Browsing by Subject "Tumor"
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Item Accurate location of tumor in head and neck cancer radiotherapy treatment with respect to machine isocentre(2017-05) Tangirala, Deepak Kumar; Razban, Ali; Chen, Jie; Tovar, AndresRadiation Therapy has been one of the most common techniques to treat various types of cancers, in particular is Head and Neck Cancer (HNC) which accounts for three percent of all cancers in the United States. During the treatment procedure, the patient is immobilized using immobilization devices such as the full head face mask, bite blocks, stereotactic frame, etc. to get accurate location of tumor. The disadvantage of these devices is that they are very uncomfortable to the patient especially people suffering from Post-Traumatic Stress Disorder (PTSD) and claustrophobia who cannot wear any confined masked system such as the full head mask or bite block during the treatment procedure. To mitigate this problem, there has been a lot of research in modifying such immobilizing devices without neglecting the accurate location of tumor. To this end, the research presented in this thesis focuses on developing a mask less system with accurately locating the position of tumor using the technique of coordinate transformation at the same time fulfilling the three important characteristics: • Comfort • Accuracy • Low price Such a system is comfortable to the patient because no confining mask system is used and we choose minimal contact points on the patient for fixing the patient. Traditionally, such type of cancer treatment is carried out in two stages: Diagnosis stage, which identifies the location of the tumor and the external markers and the Treatment stage where the tumor is treated with immobilization device being common in both the stages. In the new system, the immobilization devices vary at the two stages. The head position is monitored by using pressure sensor assembly where spring and pressure sensor setup detects the amount and direction of head deviation. We also prepare a customized 3D printed nose bridge part for extra referencing in the treatment room. Also, it is important that we use material for our immobilization devices which does not contain any metal and MRI compatible. Once the patient lies down on the treatment couch and is immobilized using the immobilization devices, then tumor location is calculated using the theory of coordinate transformation and transformation matrix in the Diagnosis and Treatment Stage. To validate the system, simulation of immobilization devices used in the new design was carried out using ANSYS Workbench 15.0 and LS-Dyna software’s Explicit Dynamics method. The simulation for the head-fixing device showed a deflection of ±0.1974 mm with respect to machine isocenter with a load of 60 N, which is lower than the customer requirement of ±3 mm with respect to machine isocenter of head deviation. The material used for the external markers for patient positioning was selected to be polyetheretherketone (PEEK) which is a radiolucent and widely used MRI compatible material. The system also takes into consideration the effect of weight loss, which is one of the drawbacks of the current systems. Although still in the development stage, this mask less system holds to be the next new variety of immobilization devices that are comfortable to the patient and less expensive to be implemented in future cancer treatment practices.Item Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts(Impact Journals, 2019-04-12) Delgado-Calle, Jesus; Kurihara, Noriyoshi; Atkinson, Emily G.; Nelson, Jessica; Miyagawa, Kazuaki; Galmarini, Carlos Maria; Roodman, G. David; Bellido, Teresita; Medicine, School of MedicineDespite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.Item IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia(BioRxiv, 2020-09-17) Rupert, Joseph E.; Bonetto, Andrea; Narasimhan, Ashok; Liu, Yunlong; O’Connell, Thomas M.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Biochemistry and Molecular Biology, School of MedicineMost patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia. Significance PDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.Item Immature teratoma in an adolescent with Proteus syndrome: A novel association(Wiley, 2021-05-04) Underwood, John S.; Ours, Christopher; Burns, R. Cartland; Ferguson, Michael J.; Pediatrics, School of MedicineProteus syndrome (PS) is a complex disorder characterized by variable clinical findings of overgrowth and tumor susceptibility. This report presents the first known association between PS and an ovarian germ cell tumor in an adolescent with immature teratoma. A review of the diagnosis of PS and associated tumors is included.Item Interleukin-1α Promotes Tumor Growth and Cachexia in MCF-7 Xenograft Model of Breast Cancer(Elsevier, 2003-12) Kumar, Suresh; Kishimoto, Hiromitsu; Chua, Hui Lin; Badve, Sunil; Miller, Kathy D.; Bigsby, Robert M.; Nakshatri, HarikrishnaProgression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1α in a subset of breast cancers and demonstrated that IL-1α is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1α in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1α (MCF-7IL-1α) in nude mice. MCF-7IL-1α cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1α expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1α-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1α cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1α cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1α cell-derived tumors, which suggests that IL-1α increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1α cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1α, induce cachexia by affecting leptin-dependent metabolic pathways.Item Lumbar Ganglioneuroma Presenting With Scoliosis(Springer Nature, 2021-07-31) Gaddipati, Ravi; Ma, Joanna; Dayawansa, Samantha; Shan, Yuan; Huang, Jason H.; Garrett, David; Qaiser, Rabia; Neurological Surgery, School of MedicineGanglioneuromas are rare, benign tumors arising from the sympathetic nervous system. The presentation of the tumor is variable and may be associated with scoliosis. Few reports of ganglioneuroma associated with scoliosis exist and most involve the thoracic spine. Here, we present a 13-year-old female with scoliosis who was found to have a lumbar ganglioneuroma. The patient was treated with a subtotal resection and lumbar spinal fusion to correct her scoliosis in a single-stage operation. The patient's symptoms and scoliosis markedly improved following treatment without any complications. Additionally, we conducted an up-to-date literature review of ganglioneuromas associated with scoliosis that have been published in the last 20 years. We discuss variations in clinical presentation and surgical approach.Item Melanoma LAMP-2C Modulates Tumor Growth and Autophagy(Frontiers, 2018-08-29) Pérez, Liliana; Sinn, Anthony L.; Sandusky, George E.; Pollok, Karen E.; Blum, Janice S.; Pathology and Laboratory Medicine, School of MedicineAutophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth in vitro and in vivo. Solid tumors such as melanomas encounter a variety of stresses in vivo including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread. Here, we report that in response to the anti-tumor, pro-inflammatory cytokine interferon-gamma, melanoma cell expression of LAMP2C mRNA significantly increased. These results prompted an investigation of whether increased melanoma cell expression of LAMP-2C might represent a mechanism to control or limit human melanoma growth and survival. In this study, enhanced expression of human LAMP-2C in melanoma cells perturbed macroautophagy and chaperone-mediated autophagy in several human melanoma lines. In vitro analysis showed increasing LAMP-2C expression in a melanoma cell line, triggered reduced cellular LAMP-2A and LAMP-2B protein expression. Melanoma cells with enhanced LAMP-2C expression displayed increased cell cycle arrest, increased expression of the cell cycle regulators Chk1 and p21, and greater apoptosis and necrosis in several cell lines tested. The increased abundance of Chk1 protein in melanoma cells with increased LAMP-2C expression was not due to higher CHEK1 mRNA levels, but rather an increase in Chk1 protein abundance including Chk1 molecules phosphorylated at Ser345. Human melanoma cell xenografts with increased LAMP-2C expression, displayed reduced growth in immune compromised murine hosts. Melanomas with high LAMP-2C expression showed increased necrosis and reduced cell density upon histological analysis. These results reveal a novel role for LAMP-2C in negatively regulating melanoma growth and survival.Item Role of High-Mobility Group Box-1 in Liver Pathogenesis(MDPI, 2019-11) Khambu, Bilon; Yan, Shengmin; Huda, Nazmul; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineHigh-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.Item SLUG/SNAI2 and Tumor Necrosis Factor Generate Breast Cells With CD44+/CD24- Phenotype(BMC, 2010-08-06) Bhat-Nakshatri, Poornima; Appaiah, Hitesh; Ballas, Christopher; Pick-Franke, Patricia; Goulet, Robert; Badve, Sunil; Srour, Edward F; Nakshatri, HarikrishnaBackground Breast cancer cells with CD44+/CD24- cell surface marker expression profile are proposed as cancer stem cells (CSCs). Normal breast epithelial cells that are CD44+/CD24- express higher levels of stem/progenitor cell associated genes. We, amongst others, have shown that cancer cells that have undergone epithelial to mesenchymal transition (EMT) display the CD44+/CD24- phenotype. However, whether all genes that induce EMT confer the CD44+/CD24- phenotype is unknown. We hypothesized that only a subset of genes associated with EMT generates CD44+/CD24- cells. Methods MCF-10A breast epithelial cells, a subpopulation of which spontaneously acquire the CD44+/CD24- phenotype, were used to identify genes that are differentially expressed in CD44+/CD24- and CD44-/CD24+ cells. Ingenuity pathway analysis was performed to identify signaling networks that linked differentially expressed genes. Two EMT-associated genes elevated in CD44+/CD24- cells, SLUG and Gli-2, were overexpressed in the CD44-/CD24+ subpopulation of MCF-10A cells and MCF-7 cells, which are CD44-/CD24+. Flow cytometry and mammosphere assays were used to assess cell surface markers and stem cell-like properties, respectively. Results Two thousand thirty five genes were differentially expressed (p < 0.001, fold change ≥ 2) between the CD44+/CD24- and CD44-/CD24+ subpopulations of MCF-10A. Thirty-two EMT-associated genes including SLUG, Gli-2, ZEB-1, and ZEB-2 were expressed at higher levels in CD44+/CD24- cells. These EMT-associated genes participate in signaling networks comprising TGFβ, NF-κB, and human chorionic gonadotropin. Treatment with tumor necrosis factor (TNF), which induces NF-κB and represses E-cadherin, or overexpression of SLUG in CD44-/CD24+ MCF-10A cells, gave rise to a subpopulation of CD44+/CD24- cells. Overexpression of constitutively active p65 subunit of NF-κB in MCF-10A resulted in a dramatic shift to the CD44+/CD24+ phenotype. SLUG overexpression in MCF-7 cells generated CD44+/CD24+ cells with enhanced mammosphere forming ability. In contrast, Gli-2 failed to alter CD44 and CD24 expression. Conclusions EMT-mediated generation of CD44+/CD24- or CD44+/CD24+ cells depends on the genes that induce or are associated with EMT. Our studies reveal a role for TNF in altering the phenotype of breast CSC. Additionally, the CD44+/CD24+ phenotype, in the context of SLUG overexpression, can be associated with breast CSC "stemness" behavior based on mammosphere forming ability.Item Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments(MDPI, 2021-02-28) Hulmi, Juha J.; Nissinen, Tuuli A.; Penna, Fabio; Bonetto, Andrea; Surgery, School of MedicineMuscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.