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| Open AccessHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.
- Xiaoyan Xu
- , Tingxue Xie
- & Hongguang Xia
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessBone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).
- Moritz Binder
- , Raphael E. Szalat
- & Nikhil C. Munshi
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Article
| Open AccessIdentifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank
Plasma proteins are a potential diagnostic tool to detect multiple diseases, including cancer. Here, the authors leverage multi-omics data to identify 1,463 proteins associated with 19 common cancers in UK Biobank participants. Reviewer Recognition:
- Keren Papier
- , Joshua R. Atkins
- & Ruth C. Travis
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Article
| Open AccessCEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials
Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.
- Neil H. Segal
- , Ignacio Melero
- & Guillem Argilés
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Article
| Open AccessDysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation
The impact of obesity on cancer remains insufficiently explored. Here the authors show that in mouse models, dysfunctional adipocytes exhibit low levels of BECN1 which induce YAP/TAZ activity to promote breast and colorectal tumor progression.
- Yaechan Song
- , Heeju Na
- & Han-Woong Lee
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Article
| Open AccessdsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly.
- Joana S. Rodrigues
- , Miguel Chenlo
- & Clara V. Alvarez
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Article
| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park
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Article
| Open AccessVOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology
While machine learning platforms can improve the assessment of Hematoxylin & Eosin (H&E) stained-tumour tissue images, current models typically require manual cell-type annotations in training. Here, the authors develop VOLTA, a self-supervised machine learning framework to improve cell representation learning in H&E images based on the cells environment
- Ramin Nakhli
- , Katherine Rich
- & Ali Bashashati
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Article
| Open AccessPretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation
Natural killer (NK) cells are assessed for various therapies, but sub-optimal cryopreservation dampens their clinical feasibility. Here the authors show that pretreating human NK cells with IL-15/IL-18 prior to cryopreservation improves NK cell post-thaw viability and functions, potentially via anti-apoptosis gene induction and granzyme B degranulation.
- Abdulla Berjis
- , Deeksha Muthumani
- & Neil C. Sheppard
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Article
| Open AccessTLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial
Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.
- Richard G. Everson
- , Willy Hugo
- & Robert M. Prins
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Article
| Open AccessFGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
FGFR inhibitors (FGFRi) benefit patients with FGFR2-fusion positive intrahepatic cholangiocarcinoma (ICC) but depth and duration of response is often limited. Here, the authors demonstrate that oncogenic FGFR2 signaling promotes a glycolytic phenotype, which is blocked by FGFRi, resulting in a targetable dependence on mitochondrial metabolism.
- Yuanli Zhen
- , Kai Liu
- & Nabeel Bardeesy
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Article
| Open AccessLongitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer
Although metabolic reprogramming within the tumour microenvironment (TME) has been reported in breast cancer, whether and how this evolves during treatment remains unclear. Here, the authors use multiple ‘omic’ analyses to examine this question in patients with breast cancer undergoing neoadjuvant chemotherapy.
- Kang Wang
- , Ioannis Zerdes
- & Theodoros Foukakis
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Article
| Open AccessA multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma
Correct diagnosis of primary central nervous system lymphoma is key in determining treatment, however, this depends on pathology analysis. Here, the authors develop a deep learning method to diagnose primary nervous system lymphoma from stained whole-slide images.
- Xinke Zhang
- , Zihan Zhao
- & Muyan Cai
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Article
| Open AccessCD74 supports accumulation and function of regulatory T cells in tumors
CD74, the MHC class II invariant chain, was thought to be mainly expressed by antigen presenting cells. Here the authors report that CD74 is overexpressed by human tumor infiltrating regulatory T cells (Tregs) and that its loss affects Treg accumulation and function in tumors.
- Elisa Bonnin
- , Maria Rodrigo Riestra
- & Eliane Piaggio
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Article
| Open AccessResponse of treatment-naive brain metastases to stereotactic radiosurgery
Current guidelines recommend stereotactic radiosurgery for brain metastasis measuring less than 3 cm but there is significant variability in outcomes following treatment. This study shows that in treatment naïve brain metastasis less than 3 cm, intrinsic biological differences across multiple histologies may influence response to stereotactic radiosurgery.
- Chibawanye I. Ene
- , Christina Abi Faraj
- & Raymond E. Sawaya
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Article
| Open AccessMultimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions
Esophageal squamous cell carcinoma is most commonly detected at a late stage, which limits survival and treatment options. Here, the authors utilise whole genome bisulfite sequencing to create a cfDNA framework to detect cfDNA methylation, copy number variants and fragmentation.
- Jiaqi Liu
- , Lijun Dai
- & Zhihua Liu
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Article
| Open AccessFn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity
The potential of oncolytic virus (OV) for cancer therapy is limited by the efficiency of immune response induced. Here the authors show that HSV-1-based OV is capable of triggering ZBP1-mediated PANoptosis resulting in effective tumor growth inhibition.
- Shuo Wang
- , An Song
- & Zhi-Jun Sun
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Article
| Open AccessPrimary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma
Cutaneous squamous cell carcinoma is more frequent and more aggressive in the organ transplanted and represent a therapeutic challenge due to the ongoing transplantrelated immune suppression. Here, the authors present a case report of a patient whose T cell responses were successfully strengthened via primary prophylactic therapy with mammalian target of rapamycin inhibition and intra-lesion injection of the oncolytic herpesvirus T-VEC.
- Victor Joo
- , Karim Abdelhamid
- & Michel Obeid
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Article
| Open AccessMacrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
- Meirion Raymant
- , Yuliana Astuti
- & Michael C. Schmid
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Article
| Open AccessAn individualized protein-based prognostic model to stratify pediatric patients with papillary thyroid carcinoma
Papillary thyroid carcinoma has a heterogenous outcome, particularly in paediatric patients. Here, the authors utilise machine learning to create a protein-based prognostic model to predict recurrence risk.
- Zhihong Wang
- , He Wang
- & Yaoting Sun
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Article
| Open AccessCAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition
It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.
- Irene Andreu-Saumell
- , Alba Rodriguez-Garcia
- & Sonia Guedan
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Article
| Open AccessLineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation
This study identifies temporal and coordinately regulated cell-state-specific super-enhancers driving the expression of transcription factors that control circuits needed to switch neuroblastoma tumor cells from self-renewal to differentiation.
- Deblina Banerjee
- , Sukriti Bagchi
- & Carol J. Thiele
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Article
| Open AccessThe gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids
Here, using murine models of prostate cancer, the authors show that reduced fecal microbiota alpha-diversity correlates with increased prostate tumor burden, and that Omega-3 prebiotic supplementation reduces prostate cancer up-grading associated with a reduction of gut Ruminococcaceae and fecal butyrate levels.
- Gabriel Lachance
- , Karine Robitaille
- & Vincent Fradet
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Article
| Open AccessBispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial
CAR-T cell therapies targeting BCMA have shown promising responses in patients with multiple myeloma (MM), however primary resistance and relapse are frequently observed. Here the authors report the results of a phase I//II study of bispecific CAR T-cells targeting BCMA and CD19 in relapsed/refractory MM.
- Ming Shi
- , Jiaojiao Wang
- & Jiang Cao
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Article
| Open AccessNeoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
| Open AccessUveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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Article
| Open AccessThe physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessEnhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights
Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.
- Sheeba J. Sujit
- , Muhammad Aminu
- & Jia Wu
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Comment
| Open AccessReporting outcome comparisons by sex in oncology clinical trials
Many aspects of human health and disease are influenced by sex as a biological variable and gender as a social construct. A recent study from Nature Communications reported the landscape of outcome comparisions by sex in oncology clinical trials, highlighting the need for a more thorough reporting of sex differences.
- Guo Zhao
- , Yuning Wang
- & Ning Li
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Article
| Open AccessMolecular patterns of resistance to immune checkpoint blockade in melanoma
A large fraction of patients with melanoma still does not benefit from immune checkpoint blockade, associated with both primary and acquired resistance. Here the authors report genetic and immunological patterns of resistance in patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy.
- Martin Lauss
- , Bengt Phung
- & Göran Jönsson
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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Article
| Open AccessGadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Different gene mutations have been reported as drivers for myeloproliferative neoplasms (MPN). Here, the authors show that Gadd45g insufficiency induces MPN in mouse models and associates with MPN in patients.
- Peiwen Zhang
- , Na You
- & Xiaotong Ma
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Article
| Open AccessConcomitant medication, comorbidity and survival in patients with breast cancer
Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this study, the authors utilized a nationwide database of breast cancer patients to estimate the association between frequently used drugs taken prior to diagnosis and breast cancer prognosis. And they identified 16 drugs associated with breast cancer outcomes.
- Elise Dumas
- , Beatriz Grandal Rejo
- & Anne-Sophie Hamy
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Article
| Open AccessA population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk
High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. Here, the authors show the association between longitudinal changes of HDL-C and risk of gastrointestinal cancer in a patients.
- Su Youn Nam
- , Junwoo Jo
- & Chang-Min Cho
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Article
| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Article
| Open AccessMesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
- Cristiana Spinelli
- , Lata Adnani
- & Janusz Rak
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Article
| Open AccessTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Cancer cells can employ aberrant glycosylation patterns to evade the host immune response. Here the authors report that inhibition of branched N-glycans sensitizes homologous recombination (HR)-proficient, but not HR-deficient, epithelial ovarian cancer to immune checkpoint inhibitors.
- Hao Nie
- , Pratima Saini
- & Rugang Zhang
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Article
| Open AccessSystematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.
- Yang Zhou
- , Partho Sarothi Ray
- & Andreas E. Kulozik
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Article
| Open AccessDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessCombination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial
Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.
- Changhee Park
- , Ho Sup Lee
- & Youngil Koh
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Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessDevelopment and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis
Ovarian cancer diagnosis can be complex and can be improved through integration of multimodal data. Here, the authors develop OvcaFinder which can significantly outperform clinical models using ultrasound images and known clinical characteristics.
- Huiling Xiang
- , Yongjie Xiao
- & Hao Chen
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Article
| Open AccessPhenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers
Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.
- Molly Went
- , Amit Sud
- & Richard Houlston
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Article
| Open AccessOutcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
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Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari