tbuckley/cabot-search huggingface dataset:
Corrigendum to “Improvement of TNBC immune checkpoint blockade with a microwave-controlled ozone release nanosystem” [Journal of Controlled Release, 351 (2022), 954–969]
Authors: Linlin Song, Dan Zheng, Jinshun Xu, Tianyue Xu, Zhihui Liu, Huan Zhang, Yi Li, Yulan Peng, Hubing Shi
Journal: Journal of Controlled Release (2024)
Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma
Authors: Francine M. Foss, Youn H. Kim, H. Miles Prince, Oleg E. Akilov, Christiane Querfeld, Lucia Seminario-Vidal, David C. Fisher, Timothy M. Kuzel, Costas K. Yannakou, Larisa J. Geskin, Tatyana Feldman, Lubomir Sokol, Pamela Blair Allen, Nam Hoang Dang, Fernando Cabanillas, Henry K. Wong, Chean Eng Ooi, Dongyuan Xing, Nicholas Sauter, Preeti Singh, Myron Czuczman, Madeleine Duvic
Journal: Journal of Clinical Oncology (2024)

PURPOSE Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability. RESULTS The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%). CONCLUSION Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.
Reply to: Human Leukocyte Antigen Mismatching and the Role of Killer Cell Immunoglobulin-Like Receptor Mismatch in Hematopoietic Cell Transplantation for Hematologic Malignancies
Authors: Esteban Arrieta-Bolaños, Edouard F. Bonneville, Annalisa Ruggeri, Katharina Fleischhauer
Journal: Journal of Clinical Oncology (2024)
Long-Term Follow-Up and Overall Survival in NRG258, a Randomized Phase III Trial of Chemoradiation Versus Chemotherapy for Locally Advanced Endometrial Carcinoma
Authors: Daniela E. Matei, Danielle M. Enserro, Marcus E. Randall, David Mutch, William Small, Paul A. DiSilvestro, Nick M. Spirtos, David M. O’Malley, Guilherme H. Cantuaria, David Michelin, Steven Waggoner, Mark Shahin, Saketh Guntupalli, Olivia Lara, Frederick R. Ueland, David Warshal, Albert Bonebrake, Krishnansu S. Tewari, Annie Tan, Matthew A. Powell, Joan L. Walker, Alessandro D. Santin, Jong Hyeok Kim, David S. Miller
Journal: Journal of Clinical Oncology (2024)

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis. Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IVA UC or stage I/II serous or clear cell UC and positive cytology were enrolled. The primary objective was RFS. Secondary objectives were OS, toxicity, and quality of life. Cumulative probabilities of OS were estimated using the Kaplan-Meier method. Subgroup analyses of treatment effect for FIGO stage, age, race, gross residual disease, histology, lymph-vascular space invasion, and body mass index were performed. In total, 813 patients were randomly assigned (407 C-RT and 406 CT). The median follow-up was 112 months. Median OS was not achieved in either arm. The stratified hazard ratio for death comparing C-RT versus CT was 1.05 (95% CI, 0.82 to 1.34, log-rank two-sided P value = .72). None of the factors analyzed predicted OS benefit from C-RT. Although C-RT reduced the rate of local recurrence compared with CT, it did not increase OS or RFS in stage III/IVA UC.
Gynecologic cancer clinical trial eligibility criteria as a marker for equitable clinical trial access
Authors: Ann Oluloro, Elizabeth M Swisher, Heidi J Gray, Barbara Goff, Kemi M Doll
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Racial and ethnic minorities remain underrepresented in gynecologic cancer clinical trials despite disproportionately worse oncologic outcomes. Research shows differential racial enrollment patterns due to comorbidity-based exclusion criteria (CEC). Our objective was to evaluate contemporary trends in CECs among NCI-sponsored gynecologic cancer clinical trials and protocol adherence to broadened eligibility criteria guidelines as an assessment of equitable enrollment access. Methods The ClinicalTrials.gov registry was queried for NCI-sponsored gynecologic cancer clinical trials (1994-2021). Study characteristics and CECs were abstracted from protocols. Descriptive statistics and temporal trends were calculated using chi-square testing with STATA v17 software. Results Among 279 clinical trials identified, 65% completed enrollment, 53% were Phase II, and 48% focused on ovarian cancer. Pharmaceutical agents (85%) were the primary therapeutic interventions. Several inequitably restrictive exclusion criteria increased over time such as hepatitis infection (17% in 1994-2000 vs 49% in 2015-2021, p &amp;lt; .001) and cardiovascular disease (47% in 1994-2000 vs 66% in 2015-2021, p = .002). A previously rare exclusion, “mental illness/social situations,” dramatically increased from 5% to 51% (p &amp;lt; .001) over three decades. Adherence to broadened eligibility criteria recommendations was mixed. Renal function, cardiovascular disease, and performance status criteria were not broadened but HIV, prior/concurrent malignancies, and brain metastasis criteria were. Conclusions Some, but not all, of the known restrictive CECs have increased in gynecologic cancer clinical trial design, despite calls for improving racial and ethnic minority representation. While exclusion criteria are critical for trial safety, they must be carefully considered given the differential racial impact on eligibility.
Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial
Authors: Karsten Nysom, Lindsay B Kilburn, Sarah E S Leary, Daniel B Landi, Evelien de Vos-Kerkhof, Sébastien Perreault, Olaf Witt, David S Ziegler, Pablo Hernáiz Driever, Andrea T Franson, Patricia A Baxter, Nicholas S Whipple, Cassie Kline, Devorah Segal, Nada Jabado, Simon Bailey, Geoffrey McCowage, Jordan R Hansford, Dong-Anh Khuong-Quang, Nicholas G Gottardo, Timothy Hassall, Jung Woo Han, Michal Yalon Oren, Susan N Chi, Jiaheng Qiu, Daniel Da Costa, Sandya Govinda Raju, Peter Manley, Darren Hargrave
Journal: Neuro-Oncology (2024)

Abstract Background Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial. Methods FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO) and RANO-LGG criteria. The data cutoff was June 5, 2023. Results Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set. Conclusions Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.
Complex endocarditis in a young patient
Authors: Marie-Luise Dikou, Abigail Gowland, Sara Volpi, Julia Grapsa, Gianluca Lucchese
Journal:  (2024)

A 36-year-old female patient presented to her local district general hospital feeling breathless, generally unwell and lethargic on a background of a complex past medical history including an episode of Libman -Sacks endocarditis a year previously.She also had systemic lupus erythematosus with lupus nephritis and
Spatiotemporal Profiling Defines Persistence and Resistance Dynamics During Targeted Treatment of Melanoma
Authors: Jill C. Rubinstein, Sergii Domanskyi, Todd B. Sheridan, Brian Sanderson, SungHee Park, Jessica Kaster, Haiyin Li, Olga Anczukow, Meenhard Herlyn, Jeffrey H. Chuang
Journal: Cancer Research (2024)

Abstract Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment. The persister state showed increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identified intrinsic and acquired resistance mechanisms (e.g., dual specific phosphatases, reticulon-4, and CDK2) and suggested specific temporal windows of potential therapeutic susceptibility. Deep learning-enabled analysis of histopathological slides revealed morphological features correlating with specific cell states, demonstrating that juxtaposition of transcriptomics and histological data enabled identification of phenotypically distinct populations from using imaging data alone. In summary, this study defined state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones.
DOT1L mediates stem cell maintenance and represents a therapeutic vulnerability in cancer
Authors: Hetakshi P. Kurani, Joyce M. Slingerland
Journal: Cancer Research (2024)

Abstract Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies since they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase DOT1L, which methylates H3K79 and is a key epigenetic regulator governing embryonic organogenesis and adult tissue stem cell maintenance. DOT1L is overexpressed in many human malignancies, and dysregulated H3K79 methylation is pathogenic in acute myeloid leukemia and several solid tumors. DOT1L regulates core stem cell genes governing CSC self-renewal, tumorigenesis, and multidrug resistance. Recent work has situated DOT1L as an attractive stem cell target in cancer. These reports showed that DOT1L is overexpressed and its protein activated specifically in malignant stem cells compared to bulk tumor cells, making them vulnerable to DOT1L inhibition in vitro and in vivo. While early DOT1L inhibitor clinical trials were limited by inadequate drug bioavailability, accumulating preclinical data indicate that DOT1L critically regulates CSC self-renewal and might be more effective when given with other anticancer therapies. The appropriate combinations of DOT1L inhibitors with other agents and the sequence and timing of drug delivery for maximum efficacy warrant further investigation.
RPL36-mediated selective loading of miR-4432 into extracellular vesicles contributes to perivascular cell dysfunction in venous malformations
Authors: Gao-Hong Chen, Jian-Gang Ren, Hou-Fu Xia, He-Jing Zhang, Kui-Ming Wang, Lin-Zhou Zhang, Gang Chen
Journal: British Journal of Dermatology (2024)

Abstract Background Venous malformations (VMs), predominantly arising from activating mutations of TIE2 in endothelial cells (ECs), are characterized by dilated and tortuous vessels with a paucity of perivascular cells (PCs). The mechanisms of interaction between mutant ECs and PCs remain largely elusive. Objectives To investigate the characteristics of extracellular vesicles (EVs) from VM ECs, especially the microRNAs (miRNAs) carried and their roles in crosstalk between ECs and PCs in VM pathogenesis. Methods miRNA profiles of human umbilical vein endothelial cells overexpressing TIE2L914F (L914F cells) and TIE2WT [wildtype (WT) cells], along with their EVs, were analysed by RNA sequencing. In vitro studies using umbilical cord stem cells (UCSCs) were done to carry out functional assays of VM EVs and their enriched miRNA-4432 (miR-4432). miRNA pulldown and RNA interference techniques were used to identify the sorting regulator of miR-4432 into VM EVs. Results RNA secretion was upregulated in L914F EVs vs. WT EVs. miRNA sequencing revealed a distinct profile of L914F EVs vs. L914F cells, WT cells and WT EVs, identifying miR-4432 as being preferentially encapsulated in EVs from L914F cells. Functional assays demonstrated that VM EVs and EV-carried miR-4432 inhibited the differentiation, adhesion and proliferation of UCSCs. Furthermore, ribosomal protein L36 (RPL36) was identified as an RNA binding protein and sorting regulator of miR-4432 during the EV secretion process in L914F cells. Conclusions This study, for the first time, identified an interaction between VM ECs and PCs via EVs, and offers valuable data on the miRNA profiles of VM ECs and normal ECs, along with their EVs. Our findings suggest that the RPL36-mediated selective loading of miR-4432 into EVs may contribute to the aberrant PC coverage in VMs, providing novel insights into VM pathogenesis and potential treatment strategies.
Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity
Authors: Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan
Journal: Cancer Research (2024)

Abstract Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.
Early Diagnosis of Type 2 Diabetes Mellitus in Patients with Psoriasis: Construction of a Multifactorial Diagnostic Model
Authors: Pengbo Gao, Chunxiao Wang, Sihan Wang, Xiaoce Cai, Jiao Wang, Xiaoying Sun, Fengming Hu, Xin Li
Journal: Journal of the American Academy of Dermatology (2024)
THE STING AGONIST VB-85247 INDUCES DURABLE ANTITUMOR IMMUNE RESPONSES BY INTRAVESICAL ADMINISTRATION IN A NON-MUSCLE INVASIVE BLADDER CANCER
Authors: Miglena G. Prabagar, Michael McQueney, Venu Bommireddy, Rachael Siegel, Gary L. Schieven, Ku Lu, Ruziboy Husanov, Reema Deepak, David Diller, Chia-Yu Huang, Eli Mordechai, Rukiye-Nazan Eraslan
Journal: Cancer Research (2024)

Abstract Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. Here, we developed the STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonist, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficasious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory which protected from re-challenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFN-/β, TNF-, IL-6 and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.
The Association between Obesity and Efficacy of Psoriasis Therapies: An Expert Consensus Panel
Authors: Joshua Burshtein, April Armstrong, May Chow, Lauren DeBusk, Brad Glick, Alice B Gottlieb, Linda Stein Gold, Neil J Korman, Peter Lio, Joseph Merola, David Rosmarin, Angela Rosenberg, Abby Van Voorhees, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2024)
Probabilistic medical predictions of large language models
Authors: Bowen Gu, Rishi J. Desai, Kueiyu Joshua Lin, Jie Yang
Journal: npj Digital Medicine (2024)

Large Language Models (LLMs) have shown promise in clinical applications through prompt engineering, allowing flexible clinical predictions. However, they struggle to produce reliable prediction probabilities, which are crucial for transparency and decision-making. While explicit prompts can lead LLMs to generate probability estimates, their numerical reasoning limitations raise concerns about reliability. We compared explicit probabilities from text generation to implicit probabilities derived from the likelihood of predicting the correct label token. Across six advanced open-source LLMs and five medical datasets, explicit probabilities consistently underperformed implicit probabilities in discrimination, precision, and recall. This discrepancy is more pronounced with smaller LLMs and imbalanced datasets, highlighting the need for cautious interpretation, improved probability estimation methods, and further research for clinical use of LLMs.
A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer
Authors: Jeremy B. Foote, Tyler E. Mattox, Adam B. Keeton, Xi Chen, Forrest T. Smith, Kristy Berry, Thomas W. Holmes, Junwei Wang, Chung-hui Huang, Antonio Ward, AMIT K. Mitra, Veronica Ramirez-Alcantara, Cherlene Hardy, Karianne G. Fleten, Kjersti Flatmark, Karina J. Yoon, Sujith Sarvesh, Ganji P. Nagaraju, Dhana Sekhar Reddy Bandi, Yulia Y. Maxuitenko, Jacaob Valiyaveettil, Julienne L. Carstens, Donald J. Buchsbaum, Jennifer Yang, Gang Zhou, Elmar Nurmemmedov, Ivan Babic, Vadim Gaponeko, Hazem Abdelkarim, Michael R. Boyd, Greg Gorman, Upender Manne, Sejong Bae, Bassel F. El-Rayes, Gary A. Piazza
Journal: Cancer Research (2024)

RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme, and RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.