Featured
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| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Article
| Open AccessThe EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Eukaryotic initiation translation factor 3 subunit h (EIF3H) possesses an alternative “moonlighting” function of deubiquitinase, while its role in colorectal carcinogenesis remains to be explored. Here the authors show that EIF3H deubiquitinates and stabilizes HAX1, which enhances RAF-MEK-ERK signaling to promote colorectal tumor growth and metastasis.
- Huilin Jin
- , Xiaoling Huang
- & Mong-Hong Lee
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Article
| Open AccessTertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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Article
| Open AccessAberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open AccessGAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open AccessOxygen-independent organic photosensitizer with ultralow-power NIR photoexcitation for tumor-specific photodynamic therapy
Conventional photodynamic therapy (PDT) is hindered by oxygen-dependent photosensitization pathways and high-power-density photoexcitation. Here, the authors develop polymer-based organic photosensitizers (PSs) through PS skeleton design and side-chain engineering to allow tumor-specific PDT under oxygen-free conditions using ultralow-power 808 nm photoexcitation.
- Yufu Tang
- , Yuanyuan Li
- & Bin Liu
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Article
| Open AccessMetabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.
- Marina T. Broz
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessReciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open AccessCombined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.
- Ashenafi Bulle
- , Peng Liu
- & Kian-Huat Lim
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Article
| Open AccessAllele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells
Quantifying the impact of copy-number alterations (CNAs) on gene expression at the subclone level in cancer remains a challenge. Here, the authors develop TreeAlign, a method that integrates sample-matched single-cell DNA and RNA sequencing data to infer the impact of CNAs on subclonal gene expression.
- Hongyu Shi
- , Marc J. Williams
- & Sohrab P. Shah
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Article
| Open AccessThe bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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Article
| Open AccessPolyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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Article
| Open AccessNMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection
Metabolic changes often occur during the early stages of cancer development. Here, the authors develop metabolomics signatures from tissues, pre- and post-operative sera and urines in esophageal squamous cell carcinoma, which may aid in early diagnosis.
- Yan Zhao
- , Changchun Ma
- & Yan Lin
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Article
| Open AccessOncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessThe evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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Article
| Open AccessHematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
Secondary resistance to venetoclax in patients with myelodysplastic syndromes (MDS) is not completely elucidated. Here, the authors show that haematopoietic stem cells with a granulo-monocytic differentiation transcriptional state drive secondary resistance to venetoclax in MDS patients who previously failed hypomethylating agent therapy.
- Juan Jose Rodriguez-Sevilla
- , Irene Ganan-Gomez
- & Simona Colla
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Article
| Open AccessSenescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment
Recent evidence suggests that senescence can negatively affect immune cell function. Here the authors show that accumulation of senescent cells in tumor-bearing mice previously exposed to irradiation or chemotherapy is associated with resistance to immune checkpoint inhibitors, associated with an exacerbated immunosuppressive profile of tumor-infiltrating myeloid cells.
- Damien Maggiorani
- , Oanh Le
- & Christian Beauséjour
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Article
| Open AccessMesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer. This study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their substrate selectivity.
- Ambrocio Sanchez
- , Pedro Ortega
- & Rémi Buisson
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Article
| Open AccessTherapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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Article
| Open AccessLong noncoding RNA Malat1 protects against osteoporosis and bone metastasis
MALAT1 is a long non-coding RNA that is known to suppress breast cancer lung metastasis. Here the authors show that MALAT1 is downregulated during osteoclastogenesis and its loss derepresses Tead3, promoting Nfatc1-mediated osteoclast differentiation and enhancing bone metastasis.
- Yang Zhao
- , Jingyuan Ning
- & Li Ma
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Article
| Open AccessProinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy
Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.
- Yanan Xue
- , Xiaojie Yan
- & Yuan Ping
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Article
| Open AccessImmunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides
Abnormally expressed circular RNAs (circRNAs) represent an unexplored source of tumor-specific antigens in cancer. Here, the authors developed an immunopeptidomics workflow to identify human leukocyte antigen bound peptides specifically derived from the potential translation of these transcripts.
- Humberto J. Ferreira
- , Brian J. Stevenson
- & Michal Bassani-Sternberg
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Article
| Open AccessTranslation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Here the authors uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in leukemia. The work pointed to the potential of targeting the posttranscriptional circuitry via CNOT3 as a therapeutic vulnerability in acute myeloid leukemia.
- Maryam Ghashghaei
- , Yilin Liu
- & Ly P. Vu
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Article
| Open AccessDendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.
- Lucía López
- , Luciano Gastón Morosi
- & Federica Benvenuti
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Article
| Open AccessPRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
CDK4/6 inhibitors have improved outcomes for patients with ER+ breast cancer, however, those with loss of RB1 function often fail to respond. Here, the authors identify a vulnerability of ER + /RB1- breast cancer on PRMT5 and via dual blockade of ER and PRMT5 therapeutically target this in patient-derived xenograft models.
- Chang-Ching Lin
- , Tsung-Cheng Chang
- & Carlos L. Arteaga
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Article
| Open AccessHLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice
The use of TCR engineered T cells holds promise for treatment of tumours, but is limited by awareness of clinically effective TCR molecules. Here the authors identify an MHC II restricted TCR that targets viral E7 of human papillomavirus type 18 and show effectivity in a murine model of solid tumour.
- Jianting Long
- , Xihe Chen
- & Yanyan Han
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Article
| Open AccessCell type signatures in cell-free DNA fragmentation profiles reveal disease biology
Deconvolution of cfDNA fragmentation benefits from cell type-specific reference data. Here, the authors create a disease agnostic cfDNA cell type of origin analysis and show it can successfully predict cell types of origin from plasma samples.
- Kate E. Stanley
- , Tatjana Jatsenko
- & Joris Robert Vermeesch
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Article
| Open AccessIdentifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer. Here, authors develop a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation programs, showing that SMARCB1 restricts differentiation, and nominating other regulators with therapeutic potential.
- Sandor Spisak
- , David Chen
- & Nilay S. Sethi
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Article
| Open AccessDelivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models
Therapeutic options for pancreatic ductal adenocarcinoma (PDAC) are limited. Here the authors report the characterization of a CEACAM6-targeting antibody drug conjugate loaded with a BET protein degrader, showing antitumour activity in PDAC preclinical models.
- Youya Nakazawa
- , Masayuki Miyano
- & Akihito Machinaga
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Article
| Open AccessNeoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial
Neoadjuvant chemo-immunotherapy represents a therapeutic option for resectable head and neck squamous cell carcinoma (HNSCC). Here the authors report the results of a phase II trial of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced HNSCC.
- Di Wu
- , Yong Li
- & Xuekui Liu
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Article
| Open AccessThe phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial
Bavituximab is a genetically engineered IgG1 chimeric antibody that targets phosphatidylserine. Here the authors report the results of a single-arm phase 2 trial of bavituximab in combination with pembrolizumab (anti-PD1) for patients with unresectable hepatocellular carcinoma.
- David Hsiehchen
- , Muhammad S. Beg
- & Adam C. Yopp
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Article
| Open AccessEnabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| Open AccessMi-2β promotes immune evasion in melanoma by activating EZH2 methylation
Mi-2β is an enzyme of the chromodomain helicase DNA family with roles in chromatin assembly, genomic stability and gene repression. Here the authors report that Mi-2β promotes immune evasion by activating EZH2 methylation and that loss of Mi-2β or its inhibition promote anti-tumor immune responses in preclinical melanoma models.
- Cang Li
- , Zhengyu Wang
- & Rutao Cui
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Article
| Open AccessNeoadjuvant–adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial
Previously, the authors reported the primary analysis of a phase III randomized control trial investigating dual HER2 blockade in HER2-positive early/locally advanced breast cancer. Here, the authors report the long-term efficacy and safety analysis of this trial.
- Liang Huang
- , Da Pang
- & Zhimin Shao
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Article
| Open AccessSpatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma
Macrophages are abundant in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Here, the authors use spatial transcriptomics to characterize macrophages in DLBCL and reactive lymphoid tissues, and propose six spatially-derived macrophage signatures that are associated with features like cell of origin and clinical outcomes.
- Min Liu
- , Giorgio Bertolazzi
- & Anand D. Jeyasekharan
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Article
| Open AccessStructural basis for self-discrimination by neoantigen-specific TCRs
Neoantigen-specific T cells recognise neoantigen-MHC complexes on target tumour cells. Here, the authors describe a molecular mechanism by which the neoantigen Hsf2 p.K72N is recognised by a corresponding high affinity Hsf2 p.K72N-reactive T cell receptor, 47BE7, from the mouse melanoma line B16F10.
- John P. Finnigan
- , Jenna H. Newman
- & Nina Bhardwaj
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Article
| Open AccessAcidity-activatable upconversion afterglow luminescence cocktail nanoparticles for ultrasensitive in vivo imaging
Activatable afterglow luminescence nanoprobes reduce unspecific signals and improve imaging fidelity, but their utility is limited by a requisition of donor-acceptor distance (>10 nm) in common biomarker-activatable designs. Here, the authors address this issue by developing organic afterglow luminescence cocktail nanoparticles for acid-activatable upconversion afterglow luminescence imaging.
- Yue Jiang
- , Min Zhao
- & Qingqing Miao
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Article
| Open AccessGRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer
GRB2 is known for its role in Receptor Tyrosine Kinase and RAS signaling. Here the authors unveil a GRB2 function and mechanism for DNA replication fork protection. GRB2 alleviates oncogenic replication stress, and in doing so, averts cancer immune destruction by inhibiting cGAS/STING and pro-inflammatory cytokine production.
- Zu Ye
- , Shengfeng Xu
- & Zamal Ahmed
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Article
| Open AccessComprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation
The benefit of hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer remains controversial. Here, the authors perform a multi-omics analysis of hyperthermia-treated ovarian cancer cells, show that CDK1 becomes hyperactivated and regulates signalling upon hyperthermia, and identify WEE1 as a synergistic therapeutic target for hyperthermic intraperitoneal therapy.
- Xiaohang Yang
- , Xingyuan Hu
- & Chaoyang Sun
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Article
| Open AccessA SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
POU2AF2 is a co-activator of POU2F3 in normal and neoplastic tuft cells, such as small cell lung cancer. Here, the authors report that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements.
- Aileen Szczepanski
- , Natsumi Tsuboyama
- & Lu Wang
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Article
| Open AccessCRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
The molecular basis of the metastatic disease in prostate cancer remains poorly characterised. Here, the authors investigate the interaction of tumor suppressor and epigenetic factor genes and highlight the role of Kmt2c deficiency in facilitating lung metastasis.
- Huiqiang Cai
- , Bin Zhang
- & Martin K. Thomsen
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Article
| Open AccessEvolving copy number gains promote tumor expansion and bolster mutational diversification
Understanding the timing and fitness of somatic copy number alterations (SCNAs) in cancer would shed light on cancer progression and evolution. Here, the authors develop Butte, a computational framework to estimate the timing of clonal SCNAs that encompass multiple gains, and apply it on whole-genome sequencing data from 184 samples.
- Zicheng Wang
- , Yunong Xia
- & Ruping Sun
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Article
| Open AccessDevelopment of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma
Rational antibody engineering can greatly improve the clinical value of therapeutic antibodies. Here authors describe ISB 1442, a fully human bispecific antibody, consisting of two targeting modules against two different epitopes on CD38, combined with a targeting module blocking CD47 and engineered effector properties, to enhance complement dependent cytotoxicity, antibody dependent cells cytotoxicity and antibody dependent cell phagocytosis to combat multiple myeloma.
- C. Grandclément
- , C. Estoppey
- & S. Sammicheli
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Article
| Open AccessBevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group
Prognosis for patients diagnosed with advanced stage ovarian cancer remains poor. Here the authors report the results of a phase 2 study of a triple combination of the PARP inhibitor olaparib in combination with durvalumab (anti-PD1) and bevacizumab (antiVEGF) in advanced ovarian cancer.
- Gilles Freyer
- , Anne Floquet
- & Michele Lamuraglia
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Article
| Open AccessLactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
| Open AccessTrans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma
Glioblastoma (GBM) is refractory to the chemotherapeutic genotoxin temozolomide (TMZ). Here, the authors show that GBM cells deploy RAD18-mediated Trans-Lesion Synthesis to promote error-free repair of TMZ-induced O6mG DNA lesions and avert lethality.
- Xing Cheng
- , Jing An
- & Yang Yang
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Article
| Open AccessEnhancing the fairness of AI prediction models by Quasi-Pareto improvement among heterogeneous thyroid nodule population
Artificial Intelligence (AI) models for medical diagnosis often face challenges of generalizability and fairness. Here, the authors show that the Quasi-Pareto Improvement approach is widely applicable to improving AI models among less-prevalent subgroups, promoting equitable healthcare outcomes.
- Siqiong Yao
- , Fang Dai
- & Hui Lu
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