Genetic Phenomena Commons^™

Monitoring Variations In The Use Of Automated Contouring Software, Kelly A Nealon, Eun Young Han, Stephen F Kry, Callistus Nguyen, Mary Pham, Valerie K Reed, David Rosenthal, Samantha Simiele, Laurence E Court

Faculty, Staff and Student Publications

PURPOSE: Our purpose was to identify variations in the clinical use of automatically generated contours that could be attributed to software error, off-label use, or automation bias.

METHODS AND MATERIALS: For 500 head and neck patients who were contoured by an in-house automated contouring system, Dice similarity coefficient and added path length were calculated between the contours generated by the automated system and the final contours after editing for clinical use. Statistical process control was used and control charts were generated with control limits at 3 standard deviations. Contours that exceeded the thresholds were investigated to determine the cause. Moving …

Obesity Is Associated With Improved Progression-Free Survival In Microsatellite-Instability-High Endometrial Cancer Treated With Pembrolizumab, Laurence Bernard, Jeffrey A How, Shrina Patel, Melinda S Yates, Amir Jazaeri

Faculty, Staff and Student Publications

Objectives: To determine the clinical predictors of response rate, progression-free survival (PFS), and overall survival (OS) to pembrolizumab in advanced or recurrent, mismatch repair deficient (MMRd) or Microsatellite Instability-High (MSI-H) endometrial adenocarcinomas.

Methods: A retrospective, single institution study was conducted among women with recurrent or advanced MMRd or MSI-H endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Logistic regression was used for univariable and multivariable analyses. PFS and OS were estimated using the methods of Kaplan and Meier and modeled via Cox proportional hazards regression. Log-rank test was used for intergroup comparisons based on body …

Research Hot Spots And Trends In Endocrine-Related Adverse Events Caused By Immune Checkpoint Inhibitors: A Bibliometric Analysis And Visualization Research, Jun Zhao, Guangwei Liu, Xue Yang, Chuanzhou Zhang, Bing Han, Man Jiang

Faculty, Staff and Student Publications

Background: In recent years, with the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment, the toxicity associated with immunotherapy of ICIs has attracted more attention from scholars. Endocrine toxicity is the most likely immune-related adverse events (irAEs) and is often irreversible, posing a significant clinical treatment challenge.

Methods: In this study, bibliometric methods were used to analyze relevant literature in screening endocrine-related adverse events caused by ICIs in the Web of Science core collection database (WoSCC) and to summarize the status, research hot spots, and future trends in this field.

Results: 321 countries, 297 institutions, 365 authors, and …

Interleukin-1beta And Inflammasome Expression In Spinal Cord Following Chronic Constriction Injury In Male And Female Rats, Suzanne M Green-Fulgham, Jayson B Ball, Andrew J Kwilasz, Michael E Harland, Matthew G Frank, Joseph M Dragavon, Peter M Grace, Linda R Watkins

Faculty, Staff and Student Publications

Females represent a majority of chronic pain patients and show greater inflammatory immune responses in human chronic pain patient populations as well as in animal models of neuropathic pain. Recent discoveries in chronic pain research have revealed sex differences in inflammatory signaling, a key component of sensory pathology in chronic neuropathic pain, inviting more research into the nuances of these sex differences. Here we use the chronic constriction injury (CCI) model to explore similarities and differences in expression and production of Inflammatory cytokine IL-1beta in the lumbar spinal cord, as well as its role in chronic pain. We have discovered …

The Contribution Of Dna Ligase 4 Polymorphisms To Colorectal Cancer, Yang Deng, Tao-Wei Ke, Te-Cheng Yueh, Yu-Ting Chin, Yun-Chi Wang, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Wen-Tzu Wu, Wen-Shin Chang, Jian Gu, Da-Tian Bau, Chia-Wen Tsai

Faculty, Staff and Student Publications

Background/aim: While numerous biomarkers associated with genetic susceptibility to colorectal cancer (CRC) have been identified and validated through epidemiological studies, the specific influence of DNA ligase 4 (Lig4) genotypes remains unexplored. This study aimed to elucidate the hitherto unexamined relationship between Lig4 genotypes and CRC risk.

Materials and methods: The genotypes of Lig4 rs1805388 were determined applying the polymerase chain reaction-restriction fragment length polymorphism methodology. The potential association between these genotypes and CRC risk was assessed in a Taiwanese population comprising 362 CRC cases and an equal number of age- and sex-matched controls.

Results: In the genotypic analysis, the distribution …

Non-Homologous End-Joining Genotype, Mrna Expression, And Dna Repair Capacity In Childhood Acute Lymphocytic Leukemia, Chao-Chun Chen, Wen-Shin Chang, Jen-Sheng Pei, Chien-Chung Kuo, Chung-Hsing Wang, Yun-Chi Wang, Pei-Chen Hsu, Jie-Long He, Jian Gu, Da-Tian Bau, Chia-Wen Tsai

Faculty, Staff and Student Publications

Background/aim: The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature on the involvement of NHEJ-related genes in childhood acute lymphocytic leukemia (ALL). Our study aimed to elucidate the impact of polymorphisms of X-ray repair cross-complementing group 4 (XRCC4) (rs6869366, rs2075685, rs2075686, rs28360071, rs3734091, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and DNA ligase IV (LIG4) rs1805388, on the odds of childhood ALL.

Materials and methods: Genotypes NHEJ-related genes of 266 cases and 266 controls were determined, and the genotype-phenotype correlation …

Polaris: A Phase 2 Trial Of Encorafenib Plus Binimetinib Evaluating High-Dose And Standard-Dose Regimens In Patients With Braf V600-Mutant Melanoma With Brain Metastasis, Alexander M Menzies, Georgina V Long, Amiee Kohn, Hussein Tawbi, Jeffrey Weber, Keith Flaherty, Grant A Mcarthur, Paolo A Ascierto, Yanina Pfluger, Karl Lewis, Katy K Tsai, Omid Hamid, Hans Prenen, Luis Fein, Erjian Wang, Carolin Guenzel, Fan Zhang, Joseph F Kleha, Alessandra Di Pietro, Michael A Davies

Faculty, Staff and Student Publications

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases.

Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose …

Association Of Preoperative Lung Function With Complications After Lobectomy Using Race-Neutral And Race-Specific Normative Equations, Ajay Sheshadri, Ravi Rajaram, Aaron Baugh, Mario Castro, Arlene M Correa, Felipe Soto, Carrie R Daniel, Liang Li, Scott E Evans, Burton F Dickey, Ara A Vaporciyan, David E Ost

Faculty, Staff and Student Publications

Rationale: Pulmonary function testing (PFT) is performed to aid patient selection before surgical resection for non-small cell lung cancer (NSCLC). The interpretation of PFT data relies on normative equations, which vary by race, but the relative strength of association of lung function using race-specific or race-neutral normative equations with postoperative pulmonary complications is unknown. Objectives: To compare the strength of association of lung function, using race-neutral or race-specific equations, with surgical complications after lobectomy for NSCLC.

Methods: We studied 3,311 patients who underwent lobectomy for NSCLC and underwent preoperative PFT from 2001 to 2021. We used Global Lung Function Initiative …

Chronic Lymphocytic Leukemia: Novel Perspectives - How To Teach An Old Dog New Tricks, Tamar Tadmor, Jan Burger

Faculty, Staff and Student Publications

No abstract provided.

First-In-Human Phase 1 Study Of The Arginase Inhibitor Incb001158 Alone Or Combined With Pembrolizumab In Patients With Advanced Or Metastatic Solid Tumours, Aung Naing, Kyriakos P Papadopoulos, Michael J Pishvaian, Osama Rahma, Glenn J Hanna, Elena Garralda, Omar Saavedra, Sven Gogov, Howard Kallender, Lulu Cheng, Michael Smith, Xuejun Chen, Emil Kuriakose, Todd Bauer

Faculty, Staff and Student Publications

Objective: The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.

Methods and analysis: In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).

Results: A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate …

Tumor Treating Fields (Ttfields) For Spinal Metastasis–The Case For Bone Removal And Spinal Implants As Waveguides To Enhance Field Strength At The Target, Claudio E Tatsui, Kristen W Carlson, Chirag B Patel

Faculty, Staff and Student Publications

No abstract provided.

Voluntary Wheel Running Prevents Formation Of Membrane Attack Complexes And Myelin Degradation After Peripheral Nerve Injury, Suzanne M Green-Fulgham, Michael J Lacagnina, Kendal F Willcox, Jiahe Li, Michael E Harland, Adriano Polican Ciena, Igor R Correia Rocha, Jayson B Ball, Renee A Dreher, Younus A Zuberi, Joseph M Dragavon, Marucia Chacur, Steven F Maier, Linda R Watkins, Peter M Grace

Faculty, Staff and Student Publications

Regular aerobic activity is associated with a reduced risk of chronic pain in humans and rodents. Our previous studies in rodents have shown that prior voluntary wheel running can normalize redox signaling at the site of peripheral nerve injury, attenuating subsequent neuropathic pain. However, the full extent of neuroprotection offered by voluntary wheel running after peripheral nerve injury is unknown. Here, we show that six weeks of voluntary wheel running prior to chronic constriction injury (CCI) reduced the terminal complement membrane attack complex (MAC) at the sciatic nerve injury site. This was associated with increased expression of the MAC inhibitor …

Case Report: Early Acute Kidney Failure In An 11-Year-Old Boy With Dent Disease Type 1, Nicolette Murphey, Craig Authement, Paul Hillman, Samhar I Al-Akash, Kate Richardson

Faculty, Staff and Student Publications

Dent disease type 1 (Dent 1) is a rare X-linked genetic condition which impacts kidney function and is caused by pathogenic variants in CLCN5. Affected males typically develop low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and other symptoms. Kidney failure often occurs between the third to fifth decade of life. Here, we report an 11-year-old boy with Dent 1 and a severe kidney disease phenotype. The patient presented with flank pain, nocturnal enuresis, foamy urine, and increased urinary frequency. He was found to have nephrotic-range proteinuria, without hypoalbuminemia, and a significantly decreased estimated glomerular filtration rate at presentation. Further, he …

Diet-Stimulated Marrow Adiposity Fails To Worsen Early, Age-Related Bone Loss, Cody Mcgrath, Sarah E Little-Letsinger, Gabriel M Pagnotti, Buer Sen, Zhihui Xie, Gunes Uzer, Guniz B Uzer, Xiaopeng Zong, Martin A Styner, Janet Rubin, Maya Styner

Faculty, Staff and Student Publications

Introduction: Longitudinal effect of diet-induced obesity on bone is uncertain. Prior work showed both no effect and a decrement in bone density or quality when obesity begins prior to skeletal maturity. We aimed to quantify long-term effects of obesity on bone and bone marrow adipose tissue (BMAT) in adulthood.

Methods: Skeletally mature, female C57BL/6 mice (n = 70) aged 12 weeks were randomly allocated to low-fat diet (LFD; 10% kcal fat; n = 30) or high-fat diet (HFD; 60% kcal fat; n = 30), with analyses at 12, 15, 18, and 24 weeks (n = 10/group). Tibial microarchitecture was analyzed …

Sustained Pain And Macrophage Infiltration In A Mouse Muscle Contusion Model, Ibdanelo Cortez, Caitlyn M Gaffney, Caitlin V Crelli, Eric Lee, James M Nichols, Hoang Vu Pham, Syed Mehdi, Jelena M Janjic, Andrew J Shepherd

Faculty, Staff and Student Publications

Introduction/aims: Prior studies have emphasized the role of inflammation in the response to injury and muscle regeneration, but little emphasis has been placed on characterizing the relationship between innate inflammation, pain, and functional impairment. The aim of our study was to determine the contribution of innate immunity to prolonged pain following muscle contusion.

Methods: We developed a closed-impact mouse model of muscle contusion and a macrophage-targeted near-infrared fluorescent nanoemulsion. Closed-impact contusions were delivered to the lower left limb. Pain sensitivity, gait dysfunction, and inflammation were assessed in the days and weeks post-contusion. Macrophage accumulation was imaged in vivo by injecting …

Multi-Task Learning With High-Dimensional Noisy Images, Xin Ma, Suprateek Kundu

Faculty, Staff and Student Publications

Recent medical imaging studies have given rise to distinct but inter-related datasets corresponding to multiple experimental tasks or longitudinal visits. Standard scalar-on-image regression models that fit each dataset separately are not equipped to leverage information across inter-related images, and existing multi-task learning approaches are compromised by the inability to account for the noise that is often observed in images. We propose a novel joint scalar-on-image regression framework involving wavelet-based image representations with grouped penalties that are designed to pool information across inter-related images for joint learning, and which explicitly accounts for noise in high-dimensional images via a projection-based approach. In …

Single-Cell Rna Sequencing Analysis Identifies Acute Changes In The Tumor Microenvironment Induced By Interferon Α Gene Therapy In A Murine Bladder Cancer Model, Alexis R Steinmetz, Morgan Pierce, Alberto Martini, Come Tholomier, Ganiraju Manyam, Yan Chen, Akshay Sood, Jonathan J Duplisea, Burles A Johnson, Bogdan A Czerniak, Byron H Lee, Chinnaswamy Jagannath, Seppo Yla-Herttuala, Nigel R Parker, David J Mcconkey, Colin P Dinney, Sharada Mokkapati

Faculty, Staff and Student Publications

Introduction: Nadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα).

Methods: Tumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα …

Analysis Of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance, Juliana Mota Siqueira, Yoshitsugu Mitani, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mario L Marques-Piubelli, Anurag Purushothaman, Mutsumi Mitani, Hui Dai, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (< 5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high ( …

Meta-Analysis Of The Vmp-Like Sequences Of Lyme Disease Borrelia: Evidence For The Evolution Of An Elaborate Antigenic Variation System, Steven J Norris, Kalvis Brangulis

Faculty, Staff and Student Publications

VMP-like sequence (vls) antigenic variation systems are present in every Lyme disease Borrelia strain with complete genome sequences. The linear plasmid-encoded vls system consists of a single expression site (vlsE) and contiguous array(s) of silent cassettes that have ~90% identity with the central cassette region of the cognate vlsE gene; antigenic variation occurs through random, segmental, and unidirectional recombination of vls silent cassette sequences into the vlsE expression site. Automated annotation programs do not accurately recognize vls silent cassette sequences, so these regions are not correctly annotated in most genomic sequences. In this study, the vls …

Best Practice Recommendations For The Management Of Anxiety During The Pegvaliase Journey, Kendra J Bjoraker, Caroline Eggerding, Elisheva Ellenberg, Suzanne Hollander, Brittany M Holmes, Kristin Lindstrom, Markey Mcnutt, Suzanne Miller, Hope Northrup, Meaghan Rogers, Sarah Rose, Mia Scott, Soo Shim, Bridget Wardley, Leah Wessenberg, Deborah A Bilder

Faculty, Staff and Student Publications

Background: Pegvaliase, an enzyme substitution therapy, is a treatment option for phenylketonuria (PKU). Due to the neuropathophysiology and disease burden of PKU, individuals can experience baseline anxiety unrelated to pegvaliase therapy. In addition, there are aspects of pegvaliase therapy that may be anxiety-inducing for those considering or receiving treatment. The aim of this manuscript is to present best practice recommendations for the identification and management of anxiety symptoms that can occur along the pegvaliase journey.

Methods: A modified Delphi approach was used to seek consensus among a multidisciplinary panel of experts. To this end, an in-person meeting was held that …