Pancreatic ductal adenocarcinoma(PDAC)is an aggressive tumor with high lethality.Even with surgery,radiotherapy,chemotherapy,and other locoregional or systemic therapies,the survival rates for PDAC are low and have no...Pancreatic ductal adenocarcinoma(PDAC)is an aggressive tumor with high lethality.Even with surgery,radiotherapy,chemotherapy,and other locoregional or systemic therapies,the survival rates for PDAC are low and have not significantly changed in the past decades.The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease.PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells.The pancreatic microenvironment is a fibrotic,microvascularized stroma that isolates the tumor from systemic vascularization.Immunotherapy,a novel approach that has demonstrated effectiveness in certain solid tumors,has failed to show any practice-changing results in pancreatic cancer,with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden,which show prolonged survival rates with immunotherapy.Currently,numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell transfer,alone or in combination with other immunotherapeutic agents,chemoradiotherapy,and other targeted therapies.A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.展开更多
Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexp...Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.展开更多
Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their ...Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their histopathological characteristics and clinical behaviour, the classification of these tumours is still under debate. Alterations in morphogenesis pathways such as the Hedgehog,MAPK and WNT/β-catenin pathways are implicated in the formation of odontogenic lesions, but the molecular bases of many of these lesions are still unknown. In this study, we used genetically modified mice to study the role of IKKβ(a fundamental regulator of NF-κB activity and many other proteins) in oral epithelial cells and odontogenic tissues. Transgenic mice overexpressing IKKβ in oral epithelial cells show a significant increase in immune cells in both the oral epithelia and oral submucosa. They also show changes in the expression of several proteins and mi RNAs that are important for cancer development. Interestingly, we found that overactivity of IKKβ in oral epithelia and odontogenic tissues, in conjunction with the loss of tumour suppressor proteins(p53, or p16 and p19), leads to the appearance of odontogenic tumours that can be classified as ameloblastic odontomas, sometimes accompanied by foci of secondary ameloblastic carcinomas. These tumours show NF-κB activation and increased β-catenin activity.These findings may help to elucidate the molecular determinants of odontogenic tumourigenesis and the role of IKKβ in the homoeostasis and tumoural transformation of oral and odontogenic epithelia.展开更多
BACKGROUNDPatients with advanced gastrointestinal cancer must cope with the negative effects of cancer and complications.AIM To evaluate psychological distress,quality of life,and coping strategies in patients with ad...BACKGROUNDPatients with advanced gastrointestinal cancer must cope with the negative effects of cancer and complications.AIM To evaluate psychological distress,quality of life,and coping strategies in patients with advanced colorectal cancer compared to non-colorectal cancer based on sex.METHODS A prospective,transversal,multicenter study was conducted in 203 patients;101(50%)had a colorectal and 102(50%)had digestive,non-colorectal advanced cancer.Participants completed questionnaires evaluating psychological distress(Brief Symptom Inventory-18),quality of life(EORTC QLQ-C30),and coping strategies(Mini-Mental Adjustment to Cancer)before starting systemic cancer treatment.RESULTS The study included 42.4%women.Women exhibited more depressive symptoms,anxiety,functional limitations,and anxious preoccupation than men.Patients with non-colorectal digestive cancer and women showed more somatization and physical symptoms than subjects with colorectal cancer and men.Men with colorectal cancer reported the best health status.CONCLUSION The degree of disease acceptance in gastrointestinal malignancies may depend on sex and location of the primary digestive neoplasm.Future interventions should specifically address sex and tumor site differences in individuals with advanced digestive cancer.展开更多
Chimeric antigen receptor T(CAR-T)cell therapies have transformed the treatment of relapsed/refractory(R/R)B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19-or BCMA-expressing tumor cel...Chimeric antigen receptor T(CAR-T)cell therapies have transformed the treatment of relapsed/refractory(R/R)B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19-or BCMA-expressing tumor cells.However,this approach has yet to be approved for acute myeloid leukemia(AML),the most common acute leukemia in adults and the elderly.Simultaneously,CAR-T cell therapies continue to face significant challenges in the treatment of solid tumors.The primary challenge in developing CAR-T cell therapies for AML is the absence of an ideal target antigen that is both effective and safe,as AML cells share most surface antigens with healthy hematopoietic stem and progenitor cells(HSPCs).展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
Desmoplastic small round cell tumor(DSRCT)is an aggressive cancer that predominantly affects adolescents and young adults,typically developing at sites lined by mesothelium[1,2].DSRCT is genetically defined by a chrom...Desmoplastic small round cell tumor(DSRCT)is an aggressive cancer that predominantly affects adolescents and young adults,typically developing at sites lined by mesothelium[1,2].DSRCT is genetically defined by a chromosomal translocation that fuses the N-terminus of EWS RNA binding protein 1(EWSR1)to the C-terminus of Wilms tumor protein(WT1),forming EWSR1::WT1[3].This fusion encodes a potent transcription factor and is the only known driver of oncogenic transformation in DSRCT[4].The lack of a comprehensive understanding of DSRCT biology parallels its dismal survival rate(5%-20%)[1].These challenges are exacerbated by the absence of clinical trials,the limited systematic collection and analysis of DSRCT biomaterial[1],and the notable lack of specific diagnostic markers,necessitating resource-intensive molecular testing for an accurate diagnosis.展开更多
Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referr...Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.展开更多
Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative an...Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.展开更多
Germline activating variants in WWP1,which encodes an E3 ubiquitin ligase that antagonizes PTEN tumor suppressive function,have been proposed as an alternative mechanism of PTEN inactivation in PTEN-hamartoma-tumor sy...Germline activating variants in WWP1,which encodes an E3 ubiquitin ligase that antagonizes PTEN tumor suppressive function,have been proposed as an alternative mechanism of PTEN inactivation in PTEN-hamartoma-tumor syndrome(PHTS)-like patients with wildtype PTEN.1 More specifically,heterozygous,potentially activating wwP1 variants were first identified by Lee et al in patients affected with gastrointestinal oligopolyposis,including adenomatous,hyperplastic/serrated,and hamartomatous polyps,and occasionally with colorectal cancer(Table 1).Subsequently,based on the PHTS phenotypic features,wWP1 mutational screening was performed in patients with thyroid nodules,2 or normocephalic autism spectrum disorder(ASD),3 where germline WWP1 variants were also identified(Table S1).展开更多
The current spotlight of cancer therapeutics is shifting towards personalized medicine with the widespread use of monoclonal antibodies(mAbs).Despite their increasing potential,mAbs have an intrinsic limitation relate...The current spotlight of cancer therapeutics is shifting towards personalized medicine with the widespread use of monoclonal antibodies(mAbs).Despite their increasing potential,mAbs have an intrinsic limitation related to their inability to cross cell membranes and reach intracellular targets.Nanotechnology offers promising solutions to overcome this limitation,however,formulation challenges remain.These challenges are the limited loading capacity(often insufficient to achieve clinical dosing),the complex formulation methods,and the insufficient characterization of mAb-loaded nanocarriers.Here,we present a new nanocarrier consisting of hyaluronic acid-based nanoassemblies(HANAs)specifically designed to entrap mAbs with a high efficiency and an outstanding loading capacity(50%,w/w).HANAs composed by an mAb,modified HA and phosphatidylcholine(PC)resulted in sizes of~100 nm and neutral surface charge.Computational modeling identified the principal factors governing the high affinity of mAbs with the amphiphilic HA and PC.HANAs composition and structural configuration were analyzed using the orthogonal techniques cryogenic transmission electron microscopy(cryo-TEM),asymmetrical flow field-flow fractionation(AF4),and small-angle X-ray scattering(SAXS).These techniques provided evidence of the formation of core-shell nanostructures comprising an aqueous core surrounded by a bilayer consisting of phospholipids and amphiphilic HA.In vitro experiments in cancer cell lines and macrophages confirmed HANAs’low toxicity and ability to transport mAbs to the intracellular space.The reproducibility of this assembling process at industrial-scale batch sizes and the long-term stability was assessed.In conclusion,these results underscore the suitability of HANAs technology to load and deliver biologicals,which holds promise for future clinical translation.展开更多
Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy(ACT).The provision of proper costimulatory receptor...Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy(ACT).The provision of proper costimulatory receptor activity and cytokine stimuli,along with the repression of inhibitory mechanisms,will conceivably make the most of these treatment strategies.In this sense,T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion,last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant tissues.Their antitumor effects can be dramatically augmented with permanent or transient gene transfer maneuvers to express or delete/repress genes.A combination of such interventions seeks the creation of the ultimate bionic T cell,perfected to seek and destroy cancer cells upon systemic or local intratumor delivery.展开更多
The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The ac...The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling,while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity.A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways.Here we have focused on the role of Endoglin(Eng),a key co-receptor for members of the Tgf-β/Bmp family of growth factors.Using an Eng haploinsufficient mouse model,we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches.We further report thatβ-catenin binds to the Eng promoter depending on Bmp signalling.Moreover,we show thatβ-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription.These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.展开更多
SPINOPHILIN(SPN,PPP1R9B or NEURABIN-2)is a multifunctional protein that regulates protein-protein interactions in different cell signaling pathways.SPN is also one of the regulatory subunits of protein phosphatase 1(P...SPINOPHILIN(SPN,PPP1R9B or NEURABIN-2)is a multifunctional protein that regulates protein-protein interactions in different cell signaling pathways.SPN is also one of the regulatory subunits of protein phosphatase 1(PP1),implicated in the dephosphorylation of retinoblastoma protein(pRB)during cell cycle.The SPN gene has been described as a tumor suppressor in different human tumor contexts,in which low levels of SPN are correlated with a higher grade and worse prognosis.In addition,mutations of the SPN protein have been reported in human tumors.Recently,an oncogenic mutation of sPN,A566V,was described,which affects both the SPN-PP1 interaction and the phosphatase activity of the holoenzyme,and promotes p53-dependent tumorigenesis by increasing the cancer stem cell(CsC)pool in breast tumors.Thus,the loss or mutation of SPN could be late events that promotes tumor progression by increasing the CSC pool and,eventually,the malignant behavior of the tumor.展开更多
Background:Single-cell multi-omics technologies allow a profound system-level biology understanding of cells and tissues.However,an integrative and possibly systems-based analysis capturing the different modalities is...Background:Single-cell multi-omics technologies allow a profound system-level biology understanding of cells and tissues.However,an integrative and possibly systems-based analysis capturing the different modalities is challenging.In response,bioinformatics and machine learning methodologies are being developed for multi-omics single-cell analysis.It is unclear whether current tools can address the dual aspect of modality integration and prediction across modalities without requiring extensive parameter fine-tuning.Methods:We designed LIBRA,a neural network based framework,to learn translation between paired multi-omics profiles so that a shared latent space is constructed.Additionally,we implemented a variation,aLIBRA,that allows automatic fine-tuning by identifying parameter combinations that optimize both the integrative and predictive tasks.All model parameters and evaluation metrics are made available to users with minimal user iteration.Furthermore,aLIBRA allows experienced users to implement custom configurations.The LIBRA toolbox is freely available as R and Python libraries at GitHub(TranslationalBioinformaticsUnit/LIBRA).Results:LIBRA was evaluated in eight multi-omic single-cell data-sets,including three combinations of omics.We observed that LIBRA is a state-of-the-art tool when evaluating the ability to increase cell-type(clustering)resolution in the integrated latent space.Furthermore,when assessing the predictive power across data modalities,such as predictive chromatin accessibility from gene expression,LIBRA outperforms existing tools.As expected,adaptive parameter optimization(aLIBRA)significantly boosted the performance of learning predictive models from paired data-sets.Conclusion:LIBRA is a versatile tool that performs competitively in both“integration”and“prediction”tasks based on single-cell multi-omics data.LIBRA is a data-driven robust platform that includes an adaptive learning scheme.展开更多
Dear Editor,Breast cancer(BC)is the most commonly diagnosed cancer and the fifth cause of cancer-related death worldwide[1].Despite the advances in BC targeted therapies,cytotoxic chemotherapy is still widely used[2]....Dear Editor,Breast cancer(BC)is the most commonly diagnosed cancer and the fifth cause of cancer-related death worldwide[1].Despite the advances in BC targeted therapies,cytotoxic chemotherapy is still widely used[2].However,around 20%-30%of BC patients develop metastasis after treatment as a consequence of drug resistance[3].In this context,microRNAs have emerged as potential therapeutic targets to overcome therapy resistance[4].Therefore,we aimed to elucidate the molecular mechanisms underlying resistance to doxorubicin,one of the most effective chemotherapeutic agents used in BC.Methods are detailed in Supplementary Materials.展开更多
The availability of biologicals,such as anti-EFGR and anti-VEGF antibodies in combination with chemotherapy(ChT),has improved prognosis of metastatic colorectal cancer(mCRC).However,the administration of drug combinat...The availability of biologicals,such as anti-EFGR and anti-VEGF antibodies in combination with chemotherapy(ChT),has improved prognosis of metastatic colorectal cancer(mCRC).However,the administration of drug combinations for a prolonged time implies an increased rate of toxicities,which is why some strategies to de-escalate treatment intensity have been studied.展开更多
Dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are ...Dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are treated with chemotherapy and/or radiation therapy.The 5-year relative survival rate for patients with metastatic sarcoma is only 15%.展开更多
Cancer therapy has improved considerably in the last years;however,therapeutic resistance is still a major problem that impedes full response to the treatment and the main cause of patient relapse and death.Numerous k...Cancer therapy has improved considerably in the last years;however,therapeutic resistance is still a major problem that impedes full response to the treatment and the main cause of patient relapse and death.Numerous kinases have been reported to be overactivated in cancer and induce resistance to current therapies.Targeting kinases has proven to be useful for overcoming chemotherapy resistance and thus improving patient outcomes.Inhibitor of kappaB kinase alpha(IKKα)is a serine/threonine kinase that was first described as part of the IKK complex in the nuclear factor-κB(NF-κB)pathway,which regulates several physiological and physiopathological processes such as immunity,inflammation,and cancer.However,the IKKαsubunit has been shown to be dispensable for NF-κB activation and responsible of multiple pro-tumorigenic functions.Furthermore,we identified a nuclear active form of IKKαkinase IKKα(p45)that promotes tumor growth and therapy resistance,independent of canonical NF-κB.Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies.Here,we review the recent publications on the implications of IKKαin cancer initiation,development,and resistance.展开更多
基金by the Instituto de Salud Carlos III,Ministerio de Economia,Industria y Competitividad,No.PI18/01604.
文摘Pancreatic ductal adenocarcinoma(PDAC)is an aggressive tumor with high lethality.Even with surgery,radiotherapy,chemotherapy,and other locoregional or systemic therapies,the survival rates for PDAC are low and have not significantly changed in the past decades.The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease.PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells.The pancreatic microenvironment is a fibrotic,microvascularized stroma that isolates the tumor from systemic vascularization.Immunotherapy,a novel approach that has demonstrated effectiveness in certain solid tumors,has failed to show any practice-changing results in pancreatic cancer,with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden,which show prolonged survival rates with immunotherapy.Currently,numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell transfer,alone or in combination with other immunotherapeutic agents,chemoradiotherapy,and other targeted therapies.A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.
基金supported by a Spanish Association Against Cancer(AECC)grant,(grant No.PROYE18012ROSE)support from Julián Santamaría Vali?o to the IOR Foundation。
文摘Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.
基金This work was funded by project PI17/00578,from the“Instituto de Salud Carlos III”(Ministry of Science,Innovation and Universities)and co-funded by the European Regional Development Fund,and approved by the Ethics Committee of our Institution.It has been founded also by projects CB16/12/00228,PI16/00161,RD16/0011/0011,RD12/0019/0023 and SAF2017–84248-PWe would like to thank Rebeca Sánchez-Domínguez and Omaira Alberquilla for their help with the flow cytometry studies+3 种基金Federico Sánchez-Sierra and Pilar Hernández for their excellent histological processing of the samplesthe personnel of the CIEMAT Animal Unit for mouse careWe also thank Manuel Serrano(Institute for Research in Biomedicine,Barcelona,Spain)for his generous gift of Ink4a/Arf KO miceThanks also go to Anton Berns(Netherlands Cancer Institute,NKI,The Netherlands)for supplying the p53EKO mice.
文摘Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their histopathological characteristics and clinical behaviour, the classification of these tumours is still under debate. Alterations in morphogenesis pathways such as the Hedgehog,MAPK and WNT/β-catenin pathways are implicated in the formation of odontogenic lesions, but the molecular bases of many of these lesions are still unknown. In this study, we used genetically modified mice to study the role of IKKβ(a fundamental regulator of NF-κB activity and many other proteins) in oral epithelial cells and odontogenic tissues. Transgenic mice overexpressing IKKβ in oral epithelial cells show a significant increase in immune cells in both the oral epithelia and oral submucosa. They also show changes in the expression of several proteins and mi RNAs that are important for cancer development. Interestingly, we found that overactivity of IKKβ in oral epithelia and odontogenic tissues, in conjunction with the loss of tumour suppressor proteins(p53, or p16 and p19), leads to the appearance of odontogenic tumours that can be classified as ameloblastic odontomas, sometimes accompanied by foci of secondary ameloblastic carcinomas. These tumours show NF-κB activation and increased β-catenin activity.These findings may help to elucidate the molecular determinants of odontogenic tumourigenesis and the role of IKKβ in the homoeostasis and tumoural transformation of oral and odontogenic epithelia.
基金Supported by The FSEOM(Spanish Society of Medical Oncology Foundation)grant for Projects of the Collaborative Groups in 2018 and by an Astra Zeneca grant,No.ES2020-1939.
文摘BACKGROUNDPatients with advanced gastrointestinal cancer must cope with the negative effects of cancer and complications.AIM To evaluate psychological distress,quality of life,and coping strategies in patients with advanced colorectal cancer compared to non-colorectal cancer based on sex.METHODS A prospective,transversal,multicenter study was conducted in 203 patients;101(50%)had a colorectal and 102(50%)had digestive,non-colorectal advanced cancer.Participants completed questionnaires evaluating psychological distress(Brief Symptom Inventory-18),quality of life(EORTC QLQ-C30),and coping strategies(Mini-Mental Adjustment to Cancer)before starting systemic cancer treatment.RESULTS The study included 42.4%women.Women exhibited more depressive symptoms,anxiety,functional limitations,and anxious preoccupation than men.Patients with non-colorectal digestive cancer and women showed more somatization and physical symptoms than subjects with colorectal cancer and men.Men with colorectal cancer reported the best health status.CONCLUSION The degree of disease acceptance in gastrointestinal malignancies may depend on sex and location of the primary digestive neoplasm.Future interventions should specifically address sex and tumor site differences in individuals with advanced digestive cancer.
基金supported by CERCA/Generalitat de Catalunya and FundacióJosep Carreras-Obra Social la Caixa for core supportthe European Research Council grants(ERC-PoC-957466 IT4B-TALL,ERC-PoC-101100665 BiTE-CAR)+5 种基金H2020(101057250-CANCERNA)the MINECO(PID2022-142966OB-I00/MCIN/AEI/10.13039/501100011033 and Feder Funds)MINECO/European Union NextGenerationEU(CPP2021-008508,CPP2021-008676,CPP2022-009759)the Deutsche JoséCarreras Leukämie-Siftung(DJCLS15R/2021)the Spanish Association Against Cancer(AECC,PRYGN234975MENE)the ISCIII-RICORS within the Next Generation EU program(plan de Recuperación,Transformación y Resilencia).K.F.is supported by Marie-Sklodowska Curie-Postdoctoral fellowship(101153028).
文摘Chimeric antigen receptor T(CAR-T)cell therapies have transformed the treatment of relapsed/refractory(R/R)B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19-or BCMA-expressing tumor cells.However,this approach has yet to be approved for acute myeloid leukemia(AML),the most common acute leukemia in adults and the elderly.Simultaneously,CAR-T cell therapies continue to face significant challenges in the treatment of solid tumors.The primary challenge in developing CAR-T cell therapies for AML is the absence of an ideal target antigen that is both effective and safe,as AML cells share most surface antigens with healthy hematopoietic stem and progenitor cells(HSPCs).
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
基金supported by grants from the Matthias-Lackas Foundation,the Dr.Leopold und Carmen Ellinger Foundation,the European Research Council(ERC CoG 2023#101122595)the Deutsche Forschungsgemeinschaft(DFG 458891500)+8 种基金the German Cancer Aid(DKH-70112257,DKH-7011411,DKH-70114278,DKH-70115315)the Dr.Rolf M.Schwiete foundation,the SMARCB1 association,the Ministry of Education and Research(BMBFSMART-CARE and HEROES-AYA)the Barbara and Wilfried Mohr foundation.The research team of Florencia Cidre-Aranaz was supported by the German Cancer Aid(DHK-70114111)the Dr.Rolf M.Schwiete Stiftung(2020-028 and 2022-31)supported by the Cancer Grand Challenges partnership funded by Cancer Research UK,the National Cancer Institute,the Scientific Foundation of the Spanish Association Against Cancer And KiKa(Children Cancer Free Foundation)Florian Henning Geyer,Tobias Faehling,Endrit Vinca,and Alina Ritter were supported by the German Academic Scholarship Foundation.In addition,Endrit Vinca was supported by scholarships from the Heinrich F.C.Behr foundation and the Rudolf and Brigitte Zenner foundation,Tobias Faehling by the Heinrich F.C.Behr foundationFlorian Henning Geyer and Alina Ritter are supported by the German Cancer Aid through the‘Mildred-Scheel-Doctoral Program’(DKH-70114866)This project is co-funded by the European Union(ERC,CANCER-HARAKIRI,101122595)。
文摘Desmoplastic small round cell tumor(DSRCT)is an aggressive cancer that predominantly affects adolescents and young adults,typically developing at sites lined by mesothelium[1,2].DSRCT is genetically defined by a chromosomal translocation that fuses the N-terminus of EWS RNA binding protein 1(EWSR1)to the C-terminus of Wilms tumor protein(WT1),forming EWSR1::WT1[3].This fusion encodes a potent transcription factor and is the only known driver of oncogenic transformation in DSRCT[4].The lack of a comprehensive understanding of DSRCT biology parallels its dismal survival rate(5%-20%)[1].These challenges are exacerbated by the absence of clinical trials,the limited systematic collection and analysis of DSRCT biomaterial[1],and the notable lack of specific diagnostic markers,necessitating resource-intensive molecular testing for an accurate diagnosis.
基金supported by a fellowship from the American Italian Cancer Foundation(AICF)(#223565-01)supported by the Italian Ministry of Health,Ricerca Finalizzata 2021 Giovani Ricercatori,ID.GR-2021-12375316+19 种基金funded by the CERCA Program/Generalitat de Catalunya,MCIN/AEI/10.13039/501100011033the European Development Regional Fund,“A way to make Europe”EDRF(project PID2021-125282OB-I00)Departament de Recerca i Universitats/Generalitat de Catalunya(2021 SGR 01494)“La Caixa”Research Foundation and the Cellex Foundation(CEL007)supported(as a PI unless otherwise indicated)by one NIH R01 grant(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)by a grant from the STARR Cancer Consortium(#I16--0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291,PI:Deasy,Formenti,Weichselbaum)by the 2019 Laura Ziskin Prize in Translational Research(#ZP--6177,PI:Formenti)from the Stand Up to Cancer(SU2C)by a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PI:Demaria,Formenti),a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center(New York,US)by startup funds from the Dept.of Radiation Oncology at Weill Cornell Medicine(New York,US)by startup funds from Fox Chase Cancer Center(Philadelphia,US)by donations from Promontory(New York,US)the Luke Heller TECPR2 Foundation(Boston,US),supported by funding from Associazione Italiana per la Ricerca sul Cancro AIRC,IG 2022 ID.27685CARESS Fondazione Piemontese per la Ricerca sul Cancro(FRPC)5×1000 Intramural Grantthe European Union–Next Generation EU–PNRR M6C2-Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN(ID.PNRR-POC-2023-12378288)funds from the Italian Institute for Genomic Medicine and Compagnia di San Paolo.
文摘Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators,as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks.Such alterations(i.e.,methylation,acetylation,and ubiquitination)are catalyzed by an array of dedicated enzymes with antagonistic activity,including methyltransferases and demethylases,acetyltransferases and deacetylases,as well as ubiquitin ligases and deubiquitinating enzymes.The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues.In line with this notion,epigenetic defects have been associated with a variety of human disorders,including(but not limited to)congenital conditions as well as multiple hematological and solid tumors.Here,we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness,i.e.,the ability of a small population of poorly differentiated malignant cells to(1)self-renew while generating a more differentiated progeny,and(2)exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress.Moreover,we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.
基金Among these,patents were licensed to Bayer(WO2014020041-A1 and WO2014020043-A1)Bristol-Myers Squibb(WO2008057863-A1)+4 种基金Osasuna Therapeutics(WO2019057742A1)Pharmamar(WO2022049270A1 and WO2022048775-A1)Raptor Pharmaceuticals(EP2664326-A1)Samsara Therapeutics(GB202017553D0)Therafast Bio(EP3684471A1).The other authors declare that they have no competing interests.
文摘Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.
基金funded by the Spanish Ministry of Science and Innovation(Agencia Estatal de Investigacion),co-funded by FEDER funds-a way to build Europe-[PID2020-112595RB-I00(LV)]Instituto de Salud Carlos Ⅲ(CIBERONC CB16/12/00234)+2 种基金Government of Catalonia(AGAUR 2021SGR01112,CERCA Program for institutional support)Marie Sktodowska-Curie Individual Fellow ship(No.897064(NG-A))Scientific Foundation"Asociacion Espanola Contra el Cancer"[AECC Investigador contract(MT)].
文摘Germline activating variants in WWP1,which encodes an E3 ubiquitin ligase that antagonizes PTEN tumor suppressive function,have been proposed as an alternative mechanism of PTEN inactivation in PTEN-hamartoma-tumor syndrome(PHTS)-like patients with wildtype PTEN.1 More specifically,heterozygous,potentially activating wwP1 variants were first identified by Lee et al in patients affected with gastrointestinal oligopolyposis,including adenomatous,hyperplastic/serrated,and hamartomatous polyps,and occasionally with colorectal cancer(Table 1).Subsequently,based on the PHTS phenotypic features,wWP1 mutational screening was performed in patients with thyroid nodules,2 or normocephalic autism spectrum disorder(ASD),3 where germline WWP1 variants were also identified(Table S1).
基金supported by the government of Xunta de Galicia(Competitive Reference Groups,Consellería de Educación e Ordenación Universitaria,Xunta de Galicia,No.ED431C 2021/17)by the ISCⅢ thorough AES 2020,Award No.AC20/00028 and within the framework of EuroNanoMed Ⅲ+3 种基金part of the project Proof of Concept(No.PDC2021-120929-I00)financed by the Spanish Ministry of Science and Innovation-AEI/10.13039/501100011033the European Union NextGenerationEU/PRTRthe Spanish Ministry of Science,Innovation and Universities(No.FPU18/00095).
文摘The current spotlight of cancer therapeutics is shifting towards personalized medicine with the widespread use of monoclonal antibodies(mAbs).Despite their increasing potential,mAbs have an intrinsic limitation related to their inability to cross cell membranes and reach intracellular targets.Nanotechnology offers promising solutions to overcome this limitation,however,formulation challenges remain.These challenges are the limited loading capacity(often insufficient to achieve clinical dosing),the complex formulation methods,and the insufficient characterization of mAb-loaded nanocarriers.Here,we present a new nanocarrier consisting of hyaluronic acid-based nanoassemblies(HANAs)specifically designed to entrap mAbs with a high efficiency and an outstanding loading capacity(50%,w/w).HANAs composed by an mAb,modified HA and phosphatidylcholine(PC)resulted in sizes of~100 nm and neutral surface charge.Computational modeling identified the principal factors governing the high affinity of mAbs with the amphiphilic HA and PC.HANAs composition and structural configuration were analyzed using the orthogonal techniques cryogenic transmission electron microscopy(cryo-TEM),asymmetrical flow field-flow fractionation(AF4),and small-angle X-ray scattering(SAXS).These techniques provided evidence of the formation of core-shell nanostructures comprising an aqueous core surrounded by a bilayer consisting of phospholipids and amphiphilic HA.In vitro experiments in cancer cell lines and macrophages confirmed HANAs’low toxicity and ability to transport mAbs to the intracellular space.The reproducibility of this assembling process at industrial-scale batch sizes and the long-term stability was assessed.In conclusion,these results underscore the suitability of HANAs technology to load and deliver biologicals,which holds promise for future clinical translation.
文摘Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy(ACT).The provision of proper costimulatory receptor activity and cytokine stimuli,along with the repression of inhibitory mechanisms,will conceivably make the most of these treatment strategies.In this sense,T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion,last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant tissues.Their antitumor effects can be dramatically augmented with permanent or transient gene transfer maneuvers to express or delete/repress genes.A combination of such interventions seeks the creation of the ultimate bionic T cell,perfected to seek and destroy cancer cells upon systemic or local intratumor delivery.
文摘The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling,while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity.A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways.Here we have focused on the role of Endoglin(Eng),a key co-receptor for members of the Tgf-β/Bmp family of growth factors.Using an Eng haploinsufficient mouse model,we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches.We further report thatβ-catenin binds to the Eng promoter depending on Bmp signalling.Moreover,we show thatβ-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription.These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.
基金This work was supported by Ministerio de Ciencia,Innovacion y Universidades(MCIU),Plan Estatal de I+D+I 2018,Spain,Agencia Estatal de Investigacion(AEl),Spain,and Regional Development European Funds(FEDER),European Union(No.RTI2018-097455-B-I00 and RED2018-102723)CIBER of Cancer,Spain(No.CB16/12/00275)+2 种基金Consejeria de Salud of the Junta de Andalucia,Spain(No.Pl-0397-2017)Consejeria of Economia,Conocimiento,Empresas y Universidad of the Junta de Andalucia,Spain(No.P18-RT-2501)Fundacion AECC,Spain and Fundacion Eugenio Rodriguez Pascual,Spain.EMV-S was funded by a postdoctoral contract from Consejeria of Transformacion Economica,Industria,Conocimiento,y Universidades of the JuntadeAndalucia,Spain(No.CTEICU/PAIDI2020).
文摘SPINOPHILIN(SPN,PPP1R9B or NEURABIN-2)is a multifunctional protein that regulates protein-protein interactions in different cell signaling pathways.SPN is also one of the regulatory subunits of protein phosphatase 1(PP1),implicated in the dephosphorylation of retinoblastoma protein(pRB)during cell cycle.The SPN gene has been described as a tumor suppressor in different human tumor contexts,in which low levels of SPN are correlated with a higher grade and worse prognosis.In addition,mutations of the SPN protein have been reported in human tumors.Recently,an oncogenic mutation of sPN,A566V,was described,which affects both the SPN-PP1 interaction and the phosphatase activity of the holoenzyme,and promotes p53-dependent tumorigenesis by increasing the cancer stem cell(CsC)pool in breast tumors.Thus,the loss or mutation of SPN could be late events that promotes tumor progression by increasing the CSC pool and,eventually,the malignant behavior of the tumor.
基金supported by grants from the European Union under the Horizon 2020 programme(MultipleMS grant agreement 733161)to NKfrom the Spanish Government,through project PID2019-111192GA-I00(MICINN)to DGC.
文摘Background:Single-cell multi-omics technologies allow a profound system-level biology understanding of cells and tissues.However,an integrative and possibly systems-based analysis capturing the different modalities is challenging.In response,bioinformatics and machine learning methodologies are being developed for multi-omics single-cell analysis.It is unclear whether current tools can address the dual aspect of modality integration and prediction across modalities without requiring extensive parameter fine-tuning.Methods:We designed LIBRA,a neural network based framework,to learn translation between paired multi-omics profiles so that a shared latent space is constructed.Additionally,we implemented a variation,aLIBRA,that allows automatic fine-tuning by identifying parameter combinations that optimize both the integrative and predictive tasks.All model parameters and evaluation metrics are made available to users with minimal user iteration.Furthermore,aLIBRA allows experienced users to implement custom configurations.The LIBRA toolbox is freely available as R and Python libraries at GitHub(TranslationalBioinformaticsUnit/LIBRA).Results:LIBRA was evaluated in eight multi-omic single-cell data-sets,including three combinations of omics.We observed that LIBRA is a state-of-the-art tool when evaluating the ability to increase cell-type(clustering)resolution in the integrated latent space.Furthermore,when assessing the predictive power across data modalities,such as predictive chromatin accessibility from gene expression,LIBRA outperforms existing tools.As expected,adaptive parameter optimization(aLIBRA)significantly boosted the performance of learning predictive models from paired data-sets.Conclusion:LIBRA is a versatile tool that performs competitively in both“integration”and“prediction”tasks based on single-cell multi-omics data.LIBRA is a data-driven robust platform that includes an adaptive learning scheme.
基金supported by Spanish Government and cofinanced by FEDER Funds(PI18/01219,PI21/01351,PI18/00382,and RTI2018-100910-B-C41)CIBERBBN(CB07/01/2012)+6 种基金CIBERONC(CB16/12/00481)the Generalitat Valenciana(project PROMETEO 2018/024)funded by Generalitat Valenciana(ACIF/2016/030)funded by Asociación Española Contra el Cancer.funded by Instituto de Salud Carlos Ⅲ and the European Social Fund for the financial support“Sara Borrell”(CD19/00038)funded by Ministerio de Ciencia e Innovación(FPU grant)funded by Sociedad Española de Oncología Médica(Río Hortega-SEOM).
文摘Dear Editor,Breast cancer(BC)is the most commonly diagnosed cancer and the fifth cause of cancer-related death worldwide[1].Despite the advances in BC targeted therapies,cytotoxic chemotherapy is still widely used[2].However,around 20%-30%of BC patients develop metastasis after treatment as a consequence of drug resistance[3].In this context,microRNAs have emerged as potential therapeutic targets to overcome therapy resistance[4].Therefore,we aimed to elucidate the molecular mechanisms underlying resistance to doxorubicin,one of the most effective chemotherapeutic agents used in BC.Methods are detailed in Supplementary Materials.
基金supported in part by grants from the Spanish Government,Ministerio de Economía y Competitividad(FIS PI12/02767 and PI15/02180 to AC)Generalitat Valenciana(PROMETEO 2013-005 to AC)CIBERONC.
文摘The availability of biologicals,such as anti-EFGR and anti-VEGF antibodies in combination with chemotherapy(ChT),has improved prognosis of metastatic colorectal cancer(mCRC).However,the administration of drug combinations for a prolonged time implies an increased rate of toxicities,which is why some strategies to de-escalate treatment intensity have been studied.
基金The authors thank the donors and the Hospital Universitario Virgen del Rocío-Instituto de Biomedicina de Sevilla Biobank(Andalusian Public Health System Biobank and ISCIII-Red de Biobancos y Biomodelos-ISCIII-PT20/00069)for the human specimens used in this study.This research was funded by grants from the Ministerio de Ciencia e Innovación(MCI),Plan Estatal de I+D+I 2021,Agencia Estatal de Investigación(AEI)and Fondo Europeo de Desarrollo Regional(MCI/AEI/FEDER,UE):ID2021-122629OB-I00from CIBER de Cáncer(CB16/12/00275)+3 种基金co-funded by FEDER from Regional Development European Funds(European Union)from Consejería de Salud(PI-0397-2017)Project P18-RT-2501 from the 2018 competitive research projects call within the scope of PAIDI 2020 co-financed by the European Regional Development Fund(ERDF)from the Regional Ministry of Economic Transformation,IndustryKnowledge and Universities,Junta de Andalucía.Special thanks to the AECC(Spanish Association of Cancer Research)Founding Ref.GC16173720CARR for supporting this work.EMV-S is funded by a postdoctoral fellowship from Junta de Andalucía(DOC_00512).
文摘Dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are treated with chemotherapy and/or radiation therapy.The 5-year relative survival rate for patients with metastatic sarcoma is only 15%.
文摘Cancer therapy has improved considerably in the last years;however,therapeutic resistance is still a major problem that impedes full response to the treatment and the main cause of patient relapse and death.Numerous kinases have been reported to be overactivated in cancer and induce resistance to current therapies.Targeting kinases has proven to be useful for overcoming chemotherapy resistance and thus improving patient outcomes.Inhibitor of kappaB kinase alpha(IKKα)is a serine/threonine kinase that was first described as part of the IKK complex in the nuclear factor-κB(NF-κB)pathway,which regulates several physiological and physiopathological processes such as immunity,inflammation,and cancer.However,the IKKαsubunit has been shown to be dispensable for NF-κB activation and responsible of multiple pro-tumorigenic functions.Furthermore,we identified a nuclear active form of IKKαkinase IKKα(p45)that promotes tumor growth and therapy resistance,independent of canonical NF-κB.Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies.Here,we review the recent publications on the implications of IKKαin cancer initiation,development,and resistance.
