Genetic Phenomena Commons^™

Blood Bacterial Dna Signatures In A Prospective Cohort Of Patients With Masld Cirrhosis, Suet-Ying Kwan, Lillian I Dolapchiev, Caren I Sanchez, Tiffany L Calderone, Jessica I Sanchez, Megha B Bhongade, Ahmed El Sabagh, Darrel W Cleere, Nakul Gupta, Prasun K Jalal, David W Victor, Laura Beretta

Faculty, Staff and Student Publications

Background: Predictive biomarkers are needed to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), at high risk for HCC. Our study aimed to determine whether the detection of circulating bacterial DNA could be associated with HCC development in MASLD patients with liver cirrhosis.

Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance for HCC by contrast-enhanced magnetic resonance imaging. In a nested cohort study, we performed 16S rRNA sequencing of cell-free DNA extracted from 343 longitudinal plasma samples collected from 151 MASLD patients with cirrhosis. Among the 151 patients, 25 developed HCC during follow-up.

Results: …

Kap1 Promotes Gastric Adenocarcinoma Progression By Activating Hippo/Yap1 Signaling Via Binding To Hnrnpab, Shumei Song, Yibo Fan, Gengyi Zou, Longfei Huo, Janani Kumar, Yuan Li, Ruiping Wang, Enyu Dai, Jiankang Jin, Ailing W Scott, Shan Shao, Melissa Pool Pizzi, Jody V Vykoukal, Hiroyuki Katayama, Samir Hanash, George A Calin, Xing Zhang, Min Gyu Lee, Zhenning Wang, Yuan-Hung Lo, Qiong Gan, Rebecca E Waters, Feng Yin, Linghua Wang, Xiaodong Cheng, Jaffer A Ajani, Shilpa S Dhar

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter …

Tumour And Microenvironment Crosstalk In Nsclc Progression And Response To Therapy, Zahraa Rahal, Roy El Darzi, Seyed Javad Moghaddam, Tina Cascone, Humam Kadara

Faculty, Staff and Student Publications

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, …

Protocol To Detect M22g Modification On Single Trna Iso-Decoders By Immuno-Northern Blotting, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

Faculty, Staff and Student Publications

tRNA modifications are highly dynamic and play crucial roles in regulating gene expression. Here, we present an assay for analyzing N2, N2-dimethylguanosine (m22G) modifications on tRNAs using an antibody-based detection approach. We describe steps for isolating tRNAs from human cells via ion-exchange chromatography, capturing specific tRNA iso-decoders on streptavidin magnetic beads, and detecting modifications through immuno-northern blotting. This approach enables researchers to investigate other tRNA modifications using specific antibodies or downstream approaches such as mass spectrometry.

Risk Of Early Death After Acute Leukemia Diagnosis Among Adolescents And Young Adults, Amy M Berkman, Clark R Andersen, Vidya Puthenpura, Nicholas J Short, Kelly Merriman, Mahesh Swaminathan, Branko Cuglievan, David Mccall, Courtney Dinardo, Cesar Nunez, Nitin Jain, Tapan Kadia, Ghayas Issa, Amber Gibson, Miriam B Garcia, J Andrew Livingston, Susan Parsons, Michelle A T Hildebrandt, Michael E Roth

Faculty, Staff and Student Publications

Background: Advances in care have led to improvements in survival for adolescents and young adults (AYAs) diagnosed with cancer; however, the risk of early death remains high for certain cancers, particularly acute leukemias. Risk factors for early death in AYAs diagnosed with acute leukemia have not been well studied.

Methods: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death (within 2 months of diagnosis) in AYAs diagnosed with acute leukemia (n = 16 153). Early death proportion, by year, for AYAs diagnosed between 2006 and 2020 was described. Associations between incidence of early death …

A Phase Ii Trial Of Azacitidine With Ipilimumab, Nivolumab, Or Ipilimumab And Nivolumab In Previously Untreated Myelodysplastic Syndrome, Ian M Bouligny, Guillermo Montalban-Bravo, Koji Sasaki, Naval Daver, Elias Jabbour, Yesid Alvarado, Courtney D Dinardo, Farhad Ravandi, Gautam Borthakur, Prithviraj Bose, Naveen Pemmaraju, Steven Kornblau, Tapan Kadia, Lucia Masarova, Koichi Takahashi, Michael Andreeff, Alexandre Bazinet, Hui Yang, Rashmi Kanagal-Shamanna, Chitra Hosing, Sherry Pierce, Meghan Meyer, Xuelin Huang, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

No abstract provided.

Crem Is A Regulatory Checkpoint Of Car And Il-15 Signalling In Nk Cells, Hind Rafei, Rafet Basar, Sunil Acharya, Yu-Sung Hsu, Pinghua Liu, Deqiang Zhang, Toszka Bohn, Qingnan Liang, Vakul Mohanty, Ranjan Upadhyay, Ping Li, Pravin Phadatare, Merve Dede, Donghai Xiong, Huihui Fan, Corry Mathew Jones, Sebastian Kunz, May Daher, Ana Karen Nunez Cortes, Mayra Shanley, Bin Liu, Sadie Mae Moseley, Chenyu Zhang, Dexing Fang, Pinaki Banerjee, Nadima Uprety, Ye Li, Rejeena Shrestha, Xinhai Wan, Hong Shen, Vernikka Woods, April Lamour Gilbert, Seema Rawal, Jinzhuang Dou, Yukun Tan, Jeong-Min Park, Francia Reyes Silva, Alexander Biederstädt, Mecit Kaplan, Xin Ru Jiang, Inci Biederstädt, Bijender Kumar, Silvia Tiberti, Madison Moore, Jingling Jin, Ryan Z Yang, Luis Muniz-Feliciano, Samuel Rosemore, Paul Lin, Gary M Deyter, Natalie Wall Fowlkes, Abhinav K Jain, David Marin, Anirban Maitra, Ken Chen, Tobias Bopp, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1-3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM …

A Method For Sensitivity Analysis Of Automatic Contouring Algorithms Across Different Contrast Weightings Using Synthetic Magnetic Resonance Imaging, Lucas Mccullum, Zayne Belal, Warren Floyd, Alaa Mohamed Shawky Ali, Natalie West, Samuel Mulder, Yao Ding, Jiaofeng Xu, Dan Thill, Nicolette O'Connell, Joseph Stancanello, Kareem A Wahid, David T Fuentes, Ken-Pin Hwang, Clifton D Fuller

Faculty, Staff and Student Publications

Background and purpose: A majority of institution-specific automatic magnetic resonance imaging (MRI)-based contouring algorithms utilize one contrast-weighting (i.e., T2-weighted), however their performance within this contrast-weighting (i.e., across different repetition time, TR, and echo time, TE) is under-investigated and poorly understood. The purpose of this study was to develop a method to evaluate the robustness of automatic contouring algorithms to varying MRI contrast-weightings.

Materials and methods: One healthy volunteer and one patient were scanned using the multi-delay multi-echo (MDME) scan on a 3T MRI. The parotid and submandibular glands in these subjects were contoured using an automatic contouring algorithm trained on …

Technical Development And In Silico Implementation Of Syntheticmr In Head And Neck Adaptive Radiation Therapy: A Prospective R-Ideal Stage 0/1 Technology Development Report, Lucas Mccullum, Samuel L Mulder, Natalie A West, Robert Aghoghovbia, Alaa Mohamed Shawky Ali, Hayden Scott, Travis C Salzillo, Yao Ding, Alex Dresner, Ergys Subashi, Dan Ma, R Jason Stafford, Ken-Pin Hwang, Clifton D Fuller

Faculty, Staff and Student Publications

Background: SyntheticMR has the capability of generating quantitative relaxometry maps and synthetic contrast-weighted MRI images in rapid acquisition times. Recently, it has gained attention in the diagnostic community, however, no studies have investigated its feasibility on the MR-Simulation or MR-Linac systems, especially as part of the head and neck adaptive radiation oncology workflow.

Purpose: Demonstrating its feasibility will facilitate rapid quantitative biomarker extraction, which can be leveraged to guide adaptive radiation therapy decision making.

Methods: Two phantoms, two healthy volunteers, and one patient were scanned using SyntheticMR on the MR-Simulation and MR-Linac devices with scan times between 4 to 6 …

Long-Term Transfusion Independence With Luspatercept Versus Epoetin Alfa In Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes In The Commands Trial, Guillermo Garcia-Manero, Valeria Santini, Amer M Zeidan, Rami S Komrokji, Veronika Pozharskaya, Shelonitda Rose, Karen Keeperman, Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, Dimana Miteva, David Valcárcel, Pierre Fenaux, Jake Shortt, Matteo Giovanni Della Porta, Uwe Platzbecker

Faculty, Staff and Student Publications

Introduction: The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS.

Methods: Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and …

Long-Term Follow-Up And Combined Phase 2 Results Of Eprenetapopt And Azacitidine In Patients With Tp53 Mutant Mds/Aml, David A Sallman, Rami S Komrokji, Amy E Dezern, Marie Sebert, Guillermo Garcia-Manero, Ramy Rahmé, Eric S Winer, Jacqueline Lehmann-Che, Gail J Roboz, Isabelle Madelaine, Mikkael A Sekeres, Pierre Peterlin, Onyee Chan, Odile Beyne-Rauzy, Andrew Kuykendall, Christian Recher, Amy Mclemore, Aspasia Stamatoullas, Ling Zhang, Lise Willems, Qianxing Mo, Emmanuel Raffoux, Lisa Nardelli, Céline Berthon, Najla H Al Ali, Bruno Quesnel, Eric Padron, Hagop M Kantarjian, Alan F List, Lionel Ades, Jeffrey E Lancet, Pierre Fenaux, Thomas Cluzeau

Faculty, Staff and Student Publications

TP53 gene mutations (mTP53) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR-246) is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in mTP53 cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents-naïve mTP53 higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1-4) + azacitidine 75 mg/m2 sc/iv × 7 days in 28-day cycles. The …

Progress And Challenges Of Artificial Intelligence In Lung Cancer Clinical Translation, Erjia Zhu, Amgad Muneer, Jianjun Zhang, Yang Xia, Xiaomeng Li, Caicun Zhou, John V Heymach, Jia Wu, Xiuning Le

Faculty, Staff and Student Publications

Artificial intelligence (AI) algorithms, such as convolutional neural networks and transformers, have significantly impacted cancer care. For lung cancer, AI holds great potential in addressing smoking cessation, personalized screening, and imaging genomics. And these data could be incorporated to optimize treatment selection. This review highlights the transformative impact of AI in lung cancer management, discusses crucial barriers such as model bias and fairness, and outlines future directions for clinical application.

First-In-Human Phase 1 Study Of Khk2455 Monotherapy And In Combination With Mogamulizumab In Patients With Advanced Solid Tumors, Timothy A Yap, Olivier Rixe, Capucine Baldini, Ursa Brown-Glaberman, Sergey Efuni, David S Hong, Christophe Massard, Jameel Muzaffar, Andreea Varga, Emrullah Yilmaz, Yuta Ikawa, Lisa H Shiue, Yi Liu, Matthew W Hruska, Henry Zhao, Akihiro Tokunaga, Solmaz Sahebjam

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors. …

A Follow-Up Study On The Novel Use Of Contrast-Enhanced Susceptibility-Weighted Imaging For Extremity Desmoid Fibromatosis Response Assessment, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Ken-Pin Hwang, Jingfei Ma, R Jasson Stafford, Ravin Ratan, John E Madewell, Dejka Araujo, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Desmoid tumors are rare mesenchymal neoplasms characterized by a clonal proliferation of fibroblasts and myofibroblasts. Using the novel contrast-enhanced susceptibility-weighted imaging (CE-SWI) for characterizing desmoid tumors can enhance the separation between fibrous T2-hypointense and cellular T1-enhancing components. We aim to evaluate the effectiveness of the CE-SWI signal, volumetric, and radiomics-derived features in assessing desmoid treatment response. This IRB-approved study included 17 single-lesion extremity desmoid fibromatosis patients who underwent standard-of-care MRI, including CE-SWI, from March 2021 to February 2024. Measurements of maximum diameter, volume, and the modified Choi (m-Choi: tumor/muscle T2 ratio) were computed based on CE-SWI and T2-STIR volumetric tumor …

Memantine Inhibits Calcium-Permeable Ampa Receptors, Elisa Carrillo, Alejandra Montaño Romero, Cuauhtemoc U Gonzalez, Andreea L Turcu, Santiago Vázquez, Edward C Twomey, Vasanthi Jayaraman

Faculty, Staff and Student Publications

Memantine is an US Food and Drug Administration (FDA) approved drug that is thought to selectively inhibit NMDA-subtype of ionotropic glutamate receptors (NMDARs). NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine …

Dynamic Contrast-Enhanced Mri Processing Comparison For Distinguishing True Progression From Pseudoprogression In High-Grade Glioma, Ahmad Amer, Shehbaz Ansari, Apollo Krayyem, Suprateek Kundu, Swapnil Khose, Halyna Pokhylevych, Susana Calle, Chirag B Patel, Zixi Yang, Ho-Ling Anthony Liu, Jason M Johnson

Faculty, Staff and Student Publications

Background: Treatment-related changes may occur due to radiation and temozolomide in glioblastoma and can mimic tumor progression on conventional MRI. DCE-MRI enables quantification of the extent of blood-brain barrier (BBB) disruption, providing information about areas of suspicious postcontrast T1 enhancement. We compared DCE-MRI processing methods for distinguishing true disease progression from pseudoprogression in high-grade gliomas (HGGs).

Methods: We identified 110 patients with HGG treated with surgery and chemoradiation who underwent DCE-MRI to further interrogate areas of new/increasing enhancement. All patients had confirmatory surgery/biopsy with pathology-confirmed progression or pseudoprogression. Scans were performed at 3T and analyzed using nordicICE. The MCA, SSS, …

Supporting Administrative Time For Advanced Practitioners: A Comprehensive Approach, Merdith Beaton, Andrea Edwards, Wendy Vogel, Haleigh Mistry, Lisa Kottschade, Sara Toth, David Johnson, Heather Koniarczyk

Faculty, Staff and Student Publications

Advanced practitioners (APs), including nurse practitioners (NPs), physician assistants (PAs), clinical nurse specialists, and pharmacists, are pivotal in health care. Despite their critical role, record numbers of APs are leaving the profession, primarily due to poor work-life balance, which contributes to burnout and high turnover rates. This article explores the impact of administrative time on AP job satisfaction and retention, drawing from recent surveys and case studies. Findings indicate that dedicated administrative time significantly enhances job satisfaction and reduces burnout, with data showing that APs with administrative time are less likely to leave their roles. The Advanced Practitioner Society for …

Hyalinization-Based Pathologic Response And Immune Infiltration Following Neoadjuvant Radiotherapy With Or Without Immune-Checkpoint Blockade In Localized Undifferentiated Pleomorphic Sarcoma, R S Traweek, M Zoghbi, R Lazcano, B M Cope, A J Bishop, A Farooqi, D Mitra, A K Yoder, B A Guadagnolo, D R Ingram, K Wani, D Shamsutdinova, A J Lazar, W-L Wang, C P Scally, E Z Keung, K E Torres, K K Hunt, R Ratan, J A Livingston, M S Nakazawa, D M Araujo, S Patel, V Ravi, A P Conley, M A Zarzour, N Somaiah, C L Roland, E F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Standard-of-care treatment of localized undifferentiated pleomorphic sarcoma (UPS) involves preoperative radiotherapy (RT) and surgery. Combination of RT with immune-checkpoint blockade (ICB) represents a promising new strategy.

METHODS: Our primary objective was to assess survival outcomes and pathologically documented response in patients receiving RT with or without ICB or chemotherapy.

RESULTS: In a retrospective cohort of 68 patients with primary or locally recurrent UPS who received neoadjuvant RT with or without ICB, the ICB group had greater tumor hyalinization than the non-ICB group (89% compared with 30%, P = 0.018). In the non-ICB group, 19/37 patients (51%) achieved hyalinization-based pathologic …

Coordinated Regulation By Lncrnas Results In Tight Lncrna-Target Couplings, Hua-Sheng Chiu, Sonal Somvanshi, Chung-Te Chang, Eric James De Bony De Lavergne, Zhaowen Wei, Chih-Hung Hsieh, Wim Trypsteen, Kathleen A Scorsone, Ektaben Patel, Tien T Tang, David B Flint, Mohammad Javad Najaf Panah, Hyunjae Ryan Kim, Purva Rathi, Yan-Hwa Wu Lee, Sarah E Woodfield, Sanjeev A Vasudevan, Andras Attila Heczey, M Waleed Gaber, Gabriel O Sawakuchi, Ting-Wen Chen, Pieter Mestdagh, Xuerui Yang, Pavel Sumazin

Faculty, Staff and Student Publications

The determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research. We developed BigHorn to computationally infer lncRNA-DNA interactions that mediate transcription and chromatin-remodeling factor activity. Its accurate inference enabled the identification of lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. These lncRNAs may act as molecular chaperones, regulating the stability and translation of mRNAs they helped transcribe, leading to tightly coupled expression profiles. Our analysis suggests that lncRNAs regulate cancer genes across tumor contexts, thus propagating the effects of non-coding alterations to …

Bayesian-Weighted Mendelian Randomization Reveals Sleep Apnea Syndrome Mediates The Bmi-Chronic Pain Link, Wenbao Shi, Jing Luo, Liu Yang, Dalin Chen, Yongqin Zhang, Jun Peng, Kurt Ruetzler, Manyun Sun, Hua Jin

Faculty, Staff and Student Publications

Background: Body mass index (BMI) has a complex association with a variety of chronic pain conditions, which may be influenced by sleep apnea syndrome (SAS). However, the role of SAS within the causal pathway linking BMI to chronic pain remains unconfirmed. This study explored whether and to what extent SAS serves as a mediator between BMI and chronic pain using Bayesian-weighted Mendelian randomization (BWMR) techniques.

Methods: This study utilized genome-wide association study (GWAS) summary data for BMI (N=461,460) and SAS (N=476,853; based on ICD-10 code diagnostic registries) from the IEU OpenGWAS database, along with chronic pain GWAS data (ICD-10 code-based …

Phase Ii Basket Trial Of Dual Anti-Ctla-4 And Anti-Pd-1 Blockade In Rare Tumors (Dart) Swog S1609: Pancreatic Neuroendocrine Neoplasm (Pnen) Cohort, Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Bhavana Konda, Mark Walshauser, Edwin Parra, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative …

Letter Of Concern From The Association Of Academic Chairs Of Emergency Medicine Regarding Acgme Proposed Changes, Richard J Hamilton, Lance B Becker, Richard E Wolfe, D Adam Algren, Thomas Arnold, Michael Baumann, Ross P Berkeley, Terrell S Caffery, Chad M Cannon, Theodore J Corbin, Michael E Chansky, Harinder S Dhindsa, Charles L Emerman, David A Farcy, Chris Fox, Michael A Gibbs, Christopher S Goode, Steven Andy Godwin, Dietrich Jehle, David Johnson, Samuel M Keim, Babak Khazaeni, Barry J Knapp, Clint Hawthorne, John D Hoyle, Michael Christopher Kurz, Evan Leibner, Robert Mcnamara, Robert F Mccormack, Edward A Michelson, Chadwick Miller, Ashley Norse, Andrew Nugent, Brian J O'Neil, David T Overton, Edward A Panacek, William F Paolo, Denis R Pauzé, Amanda L Perez, Ralph J Riviello, Scott W Rodi, Peter S Pang, Juan A Gonzalez Sanchez, David Seaberg, Adam Schwartz, Stephen A Shiver, David P Sklar, Ben C Smith, Jeffrey R Stowell, Marc D Squillante, J Jeremy Thomas, Terry Vanden Hoek, Gregory A Volturo, E Lea Walters, Thomas E Wyatt, Donald M Yealy

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This letter, signed by over 50 academic chairs of emergency medicine, urges the ACGME to reconsider a proposed mandate requiring all emergency medicine residency programs to adopt a four-year training model. The authors argue that current three-year programs are supported by data demonstrating equivalent educational and clinical outcomes compared to four-year formats. They criticize the flawed survey methodology underpinning the proposal, note the loss of milestone-based training flexibility, and highlight the lack of added scholarly or clinical value in the fourth year. The letter also outlines negative consequences for fellowship participation, workforce development, trainee debt, and diversity. The signatories advocate …

Incidental Findings In Female Pelvis Mri Performed For Gynaecological Malignancies, Silvia Bottazzi, Roberta V Ninkova, Luca Russo, Andrea Ponsiglione, Benedetta Gui, Daniela Demundo, Massimo Imbriaco, Aradhana M Venkatesan, Evis Sala, Stephanie Nougaret, Lucia Manganaro, Stefania Rizzo

Faculty, Staff and Student Publications

Incidental findings on female pelvic MRI present diagnostic challenges and may have significant clinical implications. Defined as abnormalities unrelated to the primary imaging indication, these findings have become increasingly prevalent with the expanded use of MRI in gynaecological practice. Standard gynaecological MRI protocols, incorporating T1- and T2-weighted sequences, diffusion-weighted imaging, and contrast-enhanced sequences, facilitate the characterisation of numerous extra-gynaecological abnormalities, ranging from benign to critical lesions. This review proposes a compartment-based approach for identifying extra-gynaecological findings, discussing their imaging characteristics and differential diagnoses. This approach may help radiologists systematically assess incidental findings, potentially improving the recognition of clinically relevant abnormalities …

Mis-Splicing-Derived Neoantigens And Cognate Tcrs In Splicing Factor Mutant Leukemias, Won Jun Kim, Edie I Crosse, Emma De Neef, Inaki Etxeberria, Erich Y Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H Winick, Alexander M Lewis, Robert F Stanley, Susan Dewolf, Brigita Meškauskaitė Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S Chandran, Benjamin D Greenbaum, Christopher A Klebanoff, Robert K Bradley, Omar Abdel-Wahab

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Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing …

Encorafenib, Cetuximab, And Mfolfox6 In Braf-Mutated Colorectal Cancer, Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz, Breakwater Trial Investigators

Faculty, Staff and Student Publications

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P< 0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall …

A Conditional Point Cloud Diffusion Model For Deformable Liver Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection, Jiacheng Xie, Hua-Chieh Shao, Yunxiang Li, Shunyu Yan, Chenyang Shen, Jing Wang, You Zhang

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Objective. Deformable liver motion tracking using a single x-ray projection enables real-time motion monitoring and treatment intervention. We introduce a conditional point cloud diffusion (PCD) model-based framework for accurate and robust liver motion tracking from arbitrarily angled single x-ray projections. Approach. We propose a conditional PCD model for liver motion tracking (PCD-Liver), which estimates volumetric liver motion by solving deformable vector fields (DVFs) of a prior liver surface point cloud, based on a single x-ray image. It is a patient-specific model of two main components: a rigid alignment model to estimate the liver’s overall shifts, and a conditional PCD …

Cholesterol Metabolism Regulated By Camkk2-Creb Signaling Promotes Castration-Resistant Prostate Cancer, Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo

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Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family …

The Carsr Two-Component System Directly Controls Radd Expression As A Global Regulator That Senses Bacterial Coaggregation In Fusobacterium Nucleatum, Bibek G C, Chenggang Wu

Faculty, Staff and Student Publications

Two-component systems (TCS) enable bacteria to sense and respond to environmental signals, facilitating rapid adaptation. Fusobacterium nucleatum, a key oral pathobiont, employs the CarSR TCS to modulate coaggregation with various gram-positive partners by regulating the expression of radD, encoding a surface adhesion protein, as revealed by RNA-Seq analysis. However, the direct regulation of the radD-containing operon (radABCD) by the response regulator CarR, the broader CarR regulon, and the signals sensed by this system remain unclear. In this study, chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) identified approximately 161 CarR-enriched loci across the genome and …

Intratumoral Neutrophil-To-Lymphocyte Ratio Is Mirrored By Circulating Neutrophil-To-Lymphocyte Ratio In Non-Small Cell Lung Cancer, Kyle G Mitchell, Younghee Lee, Nathaniel Deboever, Marcelo V Negrao, Hai T Tran, Edwin Parra, Lauren Byers, Alexandre Reuben, Lorenzo Federico, Chantale Bernatchez, Jing Wang, Mara B Antonoff, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Daniel J Mcgrail, Boris Sepesi, Cara L Haymaker

Faculty, Staff and Student Publications

Tumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis.We analyzed tNLR (transcriptomic …

Protocol To Analyze Trna And Rrna Processing Using Biotin-Labeled Probes, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

Faculty, Staff and Student Publications

Mature tRNAs and rRNAs are derived from larger precursor transcripts through intricate endo- and exonuclease processing steps. Here, we present a protocol to analyze rRNA and tRNA processing using total RNA extracted from human cells. We describe steps for separating RNA by denaturing electrophoresis, followed by northern blotting. We detail procedures for detecting pre-rRNA intermediates or specific tRNA species using biotin-labeled probes imaged via fluorescence or chemiluminescence. This non-radioactive, high-sensitivity assay enables the investigation of rRNA and tRNA expression dynamics. For complete details on the use and execution of this protocol, please refer to Hwang et al.