Neoplasms Commons^™

Metabolic Regulation Of Cellular Signaling, Rashid John Darbandi

Theses and Dissertations (ETD)

Using the biochemically tractable Xenopus oocyte model system, we have previously characterized a novel metabolic regulation of cell death. We found that glucose-6-phosphate (G6P) via the pentose phosphate pathway leads to increased nicotinamide adenine dinucleotide phosphate (NADPH) levels, a subsequent increase in cytosolic acetyl-coenzyme A and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). We recently identified coenzyme A (CoA), derived from the breakdown of acetyl-CoA, as the key metabolic signal that mediates a novel mechanism of calmodulindependent activation of CaMKII. CoA binds directly to the calmodulin (CaM) binding domain (CaMBD) of CaMKII resulting in its activation and downstream inhibitory ...

Managing Renal Cell Carcinoma Associated Paraneoplastic Syndrome With Nephron-Sparing Surgery In A Patient With Von Hippel-Lindau., John M Dibianco, Julie Y An, Sally Tanakchi, Zachary Stanik, Aidan Mcgowan, Mahir Maruf, Abhinav Sidana, Amit Lodha Jain, Akhil Muthigi, Arvin K George, Christopher Bayne, W Marston Linehan, Shawna L Boyle, Adam R Metwalli

Urology Faculty Publications

A patient with germline von Hippel-Lindau (VHL) gene alteration and history of multiple tumors present with classical paraneoplastic syndrome (PNS) associated with renal cell carcinoma (RCC). She underwent open nephron sparing surgery with resolution of symptoms. She remained without recurrence of RCC for the initial 2 years of her follow-up. To the best of our knowledge, this case represents the first in which PNS was specifically resolved using a partial nephrectomy in a patient with VHL. This case report provides initial evidence for the potential role of nephron sparing surgery in the management of paraneoplastic symptoms associated with hereditary RCC.

Changes In The Inflammatory Potential Of Diet Over Time And Risk Of Colorectal Cancer In Postmenopausal Women, Fred K. Tabung, Susan E. Steck, Yunsheng Ma, Angela D. Liese, Jiajia Zhang, Dorothy S. Lane, Gloria Y. Ho F, Lifang Hou, Linda Snetselaar, Judith K. Ockene, James R. Hebert

University of Massachusetts Medical School Faculty Publications

We examined the associations between changes in dietary inflammatory potential and risk of colorectal cancer (CRC) in 87,042 postmenopausal women recruited from 1993-1998 into the Women's Health Initiative. Food frequency questionnaire data were used to compute patterns of change in dietary inflammatory index (DII) scores and cumulative average DII scores over 3 years. Cox regression models were used to estimate hazard ratios for CRC risk. After a median 16.2 years follow-up, 1,038 CRC cases were diagnosed. DII changes were not substantially associated with overall CRC, but proximal colon cancer risk was higher in the pro-inflammatory change ...

Rna-Sequencing Reveals Direct Targets Of Tumor Suppressor Mir-203 In Human Mammary Epithelial Cells, Alexander P. Boardman, Victoria E. Pedanou, Tessa M. Simone, Michael R. Green

Senior Scholars Program

Background: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Since a significant portion of cases present with or progress to metastatic disease, furthering our understanding of metastasis is critical to develop better treatments. Epithelial cells maintain contact with the extracellular matrix (ECM) predominantly via integrin engagement, a process required for tissue integrity and barrier function. In non-transformed cells, loss of ECM adhesion promotes a specialized form of programmed cell death, anoikis. In order for efficient metastasis to occur, breast tumor cells must evade anoikis. miR-203, known to be down-regulated in several cancers, was found by our ...

Cancer-Specific Mortality, Cure Fraction, And Noncancer Causes Of Death Among Diffuse Large B-Cell Lymphoma Patients In The Immunochemotherapy Era., Nadia Howlader, Angela B Mariotto, Caroline Besson, Gita Suneja, Kim Robien, Naji Younes, Eric A Engels

Epidemiology and Biostatistics Faculty Publications

BACKGROUND

Survival after the diagnosis of diffuse large B-cell lymphoma (DLBCL) has been increasing since 2002 because of improved therapies; however, long-term outcomes for these patients in the modern treatment era are still unknown.

METHODS

Using Surveillance, Epidemiology, and End Results data, this study first assessed factors associated with DLBCL-specific mortality during 2002-2012. An epidemiologic risk profile, based on clinical and demographic characteristics, was used to stratify DLBCL cases into low-, medium-, and high-risk groups. The proportions of DLBCL cases that might be considered cured in these 3 risk groups was estimated. Risks of death due to various noncancer causes ...

Parp Inhibitor Upregulates Pd-L1 Expression And Enhances Cancer-Associated Immunosuppression, Shiping Jiao

UT GSBS Dissertations and Theses (Open Access)

With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates ...

Choriocarcinoma With Brain, Lung And Vaginal Metastases Successfully Treated Without Brain Radiation Or Intrathecal Chemotherapy: A Case Report, Anja Frost, Jonathan Sherman, M. Katayoon Rezaei, Alivia Aron, Micael Lopez-Acevedo

Neurological Surgery Faculty Publications

Highlights:

• • There is no consensus on optimal treatment for GTN and brain metastases.
• • Brain metastasis treated with craniotomy and intravenous, EMA-CO chemotherapy
• • Intravenous high-dose methotrexate may be adequate to treat brain metastases.

Characterization Of Murine Breast Cancer Cell Lines For Anti-Cancer Vaccine, Haven N. Frazier

Biological Sciences Undergraduate Honors Theses

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States (1). While treatments involving radiation and chemotherapy currently exist, disease must be detected early in order for the treatments to be somewhat effective, and there is no effective treatment after metastasis occurs (2). Additionally, current therapies do not mitigate tumor immunosuppression. Decreasing the tumor-associated immunosuppressive conditions while activating antitumor immunity could prevent recurrence and metastasis, possibly leading to an effective treatment for cancer (3). Tumor cell vaccines could possibly address this issue and have become a ...

Systematic Analysis Of Whole Exome Sequencing Determines Ret G691s Polymorphism As Germline Variant In Melanoma, Brent J. Smith Jr, Jennifer D. Hintzsche, Carol M. Amato, Aik-Choon Tan, Keith R. Wells, Allison J. Applegate, Rita T. Gonzalez, Jodie R. Barr, William A. Robinson

Marshall Journal of Medicine

Abstract

The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by glial cell derived neutrotrophic factor (GDNF). Previous studies have found that a single nucleotide polymorphism (SNP), RETp (G691S), in the juxtamembrane domain enhances the signaling pathway and promotes tumor growth by GDNF in pancreatic and thyroid cancer in addition to melanoma. It is uncertain however whether this SNP is a germline variant or somatic mutation. A prior study reported that the RETp variant was a germline SNP in desmoplastic and non-desmoplastic melanomas. In the present study, we examined both melanoma tissue samples and matching peripheral blood DNA ...

Investigating E2f Independent Cell Cycle Control And Tumor Suppression By Prb, Michael J. Thwaites

Electronic Thesis and Dissertation Repository

Cellular division is primarily controlled at the G1 to S-phase transition of the cell cycle by the retinoblastoma tumor-suppressor protein (pRB). The ability of pRB to restrict S-phase entry is primarily attributed to the repression of E2F transcription factors required to upregulate cell cycle target genes necessary for cellular division. Interestingly, while pRB is disrupted in the vast majority of human cancers, mutations typically target upstream regulators of pRB leading to inactivation through hyperphosphorylation. The rarity of direct pRB mutations suggests that the regulation of the cell cycle by pRB may involve additional mechanisms outside of E2F repression, as this ...

Unification Of De Novo And Acquired Ibrutinib Resistance In Mantle Cell Lymphoma., Xiaohong Zhao, Tint Lwin, Ariosto Silva, Bijal Shah, Jiangchuan Tao, Bin Fang, Eduardo Sotomayor, +Several Additional Authors

Medicine Faculty Publications

The novel Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling ...

Metastasis-Associated Protein 1 Is An Upstream Regulator Of Dnmt3a And Stimulator Of Insulin-Growth Factor Binding Protein-3 In Breast Cancer., S Deivendran, Hezlin Marzook, T R Santhoshkumar, Rakesh Kumar, M Radhakrishna Pillai

Biochemistry and Molecular Medicine Faculty Publications

Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression ...

Breast Lesions Detected Via Breast Specific Gamma Imaging: Descriptor Characteristics And Positive Predictive Value, Jason Ching, Rachel Brem

GW Research Days 2016 - Present

Background:

Breast Specific Gamma Imaging (BSGI) is increasingly being used as a diagnostic tool for the detection of breast cancer, using technetium 99m sestamibi to identify physiological differences between cancerous and normal breast tissue. Our study retrospectively evaluates pathologic correlates to positive BSGI findings in the detection of breast cancer.

Methods:

A retrospective review was performed of patients with positive BSGI examinations (200 total) during a 1-year period. Using biopsy/surgical pathology or 2 years mammography/ultrasound/MRI follow-up as correlation, we determined the positive predictive values of BSGI findings when categorized by: (i) character of suspicious region [mass, non-mass ...

Mutations In Braf Are Associated With Higher Levels Of Immune Infiltrates In Microsatellite-Stable Colon Cancer, Jake Rubin, Eduard Porta Parto

GW Research Days 2016 - Present

While BRAF is among the most well-established oncogenes in human cancers, more recently it has garnered attention for its role in suppressing antitumor immunity, especially in melanoma. Because tumor-infiltrating lymphocyte (TIL) density is strongly prognostic in colorectal cancer (CRC)⁷, we decided to investigate the connection between TIL density and the BRAF-activating V600E mutation in CRC.

We used ESTIMATE to quantify immune infiltrate in samples from the TCGA colon adenocarcinoma (COAD) dataset (n = 216). This is an algorithm that uses the gene-expression signature of 141 immune-related genes to infer the presence of immune cells in the tumor infiltrate. COAD samples ...

Tgfβ/Smad3 Regulates Proliferation And Apoptosis Through Irs-1 Inhibition In Colon Cancer Cells., Katie L. Bailey, Ekta Agarwal, Sanjib Chowdhury, Jiangtao Luo, Michael G. Brattain, Jennifer D. Black, J. Wang

Journal Articles: Eppley Institute

In this study, we have uncovered a novel crosstalk between TGFβ and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGFβ/Smad3 signaling. Loss or attenuation of TGFβ activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression ...

Androgen Receptor Stimulation Decreases Pd-L1 Expression In An Androgen-Responsive Thyroid Cancer Model, Timmy O'Connell, Melanie E. Jones, Anvita Gupta, Tali Lando, Deya Jourdy, Augustine Moscatello, Raj K. Tiwari, Jan Geliebter

NYMC Faculty Posters

This work lays the foundation for investigation into the role of PD-L1 in thyroid cancer. It is the first study to show the potential link between androgen, androgen receptor, and the immune checkpoint molecule, PD-L1. Androgen may provide a protective advantage in males against thyroid cancer by decreasing PD-L1 expression thereby allowing T cell infiltration and elimination of tumors, and could potentially offer an explanation as to the lower thyroid cancer incidence in men. Higher expression levels of PD-L1 in female thyroid cancer patients may indicate an opportunity for sex-based therapeutics.

The Role Of Estradiol Metabolism In Urogenital Schistosomiasis-Induced Bladder Cancer, Nuno Vale, Maria Gouveia, Gabriel Rinaldi, Julio Santos, Lucio Lara Santos, Paul J. Brindley, Jose Correia Da Costa

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Urogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasisinduced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these ...

Principles Of Radiation Oncology, Richard S. Pieters, Linda Ding, Harry Bushe, Jesse N. Aronowitz

Cancer Concepts: A Guidebook for the Non-Oncologist

This chapter in Cancer Concepts: a Guidebook for the Non-Oncologist describes the principles of Radiation Oncology. Radiation Oncology utilizes ionizing radiation to treat cancer (and occasionally a few benign conditions). Radiotherapy or radiation therapy (RT) was initially developed in conjunction with diagnostic radiology, but has evolved into a separate specialty. Currently, more than fifty percent of cancer patients undergo RT at some point during the course of their cancer. Most receive treatment with curative intent (radical therapy); however, patients with incurable disease receive shorter, gentler courses of therapy to relieve cancer-induced symptoms.

Ipsilateral Lower Limb Weakness After Sarcoma Treatment: A Case Report, Jennifer Baima, Amanda Doodlesack, Jennifer Lafemina

Orthopedics and Physical Rehabilitation Publications and Presentations

Case Diagnosis: Our patient experienced worsening left foot neuropathy following chemotherapy and radiation treatment for sarcoma.

Case Description: A 24-year-old man underwent local resection of a 12cm x 8cm x 14.5cm rhabdomyosarcoma in the left vastus lateralis. Then, he was treated with vincristine for 40 weeks and radiation to the left lateral thigh with a maximum dose of 50.4 Gy. The sciatic nerve was outside the target area and received a lower dose. While undergoing chemotherapy, the patient experienced bilateral dysesthesias in his fingertips and feet. He had no history of neuropathy prior to treatment. After chemotherapy was ...

Cold Atmospheric Plasma, A Novel Promising Anti-Cancer Treatment Modality., Dayun Yan, Jonathan H Sherman, Michael Keidar

Neurological Surgery Faculty Publications

Over the past decade, cold atmospheric plasma (CAP), a near room temperature ionized gas has shown its promising application in cancer therapy. Two CAP devices, namely dielectric barrier discharge and plasma jet, show significantly anti-cancer capacity over dozens of cancer cell lines in vitro and several subcutaneous xenograft tumors in vivo. In contrast to conventional anti-cancer approaches and drugs, CAP is a selective anti-cancer treatment modality. Thus far establishing the chemical and molecular mechanism of the anti-cancer capacity of CAP is far from complete. In this review, we provide a comprehensive introduction of the basics of CAP, state of the ...