tbuckley/cabot-search huggingface dataset:
<scp>SHP2</scp> inhibition displays efficacy as a monotherapy and in combination with <scp>JAK2</scp> inhibition in preclinical models of myeloproliferative neoplasms
Authors: Garima Pandey, Lucia Mazzacurati, Tegan M. Rowsell, Nathan P. Horvat, Narmin E. Amin, Guolin Zhang, Afua A. Akuffo, Christelle M. Colin‐Leitzinger, Eric B. Haura, Andrew T. Kuykendall, Ling Zhang, Pearlie K. Epling‐Burnette, Gary W. Reuther
Journal: American Journal of Hematology (2024)

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.
Myeloid neoplasm with &lt;10% blasts and t(3;5)(q25.1;q34)/<i>NPM::MLF1</i>: A classification dilemma
Authors: Fnu Sameeta, Hong Fang, Wei Wang, Zhenya Tang, Sa A. Wang, Gokce A. Toruner, Xenia Parisi, Joseph D. Khoury, Ghayas Issa, Guillermo Garcia‐Manero, L. Jeffrey Medeiros, Guilin Tang, Sanam Loghavi
Journal: American Journal of Hematology (2024)
A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors
Authors: Sungjoon Park, Erica Silva, Akshat Singhal, Marcus R. Kelly, Kate Licon, Isabella Panagiotou, Catalina Fogg, Samson Fong, John J. Y. Lee, Xiaoyu Zhao, Robin Bachelder, Barbara A. Parker, Kay T. Yeung, Trey Ideker
Journal: Nature Cancer (2024)

Abstract Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, &lt;50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR–Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor’s genetic profile modulates CDK4/6i resistance.
In vivo CRISPR screening directly targeting testicular cells
Authors: Yuki Noguchi, Yasuhito Onodera, Tatsuo Miyamoto, Masahiro Maruoka, Hidetaka Kosako, Jun Suzuki
Journal: Cell Genomics (2024)

CRISPR-Cas9 short guide RNA (sgRNA) library screening is a powerful approach to understand the molecular mechanisms of biological phenomena. However, its in vivo application is currently limited. Here, we developed our previously established in vitro revival screening method into an in vivo one to identify factors involved in spermatogenesis integrity by utilizing sperm capacitation as an indicator. By introducing an sgRNA library into testicular cells, we successfully pinpointed the retinal degeneration 3 (Rd3) gene as a significant factor in spermatogenesis. Single-cell RNA sequencing (scRNA-seq) analysis highlighted the high expression of Rd3 in round spermatids, and proteomics analysis indicated that Rd3 interacts with mitochondria. To search for cell-type-specific signaling pathways based on scRNA-seq and proteomics analyses, we developed a computational tool, Hub-Explorer. Through this, we discovered that Rd3 modulates oxidative stress by regulating mitochondrial distribution upon ciliogenesis induction. Collectively, our screening system provides a valuable in vivo approach to decipher molecular mechanisms in biological processes.
Multi-ancestry polygenic mechanisms of type 2 diabetes
Authors: Kirk Smith, Aaron J. Deutsch, Carolyn McGrail, Hyunkyung Kim, Sarah Hsu, Alicia Huerta-Chagoya, Ravi Mandla, Philip H. Schroeder, Kenneth E. Westerman, Lukasz Szczerbinski, Timothy D. Majarian, Varinderpal Kaur, Alice Williamson, Noah Zaitlen, Melina Claussnitzer, Jose C. Florez, Alisa K. Manning, Josep M. Mercader, Kyle J. Gaulton, Miriam S. Udler
Journal: Nature Medicine (2024)
Development of Polymethine Dyes for NIR‐II Fluorescence Imaging and Therapy
Authors: Xin Chen, Jieyan Li, Shubham Roy, Zia Ullah, Jingsi Gu, Haiyan Huang, Chen Yu, Xuejin Wang, Han Wang, Yinghe Zhang, Bing Guo
Journal: Advanced Healthcare Materials (2024)

Fluorescence imaging in the second near-infrared window (NIR-II) is burgeoning because of its higher imaging fidelity in monitoring physiological and pathological processes than clinical visible/the second near-infrared window fluorescence imaging. Notably, the imaging fidelity is heavily dependent on fluorescence agents. So far, indocyanine green, one of the polymethine dyes, with good biocompatibility and renal clearance is the only dye approved by the Food and Drug Administration, but it shows relatively low NIR-II brightness. Importantly, tremendous efforts are devoted to synthesizing polymethine dyes for imaging preclinically and clinically. They have shown feasibility in the customization of structure and properties to fulfill various needs in imaging and therapy. Herein, a timely update on NIR-II polymethine dyes, with a special focus on molecular design strategies for fluorescent, photoacoustic, and multimodal imaging, is offered. Furthermore, the progress of polymethine dyes in sensing pathological biomarkers and even reporting drug release is illustrated. Moreover, the NIR-II fluorescence imaging-guided therapies with polymethine dyes are summarized regarding chemo-, photothermal, photodynamic, and multimodal approaches. In addition, artificial intelligence is pointed out for its potential to expedite dye development. This comprehensive review will inspire interest among a wide audience and offer a handbook for people with an interest in NIR-II polymethine dyes.
Engineered Microenvironmental Cues from Fiber‐Reinforced Hydrogel Composites Drive Tenogenesis and Aligned Collagen Deposition
Authors: Robert N. Kent, Maggie E. Jewett, Trevor P. Buck, Mohamed Said, LeeAnn A. Hold, Eileen A. Crawford, Megan L. Killian, Adam C. Abraham, Alice H. Huang, Brendon M. Baker
Journal: Advanced Healthcare Materials (2024)

Effective tendon regeneration following injury is contingent on appropriate differentiation of recruited cells and deposition of mature, aligned, collagenous extracellular matrix that can withstand the extreme mechanical demands placed on the tissue. As such, myriad biomaterial approaches have been explored to provide biochemical and physical cues that encourage tenogenesis and template aligned matrix deposition in lieu of dysfunctional scar tissue formation. Fiber-reinforced hydrogels present an ideal biomaterial system toward this end given their transdermal injectability, tunable stiffness over a range amenable to tenogenic differentiation of progenitors, and capacity for modular inclusion of biochemical cues. Here, tunable and modular, fiber-reinforced, synthetic hydrogels are employed to elucidate salient microenvironmental determinants of tenogenesis and aligned collagen deposition by tendon progenitor cells. Transforming growth factor β3 drives a cell fate switch toward pro-regenerative or pro-fibrotic phenotypes, which can be biased toward the former by culture in softer microenvironments or inhibition of the RhoA/ROCK activity. Furthermore, studies demonstrate that topographical anisotropy in fiber-reinforced hydrogels critically mediates the alignment of de novo collagen fibrils, reflecting native tendon architecture. These findings inform the design of cell-free, injectable, synthetic hydrogels for tendon tissue regeneration and, likely, that of a range of load-bearing connective tissues.
Development of NK cell-based cancer immunotherapies through receptor engineering
Authors: Audrey Page, Nicolas Chuvin, Jenny Valladeau-Guilemond, Stéphane Depil
Journal: Cellular and Molecular Immunology (2024)

Abstract Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities. This review focuses on surface receptor engineering in NK cell therapy and discusses its impact, challenges, and future directions. Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction. This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells. In addition, engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes, which broadens the range of target peptides. Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling. Indeed, engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies, thereby increasing their antibody-dependent cellular cytotoxicity. The ability of NK cell receptor engineering to promote the expansion, persistence, and infiltration of transferred cells in the tumor microenvironment has also been explored. Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed, and these strategies providing perspectives to counteract tumor-induced immunosuppression. Overall, receptor engineering has led to significant advances in NK cell-based cancer immunotherapies. As technical challenges are addressed, these innovative treatments will likely reshape cancer immunotherapy.
Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma
Authors: Irene M. Ghobrial, Nicole Gormley, Shaji K. Kumar, Maria-Victoria Mateos, P. Leif Bergsagel, Marta Chesi, Madhav V. Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y. Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R. Marinac, Francesco Maura, Gareth J. Morgan, Faith E. Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A. Shah, Romanos Sklavenitis-Pistofidis, Adam S. Sperling, George S. Vassiliou, Nikhil C. Munshi, Philip E. Castle, Kenneth C. Anderson, Jesus F. San Miguel
Journal: Blood Cancer Discovery (2024)

While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.
Differentiation route determines the functional outputs of adult megakaryopoiesis
Authors: Jing-Jing Li, Jingkun Liu, Yunqian Evelyn Li, Lin Veronica Chen, Hui Cheng, Yueying Li, Tao Cheng, Qian-Fei Wang, Bo O Zhou
Journal: Immunity (2024)

Emerging evidence has revealed a direct differentiation route from hematopoietic stem cells to megakaryocytes (direct route), in addition to the classical differentiation route through a series of restricted hematopoietic progenitors (stepwise route). This raises the question of the importance of two alternative routes for megakaryopoiesis. Here, we developed fate-mapping systems to distinguish the two routes, comparing their quantitative and functional outputs. We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes, respectively, but contributed to the platelet-producing megakaryocytes together. Megakaryocytes derived from the two routes displayed different activities and were differentially regulated by chemotherapy and inflammation. Our work links differentiation route to the heterogeneity of megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.
Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma: prospective real-world data from the DRUG Access Protocol
Authors: Karlijn Verkerk, Birgit S. Geurts, Laurien J. Zeverijn, Vincent van der Noort, Henk M.W. Verheul, John B.A.G. Haanen, Astrid A.M. van der Veldt, Ferry A.L.M. Eskens, Maureen J.B. Aarts, Carla M.L. van Herpen, Mathilde Jalving, Jourik A. Gietema, Lot A. Devriese, Mariette Labots, Sahar Barjesteh van Waalwijk van Doorn-Khosrovani, Egbert F. Smit, Haiko J. Bloemendal
Journal: The Lancet Regional Health - Europe (2024)

The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC).
Non-invasive pressure–volume loops using the elastance model and CMR: a porcine validation at transient pre-loads
Authors: Felicia Seemann, Einar Heiberg, Christopher G Bruce, Jaffar M Khan, Amanda Potersnak, Rajiv Ramasawmy, Marcus Carlsson, Håkan Arheden, Robert J Lederman, Adrienne E Campbell-Washburn
Journal:  (2024)

Pressure-volume (PV) loops have utility in the evaluation of cardiac pathophysiology but require invasive measurements. Recently, a time-varying elastance model to derive PV loops non-invasively was proposed, using left ventricular (LV) volume by cardiovascular magnetic resonance (CMR) and brachial cuff pressure as inputs. Validation was performed using CMR and pressure measurements acquired on the same day, but not simultaneously, and without varying pre-loads. This study validates the non-invasive elastance model used to estimate PV loops at varying pre-loads, compared with simultaneous measurements of invasive pressure and volume from real-time CMR, acquired concurrent to an inferior vena cava (IVC) occlusion.
Host transcriptomics and machine learning for secondary bacterial infections in patients with COVID-19: a prospective, observational cohort study
Authors: Meagan Carney, Tiana Maria Pelaia, Tracy Chew, Sally Teoh, Amy Phu, Karan Kim, Ya Wang, Jonathan Iredell, Yoann Zerbib, Anthony McLean, Klaus Schughart, Benjamin Tang, Maryam Shojaei, Kirsty R Short, Meagan Carney, Tiana M Pelaia, Tracy Chew, Sally Teoh, Amy Phu, Karan Kim, Ya Wang, Jonathan Iredell, Gabriella Cirmena, Alberto Ballestrero, Allan Cripps, Amanda Cox, Andrea De Maria, Arutha Kulasinghe, Carl Feng, Damien Chaussabel, Darawan Rinchai, Davide Bedognetti, Gabriele Zoppoli, Gunawan Gunawan, Irani Thevarajan, Jennifer Audsley, John-Sebastian Eden, Marcela Kralovcova, Marek Nalos, Marko Radic, Martin Matejovic, Michele Bedognetti, Miroslav Prucha, Mohammed Toufiq, Narasaraju Teluguakula, Nicholas West, Paolo Cremonesi, Philip Britton, Ricardo G Branco, Rostyslav Bilyy, Stephen MacDonald, Thomas Karvunidis, Tim Kwan, Velma Herwanto, Win Sen Kuan, Yoann Zerbib, Anthony McLean, Klaus Schughart, Benjamin Tang, Maryam Shojaei, Kirsty R Short
Journal: The Lancet Microbe (2024)

Viral respiratory tract infections are frequently complicated by secondary bacterial infections. This study aimed to use machine learning to predict the risk of bacterial superinfection in SARS-CoV-2-positive individuals.
ACTION: a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma
Authors: Isabel Arrillaga-Romany, Andrew Lassman, Susan L McGovern, Sabine Mueller, Burt Nabors, Martin van den Bent, Michael A Vogelbaum, Joshua E Allen, Allen S Melemed, Rohinton S Tarapore, Patrick Y Wen, Timothy Cloughesy
Journal: Neuro-Oncology (2024)

Abstract Background H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma. Methods ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.
Letter to the editor: ‘Comparative dose-response study on the infusion of norepinephrine combined with intravenous ondansetron versus placebo for preventing hypotension during spinal anesthesia for cesarean section – a randomised controlled trial’
Authors: Hanliang Fan, Ting Zheng, Peng Ye, Xiaochun Zheng
Journal: International Journal of Surgery (2024)

Fan, Hanliang PhD; Zheng, Ting PhD; Ye, Peng PhD; Zheng, Xiaochun PhD Author Information
Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer
Authors: Thomas Powles, Begoña P. Valderrama, Shilpa Gupta, Jens Bedke, Eiji Kikuchi, Jean Hoffman-Censits, Gopa Iyer, Christof Vulsteke, Se Hoon Park, Sang Joon Shin, Daniel Castellano, Giuseppe Fornarini, Jian-Ri Li, Mahmut Gümüş, Nataliya Mar, Yohann Loriot, Aude Fléchon, Ignacio Duran, Alexandra Drakaki, Sujata Narayanan, Xuesong Yu, Seema Gorla, Blanca Homet Moreno, Michiel S. van der Heijden
Journal: New England Journal of Medicine (2024)

No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Download a PDF of the Research Summary. We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin–pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. A total of 886 patients underwent randomization: 442 to the enfortumab vedotin–pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin–pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin–pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin–pembrolizumab group and in 69.5% of those in the chemotherapy group. Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.) QUICK TAKE VIDEO SUMMARYEnfortumab Vedotin–Pembrolizumab in Advanced Urothelial Cancer 02:22
Development of an active-site titrant for SARS-CoV-2 main protease as an indispensable tool for evaluating enzyme kinetics
Authors: Rabea Voget, Julian Breidenbach, Tobias Claff, Alexandra Hingst, Katharina Sylvester, Christian Steinebach, Lan Phuong Vu, Renato H. Weiße, Ulrike Bartz, Norbert Sträter, Christa E. Müller, Michael Gütschow
Journal: Acta Pharmaceutica Sinica B (2024)

A titrant for the SARS-CoV-2 main protease (Mpro) was developed that enables, for the first time, the exact determination of the concentration of the enzymatically active Mpro by active-site titration. The covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme-titrant complex. Four fluorogenic substrates of Mpro, including a prototypical, internally quenched Dabcyl-EDANS peptide, were compared in terms of solubility under typical assay conditions. By exploiting the new titrant, key kinetic parameters for the Mpro-catalyzed cleavage of these substrates were determined.