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Regulation and action of SKP2 and RhoA in cell and tumor models: Investigation into the molecular mechanisms responsible for the aggressive phenotype of triple-negative breast cancerFagan-Solis, Katerina D 01 January 2013 (has links)
Breast cancer tops the list of new cancer cases and is predicted to be the second leading cause of cancer deaths in women in 2012. The primary objective of the present study was to provide insights into the molecular mechanisms underlying the aggressive growth and metastasis of triple-negative and basal-like breast cancers. To study increased growth and invasive behavior in triple-negative and basal-like breast cancers we utilize both an interesting and relevant cell culture model and examination of human tissue. S-phase kinase-associated protein 2 (SKP2) plays an important role in cell cycle regulation by targeting p27 for degradation. The cyclin-dependent kinase (CDK) inhibitor p27 regulates G1/S transition by binding cyclin/CDK complexes and abrogating its activity. By targeting p27 for degradation, SKP2 frees the complexes needed to progress into the S phase of the cell cycle. Evaluation of SKP2 expression in TMX2-28 revealed significantly higher levels than in other breast cancer cell lines. Despite the high levels of SKP2 expression, p27 protein was not reduced. However, levels of the Serine 10 phosphorylated form of p27 (pSer10p27), which has been associated with increased proliferation rates, was found to be increased. Furthermore, suppression of SKP2 completely eliminated the pSer10p27 and slowed cycle progression confirming the role of SKP2 in the aggressive growth of TMX2-28 cells. Assessment of mRNA from 30 frozen human breast cancers demonstrated that SKP2 is more highly expressed in ER&agr;-negative and basal-like breast cancers. Immunohistochemical analysis of 188 breast cancers and 50 benign reduction mammoplasty tissues confirmed that SKP2 is more highly expressed in ER&agr;-negative breast cancers and for the first time demonstrated that triple-negative breast cancers are more likely to overexpress SKP2 than are non-triple-negative, but still ER&agr;-negative, tumors. In contrast to some previous reports, we did not observe an inverse relationship between SKP2 and p27 expression. Only 11% of tumors expressed high SKP2 and low p27, while 32% of tumors had high SKP2 and high p27. Although no significant relationship between SKP2 and p27 expression was observed in human breast cancers, a significant positive relationship was discovered between SKP2 and pSer10p27. Furthermore, high levels of SKP2 and pSer10p27 were observed significantly more often in ER&agr;-negative and triple negative breast tumors than in ER&agr;-positive breast cancers. Based on these results and those of the cell culture experiments showing complete elimination of pSer10p27 after suppression of SKP2 it appears that levels of pSer10p27 may be a better indicator of SKP2-dependent p27 degradation than are levels of p27. Therefore, that inhibiting SKP2 in triple-negative breast cancers expressing high levels of both SKP2 and pSer10p27 regardless of p27 levels may be a valid therapeutic approach. We determined that TMX2-28 lack MMP-1 mRNA, and MMP-2/MMP-9 protein expression; each of which is important in protease-dependent invasion. Furthermore, TMX2-28 cells have low expression of other genes key to protease-dependent invasion including Slug, Zeb 1, Zeb 2, Vimentin, Fibronectin and N-cadherin. RhoA is a member of the Rho superfamily of GTPases that acts as a molecular switch to control signal transduction and is critical to the amoeboid invasion mechanism. TMX2-28 cells have high expression of protease-independent invasion genes such as RhoA, ROCK 1, ROCK 2, and E-cadherin. Finally, treating TMX2-28 cells with a RhoA pathway inhibitor or an shRNA targeting RhoA significantly reduces their invasiveness. These data suggest that TMX2-28 cells use a RhoA-dependent, proteolytic-independent invasion mechanism. Collectively, the data presented here demonstrate the roles of SKP2 and RhoA in triple-negative and basal-like breast cancers, making both genes, as well as their pathways, desirable therapeutic targets. (Abstract shortened by UMI.)
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The role of YKL-40 in the progression of glioblastomaFrancescone III, Ralph A 01 January 2013 (has links)
Glioblastoma Multiforme (GBM) is the most common brain cancer and one of the most fatal forms of cancer overall. The average survival time is 10-14 months, and less than 10% of patients survive more than 5 years after diagnosis. It is characterized by extreme vasculature, chemo/radioresistance, and invasiveness into the normal brain. The current standard of care, which includes surgical removal of tumor, radiation, and the chemotherapeutic agent temozolomide, initially stunt tumor growth. Nevertheless, the tumor invariably rebounds and the patient succumbs to the disease. Therefore, there is an urgent need to develop new therapies for this devastating disease. YKL-40 is one of the most over-expressed proteins by GBM cells, and is elevated in the serum of patients with GBM. YKL-40 is implicated in a host of inflammatory diseases and has been shown to play a major role in the maturation of some cells of the immune system, especially macrophages. Thus, it has been suggested that YKL-40 may act as a prognostic biomarker for cancer and inflammatory disease. However, little is known about the role of YKL-40 in relation to cancer development and progression, and more work needs to be done to validate it as a biomarker or as a therapeutic target. It was the goal of the work described herein to uncover some of the key molecular mechanisms of GBM development and progression in the hopes of offering new therapeutic targets. Using a wide variety of in vitro and in vivo techniques, the role of a secreted glycoprotein YKL-40 in GBM was probed. It was demonstrated that YKL-40 enhanced angiogenesis, radioresistance, and progression of GBM cells. Moreover, inhibition of YKL-40 in mouse models markedly arrested tumor growth and vascularization, lending support to the idea of YKL-40 as a therapeutic target. Finally, YKL-40 drove GBM cells into a mesenchymal phenotype, where the tumor cells act as mural-like cells, supporting tumor vasculature networks. Hopefully, the results from these studies will offer the rationale to develop drugs against YKL-40 and potentially extend the lives of patients with this terrible disease.
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Effects of phytochemicals from Rhodiola crenulata on highly invasive breast cancer cell lines and embryonic models of migrationRodriguez-Cortes, Adaris 01 January 2013 (has links)
The root of the Tibetan plant Rhodiola crenulata is part of eastern traditional medicine. Studies have suggested that members of the Rhodiola genus display anticancer properties. In this study we examine the effect of R. crenulata in a cellular model of invasive breast cancer, this disease being the second cause of cancer death among women in the US. Deregulation of the Wnt/β-catenin pathway has been frequently observed in breast cancers and appears to have a key role in the transformation of benign cells to a malignant form. Although mutations of the Wnt growth factor are rarely observed in cancer, the Wnt signaling pathway is often up-regulated by either mutations that result in stabilization of β-catenin or by hypermethylation and subsequent loss of expression of Wnt signaling antagonists like secreted Frizzled-Related Protein 1 (SFRP1) (Hanahan and Weinberg 2000; Miyoshi, Rosner et al. 2002; Reya and Clevers 2005; Suzuki, Toyota et al. 2008) (Hanahan and Weinberg 2000; Miyoshi, Rosner et al. 2002; Reya and Clevers 2005; Suzuki, Toyota et al. 2008) (Hanahan and Weinberg 2000; Miyoshi, Rosner et al. 2002; Reya and Clevers 2005; Suzuki, Toyota et al. 2008). We used an engineered cell line in which SFRP1 expression has been knocked down. These cells were derived from 76NTert cell line, an immortalized human mammary epithelium cell line. The resulting 76NTert-siSFRP1 cells display a mesenchymal-like phenotype, invasive behavior and are more resistant to apoptosis triggered by anchorage independent conditions, or anoikis. Additionally we used a highly invasive estrogen receptor negative (ER-), progesterone receptor negative (PR-), Her2/neu negative (triple negative) breast cancer cells line MDA-MB-231. Treatment of MDA-MB-231 and 76NTert-siSFRP1 cells with an extract of R. crenulata inhibited migration and invasion of both cell types, as compared to untreated cells. Furthermore, R. crenulata sensitizes cells to anoikis but does not increase γ-irradiation induced cell death. We provide evidence that death induced by R. crenulata does not occur through the inhibition of an epithelial-to-mesenchymal transition (EMT). Taken together, our initial results suggest R. crenulata as a potential therapeutic agent for breast cancer patients with mutations in the Wnt/β-Catenin signaling pathway. Additionally, we present evidence that R. crenulata exerts its anti-metastasis effect by inhibiting cell migration and increasing cell attachment to a substrate. We demonstrate that this effect occurs by R. crenulata's modulation of the Rho GTPase effector ROCK1. We further show evidence that R. crenulata's effect on ROCK is not limited to cancer cells (in vitro), but also affects isolated and intact embryonic tissues. We discovered that treatment of embryos with R. crenulata can cause a spina bifida phenotype, suggesting (1) that compounds in R. crenulata may prove detrimental to a developing embryo, and (2) the active compounds in R. crenulata may prove useful in the study of developmental anomalies that lead to conditions such as spina bifida. More importantly, our results suggest that pregnant women should avoid taking R. crenulata-containing supplements during pregnancy. Compounds in R. crenulata may be contraindicative to the pregnancy and cause injury to a developing fetus. The information provided may help health providers offer better advice on natural supplements to expecting mothers. We also characterized and identified multiple R. crenulata compounds and report predicted protein targets for these compounds. Finally, we provide evidence that R. crenulata affects cancer cell metabolism and suggest potential protein targets of the chemical components of this extract. This study provides new information that will help dissect the mechanisms of action of the R. crenulata compounds and possible synergies amongst them.
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Glycoprotein-NMB and the microphthalmia-associated transcription factor regulatory circuitry in tuberous sclerosis complex associated tumorsProbst, Clemens Kemena 08 June 2020 (has links)
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic syndrome characterized by the growth of benign tumors in multiple organ systems including brain, lung, kidney, skin, and heart. Kidney angiomyolipoma (AML) are benign, slow growing renal tumors that are seen in about 80% of TSC patients, but also occur sporadically. Although heterogeneous in nature, AMLs have a relatively low somatic mutation rate compared to most other cancers, with biallelic loss of either TSC1 or TSC2 gene considered as the primary and sufficient driver for tumor development. We hypothesized that epigenetic alterations of the AML chromatin landscape change the transcriptional dynamics of the underlying genetic system that supports and gives rise to the tumor-cell phenotype. Our data have identified microphthalmia-associated transcription factor (MITF) to be an orchestrating gene in AML development, as 6 out of the top 10 differentially expressed genes in AML are putative MITF-target genes. Integrative analysis of RNA Seq (n=28), H3K27ac ChIP Seq (n=25) and MITF ChIP Seq data (n=3), obtained from fresh-frozen kidney AML specimens, has enabled us to characterize components of a tumor-specific regulatory network under the transcriptional control of MITF. This novel approach has the potential to identify a variety of therapeutic targets, as well as provide unprecedented insight into the mechanisms behind angiomyolipoma development. / 2021-06-07T00:00:00Z
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Marginal Zone Lymphoma with hyper viscosity syndrome responding to plasmapheresis and chemo immunotherapyKhalaf, Rossa, Tawadros, Fadi, SEGIE, ASHA, Jaishankar, Devapiran 05 April 2018 (has links)
Marginal zone lymphomas (MZLs) are a heterogeneous group of neoplasms that resemble the normal B-cell populations of the marginal zone of a lymph node. It includes three different subtypes, nodal, splenic, and extra -nodal, each, with overlapping features and yet unique characteristics. Nodal Marginal Zone lymphoma (NMZL) accounts for only 1% of all Non-Hodgkin Lymphoma (NHL). Marginal Zone lymphoma with plasmacytic differentiation is not very common. We report a unique case of Nodal marginal zone lymphoma initially presenting with lymphocytosis and lymphadenopathy, work up indicating low grade lymphoma, subsequently developing hyper viscosity syndrome due to symptomatic IgM monoclonal gammopathy. A 68 year old female was noted to have persistent leukocytosis with lymphocytic predominance after completing treatment for a urinary tract infection. Clinical exam revealed bilateral axillary adenopathy. CT scan of neck, chest, abdomen and pelvis revealed axillary, mediastinal and retroperitoneal adenopathy with splenomegaly. Chronic lymphocytic leukemia (CLL) was suspected and work up initiated. Peripheral blood Flow-cytometry revealed 24% small B-cells with surface kappa light chain restriction consistent with mature B-cell lymphoma or leukemia without typical immune phenotype of CLL. Lab reported significant elevation of total protein at 10 g/dl. Workup for para-proteinemia consistent with IgM level over 5000 mg/dl, with serum viscosity of 8. Axillary lymph node excisional biopsy reported marginal zone lymphoma with plasmacytic differentiation. Bone marrow biopsy demonstrated 42% monoclonal B-cells without co-expression of CD5 and CD23. FISH studies positive for duplication 1q and Molecular testing negative for MYDD88 mutation. Decision was made to initiate chemo therapy with R-CVP for a total of six cycles. Her treatment course was complicated by symptomatic hyper viscosity syndrome necessitating therapeutic plasmapheresis. Patient successfully completed chemo immunotherapy with normalization of blood counts, resolution of palpable adenopathy and splenomegaly. Nodal marginal lymphoma (NMZL) originates from nodal mono-cytoid or marginal zone B cells and the pathogenesis usually involves acquired mutations in oncogenes and tumor suppressor genes involving MLL2, PTTPRD, NOTCH2, and KLF2 genes. The median age is round 70 years with slight male predominance. The clinical picture varies and usually includes generalized lymphadenopathy along with B symptoms and infrequently with mild monoclonal gammopathy (any immunoglobulin subtype-IgM uncommon). Marginal Zone lymphoma with plasmacytic differentiation is not as common and shares immuno-histochemical features with lympho-plasmacytic lymphoma (LPL). They both express B cell markers CD19, CD20, and CD22) and not CD5, CD10 or CD23. Clinically, NMZL is more likely to present with prominent lymphadenopathy, while LPL can exclusively affect the marrow without extramedullary involvement. IgM levels in NMZL tend to be lower than in LPL, typically lower than 1000 mg/d. MYD88 mutation is very common in LPL, and can be seen in 10-15% NMZL. The presence of IgM monoclonal gammopathy increases the serum viscosity which can lead to serious neurologic and ophthalmologic complications. Treatment involves emergent plasmapheresis. Our case highlights a less common NHL, presenting with significant paraproteinemia and developing hyper viscosity syndrome with impressive response to plasmapheresis and chemo immunotherapy.
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Efficacy of prostate cancer treatments in African American menReynolds, Janeen 27 February 2021 (has links)
Prostate Cancer is one of the leading causes of male cancer related deaths. African American men who are diagnosed with this disease are over two times more likely to die from it than any other ethnic group. Even with this being a proven fact there are little to know studies that investigate why nor how to remedy the disparity. When a man begins the screening process and all the way until the beginning of treatment, the same guidelines are followed regardless of the patients’ ethnic background. This tactic has led to the developed of the disparity that: African American, even when diagnosed with prostate cancer of similar aggressiveness and receive the same treatments as other non-African American patients, are continuously found to have a less likely chance of survival. Despite all the research and the recurring disparity treatments are continued in the same manner. While the exact reasoning as to why African American males do not respond similarly to treatments as other ethnic groups remains unexplained. It could stem from internal differences, screening process, diagnosing methods, or the treatments themselves. Internal differences, like melanin levels, cannot be changed, but there are ways to circumvent these inevitable differences. Existing studies allow for parallels to be drawn about what effect these inevitable differences may have on the African American response to treatment methods; but clinical trials will need to be completed in order to determine if the parallels drawn hold any merit and if they have the ability to fix the disparity. Once those differences are understood, it will be time to conduct new research to determine if those changes are sufficient enough to eliminate the over two percent chance that African American men are more likely to die from a disease when compared to others.
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Determination of targets of LOXL2 on human gingival fibroblast stimulated by cancer cell condition mediaSingh, Varun 09 December 2020 (has links)
AIM: Lysyl oxidase-like 2 (LOXL2) has emerged as a biomarker for oral squamous cell carcinoma (OSCC). Its overexpression is associated with poor prognosis in patients, however, the reason behind it is not well understood. The aim of this study is to determine the target for LOXL2 on human gingival fibroblasts (HGF) treated with cancer-conditioned media.
MATERIAL AND METHODS: 30 large (150 x 20mm) plates of human gingival fibroblast cells (HGF) were cultured. For serum depletion, HGF or cancer cells were washed two times with PBS and treated with serum-free DMEM for 24 h. Condition media (CM) was produced by growing cancer cells till they were confluent. Then, 10 plates of HSC3 cells were washed twice with PBS, and were treated with serum-free DMEM for 24 h and the conditioned media was collected. Three (A – CMI, B - CM, C- SF) groups of 10 plates each respectively were made. After incubation for 6 hours, HGFs were washed with ice cold PBS and scraped in about and equal volume of glass beads were added and were subjected to dialysis. Proteins from human fibroblasts were extracted and bioyinylated with biotin hydrazide followed by sodium cyanoborohydride reduction. For affinity binding to Neutravidin, 200 microliters of suspended Neutravidin-agarose was then added to a Neutravidin column at room temperature and equilibrated with 1 ml binding buffer. . The bound proteins were collected and subjected to SDS Page western blot and probed for PDGF Beta, Integrin Alpha V and Beta Actin.
RESULTS: PDGFR beta in fibroblasts displayed marked reduction in oxidation when PSX-S1C inhibitor of LOXL2 was added to cancer cell condition media.
CONCLUSION: The reduction of affinity of PDGF-BB for PDGFR in both the samples indicates the priming role of LOXL2 on PDGFR, which was evident when the inhibitor was added to the samples.
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Predisposing, Precipitating, Perpetuating, and Protective Factors Related to Distress in Family Members of Children with Cancer: A Systematic ReviewMurawsky, Mackenzie 13 June 2022 (has links)
Background:
This systematic review aimed to identify factors related to psychological distress in family members of pediatric cancer patients on active treatment.
Methods:
Search strategies were entered into six academic databases. Randomized, nonrandomized, quantitative descriptive and mixed method studies, examining factors related to psychological distress in the population of study were included. Identified factors were coded as per the 4P’s of case formulation.
Results:
59 studies were included. Parental factors identified: 24 predisposing factors; 12 precipitating factors; 35 perpetuating factors; and six protective factors. Sibling factors identified: five predisposing factors; one precipitating factor; 14 perpetuating factors; and two protective factors. A text-based, narrative synthesis and tabular summaries are presented.
Discussion:
Findings can support the: (1) recognition of distress exhibited in family members; and (2) the timing of interventions specific to the chronological manifestations of distress. Assessment of risk of bias was not done.
Other:
International Prospective Register for Systematic Reviews (PROSPERO) registration number CRD42018109802. No sources of funding to declare.
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Myasthenia Gravis Induced or Exacerbated by Immune Checkpoint Inhibitors: A Rising ConcernHajihossainlou, Behnam, Vasileva, Alisa, Manthri, Sukesh, Chakraborty, Kanishka 23 August 2021 (has links)
Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options.
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Thymic Basaloid Carcinoma: A Rare Clinical EntityManthri, Sukesh, Rehman, Haroon H., Costello, Patrick N., Chakraborty, Kanishka 01 November 2019 (has links)
No description available.
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