Digital Commons Network^™

Sitravatinib In Combination With Nivolumab Plus Ipilimumab In Patients With Advanced Clear Cell Renal Cell Carcinoma: A Phase 1 Trial, Pavlos Msaouel, Kai Yu, Ying Yuan, Jianfeng Chen, Xinmiao Yan, Menuka Karki, Fei Duan, Rahul A Sheth, Priya Rao, Kanishka Sircar, Amishi Y Shah, Amado J Zurita, Giannicola Genovese, Min Li, Chih-Chen Yeh, Minghao Dang, Guangchun Han, Yanshuo Chu, Max Hallin, Peter Olson, Rui Yang, Daniela Slavin, Hirak Der-Torossian, Curtis D Chin, Nizar M Tannir, Linghua Wang, Jianjun Gao

Faculty, Staff and Student Publications

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe …

Pembrolizumab Plus Chemotherapy In Frontline Treatment Of Advanced Ovarian Cancer: Clinical And Translational Results From A Phase 2 Trial, Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.

Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, …

Tamm-Horsfall Protein Augments Neutrophil Netosis During Urinary Tract Infection, Vicki Mercado-Evans, Holly Branthoover, Claude Chew, Camille Serchejian, Alexander B Saltzman, Marlyd E Mejia, Jacob J Zulk, Ingrid Cornax, Victor Nizet, Kathryn A Patras

Faculty, Staff and Students Publications

Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared with WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the effect of …

Genome-Wide Association Study Reveals Shared And Distinct Genetic Architecture Of Fatty Acids And Oxylipins In The Hispanic Community Health Study/Study Of Latinos, Carolina G Downie, Heather M Highland, Mona Alotaibi, Barrett M Welch, Annie Green Howard, Susan Cheng, Nick Miller, Mohit Jain, Robert C Kaplan, Adam G Lilly, Tao Long, Tamar Sofer, Bharat Thyagarajan, Bing Yu, Kari E North, Christy L Avery

Faculty, Staff and Student Publications

Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom …

Molecular Logic For Cellular Specializations That Initiate The Auditory Parallel Processing Pathways, Junzhan Jing, Ming Hu, Tenzin Ngodup, Qianqian Ma, Shu-Ning Natalie Lau, M Cecilia Ljungberg, Matthew J Mcginley, Laurence O Trussell, Xiaolong Jiang

Faculty, Staff and Students Publications

The cochlear nuclear complex (CN), the starting point for all central auditory processing, encompasses a suite of neuronal cell types highly specialized for neural coding of acoustic signals. However, the molecular logic governing these specializations remains unknown. By combining single-nucleus RNA sequencing and Patch-seq analysis, we reveal a set of transcriptionally distinct cell populations encompassing all previously observed types and discover multiple hitherto unknown subtypes with anatomical and physiological identity. The resulting comprehensive cell-type taxonomy reconciles anatomical position, morphological, physiological, and molecular criteria, enabling the determination of the molecular basis of the specialized cellular phenotypes in the CN. In particular, …

Bone Marrow Transplantation Reverses Metabolic Alterations In Multiple Sulfatase Deficiency: A Case Series, Nishitha R Pillai, Ning Liu, Xiyuan Li, Xiqi Li, Rebecca Ahrens-Nicklas, Laura Adang, Julie B Eisengart, Grace Bronken, Ashish Gupta, Troy C Lund, Chester B Whitley, Sarah H Elsea, Paul J Orchard

Faculty, Staff and Students Publications

BACKGROUND: Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome.

METHODS: Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from …

Genetic Variations In Mdm2 Gene Contribute To Renal Cell Carcinoma Susceptibility: A Genotype–Phenotype Correlation Study, Shu-Yu Chang, Wen-Shin Chang, Hou-Yu Shih, Chao-Hsiang Chang, Hsi-Chin Wu, Chia-Wen Tsai, Yun-Chi Wang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Background: This study aimed to investigate the polymorphic genotypes of MDM2 rs937282, rs937283, rs2279744, and rs769412, as well as the combined effects of MDM2 genotypes and environmental factors on RCC susceptibility.

Methods: A total of 135 RCC patients and 590 controls were recruited for MDM2 genotyping using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Quantitative PCR was performed to assess MDM2 mRNA levels among 30 healthy individuals and 22 RCC patients.

Results: MDM2 rs2279744, but not other polymorphisms, was significantly associated with an increased RCC risk (p = 0.0133). The MDM2 rs2279744 G allele was identified as …

Society For Immunotherapy Of Cancer: Updates And Best Practices For Multiplex Immunohistochemistry (Ihc) And Immunofluorescence (If) Image Analysis And Data Sharing, Janis M Taube, Joel C Sunshine, Michael Angelo, Guray Akturk, Margaret Eminizer, Logan L Engle, Cláudia S Ferreira, Sacha Gnjatic, Benjamin Green, Shirley Greenbaum, Noah F Greenwald, Cyrus V Hedvat, Travis J Hollmann, Daniel Jiménez-Sánchez, Konstanty Korski, Ana Lako, Edwin R Parra, Marlon C Rebelatto, David L Rimm, Scott J Rodig, Jamie Rodriguez-Canales, Jeffrey S Roskes, Kurt A Schalper, Emanuel Schenck, Keith E Steele, Michael J Surace, Alexander S Szalay, Michael T Tetzlaff, Ignacio I Wistuba, Jennifer H Yearley, Carlo B Bifulco

Faculty, Staff and Student Publications

Objectives: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management.

Methods: The Society for Immunotherapy of Cancer convened a task …

Patient-Derived Xenografts Of Triple-Negative Breast Cancer Enable Deconvolution And Prediction Of Chemotherapy Responses, Jonathan T Lei, Lacey E Dobrolecki, Chen Huang, Ramakrishnan R Srinivasan, Suhas V Vasaikar, Alaina N Lewis, Christina Sallas, Na Zhao, Jin Cao, John D Landua, Chang In Moon, Yuxing Liao, Susan G Hilsenbeck, C Kent Osborne, Mothaffar F Rimawi, Matthew J Ellis, Varduhi Petrosyan, Bo Wen, Kai Li, Alexander B Saltzman, Antrix Jain, Anna Malovannaya, Gerburg M Wulf, Elisabetta Marangoni, Shunqiang Li, Daniel C Kraushaar, Tao Wang, Senthil Damodaran, Xiaofeng Zheng, Funda Meric-Bernstam, Gloria V Echeverria, Meenakshi Anurag, Xi Chen, Bryan E Welm, Alana L Welm, Bing Zhang, Michael T Lewis

Faculty, Staff and Students Publications

Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to multiple single agents cannot be delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination. Combination responses were usually no better than the best single agent, with enhanced response in only ~13% of PDX, and apparent antagonism in a comparable percentage. Single-omic comparisons showed largely non-overlapping results between genes associated with single agent and combination treatments that …

Evaluating The Effects Of High-Throughput Structural Neuroimaging Predictors On Whole-Brain Functional Connectome Outcomes Via Network-Based Matrix-On-Vector Regression, Tong Lu, Yuan Zhang, Vince Lyzinski, Chuan Bi, Peter Kochunov, Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

The joint analysis of multimodal neuroimaging data is vital in brain research, revealing complex interactions between brain structures and functions. Our study is motivated by the analysis of a vast dataset of brain functional connectivity (FC) and multimodal structural imaging (SI) features from the UK Biobank. Specifically, we aim to investigate the effects of SI features, such as white matter microstructure integrity (WMMI) and cortical thickness, on the whole-brain functional connectome network. This analysis is inherently challenging due to the extensive structural-functional associations and the intricate network patterns present in multimodal high-dimensional neuroimaging data. To bridge methodological gaps, we developed …

The C-Terminal Phdvc5hch Tandem Domain Of Nsd2 Is A Combinatorial Reader Of Modified H3k4 And Tri-Methylated H3k27 That Regulates Transcription Of Cell Adhesion Genes In Multiple Myeloma, Andrea Berardi, Charlotte Leonie Kaestner, Michela Ghitti, Giacomo Quilici, Paolo Cocomazzi, Jianping Li, Federico Ballabio, Chiara Zucchelli, Stefan Knapp, Jonathan Licht, Giovanna Musco

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Histone methyltransferase NSD2 (MMSET) overexpression in multiple myeloma (MM) patients plays an important role in the development of this disease subtype. Through the expansion of transcriptional activating H3K36me2 and the suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth, adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR, ITC and molecular dynamics simulations, we show that the tandem PHD domain of NSD2 (PHDVC5HCHNSD2) is a combinatorial reader of unmodified histone H3K4 and tri-methylated H3K27 …

A Case Report Of Moderate Factor X Deficiency, Harpreet Kaur, Tanmoy Das, Poonam Wade, Murtuja Shaikh

Digital Journal of Clinical Medicine

Factor X deficiency is a rare coagulation disorder with a varied clinical spectrum. It can present at any age, but most severe cases present in childhood. There are no evidence-based management guidelines for the management of factor X deficiency due to limited literature. Detailed history, clinical examination and specialized tests (coagulation profile, mixing studies, factor assay) are required for the diagnosis of factor X deficiency. In this case report, we are discussing the case of a 1-month-old, 12-day-old female child who presented with the complaint of spontaneous bleeding from the nose since 1 day with no other bleeding manifestations from …

Neural Mechanisms Of Proactive And Reactive Cognitive Control In Humans, Anas Khan

All ETDs from UAB

Cognitive control enables flexible, goal-directed behavior by dynamically adjusting our actions in response to changing task demands. This dissertation investigates the neural mechanisms underlying proactive and reactive cognitive control, particularly focusing on the dorsolateral prefrontal cortex (dlPFC) and the dorsal anterior cingulate cortex (dACC) during tasks that require response inhibition and conflict processing. Using intracranial electroencephalography (iEEG) recordings from human participants, this research examines the distinct roles of oscillatory activity in these regions in both short-term reactive adjustments and long-term proactive control strategies. Chapter 2 explores the role of low-frequency oscillations in the mid-rostral dlPFC during motor inhibition, revealing that …

Development Of Sacb-Based Counterselection For Efficient Allelic Exchange In Fusobacterium Nucleatum, Peng Zhou, Bibek G C, Bo Hu, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum, prevalent in the oral cavity, is significantly linked to overall human health. Our molecular comprehension of its role in oral biofilm formation and its interactions with the host under various pathological circumstances has seen considerable advancements in recent years, primarily due to the development of various genetic tools for DNA manipulation in this bacterium. Of these, counterselection-based unmarked in-frame mutation methods have proved notably effective. Under suitable growth conditions, cells carrying a counterselectable gene die, enabling efficient selection of rare, defined allelic exchange mutants. The sacB gene from Bacillus subtilis, encoding levansucrase, is a widely used …

Yap Overcomes Mechanical Barriers To Induce Mitotic Rounding And Adult Cardiomyocyte Division, Yuka Morikawa, Jong H Kim, Rich Gang Li, Lin Liu, Shijie Liu, Vaibhav Deshmukh, Matthew C Hill, James F Martin

Faculty, Staff and Students Publications

Background: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.

Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed …

Modulation Of Stemness And Differentiation Regulators By Valproic Acid In Medulloblastoma Neurospheres, Natália Hogetop Freire, Alice Laschuk Herlinger, Julia Vanini, Matheus Dalmolin, Marcelo A C Fernandes, Carolina Nör, Vijay Ramaswamy, Caroline Brunetto De Farias, André Tesainer Brunetto, Algemir Lunardi Brunetto, Lauro José Gregianin, Mariane Da Cunha Jaeger, Michael D Taylor, Rafael Roesler

Faculty, Staff and Students Publications

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 …

Myo5b And The Polygenic Landscape Of Very Early-Onset Inflammatory Bowel Disease In An Ethnically Diverse Population, Ashleigh Watson, R Alan Harris, Amy C Engevik, Numan Oezguen, Maribeth R Nicholson, Sarah Dooley, Rachel Stubler, Lisa Forbes Satter, Lina B Karam, Richard Kellermayer

Faculty, Staff and Students Publications

Background: Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.

Methods: Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD "susceptibility" single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored …

Mechanisms Underlying Dilated Cardiomyopathy Associated With Fkbp12 Deficiency, Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton

Faculty, Staff and Students Publications

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

Faculty, Staff and Student Publications

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

Severe Hypercalcemia Following Hip Joint Implantation Of Calcium Sulfate Antibiotic Beads: Case Series And Review Of Literature., Andrew P. Demidowich, Mahsa Motevalli, Kevin Yi, Atena Kamali, Kristine Batty, Kendall F. Moseley, Robert Raymond Buber, Mehdi Hashemipour`, Mihail Zilbermint

Journal of Community Hospital Internal Medicine Perspectives

Purpose: The diagnosis and management of hypercalcemia in hospitalized patients can be challenging. Hypercalcemia is often associated with significant morbidity and end-organ damage which may delay a patient’s recovery.

Methods: We report a case series of three patients who underwent orthopedic procedures with intraoperative placement of vancomycin-loaded calcium sulfate beads. Patients had no known history of malignancy or excess intake of calcium, vitamin A or vitamin D. Laboratory workup showed low parathyroid (PTH) levels and normal PTH-related peptide levels. The temporal nature of the non-PTH mediated hypercalcemia in relation to implantation of the antibiotic beads suggests causality of exogenous calcium …

Us Military Veterans’ Perceived Concordance With Their Providers Regarding Persistent Physical Symptoms Prospectively Predicts Satisfaction With Care And Adherence To Care Plans, L Alison Phillips, Laura M Lesnewich, Katharine Bloeser, Yong Lin, Rachel L Boska, Justeen K Hyde, Peter J Bayley, Helena K Chandler, Matthew J Reinhard, Susan L Santos, Rachel Stewart, Drew A Helmer, Lisa M Mcandrew

Center for Medical Ethics and Health Policy Staff Publications

Background: Medically unexplained, persistent physical symptoms and syndromes are commonly seen in primary care. These are debilitating for patients and difficult to treat, causing frustration for patients and providers.

Purpose: This study investigates how well US military veterans with multiple persistent physical symptoms (PPS), called Gulf War illness (GWI), agree with their healthcare providers about their illness. This agreement, called perceived concordance, is hypothesized to influence veterans' satisfaction with care, adherence to care plans, and disability levels.

Methods: Participants were 230 veterans with GWI deployed to the 1990-1991 Gulf War who were recruited from Veteran Affairs primary care and War …

Adverse Prehospital Events And Outcomes After Traumatic Brain Injury, Amelia W Maiga, Hsing-Hua Sylvia Lin, Stephen R Wisniewski, Joshua B Brown, Ernest E Moore, Martin A Schreiber, Bellal Joseph, Chad T Wilson, Bryan A Cotton, Daniel G Ostermayer, Brian G Harbrecht, Mayur B Patel, Jason L Sperry, Francis X Guyette, Henry E Wang

Faculty, Staff and Student Publications

Importance: While national guidelines recommend avoidance of hypoxia, hypotension, and hypocarbia in the prehospital care of traumatic brain injury (TBI), limited data validate the association of these adverse physiologic events with TBI outcomes.

Objective: To validate the associations of prehospital hypoxia, hypotension, and hypocarbia with TBI outcomes in a US national trauma network.

Design, setting, and participants: This cohort study examined data from 8 level I trauma centers and their affiliated ground and air emergency medical services (EMS) agencies in the Linking Investigations in Trauma and Emergency Services (LITES) Network from January 1, 2017, to June 30, 2021. Adult patients …

Optimizing Electrode Configurations For Eeg Mild Cognitive Impairment Detection, Yi Jiang, Xin Zhang, Zhiwei Guo, Xiaobo Zhou, Jiayuan He, Ning Jiang

Faculty, Staff and Student Publications

The Optimal electrode configuration of Electroencephalograms (EEG) systems for mild cognitive impairment (MCI) detection and monitoring in non-clinical settings, i.e. number of electrodes and the positions of the electrodes, remains to be explored. In the current study, we explored the optimization of electrode configuration for MCI detection. We used a 32-channel EEG device to record the data of 21 MCI patients and 20 cognitively normal elderly (NC) undergoing working memory (WM) tasks. Based on the differential value (MCI group vs. NC group) from the Power Spectral Density (PSD) value of each electrode in θ and α frequency band during WM …

Minimally Invasive Non-Expansile Tubular Extradural Posterior Fossa Decompression (Minted Technique) For The Management Of Chiari I.5 Malformation: Historical Overview Of Surgical Techniques, Technical Note, Proof Of Concept, Illustrative Case And Case Series. Lesser Is Better, José Alberto Israel Romero Rangel, Manuel Eduardo Soto García, Sergio Soriano Solís, Carlos Raúl Rangel Morales, Gerson Reyes Rodríguez, José Antonio Soriano Sánchez

Archives of Neurosurgery

BACKGROUND: Chiari's Malformation surgical treatment has significantly changed since the "classical" technique description by Gardner (1950). It is probably the most commonly performed approach, even when multiple techniques are available because no substantial changes nor any clear surgical objectives have been made. OBJECTIVE: To demonstrate a new cutting-edge surgical technique mastering the advantage of each surgical procedure ever described in the history of Chiari's Malformation establishing three critical points in surgical technique: clear patient-specific surgical goals, dynamic posterior fossa reconstruction, and extradural occipitoatlantal dense-adhesions release. METHODS: A comprehensive review of historically described approaches, proof of concept of surgical technique in …

A Thermodynamic Bottleneck In The Tca Cycle Contributes To Acetate Overflow In Staphylococcus Aureus, Nabia Shahreen, Jong-Sam Ahn, Adil Alsiyabi, Niaz Bahar Chowdhury, Dhananjay Shinde, Sujata S. Chaudhari, Kenneth W. Bayles, Vinai Chittezham Thomas, Rajib Saha

Journal Articles: Pathology and Microbiology

During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate …

High-Grade Avm. Educational Vignette And Clinical Cases, Marcos Devanir Silva Da Costa, Marcelo Augusto Acosta Goiri, Daniela Coelho, Juan Alberto Paz Archila, Talita Helena Martins Sarti, Feres Chaddad-Neto

Archives of Neurosurgery

The arteriovenous malformation (AVM) is a vascular malformation characterized by fistulas between arteries and veins forming a nidus, without interposition of capillary vessels and of which early draining vein is identified at the digital angiography. Potential reports of its existence date from the second century AD. Spetzler and Martin (S-M) proposed a classification considering three features and Lawton then added new predictors. A maximum of 10 score can be achieved by applying the modified S-M grade system. This classification guides decision-making and the possible choice of the multimodal treatment (surgery, radiosurgery and embolization). We discuss historical, pathological, clinical and therapeutic …

Cd4+ T Cell-Innate Immune Crosstalk Is Critical During Staphylococcus Aureus Craniotomy Infection, Gunjan Kak, Zachary A. Van Roy, Rachel W. Fallet, Lee E. Korshoj, Tammy Kielian

Journal Articles: Pathology and Microbiology

Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed …

Species-Specific Discrimination Of Bacterial Biofilms Using A Ratiometric Fluorescence Sensor Array And Machine Learning, Ritika Gupta, Aayushi Laliwala, Elena Muldiiarova, Kenneth W. Bayles, Denis Svechkarev, Marat Sadykov, Aaron M. Mohs

Journal Articles: Pathology and Microbiology

Biofilms are intricate bacterial communities encased in a self-produced extracellular matrix (ECM) of DNA, lipids, proteins, and polysaccharides. The diverse ECM composition across bacterial species significantly influences the progression of biofilm-associated infections, making precise identification crucial for effective treatment. Traditional methods such as biochemical assays, MALDI-TOF mass spectrometry, DNA sequencing and culturing provide valuable insights but have notable drawbacks, including time-consuming procedures, high costs, and the need for specialized equipment and trained personnel. These limitations hinder the rapid and widespread adoption of biofilm identification in clinical settings, underscoring the need for more streamlined, accurate, and accessible methods. In this study, …

Determining Localization Of Surf-4 In Drosophila Melanogaster In The Secretory Pathway, Jada Scott

Mahurin Honors College Capstone Experience/Thesis Projects

The purpose of this research is to determine the role of the Surfeit-4 gene, or Surf-4 locus protein, during Drosophila melanogaster development. Surf-4 was identified in the Srivastava lab in a biochemical screen for proteins that associate with the basement membrane (BM): a structure needed and required for normal development and its degradation is a hallmark of tumor metastasis. Surf-4 has been predicted to function within intracellular compartments and is known to be expressed in many parts of the developing fly. We are currently determining why Surf-4 is important in development and what role, if any, it could play during …

Covariate Selection For Rna-Seq Differential Expression Analysis With Hidden Factor Adjustment, Farzana Noorzahan, Hyeongseon Jeon, Yet Nguyen

Mathematics & Statistics Faculty Publications

In RNA-seq data analysis, a primary objective is the identification of differentially expressed genes, which are genes that exhibit varying expression levels across different conditions of interest. It is widely known that hidden factors, such as batch effects, can substantially influence the differential expression analysis. Furthermore, apart from the primary factor of interest and unforeseen artifacts, an RNA-seq experiment typically contains multiple measured covariates, some of which may significantly affect gene expression levels, while others may not. Existing methods either address the covariate selection or the unknown artifacts separately. In this study, we investigate two integrated strategies, FSR_sva and SVAall_FSR, …