Medicine and Health Sciences Commons^™

A Multidisciplinary Approach To Triage Patients With Breast Disease During The Covid-19 Pandemic: Experience From A Tertiary Care Center In The Developing World, Abida K. Sattar, Hania Shahzad, Adnan Abdul Jabbar, Azmina Tajdin Valimohammad, Sadaf Khan, Yasmin Vellani, Romana Idrees, Nasir Ali, Imrana Masroor, Humera Saeed, Gulzar S. Lakhani, Nadia Ayoub, Atif Waqar, Muhammad Zia-Ul Islam, Salman Kirmani, Asad Latif, Ather Enam

Section of General Surgery

Background: The COVID-19 pandemic has created a need to prioritize care because of limitation of resources. Owing to the heterogeneity and high prevalence of breast cancers, the need to prioritize care in this vulnerable population is essential. While various medical societies have published recommendations to manage breast disease during the COVID-19 pandemic, most are focused on the Western world and do not necessarily address the challenges of a resource-limited setting.
Aim: In this article, we describe our institutional approach for prioritizing care for patients presenting with breast disease.
Methods and results: The breast disease management guidelines were developed and approved …

Improved Prognostic Stratification Using Circulating Tumor Cell Clusters In Patients With Metastatic Castration-Resistant Prostate Cancer., Chun Wang, Zhenchao Zhang, Weelic Chong, Rui Luo, Ronald E Myers, Jian Gu, Jianqing Lin, Qiang Wei, Bingshan Li, Timothy R Rebbeck, Grace Lu-Yao, William K Kelly, Hushan Yang

Department of Medical Oncology Faculty Papers

Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 …

Discovery Of Small Molecules Targeting The Tandem Tudor Domain Of The Epigenetic Factor Uhrf1 Using Fragment-Based Ligand Discovery, Lyra Chang, James Campbell, Idris O Raji, Shiva K R Guduru, Prasanna Kandel, Michelle Nguyen, Steven Liu, Kevin Tran, Navneet K Venugopal, Bethany C Taylor, Matthew V Holt, Nicolas L Young, Errol L G Samuel, Prashi Jain, Conrad Santini, Banumathi Sankaran, Kevin R Mackenzie, Damian W Young

Faculty, Staff and Students Publications

Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and …

'Educated' Osteoblasts Reduce Osteoclastogenesis In A Bone-Tumor Mimetic Microenvironment., Alexus D. Kolb, Jinlu Dai, Evan T. Keller, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on …

Mithramycin And Analogs For Overcoming Cisplatin Resistance In Ovarian Cancer, David Schweer, J. Robert Mccorkle, Jurgen Rohr, Oleg V. Tsodikov, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, …

Integrated Genetic And Metabolic Landscapes Predict Vulnerabilities Of Temozolomide Resistant Glioblastoma Cells., Selva Rupa Christinal Immanuel, Avinash D Ghanate, Dharmeshkumar S Parmar, Ritu Yadav, Riya Uthup, Venkateswarlu Panchagnula, Anu Raghunathan

Articles, Abstracts, and Reports

Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, …

Myc Regulates Ribosome Biogenesis And Mitochondrial Gene Expression Programs Through Its Interaction With Host Cell Factor-1., Tessa M. Popay, Jing Wang, Clare M. Adams, Gregory Caleb Howard, Simona G. Codreanu, Stacy D. Sherrod, John A. Mclean, Lance R. Thomas, Shelly L. Lorey, Yuichi J. Machida, April M. Weissmiller, Christine M. Eischen, Qi Liu, William P. Tansey

Department of Cancer Biology Faculty Papers

The oncoprotein transcription factor MYC is a major driver of malignancy and a highly validated but challenging target for the development of anticancer therapies. Novel strategies to inhibit MYC may come from understanding the co-factors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here we interrogate how one MYC co-factor, host cell factor (HCF)-1, contributes to MYC activity in a human Burkitt lymphoma setting. We identify genes connected to mitochondrial function and ribosome biogenesis as direct MYC/HCF-1 targets and demonstrate how modulation of the MYC-HCF-1 interaction influences cell growth, metabolite profiles, global …

Prognostic Gene Expression Signatures Of Breast Cancer Are Lacking A Sensible Biological Meaning., Kalifa Manjang, Shailesh Tripathi, Olli Yli-Harja, Matthias Dehmer, Galina Glazko, Frank Emmert-Streib

Articles, Abstracts, and Reports

The identification of prognostic biomarkers for predicting cancer progression is an important problem for two reasons. First, such biomarkers find practical application in a clinical context for the treatment of patients. Second, interrogation of the biomarkers themselves is assumed to lead to novel insights of disease mechanisms and the underlying molecular processes that cause the pathological behavior. For breast cancer, many signatures based on gene expression values have been reported to be associated with overall survival. Consequently, such signatures have been used for suggesting biological explanations of breast cancer and drug mechanisms. In this paper, we demonstrate for a large …

Multiplex Immunofluorescence To Measure Dynamic Changes In Tumor-Infiltrating Lymphocytes And Pd-L1 In Early-Stage Breast Cancer., Katherine Sanchez, Isaac Kim, Brie Chun, Joanna Pucilowska, William L. Redmond, Walter Urba, Maritza Martel, Yaping Wu, Mary Campbell, Zhaoyu Sun, Gary Grunkemeier, Shu-Ching Chang, Brady Bernard, David B Page

Articles, Abstracts, and Reports

BACKGROUND: The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents.

METHODS: Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine …

Identifying The Mirna Signature Association With Aging-Related Senescence In Glioblastoma., Mutharasu Gnanavel, Akshaya Murugesan, Saravanan Konda Mani, Olli Yli-Harja, Meenakshisundaram Kandhavelu

Articles, Abstracts, and Reports

Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein-protein, protein-ncRNA, and protein-peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from …

Guillain-Barre Syndrome Amid Osteosarcoma Treatment: A Therapeutic Dilemma And Literature Review., Geraldine Peralta Suarez, David W Deng, Raquel Silva, Gabriel Tinoco

Oncology Articles

Guillain-Barre syndrome (GBS) is a clinical syndrome with multiple variants. GBS is defined as an acute demyelinating polyneuropathy commonly preceded by infection (bacterial or viral), trauma, or inflammatory processes, which triggers an autoimmune response that affects the peripheral nervous system. This case report describes a patient with high-grade osteosarcoma that completed neoadjuvant chemotherapy and underwent surgical resection with no immediate complications. Fourteen days after the surgery, the patient developed an acute inflammatory demyelinating polyradiculopathy consistent with GBS. As the five-year survival without chemotherapy is only around 20%, this challenging clinical scenario raised questions regarding adjuvant chemotherapy's safe completion in this …

The U-Net-Based Active Learning Framework For Enhancing Cancer Immunotherapy, Vishwanshi Joshi

Theses, Dissertations and Capstones

Breast cancer is the most common cancer in the world. According to the U.S. Breast Cancer Statistics, about 281,000 new cases of invasive breast cancer are expected to be diagnosed in 2021 (Smith et al., 2019). The death rate of breast cancer is higher than any other cancer type. Early detection and treatment of breast cancer have been challenging over the last few decades. Meanwhile, deep learning algorithms using Convolutional Neural Networks to segment images have achieved considerable success in recent years. These algorithms have continued to assist in exploring the quantitative measurement of cancer cells in the tumor microenvironment. …

The Epigenetic Effects Of Omega-3 Fatty Acids In Diffuse Large B-Cell Lymphoma, Tanner Jeffrey Bakhshi

Theses, Dissertations and Capstones

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It is an aggressive cancer, with 50-70% of patients diagnosed at an advanced stage and 30-50% of patients not cured by chemoimmunotherapy. DLBCL is almost always caused by genetic damage sustained during the germinal center (GC) reaction. The mechanisms that govern the GC reaction bear a striking resemblance to those that drive DLBCL. Genomic studies have shown that some of its most common mutations occur in genes that encode epigenetic modifiers, including the lysine (histone) acetyltransferases CREBBP and p300. These mutations prevent the acetylation of multiple histone residues, …

Mechanisms Of Apoptosis Induced By Actinomycin D In Aerodigestive Tract Cancers, Adeoluwa Ayodeji Adeluola

Theses, Dissertations and Capstones

Upper aerodigestive tract cancers including cancers of the oral cavity, pharynx, larynx, esophagus, and lungs are the most prevalent cancers and leading causes of cancer-related deaths. Collectively, over 300,000 new cases and 146,500 deaths are projected within the US in the year 2021. Drug-associated toxicities, as well as resistance to therapy (intrinsic and acquired), are big challenges for successfully treating these cancers. Recent studies have shown that combining low-dose actinomycin D with existing therapies is a promising strategy to reduce toxicity (cyclotherapy) and to overcome resistance. The development of these treatment strategies however requires an understanding of the molecular mechanisms …

Multiple Myeloma Cells Graphs And Figures Inhibit Adipogenesis, Increase Senescencerelated And Inflammatory Gene Transcript Expression, And Alter Metabolism In Preadipocytes, Michaela R. Reagan, Heather Fairfield, Samantha Costa, Carolyne Falank, Mariah Farrell, Connor S. Murphy, Anastasia D'Amico, Heather Driscoll

Costas T. Lambrew Research Retreat 2021

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.

Investigation Of The Relationship Between Obesity, Weight Cycling, And Tumor Progression In Murine Myeloma Models, Heather Fairfield, Catherine R. Marinac, Mariah Farrell, Brenda M. Birmann, Michaela R. Reagan

Costas T. Lambrew Research Retreat 2021

We investigated this relationship in two murine myeloma models with a high fat diet (HFD) to induce obesity, and a diet cycling (DC) regimen to model weight cycling.

Propranolol Sensitizes Vascular Sarcoma Cells To Doxorubicin By Altering Lysosomal Drug Sequestration And Drug Efflux, Jhuma Saha, Jong Hyuk Kim, Clarissa N. Amaya, Caleb M. Witcher, Ali Khammanivong, Derek M. Korpela, David R. Brown, Josephine Taylor, Brad A. Bryan, Erin B. Dickerson

Faculty Publications

Angiosarcoma is a rare cancer of blood vessel–forming cells with a high patient mortality and few treatment options. Although chemotherapy often produces initial clinical responses, outcomes remain poor, largely due to the development of drug resistance. We previously identified a subset of doxorubicin-resistant cells in human angiosarcoma and canine hemangiosarcoma cell lines that exhibit high lysosomal accumulation of doxorubicin. Hydrophobic, weak base chemotherapeutics, like doxorubicin, are known to sequester within lysosomes, promoting resistance by limiting drug accessibility to cellular targets. Drug synergy between the beta adrenergic receptor (β-AR) antagonist, propranolol, and multiple chemotherapeutics has been documented in vitro, and …

Treatment Of Orbital Lesions Using Cyberknife Stereotactic Radiosurgery, Emily Morahan

Student Research Poster Presentations 2021

The purpose of the research done was to evaluate the use of CyberKnife Stereotactic Radiosurgery (SRS) for treating orbital lesions. Efficacy and tolerability of such treatment was analyzed with data drawn from multiple sources, regarding dose and fractionation, quality of life following treatment(s) and prognosis. CyberKnife SRS is the newest, most advanced model of radiation delivery systems, featuring a robotic arm capable of manipulating the linear accelerator into thousands of unique angles. The addition of new angles allows for a more precise concentration of radiation delivered to the lesions. In the case of optic lesions, it is crucial to minimize …

Effect Of Inhibition Of Glycogen Catabolism In Hepatocellular Carcinoma Cells, Shrikant Barot

Theses and Dissertations

Metabolic reprogramming is one of the important features of cancers, and there has been growing interest in targeting metabolic proteins to treat cancer. Glycogen is a polymer of glucose and serves as its storage unit in cells. Glycogen can provide energy to cells during the situations of high energy demand. A number of tumors are known to contain high levels of glycogen than their normal tissue counterparts. The liver plays an essential role in maintaining glucose homeostasis in the body via storing it into glycogen. The significance of glycogen metabolism in patients suffering from hepatocellular carcinoma (HCC) has not been …

Crippling Rapid Evolution Of Metastasis And Drug Resistance In A549 Non-Small Cell Lung Cancer Cells With The Clinically Relevant Hsp90 Inhibitor Auy922, Nickolas Anthony Bacon

Theses, Dissertations and Capstones

The ability for species to evolve new features in response to changing circumstances in order to survive and propagate is a ubiquitous observation on both the macroscopic and microscopic levels of living systems. It should be no surprise, then, that diseases such as cancer utilize their own forms of adaptation to perpetuate themselves when exposed to external threats. Indeed, concepts drawn from Darwinian evolution are now widely accepted to help explain certain aspects of carcinogenesis and malignant progression, the sum of which have come to be known as the theory of tumor evolution. Since metastasis and drug resistance are features …

Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting The Myc Pathway, Mariah Farrell, Heather Fairfield, Anastasia D'Amico, Carolyne Falank, Connor Murphy, Michaela Reagan

Costas T. Lambrew Research Retreat 2021

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.

The Nci/Nih Cancer Moonshot Biobank (Cmb) And The Maine Cancer Genetics/Genomics Education Core (Me-Cgec) Collaborate To Improve Cancer Care In Maine, Anne C. Breggia, Sue Miesfeldt, Neil Korsen, Jill Prescott, Lisa Lemire, Meghan Searight, Jamie Saunders, Scot Remick

Costas T. Lambrew Research Retreat 2021

Goal: To better understand drug resistance and sensitivity in patients with late stage (Stage III & IV) cancers that are receiving standard of care molecularly targeted therapies through next generation sequencing (NGS) of biopsy and blood samples collected longitudinally (diagnosis-- treatment--progression).

The Maine Lung Cancer Coalition: A Statewide, Multi-Sector Partnership To Improve Evidence-Based Lung Cancer Prevention & Screening, Leo B Waterston, Liz Scharnetzki, Susan Leeds, Jaclyn A. Janis, Lee Lucas, Deborah Deatrick, Rebecca Boulos, Neil Korsen, Paul K.J. Han

Costas T. Lambrew Research Retreat 2021

MLCC has two primary goals:

1. Engage and educate about evidence based lung cancer prevention and screening practices

2. Develop, implement, and evaluate innovative programs to increase access to prevention, screening, and treatment services for all Mainers

Role Of Preoperative Embolization In Management Of Central Nervous System Tumours, Ummey Hani, Ahmer Nasir Baig, Muhammad Shahzad Shamim, Basit Salam

Section of Neurosurgery

Preoperative embolization plays a significant role as an adjunct to surgical intervention in the cases of certain vascular tumours of the brain. While the procedure has resulted in facilitated resection of the tumour, and has reduced morbidity and mortality, its application remains debatable within the neurosurgical community, owing to rare, but major post-procedural complications. Herein, we have reviewed the literature to assess the safety and efficacy of preoperative angiographic embolization for brain tumours.

The Demographic, Behavioral, And Clinical Factors Associated With The Quality Of Life Of Cancer Survivors, Odette Chirinos

Honors Undergraduate Theses

The objective of this thesis is to assess the prevalence of low quality of life in adult cancer survivors and predictors for these low scores, separately for physical and mental quality of life. Possible predictors can include sociodemographic, clinical, and behavioral factors. The data source for this thesis is the National Health and Nutrition Examination Survey (NHANES) 2005-2012. The sample population included 1244 cancer survivors 20 years or older that answered “yes” to the question “have you ever been told by a doctor or other health professional that had cancer or malignancy of any kind?” Mental and physical health scores …

Awareness Of Genetic Predispositions That Increase The Risk Of Breast Cancer, Carly Huber

Honors Undergraduate Theses

Breast cancer is the most commonly diagnosed cancer in women in the United States and is the leading cause of cancer-related death among women worldwide. Certain demographics, such as racial/ethnic, age, and gender groups, are underrepresented in breast cancer studies. This lack of representation results in issues with creating genetic tests, as variants associated with those groups are not being detected. Furthermore, these underrepresented demographics are receiving a worse prognosis than those that are overrepresented in research. This study aimed to understand how informed the understudied racial/ethnic, gender, and age populations are regarding breast cancer and genetic testing compared to …

Targeting T Cell Glycolysis To Mitigate Graft-Versus-Host Disease, Kevin Ezhakunnel

Honors Undergraduate Theses

Hematological cancers account for nearly ten percent of cancer cases diagnosed annually in the United States. Patients who fail to respond to chemotherapy or radiotherapy must often undergo a bone marrow transplant to treat their malignancy. A significant complication following this procedure is Graft versus Host Disease (GvHD), which occurs when donor T cells mount an immune response against recipient tissues. Immunological research has highlighted the role of aberrant T cell metabolism, specifically a shift toward aerobic glycolysis, as a key driver behind the occurrence of this condition. The transcription factor FoxK1 has been revealed to be a key regulator …

Cytopenias After Cd19 Chimeric Antigen Receptor T-Cells (Car-T) Therapy For Diffuse Large B-Cell Lymphomas Or Transformed Follicular Lymphoma: A Single Institution Experience., Andrew Schaefer, Ying Huang, Adam Kittai, Joseph E Maakaron, Caner Saygin, Jonathan Brammer, Sam Penza, Ayman Saad, Samantha M Jaglowski, Basem M William

Oncology Articles

INTRODUCTION: Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have poor outcomes. Treatment with CD19 chimeric antigen receptor (CAR-T) cells, tisagenlecleucel and axicabtagene ciloleucel, has been associated with improved outcomes. Cytopenias were observed in clinical trials with both products; however, little is known regarding the patterns and outcomes of these cytopenias.

SUBJECTS AND METHODS: We reviewed DLBCL patients (

RESULTS: Median duration of leukopenia, neutropenia, lymphopenia, anemia, and thrombocytopenia was 49, 9, 117.5, 125, and 95.5 days after CAR-T infusion, respectively. Filgrastim was used in 63% of patients, and 50% of patients received red cell or platelet transfusions. With the …

A Semiparametric Modeling Approach For Analyzing Clinical Biomarkers Restricted To Limits Of Detection, Sandipan Dutta, Susan Halabi

Mathematics & Statistics Faculty Publications

Before biomarkers can be used in clinical trials or patients' management, the laboratory assays that measure their levels have to go through development and analytical validation. One of the most critical performance metrics for validation of any assay is related to the minimum amount of values that can be detected and any value below this limit is referred to as below the limit of detection (LOD). Most of the existing approaches that model such biomarkers, restricted by LOD, are parametric in nature. These parametric models, however, heavily depend on the distributional assumptions, and can result in loss of precision under …

Targeting Accuracy Considerations For Simultaneous Tumor Treating Fields Antimitotic Therapy During Robotic Hypofractionated Radiation Therapy., Sharmi Biswas, Irina Kapitanova, Sabrina Divekar, Jimm Grimm, Ian J Butterwick, Daniel Garren, Lawrence R Kleinberg, Kristin J Redmond, Michel Lacroix, Anand Mahadevan, Kenneth M Forster

College of Health Professions Faculty Papers

Purpose: Tumor treating fields (TTFields) is a novel antimitotic treatment that was first proven effective for glioblastoma multiforme, now with trials for several extracranial indications underway. Several studies focused on concurrent TTFields therapy with radiation in the same time period, but were not given simultaneously. This study evaluates the targeting accuracy of simultaneous radiation therapy while TTFields arrays are in place and powered on, ensuring that radiation does not interfere with TTFields and TTFields does not interfere with radiation. This is one of several options to enable TTFields to begin several weeks sooner, and opens potential for synergistic effects of …