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| Open AccessSingle-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia
Single-cell RNA-seq could help identify acute myeloid leukaemia (AML) patients at high risk of relapse after therapy. Here, the authors use single-cell RNA-seq from paediatric AML samples to construct a 7-gene signature that can identify malignant cells at diagnosis, which are distinctly associated with relapse or complete remission.
- Hope Mumme
- , Beena E. Thomas
- & Manoj Bhasin
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Article
| Open AccessMyoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy
Researchers have been working on radiosensitizers to improve radiotherapy efficacy. Here the authors generate gadolinium nanotexaphyrins (Gd-NTs) that self-assemble and further load it with myoglobulin to relieve hypoxia, improve radiosensitization effects of Gd-coordinated Texaphyrin, and suppress tumor recurrence.
- Xiaotu Ma
- , Xiaolong Liang
- & Fan Wang
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Article
| Open AccessUncovering the complex relationship between balding, testosterone and skin cancers in men
Male-pattern baldness (MPB) is related to dysregulation of androgens. Here, authors show that MPB (but not androgens) is associated with skin cancer risk, particularly in the scalp region, suggesting that sun exposure, rather than androgens, is the main driver.
- Jue-Sheng Ong
- , Mathias Seviiri
- & Matthew H. Law
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Article
| Open AccessRepressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress
Chronic stress can promote breast cancer progression. Here the authors show that a reduction in the levels of Blautia and its metabolite acetate contributes to chronic stress-promoted breast cancer progression, associated with decreased CD8 + T cell anti-tumor immunity.
- Ling Ye
- , Yuanlong Hou
- & Haiping Hao
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Article
| Open AccessPARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models
IFNγ signalling has been described as a potential driver of resistance to immune checkpoint blockade (ICB) therapy. Here the authors report that PARP14 is upregulated in chronic IFNγ-treated cancer cell models and that its inhibition restores response to anti-PD-1 therapy in preclinical cancer models.
- Chun Wai Wong
- , Christos Evangelou
- & Adam F. L. Hurlstone
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Article
| Open AccessGenome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
| Open AccessEvolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients
The identification of cancer type-specific evolutionary signatures could be used for patient stratification. Here, the authors develop a method, ASCETIC, that utilises bulk and single-cell sequencing data and identifies evolutionary signatures associated with different prognostic outcomes across different cancer types.
- Diletta Fontana
- , Ilaria Crespiatico
- & Daniele Ramazzotti
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Article
| Open AccessDeep learning-enabled realistic virtual histology with ultraviolet photoacoustic remote sensing microscopy
Oncologic tumour resection is not fully accurate. Here the authors report a label-free virtual histological imaging method based on a non-contact, reflection-mode ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent GAN.
- Matthew T. Martell
- , Nathaniel J. M. Haven
- & Roger J. Zemp
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Article
| Open AccessGuadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial
The NIBIT-M4 trial was designed to assess the safety, biological and clinical activity of anti-CTLA4 ipilimumab with the DNA hypomethylating agent guadecitabine in advanced melanoma patients. Here the authors report the five-year follow-up results of the trial and an integrated multi-omics analysis of pre- and on-treatment tumor biopsies.
- Teresa Maria Rosaria Noviello
- , Anna Maria Di Giacomo
- & Michele Ceccarelli
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Article
| Open AccessDisentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study
Multiple myeloma (MM) is a haematological malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS). Here, the authors use a mechanistic model fitted to surveillance data from the United States to investigate whether variation in MM is best explained by incidence of MGUS or rate of progression to MM.
- John H. Huber
- , Mengmeng Ji
- & Su-Hsin Chang
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Article
| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessActivation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity
Aberrant G protein-coupled receptor (GPCR) signaling has been associated with tumor progression and metastasis. Here the authors show that depletion of the GPCR melanocortin-1 receptor (MC1R) in melanoma cells is associated with enhanced T cell infiltration and anti-tumor immune responses.
- Yazhong Cui
- , Yang Miao
- & Ting Han
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Article
| Open AccessStromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
Breast cancer patients of African ancestry face worse clinical outcomes, so understanding related cellular and molecular features remains critical. Here, the authors show that stromal cells that are particularly enriched in breast cancer patients with African ancestry can trans-differentiate into different lineages and can be transformed into metaplastic carcinoma.
- Brijesh Kumar
- , Aditi S. Khatpe
- & Harikrishna Nakshatri
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Article
| Open AccessCell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy
Tumor associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment, including hepatocellular carcinoma (HCC). Here the authors show that macrophage-derived microparticles modified with a M2-like macrophage targeting peptide and loaded with the TLR7/8 agonist resiquimod reprogram TAMs from immunosuppressive to inflammatory, promoting anti-tumor immune responses in preclinical HCC models.
- Xiaoqiong Zhang
- , Zhaohan Wei
- & Lu Gan
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Article
| Open AccessMYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer
Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.
- Zinab O. Doha
- , Xiaoyan Wang
- & Rosalie C. Sears
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| Open AccessFasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
The use of immune checkpoint inhibitors is associated with a wide range of side effects. Here the authors explore the use of periodic cycles of a diet that mimics fasting and see reduction in side effects caused by a range of immune checkpoint blockade antibodies in a preclinical cancer model.
- S. Cortellino
- , V. Quagliariello
- & V. D. Longo
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Article
| Open AccessTriplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4
Even in patients who are initially sensitive, patients treated with platinum-based therapies often go on to relapse and have limited treatment options. Here, the authors report the efficacy and safety of a phase II trial investigating olaparib, pembrolizumab and bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer.
- Yoo-Na Kim
- , Boram Park
- & Jung-Yun Lee
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Article
| Open AccessThe mutational landscape of the adult healthy parous and nulliparous human breast
While many tissues have been investigated for natural somatic mutations, human breast tissue has not been well studied. Here, the authors characterize somatic mutations in human breast tissue, finding effects of age and parity.
- Biancastella Cereser
- , Angela Yiu
- & Justin Stebbing
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Article
| Open AccessAtezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open AccessLow-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models
Although CAR T therapy has greatly improved the therapeutic prospects for haematological malignancies, it is not yet widely used for solid tumors, such as prostate cancer. Here, using prostate cancer patient-derived xenografts, the authors demonstrate the efficacy of CAR T cells specific for Lewis Y antigen when combined with low-dose carboplatin.
- L. H. Porter
- , J. J. Zhu
- & G. P. Risbridger
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Article
| Open AccessAcquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open AccessDNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability
Genomic instability can induce an anti-tumour immune response via activation of the cGAS-STING pathway following the formation of micronuclei (MN). Here, the authors identify a role for DNAJA2 in maintenance of chromosomal segregation. Loss of which increased MN formation and cGAS-STING pathway activation, increasing response to immune checkpoint blockade.
- Yaping Huang
- , Changzheng Lu
- & Guo-Min Li
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Article
| Open AccessCoordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype
Multiple studies have characterised the tumour microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) using single-cell RNA-seq. Here, the authors integrate the data from such single-cell studies to provide a cohesive analysis of the PDAC TME, revealing cell types and interactions that are associated with PDAC phenotypes.
- Ki Oh
- , Yun Jae Yoo
- & Richard A. Moffitt
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Article
| Open AccessMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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Article
| Open AccessImmune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice
Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.
- Marta Isidro-Hernández
- , Ana Casado-García
- & Isidro Sánchez-García
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| Open AccessAcquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro
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Article
| Open AccessBiosynthesized gold nanoparticles that activate Toll-like receptors and elicit localized light-converting hyperthermia for pleiotropic tumor immunoregulation
Bacteria have been exploited as a potential bio-factory for the synthesis of nanoparticles. Here the authors report the generation of gold nanoparticles from Escherichia coli and show their application for eliciting hyperthermia and anti-tumor immune responses in preclinical cancer models.
- Hao Qin
- , Yang Chen
- & Ruifang Zhao
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Article
| Open AccessBiology-guided deep learning predicts prognosis and cancer immunotherapy response
The clinical application of data-driven deep learning models remains challenging. Here, a biology-guided deep learning approach allows the simultaneous prediction of the tumour immune and stromal microenvironment status as well as treatment outcomes from medical images in gastric cancer.
- Yuming Jiang
- , Zhicheng Zhang
- & Ruijiang Li
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Article
| Open AccessAndrogen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects
The prediction of mortality due to prostate cancer remains challenging. Here, the authors perform trans-ancestry metaanalysis with a focus on binding sites of the androgen receptor and develop a polygenic risk score.
- Shuji Ito
- , Xiaoxi Liu
- & Chikashi Terao
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Article
| Open AccessSingle cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
The metastatic tumour microenvironment in pancreatic ductal adenocarcinoma (PDAC) remains to be explored. Here, the authors perform single cell RNA sequencing analysis for synchronously resected PDAC primary tumours and matched liver metastases and find differences in cellular composition.
- Shu Zhang
- , Wen Fang
- & Ying Lv
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Article
| Open AccessMolecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer
HER2-low breast cancer has recently been defined as a potential subtype for sensitivity to novel antibody-drug conjugates. Here, the authors analyse a multiomics cohort of 434 HER2-low patients and find an altered molecular status compared to other subtypes and the interpatient heterogeneity within this subtype.
- Lei-Jie Dai
- , Ding Ma
- & Zhi-Ming Shao
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Article
| Open AccessDesmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
Tumor stroma is a key component of the immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Here, in preclinical PDAC models, the authors show that depletion of FAP-expressing cancer associated fibroblasts with FAP-targeted CAR T cells results in a loss of the integrity of the desmoplastic matrix, rendering tumors more susceptible to sequential treatment with mesothelin-targeted CAR-T cells.
- Zebin Xiao
- , Leslie Todd
- & Ellen Puré
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Article
| Open AccessEpigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics
The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.
- Ravinder K. Bahia
- , Xiaoguang Hao
- & Samuel Weiss
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Article
| Open AccessPhase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
Here, Heitmann et al. report results from a Phase I/II trial evaluating CoVac-1, a peptide-based T-cell activator, in patients with B-cell deficiency, demonstrating potent induction of SARS-CoV-2-specific T-cell responses along with a favorable safety profile.
- Jonas S. Heitmann
- , Claudia Tandler
- & Juliane S. Walz
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Article
| Open AccessResolving the spatial architecture of myeloma and its microenvironment at the single-cell level
The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.
- Lukas John
- , Alexandra M. Poos
- & Niels Weinhold
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Article
| Open AccessGenomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.
- Anna Skakodub
- , Henry Walch
- & Luke R. G. Pike
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Article
| Open AccessEGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial
By using tumor-specific fluorescent tracers, fluorescence molecular imaging (FMI) can be used to visualize tumor tissues with high specificity. Here the authors report the results of a phase II trial to evaluate the diagnostic accuracy of an EGFR-targeted FMI for intraoperative margin assessment in patients with oral squamous cell carcinoma.
- Jaron G. de Wit
- , Jasper Vonk
- & Max J. H. Witjes
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Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
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Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
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Article
| Open AccessCopy number architectures define treatment-mediated selection of lethal prostate cancer clones
The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.
- A. M. Mahedi Hasan
- , Paolo Cremaschi
- & Gerhardt Attard
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Article
| Open AccessCombined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors
It has been previously shown that combining immune checkpoint inhibitors with TGFβ blockade potentiates anti-tumor immune responses. Here the authors show that, in an immune excluded preclinical tumor model, combining therapeutic anti-PD-L1 with anti-TGFβ treatment promotes expansion and differentiation of stem-cell like CD8 + T cells.
- Alessandra Castiglioni
- , Yagai Yang
- & Sören Müller
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Article
| Open AccessTargeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
KRAS mutations are associated with an immunosuppressive microenvironment in patients with colorectal cancer (CRC). Here the authors show that knockout of SLC25A22, a mitochondrial glutamate carrier, reverts KRAS-mediated immunosuppression in preclinical CRC models, by suppressing CXCL1 production and impairing MDSC recruitment.
- Qiming Zhou
- , Yao Peng
- & Chi Chun Wong
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Article
| Open AccessNeoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study
Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.
- Dongliang Bian
- , Liangdong Sun
- & Peng Zhang
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Article
| Open AccessCombining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma
Magnetic Resonance Imaging (MRI) is normally used to define glioma boundaries for biopsies, surgery and radiotherapy. Here, the authors show that adding FET/PET imaging improves accuracy to define malignant areas of contrast-enhancing gliomas.
- Maciej Harat
- , Józefina Rakowska
- & Bogdan Małkowski
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Article
| Open AccessA phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors
The majority of cancer patients do not respond to single agent immune checkpoint blockade and several combinatorial approaches have now been tested. Here the authors report the results of a phase I dose escalation trial of nivolumab (anti-PD1) in combination with IFN-γ in patients with advanced solid tumors.
- Matthew Zibelman
- , Alexander W. MacFarlane IV
- & Elizabeth R. Plimack
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Article
| Open AccessEnrichment and sensing tumor cells by embedded immunomodulatory DNA hydrogel to inhibit postoperative tumor recurrence
Decreased survival after surgery is often associated to post-operative tumor recurrence and metastasis. Here the authors describe a DNA hydrogel enabling monitoring of tumor recurrence and spatiotemporally controlled photodynamic immunotherapy to prevent post-operative tumor recurrence and metastasis.
- Danyu Wang
- , Jingwen Liu
- & Kaixiang Zhang
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Article
| Open AccessSafety and anti-tumour activity of the IgE antibody MOv18 in patients with advanced solid tumours expressing folate receptor-alpha: a phase I trial
IgE antibodies have shown anti-tumor activity, even superior to IgG, in preclinical models. However, all monoclonal antibodies in clinical use for cancer therapy are members of the IgG class. Here the authors report the results of a phase I clinical trial of a chimeric monoclonal IgE antibody, specific for the folate receptor-alpha, in patients with advanced solid cancer.
- James Spicer
- , Bristi Basu
- & Sophia N. Karagiannis
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Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
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Article
| Open AccessDose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
- R. C. Coombes
- , Sacha Howell
- & Matthew G. Krebs