-approved treatments to combat the disease. With the current pipeline for drug discovery taking 10 to 15 years from the laboratory to use, and an estimated 41,780 who will die from the disease this year alone, time is of the essence. Now, patients suffering from pancreatic cancer may soon face better treatment options due to the latest discovery by Dr. Reginald Hill, Archibald Assistant Professor of Cancer Biology at the University of Notre Dame and researcher at the Harper Cancer Research Institute. Hill's research focuses on drugs that are already approved by the FDA to find out why those drugs are not working in patients with pancreatic cancer. "The bulk of a pancreatic cancer tumor is made of approximately 10 percent cancer cells and 90 percent supporting cells. Somehow, the supporting cells have figured out how to survive the chemotherapy," Hill said. "Microscopic vesicles called exosomes, bubbles with genetic material released by cells during chemotherapy exposure, are released from supporting cells, educating the cancer cells on how to survive, resulting in a tumor becoming chemoresistant." Research in the New England Journal of Medicine has revealed a majority of pancreatic cancer cases have proven to be resistant to chemotherapy and unresponsive to drug treatments found to be effective in other types of cancer. Most new research has focused on destroying supportive cells. However, those studies concluded that when the supportive cells were attacked, patients actually developed more advanced cancer. "It was like poking holes into the area around the cancer cells and allowing it to spread," he said. Hill focused on blocking the release of exosomes, preventing the relay of information from supporting cells to cancer cells -- which increased the efficacy of chemotherapy. This recently published study suggests that using an exosome blocker, which is nontoxic, in combination with standard-of-care chemotherapy will those with pancreatic and many other cancers as well. The lack of effective treatments available to help thousands of those with pancreatic cancer is what drew Hill to his research. This latest discovery paves the way for those patients to have greater hope. The Harper Cancer Research Institute is how Notre Dame fights cancer. Located in South Bend, Indiana, its researchers are dedicated to conducting innovative and integrative research that confronts the complex challenges of cancer. Learn more at harpercancer.nd.edu.


Navari R.M.,Indiana University | Navari R.M.,Harper Cancer Research Institute
Drugs | Year: 2013

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a serotonin 5-HT 3 receptor antagonist, dexamethasone and a neurokinin 1 (NK 1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first and only agent clinically available in the NK1 receptor antagonist drug class has been used effectively as an additive agent to the 5-HT3 receptor antagonists and dexamethasone to control CINV. Rolapitant and netupitant are other NK1 receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a US-FDA approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as a very effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. © 2013 Springer International Publishing Switzerland.


PubMed | Harper Cancer Research Institute
Type: | Journal: BMC cancer | Year: 2015

The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70% of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown.We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment.Cells obtained from MMTV-PyMT;ApcMin/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;ApcMin/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin resistance.APC loss-of-function significantly increases resistance to cisplatin-mediated apoptosis in both MDA-MB-157 and the PyMT derived cells. We also demonstrated that cisplatin in combination with PP2 or SP600125 could be clinically beneficial, as inhibition of Src or JNK in an APC-mutant breast cancer patient may alleviate the resistance induced by mutant APC.

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