tbuckley/cabot-search huggingface dataset:
Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancer
Authors: Allison M. Barrett, Zachary T. Britton, Rosa A. Carrasco, Shannon Breen, Maria A.S. Broggi, Amy Hatke, Benjamin Clark, Chunning Yang, Sandrina Phipps, Lorenzo Ortiz, Brianna Janocha, Peter Zanvit, Nicolas A. Giraldo, Philip L. Martin, Jean-Martin Lapointe, Nathalie Harder, Georgina H. Cornish, Bala N.N.R. Attili, Yariv Mazor, Melissa Damschroder, Mark Cobbold, Gordon Moody, Emily E. Bosco
Journal: Clinical Cancer Research (2024)

Abstract Purpose: CLDN18.2 is a surface membrane protein crucial for maintaining tight junctions in gastric mucosal cells and is highly expressed in gastric, esophageal, and pancreatic cancers. Thus, CLDN18.2 is suited for exploration as a clinical target for chimeric antigen receptor T-cell (CAR-T) therapy in these indications. Although CAR-T therapies show promise, a challenge faced in their development for solid tumors is the immunosuppressive tumor microenvironment, often characterized by the presence of immune and stromal cells secreting high levels of transforming growth factor beta (TGF-β). Addition of TGF-β armoring can potentially expand CAR-T activity in solid tumors. We report on the preclinical development of a CLDN18.2-targeting CAR-T showing effectiveness in CLDN18.2-positive gastric, esophageal, and pancreatic tumor models. Experimental Design: The lead lentivirus product contains a unique single-chain variable fragment, CD28 and CD3z costimulatory and signaling domains, and dominant negative TGF-β receptor armoring, enhancing targeting and safety and counteracting suppression. We developed a shortened cell manufacturing process to enhance the potency of the final product, AZD6422. Results: AZD6422 exhibited significant antitumor activity and tolerability in multiple patient-derived tumor xenograft models with various CLDN18.2 and TGF-β levels, as determined by immunohistochemistry. Efficacy of armored CAR-Ts in tumor models with elevated TGF-β was increased in vitro and in vivo. In vitro restimulation assays established greater persistence and cytolytic function of AZD6422 compared with a traditionally manufactured CAR-T. Conclusions: AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.
Synthetic Lethal Targeting of Cyclin Dependent Kinase-12-Deficient Prostate Cancer with PARP Inhibitors
Authors: Jonathan Chou, Troy M. Robinson, Emily A. Egusa, Roshan Lodha, Meng Zhang, Michelle Badura, Mane Mikayelyan, Henry Delavan, Jason Swinderman, Chris Wilson, Jun Zhu, Rajdeep Das, Minh Nguyen, Andrea Loehr, Tony Golsorkhi, Andrew Simmons, Wassim Abida, Arul M. Chinnaiyan, Michelle R. Arkin, Eric J. Small, David A. Quigley, Lixing Yang, Minkyu Kim, Alan Ashworth, Felix Y. Feng
Journal: Clinical Cancer Research (2024)

Abstract Purpose: CDK12 is a cyclin-dependent kinase (CDK) that is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer (PC) characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features. Experimental Design: Using isogenic PC models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ~1800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on poly ADP-ribose polymerase inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine effects on PARPi sensitivity. Mice bearing control and CDK12 mutant prostate tumors were treated with rucaparib. Finally, we evaluated prostate specific antigen (PSA) responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial. Results: Cancer cells lacking CDK12 are more sensitive to PARPi than isogenic wild-type cells, and sensitivity depends on the degree of CDK12 inhibition. Inhibiting cyclin K, but not CDK13, also led to PARPi sensitivity and suppressed homologous recombination. CDK12 truncation mutants remained sensitive to PARPi, whereas kinase domain mutants exhibited intermediate sensitivity. The PARPi rucaparib suppressed tumor growth in mice bearing CDK12-mutated tumors. Finally, 6 of 11 (55%) PC patients with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial. Conclusions: In PC, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in PC patients with biallelic inactivating CDK12 alterations.
Renal denervation achieves its antiarrhythmic effect through attenuating macrophage activation and neuroinflammation in stellate ganglia in chronic heart failure
Authors: Wenfeng Hu, Huiyin Tu, Michael C Wadman, Yu-Long Li, Dongze Zhang
Journal: Cardiovascular Research (2024)

Abstract Aims Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for its antiarrhythmic effect are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study investigates if and how RDN decreases ventricular arrhythmias by attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. Methods and Results Rat CHF was induced by surgical ligation of the left anterior descending coronary artery (LAD). At 12 weeks after LAD ligation, completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein, followed by applying of 70% ethanol around the vessels. Immunofluorescence staining and Western blot data showed that expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor-α subunit (GM-CSFRα) in SGs was increased in CHF rats. RDN not only reduced CHF-elevated GM-CSF levels in kidney, serum and SGs, but also attenuated macrophage expansion and neuroinflammation in SGs from CHF rats. Using flow cytometry, we confirmed that RDN reduced the percentage of macrophages in SGs, which is pathologically increased in CHF. RDN also decreased CHF-enhanced N-type Ca2+ currents in CSP neurons and attenuated CHF-elevated cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN improved CHF-induced heterogeneity of ventricular electrical activities and reduced the duration of spontaneous ventricular tachyarrhythmias in CHF rats. Conclusions RDN alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis through attenuating GM-CSF-induced macrophage activation and neuroinflammation within SGs in CHF. This suggests that manipulation of the GM-CSF signaling pathway could be a novel strategy for achieving the antiarrhythmic effect of RDN in CHF.
Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia
Authors: Hui Zhou, Dongmei Qin, Chendi Xie, Jie Zhou, Shuman Jia, Ziwei Zhou, Yi Qiu, Bing Xu, Jie Zha
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Leukemic stem cells (LSC) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with acute myeloid leukemia (AML). Experimental Design: The LSC-like cell lines (KG-1α and Kasumi-1) and CD34+ primary AML cells purified from patients with AML (n = 23) treated with CS055 and/or chiglitazar and were analyzed for viability, death, and colony formation assay. We performed RNA sequencing, glutamate release, intracellular glutathione, lipid reactive oxygen species, transmission electron microscopy, and Western blotting assay and confirmed ferroptosis in LSC-like cells. The luciferase reporter, co-immunoprecipitation, histone deacetylase 3 (HDAC3)-shRNA/HDAC3/deacetylase-deficient LSC-like cell lines, histidine pull-down, and chromatin immunoprecipitation assays performed to clarify the molecular mechanism of CS055/chiglitazar in LSC-like cells. We also established cell-derived xenograft and patient-derived xenograft mouse models to evaluate the therapeutic efficacy of CS055/chiglitazar against AML in vivo. Results: We report that the HDAC inhibitor CS055, in combination with peroxisome proliferator–activated receptor pan-agonist (chiglitazar), synergistically targets leukemic stem-like cells from leukemia cell lines and patient samples while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in LSC-like cells by downregulating the expression of ferroptosis suppressor SLC7A11. In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition. Conclusions: Our findings suggest that treatment with CS055 combined with chiglitazar will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.
A novel human <i>SDHA</i>‑knockout cell line model for the functional analysis of clinically‑relevant SDHA variants
Authors: Jason D. Kent, Lillian R. Klug, Michael C. Heinrich
Journal: Clinical Cancer Research (2024)

SDHA mutations are the most common cause of succinate dehydrogenase (SDH)-deficient GIST. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for improved patient outcomes. However, more than 95% of the >1,000 SDHA missense variants listed in ClinVar are variants of uncertain significance. Our ability to interpret the significance of SDHA variants must improve before genetic sequencing can be utilized to its full potential.
Effect of mesenchymal stem cells on the host response in severe community-acquired pneumonia
Authors: Tom D Y Reijnders, Pierre-François Laterre, Bruno François, Miguel Sánchez García, Tjitske S R van Engelen, Daoud Sie, Brendon P Scicluna, Dmitry V Ostanin, Kevin J Galinsky, Joe M Butler, Eleuterio Lombardo, Tom van der Poll
Journal: Thorax (2024)

Mesenchymal stem cells (MSC) have immune regulatory properties that may ameliorate pathophysiological processes in sepsis. We determined the effect of allogeneic adipose-derived MSCs (Cx611) on the host response during sepsis due to community-acquired bacterial pneumonia (CABP) by measuring 29 plasma biomarkers and blood transcriptomes at six time points in 82 patients randomised to two intravenous infusions of Cx611 or placebo. Cx611 treatment enhanced several endothelial cell and procoagulant response plasma biomarkers, and led to increased expression of pathways related to innate immunity, haemostasis and apoptosis. Cx611 infusion in sepsis due to CABP is associated with broad host response alterations.
T-cell redirecting bispecific antibodies in multiple myeloma: optimal dosing-schedule and duration of treatment
Authors: Niels W.C.J. van de Donk, Leo Rasche, Surbhi Sidana, Sonja Zweegman, Alfred L. Garfall
Journal: Blood Cancer Discovery (2024)

Abstract T-cell redirecting bispecific antibodies (BsAbs) induce significant responses in heavily pretreated MM. BsAbs are currently administered in a dose-dense fashion until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections, and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy.
Software using artificial intelligence for nodule and cancer detection in CT lung cancer screening: systematic review of test accuracy studies
Authors: Julia Geppert, Asra Asgharzadeh, Anna Brown, Chris Stinton, Emma J Helm, Surangi Jayakody, Daniel Todkill, Daniel Gallacher, Hesam Ghiasvand, Mubarak Patel, Peter Auguste, Alexander Tsertsvadze, Yen-Fu Chen, Amy Grove, Bethany Shinkins, Aileen Clarke, Sian Taylor-Phillips
Journal: Thorax (2024)

Objectives To examine the accuracy and impact of artificial intelligence (AI) software assistance in lung cancer screening using CT. Methods A systematic review of CE-marked, AI-based software for automated detection and analysis of nodules in CT lung cancer screening was conducted. Multiple databases including Medline, Embase and Cochrane CENTRAL were searched from 2012 to March 2023. Primary research reporting test accuracy or impact on reading time or clinical management was included. QUADAS-2 and QUADAS-C were used to assess risk of bias. We undertook narrative synthesis. Results Eleven studies evaluating six different AI-based software and reporting on 19 770 patients were eligible. All were at high risk of bias with multiple applicability concerns. Compared with unaided reading, AI-assisted reading was faster and generally improved sensitivity (+5% to +20% for detecting/categorising actionable nodules; +3% to +15% for detecting/categorising malignant nodules), with lower specificity (−7% to −3% for correctly detecting/categorising people without actionable nodules; −8% to −6% for correctly detecting/categorising people without malignant nodules). AI assistance tended to increase the proportion of nodules allocated to higher risk categories. Assuming 0.5% cancer prevalence, these results would translate into additional 150–750 cancers detected per million people attending screening but lead to an additional 59 700 to 79 600 people attending screening without cancer receiving unnecessary CT surveillance. Conclusions AI assistance in lung cancer screening may improve sensitivity but increases the number of false-positive results and unnecessary surveillance. Future research needs to increase the specificity of AI-assisted reading and minimise risk of bias and applicability concerns through improved study design. PROSPERO registration number CRD42021298449.
Rapid and unbiased enrichment of extracellular vesicles via a meticulously engineered peptide
Authors: Le Wang, Zhou Gong, Ming Wang, Yi-Zhong Liang, Jing Zhao, Qi Xie, Xiao-Wei Wu, Qin-Ying Li, Cong Zhang, Li-Yun Ma, Si-Yang Zheng, Ming Jiang, Xu Yu, Li Xu
Journal: Bioactive Materials (2024)
The Pediatric Physiatric Posterior Fossa Symptoms scale (3PFSs): Impairments and outcome in pediatric inpatient rehabilitation for posterior fossa brain tumors
Authors: Jennifer Wu, Brian D Wishart, Stephanie E Cohen, Patricia Orme, Susan S Quinn, Donna Nimec
Journal: Neuro-Oncology (2024)

Abstract Background Clinical recognition of the post-operative neurologic sequelae of posterior fossa tumors is inconsistent. This study aimed to characterize functional impairments and recovery trajectories in pediatric patients admitted to inpatient rehabilitation following surgical resection of posterior fossa brain tumors. This study also introduces the Pediatric Physiatric Posterior Fossa Symptom scale (3PFSs) for serial assessment of post-operative symptoms in pediatric posterior fossa brain tumors. Methods This retrospective cohort study included 49 patients aged 1.1 to 19.9 years admitted to a pediatric unit of a free-standing rehabilitation hospital following resection of a posterior fossa brain tumor. Functional Independence Measure for Children (WeeFIM) and 3PFSs scores at admission and discharge were the primary outcome measures. Results Across the group, WeeFIM score improved from 51.5±23.5 points at admission to 74.2±28.2 points at discharge (t=4.34, p&amp;lt;0.001). The 3PFSs score also showed improvement from 10[IQR=9-12] points at admission to 8[7-10] points at discharge (t=9.3, p&amp;lt;0.0001). While change in both the WeeFIM and 3PFSs captured statistically significant improvement in function, there was low inter-rating correlation (p&amp;gt;0.7). In addition, mortality was correlated with higher discharge 3PFSs score (p=0.007) but not discharge WeeFIM score. Conclusion In pediatric patients with post-operative neurologic sequelae due to posterior fossa brain tumors, inpatient rehabilitation resulted in global and domain specific functional improvements. This initial application of the 3PFSs demonstrates potential applicability for stratifying patients to appropriate levels of rehabilitation, capturing functionally relevant response to rehabilitation treatment, and prognosticating long-term outcomes. These initial results are promising but require additional validation in a larger cohort.
Efficacy and safety of vunakizumab in moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, placebo-controlled phase 3 trial
Authors: Kexiang Yan, Fuqiu Li, Xiaodong Bi, Ling Han, Zhenghua Zhang, Rixin Chen, Yuye Li, Litao Zhang, Xiaohua Wang, Linfeng Li, Jianyun Lu, Ai'e Xu, Sen Yang, Yan Lu, Jianfang Sun, Zhiming Li, Xiaohong Zhu, Meiying Jiang, Siping Zhang, Wenqing Wang, Yanling Li, Zudong Meng, Hongyi Li, Kuanhou Mou, Xiuping Han, Shanshan Li, Aijun Chen, Xin Li, Donghua Liu, Chunlei Zhang, Chao Ji, Yu Wang, Hao Cheng, Xiaojing Cui, Xiaoyan Yao, Xiaoyan Bai, Guangchao Dong, Jinhua Xu
Journal: Journal of the American Academy of Dermatology (2024)
Introduction to the Theme “Novel Therapeutics with the Potential to Advance Health Care”
Authors: Paul A. Insel, Susan G. Amara, Amrita Ahluwalia
Journal: The Annual Review of Pharmacology and Toxicology (2024)

The reviews in Volume 65 of the Annual Review of Pharmacology and Toxicology cover a wide variety of topics in pharmacology and toxicology focused upon the pathway from preclinical studies to clinical trials. Many of these reviews discuss the identification and validation of new therapeutic targets and/or novel therapeutic approaches. Examples include reviews that focus on the treatment of obesity, neuropsychiatric disorders, Parkinson's disease, substance use disorders, liver fibrosis, cardiac arrythmias, chronic intestinal inflammation, prostate cancer, immuno-oncology, sickle cell disease, and snakebite envenoming. Other topics include drug discovery of biologics, microphysiological systems, and human induced pluripotent stem cell–derived organoids and organ-on-chip technology integrated with artificial intelligence methodologies. Together, these and other reviews give new insights into the assessment of aspects of toxicology and provide readers a glimpse of advances in pharmacology and toxicology that we believe will advance health care and environmental safety.
Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics
Authors: Evan D. Kelly, Mark J. Ranek, Manling Zhang, David A. Kass, Grace K. Muller
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs on normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.
NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities
Authors: Milad Rasouli, Selina Troester, Florian Grebien, Bianca F. Goemans, C. Michel Zwaan, Olaf Heidenreich
Journal: HemaSphere (2024)

Abstract Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re‐wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion‐driven AML.
Update on surveillance for Wilms tumor and hepatoblastoma in Beckwith-Wiedemann Syndrome and other predisposition syndromes
Authors: Jennifer M. Kalish, Kerri D. Becktell, Gaëlle Bougeard, Garrett M. Brodeur, Lisa R. Diller, Andrea S. Doria, Jordan R. Hansford, Steven D. Klein, Wendy K. Kohlmann, Christian P. Kratz, Suzanne P. MacFarland, Kristian W. Pajtler, Surya P. Rednam, Jaclyn Schienda, Lisa J. States, Anita Villani, Rosanna Weksberg, Kristin Zelley, Gail E. Tomlinson, Jack J. Brzezinski
Journal: Clinical Cancer Research (2024)

Abstract Wilms tumors are commonly associated with predisposition syndromes many, but not all, of which include overgrowth. Several of these syndromes also include a risk of other embryonal malignancies – particularly hepatoblastoma. Guidelines for surveillance in this population were published in 2017 and recently members of the AACR Pediatric Cancer Working Group met to update those guidelines with a review of more recently published evidence and risk estimates. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines and harmonize updated surveillance recommendations in the North American and Australian context for patients with overgrowth syndromes and other syndromes associated with Wilms tumor predisposition.