Digital Commons Network^™

Cocaine Use And Head And Neck Cancer Risk: A Pooled Analysis In The International Head And Neck Cancer Epidemiology Consortium, Mingyan Zhang, Chu Chen, Guojun Li, Alzina Koric, Yuan-Chin Amy Lee, Hal Morgenstern, Stephen M Schwartz, Erich M Sturgis, Paolo Boffetta, Mia Hashibe, Zuo-Feng Zhang

Faculty, Staff and Students Publications

BACKGROUND: Cocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC).

METHODS: The analyses were conducted by pooling data from three case-control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models.

RESULTS: Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC …

Genome-Wide P63-Target Gene Analyses Reveal Tap63/Nrf2-Dependent Oxidative Stress Responses, Marco Napoli, Avani A Deshpande, Deepavali Chakravarti, Kimal Rajapakshe, Preethi H Gunaratne, Cristian Coarfa, Elsa R Flores

Faculty, Staff and Students Publications

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs …

Emotional Resilience Predicts Preserved White Matter Microstructure Following Mild Traumatic Brain Injury, Lanya T Cai, Benjamin L Brett, Eva M Palacios, Esther L Yuh, Ioanna Bourla, Jamie Wren-Jarvis, Yang Wang, Christine Mac Donald, Ramon Diaz-Arrastia, Joseph T Giacino, David O Okonkwo, Harvey S Levin, Claudia S Robertson, Nancy Temkin, Amy J Markowitz, Geoffrey T Manley, Murray B Stein, Michael A Mccrea, Ross D Zafonte, Lindsay D Nelson, Pratik Mukherjee, Track-Tbi Investigators

Faculty, Staff and Students Publications

Background: Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient mTBI phenotype compared with a neuropsychiatrically distressed mTBI phenotype.

Methods: The present study used diffusion magnetic resonance imaging to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. …

Safety, Immunogenicity, And Mechanism Of A Rotavirus Mrna-Lnp Vaccine In Mice, Chenxing Lu, Yan Li, Rong Chen, Xiaoqing Hu, Qingmei Leng, Xiaopeng Song, Xiaochen Lin, Jun Ye, Jinlan Wang, Jinmei Li, Lida Yao, Xianqiong Tang, Xiangjun Kuang, Guangming Zhang, Maosheng Sun, Yan Zhou, Hongjun Li

Faculty, Staff and Student Publications

Rotaviruses (RVs) are a major cause of diarrhea in young children worldwide. The currently available and licensed vaccines contain live attenuated RVs. Optimization of live attenuated RV vaccines or developing non-replicating RV (e.g., mRNA) vaccines is crucial for reducing the morbidity and mortality from RV infections. Herein, a nucleoside-modified mRNA vaccine encapsulated in lipid nanoparticles (LNP) and encoding the VP7 protein from the G1 type of RV was developed. The 5' untranslated region of an isolated human RV was utilized for the mRNA vaccine. After undergoing quality inspection, the VP7-mRNA vaccine was injected by subcutaneous or intramuscular routes into mice. …

The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis And The Expression Of Autism-Like Behaviors, Sreetama Basu, Eun Jeoung Ro, Zhi Liu, Hyunjung Kim, Aubrey Bennett, Seungwoo Kang, Hoonkyo Suh

The Brown Foundation: Institute of Molecular Medicine

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role …

A Novel Polymer-Encapsulated Multi-Imaging Modality Fiducial Marker With Positive Signal Contrast For Image-Guided Radiation Therapy, Li Wang, Jeremiah Sanders, John F Ward, Stephen R Lee, Falk Poenisch, David Michael Swanson, Narayan Sahoo, Xiaorong Ronald Zhu, Jingfei Ma, Rajat J Kudchadker, Seungtaek L Choi, Quynh-Nhu Nguyen, Lauren L Mayo, Shalin J Shah, Steven J Frank

Faculty, Staff and Student Publications

BACKGROUND: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA.

METHODS: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 …

Cytoskeleton Remodeling Induced By Smyd2 Methyltransferase Drives Breast Cancer Metastasis, Alexandre G Casanova, Gael S Roth, Simone Hausmann, Xiaoyin Lu, Ludivine J M Bischoff, Emilie M Froeliger, Lucid Belmudes, Ekaterina Bourova-Flin, Natasha M Flores, Ana Morales Benitez, Tourkian Chasan, Marcello Caporicci, Jessica Vayr, Sandrine Blanchet, Francesco Ielasi, Sophie Rousseaux, Pierre Hainaut, Or Gozani, Muriel Le Romancer, Yohann Couté, Andres Palencia, Pawel K Mazur, Nicolas Reynoird

Faculty, Staff and Student Publications

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as …

Delays In Intervention: A Post-Mortem Of The Uk-Reboa And Cryostat-2 Trials, Bryan A Cotton

Faculty, Staff and Student Publications

No abstract provided.

Development Of A Culinary Medicine Toolkit To Improve Implementation Of Virtual Cooking Classes For Low-Income Adults With Type 2 Diabetes, David Ai, Natalia I Heredia, Vanessa Cruz, Diana C Guevara, Shreela V Sharma, Dolores Woods, Melisa Danho, John Wesley Mcwhorter

Faculty, Staff and Student Publications

Culinary medicine (CM) addresses diseases through nutrition and culinary education. To promote access to educational material for people with diabetes and engagement in virtual classes, we created a virtual culinary medicine toolkit (VCMT) sensitive to literacy levels and language preferences. The VCMT was developed to accompany existing virtual CM programs and help improve participant interaction and retention, offering educational materials for providers and participants. The provider VCMT offers level-setting education to reduce mixed nutrition messaging, including educational resources discussing inclusive nutrition and mindful eating topics. Each handout has a QR code and link to engaging, animated videos that provide further …

Myd88 In Myofibroblasts Enhances Nonalcoholic Fatty Liver Disease-Related Hepatocarcinogenesis Via Promoting Macrophage M2 Polarization, Yu Liu, Haiqiang Chen, Xuanxuan Yan, Jie Zhang, Zhenzhong Deng, Maosheng Huang, Jianchun Gu, Jinhua Zhang

Faculty, Staff and Student Publications

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown.

Results: Myofibroblast MyD88-deficient (SMAMyD88-/-) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on …

Expression Of Atoh1, Gfi1, And Pou4f3 In The Mature Cochlea Reprograms Nonsensory Cells Into Hair Cells, Melissa M Mcgovern, Ishwar V Hosamani, Yichi Niu, Ken Y Nguyen, Chenghang Zong, Andrew K Groves

Faculty, Staff and Students Publications

Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate; consequently, loss of hair cells leads to permanent hearing loss. Although nonmammalian vertebrates can regenerate hair cells from neighboring supporting cells, many humans with severe hearing loss lack both hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of nonsensory cells. To determine whether the mature cochlea can produce hair cells in vivo, we reprogrammed nonsensory cells adjacent to the organ of Corti with three hair cell transcription factors: Gfi1, Atoh1, and Pou4f3. We generated numerous hair cell–like …

Patient-Derived Models Of Cancer In The Nci Pdmc Consortium: Selection, Pitfalls, And Practical Recommendations, Amber N Habowski, Deepthi P Budagavi, Sandra D Scherer, Arin B Aurora, Giuseppina Caligiuri, William F Flynn, Ellen M Langer, Jonathan R Brody, Rosalie C Sears, Giorgia Foggetti, Anna Arnal Estape, Don X Nguyen, Katerina A Politi, Xiling Shen, David S Hsu, Donna M Peehl, John Kurhanewicz, Renuka Sriram, Milagros Suarez, Sophie Xiao, Yuchen Du, Xiao-Nan Li, Nora M Navone, Estefania Labanca, Christopher D Willey

Faculty, Staff and Student Publications

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as …

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization In A Hind Limb Ischemia Model In Diabetic, Hyperlipidemic Rabbits, Eri Takematsu, Miles Massidda, Gretchen Howe, Julia Goldman, Patricia Felli, Lei Mei, Gregory Callahan, Andrew D Sligar, Richard Smalling, Aaron B Baker

Faculty, Staff and Student Publications

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. …

Adult Neuromuscular Choristoma, A Rare Peripheral Nerve Pathology: Illustrative Case, Ashley Ricciardelli, Alex Flores, Hsiang-Chih Lu, Ekin Guney, Arie Perry, Joey Grochmal

Faculty, Staff and Students Publications

Background: Neuromuscular choristomas (NMCs) are rare tumors involving aberrant intercalation of muscle fibers into peripheral nerves, most commonly the sciatic nerve. Although benign, these lesions risk developing into NMCs with desmoid-type fibrosis (NMC-DTFs), aggressive lesions potentially requiring amputation. Currently, information on NMCs and the link between NMCs and NMC-DTFs is limited in adults, with the majority of cases reported in children. We present the case of a 66-year-old male with a sciatic NMC alongside a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-based systematic review of similar cases to better characterize this lesion in the adult population.

Observations: A male …

Important Features For Protein Foldings In Two Acyl Carrier Proteins From Enterococcus Faecalis, Seoyeong Yoo, Jiwon Yeon, Eunhee Kim, Yangmee Kim

Faculty, Staff and Student Publications

The emergence of multi-drug resistant Enterococcus faecalis raises a serious threat to global public health. E. faecalis is a gram-positive intestinal commensal bacterium found in humans. E. faecalis can endure extreme environments such as high temperature, pressure, and high salt, which facilitates them to cause infection in hospitals. E. faecalis has two acyl carrier proteins, AcpA (EfAcpA) in de novo fatty acid synthesis (FAS) and AcpB (EfAcpB) which utilizes exogenous fatty acids. Previously, we determined the tertiary structures of these two ACPs and investigated their structure-function relationships. Solution structures revealed that overall folding of these two ACPs is similar to …

Reconstitution Of Human Pdac Using Primary Cells Reveals Oncogenic Transcriptomic Features At Tumor Onset, Yi Xu, Michael H Nipper, Angel A Dominguez, Zhenqing Ye, Naoki Akanuma, Kevin Lopez, Janice J Deng, Destiny Arenas, Ava Sanchez, Francis E Sharkey, Colin M Court, Aatur D Singhi, Huamin Wang, Martin E Fernandez-Zapico, Lu-Zhe Sun, Siyuan Zheng, Yidong Chen, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the …

Single-Cell Multiomics Decodes Regulatory Programs For Mouse Secondary Palate Development, Fangfang Yan, Akiko Suzuki, Chihiro Iwaya, Guangsheng Pei, Xian Chen, Hiroki Yoshioka, Meifang Yu, Lukas M Simon, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Perturbations in gene regulation during palatogenesis can lead to cleft palate, which is among the most common congenital birth defects. Here, we perform single-cell multiome sequencing and profile chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. We construct five trajectories representing continuous differentiation of cranial neural crest-derived multipotent cells into distinct lineages. By linking open chromatin signals to gene expression changes, we characterize the underlying lineage-determining transcription factors. In silico perturbation analysis identifies transcription factors SHOX2 and MEOX2 as important regulators …

Ubr5 Promotes Antiviral Immunity By Disengaging The Transcriptional Brake On Rig-I Like Receptors, Duomeng Yang, Tingting Geng, Andrew G Harrison, Jason G Cahoon, Jian Xing, Baihai Jiao, Mark Wang, Chao Cheng, Robert E Hill, Huadong Wang, Anthony T Vella, Gong Cheng, Yanlin Wang, Penghua Wang

Faculty, Staff and Students Publications

The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are …

Prevention And Potential Treatment Strategies For Respiratory Syncytial Virus, Bo-Wen Sun, Peng-Peng Zhang, Zong-Hao Wang, Xia Yao, Meng-Lan He, Rui-Ting Bai, Hao Che, Jing Lin, Tian Xie, Zi Hui, Xiang-Yang Ye, Li-Wei Wang

Faculty, Staff and Student Publications

Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and …

Interplay Between Atrx And Idh1 Mutations Governs Innate Immune Responses In Diffuse Gliomas, Seethalakshmi Hariharan, Benjamin T Whitfield, Christopher J Pirozzi, Matthew S Waitkus, Michael C Brown, Michelle L Bowie, David M Irvin, Kristen Roso, Rebecca Fuller, Janell Hostettler, Sharvari Dharmaiah, Emiley A Gibson, Aaron Briley, Avani Mangoli, Casey Fraley, Mariah Shobande, Kevin Stevenson, Gao Zhang, Prit Benny Malgulwar, Hannah Roberts, Martin Roskoski, Ivan Spasojevic, Stephen T Keir, Yiping He, Maria G Castro, Jason T Huse, David M Ashley

Faculty, Staff and Student Publications

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes …

The Yap1/Taz-Tead Transcriptional Network Regulates Gene Expression At Neuromuscular Junctions In Skeletal Muscle Fibers, Lea Gessler, Danyil Huraskin, Yongzhi Jian, Nane Eiber, Zhaoyong Hu, Tomasz J Prószyński, Said Hashemolhosseini

Faculty, Staff and Students Publications

We examined YAP1/TAZ-TEAD signaling pathway activity at neuromuscular junctions (NMJs) of skeletal muscle fibers in adult mice. Our investigations revealed that muscle-specific knockouts of Yap1 or Taz, or both, demonstrate that these transcriptional coactivators regulate synaptic gene expression, the number and morphology of NMJs, and synaptic nuclei. Yap1 or Taz single knockout mice display reduced grip strength, fragmentation of NMJs, and accumulation of synaptic nuclei. Yap1/Taz muscle-specific double knockout mice do not survive beyond birth and possess almost no NMJs, the few detectable show severely impaired morphology and are organized in widened endplate bands; and with motor nerve endings being …

Novel Strategies To Improve The Cardioprotective Effects Of Cardioplegia, Estefanie Osorio-Llanes, Jairo Castellar-López, Wendy Rosales-Rada, Yulieth Montoya, John Bustamante, Ricardo Zalaquett, Roberto Bravo-Sagua, Jaime A Riquelme, Gina Sánchez, Mario Chiong, Sergio Lavandero, Evelyn Mendoza-Torres

Faculty, Staff and Student Publications

The use of cardioprotective strategies as adjuvants of cardioplegic solutions has become an ideal alternative for the improvement of post-surgery heart recovery. The choice of the optimal cardioplegia, as well as its distribution mechanism, remains controversial in the field of cardiovascular surgery. There is still a need to search for new and better cardioprotective methods during cardioplegic procedures. New techniques for the management of cardiovascular complications during cardioplegia have evolved with new alternatives and additives, and each new strategy provides a tool to neutralize the damage after ischemia/reperfusion events. Researchers and clinicians have committed themselves to studying the effect of …

Crispr Screening Identifies Bet And Mtor Inhibitor Synergy In Cholangiocarcinoma Through Serine Glycine One Carbon, Yan Zhu, Dengyong Zhang, Pooja Shukla, Young-Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A Copland, Lin Tan, Philip L Lorenzi, Milind Javle, Jason T Huse, Jason Roszik, Traver Hart, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged …

Hedgehog Activation Promotes Osteogenic Fates Of Growth Plate Resting Zone Chondrocytes Through Transient Clonal Competency, Shion Orikasa, Yuki Matsushita, Hiroaki Manabe, Michael Fogge, Zachary Lee, Koji Mizuhashi, Naoko Sakagami, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-Indian hedgehog feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes …

Intratumoral Biosynthesis Of Gold Nanoclusters By Pancreatic Cancer To Overcome Delivery Barriers To Radiosensitization, Aaron S Schwartz-Duval, Yuri Mackeyev, Iqbal Mahmud, Philip L Lorenzi, Mihai Gagea, Sunil Krishnan, Konstantin V Sokolov

Faculty, Staff and Student Publications

Nanoparticle delivery to solid tumors is a prime challenge in nanomedicine. Here, we approach this challenge through the lens of biogeochemistry, the field that studies the flow of chemical elements within ecosystems as manipulated by living cellular organisms and their environments. We leverage biogeochemistry concepts related to gold cycling against pancreatic cancer, considering mammalian organisms as drivers for gold nanoparticle biosynthesis. Sequestration of gold nanoparticles within tumors has been demonstrated as an effective strategy to enhance radiotherapy; however, the desmoplasia of pancreatic cancer impedes nanoparticle delivery. Our strategy overcomes this barrier by applying an atomic-scale agent, ionic gold, for intratumoral …

Trex2 Deficiency Suppresses Spontaneous And Genotoxin-Associated Mutagenesis, Teresa Marple, Mi Young Son, Xiaodong Cheng, Jun Ho Ko, Patrick Sung, Paul Hasty

Faculty, Staff and Student Publications

TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. …

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk In Myeloproliferative Neoplasms, Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider

Faculty, Staff and Student Publications

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a …

Intratumoral Biosynthesis Of Gold Nanoclusters By Pancreatic Cancer To Overcome Delivery Barriers To Radiosensitization, Aaron S Schwartz-Duval, Yuri Mackeyev, Iqbal Mahmud, Philip L Lorenzi, Mihai Gagea, Sunil Krishnan, Konstantin V Sokolov

Faculty, Staff and Student Publications

Nanoparticle delivery to solid tumors is a prime challenge in nanomedicine. Here, we approach this challenge through the lens of biogeochemistry, the field that studies the flow of chemical elements within ecosystems as manipulated by living cellular organisms and their environments. We leverage biogeochemistry concepts related to gold cycling against pancreatic cancer, considering mammalian organisms as drivers for gold nanoparticle biosynthesis. Sequestration of gold nanoparticles within tumors has been demonstrated as an effective strategy to enhance radiotherapy; however, the desmoplasia of pancreatic cancer impedes nanoparticle delivery. Our strategy overcomes this barrier by applying an atomic-scale agent, ionic gold, for intratumoral …

Integrative Genomic Analyses Reveal Putative Cell Type-Specific Targets Of The Drosophila Ets Transcription Factor Pointed, Komal Kumar Bollepogu Raja, Kelvin Yeung, Yoon-Kyung Shim, Graeme Mardon

Faculty, Staff and Students Publications

The Ets domain transcription factors direct diverse biological processes throughout all metazoans and are implicated in development as well as in tumor initiation, progression and metastasis. The Drosophila Ets transcription factor Pointed (Pnt) is the downstream effector of the Epidermal growth factor receptor (Egfr) pathway and is required for cell cycle progression, specification, and differentiation of most cell types in the larval eye disc. Despite its critical role in development, very few targets of Pnt have been reported previously. Here, we employed an integrated approach by combining genome-wide single cell and bulk data to identify putative cell type-specific Pnt targets. …

Role Of Polyunsaturated Fat In Modifying Cardiovascular Risk Associated With Family History Of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies, Federica Laguzzi, Agneta Åkesson, Matti Marklund, Frank Qian, Bruna Gigante, Traci M Bartz, Julie K Bassett, Anna Birukov, Hannia Campos, Yoichiro Hirakawa, Fumiaki Imamura, Susanne Jäger, Maria Lankinen, Rachel A Murphy, Mackenzie Senn, Toshiko Tanaka, Nathan Tintle, Jyrki K Virtanen, Kazumasa Yamagishi, Matthew Allison, Ingeborg A Brouwer, Ulf De Faire, Gudny Eiriksdottir, Luigi Ferrucci, Nita G Forouhi, Johanna M Geleijnse, Allison M Hodge, Hitomi Kimura, Markku Laakso, Ulf Risérus, Anniek C Van Westing, Stefania Bandinelli, Ana Baylin, Graham G Giles, Vilmundur Gudnason, Hiroyasu Iso, Rozenn N Lemaitre, Toshiharu Ninomiya, Wendy S Post, Bruce M Psaty, Jukka T Salonen, Matthias B Schulze, Michael Y Tsai, Matti Uusitupa, Nicholas J Wareham, Seung-Won Oh, Alexis C Wood, William S Harris, David Siscovick, Dariush Mozaffarian, Karin Leander, Fatty Acids And Outcomes Research Consortium (Force)

Faculty, Staff and Students Publications

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were …