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| Open AccessContinuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Nanomedicine is important in cancer therapy, but loading, drug release, and therapeutic effectiveness issues limit the translation to the clinic. Here, authors report a full-API nanodrug with an ideal API content and pH-responsive release for continuous spatiotemporal cancer therapy based on PpIX-heme-CO/Fe2+/BV-BR metabolic pathway.
- Fang Fang
- , Sa Wang
- & Jinfeng Zhang
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Article
| Open AccessIntranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants
Here the authors describe a small antibody-like protein that can prevent infection by diverse SARS-CoV-2 variants in cell culture and in mice that were intranasally treated with this inhibitor before or shortly after being exposed to the virus.
- Anna R. Mäkelä
- , Hasan Uğurlu
- & Kalle Saksela
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Article
| Open AccessClinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma
Treatment options in patients with recurrent endometrial carcinoma (EC) are limited and response rates to chemotherapy are poor. Here the authors report the results of a phase II trial of niraparib (PARP inhibitor) monotherapy or in combination with dostarlimab (anti-PD1) in recurrent EC.
- Ainhoa Madariaga
- , Swati Garg
- & Stephanie Lheureux
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Article
| Open AccessA phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity
Dorzagliatin, which acts on the glucose sensor glucokinase, is a new class of anti-diabetic medicine. Here the authors report that in a phase I open-label trial co-administration of dorzagliatin and sitagliptin (a different class of anti-diabetic medicine) does not significantly change the pharmacokinetics of either medicine in patients with type 2 diabetes and obesity.
- Li Chen
- , Jiayi Zhang
- & Gregory J. Tracey
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Article
| Open AccessTopical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions
Bacteriophage therapy is evolving as a promising approach to tackling bacterial infection, even in the case of emerging antibiotic resistance. In this work, authors present the topical application of numerous Cutibacterium acnes phage in an in vivo mouse model of acne vulgaris.
- Amit Rimon
- , Chani Rakov
- & Ronen Hazan
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Article
| Open AccessASGARD is A Single-cell Guided Pipeline to Aid Repurposing of Drugs
The full potential of single-cell RNA-sequencing applied to precision medicine has yet to be reached. Here, we propose a drug recommendation system ASGARD, which predicts drugs by considering cell clusters to address the intercellular heterogeneity within each patient.
- Bing He
- , Yao Xiao
- & Lana X. Garmire
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Perspective
| Open AccessFuture therapies for cystic fibrosis
The cystic fibrosis landscape has changed dramatically over the last few decades, with improvements in patient quality of life, prognosis and predicted survival. In part, this is related to the availability of novel CFTR modulator drugs, although prior advances in symptom-directed therapies and diagnosis had already led to substantial improvements. However, the authors, part of a national CF focused group, recognize that more needs to be done and outline their considerations on research priorities in this perspective.
- Lucy Allen
- , Lorna Allen
- & Jane C. Davies
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Article
| Open AccessSmall-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model
Idiopathic pulmonary fibrosis is a disease caused by persistent micro-injuries to the lung ultimately resulting in death. Here, the authors describe the use of a small molecule OGG1 inhibitor, TH5487, as a potent and potentially clinically relevant treatment for IPF.
- L. Tanner
- , A. B. Single
- & A. Egesten
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Article
| Open AccessAtomically dispersed golds on degradable zero-valent copper nanocubes augment oxygen driven Fenton-like reaction for effective orthotopic tumor therapy
Single-atom catalysts emerge as nanocatalytic medicine in chemodynamic therapy but suffer from inefficient kinetics for the production of reactive oxygen species because of the cell’s antioxidative mechanisms. Here, the authors employ a galvanic replacement approach to create atomically dispersed Au on degradable zero-valent Cu nanocubes for tumor treatment.
- Liu-Chun Wang
- , Li-Chan Chang
- & Chen-Sheng Yeh
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Article
| Open AccessMeteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling
Lee et al. demonstrate the protein Meteorin-like can rejuvenate the body’s immune system to enhance muscle regeneration in old age – in part by inducing the death of pro-fibrotic mesenchymal progenitor cells within the muscle.
- David E. Lee
- , Lauren K. McKay
- & James P. White
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Article
| Open AccessA multicenter phase 2 trial of camrelizumab plus famitinib for women with recurrent or metastatic cervical squamous cell carcinoma
Patients with recurrent or metastatic cervical cancer have limited therapeutic options. Here the authors report efficacy and safety of camrelizumab (anti-PD-1 antibody) in combination with famitinib (anti-angiogenic agent) in pre-treated recurrent or metastatic squamous cervical cancer.
- Lingfang Xia
- , Qi Zhou
- & Xiaohua Wu
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Article
| Open AccessTRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage
TRPCs, nonselective cation channels, are involved in cardiac contraction and conduction. Here, the authors show that Trpc1/6 deficiency or pharmacological inhibition improves endotoxemic cardiac dysfunction and prolongs survival by prominently suppressing cardiac inflammation and ER Ca2+ release.
- Na Tang
- , Wen Tian
- & Wei Cao
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Article
| Open AccessCancer cell survival depends on collagen uptake into tumor-associated stroma
Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.
- Kuo-Sheng Hsu
- , James M. Dunleavey
- & Brad St. Croix
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Article
| Open AccessSelective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers
SMARCA2 has been identified as a synthetic lethal target in SMARCA4 mutated tumors, however, homology between the two has hindered the development of selective SMARCA2 inhibitors. Here, the authors synthesize a proteolysis targeting chimera (PROTAC) capable of SMARCA2 specific degradation and demonstrate its utility in the treatment of SMARCA4 mutated tumors.
- Jennifer Cantley
- , Xiaofen Ye
- & Robert L. Yauch
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Article
| Open AccessPhase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas
Generation of TNF-α in response to chemotherapy has been associated with chemo-resistance and metastasis propagation. Here the authors show that the combination of an anti-TNF antibody and cisplatin doublet chemotherapy increases anti-tumor efficacy in lung cancer preclinical models and report the results of a phase I clinical trial of the anti-TNF-α antibody certolizumab in combination with chemotherapy in patients with stage IV lung adenocarcinomas.
- Paul K. Paik
- , Jia Luo
- & Mark G. Kris
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Article
| Open AccessThe Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.
- Maximilian Brinkhaus
- , Erwin Pannecoucke
- & Gestur Vidarsson
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Article
| Open AccessDifferential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors
Patients treated with Aurora kinase inhibitors experience dose-limiting neutropenia while other cytopenias are rare. Here, Chou et al. show that this cell-type specific side effect is partly explained by loss of drug efflux pump expression during neutrophil differentiation.
- David B. Chou
- , Brooke A. Furlong
- & Donald E. Ingber
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Article
| Open AccessA selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.
- Christiane Kofink
- , Nicole Trainor
- & William Farnaby
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Article
| Open AccessGraphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells
DNA methyltransferase 3A, a mutated gene associated with hematologic malignancies in age-related clonal haematopoiesis lacks targeted therapies. Here, the authors screen carbon nanomaterials and find graphdiyne oxide binds to mutant cells and disrupts cellular processes with a therapeutic effect in vitro and in vivo.
- Qiwei Wang
- , Ying Liu
- & Pengxu Qian
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Article
| Open AccessTopical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis
Scars are a significant problem caused by excess collagen in the skin. Here the authors develop a topical drug that reduces collagen stability and leads to improved scar appearance and stiffness in preclinical models.
- Nutan Chaudhari
- , Alison D. Findlay
- & Mark W. Fear
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Article
| Open AccessAn EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms
Chemoresistance is a main limitation for the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, the authors show that an antibody drug conjugate-like compound targeting both EGFR and HER2 overcomes gemcitabine resistance in PDAC preclinical models by mechanisms involving the tumour suppressor SMAD4.
- Hongjuan Yao
- , Wenping Song
- & Liang Li
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Comment
| Open AccessPaving the way to improve therapy for Myeloproliferative Neoplasms
Long-acting IFNα induces durable molecular responses in myeloproliferative neoplasms. Emerging studies, including Saleiro et al. recently published in Nature Communications, have identified promising candidates that may synergise with IFNα by targeting stem cell function or feedback loops that mediate treatment resistance.
- Megan Bywater
- & Steven W. Lane
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Article
| Open AccessA lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
- Brian D. Ross
- , Youngsoon Jang
- & Marcian E. Van Dort
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Article
| Open AccessConnecting omics signatures and revealing biological mechanisms with iLINCS
There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here the authors present an integrative web-based platform for analysis of omics data and signatures of cellular perturbations.
- Marcin Pilarczyk
- , Mehdi Fazel-Najafabadi
- & Mario Medvedovic
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Article
| Open AccessAn intranasal ASO therapeutic targeting SARS-CoV-2
Despite approved vaccines and anti-virals to prevent and treat SARS-CoV-2 infection, there is a need for further development of efficient antiviral therapeutic strategy. Here, Zhu et al. develop locked nucleic acid antisense oligonucleotides (LNA ASOs) targeting the 5’ leader sequence of SARS-CoV-2 RNA to interfere with replication of wildtype virus and variants of concern. Daily intranasal administration in K18-hACE2 humanized mice suppresses viral infection in lung.
- Chi Zhu
- , Justin Y. Lee
- & Anders M. Näär
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Article
| Open AccessEffectiveness of REGEN-COV antibody combination in preventing severe COVID-19 outcomes
REGEN-COV is a SARS-CoV-2 combined monoclonal antibody treatment which has been shown to be effective in randomised controlled trials. Here, the authors assess its real-world effectiveness using data from Israel during the Delta wave and find that it reduced the risk of hospitalisation, severe disease and death.
- Samah Hayek
- , Yatir Ben-shlomo
- & Alon Peretz
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Article
| Open AccessDecoding kinase-adverse event associations for small molecule kinase inhibitors
Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. Here, the authors employ a machine-learning model to examine the relationships between kinase targets and adverse events in the trials of 16 FDA-approved SMKIs.
- Xiajing Gong
- , Meng Hu
- & Liang Zhao
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Article
| Open AccessCompounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance
Several neurodegenerative diseases are characterized by the aggregation of cytoplasmic proteins. Here, the authors demonstrate that the small molecule SMER28 activates VCP, which enhances both autophagic and proteasomal clearance of aggregate-prone proteins.
- Lidia Wrobel
- , Sandra M. Hill
- & David C. Rubinsztein
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Article
| Open AccessBreaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application
Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.
- Alban Guesdon-Vennerie
- , Patrick Couvreur
- & Guillaume Bort
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Article
| Open AccessRu(II) photocages enable precise control over enzyme activity with red light
The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.
- Dmytro Havrylyuk
- , Austin C. Hachey
- & Edith C. Glazer
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Article
| Open AccessA phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes
Glucagon-like peptide-1 receptor (GLP1R) agonists are used to treat type 2 diabetes (T2D), and polyagonists targeting multiple hormone receptors are investigated as potential therapeutics for T2D. Here the authors report that IBI362 (LY3305677), a balanced once-weekly GLP-1 and glucagon receptor dual agonist, showed favourable safety and tolerability in Chinese patients with type 2 diabetes in a randomized controlled phase 1b clinical trial.
- Hongwei Jiang
- , Shuguang Pang
- & Wenying Yang
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Article
| Open AccessA supramolecular photosensitizer derived from an Arene-Ru(II) complex self-assembly for NIR activated photodynamic and photothermal therapy
Photosensitisers are used in phototherapy to kill cancer cells. Here, the authors describe an organometallic Ru(II)-arene that functions as a phtotosensitiser and produces singlet oxygen and tumour regression in mice
- Gang Xu
- , Chengwei Li
- & Shaohua Gou
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Article
| Open AccessSafety and serum distribution of anti-SARS-CoV-2 monoclonal antibody MAD0004J08 after intramuscular injection
Monoclonal antibodies (mAbs) are a potential therapeutic option for treatment of COVID-19. Here, the authors report safety and pharmacokinetics of an intramuscularly injected mAb (MAD0004J08) during the first 30 days of a phase 1 clinical study.
- Simone Lanini
- , Stefano Milleri
- & Rino Rappuoli
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Article
| Open AccessGolgi apparatus-targeted aggregation-induced emission luminogens for effective cancer photodynamic therapy
Aggregation induced emission luminogen (AIEgen) based photosensitizers (PSs) have been developed for photodynamic cancer therapy. Here the authors report a series of AIEgen-based PSs that selectively target the Golgi apparatus, showing enhanced singlet oxygen generation and photodynamic therapy performance in cancer models.
- Minglun Liu
- , Yuncong Chen
- & Zijian Guo
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Article
| Open AccessPreclinical characterization and target validation of the antimalarial pantothenamide MMV693183
Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.
- Laura E. de Vries
- , Patrick A. M. Jansen
- & Koen J. Dechering
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Article
| Open AccessUSP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity.
- Jessica K. Nelson
- , May Zaw Thin
- & Axel Behrens
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Article
| Open AccessModeling the disruption of respiratory disease clinical trials by non-pharmaceutical COVID-19 interventions
A computational mechanistic viral infection model and trial simulation advocates for adaptation of respiratory disease clinical trials whose chances of success and interpretability are being degraded under COVID-19 pandemic mitigation measures.
- Simon Arsène
- , Claire Couty
- & Alexander Kulesza
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Article
| Open AccessSelective optogenetic control of Gq signaling using human Neuropsin
Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.
- Ahmed Wagdi
- , Daniela Malan
- & Tobias Bruegmann
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Article
| Open AccessA synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens
Polymyxins are often the last therapeutic option for multidrug-resistant (MDR) bacteria, but have suboptimal safety and efficacy. Here the authors report the discovery and development of a synthetic lipopeptide with an improved safety and efficacy against top-priority MDR Gram-negative pathogens.
- Kade D. Roberts
- , Yan Zhu
- & Jian Li
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Article
| Open AccessInhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis
Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.
- Corina N. D’Alessandro-Gabazza
- , Taro Yasuma
- & Esteban C. Gabazza
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Article
| Open AccessPrecise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors
“Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Here the authors present an adaptable gene circuit to harness the CRISPRa for tumorlocalized immune activation.”
- Yafeng Wang
- , Guiquan Zhang
- & Jianghuai Liu
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Article
| Open AccessThe flavonoid corylin exhibits lifespan extension properties in mouse
Various traditional Chinese herbs and complex formulas have been suggested to exhibit lifespan extension properties. Here, the authors isolated the flavonoid corylin from Psoralea corylifolia and demonstrated its longevity properties in yeast, human cells and mouse.
- Tong-Hong Wang
- , Wei-Che Tseng
- & Chin-Chuan Chen
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Article
| Open AccessDifferent gut microbial communities correlate with efficacy of albendazole-ivermectin against soil-transmitted helminthiases
Little is known about the cause of treatment failure of soil-transmitted helminth infections. Here, the authors show that pre-treatment gut microbial community composition enables predicting treatment outcome for Trichuris trichiura and hookworm infections.
- Pierre H. H. Schneeberger
- , Morgan Gueuning
- & Jennifer Keiser
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Article
| Open AccessCaffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.
- Paul F. Lebeau
- , Jae Hyun Byun
- & Richard C. Austin
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Article
| Open AccessBone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction
Here the authors show that a monoclonal antibody against a soluble isoform of Bone Morphogenetic Protein 1 prevents cardiac cell death, reducing fibrosis and preserving cardiac function after myocardial ischemia.
- Slobodan Vukicevic
- , Andrea Colliva
- & Serena Zacchigna
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Article
| Open AccessMaximizing response to intratumoral immunotherapy in mice by tuning local retention
Understanding the pharmacokinetics of locally-injected drugs could aid in the design of immunotherapies to maximize their therapeutic effect. Here, by evaluating different IL-2 fusion proteins, the authors show that molecular weight and matrix binding affect anti-tumor immune response and report a pharmacokinetic framework to predict response to intratumoral IL-2 therapy.
- Noor Momin
- , Joseph R. Palmeri
- & K. Dane Wittrup
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Article
| Open AccessEfficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors
Bleeding complications limits the use of effective antithrombotics therapeutics. Here, the authors developed next-generation direct thrombin inhibitors with low bleeding risks as safe peri-percutaneous coronary intervention anticoagulants when used in combination with antiplatelets.
- Cho Yeow Koh
- , Norrapat Shih
- & Mark Y. Chan
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Article
| Open AccessSTAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis
Autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES) is associated with mutations in STAT3, and clinical manifestations include skeletal deformities. Here, the authors show that inactivation of STAT3 in osteoblast induces AD-HIES-like skeletal defects by impairing osteogenesis, and show that pharmacological STAT3 activation rescues the phenotype.
- Siru Zhou
- , Qinggang Dai
- & Lingyong Jiang
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Article
| Open AccessCrystal structures of the elusive Rhizobium etli l-asparaginase reveal a peculiar active site
L-asparaginases catalyse the hydrolysis of L-asparagine to L-aspartic acid and ammonia. Here, the authors present high resolution crystal structures of Rhizobium etli L-asparaginase that contains a Zn2+ binding site without a catalytic role and discuss the catalytic mechanism of the enzyme.
- Joanna I. Loch
- , Barbara Imiolczyk
- & Mariusz Jaskolski