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Immune checkpoint blockade (ICB) necessitates a thorough understanding of intricate cellular interactions within the tumor microenvironment (TME). Mesenchymal stromal cells (MSCs) play a pivotal role in cancer generation, progression, and immunosuppressive tumor microenvironment. Within the TME, MSCs encompass both resident and circulating counterparts that dynamically communicate and actively participate in TME immunosurveillance and response to ICB. This review aims to reevaluate various facets of MSCs, including their potential self-transformation to function as cancer-initiating cells and contributions to the creation of a conducive environment for tumor proliferation and metastasis. Additionally, we explore the immune regulatory functions of tumor-associated MSCs (TA-MSCs) and MSC-derived extracellular vesicles (MSC-EVs) with analysis of potential connections between circulating and tissue-resident MSCs. A comprehensive understanding of the dynamics of MSC-immune cell communication and the heterogeneous cargo of tumor-educated versus naïve MSCs may unveil a new MSC-mediated immunosuppressive pathway that can be targeted to enhance cancer control by ICB.
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Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCE: Mechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk.
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HIV-1CRF08_BC is the most prevalent epidemic subtype among heterosexual (HET) and intravenous drug users (IDUs) in Kunming, Yunnan. Using the pol region of gene sequences derived from molecular epidemiological surveys, we developed a molecular transmission network for the purpose of analyzing its epidemiological characteristics, assessing its epidemiological trends, identifying its potential transmission relationships, and developing targeted interventions. HyPhy 2.2.4 was used to calculate pairwise genetic distances between sequences; GraphPad-Prism 8.0 was employed to determine the standard genetic distance; and Cytoscope 3.7.2 was applied to visualize the network. We used the network analysis tools to investigate network characteristics and the Molecular Complex Detection (MCODE) tool to observe the growth of the network. We utilized a logistic regression model to examine the factors influencing clustering and a zero-inflated Poisson model to investigate the factors influencing potential transmission links. At the standard genetic distance threshold of 0.008, 406 out of 858 study participants were clustered in 132 dissemination networks with a total network linkage of 868, and the number of links per sequence ranged from 1 to 19. The MCODE analysis identified three significant modular clusters in the networks, with network scores ranging from 4.9 to 7. In models of logistic regression, HET, middle-aged and elderly individuals, and residents of northern and southeastern Kunming were more likely to enter the transmission network. According to the zero-inflated Poisson model, age, transmission category, sampling year, marital status, and CD4+ T level had a significant effect on the size of links. The molecular clusters in Kunming's molecular transmission network are specific and aggregate to a certain extent. HIV-1 molecular network analysis provided information on local transmission characteristics, and these findings helped to determine the priority of transmission-reduction interventions.
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Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.
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@#Abstract: Objective To investigate the distribution characteristics of HCV genotypes and subtypes in patients with HIV (human immunodeficiency virus, HIV)/HCV co-infection in Kunming based on the nucleocapsid protein gene sequence of HCV (hepatitis C virus). Methods Serum was collected from HIV/HCV co-infected patients with household registration in 14 county-level cities, districts and counties under the jurisdiction of Kunming, who admitted to Yunnan Provincial Infectious Disease Hospital from March to August 2019. The viral RNA was extracted from the serum, reverse transcribed to synthesize cDNA, and the HCV nucleocapsid protein gene-specific primers were used for nested PCR amplification. The positive amplification products were sequenced, bioinformatics software such as DNAstar and MEGAX were used for sequence analysis. Results A total of 64 samples from co-infected patients with clinical diagnosis of suspected HIV/HCV were collected and amplified by HCV nucleocapsid protein gene-specific primers, of which 17 samples were amplified positively. The results of sequence analysis showed that the sequences of 9 cases were located in the same evolutionary branch as the HCV 3b subtype sequence, and the nucleotide homology was 93.3%-95.2%; the sequences of 5 cases were located in the same evolutionary branch as the HCV 1b subtype sequence, and the nucleotide homology was 96.8%-97.6%; the sequence of one case and the subtype sequence of HCV 3a gene were located in the same evolutionary branch, and the nucleotide homology was 95.2%; the sequence of one case and HCV 6n gene subtype sequence were located in the same evolutionary branch, and the nucleotide homology was 97.9%; One case was located in the same evolutionary branch as the HCV 6u gene subtype sequence, and the nucleotide homology was 98.4%. Conclusions HCV 1b, HCV 3a, HCV 3b, HCV 6n and HCV 6u genotypes or subtypes of HCV are prevalent in Kunming, and HCV 3b is the most prevalent genotype.
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@#Abstract: Objective To analyze the distribution characteristics of the main pathogens of HIV/AIDS patients with wound infections and provide basis for clinical diagnosis and treatment. Methods The clinical data of 294 patients with positive secretions or pus specimens from 2016 to 2020 were analyzed retrospectively. Results A total of 357 strains of pathogenic bacteria were isolated from 294 cases, of which 123 strains of Gram-negative bacilli (G-b), accounting for 34.5%, were mainly Escherichia coli (15.4%), Klebsiella pneumoniae (3.9%), and Pseudomonas aeruginosa (3.6%); Gram-positive bacilli (G+b) 14 strains, accounting for 3.9%; 108 Gram-positive cocci (G+c), accounting for 30.3%, of which 44 strains were coagulase-positive Staphylococcus aureus (12.3%), Coagulase-negative staphylococci were mainly Staphylococcus epidermidis (4.2%) and Staphylococcus hemolyticus (2.8%); 37 strains of fungi, accounting for 10.4%, were mainly Candida albicans (5.9%); 75 strains of Mycobacterium, accounting for 21.0%, including 41 strains of Mycobacterium tuberculosis (11.5%) and 34 strains of non-tuberculosis mycobacteria (9.5%). 52 of the 294 HIV/AIDS patients had mixed infections, accounting for 17.7%. There was significant difference in the distribution of G+c, G-b, mycobacteria and mixed infection among different specimen sources (P<0.05), and there was significant difference in the distribution of mycobacteria among different CD4+T lymphocyte counts (P<0.05). There was significant difference in the level of CD4+T lymphocytes between patients of different ages (P<0.05), and there was significant difference in the level of CD4+T lymphocytes from postoperative incision and other parts (P<0.05). Conclusions Patients with HIV/AIDS are prone to combined wound infections with various pathogenic bacteria. We should strengthen the research on wound infection in HIV/AIDS patients, and timely send patients with a low number of CD4+T lymphocytes for secretion or pus culture, so as to carry out targeted treatment and improve the prognosis of patients.
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Reasonable nitrogen fertilizer application is an important strategy to maintain optimal growth of grasslands, thereby enabling them to better fulfil their ecological functions while reducing environmental pollution caused by high nitrogen fertilizer production and application. Optimizing the ammonium (NH4 +):nitrate (NO3 -) ratio is a common approach for growth promotion in crops and vegetables, but research on this topic in grass plants has not received sufficient attention. Centipedegrass, which is widely used in landscaping and ecological protection, was used as the experimental material. Different NH4 +:NO3 - ratios (0: 100, 25:75, 50:50, 75:25, 100:0) were used as the experimental treatments under hydroponic conditions. By monitoring the physiological and morphological changes under each treatment, the appropriate NH4 +:NO3 - ratio for growth and its underlying mechanism were determined. As the proportion of ammonium increased, the growth showed a "bell-shaped" response, with the maximum biomass and total carbon and nitrogen accumulation achieved with the NH4 +:NO3 - ratio of 50:50 treatment. Compared with the situation where nitrate was supplied alone, increasing the ammonium proportion increased the whole plant biomass by 93.2%, 139.7%, 59.0%, and 30.5%, the whole plant nitrogen accumulation by 44.9%, 94.6%, 32.8%, and 54.8%, and the whole plant carbon accumulation by 90.4%, 139.9%, 58.7%, and 26.6% in order. As a gateway for nitrogen input, the roots treated with an NH4 +:NO3 - ratio of 50:50 exhibited the highest ammonium and nitrate uptake rate, which may be related to the maximum total root length, root surface area, average root diameter, root volume, and largest root xylem vessel. As a gateway for carbon input, leaves treated with an NH4 +:NO3 - ratio of 50:50 exhibited the highest stomatal aperture, stomatal conductance, photosynthetic rate, transpiration rate, and photosynthetic products. The NH4 +:NO3 - ratio of 50:50 treatment had the largest stem xylem vessel area. This structure and force caused by transpiration may synergistically facilitate root-to-shoot nutrient translocation. Notably, the change in stomatal opening occurred in the early stage (4 hours) of the NH4 +:NO3 - ratio treatments, indicating that stomates are structures that are involved in the response to changes in the root NH4 +:NO3 - ratio. In summary, we recommend 50:50 as the appropriate NH4 +:NO3 - ratio for the growth of centipedegrass, which not only improves the nitrogen use efficiency but also enhances the carbon sequestration capacity.
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During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection. Herein, we demonstrate that radiosensitivity is increased in mice with the deficient Period 2 gene (Per2def) due to impaired DNA repair and mitochondrial function in progenitor bone marrow hematopoietic stem cells and monocytes. Per2 induction and radioprotection are also identified in LDR-treated Per2wt mouse cells and in human skin (HK18) and breast (MCF-10A) epithelial cells. LDR-boosted PER2 interacts with pGSK3ß(S9) which activates ß-catenin and the LEF/TCF mediated gene transcription including Per2 and genes involved in DNA repair and mitochondrial functions. This study demonstrates that PER2 plays an active role in LDR adaptive radioprotection via PER2/pGSK3ß/ß-catenin/Per2 loop, a potential target for protecting normal cells from radiation injury.
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Low dose non-toxic disulfide cross-linked micelle (DCM) encapsulated paclitaxel (PTX) was found to be highly efficacious as a radiosensitizer against oral cancer preclinical model. Intensity-modulated radiation therapy was locally administered for three consecutive days 24 h after intravascular injection of DCM-[PTX] at 5 mg/kg PTX. DCM-[PTX] NPs combined with conventional radiotherapy (2 Gy) resulted in a 1.7-fold improvement in therapeutic efficacy compared to conventional PTX plus radiotherapy. Interestingly, we found that radiotherapy can decrease tight junctions and increase the accumulation of DCM-[PTX] in tumor sites. Stereotactic body radiotherapy (SBRT) given at 6 Gy was used to further investigate the synergistic anti-tumor effect. Tumor tissues were collected to analyze the relationship between the time interval after SBRT and the biodistribution of the nanomaterials. Compared to combination DCM-[PTX] with conventional radiation dose, combination DCM-PTX with SBRT was found to be more efficacious in inhibiting tumor growth.
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Micelas , Neoplasias de la Boca , Línea Celular Tumoral , Disulfuros , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/radioterapia , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Distribución TisularRESUMEN
Although stem cell-derived extracellular vesicles (EVs) have remarkable therapeutic potential for various diseases, the therapeutic efficacy of EVs is limited due to their degradation and rapid diffusion after administration, hindering their translational applications. Here, we developed a new generation of collagen-binding EVs, by chemically conjugating a collagen-binding peptide SILY to EVs (SILY-EVs), which were designed to bind to collagen in the extracellular matrix (ECM) and form an EV-ECM complex to improve EVs' in situ retention and therapeutic efficacy after transplantation. Methods: SILY was conjugated to the surface of mesenchymal stem/stromal cell (MSC)-derived EVs by using click chemistry to construct SILY-EVs. Nanoparticle tracking analysis (NTA), ExoView analysis, cryogenic electron microscopy (cryo-EM) and western-blot analysis were used to characterize the SILY-EVs. Fluorescence imaging (FLI), MTS assay, ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the collagen binding and biological functions of SILY-EVs in vitro. In a mouse hind limb ischemia model, the in vivo imaging system (IVIS), laser doppler perfusion imaging (LDPI), micro-CT, FLI and RT-qPCR were used to determine the SILY-EV retention, inflammatory response, blood perfusion, gene expression, and tissue regeneration. Results:In vitro, the SILY conjugation significantly enhanced EV adhesion to the collagen surface and did not alter the EVs' biological functions. In the mouse hind limb ischemia model, SILY-EVs presented longer in situ retention, suppressed inflammatory responses, and significantly augmented muscle regeneration and vascularization, compared to the unmodified EVs. Conclusion: With the broad distribution of collagen in various tissues and organs, SILY-EVs hold promise to improve the therapeutic efficacy of EV-mediated treatment in a wide range of diseases and disorders. Moreover, SILY-EVs possess the potential to functionalize collagen-based biomaterials and deliver therapeutic agents for regenerative medicine applications.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Modelos Animales de Enfermedad , Vesículas Extracelulares/metabolismo , Isquemia/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Células Madre , Cicatrización de HeridasRESUMEN
Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.
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Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A-/-, CPT2-/-, ACAD9-/- cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.
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Antígeno CD47 , Glioblastoma , Animales , Antígeno CD47/metabolismo , Línea Celular Tumoral , Ácidos Grasos , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Evasión Inmune , Ratones , FagocitosisRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continue to impact countries worldwide. At present, inadequate diagnosis and unreliable evaluation systems hinder the implementation and development of effective prevention and treatment strategies. Here, we conducted a horizontal and longitudinal study comparing the detection rates of SARS-CoV-2 nucleic acid in different types of samples collected from COVID-19 patients and SARS-CoV-2-infected monkeys. We also detected anti-SARS-CoV-2 antibodies in the above clinical and animal model samples to identify a reliable approach for the accurate diagnosis of SARS-CoV-2 infection. Results showed that, regardless of clinical symptoms, the highest detection levels of viral nucleic acid were found in sputum and tracheal brush samples, resulting in a high and stable diagnosis rate. Anti-SARS-CoV-2 immunoglobulin M (IgM) and G (IgG) antibodies were not detected in 6.90% of COVID-19 patients. Furthermore, integration of nucleic acid detection results from the various sample types did not improve the diagnosis rate. Moreover, dynamic changes in SARS-CoV-2 viral load were more obvious in sputum and tracheal brushes than in nasal and throat swabs. Thus, SARS-CoV-2 nucleic acid detection in sputum and tracheal brushes was the least affected by infection route, disease progression, and individual differences. Therefore, SARS-CoV-2 nucleic acid detection using lower respiratory tract samples alone is reliable for COVID-19 diagnosis and study.
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Prueba de COVID-19/veterinaria , COVID-19/diagnóstico , SARS-CoV-2/genética , Animales , Anticuerpos Antivirales , Modelos Animales de Enfermedad , Haplorrinos , Humanos , Estudios Longitudinales , Faringe/virología , Valor Predictivo de las Pruebas , SARS-CoV-2/inmunología , Manejo de Especímenes , Esputo/virologíaRESUMEN
Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for improving treatment. Here, we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell (PBMC) samples from 18 patients with coronavirus disease 2019 (COVID-19) during their treatment, convalescence, and rehabilitation. After analyzing the regulatory networks of differentially expressed messenger RNAs (mRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) between the different clinical stages, we found that humoral immunity and type I interferon response were significantly downregulated, while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19. The formation of this T cell immune response might be driven by the activation of activating protein-1 (AP-1) related signaling pathway and was weakly affected by other clinical features. These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.
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COVID-19/genética , Inmunidad Humoral/genética , Linfocitos T/metabolismo , Transcriptoma/genética , COVID-19/epidemiología , COVID-19/patología , Femenino , Humanos , Inmunidad Humoral/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , MicroARNs , ARN Largo no Codificante/genética , RNA-Seq , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Transcripción AP-1/genéticaRESUMEN
Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.
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Neoplasias de la Mama/metabolismo , Antígeno CD47/metabolismo , Tolerancia a Radiación , Receptor ErbB-2/metabolismo , Animales , Neoplasias de la Mama/patología , Antígeno CD47/genética , Proliferación Celular , Células Clonales , Femenino , Humanos , Células MCF-7 , Macrófagos/metabolismo , Ratones , Modelos Biológicos , FN-kappa B/metabolismo , Fagocitosis , Transducción de Señal , Transcripción Genética , Carga TumoralRESUMEN
The tumor microenvironment (TME) is an evolutionally low-level and embryonically featured tissue comprising heterogenic populations of malignant and stromal cells as well as noncellular components. Under radiotherapy (RT), the major modality for the treatment of malignant diseases [1], TME shows an adaptive response in multiple aspects that affect the efficacy of RT. With the potential clinical benefits, interests in RT combined with immunotherapy (IT) are intensified with a large scale of clinical trials underway for an array of cancer types. A better understanding of the multiple molecular aspects, especially the cross talks of RT-mediated energy reprogramming and immunoregulation in the irradiated TME (ITME), will be necessary for further enhancing the benefit of RT-IT modality. Coming studies should further reveal more mechanistic insights of radiation-induced instant or permanent consequence in tumor and stromal cells. Results from these studies will help to identify critical molecular pathways including cancer stem cell repopulation, metabolic rewiring, and specific communication between radioresistant cancer cells and the infiltrated immune active lymphocytes. In this chapter, we will focus on the following aspects: radiation-repopulated cancer stem cells (CSCs), hypoxia and re-oxygenation, reprogramming metabolism, and radiation-induced immune regulation, in which we summarize the current literature to illustrate an integrated image of the ITME. We hope that the contents in this chapter will be informative for physicians and translational researchers in cancer radiotherapy or immunotherapy.
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Neoplasias/radioterapia , Microambiente Tumoral , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células del Estroma/metabolismoRESUMEN
The acute respiratory distress syndrome (ARDS) induced by SARS-CoV-2-mediated cytokine storm (CS) in lungs leads to the high mortality in COVID-19 patients. To reduce ARDS, an ideal approach is to diminish virus loading by activating immune cells for CS prevention or to suppress the overactive cytokine-releasing immune cells for CS inhibition. Here, a potential radiation-mediated CS regulation is raised by reevaluating the radiation-mediated pneumonia control in the 1920s, with the following latent advantages of lung radiotherapy (LR) in treatment of COVID-19: (1) radiation accesses poorly circulated tissue more efficiently than blood-delivered medications; (2) low-dose radiation (LDR)-mediated metabolic rewiring and immune cell activation inhibit virus loading; (3) pre-consumption of immune reserves by LDR decreases CS severity; (4) higherdose radiation (HDR) within lung-tolerable doses relieves CS by eliminating in situ overactive cytokine-releasing cells. Thus, LDR and HDR or combined with antiviral and life-supporting modalities may mitigate SARS-CoV-2 and other virus-mediated ARDS.
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Tumor acquired radioresistance remains as the major limit in cancer radiotherapy (RT). Rab25, a receptor recycling protein, has been reported to be enhanced in tumors with aggressive phenotype and chemotherapy resistance. In this study, elevated Rab25 expression was identified in an array of radioresistant human cancer cell lines, in vivo radioresistant xenograft tumors. Clinical investigation confirmed that Rab25 expression was also associated with a worse prognosis in patients with lung adenocarcinoma (LUAD) and nasopharyngeal carcinoma (NPC). Enhanced activities of EGFR were observed in both NPC and LUAD radioresistant cells. Rab25 interacts with EGFR to enhance EGFR recycling to cell surface and to decrease degradation in cytoplasm. Inhibition of Rab25 showed synergized radiosensitivity with reduced aggressive phenotype. This study provides the clinical and experimental evidence that Rab25 is a potential therapeutic target to alleviate the hyperactive EGFR signaling and to prevent RT-acquired tumor resistance in patients with LUAD and NPC.
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Human epidermal growth factor receptor 2 (HER2) is overexpressed in >20% of breast cancers. Dimerization of HER2 receptors leads to the activation of downstream signals enabling the proliferation and survival of malignant phenotypes. Owing to the high expression levels of HER2, combination therapies are currently required for the treatment of HER2+ breast cancer. Here, we designed non-toxic transformable peptides that self-assemble into micelles under aqueous conditions but, on binding to HER2 on cancer cells, transform into nanofibrils that disrupt HER2 dimerization and subsequent downstream signalling events leading to apoptosis of cancer cells. The phase transformation of peptides enables specific HER2 targeting, and inhibition of HER2 dimerization blocks the expression of proliferation and survival genes in the nucleus. We demonstrate, in mouse xenofraft models, that these transformable peptides can be used as a monotherapy in the treatment of HER2+ breast cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Nanopartículas/química , Péptidos/farmacología , Receptor ErbB-2/metabolismo , Animales , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Ratones , Péptidos/química , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade.