Browsing by Author "Siegel, Amanda"

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    Collaborative Research from the Center for Membrane Biosciences
    (Office of the Vice Chancellor for Research, 2010-04-09) Petrache, Horia I.; Justice, Matthew J.; Rogozea, Adriana L.; Patrusca, Daniela N.; Petrache, Irina; Wassall, Stephen R.; Siegel, Amanda; Murcia, Mike; Minner, Dan; Elmendorf, Jeffrey S.; Tackett, Lixuan; Naumann, Christoph A.
    The Center for Membrane Biosciences has been facilitating new research activities between the IUPUI School of Science and IU School of Medicine in the structure, biochemistry, and physiology of biological membranes. Results from two projects resulting from these collaborations are presented. Project 1: Ceramides are sphingolipids involved in the development of lung alveolar cell apoptosis (programmed death) and possibly in the clearance of apoptotic cells by alveolar macrophages. We use a combination of molecular and cellular methods to determine the effect of ceramides on the ability of alveolar macrophages to engulf apoptotic cells. Engulfment experiments of labeled apoptotic Jurkat cells were performed with rat alveolar macrophages (AM) obtained via bronchoalveolar lavage. AM were treated with various ceramide species and efferocytosis was quantified by flow cytometry. Using small-angle X-ray scattering and solid state 2H NMR we determined how ceramides (C6:0, C18:1) affect the molecular organization and the physical properties of model membranes. These studies can lead to a better understanding of the molecular mechanisms responsible for apoptotic cell clearance. If the clearance process is impaired, apoptotic cells may progress to secondary necrosis, resulting in release of harmful cellular contents and tissue inflammation. Project 2: Highly-photostable quantum dots (QD) conjugated to lipids or antibodies can be utilized to explore changes in compartmentalization of the plasma membrane due to hyperinsulinemia using wide field single molecule fluorescence microscopy. Protocols describing the bio-inertness and monovalent binding of QDs to antibodies are outlined, as well as use of confocal fluorescence correlation spectroscopy to determine colloidal stability of CdSe/ZnS QDs in aqueous solution. Tracking experiments on QD-conjugated to transferrin receptors in healthy and insulin-resistant adipocytes detect changes in membrane compartmentalization. The impact of chromium picolinate on receptor mobility was also investigated.
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    Cross-Selectivity Enhancement of Poly(vinylidene fluoride-hexafluoropropylene)-Based Sensor Arrays for Detecting Acetone and Ethanol
    (MDPI, 2017-03-15) Daneshkhah, Ali; Shrestha, Sudhir; Siegel, Amanda; Varahramyan, Kody; Agarwal, Mangilal; Electrical and Computer Engineering, School of Engineering and Technology
    Two methods for cross-selectivity enhancement of porous poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP)/carbon black (CB) composite-based resistive sensors are provided. The sensors are tested with acetone and ethanol in the presence of humid air. Cross-selectivity is enhanced using two different methods to modify the basic response of the PVDF-HFP/CB sensing platform. In method I, the adsorption properties of PVDF-HFP/CB are altered by adding a polyethylene oxide (PEO) layer or by treating with infrared (IR). In method II, the effects of the interaction of acetone and ethanol are enhanced by adding diethylene carbonate (DEC) or PEO dispersed in DEC (PEO/DEC) to the film. The results suggest the approaches used in method I alter the composite ability to adsorb acetone and ethanol, while in method II, they alter the transduction characteristics of the composite. Using these approaches, sensor relative response to acetone was increased by 89% compared with the PVDF-HFP/CB untreated film, whereas sensor relative response to ethanol could be decreased by 57% or increased by 197%. Not only do these results demonstrate facile methods for increasing sensitivity of PVDF-HFP/CB film, used in parallel they demonstrate a roadmap for enhancing system cross-selectivity that can be applied to separate units on an array. Fabrication methods, experimental procedures and results are presented and discussed.
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    Cross-Selectivity Enhancement of Poly(vinylidene fluoride-hexafluoropropylene)-Based Sensor Arrays for Detecting Acetone and Ethanol
    (MDPI, 2017-03-15) Daneshkhah, Ali; Shrestha, Sudhir; Siegel, Amanda; Varahramyan, Kody; Agarwal, Mangilal; Mechanical Engineering, School of Engineering and Technology
    Two methods for cross-selectivity enhancement of porous poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP)/carbon black (CB) composite-based resistive sensors are provided. The sensors are tested with acetone and ethanol in the presence of humid air. Cross-selectivity is enhanced using two different methods to modify the basic response of the PVDF-HFP/CB sensing platform. In method I, the adsorption properties of PVDF-HFP/CB are altered by adding a polyethylene oxide (PEO) layer or by treating with infrared (IR). In method II, the effects of the interaction of acetone and ethanol are enhanced by adding diethylene carbonate (DEC) or PEO dispersed in DEC (PEO/DEC) to the film. The results suggest the approaches used in method I alter the composite ability to adsorb acetone and ethanol, while in method II, they alter the transduction characteristics of the composite. Using these approaches, sensor relative response to acetone was increased by 89% compared with the PVDF-HFP/CB untreated film, whereas sensor relative response to ethanol could be decreased by 57% or increased by 197%. Not only do these results demonstrate facile methods for increasing sensitivity of PVDF-HFP/CB film, used in parallel they demonstrate a roadmap for enhancing system cross-selectivity that can be applied to separate units on an array. Fabrication methods, experimental procedures and results are presented and discussed.
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    Efficacy of Endoscopic Submucosal Dissection for Superficial Gastric Neoplasia in a Large Cohort in North America
    (Elsevier, 2020) Ngamruengphong, Saowanee; Ferri, Lorenzo; Aihara, Hiroyuki; Draganov, Peter V.; Yang, Dennis J.; Perbtani, Yaseen B.; Jue, Terry L.; Munroe, Craig A.; Boparai, Eshandeep S.; Mehta, Neal A.; Bhatt, Amit; Kumta, Nikhil A.; Othman, Mohamed O.; Mercado, Michael; Javaid, Huma; Aadam, Abdul Aziz; Siegel, Amanda; James, Theodore W.; Grimm, Ian S.; DeWitt, John M.; Novikov, Aleksey; Schlachterman, Alexander; Kowalski, Thomas; Samarasena, Jason; Hashimoto, Rintaro; Chehade, Nabil El Hage; Lee, John; Chang, Kenneth; Su, Bailey; Ujiki, Michael B.; Mehta, Amit; Sharaiha, Reem Z.; Carr-Locke, David L.; Chen, Alex; Chen, Michael; Chen, Yen-I.; Khoshknab, MirMilad Pourmousavi; Wang, Rui; Kerdsirichairat, Tossapol; Tomizawa, Yutaka; von Renteln, Daniel; Kumbhari, Vivek; Khashab, Mouen A.; Bechara, Robert; Karasik, Michael; Patel, Neej J.; Fukami, Norio; Nishimura, Makoto; Hanada, Yuri; Wong Kee Song, Louis M.; Laszkowska, Monika; Wang, Andrew Y.; Hwang, Joo Ha; Friedland, Shai; Sethi, Amrita; Kalloo, Antony N.; Medicine, School of Medicine
    Background & Aims Endoscopic submucosal dissection (ESD) is a widely accepted treatment option for superficial gastric neoplasia in Asia, but there are few data on outcomes of gastric ESD from North America. We aimed to evaluate the safety and efficacy of gastric ESD in North America. Methods We analyzed data from 347 patients who underwent gastric ESD at 25 centers, from 2010 through 2019. We collected data on patient demographics, lesion characteristics, procedure details and related adverse events, treatment outcomes, local recurrence, and vital status at the last follow up. For the 277 patients with available follow-up data, the median interval between initial ESD and last clinical or endoscopic evaluation was 364 days. The primary endpoint was the rate of en bloc and R0 resection. Secondary outcomes included curative resection, rates of adverse events and recurrence, and gastric cancer-related death. Results Ninety patients (26%) had low-grade adenomas or dysplasia, 82 patients (24%) had high-grade dysplasia, 139 patients (40%) had early gastric cancer, and 36 patients (10%) had neuroendocrine tumors. Proportions of en bloc and R0 resection for all lesions were 92%/82%, for early gastric cancers were 94%/75%, for adenomas and low-grade dysplasia were 93%/ 92%, for high-grade dysplasia were 89%/ 87%, and for neuroendocrine tumors were 92%/75%. Intraprocedural perforation occurred in 6.6% of patients; 82% of these were treated successfully with endoscopic therapy. Delayed bleeding occurred in 2.6% of patients. No delayed perforation or procedure-related deaths were observed. There were local recurrences in 3.9% of cases; all occurred after non-curative ESD resection. Metachronous lesions were identified in 14 patients (6.9%). One of 277 patients with clinical follow up died of metachronous gastric cancer that occurred 2.5 years after the initial ESD. Conclusions ESD is a highly effective treatment for superficial gastric neoplasia and should be considered as a viable option for patients in North America. The risk of local recurrence is low and occurs exclusively after non-curative resection. Careful endoscopic surveillance is necessary to identify and treat metachronous lesions.
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    Electrospun Thermosetting Carbon Nanotube–Epoxy Nanofibers
    (ACS, 2021-02) Aliahmad, Nojan; Biswas, Pias Kumar; Wable, Vidya; Hernandez, Iran; Siegel, Amanda; Dalir, Hamid; Agarwal, Mangilal; Mechanical and Energy Engineering, School of Engineering and Technology
    This paper represents the process of fabrication and characterization of submicron carbon nanotube (CNT)–epoxy nanocomposite filaments through an electrospinning process. Electrospinning is one of the most versatile, inexpensive, and environmentally well-known techniques for producing continuous fibers from submicron diameter all the way to tens of nanometer diameter. Here, electrospinning of submicron epoxy filaments was made possible by partial curing of the epoxy by mixing the hardener and through a thermal treatment process without the need for adding any plasticizers or thermoplastic binders. This semicuring approach makes the epoxy solution viscous enough for the electrospinning process, that is, without any solidification or nonuniformity caused by the presence of the hardener inside the mixture. The filaments were spun using a CNT/epoxy solution with a viscosity of 65 p using 16 kV and a collector distance of 10 cm. The diameter of these filaments can be tuned as low as 100 nm with adjustment of electrospinning parameters. By incorporating a low amount of CNT into epoxy, better structural, electrical, and thermal stabilities were achieved. The CNT fibers have been aligned inside the epoxy filaments because of the presence of the electrostatic field during the electrospinning process. The modulus of the epoxy and CNT/epoxy filaments were found to be 3.24 and 4.84 GPa, respectively. The presence of the CNT can lead up to 49% improvement on modulus. Accordingly, using a commercially available epoxy suitable for industrial composite productions makes the developed filament suitable for many applications.
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    Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1
    (Wiley, 2020-09) Liu, Shengzhi; Wu, Di; Sun, Xun; Fan, Yao; Zha, Rongrong; Jalali, Aydin; Teli, Meghana; Sano, Tomonori; Siegel, Amanda; Sudo, Akihiro; Agarwal, Mangilal; Robling, Alexander; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Mechanical stimulations can prevent bone loss, but their effects on the tumor-invaded bone or solid tumors are elusive. Here, we evaluated the effect of knee loading, dynamic loads applied to the knee, on metastasized bone and mammary tumors. In a mouse model, tumor cells were inoculated to the mammary fat pad or the proximal tibia. Daily knee loading was then applied and metabolic changes were monitored mainly through urine. Urine samples were also collected from human subjects before and after step aerobics. The result showed that knee loading inhibited tumor progression in the loaded tibia. Notably, it also reduced remotely the growth of mammary tumors. In the urine, an altered level of cholesterol was observed with an increase in calcitriol, which is synthesized from a cholesterol derivative. In urinary proteins, knee loading in mice and step aerobics in humans markedly reduced WNT1-inducible signaling pathway protein 1, WISP1, which leads to poor survival among patients with breast cancer. In the ex vivo breast cancer tissue assay, WISP1 promoted the growth of cancer fragments and upregulated tumor-promoting genes, such as Runx2, MMP9, and Snail. Collectively, the present preclinical and human study demonstrated that mechanical stimulations, such as knee loading and step aerobics, altered urinary metabolism and downregulated WISP1. The study supports the benefit of mechanical stimulations for locally and remotely suppressing tumor progression. It also indicated the role of WISP1 downregulation as a potential mechanism of loading-driven tumor suppression.
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    Pitavastatin slows tumor progression and alters urine-derived volatile organic compounds through the mevalonate pathway
    (Wiley, 2019-10-04) Wang, Luqi; Wang, Yue; Chen, Andy; Teli, Meghana; Kondo, Rika; Jalali, Aydin; Fan, Yao; Liu, Shengzhi; Zhao, Xinyu; Siegel, Amanda; Minami, Kazumasa; Agarwal, Mangilal; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Bone is a frequent site of metastasis from breast cancer, and a desirable drug could suppress tumor growth as well as metastasis-linked bone loss. Currently, no drug is able to cure breast cancer–associated bone metastasis. In this study, we focused on statins that are known to inhibit cholesterol production and act as antitumor agents. After an initial potency screening of 7 U.S. Food and Drug Administration–approved statins, we examined pitavastatin as a drug candidate for inhibiting tumor and tumor-induced bone loss. In vitro analysis revealed that pitavastatin acted as an inhibitor of tumor progression by altering stress to the endoplasmic reticulum, down-regulating peroxisome proliferator–activated receptor γ, and reducing Snail and matrix metalloproteinase 9. In bone homeostasis, it blocked osteoclast development by suppressing transcription factors c-Fos and JunB, but stimulated osteoblast mineralization by regulating bone morphogenetic protein 2 and p53. In a mouse model, pitavastatin presented a dual role in tumor inhibition in the mammary fat pad, as well as in bone protection in the osteolytic tibia. In mass spectrometry–based analysis, volatile organic compounds (VOCs) that were linked to lipid metabolism and cholesterol synthesis were elevated in mice from the tumor-grown placebo group. Notably, pitavastatin-treated mice reduced specific VOCs that are linked to lipid metabolites in the mevalonate pathway. Collectively, the results lay a foundation for further investigation of pitavastatin’s therapeutic efficacy in tumor-induced bone loss, as well as VOC-based diagnosis of tumor progression and treatment efficacy.—Wang, L., Wang, Y., Chen, A., Teli, M., Kondo, R., Jalali, A., Fan, Y., Liu, S., Zhao, X., Siegel, A., Minami, K., Agarwal, M., Li, B.-Y., Yokota, H. Pitavastatin slows tumor progression and alters urine-derived volatile organic compounds through the mevalonate pathway.
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    Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion
    (Springer Nature, 2020-02-14) Fan, Yao; Jalali, Aydin; Chen, Andy; Zhao, Xinyu; Liu, Shengzhi; Teli, Meghana; Guo, Yunxia; Li, Fangjia; Li, Junrui; Siegel, Amanda; Yang, Lianxiang; Liu, Jing; Na, Sungsoo; Agarwal, Mangilal; Robling, Alexander G.; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumor-induced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGFβ levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumor-osteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment.