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| Open AccessNanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer
In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.
- Yu-Yang Bi
- , Qiu Chen
- & Hu-Lin Jiang
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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 AccessDetection of senescence using machine learning algorithms based on nuclear features
Identifying senescence is complicated by a lack of universal markers. Here, Duran et al. use nuclear morphology features to devise machine-learning classifiers that detect senescence in cell lines and liver sections of patients and mouse models of aging and disease.
- Imanol Duran
- , Joaquim Pombo
- & Jesús Gil
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Article
| Open AccessA CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics
Combining chemotherapeutics can be beneficial but identifying effective combinations from the vast array of possibilities is resource and time consuming. Here, the authors perform a high-throughput targeted CRISPR knock-out screen identify druggable gene targets which alter sensitivity to chemotherapies. In doing so, they identify DNA-PK inhibition as a sensitiser of neuroblastomas to doxorubicin.
- Hyeong-Min Lee
- , William C. Wright
- & Paul Geeleher
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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 AccessCombining gut microbiota modulation and chemotherapy by capecitabine-loaded prebiotic nanoparticle improves colorectal cancer therapy
Gut microbiota regulates colorectal cancer (CRC) progression and respond to therapy. Here the authors generate nanoparticles using prebiotic micelles and loaded with the chemo drug capecitabine that boost gastrointestinal probiotic response, increase anti-tumour immunity and improve survival when provided orally in CRC preclinical murine models.
- Tianqun Lang
- , Runqi Zhu
- & Yaping Li
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Article
| Open AccessThe intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal
Senescence and quiescence are considered different cell states but are hard to distinguish. Here, single-cell imaging followed by immunostaining reveals that the intensities of senescence biomarkers are graded rather than binary, reflecting the duration of cell-cycle withdrawal rather than irreversible cell-cycle arrest.
- Humza M. Ashraf
- , Brianna Fernandez
- & Sabrina L. Spencer
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessLysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma
EGFR amplification can affect temozolomide sensitivity in glioblastomas (GBM). Here the authors show that EGFR signalling mediates lysine methylation of NFAT5 which contributes to reduced efficacy of temozolomide in GBM.
- Yatian Li
- , Zhenyue Gao
- & Yu Ren
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Article
| Open AccessCisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans
In contrast to mammalian cells, C. elegans models can be useful because of cells being post-mitotic in adults. Here the authors show activation of the p38 pathway in cisplatin resistant adult animals and characterise the proteins upstream and downstream of the p38 MAPK signalling pathway that are involved in the cisplatin response.
- Dorota Raj
- , Bashar Kraish
- & Peter Naredi
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Article
| Open AccessTRPV1 inhibition overcomes cisplatin resistance by blocking autophagy-mediated hyperactivation of EGFR signaling pathway
The emergence of cisplatin resistance and side-effects are important factors in cancer treatment failure. Here, the authors identify autophagy-mediated EGFR hyperactivation by TRPV1 promotion as a mechanism of cisplatin resistance and demonstrate the efficacy of a TRPV1 inhibitor to sensitize lung cancer to cisplatin.
- Se Jin Oh
- , Ji Yeon Lim
- & Tae Woo Kim
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Article
| Open AccessControlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics
Manipulating molecular self-assembly and disassembly in vivo may permit temporal control of drug delivery and release. Here, the authors report a fluorogenic cisplatin prodrug for cancer theranostics by leveraging stimuli-triggered in situ self-assembly and intracellular disassembly processes.
- Xidan Wen
- , Rui Zhang
- & Deju Ye
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Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
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Article
| Open AccessEfficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer
Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.
- Lingzhi Hong
- , Muhammad Aminu
- & Natalie I. Vokes
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Article
| Open AccessmTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters
Chemotherapy resistance poses a major obstacle in cancer therapy. Here, the authors identify the mTOR pathway as a determinant of chemosensitivity and demonstrate that inhibition of mTOR promotes the persistence of a chemotherapy-resistant cancer-cell subpopulation.
- Yuanhui Liu
- , Nancy G. Azizian
- & Yulin Li
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Article
| Open AccessZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer
Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance.
- Chen Ni
- , Xiaohan Lou
- & Zhihai Qin
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Article
| Open AccessCommon anti-cancer therapies induce somatic mutations in stem cells of healthy tissue
Specific anti-cancer therapies are highly mutagenic to cancer cells but the mutational impact on healthy tissues remains elusive. Here, the authors use organoids and whole-genome sequencing to characterise somatic mutations in healthy colon and liver adult stem cells after chemo- or radiotherapy.
- Ewart Kuijk
- , Onno Kranenburg
- & Arne Van Hoeck
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Article
| Open AccessFatty acids homeostasis during fasting predicts protection from chemotherapy toxicity
Fasting has been reported to protect from chemotherapy-associated toxicity. Here, the authors show that fatty acid profiles in erythrocyte membranes and gene expression from peripheral blood mononuclear cells are associated to the fasting-mediated benefits during cancer treatment in mice and patients.
- Marta Barradas
- , Adrián Plaza
- & Pablo J. Fernandez-Marcos
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| Open AccessCombination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours
T-cell redirecting bispecific antibodies have emerged as therapeutic agents to promote T-cell mediated killing of tumor cells. Here the authors show that a combination of chemotherapy and ERY974, a bispecific antibody that targets glypican-3 and CD3, facilitates T cell infiltration and promotes anti-tumor responses also in non-inflamed tumors.
- Yuji Sano
- , Yumiko Azuma
- & Mika Endo
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Article
| Open AccessA nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer
Cisplatin is the most frequently used chemotherapeutic agent for the treatment of patients with oral cavity squamous cell carcinoma (OCSCC), however, systemic administration is often associated with dose limiting side effects. Here the authors design and test a nano-engineered patch system (PRV111) for the local delivery of cisplatin-loaded chitosan nanoparticles and report the results of a phase 1/2 clinical trial of PRV111 in patients with OCSCC.
- Manijeh Goldberg
- , Aaron Manzi
- & Evgeny Izumchenko
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Article
| Open AccessCell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.
- Fotis Nikolos
- , Kazukuni Hayashi
- & Keith Syson Chan
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Comment
| Open AccessHow the glucocorticoid receptor contributes to platinum-based therapy resistance in solid cancer
Synthetic glucocorticoids serve as co-medication against solid malignant tumors. However, glucocorticoid receptor activation may promote unsolicited cancer resistance to chemotherapy. The Kang team elucidated a glucocorticoid receptor-centred chemotherapy-resistance mechanism to cisplatin and characterized avenues towards a viable escape strategy.
- Dorien Clarisse
- & Karolien De Bosscher
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Article
| Open AccessDynamics of replication origin over-activation
DNA replication processes are often dysregulated in cancer. Here the authors analyse DNA synthesis patterns in cancer cells undergoing partial genome re-replication to reveal that re-replication exhibits aberrant replication fork dynamics and a skewed distribution of replication initiation that over-duplicates early-replicating genomic regions.
- Haiqing Fu
- , Christophe E. Redon
- & Mirit I. Aladjem
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Article
| Open AccessMitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance
Drug efflux through ABC transporters is a common mechanism leading to chemoresistance in cancer. Here, the authors show that mitochondrial respiration provides ATP to allow ABC transporters activity so mitochondrial respiration inhibition overcomes chemoresistance in preclinical cancer models.
- Emily L. Giddings
- , Devin P. Champagne
- & Mercedes Rincon
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Article
| Open AccessCo-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy
Some chemotherapeutic drugs, such as doxorubicin, induce immunogenic cell death (ICD) and promote anti-tumor immune responses. Here the authors report that the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) reduces the expression of PD-L1 in cancer cells and enhances doxorubicin-induced ICD, promoting T cell infiltration and reducing tumor growth in preclinical models.
- Jing Liu
- , Zhihao Zhao
- & Youqing Shen
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Article
| Open AccessCatalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics
Reactive oxygen species management is a practical strategy that can reduce the risk of chemotherapy-induced acute kidney injury, but at the cost of chemotherapeutic efficacy. Here the authors report catalytic activity tunable ceria nanoparticles as context-dependent reactive oxygen species scavengers, which can prevent chemotherapy-induced acute kidney injury without interfering with chemotherapeutic agents.
- Qinjie Weng
- , Heng Sun
- & Daishun Ling
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Article
| Open AccessImaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML
The role of mTORC1 in AML has not yet been proven due to the mixed results of its inhibitors in clinical trials. Here the authors show the real-time dynamics of the mTORC1 pathway in association with AML growth and response to chemotherapy with fluorescent markers, providing guidance for timed intervention with pathway-specific inhibitors.
- Toshihiko Oki
- , Francois Mercier
- & David T. Scadden
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Article
| Open AccessTipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
Most chemotherapeutic agents, including gemcitabine, do not elicit immunogenic cell death, a phenomenon associated with the release of damage-associated molecule patterns (DAMPs). Here, the authors show that gemcitabine-treated dying cancer cells express hallmark DAMPs but their immunogenic properties are hindered by the concomitant release of the inhibitory DAMP PGE2.
- K. Hayashi
- , F. Nikolos
- & K. S. Chan
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Article
| Open AccessChemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome
Neoadjuvant chemotherapy is a therapeutic option for the treatment of breast cancer. Here, the authors characterize changes in the gene expression profiles and immune microenvironment in serial breast cancer biopsies taken before, during and after neoadjuvant chemotherapy.
- Yeon Hee Park
- , Samir Lal
- & Zhengyan Kan
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Article
| Open AccessComputationally predicting clinical drug combination efficacy with cancer cell line screens and independent drug action
Computational models that can predict drug combination efficacy are often based on drug synergy. Here, the authors develop a different approach to computationally predict the efficacy of drug combinations using monotherapy data from high-throughput cancer cell line screens.
- Alexander Ling
- & R. Stephanie Huang
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Article
| Open AccessMechanisms of telomerase inhibition by oxidized and therapeutic dNTPs
Telomerase enzymes add telomeric repeats to the end of linear chromosomes. Here the authors reveal mechanisms by which oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.
- Samantha L. Sanford
- , Griffin A. Welfer
- & Patricia L. Opresko
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Article
| Open AccessFaecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma
Tyrosine kinase inhibitors (TKIs) have improved the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), however TKI-related diarrhoea is a common and serious adverse effect. Here the authors show in a randomized clinical trial that faecal microbiota transplantation from healthy donors can improve TKI-induced diarrhoea in patients with mRCC.
- Gianluca Ianiro
- , Ernesto Rossi
- & Giovanni Cammarota
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Article
| Open AccessAccelerated single cell seeding in relapsed multiple myeloma
In multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.
- Heather J. Landau
- , Venkata Yellapantula
- & Francesco Maura
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Article
| Open AccessFasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial
Preclinical evidence suggests that a fasting mimicking diet (FMD) can make cancer cells more vulnerable to chemotherapy, while protecting normal cells. In this randomized phase II clinical trial of 131 patients with HER2 negative early stage breast cancer, the authors demonstrate that FMD is safe and enhances the effects of neoadjuvant chemotherapy on radiological and pathological tumor response.
- Stefanie de Groot
- , Rieneke T. Lugtenberg
- & Judith R. Kroep
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Article
| Open AccessABCG2 transports anticancer drugs via a closed-to-open switch
ABCG2 is a human ABC transporter that actively extrudes a wide variety of compounds from cells but the mechanisms of multidrug transport remain obscure. Here authors present cryo-EM structures of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics and demonstrate how these molecules open the closed conformation of the transporter.
- Benjamin J. Orlando
- & Maofu Liao
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Article
| Open AccessFAM111A protects replication forks from protein obstacles via its trypsin-like domain
DNA-protein crosslinks represent obstacles on genomic DNA that can hamper progression of replication forks. Here, the authors reveal that FAM111A, a PCNA-interacting protein, plays part in mitigating the effect of protein obstacles on replication forks.
- Yusuke Kojima
- , Yuka Machida
- & Yuichi J. Machida
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Article
| Open AccessChromosome arm aneuploidies shape tumour evolution and drug response
Chromosome arm-level aneuploidies (CAAs) are frequently observed in cancer. Here, the authors analyse CAA landscapes across different tumour types, relating these chromosome arm gains and losses to tumour evolution, metastasis, patient survival and response to a range of anti-cancer therapies.
- Ankit Shukla
- , Thu H. M. Nguyen
- & Pascal H. G. Duijf
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Article
| Open AccessPriming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy
Hair follicles (HFs) are sensitive to chemotherapy but recover from quiescent HF stem cells, although sometimes chemotherapy results in permanent loss. Here, Kim et al. establish a model of permanent chemotherapy-induced alopecia to uncover the underlying mechanisms depleting human HF stem cells.
- Jin Yong Kim
- , Jungyoon Ohn
- & Ohsang Kwon
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Article
| Open AccessSynergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems
The side effects of cancer drugs limit their utility. Here, the authors developed a method in which an inactive (prodrug) version of the cancer drug doxorubicin enters tumour cells and then gets activated inside the cells upon a trigger facilitated by enzyme-instructed supramolecular self-assembly.
- Qingxin Yao
- , Feng Lin
- & Yuan Gao
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Article
| Open AccessMitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.
- R. Kumar
- , L. Coronel
- & C. F. Cheok
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Article
| Open AccessA PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine
Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα regulated-protein involved in the response to vinstabline.
- Hyun Jung Jun
- , Vicky A. Appleman
- & Al Charest
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Article
| Open AccessDrug capture materials based on genomic DNA-functionalized magnetic nanoparticles
Chemotherapy agents are prone to producing severe side-effects, and their sequestration prior to their entering of the circulatory system is thus highly desirable. Here, the authors functionalize iron oxide nanoparticles with genomic DNA and achieve sequestration of doxorubicin, cisplatin, and epirubicin from biological solutions.
- Carl M. Blumenfeld
- , Michael D. Schulz
- & Robert H. Grubbs
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Article
| Open AccessControlled gene and drug release from a liposomal delivery platform triggered by X-ray radiation
X-ray radiation has excellent tissue penetration depth, making it a useful trigger for deep tissue cancer therapy. Here, the authors design X-ray triggered drug/gene-loaded liposomes by embedding photosensitizers and gold nanoparticles in the liposome bilayer, and demonstrate their efficacy in cancer and gene therapy.
- Wei Deng
- , Wenjie Chen
- & Ewa M. Goldys
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Article
| Open AccessUpconversion nanocomposite for programming combination cancer therapy by precise control of microscopic temperature
The combination of chemo and photothermal therapy is widely used to treat cancer but control of chemo and thermal effects is needed for optimized treatment. Here, the authors describe an upconversion nanoparticle which can be used for controlled sequential treatment by controlling laser power.
- Xingjun Zhu
- , Jiachang Li
- & Fuyou Li
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Article
| Open AccessOxygen and Pt(II) self-generating conjugate for synergistic photo-chemo therapy of hypoxic tumor
Photodynamic therapy has attracted interest in treating cancer but it is limited in hypoxic tumors due to a lack of oxygen. Here, the authors describe a nano-composite capable of generating oxygen under near-infrared light for improved photodynamic and chemotherapy for treating cancer.
- Shuting Xu
- , Xinyuan Zhu
- & Deyue Yan
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Article
| Open AccessNanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer
Improving the safety and efficacy of chemotherapeutics will help to enhance their effects. Here, the authors show that intraperitoneal delivery of nanoparticle conjugates of a potent toxin prolongs tumor inhibition and survival as compared to cisplatin in advanced-stage and platinum-resistant ovarian cancer mouse models.
- Ruogu Qi
- , Yongheng Wang
- & P. Peter Ghoroghchian
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Article
| Open AccessCisplatin is retained in the cochlea indefinitely following chemotherapy
Permanent hearing loss occurs in many cancer patients treated with cisplatin. In this study, the authors examine cisplatin pharmacokinetics in the cochleae of mice and humans showing that cisplatin is retained for months to years after treatment.
- Andrew M. Breglio
- , Aaron E. Rusheen
- & Lisa L. Cunningham
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Article
| Open AccessNano-palladium is a cellular catalyst for in vivo chemistry
Palladium (Pd) is a well-known catalyst in organic chemistry but its use in nanomedicine is limited. Here, the authors design a Pd nanoparticle that triggers the activation of an antitumour prodrugin vivo, which shows efficacy and improves toxicity compared to traditional solvent- and nanoparticle-drug formulations.
- Miles A. Miller
- , Bjorn Askevold
- & Ralph Weissleder
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Article
| Open AccessVHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2
The VHL tumour suppressor gene is lost in approximately 70% of clear cell renal cell carcinoma (ccRCC). In this study, the authors demonstrate that VHL loss in these tumours augments anthracyclines chemotherapy by down-regulation of ALDH2.
- Yao-Hui Gao
- , Zhao-Xia Wu
- & Li-Shun Wang