Digital Commons Network^™

Maternal Hyperleptinemia Alters Placental Transcriptome And Progesterone Regulation Without Affecting Early Equine Fetal Growth, Lucinda L. Thorburn

LSU Master's Theses

While consequences of equine obesity are well defined, the extent to which persistent hyperleptinemia and accompanying leptin (Lep) resistance affect the fetal-maternal environment warrants further exploration. This study compared endocrine, fetal, placental, and uterine parameters during early pregnancy (through day 70) in mares with elevated leptin versus normal leptin (NL) concentrations. Fourteen mares were classified as either NL (n = 6; Lep 0.9 ± 0.3 ng/mL), moderate leptin (ML; n = 4; Lep 3.0 ± 0.3 ng/mL), or high leptin (HL; n = 4; Lep 5.8 ± 0.7 ng/mL) based on annual plasma leptin. Mares were artificially inseminated and induced …

Evaluation Of Diy Pest Management Strategies For The German Cockroach (Blattella Germanica) In The Presence Of Vitamin K Precursors And Synthetic Amorphous Silica, Mohamed S. Shaik

LSU Master's Theses

The German cockroach, Blattella germanica (Linnaeus) is a globally distributed indoor dwelling pest of medical concern. Insecticides are the preferred method of cockroach management due to their low cost, quick action, and availability. However, after continuous use, the development of insecticide resistance has emerged as a challenge for the pest management industry to effectively eliminate German cockroaches. Integrated pest management (IPM) is a sustainable framework which includes the use of glue board traps, vacuuming, in combination with different insecticide formulations such as sprays, gel or dust baits, and insecticide rotation has been successful for the management of German cockroaches. This …

Role And Electrophysiological Properties Of Sexually Dimorphic Oxytocin Receptor Expressing Neurons In The Anteroventral Periventricular Nucleus Of The Female Mice, Armita Abdollahi Govar

LSU Doctoral Dissertations

Oxytocin is a neurohypophyseal hormone that plays a crucial role in regulating mother-infant bonding and maternal behavior. Oxytocin modulates sex-specific parental behaviors by binding to the oxytocin receptor (OXTR)-expressing neurons in the brain. This study investigates the sexually dimorphic OXTR neurons in the anteroventral periventricular nucleus (AVPV) to understand how oxytocin modulates behavior in females. Specifically, we explored the behavioral roles, neural projections, and intrinsic electrophysiological characteristics of these neurons in the female mice. Using immunohistochemistry revealed that the number of OXTR-expressing neurons was enhanced in postpartum females compared with virgin females, suggesting that these neurons are involved in female-specific …

Impacts Of Artificial Habitat Structures On Overwinter Fish Survival And Fish Presence In South-Central Nebraska, Logan Dietrich

Biology Theses, Dissertations, and Student Creative Activity

Artificial lentic systems, such as borrow pits, often lack structural complexity due to construction practices and steep bathymetry, limiting features like vegetation and woody debris essential for fish communities. To address this, artificial structures made of materials such as polyvinyl chloride are increasingly used by state and federal agencies to supplement habitat. However, little information is known about the impact these structures have on fish communities. Thus, the objectives of this study were to examine the influence of Georgia cubes in borrow pit impoundments on overwinter survival of sub-stock and ≥ stock Bluegill (Lepomis macrochirus) and Largemouth Bass …

Human Development, Inequality, And Their Associations With Brain Structure Across 29 Countries, Vicente Medel, Luz M. Alliende, Richard Bethlehem, Jakob Seidlitz, Grace Ringlein, Celso Arango, Aurina Arnatkevičiūtė, Laila Asmal, Mark Bellgrove, Anderson M. Winkler

Human Genetics Publications

Background: The macro-social and environmental conditions in which people live, such as the level of a country’s development or inequality, are associated with brain-related disorders. However, the relationship between these systemic environmental factors and the brain remains unclear. We here aimed to determine the association between the level of development and inequality of a country and the brain structure of healthy adults.

Methods: We conducted a cross-sectional study pooling brain imaging (T1-based) data from 145 magnetic resonance imaging (MRI) studies in 7,962 healthy adults (4,110 women) in 29 different countries. We used a meta-regression approach to relate the brain structure …

Examining Weight Bias Attitude Changes After Exposure To A Brief Photovoice Assignment, Gretchen L. George, Hillary L. Roberts, Kristin Rose, Madison Clemens, Kate G. Burt

Journal of Dietetic Education

Weight bias is present among pre-health professional students (e.g., nutrition, dietetics, nursing, physical therapy, medicine). Educators need support and guidelines about how to enhance learning through engaging assignments while also meeting accreditation requirements. This pilot study examined the impact of an innovative weight bias assignment using photovoice and reflection within existing nutrition education courses, measured through pre-post assessments from the Fat Attitudes Assessment Toolkit. While not all subscales showed significant change, improvements in the Fat Acceptance and Attribution Complexity Composites suggest these methods may be effective in shifting attitudes about fatness. Further research is needed to assess the long-term impact …

Development Of Dietetics Students’ Skills And Self-Efficacy In The Nutrition Care Process, Kristen Heitman, Marcia Nahikian-Nelms, Holly Estes-Doetsch, Kristen M. Roberts, Jennifer A. Garner, Julie Kennel, Christopher A. Taylor

Journal of Dietetic Education

The Nutrition Care Process (NCP) is a systematic framework for providing nutrition care and a cornerstone of dietetics practice. Dietetics education relies on development of skills to achieve competence and demonstrate readiness for practice. The relationship between development of fundamental skills and self-efficacy among dietetics students preparing for clinical practice remains unclear. The purpose of this study was to examine the development of dietetics students’ skills in NCP documentation and their self-efficacy in performing the skills over one academic year. Student nutrition notes (n = 120 notes, n = 30 students) from standardized patient encounters were evaluated for quality using …

Burnout And Turnover Among Program Directors In Acend-Accredited Registered Dietitian Nutritionist Programs, Heather Frazier, Patricia Grace-Farfaglia

Journal of Dietetic Education

Background: Knowledge about program director burnout in ACEND-accredited registered dietitian nutritionist programs is severely limited. Objective: To measure the changes in program director burnout and turnover over a two-year period. Methods: An online questionnaire was distributed to program directors via e-mail in 2021 and 2023. The validated Maslach Burnout Inventory-Educators Survey (MBI-ES) was used to measure burnout, which had three scales: emotional exhaustion, depersonalization, and personal accomplishment. Demographic and program information was also obtained. Results: Over the two-year period, program directors scores for emotional exhaustion (p < 0.001) and depersonalization (p < 0.001) significantly worsened. Interestingly, personal accomplishment scores significantly improved (p < 0.001) during the same time frame. Sixty-six percent of program directors in 2023 reported consideration for leaving their position in the next 5 years, which increased from 58%. Since 2021, 29.9% Didactic Program in Dietetics directors, 28.8% Dietetic Internship directors, and 37.5% Coordinated Program in Dietetics directors have resigned. Conclusion: Program directors show increased signs of burnout. Efforts are needed to investigate ways to support program directors to reduce burnout and increase retention of program directors.

Integrated Advanced Education Supports Future Registered Dietitian Nutritionists’ Breastfeeding Self-Efficacy In Practice, Crystal C. Douglas, Simone Camel

Journal of Dietetic Education

Objective: Evaluate the effectiveness of graduate-level breastfeeding and lactation management education that includes didactive and active learning components on future RDNs’ knowledge, attitudes, and self-efficacy. Design: A pre-and post-test design, utilizing a 41-item pre-intervention survey, learning modules, and a 35-item post-intervention survey. Setting: Three U.S. public universities located in Texas, Louisiana, and Arkansas. Participants: Graduate-level dietetic internship students. Intervention: Four advanced education modules (2 didactive; 2 active learning) developed by Registered Dietitian Nutritionists. Main outcome measures: Gains in breastfeeding knowledge, attitudes, and self-efficacy to assist with breastfeeding education and problem-solving using validated and newly developed survey items. Analysis: Descriptive statistics, …

Sense Of Belonging In The Profession And Program Of Study Among Nutrition And Dietetics Students, Jessica Torro, Melissa Masters, Rachel C. Sinley, Jesse Lunsford, Heidi Masching, Miranda Chen Musgrove

Journal of Dietetic Education

Sense of belonging may positively impact student performance, especially in marginalized groups. This study aimed to examine sense of belonging among a diverse group of nutrition and dietetics students. An online survey investigated students’ feelings of belonging, isolation, and connection to the field of nutrition and dietetics and department of study. The survey was distributed through email to the nutrition and dietetics student body in the Department of Nutrition at Metropolitan State University of Denver. Quantitative data were analyzed as count and percentage. Overall sense of belonging scores were calculated as an average on a 5-point scale (1-strongly disagree to …

Cover, Table Of Contents, About The Journal, Diana Cuy Castellanos, M Elizabeth (Beth) Miller

Journal of Dietetic Education

No abstract provided.

Editors' Message, Diana Cuy Castellanos, M Elizabeth (Beth) Miller

Journal of Dietetic Education

No abstract provided.

Preparation Of Human Asprosin Nanobodies Based On A Natural Nanobody Phage Display Library, Yun Liang, Yi Huang, Qinghua He

Journal of Food Science and Biotechnology

[Objective ] Asprosin (ASP ),an adipokine produced from fibrillin- 1 (FBN 1) cleavage,is closely linked to type 2 diabetes mellitus and obesity when its level is abnormal,demonstrating significant effect on human health.Therefore,monitoring the ASP level is crucial.The author aims to screen the nanobodies specifically binding to ASP via phage display technology,offering a new antibody component for the research on ASP.[Method ] The antigenic epitopes of ASP were predicted by the online tools ABCpred and NovoPro,and then coupled with bovine serum albumin (BSA ) to form the coating antigen (ASP-Epitope-BSA ).After five rounds of bio-panning,the nanobodies specifically binding to ASP were …

Modulatory Effects Of Flavonoids On Il- 4/Il-13 In Atopic Dermatitis And Their Structure-Activity Relationships, Yueyuan Wang, Jing Liu, Chen Li, Fengfeng Chen, Cheng Yang, Bingtian Zhao

Journal of Food Science and Biotechnology

[Objective ] This study aims to explore the ameliorating effects of flavonoids on atopic dermatitis (AD) and their structure-activity relationships.[Method ] Flavonoids were selected through network pharmacology with interleukin- 4 (IL-4) and interleukin- 13 (IL-13) as key targets.The immunoglobulin E (IgE)-induced RBL- 2H3 cell model was employed to evaluate the effects of flavonoids on inflammatory factors,degranulation activities,and calcium ion influx,and the structure-activity relationships were analyzed.Finally,molecular docking was utilized to assist in exploring the action mechanism.[Result ] All of the six flavonoids (luteolin,apigenin,chrysin,quercetin,kaempferol,and fisetin ) screened by network pharmacology had significant inhibitory effects on the expression of IL- 4,IL- 13,tumor necrosis …

Research And Preliminary Application Of A Rapid Immunoassay Method For Eugenol Based On Quantum Dots, Junjie Sun, Xiaoxia Liu, Ziyi Chen, Yinlai Li, Lu Zhai, Qinzhou Chen, Renyao Jin

Journal of Food Science and Biotechnology

[Objective ] This study aims to establish a rapid immunoassay method for the quantitative detection of eugenol.[Method ] The eugenol monoclonal antibody was conjugated to the surface of quantum dots by the 1-ethyl- 3- (3-dimethylaminopropyl ) carbodiimide (EDC ) and N-hydroxy-succinamide (NHS ) (EDC-NHS ) coupling method,with quantum dots as fluorescent markers.Bovine serum albumin (BSA ) was used for blocking,and fluorescence microscopy,agarose gel electrophoresis,and a microplate reader were used for identification.Furthermore,the established method was compared with high performance liquid chromatography (HPLC ).[Result ] The optimal synthesis conditions were as follows:quantum dot activation time of 30 min,conjugation pH with 8.0,antibody addition …

Effects Of Tea Polysaccharides On The Properties Of Chestnut Starch, Lei Lei, Wenjun Fu, Lingling Yang, Haibo Liu, Daxi Sang, Qing Wang

Journal of Food Science and Biotechnology

[Objective ] This study aims to improve the properties of chestnut starch.[Method ] Tea polysaccharides were added to chestnut starch in different proportions,and the effects of tea polysaccharides on the water-holding capacity,digestive properties,textural properties,and other properties of chestnut starch were investigated.[Result ] The water-holding and oil-holding properties of chestnut starch were the largest when tea polysaccharides were added at 1% and then gradually decreased with the increase in the proportion of tea polysaccharides added.The transparency of chestnut starch gradually increased when tea polysaccharides were added from 1% to 8% and decreased significantly when tea polysaccharides were added at 16%.Adding tea …

Mechanisms Of Antioxidant Activity Of Lactic Acid Bacteria And Its Application In Oxidative Stress-Related Diseases, Yixiao Shao, Chuang Huang, Chenjian Liu, Xiaoran Li

Journal of Food Science and Biotechnology

The antioxidant properties of lactic acid bacteria are related to various probiotic activities,which can prevent and alleviate a variety of chronic diseases caused by oxidation in the host.The antioxidant mechanisms of lactic acid bacteria,including the action mechanisms of antioxidant enzymes and non-enzymatic antioxidants and regulation of host signaling pathways,were expounded.Furthermore,the application status of antioxidant properties of lactic acid bacteria in diseases of the nervous system,digestive system,and skin system were summarized.The aim is to explore how to enhance the antioxidant activity of lactic acid bacteria in oxidative stress-related diseases and give new insights into the development of related treatment strategies.

Effects Of Extraction Methods On The Composition And Immunological Activities Of Yeast Mannoproteins, Haibo Zhang, Yongjun Xia, Guangqiang Wang, Ning Peng, Zhixian Chen, Lianzhong Ai

Journal of Food Science and Biotechnology

[Objective ] The extraction efficiency of different methods and the effects of these methods on the composition of mannoproteins extracted from yeast cell walls were compared.Furthermore,the anti-inflammatory activities of the extracted mannoprotein were evaluated.[Method ] Three yeast mannoproteins (MP-W,MP-B,and MP-E ) were extracted via high-temperature water,alkali,and enzyme-assisted extraction methods and purified via ethanol precipitation.The identification of monosaccharide composition and amino acid composition,distribution of relative molecular mass,and Fourier transform infrared spectroscopy were employed to analyze the composition and chemical structures of yeast mannoproteins.A cell experiment was carried out to examine the anti-inflammatory activity.[Result ] The yields of yeast mannoproteins extracted by …

In Vitro Antioxidant And Anti-Inflammatory Activities Of Tea Flower Extract And Its Inhibitory Effect On Cell Aging, Shishuai Yu, Yining Hao, Bo Peng, Youyun Liu, Liping Qu

Journal of Food Science and Biotechnology

[Objective ] This study aims to investigate the in vitro antioxidant and anti-inflammatory activities of Yunnan tea flower extract (TFE ) and its Inhibitory effect on cell aging.[Method ] The main active components in TFE were determined by ultraviolet (UV)-visible spectrophotometry and high performance liquid chromatography (HPLC ).The antioxidant and anti-inflammatory activities of TFE were determined by the free radical scavenging assay and UV-induced photoaging model of human keratinocytes (HaCaT ),respectively.After the aging model of fibroblasts was established,the aging level of cells was assessed by the β-galactosidase (β-gal) staining assay,and the expression of matrix metalloproteinase- 1 (MMP- 1),matrix metalloproteinase- 3 …

Health Risk Assessment Of Multiple Mycotoxins In Rice , Maize , Soybean , And Wheat Flour Marketed In Shanghai, Zuoyin Zhu, Jie Wang, Junmei Ma, Hanke Zhao, Haisheng Cheng, Chengbao Huang, Junhua Yang

Journal of Food Science and Biotechnology

[Objective ] This study aims to evaluate the potential health risks to consumers from exposure to multiple mycotoxins in grains.[Method ] Point and probabilistic assessment models were adopted to analyze the dietary exposure risks of adult residents in Shanghai to aflatoxins (AFs),ochratoxin A (OTA ),zearalenone (ZEN ),deoxynivalenols (DONs ),and fumonisins (FBs) through consumption of rice,maize,soybeans,and wheat flour.[Result ] The margin of exposure values (MoE ) for AFs in maize and aflatoxin G 1 (AFG 1) in soybeans exceeded 10 000,indicating no dietary exposure risk.In contrast,AFs in rice and wheat flour,as well as aflatoxin B 1 (AFB 1),aflatoxin B 2 (AFB …

Establishment And Application Of A Uplc-Ms/Ms Method For Simultaneous Determination Of 39 Veterinary Drugs And Their Metabolites In Black Bone Chicken, Jiawei Du, Yongqin Li, Shuangyuan Jin, Xueyan Wang, Hongwu Wen, Xuelian Guo, Hao Li, Lihua Xu

Journal of Food Science and Biotechnology

[Objective ] This study aims to comprehensively investigate the risk of veterinary drug residues in black bone chicken.[Method ] A method for rapid and simultaneous analysis of 39 veterinary drugs and their metabolites in three categories was established based on low-temperature ultrasonic extraction,solid-phase extraction pretreatment,and ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS ).The samples were extracted by Mcllvaine-Na 2EDTA and phosphate buffer via ultrasonic treatment at low temperatures,purified by Oasis HLB solid-phase extraction column,separated by T 3 chromatographic column,and quantified by the matrix matching external standard method.[Result ] The 39 veterinary drugs and their metabolites showed good linear relationships in …

Serum Metabolomic Profiling Of Incident Type 2 Diabetes Mellitus In The Multi-Ethnic Study Of Atherosclerosis And Rotterdam Study, Xuanwei Jiang, Fang Zhu, Gonçalo Graça, Xihao Du, Jinjun Ran, Fariba Ahmadizar, Alexis C Wood, Yanqiu Zhou, Denise M Scholtens, Ali Farzaneh, M Arfan Ikram, Alan Kuang, Carel W Le Roux, Meghana D Gadgil, Marilyn C Cornelis, Kent D Taylor, Xiuqing Guo, Mohsen Ghanbari, Laura J Rasmussen-Torvik, Russell P Tracy, Alain G Bertoni, Jerome I Rotter, David M Herrington, Philip Greenland, Maryam Kavousi, Victor W Zhong

Children’s Nutrition Research Center Staff Publications

Objective: This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.

Methods: Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 3460; discovery cohort) and The Rotterdam Study (RS; n = 1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23 571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an false discovery rate-adjusted P < .01 in MESA, P < .05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. The utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.

Results: Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses …

Technology Roadmap Of Micro/Nanorobots, Xiaohui Ju, Chuanrui Chen, Cagatay M Oral, Semih Sevim, Ramin Golestanian, Mengmeng Sun, Negin Bouzari, Xiankun Lin, Mario Urso, Jong Seok Nam, Yujang Cho, Xia Peng, Fabian C Landers, Shihao Yang, Azin Adibi, Nahid Taz, Raphael Wittkowski, Daniel Ahmed, Wei Wang, Veronika Magdanz, Mariana Medina-Sánchez, Maria Guix, Naimat Bari, Bahareh Behkam, Raymond Kapral, Yaxin Huang, Jinyao Tang, Ben Wang, Konstantin Morozov, Alexander Leshansky, Sarmad Ahmad Abbasi, Hongsoo Choi, Subhadip Ghosh, Bárbara Borges Fernandes, Giuseppe Battaglia, Peer Fischer, Ambarish Ghosh, Beatriz Jurado Sánchez, Alberto Escarpa, Quentin Martinet, Jérémie Palacci, Eric Lauga, Jeffrey Moran, Miguel A Ramos-Docampo, Brigitte Städler, Ramón Santiago Herrera Restrepo, Gilad Yossifon, James D Nicholas, Jordi Ignés-Mullol, Josep Puigmartí-Luis, Yutong Liu, Lauren D Zarzar, C Wyatt Shields, Longqiu Li, Shanshan Li, Xing Ma, David H Gracias, Orlin Velev, Samuel Sánchez, Maria Jose Esplandiu, Juliane Simmchen, Antonio Lobosco, Sarthak Misra, Zhiguang Wu, Jinxing Li, Alexander Kuhn, Amir Nourhani, Tijana Maric, Ze Xiong, Amirreza Aghakhani, Yongfeng Mei, Yingfeng Tu, Fei Peng, Eric Diller, Mahmut Selman Sakar, Ayusman Sen, Junhui Law, Yu Sun, Abdon Pena-Francesch, Katherine Villa, Huaizhi Li, Donglei Emma Fan, Kang Liang, Tony Jun Huang, Xiang-Zhong Chen, Songsong Tang, Xueji Zhang, Jizhai Cui, Hong Wang, Wei Gao, Vineeth Kumar Bandari, Oliver G Schmidt, Xianghua Wu, Jianguo Guan, Metin Sitti, Bradley J Nelson, Salvador Pané, Li Zhang, Hamed Shahsavan, Qiang He, Il-Doo Kim, Joseph Wang, Martin Pumera

Faculty, Staff and Student Publications

Inspired by Richard Feynman’s 1959 lecture and the 1966 film Fantastic Voyage, the field of micro/nanorobots has evolved from science fiction to reality, with significant advancements in biomedical and environmental applications. Despite the rapid progress, the deployment of functional micro/nanorobots remains limited. This review of the technology roadmap identifies key challenges hindering their widespread use, focusing on propulsion mechanisms, fundamental theoretical aspects, collective behavior, material design, and embodied intelligence. We explore the current state of micro/nanorobot technology, with an emphasis on applications in biomedicine, environmental remediation, analytical sensing, and other industrial technological aspects. Additionally, we analyze issues related to …

Synergistic Activity Of Combined Flt3-Itd And Mdm2 Inhibition With Quizartinib And Milademetan In Flt3-Itd Mutant/Tp53 Wild-Type Acute Myeloid Leukemias, Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff

Faculty, Staff and Student Publications

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.

Experimental design: Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, …

Fgfr3-Induced Y158 Parp1 Phosphorylation Promotes Parp Inhibitor Resistance Via Brg1/Mre11-Mediated Dna Repair In Breast Cancer Models, Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T Chang, Yu-Chun Hsiao, Tewodros W Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively …

Antitumor Efficacy Of Intermittent Low-Dose Erlotinib Plus Sulindac Via Mhc Upregulation And Remodeling Of The Immune Cell Niche, Chakrapani Tripathi, Jorge E Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Yunus Demirhan, Melek Demirhan, Alessandro Shapiro, Altaf Mohammed, Shizuko Sei, Jacklyn Thompson, Mahira Zaheer, Krishna M Sinha, Powel H Brown, Michelle I Savage, Eduardo Vilar, Praveen Rajendran, Roderick H Dashwood

Faculty, Staff and Student Publications

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Targeting The Cd40 Costimulatory Receptor To Improve Virotherapy Efficacy In Diffuse Midline Gliomas, Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel De La Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and …

Ctdna Analysis In Erbb2-Amplified Colorectal Cancer: Biomarker Analysis Of The Mypathway Trial, Funda Meric-Bernstam, Kanwal Pratap Singh Raghav, Christopher J Sweeney, Charles Swanton, David R Spigel, Ron Bose, Howard A Burris, Claire F Friedman, Carin R Espenschied, Jessica M Grindheim, Julia Malato, Katja Schulze, Richard Price, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.

Patients and methods: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA …

Facts And Hopes: Toward The Next Quantum Leap In Melanoma, Keith T Flaherty, Andrew E Aplin, Michael A Davies, Nir Hacohen, Meenhard Herlyn, Dave Hoon, Patrick Hwu, Michal Lotem, James Mulé, Jennifer A Wargo, David E Fisher

Faculty, Staff and Student Publications

Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved, with death rates decreasing for patients with American Joint Committee on Cancer stage 4 melanoma by 3% to 5% annually over the past 10 years. This improvement is a result of advances in both targeted therapy and immunotherapy. BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first-in-class approvals for immune checkpoint blockers targeting CTLA4, PD-1, and LAG3; T-cell engager therapy targeting the antigen gp100; and tumor-infiltrating lymphocyte therapy. All of these …

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …