Medical Genetics Commons^™

Rragd-Associated Autosomal Dominant Kidney Hypomagnesemia With Cardiomyopathy: A Review On The Clinical Manifestations And Therapeutic Options, Francesco Trepiccione, Irene Sambri, Barbara Ruggiero, Francesco Emma, Andrea Ballabio, Giulia Florio, Ines Vanderheyden, Anna Iervolino, François Jouret

Duncan NRI Faculty and Staff Publications

Background: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function.

Summary: All identified RRAGD variants compromise …

Fgf5, Evelyn A Carrion, Malcolm M Moses, Richard R Behringer

Faculty, Staff and Student Publications

FGF5 functions as a negative regulator of the hair cycle in mammals. It is expressed in the outer root sheath of hair follicles during the late anagen phase of the hair cycle. It functions as a signaling molecule, mediating the transition of the anagen growth phase to catagen regression phase of the hair cycle. Spontaneous and engineered FGF5 mutations in mammalian animal models result in long hair phenotypes. In humans, inherited FGF5 mutations result in trichomegaly (long eyelashes). Knockdown of fgf5 in zebrafish embryos results in inner ear alterations. Alterations in FGF5 expression are also associated with various human pathologies.

Failure To Mate Enhances Investment In Behaviors That May Promote Mating Reward And Impairs The Ability To Cope With Stressors Via A Subpopulation Of Neuropeptide F Receptor Neurons, Julia Ryvkin, Liora Omesi, Yong-Kyu Kim, Mali Levi, Hadar Pozeilov, Lital Barak-Buchris, Bella Agranovich, Ifat Abramovich, Eyal Gottlieb, Avi Jacob, Dick R Nässel, Ulrike Heberlein, Galit Shohat-Ophir

Faculty, Staff and Student Publications

Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward …

Sudden Unexpected Intrapartum Death And Left Ventricular Noncompaction Involving The Right Ventricle, Giulia Ottaviani, Tobia Tomasello, Francesca Boggio, Letterio Runza, Alessandro Del Gobbo, L Maximilian Buja

Faculty, Staff and Student Publications

Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle …

Chronic Lymphocytic Leukemia: Disease Biology, Stefan Koehrer, Jan A Burger

Faculty, Staff and Student Publications

Background: B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and …

Enhancing Associative Learning In Rats With A Computationally Designed Training Protocol, Xu O Zhang, Yili Zhang, Claire E Cho, Douglas S Engelke, Paul Smolen, John H Byrne, Fabricio H Do-Monte

Faculty, Staff and Student Publications

Background: Learning requires the activation of protein kinases with distinct temporal dynamics. In Aplysia, nonassociative learning can be enhanced by a computationally designed learning protocol with intertrial intervals (ITIs) that maximize the interaction between fast-activated PKA (protein kinase A) and slow-activated ERK (extracellular signal-regulated kinase). Whether a similar strategy can enhance associative learning in mammals is unknown.

Methods: We simulated 1000 training protocols with varying ITIs to predict an optimal protocol based on empirical data for PKA and ERK dynamics in rat hippocampus. Adult male rats received the optimal protocol or control protocols in auditory fear conditioning and fear …

Author Correction: Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

No abstract provided.

Risk Stratification And Prediction Of Severity Of Covid-19 Infection In Patients With Preexisting Cardiovascular Disease, Stanislava Matejin, Igor D Gregoric, Rajko Radovancevic, Slobodan Paessler, Vladimir Perovic

Faculty, Staff and Student Publications

Introduction: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a highly contagious viral disease. Cardiovascular diseases and heart failure elevate the risk of mechanical ventilation and fatal outcomes among COVID-19 patients, while COVID-19 itself increases the likelihood of adverse cardiovascular outcomes.

Methods: We collected blood samples and clinical data from hospitalized cardiovascular patients with and without proven COVID-19 infection in the time period before the vaccine became available. Statistical correlation analysis and machine learning were used to evaluate and identify individual parameters that could predict the risk of needing mechanical ventilation and patient survival.

Results: Our results confirmed that COVID-19 …

Clinical Characteristics And Outcomes Of Adult Alveolar Rhabdomyosarcoma Patients On First-Line Systemic Therapies: A Single-Institution Cohort, Michael S Nakazawa, J Andrew Livingston, Maria A Zarzour, Andrew J Bishop, Ravin Ratan, Joseph A Ludwig, Dejka M Araujo, Neeta Somaiah, Vinod Ravi, Elise F Nassif, Christina L Roland, Alexander J Lazar, B Ashleigh Guadagnolo, Douglas J Harrison, Robert S Benjamin, Shreyaskumar R Patel, Anthony P Conley

Faculty, Staff and Student Publications

Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. ]

Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 …

Bayesian Optimal Designs For Multi-Arm Multi-Stage Phase Ii Randomized Clinical Trials With Multiple Endpoints, Guillaume Mulier, Sylvie Chevret, Ruitao Lin, Lucie Biard

Faculty, Staff and Student Publications

There is a growing need to evaluate of multiple competing drugs in phase II trials where the number of patients is often limited, and simultaneous assessment of both efficacy and toxicity is crucial. To avoid the waste of research resources, it is indeed more efficient to screen multiple drugs at once in a platform phase II setting. We aim to adapt the Bayesian optimal phase II (BOP2) design to multi-arm trials for both uncontrolled and controlled settings. The binary efficacy and toxicity endpoints are modeled by a Dirichlet distribution as a vector of four outcomes. Posterior marginal distributions at each …

On The Relative Conservativeness Of Bayesian Logistic Regression Method In Oncology Dose-Finding Studies, Cheng-Han Yang, Guanghui Cheng, Ruitao Lin

Faculty, Staff and Student Publications

The Bayesian logistic regression method (BLRM) is a widely adopted and flexible design for finding the maximum tolerated dose in oncology phase I studies. However, the BLRM design has been criticized in the literature for being overly conservative due to the use of the overdose control rule. Recently, a discussion paper titled "Improving the performance of Bayesian logistic regression model with overall control in oncology dose-finding studies" in Statistics in Medicine has proposed an overall control rule to address the "excessive conservativeness" of the standard BLRM design. In this short communication, we discuss the relative conservativeness of the standard BLRM …

Systematic Review And Meta-Analysis Of Acupuncture For Modulation Of Immune And Inflammatory Markers In Cancer Patients, Wenli Liu, Baisong Zhong, Richard W Wagner, M Kay Garcia, Jennifer L Mcquade, Wen Huang, Yisheng Li, Graciela M Nogueras Gonzalez, Michael R Spano, Alessandro Cohen, Yimin Geng, Lorenzo Cohen

Faculty, Staff and Student Publications

Introduction: Inflammation is associated with tumor initiation, and existing tumors are associated with immune suppression locally and systemically. Cancer treatment is also associated with immune suppression. This review evaluates evidence related to the use of acupuncture for modulation of inflammation and the immune system in cancer patients.

Methods: Nine databases were searched for prospective, randomized, controlled trials evaluating the use of acupuncture for modulation of the immune system in cancer patients through March 2024. Only studies involving needle insertion into acupuncture points were included. No language limitations were applied. Studies were assessed for risk of bias (ROB) according to Cochrane …

Commitment Complex Splicing Factors In Cancers Of The Gastrointestinal Tract-An In Silico Study, Yun Zhang, Alexandria Carrasquillo Simko, Uzondu Okoro, Deja Jamese Sibert, Jin Hyung Moon, Bin Liu, Angabin Matin

Faculty, Staff and Student Publications

The initial step in pre-mRNA splicing involves formation of a spliceosome commitment complex (CC) or E-complex by factors that serve to bind and mark the exon-intron boundaries that will undergo splicing. The CC component U1 snRNP assembles at the 5'-splice site (ss), whereas SF1, U2AF2, and U2AF1 define the 3'-ss of the intron. A PRP40 protein bridges U1 snRNP with factors at the 3'-ss. To determine how defects in CC components impact cancers, we analyzed human gastrointestinal (GI) cancer patient tissue and clinical data from cBioPortal. cBioPortal datasets were analyzed for CC factor alterations and patient outcomes in GI cancers …

Pancreatic Cancer Action Network's Spark: A Cloud-Based Patient Health Data And Analytics Platform For Pancreatic Cancer, Kawther Abdilleh, Omar Khalid, Dennis Ladnier, Wenshuai Wan, Sara Seepo, Garrett Rupp, Valentin Corelj, Zelia F Worman, Divya Sain, Jack Digiovanna, Bruce Press, Satty Chandrashekhar, Eric Collisson, Karen Y Cui, Anirban Maitra, Paul A Rejto, Kevin P White, Lynn Matrisian, Sudheer Doss

Faculty, Staff and Student Publications

Purpose: Pancreatic cancer currently holds the position of third deadliest cancer in the United States and the 5-year survival rate is among the lowest for major cancers at just 12%. Thus, continued research efforts to better understand the clinical and molecular underpinnings of pancreatic cancer are critical to developing both early detection methodologies as well as improved therapeutic options. This study introduces Pancreatic Cancer Action Network's (PanCAN's) SPARK, a cloud-based data and analytics platform that integrates patient health data from the PanCAN's research initiatives and aims to accelerate pancreatic cancer research by making real-world patient health data and analysis tools …

Harnessing Endoscopic Ultrasound-Guided Radiofrequency Ablation To Reshape The Pancreatic Ductal Adenocarcinoma Microenvironment And Elicit Systemic Immunomodulation, Vishali Moond, Bhumi Maniyar, Prateek Suresh Harne, Jennifer M Bailey-Lundberg, Nirav C Thosani

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response-the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in …

Individual Ingredients Of Np-101 (Thymoquinone Formula) Inhibit Sars-Cov-2 Pseudovirus Infection, Abdelrahim Maen, Betul Gok Yavuz, Yehia I Mohamed, Abdullah Esmail, Jianming Lu, Amr Mohamed, Asfar S Azmi, Mohamed Kaseb, Osama Kasseb, Dan Li, Michelle Gocio, Mehmet Kocak, Abdelhafez Selim, Qing Ma, Ahmed O Kaseb

Faculty, Staff and Student Publications

Thymoquinone TQ, an active ingredient of Nigella Sativa, has been shown to inhibit COVID-19 symptoms in clinical trials. Thymoquinone Formulation (TQF or NP-101) is developed as a novel enteric-coated medication derivative from Nigella Sativa. TQF consists of TQ with a favorable concentration and fatty acids, including palmitic, oleic, and linoleic acids. In this study, we aimed to investigate the roles of individual ingredients of TQF on infection of SARS-CoV-2 variants

Effects Of Huoxue Qufeng Decoction Combined With Tongguan Liquefying Acupoint Penetration Therapy On Swallowing Function And Quality Of Life In Patients With Ischemic Stroke, Xuzhong Liang, Li Ma, Lixia Zhang, Dongnian Yang, Lanrui Zeng

Faculty, Staff and Student Publications

Objective: To analyze the effects of Huoxue Qufeng Decoction combined with Tongguan Liquefying Acupoint Penetration therapy on swallowing function and quality of life in patients with ischemic stroke.

Methods: A total of 145 patients with post-stroke dysphagia admitted to Dingxi People's Hospital from January 2019 to May 2022 were selected with 65 patients in the control group and 80 patients in the observation group. The control group received Huoxue Qufeng Decoction alone, while the observation group received additional Tongguan Liquefying Acupoint Penetration therapy. Clinical efficacy, NIH Stroke Scale (NIHSS) score, Water Swallow Test, Swallowing Function Assessment (SSA) score, MD Anderson …

Leptomeningeal Disease In Melanoma: An Update On The Developments In Pathophysiology And Clinical Care, Inna Smalley, Adrienne Boire, Priscilla Brastianos, Harriet M Kluger, Eva Hernando-Monge, Peter A Forsyth, Kamran A Ahmed, Keiran S M Smalley, Sherise Ferguson, Michael A Davies, Isabella C Glitza Oliva

Faculty, Staff and Student Publications

Leptomeningeal disease (LMD) remains a major challenge in the clinical management of metastatic melanoma patients. Outcomes for patient remain poor, and patients with LMD continue to be excluded from almost all clinical trials. However, recent trials have demonstrated the feasibility of conducting prospective clinical trials in these patients. Further, new insights into the pathophysiology of LMD are identifying rational new therapeutic strategies. Here we present recent advances in the understanding of, and treatment options for, LMD from metastatic melanoma. We also annotate key areas of future focus to accelerate progress for this challenging but emerging field.

Myeloid Lineage Switch In Kmt2a- Rearranged Acute Lymphoblastic Leukemia Treated With Lymphoid Lineagedirected Therapies, Alex Bataller, Tareq Abuasab, David Mccall, Wei Wang, Branko Cuglievan, Ghayas C Issa, Elias Jabbour, Nicholas Short, Courtney D Dinardo, Guilin Tang, Guillermo Garcia-Manero, Hagop M Kantarjian, Koji Sasaki

Faculty, Staff and Student Publications

No abstract provided.

Editorial: Mathematical Modeling And Computational Predictions In Oncoimmunology, Vladimir A Kuznetsov, Heiko Enderling, Mark Chaplain

Faculty, Staff and Student Publications

No abstract provided.

Spatial Multiplexing And Omics, Julienne L Carstens, Santhoshi N Krishnan, Arvind Rao, Anna G Sorace, Erin H Seeley, Sammy Ferri-Borgogno, Jared K Burks

Faculty, Staff and Student Publications

Much like solving a game of Clue, understanding physiological mysteries involves answering who, what, when, and where. Multi-omics approaches delve into cellular and molecular identities (the who and what), while longitudinal data collection addresses the when. Spatial dimensions address the where. This Primer discusses current technologies enabling quantification across biological scales, emphasizing the importance of retaining the spatial dimension of that data. We outline experimental design considerations, including targeted versus untargeted approaches, sample types, biological scale, and four main classes of molecule detection. Spatial analytics are explored, covering questioning approaches, analytical platforms, image segmentation and sampling. Example applications, reproducibility considerations, …

Weak Supervision, Strong Results: Achieving High Performance In Intracranial Hemorrhage Detection With Fewer Annotation Labels, Kareem A Wahid, David Fuentes

Faculty, Staff and Student Publications

No abstract provided.

The Impact Of Psychological Strengths On Veteran Populations' Mental Health Trajectories During The Covid-19 Pandemic, Amanda Mccleery, Jonathan K Wynn, Derek M Novacek, Eric A Reavis, Damla Senturk, Catherine A Sugar, Jack Tsai, Michael F Green

Faculty, Staff and Student Publications

Purpose: Mental health trajectories during the COVID-19 pandemic have been examined in Veterans with tenuous social connections, i.e., those with recent homelessness (RHV) or a psychotic disorder (PSY), and in control Veterans (CTL). We test potential moderating effects on these trajectories by psychological factors that may help individuals weather the socio-emotional challenges associated with the pandemic (i.e., 'psychological strengths').

Methods: We assessed 81 PSY, 76 RHV, and 74 CTL over 5 periods between 05/2020 and 07/2021. Mental health outcomes (i.e., symptoms of depression, anxiety, contamination concerns, loneliness) were assessed at each period, and psychological strengths (i.e., a composite score based …

Fueling Cardiac Myocyte Proliferation, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

No abstract provided.

Precision Needle-Punch Tumor Enrichment From Paraffin Blocks Improves The Detection Of Clinically Actionable Genomic Alterations And Biomarkers, Douglas I Lin, Richard S P Huang, Ioannis Ladas, Rachel B Keller, Nimesh R Patel, Sotirios Lakis, Brennan Decker, Tyler Janovitz, Douglas A Mata, Jeffrey S Ross, Jo-Anne Vergilio, Julia A Elvin, Roy S Herbst, Philip C Mack, Jonathan K Killian

Faculty, Staff and Student Publications

BACKGROUND: While many molecular assays can detect mutations at low tumor purity and variant allele frequencies, complex biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) require higher tumor purity for accurate measurement. Scalable, quality-controlled, tissue-conserving methods to increase tumor nuclei percentage (TN%) from tumor specimens are needed for complex biomarkers and hence necessary to maximize patient matching to approved therapies or clinical trial enrollment. We evaluated the clinical utility and performance of precision needle-punch enrichment (NPE) compared with traditional razor blade macroenrichment of tumor specimens on molecular testing success.

METHODS: Pathologist-directed NPE …

Metformin In Conjunction With Stereotactic Radiotherapy For Early-Stage Non-Small Cell Lung Cancer: Long-Term Results Of A Prospective Phase Ii Clinical Trial, Molly K Tate, Mike Hernandez, Joe Y Chang, Steven H Lin, Zhongxing Liao, Suja M Koshy, Heath D Skinner, Stephen G Chun

Faculty, Staff and Student Publications

Background/aim: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC.

Patients and methods: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure …

Predicting Suicidality In Late-Life Depression By 3d Convolutional Neural Network And Cross-Sample Entropy Analysis Of Resting-State Fmri, Chemin Lin, Chih-Mao Huang, Wei Chang, You-Xun Chang, Ho-Ling Liu, Shu-Hang Ng, Huang-Li Lin, Tatia Mei-Chun Lee, Shwu-Hua Lee, Shun-Chi Wu

Faculty, Staff and Student Publications

Background: Predicting suicide is a pressing issue among older adults; however, predicting its risk is difficult. Capitalizing on the recent development of machine learning, considerable progress has been made in predicting complex behavior such as suicide. As depression remained the strongest risk for suicide, we aimed to apply deep learning algorithms to identify suicidality in a group with late-life depression (LLD).

Methods: We enrolled 83 patients with LLD, 35 of which were non-suicidal and 48 were suicidal, including 26 with only suicidal ideation and 22 with past suicide attempts, for resting-state functional magnetic resonance imaging (MRI). Cross-sample entropy (CSE) analysis …

A Milestone In Epithelial-Mesenchymal Transition, Yutong Sun, Li Ma

Faculty, Staff and Student Publications

No abstract provided.

A Reinforcement Learning (Rl)-Motivated Simulation Framework For Evaluating Vancomycin Dosing Strategies, Bingyu Mao, Ziqian Xie, Laila Rasmy, Masayuki Nigo, Degui Zhi

Faculty, Staff and Student Publications

Achieving and maintaining the therapeutic range in vancomycin treatment is important for optimal outcomes. While guidelines and best practices based on empirical studies exist, the theoretical best dosing strategies under various conditions remain illusive. We developed an RL-based simulation framework using a deep learning two-compartment pharmacokinetic model (PK-RNN-2CM) and introduced the area under the time-concentration curve (AUC) reward score, which translates clinical guidelines into an RL reward. Ground truth time-concentration curves were generated from patient-specific data, and simulated curves were produced under different dosing strategies with optional noise perturbations to mimic real-world settings. Evaluation metrics included 24-hour AUC assessments and …

Correction: Preclinical Development Of 1b7/Cd3, A Novel Anti-Tslpr Bispecific Antibody That Targets Crlf2-Rearranged Ph-Like B-All, Ze Tian, Chunhua Shi, Guojun Yang, Jason K Allen, Qing Shi, Amin Al-Shami, Jill Wardell Olson, Melinda G Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy E Lofton, Michelle A Gonzalez, Qi Zhang, Dongxing Zha, Sarah K Tasian, Nitin Jain, Marina Y Konopleva, Timothy Heffernan, Jeffrey J Molldrem

Faculty, Staff and Student Publications

No abstract provided.