Medical Specialties Commons^™

Klf5 Governs Sphingolipid Metabolism And Barrier Function Of The Skin, Ying Lyu, Yinglu Guan, Lisa Deliu, Ericka Humphrey, Joanna K Frontera, Youn Joo Yang, Daniel Zamler, Kun Hee Kim, Vakul Mohanty, Kevin Jin, Vakul Mohanty, Virginia Liu, Jinzhuang Dou, Lucas J Veillon, Shwetha V Kumar, Philip L Lorenzi, Yang Chen, Kathleen M Mcandrews, Sergei Grivennikov, Xingzhi Song, Jianhua Zhang, Yuanxin Xi, Jing Wang, Ken Chen, Priyadharsini Nagarajan, Yejing Ge

Faculty, Staff and Student Publications

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. …

Terrestrial Health Applications Of Visual Assessment Technology And Machine Learning In Spaceflight Associated Neuro-Ocular Syndrome, Joshua Ong, Alireza Tavakkoli, Nasif Zaman, Sharif Amit Kamran, Ethan Waisberg, Nikhil Gautam, Andrew G Lee

Faculty, Staff and Student Publications

The neuro-ocular effects of long-duration spaceflight have been termed Spaceflight Associated Neuro-Ocular Syndrome (SANS) and are a potential challenge for future, human space exploration. The underlying pathogenesis of SANS remains ill-defined, but several emerging translational applications of terrestrial head-mounted, visual assessment technology and machine learning frameworks are being studied for potential use in SANS. To develop such technology requires close consideration of the spaceflight environment which is limited in medical resources and imaging modalities. This austere environment necessitates the utilization of low mass, low footprint technology to build a visual assessment system that is comprehensive, accessible, and efficient. In this …

The Roles Of Gut Microbiome And Plasma Metabolites In The Associations Between Abo Blood Groups And Insulin Homeostasis: The Microbiome And Insulin Longitudinal Evaluation Study (Miles), Ruifang Li-Gao, Kirk Grubbs, Alain G Bertoni, Kristi L Hoffman, Joseph F Petrosino, Gautam Ramesh, Martin Wu, Jerome I Rotter, Yii-Der Ida Chen, Anne M Evans, Richard J Robinson, Laura Sommerville, Dennis Mook-Kanamori, Mark O Goodarzi, Gregory A Michelotti, Patricia A Sheridan

Faculty, Staff and Students Publications

Non-O blood groups are associated with decreased insulin sensitivity and risk of type 2 diabetes. A recent study pinpointed the associations between ABO blood groups and gut microbiome, which may serve as potential mediators for the observed increased disease risks. We aimed to characterize associations between ABO haplotypes and insulin-related traits as well as potential mediating pathways. We assessed insulin homeostasis in African Americans (AAs; n = 109) and non-Hispanic whites (n = 210) from the Microbiome and Insulin Longitudinal Evaluation Study. The ABO haplotype was determined by six SNPs located in the ABO gene. Based on prior knowledge, …

Igg Antibodies To Sars-Cov-2 In Asymptomatic Blood Donors At Two Time Points In Karachi, Muhammad Hasan, Bushra Moiz, Shama Qaiser, Kiran I. Masood, Zara Ghous, Areeba Hussain, Natasha Bahadur Ali, Syed Hani Abidi, Kulsoom Ghias, Erum Khan, Zahra Hasan

Department of Pathology and Laboratory Medicine

Introduction: An estimated 1.5 million cases were reported in Pakistan until 23 March, 2022. However, SARS-CoV-2 PCR testing capacity has been limited and the incidence of COVID-19 infections is unknown. Volunteer healthy blood donors can be a control population for assessment of SARS-CoV-2 exposure in the population. We determined COVID-19 seroprevalence during the second pandemic wave in Karachi in donors without known infections or symptoms in 4 weeks prior to enrollment.
Materials and methods: We enrolled 558 healthy blood donors at the Aga Khan University Hospital between December 2020 and February 2021. ABO blood groups were determined. Serum IgG reactivity …

Two Interaction Surfaces Between Xpa And Rpa Organize The Preincision Complex In Nucleotide Excision Repair, Mihyun Kim, Hyun-Suk Kim, Areetha D'Souza, Kaitlyn Gallagher, Eunwoo Jeong, Agnieszka Topolska-Wós, Kateryna Ogorodnik Le Meur, Chi-Lin Tsai, Miaw-Sheue Tsai, Minyong Kee, John A Tainer, Jung-Eun Yeo, Walter J Chazin, Orlando D Schärer

Faculty, Staff and Student Publications

The xeroderma pigmentosum protein A (XPA) and replication protein A (RPA) proteins fulfill essential roles in the assembly of the preincision complex in the nucleotide excision repair (NER) pathway. We have previously characterized the two interaction sites, one between the XPA N-terminal (XPA-N) disordered domain and the RPA32 C-terminal domain (RPA32C), and the other with the XPA DNA binding domain (DBD) and the RPA70AB DBDs. Here, we show that XPA mutations that inhibit the physical interaction in either site reduce NER activity in biochemical and cellular systems. Combining mutations in the two sites leads to an additive inhibition of NER, …

Grk3 Is A Poor Prognosticator And Serves As A Therapeutic Target In Advanced Gastric Adenocarcinoma, Yuan Li, Yibo Fan, Jinbang Xu, Longfei Huo, Ailing W Scott, Jiankang Jin, Boxuan Yang, Shan Shao, Lang Ma, Ying Wang, Xiaodan Yao, Melissa Pool Pizzi, Matheus Sewastjanow Da Silva, Guoliang Zhang, Lijuan Zhuo, Eun Jeong Cho, Kevin N Dalby, Namita D Shanbhag, Zhenning Wang, Wenliang Li, Shumei Song, Jaffer A Ajani

Faculty, Staff and Student Publications

Background: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown.

Methods: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on …

Behavioural Support And Nicotine Replacement Therapy For Smokeless Tobacco Cessation: Protocol For A Pilot Randomised-Controlled Multi-Country Trial, Faraz Siddiqui, Linda Bauld, Ray Croucher, Cath Jackson, Ian Kellar, Mona Kanaan, Subhash Pokhrel, Rumana Huque, Romaina Iqbal, Javaid Ahmed Khan

Community Health Sciences

Background: Smokeless tobacco (ST) is consumed globally by more than 350 million people, with approximately 85% of all users based in South and Southeast Asia. In this region, ST products are cheap and easily accessible. Evidence-based interventions to people quit ST use are lacking. This study aims to test the feasibility of conducting a future definitive trial of ST cessation, using a culturally adapted behavioural intervention, and/or nicotine replacement therapy (NRT) in three South Asian countries.
Methods: We will conduct a factorial design, randomised-controlled pilot trial in Bangladesh, India and Pakistan. Daily ST users will be recruited from primary health …

Lysyl Hydroxylase 2 Mediated Collagen Post-Translational Modifications And Functional Outcomes, Masahiko Terajima, Yuki Taga, Tomoyuki Nakamura, Hou-Fu Guo, Yukako Kayashima, Nobuyo Maeda-Smithies, Kshitij Parag-Sharma, Jeong Seon Kim, Antonio L Amelio, Kazunori Mizuno, Jonathan M Kurie, Mitsuo Yamauchi

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) is a member of LH family that catalyzes the hydroxylation of lysine (Lys) residues on collagen, and this particular isozyme has been implicated in various diseases. While its function as a telopeptidyl LH is generally accepted, several fundamental questions remain unanswered: 1. Does LH2 catalyze the hydroxylation of all telopeptidyl Lys residues of collagen? 2. Is LH2 involved in the helical Lys hydroxylation? 3. What are the functional consequences when LH2 is completely absent? To answer these questions, we generated LH2-null MC3T3 cells (LH2KO), and extensively characterized the type I collagen phenotypes in comparison with controls. …

Practical Approaches To Improve Vancomycin-Related Patient Outcomes In Pediatrics- An Alternative Strategy When Auc/Mic Is Not Feasible, Kashif Hussain, Muhammad Sohail Salat, Shahzad Rauf, Manoj Rathi, Midhat Khan, Fizzah Naz, Wasif Ahmed Khan, Rahila Ikram, Gul Ambreen

Department of Biological & Biomedical Sciences

Background: Anecdotal experience and studies have shown that most pediatric patients fail to reach target therapeutic vancomycin trough levels (VTLs) and required higher total daily doses (TDD). This retrospective study aims to evaluate the frequency of hospitalized children who achieved target VTLs with a vancomycin (VNCO) dosing regimen of 40-60 mg/kg/d q6h and to assess the VNCO-TDD required to attain the target and their effects on clinical outcomes in pediatric patients.
Methods: After ethical approval, patients of 3 month-12 years were evaluated in this chart review study who received ≥ 3 intravenous-VNCO doses and appropriately drawn blood samples of VTLs …

Human Total, Basal And Activity Energy Expenditures Are Independent Of Ambient Environmental Temperature, Xueying Zhang, Yosuke Yamada, Hiroyuki Sagayama, Philip N Ainslie, Ellen E Blaak, Maciej S Buchowski, Graeme L Close, Jamie A Cooper, Sai Krupa Das, Lara R Dugas, Michael Gurven, Asmaa El Hamdouchi, Sumei Hu, Noorjehan Joonas, Peter Katzmarzyk, William E Kraus, Robert F Kushner, William R Leonard, Corby K Martin, Erwin P Meijer, Marian L Neuhouser, Robert M Ojiambo, Yannis P Pitsiladis, Guy Plasqui, Ross L Prentice, Susan B Racette, Eric Ravussin, Leanne M Redman, Rebecca M Reynolds, Susan B Roberts, Luis B Sardinha, Analiza M Silva, Eric Stice, Samuel S Urlacher, Edgar A Van Mil, Brian M Wood, Alexia J Murphy-Alford, Cornelia Loechl, Amy H Luke, Jennifer Rood, Dale A Schoeller, Klaas R Westerterp, William W Wong, Herman Pontzer, John R Speakman, Iaea Dlw Database Consortium

Children’s Nutrition Research Center Staff Publications

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (−10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p < 0.01) relationships between TEE, BEE and Ta emerged in females but the effect sizes were not biologically meaningful. Temperatures inside buildings are regulated at 18–25°C independent of latitude. Hence, adults in the US modify their environments to keep TEE constant across a wide range of external ambient temperatures.

Phase 2 Of Extracellular Rna Communication Consortium Charts Next-Generation Approaches For Extracellular Rna Research, Bogdan Mateescu, Jennifer C Jones, Roger P Alexander, Eric Alsop, Ji Yeong An, Mohammad Asghari, Alex Boomgarden, Laura Bouchareychas, Alfonso Cayota, Hsueh-Chia Chang, Al Charest, Daniel T Chiu, Robert J Coffey, Saumya Das, Peter De Hoff, Andrew Demello, Crislyn D'Souza-Schorey, David Elashoff, Kiarash R Eliato, Jeffrey L Franklin, David J Galas, Mark B Gerstein, Ionita H Ghiran, David B Go, Stephen Gould, Tristan R Grogan, James N Higginbotham, Florian Hladik, Tony Jun Huang, Xiaoye Huo, Elizabeth Hutchins, Dennis K Jeppesen, Tijana Jovanovic-Talisman, Betty Y S Kim, Sung Kim, Kyoung-Mee Kim, Yong Kim, Robert R Kitchen, Vaughan Knouse, Emily L Laplante, Carlito B Lebrilla, L James Lee, Kathleen M Lennon, Guoping Li, Feng Li, Tieyi Li, Tao Liu, Zirui Liu, Adam L Maddox, Kyle Mccarthy, Bessie Meechoovet, Nalin Maniya, Yingchao Meng, Aleksandar Milosavljevic, Byoung-Hoon Min, Amber Morey, Martin Ng, John Nolan, Getulio P De Oliveira Junior, Michael E Paulaitis, Tuan Anh Phu, Robert L Raffai, Eduardo Reátegui, Matthew E Roth, David A Routenberg, Joel Rozowsky, Joseph Rufo, Satyajyoti Senapati, Sigal Shachar, Himani Sharma, Anil K Sood, Stavros Stavrakis, Alessandra Stürchler, Muneesh Tewari, Juan P Tosar, Alexander K Tucker-Schwartz, Andrey Turchinovich, Nedyalka Valkov, Kendall Van Keuren-Jensen, Kasey C Vickers, Lucia Vojtech, Wyatt N Vreeland, Ceming Wang, Kai Wang, Zeyu Wang, Joshua A Welsh, Kenneth W Witwer, David T W Wong, Jianping Xia, Ya-Hong Xie, Kaichun Yang, Mikołaj P Zaborowski, Chenguang Zhang, Qin Zhang, Angela M Zivkovic, Louise C Laurent

Faculty, Staff and Student Publications

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, …

Dietary Intake Among Children Attending Childcare Centers: Impact Of The New Cacfp Meal Guidelines, Jayna M Dave, Tzuan A Chen, Maha Almohamad, Sonia Cotto-Moreno

Children’s Nutrition Research Center Staff Publications

Through the Healthy, Hunger-Free Kids Act of 2010, USDA (US Department of Agriculture) made the first major changes in the CACFP (Child and Adult Care Food Program) meal and snack menu patterns. Childcare centers that serve low-income families qualify to participate and receive reimbursement for meals and snacks served. The purpose of this study was to assess what changes in children's dietary behaviors occurred as a result of the new CACFP meal pattern requirements. This study evaluated these changes at childcare centers operating in Houston and San Antonio, Texas, USA, areas enrolled in the CACFP, pre- (Spring 2016) and post-implementation …

Structure-Based Design Of Stapled Peptides That Bind Gabarap And Inhibit Autophagy, Hawley Brown, Mia Chung, Alina Üffing, Nefeli Batistatou, Tiffany Tsang, Samantha Doskocil, Weiqun Mao, Dieter Willbold, Robert C Bast, Zhen Lu, Oliver H Weiergräber, Joshua A Kritzer

Faculty, Staff and Student Publications

The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized …

Cyclase-Associated Protein 1 (Cap1) In Cyclic Adenosine Monophosphate (Camp) And Protein Kinase C (Pkc) Signals To Regulate Cancer Cell Functions, Lokesh Kalki Mani Sai Akana

Student Theses and Dissertations

Cyclase-Associated Protein 1 (CAP1) is an actin-regulating protein that promotes actin dynamics and is also involved in cell adhesion and proliferation as well as implicated in human cancers. We previously found that phosphorylation at the Ser307/Ser309 tandem regulatory site on CAP1 is critical for CAP1 functions in breast and pancreatic cancer cells. We silenced CAP1 through RNAi in HCT116 and SW480 colon cancer cells as confirmed in Western blotting. We have found that depletion of CAP1 led to reduced FAK (Focal Adhesion Kinase) activity and matrix adhesion in SW480 cells, while it stimulated FAK activity and cell adhesion in HCT116 …

Immuno-Genomic Profiling Of Biopsy Specimens Predicts Neoadjuvant Chemotherapy Response In Esophageal Squamous Cell Carcinoma, Shota Sasagawa, Hiroaki Kato, Koji Nagaoka, Changbo Sun, Motohiro Imano, Takao Sato, Todd A Johnson, Masashi Fujita, Kazuhiro Maejima, Yuki Okawa, Kazuhiro Kakimi, Takushi Yasuda, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is primarily treated with platinum-based neoadjuvant chemotherapy (NAC). Some ESCCs respond well to NAC. However, biomarkers to predict NAC sensitivity and their response mechanism in ESCC remain unclear. We perform whole-genome sequencing and RNA sequencing analysis of 141 ESCC biopsy specimens before NAC treatment to generate a machine-learning-based diagnostic model to predict NAC reactivity in ESCC and analyzed the association between immunogenomic features and NAC response. Neutrophil infiltration may play an important role in ESCC response to NAC. We also demonstrate that specific copy-number alterations and copy-number …

Secure Human Action Recognition By Encrypted Neural Network Inference, Miran Kim, Xiaoqian Jiang, Kristin Lauter, Elkhan Ismayilzada, Shayan Shams

Faculty, Staff and Student Publications

Advanced computer vision technology can provide near real-time home monitoring to support "aging in place" by detecting falls and symptoms related to seizures and stroke. Affordable webcams, together with cloud computing services (to run machine learning algorithms), can potentially bring significant social benefits. However, it has not been deployed in practice because of privacy concerns. In this paper, we propose a strategy that uses homomorphic encryption to resolve this dilemma, which guarantees information confidentiality while retaining action detection. Our protocol for secure inference can distinguish falls from activities of daily living with 86.21% sensitivity and 99.14% specificity, with an average …

Re-Analysis And Additional Information Needed To Inform Conclusions Comment On Halenova Et Al Deuterium-Depleted Water As Adjuvant Therapeutic Agent For Treatment Of Diet-Induced Obesity In Rats, Colby J Vorland, Xiwei Chen, Daniella E Chusyd, Luis M Mestre, Stephanie L Dickinson, David B Allison, Andrew W Brown

Children’s Nutrition Research Center Staff Publications

We were interested to read the report by Halenova et al. [...].

A Multi-Institutional Prediction Model To Estimate The Risk Of Recurrence And Mortality After Mastectomy For T1-2n1 Breast Cancer, Sarah M C Sittenfeld, Emily C Zabor, Sarah N Hamilton, Henry M Kuerer, Mahmoud El-Tamer, George E Naoum, Pauline T Truong, Alan Nichol, Benjamin D Smith, Wendy A Woodward, Tracy-Ann Moo, Simon N Powell, Chirag S Shah, Alphonse G Taghian, Ibrahim Abu-Gheida, Rahul D Tendulkar

Faculty, Staff and Student Publications

Background: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial.

Methods: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM).

Results: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more …

Intrinsic Cardiac Effects Of Severe Acute Respiratory Syndrome Coronavirus 2 In Coronavirus Disease 2019, Brittany Danielle Brumback

McKelvey School of Engineering Graduate Student Theses & Dissertations

Cardiac arrhythmias, particularly ventricular arrhythmias, can be life-threatening and caused by both congenital genetic mutations and acquired cardiac injury. My thesis work was originally focused on delineating the effects of genetic mutation-driven dysregulation of a protein called Hey2 in Brugada Syndrome, a complex disease characterized by a predisposition to dangerous arrhythmias originating in the right ventricular outflow tract. In response to the pandemic, my thesis work shifted toward understanding the mechanisms of cardiovascular injury in Coronavirus disease 2019 (COVID-19), which is associated with serious cardiovascular complications, including ventricular arrhythmias and sudden cardiac death as well as endothelial dysfunction and coagulopathies. …

Machine Learning And Scalable Informatics Methods To Predict Disease Status From Multimodal Biomedical Data, Hossein Mohammadian Foroushani

McKelvey School of Engineering Graduate Student Theses & Dissertations

Biological understanding of complex diseases such as stroke and obesity is critical for the advancement of medicine. Further knowledge discovery can provide effective biomarkers to improve disease diagnosis and prognosis, identify driver mutations, predict individual genetic susceptibility for early prevention and effective disease management, and facilitate development of personalized drugs. Stroke is the second leading cause of death and long-term disability in the world. Thus, stroke management is a time-sensitive emergency. The initial hours after stroke onset map the trajectory of subsequent neurologic complications. Cerebral edema develops hours to days after acute ischemic stroke and may result in midline shift …

Association Between The Baseline Gene Expression Profile In Periapical Granuloma And Periapical Wound Healing After Surgical Endodontic Treatment, Muhammad Adeel Ahmed, Fizza Nazim, Khalid Ahmed, Muhammad Furqan Bari, Abdulaziz Abdulwahed, Ahmed A. Almokhatieb, Yaseen Alalvi, Tariq Abduljabbar, Muhammad Nouman Mughal, Syed Hani Abidi

Department of Biological & Biomedical Sciences

In this study, we have investigated the association between the baseline gene expression profile in periapical granuloma and periapical wound healing after surgical endodontic treatment. Twenty-seven patients aged between 15 and 57 years underwent periapical surgery. The retrieved periapical tissue sample was used for mRNA expression analysis of COL1A1, VTN, ITGA5, IL-4, TNF, ANGPT, VEGFA, and CTGF. All patients were recalled after 6 and 12 months for periapical healing evaluation. Healing was then correlated with baseline gene expression. Healing was observed in 15 patients at the end of 6 months, which increased to 21 patients after 12 months. Six patients …

Immunotherapy For Type 1 Diabetes Mellitus By Adjuvant-Free Schistosoma Japonicum-Egg Tip-Loaded Asymmetric Microneedle Patch (Stamp), Haoming Huang, Dian Hu, Zhuo Chen, Jiarong Xu, Rengui Xu, Yusheng Gong, Zhengming Fang, Ting Wang, Wei Chen

Faculty, Staff and Student Publications

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy …

Current Challenges In Image-Guided Magnetic Hyperthermia Therapy For Liver Cancer, Anirudh Sharma, Erik Cressman, Anilchandra Attaluri, Dara L Kraitchman, Robert Ivkov

Faculty, Staff and Student Publications

For patients diagnosed with advanced and unresectable hepatocellular carcinoma (HCC), liver transplantation remains the best option to extend life. Challenges with organ supply often preclude liver transplantation, making palliative non-surgical options the default front-line treatments for many patients. Even with imaging guidance, success following treatment remains inconsistent and below expectations, so new approaches are needed. Imaging-guided thermal therapy interventions have emerged as attractive procedures that offer individualized tumor targeting with the potential for the selective targeting of tumor nodules without impairing liver function. Furthermore, imaging-guided thermal therapy with added standard-of-care chemotherapies targeted to the liver tumor can directly reduce the …

A Comprehensive Search Of Non-Canonical Proteins In Non-Small Cell Lung Cancer And Their Impact On The Immune Response, Ehsan Irajizad, Johannes F Fahrmann, James P Long, Jody Vykoukal, Makoto Kobayashi, Michela Capello, Chuan-Yih Yu, Yining Cai, Fu Chung Hsiao, Nikul Patel, Soyoung Park, Qian Peng, Jennifer B Dennison, Taketo Kato, Mei Chee Tai, Ayumu Taguchi, Humam Kadara, Ignacio I Wistuba, Hiroyuki Katayama, Kim-Anh Do, Samir M Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess …

Qualitative Interviews To Understand Health Care Providers’ Experiences Of Prescribing Licensed Peanut Oral Immunotherapy, Aikaterini Anagnostou, Claire Lawrence, Stephen A Tilles, Susan Laubach, Sarah M Donelson, Mohamed Yassine, Anna Nowak-Wegrzyn

Faculty, Staff and Students Publications

OBJECTIVE: This research sought to explore health care providers' (HCPs) experiences of delivering the first US Food and Drug Administration (FDA) and European Commission (EC) approved peanut oral immunotherapy (peanut OIT; Palforzia). Semi-structured qualitative interviews with HCPs who had initiated treatment with ≥ 3 patients in the first nine months following FDA approval sought to identify challenges faced and successful implementation strategies.

RESULTS: Eight allergists and three nurse practitioners from eight sites based in the United States participated. The HCPs included in this research were motivated to implement this novel treatment, however, entered the process with some reservations. HCPs described …

Oncogenic Collagen I Homotrimers From Cancer Cells Bind To Α3Β1 Integrin And Impact Tumor Microbiome And Immunity To Promote Pancreatic Cancer, Yang Chen, Sujuan Yang, Jena Tavormina, Desiree Tampe, Michael Zeisberg, Huamin Wang, Krishnan K Mahadevan, Chang-Jiun Wu, Hikaru Sugimoto, Chia-Chi Chang, Robert R Jenq, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances …

A Mouse Holder For Awake Functional Imaging In Unanesthetized Mice: Applications In 31p Spectroscopy, Manganese-Enhanced Magnetic Resonance Imaging Studies, And Resting-State Functional Magnetic Resonance Imaging, Lindsay C Fadel, Ivany V Patel, Jonathan Romero, I-Chih Tan, Shelli R Kesler, Vikram Rao, S A Amali S Subasinghe, Russell S Ray, Jason T Yustein, Matthew J Allen, Brian W Gibson, Justin J Verlinden, Stanley Fayn, Nicole Ruggiero, Caitlyn Ortiz, Elizabeth Hipskind, Aaron Feng, Chijindu Iheanacho, Alex Wang, Robia G Pautler

Faculty, Staff and Students Publications

Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia. Here, we describe a newly designed mouse holder that is interfaceable with existing MRI systems and enables awake in vivo mouse imaging. This holder significantly reduces head movement of the awake animal compared to previously designed holders and allows for the acquisition of improved anatomical images. In addition to applications in …

Spectral Library-Based Single-Cell Proteomics Resolves Cellular Heterogeneity, Lakmini Senavirathna, Cheng Ma, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant challenges remain in analyzing an extremely small amount of proteins collected from a single cell, as a proteome-wide amplification of proteins is not currently feasible. Here, we report an integrated spectral library-based single-cell proteomics (SLB-SCP) platform that is ultrasensitive and well suited for a large-scale analysis. To overcome the low MS/MS signal intensity intrinsically associated with a …

Miracle Of Microrna-Driven Cancer Nanotherapeutics, Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics …

Adaptation And Dosimetric Commissioning Of A Synchrotron-Based Proton Beamline For Flash Experiments, Ming Yang, Xiaochun Wang, Fada Guan, Uwe Titt, Kiminori Iga, Dadi Jiang, Takeshi Takaoka, Satoshi Tootake, Tadashi Katayose, Masumi Umezawa, Emil Schüler, Steven Frank, Steven H Lin, Narayan Sahoo, Albert C Koong, Radhe Mohan, X Ronald Zhu

Faculty, Staff and Student Publications

Objective. Irradiation with ultra-high dose rates (>40 Gy s^-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.

Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length …