Featured
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| 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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Article
| Open AccessFilament formation drives catalysis by glutaminase enzymes important in cancer progression
Mitochondrial enzymes, collectively known as glutaminase, satisfy the metabolic requirements of cancer cells. Here the authors show that glutaminases form filamentous structures necessary for their catalytic activity.
- Shi Feng
- , Cody Aplin
- & Richard A. Cerione
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Article
| Open AccessInhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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Article
| Open AccessDomain generalization enables general cancer cell annotation in single-cell and spatial transcriptomics
Efficient and accurate annotation of malignant cells is crucial for single-cell and spatial transcriptomics in cancer. Here, the authors develop Cancer-Finder, a deep-learning algorithm that can identify malignant cells in cancer single-cell and spatial transcriptomics data with speed and precision.
- Zhixing Zhong
- , Junchen Hou
- & Jia Song
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Article
| Open AccessPredictive role of ctDNA in esophageal squamous cell carcinoma receiving definitive chemoradiotherapy combined with toripalimab
Toripalimab with definitive chemoradiotherapy is a promising treatment strategy for esophageal squamous cell carcinoma. Here, the authors show that ctDNA positivity and bTMB are predictive of response in patients within the EC-CRT-001 phase II trial.
- Baoqing Chen
- , Shiliang Liu
- & Mian Xi
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Article
| Open AccesssynNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy
Given its immunosuppressive effect in glioblastoma (GBM), targeting the TIGIT-CD155 axis presents an attractive therapeutic strategy. Here, the authors develop an adoptive natural killer (iNK) cells therapy with anti-CD155 synNotch-inducible CD73 antibody production to reverse the effect of TIGIT-CD155 signaling for the treatment of GBM.
- Kyle B. Lupo
- , Xue Yao
- & Sandro Matosevic
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Article
| Open AccessCD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs
Antibodies stimulating the T cell co-activator 4-1BB (CD137) do enhance anti-tumour T cell function, but their utility is hampered by on target, off tumor toxicity. Here authors show that anchoring anti-4-1BB to tumours via fusion with the collagen binding protein LAIR diminishes systemic dissemination of the drug, and they demonstrate a curative effect in a triple-combination-therapy that relieves regulatory T cell immunosuppression in a mouse model of cancer.
- Joseph R. Palmeri
- , Brianna M. Lax
- & K. Dane Wittrup
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Article
| Open AccessThe transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Cancer cells adapt to changes in metabolism to ensure their survival. Here the authors show that glucose responsive transcription factor ChREBP reprograms liver cancer metabolism in part via enhancing the PI3K/AKT signaling.
- Emmanuel Benichou
- , Bolaji Seffou
- & Renaud Dentin
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Article
| Open AccessMYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Several molecular mechanisms, including retinoblastoma protein RB1 deficiency, explain CDK4/6 inhibitors resistance in cancer. Here, the authors show that MYC amplification induces CDK4/6 inhibitors resistance through transcriptional regulation of KLHL42, leading to RB1 degradation and targeting MYC overcomes CDK4/6 resistance in preclinical cancer models.
- Jian Ma
- , Lei Li
- & Lei Li
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Article
| Open AccessThe evolutionary impact of childhood cancer on the human gene pool
Pathogenic germline variants associated with childhood cancer risk could be subject to evolutionary constraints. Here, the authors analyse publicly available germline data in large cohorts and observe that paediatric cancer predisposition syndrome genes are highly constrained in the general population.
- Ulrik Kristoffer Stoltze
- , Jon Foss-Skiftesvik
- & Kjeld Schmiegelow
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Article
| Open AccessA druggable conformational switch in the c-MYC transactivation domain
Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation.
- Dilraj Lama
- , Thibault Vosselman
- & Marie Arsenian Henriksson
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Article
| Open AccessA Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE
Alterations of therapeutic pressures have been shown to affect clonal evolution of resistance. Here, the authors conducted a single arm, phase 2 trial consisting of alternating osimertinib and gefitinib in non-small cell lung cancer, and found ctDNA dynamics were predictive of response.
- Lavinia Tan
- , Chris Brown
- & Benjamin J. Solomon
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Article
| Open AccessPrediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer
Metastatic castration-resistant prostate cancer is a highly aggressive disease, with a variable response to treatment. Here, the authors validate ctDNA fraction as a poor prognostic factor and develop a model to predict whether patients harbor sufficient ctDNA for informative blood-based genotyping.
- Nicolette M. Fonseca
- , Corinne Maurice-Dror
- & Alexander W. Wyatt
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Article
| Open AccessStructure of the p53 degradation complex from HPV16
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
- John C. K. Wang
- , Hannah T. Baddock
- & Aaron H. Nile
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Article
| Open AccessComprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
IFNγ signaling is important in the pathogenesis and immune response, emphasizing the need for investigation of its role. Here, the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance, providing insights for potential therapeutic strategies.
- Bofei Wang
- , Patrick K. Reville
- & Hussein A. Abbas
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Article
| Open AccessMolecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting
PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- , Xiaorong Gu
- & Jaroslaw P. Maciejewski
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Article
| Open AccessComparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Article
| Open AccessA distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study
Alternative polyadenylation (APA) can play a key role in cancer initiation and progression. Here, the authors conducted a comprehensive pan-cancer APA TWAS analysis and discovered a distinct class of APA-mediated cancer susceptibility genes across 22 cancer types.
- Hui Chen
- , Zeyang Wang
- & Lei Li
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Article
| Open AccessKDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Yong Yean Kim
- , Berkley E. Gryder
- & Javed Khan
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Article
| Open AccessThe ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.
- Elizabeth L. Hardaker
- , Emilio Sanseviero
- & Simon T. Barry
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Article
| Open AccessFusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15
Several studies have shown that Fusobacterium nucleatum aggravates colorectal cancer (CRC) development and chemoresistance. Here the authors show that F. nucleatum is enriched preferentially in patients with KRAS p.G12D mutant CRC and that it promotes colorectal tumorigenesis in preclinical models by binding DHX15 on tumor cells.
- Huiyuan Zhu
- , Man Li
- & Huanlong Qin
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Article
| Open AccessElevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions
Extracellular vesicles are reported to regulate tumorigenesis. Here, the authors show that under obesity conditions, increased extracellular matrix protein 1 protein levels in circulating small extracellular vesicles induce breast cancer growth and metastasis.
- Keyang Xu
- , Ai Fu
- & Hiu Yee Kwan
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Article
| Open AccessMetabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Article
| Open AccessInfluence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial
MIND-DC was a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived natural dendritic cell (nDC)-based therapy in patients with stage III melanoma, showing that nDC-induced immune responses did not translate into survival benefit. Here the authors report that, despite randomization, baseline differences in fecal metagenomics and serum metabolomics profiles between treatment arms might have influenced the clinical outcome of the trial.
- Carolina Alves Costa Silva
- , Gianmarco Piccinno
- & I. Jolanda M. de Vries
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Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open AccessRepeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial
Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.
- Alexandre Carpentier
- , Roger Stupp
- & Ahmed Idbaih
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Article
| Open AccessUltrasmall metal alloy nanozymes mimicking neutrophil enzymatic cascades for tumor catalytic therapy
Emulating the killing function of neutrophils, which involves the enzymatic cascade of superoxide dismutase (SOD) and myeloperoxidase (MPO), is promising for cancer therapy, but developing SOD-MPO cascade in one nanozyme is challenging. Here the authors report ultrasmall AuPd alloy nanozymes that mimic neutrophil enzymatic cascades for catalytic treatment of tumors.
- Xiangqin Meng
- , Huizhen Fan
- & Kelong Fan
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Article
| Open AccessMicrobes translocation from oral cavity to nasopharyngeal carcinoma in patients
Oral microbes in non-oral locations are noted across various cancers. This study highlights the abnormal translocation of oral microbes to the nasopharynx, raising the risk of nasopharyngeal cancer by remodeling the tumor microenvironment and potentially influencing EBV infection.
- Ying Liao
- , Yan-Xia Wu
- & Wei-Hua Jia
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Article
| Open AccessExosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma
The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.
- Bárbara Adem
- , Nuno Bastos
- & Sonia A. Melo
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Article
| Open AccessTumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 in head and neck cancer
Tumor histocultures have been exploited as tools to predict response to cancer therapy. Here the authors report the development and testing of a tumor histoculture platform to study response to immune checkpoint inhibitors in head and neck squamous cell carcinoma.
- Nandini Pal Basak
- , Kowshik Jaganathan
- & Satish Sankaran
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