tbuckley/cabot-search huggingface dataset:
Efficacy and safety of <scp>mammalian target of rapamycin</scp> inhibitors in systemic mastocytosis: A nationwide French pilot study
Authors: Josquin Moraly, Julien Rossignol, Claire Rouzaud, Thomas Gabas, Hassiba Bouktit, Ludovic Lhermitte, Danielle Canioni, Sylvie Fraitag, Julie Bruneau, Stéphane Barete, Felipe Suarez, Thomas Ballul, Cécile Meni, Laura Polivka, Louis Terriou, David Launay, Laurence Bouillet, Caroline Gaudy‐Marqueste, Marie Gousseff, Edwige Le Mouel, Antoine Neel, Dana Ranta, Roland Jaussaud, Philippe Guilpain, Laurent Frenzel, Julie Agopian, Patrice Dubreuil, Céline Greco, Sophie Dimicoli‐Salazar, Mael Heiblig, Clément Gourguechon, Olivier Tournilhac, Rose‐Marie Javier, Florence Castelain, Quentin Cabrera, Marie Pierre Gourin, Ewa Wierzbicka‐Hainaut, Jose Miguel Torregrosa‐Diaz, Cristina Bulai, Christian Lavigne, Cyrille Hoarau, Michel Arock, Gandhi Damaj, Olivier Lortholary, Olivier Hermine
Journal: American Journal of Hematology (2024)

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.
Secondary cerebro-cerebellar and intra-cerebellar dysfunction in cerebellar mutism syndrome
Authors: Samuel S McAfee, Giles Robinson, Amar Gajjar, Nicholas S Phillips, Silu Zhang, Ping Zou Stinnett, Ranganatha Sitaram, Darcy Raches, Heather M Conklin, Raja B Khan, Matthew A Scoggins
Journal: Neuro-Oncology (2024)

Abstract Background Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology. Methods We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury. Results CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere. Conclusions The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal gray and other critical midbrain targets.
AM‐301, a barrier‐forming nasal spray, versus saline spray in seasonal allergic rhinitis: A randomized clinical trial
Authors: Sven Becker, Sachin Deshmukh, Ferdinandus De Looze, Veronica Francardo, Jessie Lee, Anthony McGirr, Zachary Nathan, Christopher Rook, Thomas Meyer
Journal: Allergy (2024)

Abstract Rationale Saline nasal sprays are frequently used in the management of seasonal allergic rhinitis (SAR) for the cleansing and clearing of aeroallergens from the nasal cavity. Also using a drug‐free approach, AM‐301 nasal spray is forming a thin film barrier on the nasal mucosa to prevent contact with allergens, trap them, and facilitate their discharge. A clinical trial compared the efficacy, safety, and tolerability of AM‐301 and saline spray in SAR. Methods A total of 100 patients were randomized 1:1 to self‐administer AM‐301 or saline 3 × daily for 2 weeks. Primary efficacy endpoint: reduction in mean daily reflective Total Nasal Symptom Score (rTNSS). Secondary efficacy endpoints: reduction in mean instantaneous TNSS and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), global impression of efficacy. Safety and tolerability: adverse events, relief medication use, symptom‐free days, global impression of tolerability. Results AM‐301‐treated patients achieved a significantly lower rTNSS than the saline group (LS square means difference −1.1, 95% CI −1.959 to −0.241, p = .013) with improvement observed across all individual nasal symptoms. Likewise, all secondary endpoints showed statistical significance in favor of AM‐301; for example, quality of life was significantly improved overall ( p &lt; .001) as well as for each individual RQLQ domain. Both treatments showed similarly good safety and tolerability. With AM‐301, fewer patients used relief medication and more enjoyed symptom‐free days compared to saline treatment. Conclusions AM‐301 was more effective than saline in improving SAR nasal symptoms and related quality of life while offering similar tolerability, demonstrating the benefits of a barrier approach.
Cell Membrane‐Camouflaged Chitosan‐Polypyrrole Nanogels Co‐Deliver Drug and Gene for Targeted Chemotherapy and Bone Metastasis Inhibition of Prostate Cancer
Authors: Qiuyu Yu, Yue Gao, Waicong Dai, Danni Li, Lu Zhang, Meera Moydeen Abdul Hameed, Rui Guo, Min Liu, Xiangyang Shi, Xueyan Cao
Journal: Advanced Healthcare Materials (2024)

Abstract The development of functional nanoplatforms to improve the chemotherapy outcome and inhibit distal cancer cell metastasis remains an extreme challenge in cancer management. In this work, a human‐derived PC‐3 cancer cell membrane‐camouflaged chitosan‐polypyrrole nanogel (CH‐PPy NG) platform, which can be loaded with chemotherapeutic drug docetaxel (DTX) and RANK siRNA for targeted chemotherapy and gene silencing‐mediated metastasis inhibition of late‐stage prostate cancer in a mouse model, is reported. The prepared NGs with a size of 155.8 nm show good biocompatibility, pH‐responsive drug release profile, and homologous targeting specificity to cancer cells, allowing for efficient and precise drug/gene co‐delivery. Through in‐vivo antitumor treatment in a xenografted PC‐3 mouse tumor model, it is shown that such a CH‐PPy NG‐facilitated co‐delivery system allows for effective chemotherapy to slow down the tumor growth rate, and effectively inhibits the metastasis of prostate cancer to the bone via downregulation of the RANK/RANKL signaling pathway. The created CH‐Ppy NGs may be utilized as a promising platform for enhanced chemotherapy and anti‐metastasis treatment of prostate cancer.
A Pragmatic Approach to Prostate Cancer Screening
Authors: Jeffrey J. Tosoian, David F. Penson, Arul M. Chinnaiyan
Journal: JAMA (2024)

Anssi Auvinen, MD, PhD; Teuvo L. J. Tammela, MD, PhD; Tuomas Mirtti, MD, PhD; Hans Lilja, MD, PhD; Teemu Tolonen, MD, PhD; Anu Kenttämies, MD, PhD; Irina Rinta-Kiikka, MD, PhD; Terho Lehtimäki, MD, PhD; Kari Natunen, MSc; Jaakko Nevalainen, PhD; Jani Raitanen, MSc; Johanna Ronkainen, MD, PhD; Theodorus van der Kwast, MD, PhD; Jarno Riikonen, MD, PhD; Anssi Pétas, MD, PhD; Mika Matikainen, MD, PhD; Kimmo Taari, MD, PhD; Tuomas Kilpeläinen, MD, PhD; Antti S. Rannikko, MD, PhD; ProScreen Trial Investigators; Paula Kujala; Teemu Murtola; Juha Koskimäki; Antti Kaipia; Tomi Pakarainen; Suvi Marjasuo; Juha Oksala; Tuomas Saarinen; Kirsty Ijäs; Into Kiviluoto; Juhani Kosunen; Arja Pauna; Arya Yar; Pekka Ruusuvuori; Neill Booth; Jill Hannus; Sanna Huovinen; Marita Laurila; Johanna Pulkkinen; Mika Tirkkonen; Mona Hassan Al-Battat
Polymer Backpack‐Loaded Tissue Infiltrating Monocytes for Treating Cancer
Authors: Neha Kapate, Michael Dunne, Alexander P. Gottlieb, Malini Mukherji, Vineeth Chandran Suja, Supriya Prakash, Kyung Soo Park, Ninad Kumbhojkar, Jennifer L. Guerriero, Samir Mitragotri
Journal: Advanced Healthcare Materials (2024)

Abstract Adoptive cell therapies are dramatically altering the treatment landscape of cancer. However, treatment of solid tumors remains a major unmet need, in part due to limited adoptive cell infiltration into the tumor and in part due to the immunosuppressive tumor microenvironment. The heterogeneity of tumors and presence of nonresponders also call for development of antigen‐independent therapeutic approaches. Myeloid cells offer such an opportunity, given their large presence in the immunosuppressive tumor microenvironment, such as in triple negative breast cancer. However, their therapeutic utility is hindered by their phenotypic plasticity. Here, the impressive trafficking ability of adoptively transferred monocytes is leveraged into the immunosuppressive 4T1 tumor to develop an antitumor therapy. To control monocyte differentiation in the tumor microenvironment, surface‐adherent “backpacks” stably modified with interferon gamma (IFNγ) are developed to stimulate macrophage plasticity into a pro‐inflammatory, antitumor phenotype, a strategy as referred to as Ornate Polymer backpacks on Tissue Infiltrating Monocytes (OPTIMs). Treatment with OPTIMs substantially reduces tumor burden in a mouse 4T1 model and significantly increases survival. Cytokine and immune cell profiling reveal that OPTIMs remodeled the tumor microenvironment into a pro‐inflammatory state.
Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC
Authors: Yau-Tuen Chan, Junyu Wu, Yuanjun Lu, Qiucheng Li, Zixin Feng, Lin Xu, Hongchao Yuan, Tingyuan Xing, Cheng Zhang, Hor-Yue Tan, Yibin Feng, Ning Wang
Journal: Molecular Cancer (2024)

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. Materials and methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. Results CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. Conclusion Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.
Decreasing the Risk of Heart Failure in a Changing Post–Myocardial Infarction Environment
Authors: Jean Rouleau
Journal: New England Journal of Medicine (2024)

A number of therapies that have been shown to be effective in patients with chronic heart failure, including beta-blockers, mineralocorticoid receptor antagonists, and renin–angiotensin system inhibitors, have also been shown to be beneficial in patients with evidence of left ventricular systolic dysfunction, pulmonary congestion, or both after an acute myocardial infarction.1 However, the effectiveness of an agent in patients with chronic heart failure does not necessarily imply that the agent will be effective in patients who have had an acute myocardial infarction. For example, despite the effectiveness of sacubitril–valsartan in decreasing the risk of death from cardiovascular causes or hospitalization . . .
Fast, accurate ranking of engineered proteins by target-binding propensity using structure modeling
Authors: Xiaozhe Ding, Xinhong Chen, Erin E Sullivan, Timothy F Shay, Viviana Gradinaru
Journal: Molecular Therapy (2024)

Deep-learning-based methods for protein structure prediction have achieved unprecedented accuracy, yet their utility in the engineering of protein-based binders remains constrained due to a gap between the ability to predict the structures of candidate proteins and the ability toprioritize proteins by their potential to bind to a target. To bridge this gap, we introduce Automated Pairwise Peptide-Receptor Analysis for Screening Engineered proteins (APPRAISE), a method for predicting the target-binding propensity of engineered proteins. After generating structural models of engineered proteins competing for binding to a target using an established structure prediction tool such as AlphaFold-Multimer or ESMFold, APPRAISE performs a rapid (under 1 CPU second per model) scoring analysis that takes into account biophysical and geometrical constraints. As proof-of-concept cases, we demonstrate that APPRAISE can accurately classify receptor-dependent vs. receptor-independent adeno-associated viral vectors and diverse classes of engineered proteins such as miniproteins targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, nanobodies targeting a G-protein-coupled receptor, and peptides that specifically bind to transferrin receptor or programmed death-ligand 1 (PD-L1). APPRAISE is accessible through a web-based notebook interface using Google Colaboratory (https://tiny.cc/APPRAISE). With its accuracy, interpretability, and generalizability, APPRAISE promises to expand the utility of protein structure prediction and accelerate protein engineering for biomedical applications.
Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction
Authors: C Michael Gibson, Danielle Duffy, Serge Korjian, M Cecilia Bahit, Gerald Chi, John H Alexander, A Michael Lincoff, Mark Heise, Pierluigi Tricoci, Lawrence I Deckelbaum, Sojaita Jenny Mears, Jose C Nicolau, Renato D Lopes, Bela Merkely, Basil S Lewis, Jan H Cornel, Jaroslaw Trebacz, Alexander Parkhomenko, Peter Libby, Frank M Sacks, Thomas J Povsic, Marc Bonaca, Shaun G Goodman, Deepak L Bhatt, Michal Tendera, P Gabriel Steg, Paul M Ridker, Philip Aylward, John J P Kastelein, Christoph Bode, Kenneth W Mahaffey, Stephen J Nicholls, Stuart J Pocock, Roxana Mehran, Robert A Harrington
Journal: New England Journal of Medicine (2024)

Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear.
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials
Authors: Connor Prosty, Khaled Katergi, Mark Sorin, Marianne Bou Rjeily, Guillaume Butler-Laporte, Emily G. McDonald, Todd C. Lee
Journal: Clinical Microbiology and Infection (2024)

BackgroundPneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PLWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.ObjectiveTo compare the efficacy and safety of PCP prophylaxis regimens in PLWH by network meta-analysis.Data SourcesEmbase, MedLine, and CENTRAL from inception to June 21, 2023.Study Eligibility CriteriaComparative randomized controlled trials (RCTs).ParticipantsPLWH.InterventionsRegimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.Assessment of Risk of BiasCochrane risk-of-bias tool for RCTs 2.Methods of Data SynthesisTitle/abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked via a network meta-analysis. Subgroup analyses of primary vs. secondary prophylaxis, by year, and by dosage were conducted.ResultsA total of 26 RCTs, comprising 55 treatment arms involving 7516 PLWH were included. For the prevention of PCP, TMP-SMX was ranked the most favorable agent and was superior to DBRs (Risk Ratio [RR]=0.54, 95%Confidence Interval [95%CI]=0.36-0.83) and AP (RR=0.53, 95%CI=0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared to no treatment/placebo (RR=0.79, 95%CI=0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR=1.25, 95%CI=1.01-1.54) and AP (7.20, 95%CI=5.37-9.66). No significant differences in PCP prevention or mortality were detected amongst the other regimens. Findings remained consistent within subgroups.ConclusionTMP-SMX is the most effective agent for PCP prophylaxis in PLWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Integration of Pan-Cancer Cell Line and Single-Cell Transcriptomic Profiles Enables Inference of Therapeutic Vulnerabilities in Heterogeneous Tumors
Authors: Weijie Zhang, Danielle Maeser, Adam Lee, Yingbo Huang, Robert F. Gruener, Israa G. Abdelbar, Sampreeti Jena, Anand G. Patel, R. Stephanie Huang
Journal: Cancer Research (2024)

Single-cell RNA sequencing (scRNA-seq) greatly advanced the understanding of intratumoral heterogeneity by identifying distinct cancer cell subpopulations. However, translating biological differences into treatment strategies is challenging due to a lack of tools to facilitate efficient drug discovery that tackles heterogeneous tumors. Developing such approaches requires accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we developed a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening data sets. This method achieved high accuracy in separating cells into their correct cellular drug response statuses. In three distinct prospective tests covering different diseases (rhabdomyosarcoma, pancreatic ductal adenocarcinoma, and castration-resistant prostate cancer), the predicted results using scIDUC were accurate and mirrored biological expectations. In the first two tests, the framework identified drugs for cell subpopulations that were resistant to standard-of-care (SOC) therapies due to intrinsic resistance or tumor microenvironmental effects, and the results showed high consistency with experimental findings from the original studies. In the third test using newly generated SOC therapy-resistant cell lines, scIDUC identified efficacious drugs for the resistant line, and the predictions were validated with in vitro experiments. Together, this study demonstrates the potential of scIDUC to quickly translate scRNA-seq data into drug responses for individual cells, displaying the potential as a tool to improve the treatment of heterogenous tumors.