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Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.
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Reparo de Erro de Pareamento de DNA , Linfoma Difuso de Grandes Células B , Microambiente Tumoral , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Reparo de Erro de Pareamento de DNA/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Masculino , Feminino , Mutação , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Adulto , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Emerging evidence highlights the regulatory role of paired-like (PRD-like) homeobox transcription factors (TFs) in embryonic genome activation (EGA). However, the majority of PRD-like genes are lost in rodents, thus prompting an investigation into PRD-like TFs in other mammals. Here, we showed that PRD-like TFs were transiently expressed during EGA in human, monkey, and porcine fertilized embryos, yet they exhibited inadequate expression in their cloned embryos. This study, using pig as the research model, identified LEUTX as a key PRD-like activator of porcine EGA through genomic profiling and found that LEUTX overexpression restored EGA failure and improved preimplantation development and cloning efficiency in porcine cloned embryos. Mechanistically, LEUTX opened EGA-related genomic regions and established histone acetylation via recruiting acetyltransferases p300 and KAT2A. These findings reveal the regulatory mechanism of LEUTX to govern EGA in pigs, which may provide valuable insights into the study of early embryo development for other non-rodent mammals.
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Genoma , Técnicas de Transferência Nuclear , Animais , Suínos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Desenvolvimento Embrionário/genética , Embrião de Mamíferos/metabolismo , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Acetilação , Clonagem de Organismos/métodos , Histonas/metabolismo , Blastocisto/metabolismoRESUMO
Cellular senescence has a complex role in lymphocyte carcinogenesis and drug resistance of lymphomas. Senescent lymphoma cells combine with immunocytes to create an ageing environment that can be reprogrammed with a senescenceassociated secretory phenotype, which gradually promotes therapeutic resistance. Certain signalling pathways, such as the NFκB, Wnt and PI3K/AKT/mTOR pathways, regulate the tumour ageing microenvironment and induce the proliferation and progression of lymphoma cells. Therefore, targeting senescencerelated enzymes or their signal transduction pathways may overcome radiotherapy or chemotherapy resistance and enhance the efficacy of relapsed/refractory lymphoma treatments. Mechanisms underlying drug resistance in lymphomas are complex. The ageing microenvironment is a novel factor that contributes to drug resistance in lymphomas. In terms of clinical translation, some senolytics have been used in clinical trials on patients with relapsed or refractory lymphoma. Combining immunotherapy with epigenetic drugs may achieve better therapeutic effects; however, senescent cells exhibit considerable heterogeneity and lymphoma has several subtypes. Extensive research is necessary to achieve the practical application of senolytics in relapsed or refractory lymphomas. This review summarises the mechanisms of senescenceassociated drug resistance in lymphoma, as well as emerging strategies using senolytics, to overcome therapeutic resistance in lymphoma.
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Senescência Celular , Resistencia a Medicamentos Antineoplásicos , Linfoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Senescência Celular/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfócitos/imunologia , Linfócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Senoterapia/farmacologia , Senoterapia/uso terapêutico , EnvelhecimentoRESUMO
BACKGROUND: Studies on mNGS application in pediatric oncology patients, who are at high risk of infection, are quite limited. METHODS: From March 2020 to June 2022, a total of 224 blood samples from 195 pediatric oncology patients who were suspected as bloodstream infections were enrolled in this study. Their clinical and laboratory data were retrospectively reviewed, and the diagnostic performance of mNGS was assessed. RESULTS: Compared to the reference tests, mNGS showed significantly higher sensitivity (89.8% vs 32.5%, P < 0.001) and clinical agreement (76.3% vs 51.3%, P < 0.001) in detecting potential pathogens and distinguishing BSI from non-BSI. Especially, mNGS had an outstanding performance for virus detection, contributing to 100% clinical diagnosed virus. Samples from patients with neutropenia showed higher incidence of bacterial infections (P = 0.035). The most identified bacteria were Escherichia coli, and the overall infections by gram-negative bacteria were significantly more prevalent than those by gram-positive ones (90% vs 10%, P < 0.001). Overall, mNGS had an impact on the antimicrobial regimens' usage in 54.3% of the samples in this study. CONCLUSIONS: mNGS has the advantage of rapid and effective pathogen diagnosis in pediatric oncology patients with suspected BSI, especially for virus. IMPACT: Compared with reference tests, mNGS showed significantly higher sensitivity and clinical agreement in detecting potential pathogens and distinguishing bloodstream infections (BSI) from non-BSI. mNGS is particularly prominent in clinical diagnosed virus detection. The incidence of bacterial infection was higher in patients with neutropenia, and the overall infection rate of Gram-negative bacteria was significantly higher than that of Gram-positive bacteria. mNGS affects the antimicrobial regimens' usage in more than half of patients.
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Anti-Infecciosos , Neoplasias , Neutropenia , Sepse , Criança , Humanos , Estudos Retrospectivos , Sepse/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Neutropenia/diagnóstico , Escherichia coli , Neoplasias/complicações , Neoplasias/diagnóstico , Sensibilidade e EspecificidadeRESUMO
The presence of serum monoclonal components has been associated with poor outcomes in various hematological malignancies. The current study focused on exploring its prognostic role in B-cell non-Hodgkin lymphoma. Our study represented 314 patients with information on serum immunofixation electrophoresis at diagnosis that were available with B-cell non-Hodgkin lymphoma. IFE was positive in 61 patients (19%). Baseline features were comparable between pairs of groups, poor ECOG PS, B symptoms, advanced stage, and high-risk IPI score were significantly more frequent in the + IFE group. Shorter PFS and OS of B-NHL patients were observed in patients who presented at diagnosis with a + IFE, and IFE was the independent predictor of PFS and OS in multivariate analysis. Moreover, integrating IFE into the IPI-M1, IPI-M2, and IPI-M3 models improved the area under the curve for more accurate survival prediction and prognosis. Serum monoclonal proteins are significant prognostic indicators for newly diagnosed B-cell non-Hodgkin lymphoma that can early identify patients with poor prognosis and guide clinical treatment decisions.
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Linfoma Difuso de Grandes Células B , Humanos , Prognóstico , Linfoma Difuso de Grandes Células B/patologia , Análise Multivariada , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , EletroforeseRESUMO
This study aims to investigate the effects of baicalein(BAI) on lipopolysaccharide(LPS)-induced human microglial clone 3(HMC3) cells, with a focus on suppressing inflammatory responses and elucidating the potential mechanism underlying the therapeutic effects of BAI on ischemic stroke via modulating the cAMP-PKA-NF-κB/CREB pathway. The findings have significant implications for the application of traditional Chinese medicine in treating cerebral ischemic diseases. First, the safe dosage of BAI was screened, and then an inflammation model was established with HMC3 cells by induction with LPS for 24 h. The cells were assigned into a control group, a model group, and high-, medium-, and low-dose(5, 2.5, and 1.25 µmol·L~(-1), respectively) BAI groups. The levels of superoxide dismutase(SOD) and malondialdehyde(MDA) in cell extracts, as well as the levels of interleukin-1ß(IL-1ß), IL-6, tumor necrosis factor-α(TNF-α), and cyclic adenosine monophosphate(cAMP) in the cell supernatant, were measured. Western blot was performed to determine the expression of protein kinase A(PKA), phosphorylated cAMP-response element binding protein(p-CREB), and nuclear factor-kappa B p65(NF-κB p65). Hoechst 33342/PI staining was employed to assess cell apoptosis. High and low doses of BAI were used for treatment in the research on the mechanism. The results revealed that BAI at the concentrations of 10 µmol·L~(-1) and below had no impact on normally cultured HMC3 cells. LPS induction at 200 ng·mL~(-1) for 24 h reduced the SOD activity and increased the MDA content in HMC3 cells. However, 5, 2.5, and 1.25 µmol·L~(-1) BAI significantly increased the SOD activity and 5 µmol·L~(-1) BAI significantly decreased the MDA content. In addition, BAI ameliorated the M1 polarization of HMC3 cells induced by LPS, as indicated by cellular morphology. The results of ELISA demonstrated that BAI significantly lowered the levels of TNF-α, IL-1ß, IL-6, and cAMP in the cell supernatant. Western blot revealed that BAI up-regulated the protein levels of PKA and p-CREB while down-regulating the expression of NF-κB p65. Hoechst 33342/PI staining results indicated that BAI mitigated the apoptosis of HMC3 cells. Overall, the results indicated that BAI had protective effects on the HMC3 cells induced by LPS, and could inhi-bit inflammatory response and improve cell apoptosis, which might be related to the regulation of the cAMP-PKA-NF-κB/CREB pathway.
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Microglia , NF-kappa B , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Natural killer/T cell lymphoma (NKTCL) is an aggressive lymphoma with a poor prognosis. Chimeric antigen receptor-transduced T (CAR-T) cell therapy has become a promising immunotherapeutic strategy against haematologic malignancies. METHODS: In this study, four CAR-T cell lines (CD38-CAR, LMP1-CAR, CD38-LMP1 tandem CAR 1 and CD38-LMP1 tandem CAR 2) were generated. The effect of CAR-T cells against NKTCL cells was evaluated both in vitro and in vivo. Expression of T cell activation markers and cytokines produced by CAR-T cells were detected by flow cytometry. RESULTS: The four CAR-T cell lines could effectively eliminate malignant NKTCL cells. They could be activated and produce inflammatory cytokines in a target-dependent manner. In vivo tests showed that the CAR-T cells exhibited significant antitumour effects in a xenotransplanted NKTCL mouse model. CONCLUSIONS: In summary, four CAR-T cell lines exhibited significant cytotoxicity against NKTCL cells both in vitro and in vivo. These results indicated the effective therapeutic promise of CD38 and LMP1 CAR-T cells in NKTCL.
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Linfoma de Células T , Receptores de Antígenos Quiméricos , Animais , Camundongos , Receptores de Antígenos Quiméricos/genética , Citocinas , Modelos Animais de Doenças , Linfócitos TRESUMO
BACKGROUND: PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL. METHODS: The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo. RESULTS: PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo. CONCLUSIONS: In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.
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Antineoplásicos , Linfoma de Células T , Linfoma , Humanos , Cisplatino/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Células Matadoras Naturais , RNA Mensageiro , Proteínas Proto-Oncogênicas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Proteínas com Domínio LIM/farmacologiaRESUMO
The treatment of natural killer/T-cell lymphoma (NKTCL) presents an onerous challenge, and a search for new therapeutic targets is urgently needed. Poly ADP-ribose polymerase inhibitors (PARPi) were initially used to treat breast and ovarian cancers with BRCA1/2 mutations. Their excellent antitumor efficacy led to a series of clinical trials conducted in other malignancies. However, the exploration of PARPi and their potential use in combination treatments for NKTCL remains unexplored. We treated NKTCL cell lines with fluzoparib (a novel inhibitor of PARP) and chidamide (a classical inhibitor of HDACs) to explore their cytotoxic effects in vitro. Then, their antitumor efficacy in vivo was confirmed in YT-luciferin xenograft mouse models. Fluzoparib or chidamide alone inhibited NKTCL cell proliferation in a dose-dependent manner. Cotreatment with both drugs synergistically induced excessive accumulation of DNA double-strand breaks and massive apoptotic cell death by inhibiting the DNA damage repair pathway, as shown by the decreased protein levels of p-ATM, p-BRCA1, p-ATR, and Rad51. Moreover, the combination treatment apparently increased the level of intracellular reactive oxygen species (ROS) to enhance apoptosis, and pretreatment with an ROS scavenger reduced the proapoptotic effect by 30-60% in NKTCL cell lines. In vivo, this combined regimen also showed synergistic antitumor effects in xenograft mouse models. The combination of fluzoparib and chidamide showed synergistic effects against NKTCL both in vitro and in vivo and deserves further exploration in clinical trials.
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Linfoma de Células T , Linfoma , Humanos , Camundongos , Animais , Proteína BRCA1 , Espécies Reativas de Oxigênio , Proteína BRCA2 , Células Matadoras Naturais , Linhagem Celular TumoralRESUMO
Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with EpsteinâBarr virus (EBV) infection. Chronic and consistent viral infection induces T-cell exhaustion. Herein, we describe T-cell dysfunction in NKTCL patients for the first time. Peripheral blood mononuclear cells (PBMCs) from age-matched healthy donors (HDs) and NKTCL patients were collected, and lymphocyte distributions, multiple surface inhibitory receptors (IRs), effector cytokine production and cell proliferation were determined by flow cytometry. PBMCs from HDs were cocultured with NKTCL cell lines to verify the clinical findings. IR expression was further assessed in NKTCL tumor biopsies using multiplex immunohistochemistry (mIHC). NKTCL patients have higher frequencies than HDs of inhibitory T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). T-cell distribution also varies between NKTCL patients and HDs. T cells from NKTCL patients demonstrated higher expression levels of multiple IRs than HDs. Meanwhile, T-cell proliferation and interferon-γ production was significantly reduced in NKTCL patients. More importantly, the number of EBV-specific cytotoxic cells was lower in NTKCL patients, and these cells demonstrated upregulation of multiple IRs and secreted fewer effector cytokines. Interestingly, NKTCL cells caused normal PBMCs to acquire T-cell exhaustion phenotypes and induced generation of Tregs and MDSCs. In line with ex vivo finding, mIHC results showed that CD8+ T cells from NKTCL tumor biopsies expressed much higher level of IRs compared with reactive lymphoid hyperplasia individuals. The immune microenvironment of NKTCL patients exhibited T-cell dysfunction and accumulation of inhibitory cell components, which may contribute to impaired antitumor immunity.
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Infecções por Vírus Epstein-Barr , Linfoma Extranodal de Células T-NK , Humanos , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Herpesvirus Humano 4/genética , Leucócitos Mononucleares/metabolismo , Células Matadoras Naturais/metabolismo , Microambiente TumoralRESUMO
Purpose: This study aimed to evaluate and analyze the efficacy and safety of low concentration (0.15%) hydrogen peroxide as nasopharyngeal lavage fluid in the treatment for nasopharyngeal carcinoma radiotherapy. Methods: Patients with nasopharyngeal carcinoma from Jiangxi cancer hospital were randomly divided into two cohorts. The training cohort (n= 50) received low concentration (0.15%) hydrogen peroxide as nasopharyngeal lavage fluid in the treatment for nasopharyngeal carcinoma radiotherapy, and the control cohort (n= 50) received 0.02% nitrofurazone lavage fluid. The primary endpoint of the study was result of short-term efficacy. Second endpoints were assessment of the linear visual analogue scale score and the incidences rate of nasopharyngeal radiation related toxicity. Results: All patients had completed the scheduled nasopharyngeal radiotherapy except two patients in control cohort. The complete response, partial response, stable disease and disease objective response of nasopharyngeal primary tumor observed in the training cohort included 18 cases, 23 cases, 9 cases and 41 cases respectively, while in the control cohort 20 cases, 25 cases, 5 cases and 45 cases were recorded, respectively. The study showed a significant discrepancy in the incidence rate of radiation-related mucosa damage between the two. Specifically, Grade 1 and 2 included 37 cases (74.0%) in the training cohort, while in the control cohort the cases were 20 (40.0%). Grade 3 and 4 damage however reported an incidence of 26.0% and 60%, respectively, which clearly constitutes a significant statistical difference (P = 0.002). The assessment of linear visual analogue scale showed that the patients self-conscious comfortable feeling in the training cohort were significantly higher than in the control cohort (P = 0.003). Conclusions: low concentration (0.15%) hydrogen peroxide as nasopharyngeal lavage fluid in the treatment for nasopharyngeal carcinoma patients is effective and safe, and can reduce nasopharyngeal local mucosa radiation related toxicity after radiotherapy.
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Gegen Decoction as anti-inflammatory medicine is used in clinic widespread, however the specific anti-inflammatory molecular mechanism of Gegen Decoction is still unclear. The purpose was to study the anti-inflammatory activity of Gegen Decoction in vivo and to research its anti-inflammatory molecular mechanism. The content of main essential components in Gegen Decoction were determined by HPLC method. The anti-inflammatory activity of Gegen Decoction was confirmed through in vivo animal experiments. Furthermore, RAW 264.7 cells were stimulated by lipopolysaccharides to induce inflammatory reaction, the modulatory effect of Gegen Decoction on the activation process of mitogen-activated protein kinases and nuclear factor-κB signaling pathways was investigated. The content of puerarin was the highest among all the index components. Gegen Decoction inhibited carrageenan-induced paw edema in rats and xylene-induced ear swelling in mice. Gegen Decoction had no obvious toxicity against RAW 264.7 cells at the concentrations of 10-40 mg/mL; significantly inhibited the release of nitric oxide, prostaglandin E2, tumor necrosis factor-α and interleukin-6; down-regulated the high expression of inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. It inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs)/extracellular regulated protein kinases (ERK)/c-Jun N-terminal kinase (JNK), the degradation of nuclear factor-κB (NF-κB)/inhibitor of NF-κB-α (IκB-α) and the nuclear translocation of NF-κB/p65 into nucleus. Gegen Decoction exerts significant anti-inflammatory activity, mainly by blocking the activation of both MAPKs and NF-κB pathway.
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Anti-Inflamatórios , NF-kappa B , Ratos , Camundongos , Animais , NF-kappa B/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteínas I-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Óxido Nítrico Sintase Tipo II/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico/metabolismo , Ciclo-Oxigenase 2/metabolismoRESUMO
BACKGROUND: Multiple myeloma (MM) is an aggressive plasma cell malignancy, causing a number of deaths worldwide every year. Chimeric antigen receptor (CAR) transduced T-cell therapy has been a promising immunotherapy against hematological malignancies. METHODS: In this study, we developed a second-generation CAR construct and generated CAR-T cells targeting CD38 molecule. Then effects of CAR-T cells against MM cell lines were evaluated. RESULTS: CD38-CAR-T cells showed higher cytotoxicity to MM cell lines and primary MM cells than that of control T cells in vitro. Over 50% MM1.s and RPMI8226 cells were killed by CAR-T cells even at effector to target ratio of 1:100. CAR-T cells also showed an enhanced cytotoxicity against primary MM cells. CAR-T cells could be activated and produced a variety of cytokines in a target-dependent manner. In vivo test indicated that CAR-T cells also showed significant antitumor effect on xenograft mice models. CONCLUSION: These results indicated a promising therapeutic strategy of CD38-CAR-T cells against MM.
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Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Animais , Camundongos , Linfócitos T , Mieloma Múltiplo/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia/métodos , Imunoterapia Adotiva , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gut microbiota represents a hidden treasure vault encompassing trillions of microorganisms that inhabit the intestinal epithelial barrier of the host. In the past decade, numerous in-vitro, animal and clinical studies have revealed the profound roles of gut microbiota in maintaining the homeostasis of various physiological functions, especially immune modulation, and remarkable differences in the configuration of microbial communities between cancers and healthy individuals. In addition, although considerable efforts have been devoted to cancer treatments, there remain many patients succumb to their disease with the incremental cancer burden worldwide. Nevertheless, compared with the stability of human genome, the plasticity of gut microbiota renders it a promising opportunity for individualized treatment. Meanwhile, burgeoning findings indicate that gut microbiota is involved in close interactions with the outcomes of diverse cancer immunotherapy protocols, including immune checkpoint blockade therapy, allogeneic hematopoietic stem cell transplantation, and chimeric antigen receptor T cell therapy. Here, we reviewed the evidence for the capacity of gut microflora to modulate cancer immunotherapies, and highlighted the opportunities of microbiota-based prognostic prediction, as well as microbiotherapy by targeting the microflora to potentiate anticancer efficacy while attenuating toxicity, which will be pivotal to the development of personalized cancer treatment strategies.
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Microbioma Gastrointestinal , Microbiota , Neoplasias , Animais , Humanos , Imunoterapia/métodos , Microbiota/fisiologia , Intestinos/fisiologiaRESUMO
Natural killer/T cell lymphoma (NKTCL) is a highly aggressive hematological malignancy. However, there is currently no consensus on therapies for refractory/relapsed patients. In this study, we investigated the synergistic anticancer effect and potential mechanism of combining chidamide, a histone deacetylases (HDACs) inhibitor, and etoposide, a DNA-damaging agent, in NKTCL. We demonstrated that chidamide or etoposide alone dose- and time-dependently inhibited the cell viability of NKTCL cell lines, YT, NKYS and KHYG-1. Functional experiments suggested that combined chidamide and etoposide treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic death in vitro and in vivo. Furthermore, the expression of DNA damage related proteins was detected and we also examined the alternations in histone acetylation, cell cycle progression, and mitochondrial membrane potential (MMP). The results suggested that increased histone acetylation, cell cycle arrest at the G2/M phase and loss of MMP, converging to greater DNA damage, might account for the synergism of the combination of chidamide and etoposide in NKTCL. Taken together, our study provides an evident for possible application on combining HDACs inhibitors and DNA-damaging agents for the treatment of NKTCL.
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Aminopiridinas , Benzamidas , Etoposídeo , Linfoma de Células T Periférico , Humanos , Linhagem Celular Tumoral , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Sinergismo FarmacológicoRESUMO
The development of chimeric antigen receptor T (CAR-T) cell therapy, a specific type of immunotherapy, in recent decades was a fantastic breakthrough for the treatment of hematological malignancies. However, difficulties in collecting normal T cells from patients and the time cost of manufacturing CAR-T cells have limited the application of CAR-T-cell therapy. In addition, the termination of related clinical trials on universal CAR-T cell therapy has made further research more difficult. Natural killer (NK) cells have drawn great attention in recent years. Chimeric antigen receptor-NK (CAR-NK) cell therapy is a promising strategy in the treatment of malignant tumors because of its lack of potential for causing graft-versus-host disease (GVHD). In this review, we will address the advances in and achievements of CAR-NK cell therapy.
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Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais , Terapia Baseada em Transplante de Células e TecidosRESUMO
[This corrects the article DOI: 10.1515/med-2022-0506.].
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Circular RNAs (circRNAs) can regulate autophagy and ovarian cancer (OC) progression. However, autophagy-associated circRNAs involved in OC progression are largely unknown. Bioinformatics, RNA sequencing, and qRT-PCR were conducted to detect circRNF144B expression in OC as well as its relationship with patient prognosis. Functional experiments were used to determine the effects of circRNF144B on the proliferation, mobility and autophagy of OC. Double luciferase reporter assays, immunoprecipitation, and ubiquitination detection were performed to determine the molecular mechanisms of circRNF144B in autophagy and OC progression. CircRNF144B was elevated in OC tissues with low autophagy levels, and associated with poor prognosis. CircRNF144B promoted the malignant biological properties of OC cells, and inhibited the autophagy. Mechanistically, circRNF144B acts as a sponge for miR-342-3p and inhibits miR-342-3p-induced degradation of lysine demethylase 2 A (FBXL11) mRNA, leading to elevated FBXL11 protein levels. Elevated FBXL11 promoted the ubiquitination and degradation of Beclin-1, thus inhibiting autophagy. In conclusion, CircRNF144B increased FBXL11 level by sponging miR-342-3p, whereas elevated FBXL11 promoted the ubiquitination and protein degradation of Beclin-1, thus suppressing autophagy flux and promoting OC progression. Thus, circRNF144B may be an effective target for OC therapy.
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MicroRNAs , Neoplasias Ovarianas , Autofagia/genética , Proteína Beclina-1/genética , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas F-Box/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Circular/genética , RNA Mensageiro , UbiquitinaçãoRESUMO
Many patients with prostate cancer (PCa) cannot be diagnosed until an advanced stage, which make PCa become a large threat to human health. It is an urgent need to explore novel biomarkers for accurate diagnosis and targets for the effective treatment of PCa. This study aimed to investigate the effects of RAB3D (which belongs to the secretory Rab GTPases) on the progression of PCa. The results showed that RAB3D was highly expressed in PCa tissues compared to normal tissues according to the gene expression omnibus dataset. Consistent with the bioinformatics results, RAB3D exhibited a higher expression in PCa cells. Overexpression of RAB3D promoted the proliferation, migration, and invasion of PCa cells, whereas the knockdown of RAB3D led to the opposite results. The procancer effects of RAB3D were further confirmed by the in vivo growth of xenograft model. Subsequently, RAB3D upregulated the PI3K/AKT signaling pathway both in vivo and in vitro. LY294002 (a PI3K inhibitor) rescued the RAB3D upregulation-induced promotion of malignant phenotypes of PCa cells. Furthermore, the transcription activity of RAB3D was found to be enhanced by aryl hydrocarbon receptor (AhR; a transcription factor). The AhR silencing-induced inhibition of the proliferation and migration of PCa cells was reversed by the overexpression of RAB3D. Taken together, RAB3D, upregulated by AhR, promotes the PCa progression by activating the PI3K/AKT signaling pathway.
Assuntos
Fosfatidilinositol 3-Quinases , Neoplasias da Próstata , Masculino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias da Próstata/metabolismo , Proliferação de Células , Proteínas rab3 de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/metabolismo , Proteínas rab3 de Ligação ao GTP/farmacologiaRESUMO
The purpose of this study was to investigate the effect of cystic areas of osteonecrosis of the femoral head (ONFH) on stress distribution and disease progression in the femoral head. A total of 85 patients (106 hips) diagnosed with Association Research Circulation Osseous stage II non-traumatic and non-surgical treatment were retrospectively analyzed. The presence of cystic areas and diameter of cystic areas were compared between the two groups. In addition, five spherical cystic areas of different diameters were constructed and the maximum stress was observed. There was a difference between the two groups in whether cystic areas appeared in the femoral head, with 49.1% in the collapse group showing cystic areas, which was significantly higher than that in the non-collapse group (18.4%) (P < 0.05). In addition, the diameter of the cystic areas was significantly larger in the collapsed group than in the non-collapsed group (P < 0.05). The maximum and mean von Mises stress value around the necrotic area and around the cystic area of the femoral head increased with the increase of the cystic diameter. Stress concentration areas can be generated around the cystic areas. The presence and increased diameter of the cystic areas accelerates the collapse of the ONFH femoral head.