Genetic Phenomena Commons^™

Adipose Tissue Deficiency Impairs Transient Lipid Accumulation And Delays Liver Regeneration Following Partial Hepatectomy In Male Seipin Knockout Mice, Qianqian Dong, Ziwei Liu, Yidan Ma, Xin Chen, Xiaowei Wang, Jinye Tang, Kexin Ma, Chenxi Liang, Mengyu Wang, Xiaoqin Wu, Yang Liu, Yaru Zhou, Hongyuan Yang, Mingming Gao

Faculty, Staff and Student Publications

Background: Liver diseases pose significant health challenges, underscoring the importance of understanding liver regeneration mechanisms. Systemic adipose tissue is thought to be a primary source of lipids and energy during this process; however, empirical data on the effects of adipose tissue deficiency are limited. This study investigates the role of adipose tissue in liver regeneration, focusing on transient regeneration-associated steatosis (TRAS) and hepatocyte proliferation using a Seipin knockout mouse model that mimics severe human lipodystrophy. Additionally, the study explores therapeutic strategies through adipose tissue transplantation.

Methods: Male Seipin knockout (Seipin-/-) and wild-type (WT) mice underwent 2/3 partial hepatectomy (PHx). Liver …

The Role Of Double-Zero-Event Studies In Evidence Synthesis: Evaluating Robustness Using The Fragility Index, Zelin Wang, Xing Xing, Eun-Young Mun, Chong Wu, Lifeng Lin

Faculty, Staff and Student Publications

Rationale: Zero-event counts are common in clinical studies, particularly when assessing rare adverse events. These occurrences can result from low event rates, short follow-up periods, and small sample sizes. When both intervention and control groups report zero events in a clinical trial, the study is referred to as a double-zero-event study, which presents methodological challenges for evidence synthesis. There has been ongoing debate about whether these studies should be excluded from evidence synthesis, as traditional two-stage meta-analysis methods may not estimate an effect size for them. Recent research suggests that these studies may still contain valuable clinical and statistical information. …

The Dynamics Of Tubulogenesis In Development And Disease, Adrian Romero, Brandy L Walker, Vanja Krneta-Stankic, Kamryn Gerner-Mauro, Lydia Youmans, Rachel K Miller

Faculty, Staff and Student Publications

Tubes are crucial for the function of many organs in animals given their fundamental roles in transporting and exchanging substances to maintain homeostasis within an organism. Therefore, the development and maintenance of these tube-like structures within organs is a vital process. Tubes can form in diverse ways, and advances in our understanding of the molecular and cellular mechanisms underpinning these different modes of tubulogenesis have significant impacts in many biological contexts, including development and disease. This Review discusses recent progress in understanding developmental mechanisms underlying tube formation.

A Phase 2 Basket Study Of Talabostat, A Small-Molecule Inhibitor Of Dipeptidyl Peptidases, Administered In Combination With Pembrolizumab In Patients With Advanced Solid Cancers, Jibran Ahmed, Filip Janku, Daniel D Karp, Sarina A Piha-Paul, Apostolia M Tsimberidou, Timothy Anthony Yap, Bettzy Stephen, Yali Yang, Serdar Gurses, Qian Liu, Juhee Song, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

Background: Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients.

Methods: The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST …

Establishment Of The Nichols Strain As The Type Strain Of Treponema Pallidum, Steven J Norris

Faculty, Staff and Student Publications

In this article, it is proposed that the Nichols strain of Treponema pallidum be established as the type strain. T. pallidum was first identified as the causative agent of syphilis in 1905, and the Nichols strain was isolated in 1912 by inoculation of a rabbit with cerebrospinal fluid from a patient with neurosyphilis. The Nichols strain has been maintained by serial passage in rabbits for over a century, and historically most studies of T. pallidum have been conducted using this strain. In recent years, a procedure for continuous in vitro culture of T. pallidum in a tissue culture system has …

Impact Of Body Mass Index On Outcomes Of Multiple Myeloma Patients Undergoing Upfront Autologous Stem Cell Transplant, Curtis Marcoux, Sarah Pasyar, Denái R Milton, Hina N Khan, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Niraj Neupane, Hans C Lee, Krina K Patel, Guilin Tang, Yosra Aljawai, Partow Kebriaei, Sheeba K Thomas, Robert Z Orlowski, Elizabeth J Shpall, Richard Champlin, Muzaffar H Qazilbash, Oren Pasvolsky

Faculty, Staff and Student Publications

No abstract provided.

Optimizing Care And Maintenance Of Enteric Tubes: Insights Into Percutaneous Radiologically Placed Gastrointestinal Luminal Tubes, Mohammad Mahdi Khavandi, Nariman Nezami, Steven Y Huang, Alda L Tam, Bruno C Odisio, Armeen Mahvash, Mohamed E Abdelsalam, Joshua D Kuban, Rahul A Sheth, Peiman Habibollahi

Faculty, Staff and Student Publications

Percutaneous enteric tubes, including gastrostomy, gastrojejunostomy, and percutaneous transesophageal gastrostomy, are essential for patients who cannot maintain adequate oral nutrition or require gastric decompression due to conditions like malignant bowel obstruction. Proper care and maintenance are crucial to prevent complications and maintain function. Enteric tubes are inserted using various techniques at different locations based on patient needs and anatomical considerations. Enteric tubes play a vital role in patient care, and continued research and innovation are necessary to improve outcomes and reduce complications. Routine care involves regular flushing and site maintenance to prevent occlusion and infection. While complications are common, they …

Recurrence-Free Survival Prediction For Anal Squamous Cell Carcinoma After Chemoradiotherapy Using Planning Ct-Based Radiomics Model, Shanshan Tang, Kai Wang, David Hein, Gloria Lin, Nina N Sanford, Jing Wang

Faculty, Staff and Student Publications

Objectives: Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT.

Methods: Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature …

Identification Of Activating Hotspot Mutations In Acrochordons Through Next-Generation Sequencing, Justin L Jia, Jennifer Y Wang, Warren H Chan, Julien Lanoue, Hanh Do, Kerri E Rieger, S Tyler Hollmig, Kavita Y Sarin

Faculty, Staff and Student Publications

No abstract provided.

Somatic Copy Number Deletion Of Chromosome 22q In Papillary Thyroid Carcinoma, Olivia W Lee, Danielle M Karyadi, Stephen W Hartley, Weyin Zhou, Mitchell J Machiela, Shahriar A Zamani, Liudmyla Yu Zurnadzhy, John N Weinstein, Young Joo Park, Jeong-Sun Seo, Gerry A Thomas, Tetiana I Bogdanova, Mykola D Tronko, Lindsay M Morton, Stephen J Chanock

Faculty, Staff and Student Publications

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point …

Advances And Challenges In Chimeric Antigen Receptor-Natural Killer Cell Immunotherapy For Cancer, Hind Rafei, Katayoun Rezvani

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR)-natural killer (NK)-cell therapy has emerged as a promising strategy in the treatment of haematological malignancies and solid cancers. Leveraging the innate immune properties of NK cells, CAR-NK-cell therapies offer potential advantages for cell therapy, including safety of use in the allogeneic setting and reduced risk of toxicity. This Nutshell provides an overview of the latest advancements in CAR-NK-cell therapy and the challenges that remain.

Angiotensin-(1-9) Improves The Cardioprotective Effects Of Del Nido Cardioplegia Against Ischemia/Reperfusion Injury, Evelyn Mendoza-Torres, Gina Sanchez, Wendy Rosales, María Clara Ospino, Luis Antonio Díaz-Ariza, Yuliet Montoya, John Bustamante, Jaime A Riquelme, Mario Chiong, Sergio Lavandero

Faculty, Staff and Student Publications

Del Nido cardioplegia (DNC), a blood-and-crystalloid solution containing high and low concentrations of potassium and calcium, respectively, is used as a single-dose antegrade infusion to induce immediate cardiac arrest in the surgery of patients with cardiovascular diseases requiring extracorporeal circulation. Adding cardioprotective molecules may further reduce the damage-triggered ischemia/reperfusion (I/R) injury. Angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), members of the counter-regulatory renin-angiotensin system, have shown cardioprotective effects in cardiac hypertrophy and I/R models. This study aimed to evaluate the effects of Ang-(1-9) and Ang-(1-7), as adjuvants of the DNC, on cardioprotection and ventricular function in isolated rat hearts subjected to I/R …

Nadh-Bound Aif Activates The Mitochondrial Chchd4/Mia40 Chaperone By A Substrate-Mimicry Mechanism, Chris A Brosey, Runze Shen, John A Tainer

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Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4's redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain …

Obesity Predisposes Anthracycline-Treated Survivors Of Childhood And Adolescent Cancers To Subclinical Cardiac Dysfunction, Ian A George, Brianna Souder, Amy Berkman, David H Noyd, M Jay Campbell, Piers C A Barker, Michael Roth, Michelle A T Hildebrandt, Kevin C Oeffinger, Andrew W Mccrary, Andrew P Landstrom

Faculty, Staff and Student Publications

Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of diagnosis. The goal of this study is to leverage the advanced sensitivity of strain echocardiography to identify pre-existing risk factors for early subclinical cardiac dysfunction among anthracycline-exposed pediatric patients. We identified 115 pediatric patients with cancer who were treated with an anthracycline between 2013 and 2019. Peak longitudinal left ventricular strain was retroactively calculated on 495 surveillance echocardiograms via the TOMTEC AutoSTRAIN software. Cox proportional hazards …

Rezilient3: Randomized Phase Iii Study Of First-Line Zipalertinib Plus Chemotherapy In Patients With Egfr Exon 20 Insertion-Mutated Nsclc, John V Heymach, Helena A Yu, Benjamin Besse, Ying Cheng, Daniel Sw Tan, Li Wei, Volker Wacheck, Makoto Nishio

Faculty, Staff and Student Publications

There remains a significant unmet need for effective and tolerable treatments for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (

Durable Remission After Targeted Therapy In Braf V600e–Mutant Metastatic Colorectal Cancer: Case Report, Daniel A Fox, Deepak Bhamidipati, Scott Kopetz, David S Hong

Faculty, Staff and Student Publications

BRAF mutation leads to constitutive activation of the MAPK pathway and is associated with the immune-activating molecular subtype of colorectal cancer. Targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (CRC) has significantly improved outcomes for these patients when combined with anti–epithelial growth factor receptor (EGFR) therapy. However, most patients ultimately develop disease progression. We report a case of a patient with metastatic-deficient mismatch repair, BRAF V600E–mutated CRC, who achieved a durable complete response to vemurafenib plus cetuximab and chemotherapy despite initial high burden of disease, including peritoneal involvement. Recent clinical trials of combined anti-EGFR/anti–BRAF V600E therapy in …

A Phase Ib Trial Of Selinexor In Combination With Immune Checkpoint Blockade In Patients With Advanced Renal Cell Carcinoma, Omar Alhalabi, Mohamed A Gouda, Denái R Milton, Hassan Ahmed Momin, Bulent Yilmaz, Bettzy Stephen, Chinenye Lynette Ejezie, Justin Tyler Moyers, Serdar A Gurses, Jeffrey How, Siqing Fu, Jordi Rodon, David S Hong, Sarina A Piha-Paul, Vivek Subbiah, Ecaterina Elena Dumbrava, Daniel D Karp, Filip Janku, Funda Meric-Bernstam, Nizar M Tannir, Aung Naing

Faculty, Staff and Student Publications

Background: Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods: NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL …

Hsp90: Bringing It All Together, Georgios Ioannis Karras, Giorgio Colombo, Andrea N Kravats

Faculty, Staff and Student Publications

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs most other machines in the cell in sophistication. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90's complexity. Together, these …

Stereotactic Body Radiotherapy Vs Sorafenib Alone In Hepatocellular Carcinoma: The Nrg Oncology/Rtog 1112 Phase 3 Randomized Clinical Trial, Laura A Dawson, Kathryn A Winter, Jennifer J Knox, Andrew X Zhu, Sunil Krishnan, Chandan Guha, Lisa A Kachnic, Michael T Gillin, Theodore S Hong, Timothy D Craig, Terence M Williams, Ali Hosni, Eric Chen, Anne M Noonan, Eugene J Koay, Rishi Sinha, Michael I Lock, Nitin Ohri, Jennifer A Dorth, Guila Delouya, Anand Swaminath, Jennifer Moughan, Christopher H Crane

Faculty, Staff and Student Publications

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

Design, setting, and participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, …

Best Practices For Delivering Neoadjuvant Therapy In Pancreatic Ductal Adenocarcinoma, Jordan M Cloyd, Angela Sarna, Matthew J Arango, Susan E Bates, Manoop S Bhutani, Mark Bloomston, Vincent Chung, Efrat Dotan, Cristina R Ferrone, Patricia F Gambino, Ajit H Goenka, Karyn A Goodman, William A Hall, Jin He, Melissa E Hogg, Shiva Jayaraman, Avinash Kambadakone, Matthew H G Katz, Alok A Khorana, Andrew H Ko, Eugene J Koay, David A Kooby, Somashekar G Krishna, Liliana K Larsson, Richard T Lee, Anirban Maitra, Nader N Massarweh, Sameh Mikhail, Mahvish Muzaffar, Eileen M O'Reilly, Manisha Palta, Maria Q B Petzel, Philip A Philip, Marsha Reyngold, Daniel Santa Mina, Davendra P S Sohal, Tilak K Sundaresan, Susan Tsai, Kea L Turner, Timothy J Vreeland, Steve Walston, M Kay Washington, Terence M Williams, Jennifer Y Wo, Rebecca A Snyder

Faculty, Staff and Student Publications

Importance: Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined.

Objective: To develop consensus best practices for delivering NT to patients with localized PDAC.

Design, setting, and participants: This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature …