Mario Soliman: May Research Spotlight Award Recipient
Posted: Jun. 21, 2019

Mario Soliman

Title: Transcriptional Regulation of Cellular Proliferation in T-Cell Acute Lymphoblastic Leukemia

Abstract:
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that represents a therapeutic challenge. Next-generation sequencing revealed that a subset of T-ALL harbors inactivating mutations or deletion of one allele of the IKZF1 tumor suppressor. These data suggest that IKZF1 acts as a tumor suppressor in T-ALL. The IKZF1 gene encodes the Ikaros protein that functions as a regulator of transcription and a tumor suppressor in B-cell acute lymphoblastic leukemia. However, the molecular mechanism of Ikaros tumor suppressor function in T-ALL is unclear. Using quantitative chromatin immunoprecipitation (qChIP), we determined that Ikaros binds to the promoter regions of the CDC2 and CDC7 cell cycle genes in primary T-ALL cells in vivo. Gain-of-function experiments showed that Ikaros overexpression in T-ALL results in reduced expression of CDC2 and CDC7, as evidenced by quantitative RT-PCR (qRT-PCR) and Western blot. The knock-down of Ikaros with shRNA in T-ALL cells resulted in increased transcription of CDC2 and CDC7 as indicated by qRT-PCR. These data suggest that Ikaros can regulate cell cycle progression in T-ALL by repressing transcription of the CDC2 and CDC7 genes. Next, we studied the mechanisms that regulate Ikaros’ ability to repress CDC2 and CDC7 in T-ALL. Ikaros’ function as a transcriptional repressor is regulated by Casein Kinase II (CK2). CK2 is overexpressed in hematopoietic malignancies and increased expression of CK2 results in T-ALL in murine models. We tested the effect of CK2 inhibition on Ikaros’ ability to regulate transcription of CDC2 and CDC7 in human T-ALL. Molecular inhibition of CK2 with shRNA against the CK2 catalytic subunit resulted in reduced transcription of CDC2 and CDC7, as evidenced by qRT-PCR. This was associated with increased DNA-binding of Ikaros to promoters of CDC2 and CDC7, as shown by qChIP. These data suggest that CK2 impairs Ikaros’ ability to transcriptionally repress CDC2 and CDC7 and to regulate cell cycle progression in T-ALL. Inhibition of CK2 enhances transcriptional repression of CDC2 and CDC7 by Ikaros, resulting in improved control of cell cycle progression in T-ALL. In conclusion, results show that control of cell cycle progression in T-ALL occurs trough Ikaros-mediated transcriptional regulation of CDC2 and CDC7. Overexpression of CK2 impairs Ikaros’ ability to repress CDC2 and CDC7 expression, which contributes to deregulation of cell cycle control in T-ALL. Results suggest a potential mechanism of therapeutic action of CK2 inhibitors for the treatment of T-ALL.

Personal Statement: Working as a researcher in a hematology and oncology lab at Pennsylvania State Unversity prior to medical school gave me a unique perspective on the present research gaps that still remain in the cancer field, particularly in the field of targeted oncology therapeutics. Conducting research under the mentorship of Dr. Sinisa Dovat has taught me the underlying basic sciences and clinical work in cancer therapeutics while being able to recognize and critically problem-solve challenges through the lens of research. My long-term career goal is to become a physician scientist focusing in the development of targeted therapeutic tools for cancer patients.

I chose this specific research topic as it combined two areas that I grew to love—cancer pathology and targeted therapeutics. My research contributions to the role of Ikaros, a tumor suppressor, in T-cell acute lymphoblastic leukemia (T-ALL) patients has led to the development of a novel drug suggesting a potential targeted mechanism of therapeutic action in T-ALL patients. Furthermore, my research work, which were part of a high impact journal, includes discovering a regulatory protein that govern the functional capacity of the tumor suppressor Ikaros in T-ALL patients. As I continue my research work in leukemia this summer, I will be exploring other regulatory aspects of the mechanism as means of targeted drug therapy for patients with T-ALL and B-ALL. I will also be exploring the efficacy and potency of several targeted novel drug therapies in mouse models.


 
Mariko Feuz: April Research Spotlight Award Recipient
Posted: Jun. 21, 2019

Mariko Feuz

Title: Leveraging In-Home Supportive Services Programs to Engage People in Advance Care Planning: Input from Staff, Caregivers, and Client Stakeholders

Abstract:
Background: In-Home Supportive Services (IHSS) cares for millions of Medicaid-eligible older adults who are often homebound and socially isolated. Advance care planning (ACP) can be challenging for this population, and IHSS programs may play an important role. This study sought to explore the feasibility of an IHSS-ACP program for frail older adults.

Methods: Fifty stakeholders (administrators, case managers, in-home caregivers, and clients) were recruited to 10 semi-structured focus groups conducted in San Francisco. Participants were recruited by convenience sample through snowball sampling of English-speaking stakeholders. All discussions were audio-recorded and transcribed. Thematic content analysis was conducted by two independent coders.

Results: Four main themes emerged: 1) Unmet needs: patients’ wishes unknown during a medical crisis, lack of education/training for clients and staff; 2) Barriers: conflict of interest and potential overreach of IHSS-caregivers, lack of billing avenues, time limitations, and cultural/literacy barriers; 3) Facilitators: leveraging established workflows, available technology, and training programs; and 4) Implementation: use a tailored, optional approach, focus on case-managers not caregivers to prevent conflict of interest, use established intake, follow-up, and training procedures, consider cultural and literacy-appropriate messaging, and standardize easy-to-use scripts and educational guides within established workflow.

Conclusions: An In-Home Supportive Services ACP program is important and feasible for frail older adults. Implementation suggestions for success by IHSS-stakeholders include focusing on case-managers rather than in-home caregivers to prevent conflict of interest; tailoring programs to clients’ readiness, literacy, and language; creating educational programs for IHSS staff, clients, and community; and standardizing easy-to-use guides and procedures into IHSS workflows.

Personal Statement: Advance care planning is an often overlooked but crucial aspect of quality healthcare. My passion for patient education and advance care planning was a perfect fit for this project examining how to empower frail, isolated adults to receive the medical care they want. I am very interested in how to best disseminate medical education with the help and support of stakeholders at every level. To me, research represents the opportunity to address the problems or shortcomings we experience as practicing physicians in an impactful and meaningful way. It is a way to be connected to our scientific community.

I hope to become a physician researcher in geriatrics. My research experience prior to medical school has involved advance care planning in vulnerable populations, including Veterans, older adults, those with low literacy, and non-English speakers. I have been lucky enough to continue my work with Dr. Rebecca Sudore the summer after my first year of medical school, allowing me to complete this project. I will be presenting this abstract at the 2019 American Geriatrics Society National Meeting in May.


 
Jordan Hiegel, OMS-II: March Research Spotlight Award Recipient
Posted: Apr. 11, 2019

Jordan Hiegel, OMS-II

Title: Caregivers’ Behaviors and Attitudes about Child Nutrition at a Local Pediatric Clinic

Abstract:
Student interest in nutrition intervention in our local community was initiated and contact made with pediatricians at New Beginnings Pediatrics in Blacksburg, VA. Concern for local nutrition
practices is justified, seeing as how Virginia has the nation’s highest rate of obese children ages 2 to 4 years old enrolled in WIC, a federally supported, Women, Infants and Children Nutrition program. Further emphasis should be placed on investigation in the Southwest Region of Virginia, which has consistently had higher rates of childhood obesity when compared to the rest of the state. In 2010, the Virginia Obesity Survey Research Report published a statistic that 28% of youth under the age of 18 in the Southwest Region were overweight or obese. Blacksburg is in Montgomery county within the Central Appalachian Regional Commission and Southwest region of Virginia, which has an interestingly mixed population of low-income residents juxtaposed to high income residents, due to its proximity to two nearby universities (Virginia Tech and Radford). Despite internationally renowned educational opportunities in the county, where 44.5% of the population had a bachelor’s degree or more (2011-2015), double that of the Appalachian Commission Region, per capital income (2015) was $33,000 (VA, $52,000) and the poverty rate (2011-2015) was 26.8 % (VA, 11.5%, Appalachian region 17.1%). An anonymous survey was administered to caregivers of patients ages newborn to 6 years old in a local pediatric clinic in Blacksburg, interested in obtaining a better understanding of this population’s nutrition habits and beliefs. Preliminary descriptive data in the original phase so far has yielded 41 respondents, 28 with children (12 mo – 6 yo) and 13 with infants. This presentation focuses on the 12 mo – 6 yo age group. This population has demographics that are not completely reflective of our region, with 40% having an income of greater than $75,000 and 64% possessing a bachelor’s degree. Our results seem to show conflicting behaviors and attitudes in our parent population. Our highly educated population is confident in their ability to monitor what their child eats and believe that it is important for parents to have rules about when a child eats, what they eat and how much they eat. However, when asked about their own behaviors toward their own child, parents were more inclined to try to get their child to finish his/her food, finish their food even if they are not hungry, and letting their child decide how much to eat. Research has interestingly shown a correlation with restrictive parenting behaviors with food as leading to problems such as over eating and decreased fruit and vegetable intake (Fisher). We are using the information gained from this study to develop nutrition intervention strategies within the New Beginnings clinic.

Personal Statement: Without the proper tools, we would have no idea how to best serve our communities. I believe one of the most valuable and underutilized tools to help physicians cater to their local population’s needs is research. That is why I started my project, “Caregivers’ Behaviors and Attitudes About Child Nutrition at a Local Pediatric Clinic”, in October of 2017. My medical school, Edward Via College of
Osteopathic Medicine, has always prided itself on cultivating future physicians focused on underserved rural populations, particularly in the Appalachia Region where there is growing concern for physician shortage and less access to healthcare resources. Wanting to uphold this sentiment and make an actual difference in my community, I turned to research. Seeing as how the Southwestern portion has had the highest rates of childhood obesity in Virginia, and Virginia being the number one in the country for childhood obesity of children on WIC ages 2-4, I decided to try to make an impact in my local community.


 
Leena Owen, OMS-III: February Research Spotlight Award Recipient
Posted: Feb. 28, 2019

Leena Owen, OMS-III

Title: The Discharge Conversation. Where Can Residents Improve?

Abstract:
Background: The discharge conversation is a critical component of the Emergency Department encounter. Studies suggest that Emergency Medicine residency education is deficient in formally
training and assessing residents on the patient discharge discussion. Objectives. The aim of this study is to assess the proficiency of Emergency Medicine residents in addressing essential elements of a comprehensive discharge plan during the discharge conversation and to identify which components of the discharge conversation are repeatedly omitted and require further formalized education. Methods. This is a prospective observational study of 200 resident discharge encounters. Emergency Medicine residents were observed and evaluated during the discharge conversation by attending physicians, who completed an observation evaluation, answering binary questions (“Yes” or “No”) as to whether residents addressed 6 different components of a comprehensive discharge conversation. The percentage distribution of “Yes” and “No” responses for each question was calculated.

Results: Resident physicians were proficient at providing patients with a discharge diagnosis and at explaining the care rendered during their stay in the Emergency Department in 95.5% and 88.5% of discharge encounters, respectively. However, failure to address health and lifestyle modifications and obstacles after discharge was observed in 76% and 77% of discharges, respectively. About 19% of the time, resident physicians did not provide patients with information about newly prescribed medications and expectations after discharge. Conclusion. Even when observed by attending physicians, Emergency Medicine residents frequently fail to address key components of the discharge conversation. This study highlights the necessity for formal education on the discharge conversation during residency training.

Personal Statement: Working as a medical scribe in an Emergency Department prior to medical school, one of my least favorite tasks was printing the pre-typed discharge instructions to be given to the patient. Looking through the instructions I found them to be very generic and broad, and sometimes unavailable for the specific diagnosis for the patient. Watching the patients receive these upon discharge, I never felt reassured that they truly understood what they were being told and I told myself one day I would work to improve this process. I think the best way to solve a problem is to first step back and analyze it fully. This is why I chose to pursue an in depth analysis of the discharge process performed by residents. By identifying areas with room for improvement we can more effectively create an educational program targeting resident physicians before they make habits that will be carried on throughout their career. Improvement of the Emergency Department discharge process could have large implications for public health and health education. It could not only improve recovery, health and knowledge in the community, but also prevent recurrent visits to the Emergency Department. I find research essential for progress in any field. Only through research can we see where we stand and move forward to make change. I plan on continuing research on the Emergency Department discharge process, as well as pursuing research in the public health field specifically in health education.


 
Jermeen El-Zabet: January Research Spotlight Award Recipient
Posted: Jan. 23, 2019

Jermeen El-Zabet

Title: Analysis of Biological Network: Ailanthus altissima and Protein Homology Network

Abstract: A network is a group of elements connected by links. Networks consist of two components. The first component is the nodes which represent the elements themselves; the second component is the edges which represent the connections between the nodes. Here, we use networks to study dispersal of the plant Ailanthus altissima, an invasive species known commonly as the Tree of Heaven or the stinking ash. It is native to China and it has no natural herbivores in the United States, so it has become invasive. The goal for this project is to look at how this species is spread throughout the U.S. and compare that with network models of U.S. transportation systems on the hypothesis that its seeds are dispersed long distances by automobiles and trains. Raw transportation systems data were from the U.S. Department of Transportation for both railroads and highways. Data were extracted from GIS flat files using a Geographic Information Systems software package, System for Automated Geoscientific Analyses (SAGA-GIS). Estimates of Ailanthus altissima stem density were obtained from the United States Department of Agriculture (USDA) online data bank, Forest Inventory Data Online (FIDO). Perl script was written to extract data and organize it into networks that could be used to test if Ailanthus altissima density is explained by the connectivity of the U.S. counties. In an unrelated project on Protein Homology Networks, we are using this same network-based approach to study the similarities among proteins in the proteasomes of several model organisms.

Personal Statement: I chose this research project because it opened the door for me to experience computer-based research. Since I had taken Computer Science courses in high school, I wanted to use what I had learned toward the Biological Sciences field. I started this research project in the summer after my freshman year as an undergraduate student, and I worked on it for another year after graduation. In June of 2015, I co-authored a publication in the PhysicaA Journal. I’ve also conducted field research in China with a group of students as we studied plant-animal interactions in the process of pollination. These different opportunities allowed me to experience research in a wet lab throughout my undergraduate classes, computer-based as I obtained data and wrote codes to extract subsets of data, and field research in China. I am hoping that I can further my research in the area of Protein Homology Networks in a clinical setting. In my last year of research, we looked at the proteome of viruses to study amino acid sequence similarities. I am looking for an opportunity to use this background research to see if any drugs or vaccinations could be developed to combat these viruses.


 
Patrick O’Connell: December Research Spotlight Award Recipient
Posted: Jan. 14, 2019

Patrick O’Connell

Title: SLAMF7 is a critical negative regulator of interferon- ⍺ -mediated CXCL10 production in chronic HIV infection

Abstract: Current advances in combined anti-retroviral therapy (cART) have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. Here, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation. We observed increased frequencies of SLAMF7 + PBMCs in HIV+ individuals in a clinical phenotype-dependent manner, with discordant and long-term nonprogressor patients showing elevated SLAMF7 levels, and elite controllers showing levels comparable to healthy controls. We also noted that SLAMF7 was sensitive to IFN ⍺ stimulation; a factor elevated during HIV infection. Further studies revealed SLAMF7 to be a potent inhibitor of the monocyte-derived proinflammatory chemokine CXCL10 (IP-10) and other CXCR3 ligands, except in a subset of HIV+ patients termed SLAMF7 silent (SF7S). Studies utilizing small molecule inhibitors revealed that the mechanism of CXCL10 inhibition is independent of known SLAMF7 binding partners. Furthermore, we determined that SLAMF7 activation on monocytes is able to decrease their susceptibility to HIV-1 infection in vitro via down-regulation of CCR5 and up-regulation of the CCL3L1 chemokine. Finally, we discovered that neutrophils do not express SLAMF7, are CXCL10 + at baseline, are able to secrete CXCL10 in response to IFN ⍺ and LPS, and are non-responsive to SLAMF7 signaling. These findings implicate the SLAMF7 receptor as an important regulator of IFN ⍺ -driven innate immune responses during HIV infection.

Personal Statement: My longterm career goal is to become a physician scientist specializing in the development of novel immuno-therapeutics. In particular, I would like to direct my efforts toward ameliorating suffering in children, both directly through clinical work, and indirectly by bringing new drugs to market. Thus far in my training I have taken the first step along this path by joining the DO-PhD program and selecting a mentor who has already accomplished many of my stated goals. Working under the direction of Dr. Andrea Amalfitano has taught me quite a bit about not only science, but also many of the other regulatory and related complications involved in developing and bring a new therapeutic to market.

Patrick O’Connell presenting at the Michigan Osteopathic Association annual Autumn Convention.

My previous research contributions include solving protein structures which were a part of a high impact publication and uncovering the role that human ERAP1 variants have on immune cell functions. Since coming to MSUCOM my recent achievements include the discovery of a novel regulatory mechanism in monocytes and microglia which I have just published a paper on. We are currently working to set up industry collaborations to begin to identify novel small molecules that can modulate this pathway.

I choose this project because of my interests in immune regulation and therapeutic development. My interests lie in becoming a physician scientist, of which there are little to no Osteopathic physicians currently. In the future I hope to develop, and bring to clinic, novel, immune-modulatory therapeutics that will help patients will various immune-mediated diseases.