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OBJECTIVE: This study aims to quantitatively assess the relationship between the patella alignment and morphology and knee osteoarthritis (KOA), as well as the kinematics and kinetics of the knee, using gait analysis. METHODS: Eighty age-matched patients with KOA and control subjects were evaluated. Incident radiographic osteoarthritis (iROA) was identified using a Kellgren-Lawrence (KL) grade of ≥ 2. The modified Insall-Salvati ratio (Mod-ISR), patellar tilt angle (PTA), and patella index (PI) were utilized to evaluate the sagittal and transverse alignment of the patella and its morphology, respectively. Regression analyses were conducted to explore associations between patellar measurements and KOA, iROA, kinematics, and kinetics. RESULTS: Significant differences were observed between the control and KOA groups in terms of KL grade, patella alta, abduction angle, and reaction force to the ground (P < 0.05, respectively). Following adjustment for covariates, a significant positive association was found between patella alta and KOA (OR = 0.307, 95%CI: 0.103 to 0.918, P = 0.035). Additionally, a significant negative association was observed between PTA and abduction angle (B = -0.376, 95%CI: -0.751 to -0.002; P = 0.049). The PI exhibited a statistically significant association with log-transformed vertical ground reaction force (B = 0.002, 95%CI: 0.001 to 0.003, P = 0.002). Furthermore, adjustment for covariates did not reveal any significant correlations with other indicators (P > 0.05, respectively). CONCLUSION: This study provides further evidence that proper alignment and morphology of the patella might be associated with maintaining normal biomechanical function. In addition, intervention measures targeting relevant patellar parameters, such as Mod-ISR, PTA, and PI, may positively impact KOA treatment outcomes.
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Osteoartrite do Joelho , Patela , Humanos , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/patologia , Patela/diagnóstico por imagem , Patela/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fenômenos Biomecânicos , Marcha/fisiologiaRESUMO
BACKGROUND: Increasing evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in biological processes and are dysregulated in numerous tumors. The lncRNA GRASLND functions as an oncogene in many cancers, but its role in skin cutaneous melanoma (SKCM) requires further investigation. METHODS: SiRNA transfection, wound - healing and transwell assays were performed to evaluate the effect of GRASLND on cellular function. RESULTS: The present study demonstrated that GRASLND expression is increased in SKCM tissues and cell lines. The high expression of GRASLND was correlated with poor prognosis and immunotherapy outcomes. Knockdown of GRASLND significantly inhibited cell migration and invasion. In addition, we found that miR-218-5p directly binds to its binding site on GRASLND, and GRASLND and miR-218-5p demonstrate mutual inhibition. Furthermore, the miR-218-5p inhibitor partially eliminated the knockdown of GRASLND and inhibited its expression. We also demonstrated that GRASLND acts as a miR-218-5p sponge that positively regulates STAM2 expression in SKCM cells. CONCLUSION: In summary, these data suggest that GRASLND functions by regulating miR-218-5p/STAM2 expression, suggesting an important role for the lncRNAâmiRNA-mRNA functional network and a new potential therapeutic target for SKCM.
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Sequência de Bases , Movimento Celular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Melanoma , MicroRNAs , RNA Longo não Codificante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismoRESUMO
Photoaffinity probes are routinely utilized to identify proteins that interact with small molecules. However, despite this common usage, resolving the specific sites of these interactions remains a challenge. Here we developed a chemoproteomic workflow to determine precise protein binding sites of photoaffinity probes in cells. Deconvolution of features unique to probe-modified peptides, such as their tendency to produce chimeric spectra, facilitated the development of predictive models to confidently determine labeled sites. This yielded an expansive map of small-molecule binding sites on endogenous proteins and enabled the integration with multiplexed quantitation, increasing the throughput and dimensionality of experiments. Finally, using structural information, we characterized diverse binding sites across the proteome, providing direct evidence of their tractability to small molecules. Together, our findings reveal new knowledge for the analysis of photoaffinity probes and provide a robust method for high-resolution mapping of reversible small-molecule interactions en masse in native systems.
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Marcadores de Fotoafinidade , Bibliotecas de Moléculas Pequenas , Sítios de Ligação , Humanos , Marcadores de Fotoafinidade/química , Bibliotecas de Moléculas Pequenas/química , Ligação Proteica , Proteômica/métodos , Proteoma/metabolismo , Proteínas/química , Proteínas/metabolismo , Peptídeos/química , Peptídeos/metabolismoRESUMO
The excessive use of quaternary ammonium compounds (QACs) following the COVID-19 pandemic has raised substantial concerns regarding their biosafety. Overuse of QACs has been associated with chronic biological adverse effects, including genotoxicity or carcinogenicity. In particular, inadvertent intravascular administration or oral ingestion of QACs can lead to fatal acute toxicity. To enhance the biosafety and antimicrobial efficacy of QACs, this study reports a new series of QACs, termed as PACs, with the alkyl chain of benzalkonium substituted by a phthalocyanine moiety. Firstly, the rigid phthalocyanine moiety enhances the selectivity of QACs to bacteria over human cells and reduces alkyl chain's entropic penalty of binding to bacterial membranes. Furthermore, phthalocyanine neutralizes hemolysis and cytotoxicity of QACs by binding with albumin in plasma. Our experimental results demonstrate that PACs inherit the optical properties of phthalocyanine and validate the broad-spectrum antibacterial activity of PACs in vitro. Moreover, the intravascular administration of the most potent PAC, PAC1a, significantly reduced bacterial burden and ameliorated inflammation level in a bacteria-induced septic mouse model. This study presents a new strategy to improve the antimicrobial efficacy and biosafety of QACs, thus expanding their range of applications to the treatment of systemic infections.
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COVID-19 , Desinfetantes , Animais , Camundongos , Humanos , Antibacterianos/toxicidade , Compostos de Amônio Quaternário/toxicidade , Contenção de Riscos Biológicos , Pandemias , Indóis/toxicidadeRESUMO
Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b+ myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT.
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Calgranulina A , Serpinas , Camundongos , Animais , Humanos , Calgranulina A/genética , Calgranulina B/genética , Serpinas/genética , Quimiocinas/metabolismoRESUMO
We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.
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Antígenos CD19 , Imunoterapia Adotiva , Linfoma de Células B , Síndromes Neurotóxicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Idoso , Humanos , Antígenos CD19/imunologia , Antígenos CD19/uso terapêutico , Quimioterapia de Consolidação , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T , Imunoterapia Adotiva/métodosRESUMO
We isolated a paraffin oil-degrading bacterial strain from a mixture of oil-based drill cutting and paddy soil, and characterized the strain using a polyphasic approach. The Gram-positive, aerobic, rod-shaped and non-spore-forming strain (SCAU 2101T) grew optimally at 50 °C, pH 7.0 and 0.5â% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence indicated that the strain represented a distinct clade in the genus Chelativorans, neighbouring Chelativorans intermedius LMG 28482T (97.1 %). The genome size and DNA G+C content of the strain were 3 969 430 bp and 63.1 mol%, respectively. Whole genome based phylogenomic analyses showed that the average nucleotide identity and digital DNA-DNA hybridization values between strain SCAU 2101T and C. intermedius LMG 28482T were 77.5 and 21.2â%, respectively. The major respiratory quinone was Q-10. The dominant fatty acids were C19â:â0 cyclo ω8c (50.6â%), summed feature 8 (C18â:â1 ω7c and/or C18â:â1 ω6c; 22.5â%) and C18â:â0 (13.8â%). The polar lipids of the strain included phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, phosphatidylcholine and diphosphatidylglycerol. Based on the results, strain SCAU 2101T was considered to represent a novel species in the genus Chelativorans, for which the name Chelativorans petroleitrophicus sp. nov. is proposed. The type strain is SCAU 2101T (= CCTCC AB 2021125T=KCTC 92067T).
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Ácidos Graxos , Phyllobacteriaceae , Ácidos Graxos/química , Fosfolipídeos/química , Filogenia , RNA Ribossômico 16S/genética , Ubiquinona/química , DNA Bacteriano/genética , Composição de Bases , Técnicas de Tipagem Bacteriana , Análise de Sequência de DNA , Phyllobacteriaceae/genéticaRESUMO
Radiotherapy is a commonly used cancer treatment; however, patients with high serum squamous cell carcinoma antigen (SCCA1/SERPINB3) are associated with resistance and poor prognosis. Despite being a strong clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We investigated the microenvironment of SERPINB3 high tumors through RNAseq of primary cervix tumors and found that SERPINB3 was positively correlated with CXCL1/8, S100A8/A9 and myeloid cell infiltration. Induction of SERPINB3 in vitro resulted in increased CXCL1/8 and S100A8/A9 production, and supernatants from SERPINB3-expressing cultures attracted monocytes and MDSCs. In murine tumors, the orthologue mSerpinB3a promoted MDSC, TAM, and M2 macrophage infiltration contributing to an immunosuppressive phenotype, which was further augmented upon radiation. Radiation-enhanced T cell response was muted in SERPINB3 tumors, whereas Treg expansion was observed. A STAT-dependent mechanism was implicated, whereby inhibiting STAT signaling with ruxolitinib abrogated suppressive chemokine production. Patients with elevated pre-treatment serum SCCA and high pSTAT3 had increased intratumoral CD11b+ myeloid cell compared to patients with low SCCA and pSTAT3 cohort that had overall improved cancer specific survival after radiotherapy. These findings provide a preclinical rationale for targeting STAT signaling in tumors with high SERPINB3 to counteract the immunosuppressive microenvironment and improve response to radiation.
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We developed a continuous learning system (CLS) based on deep learning and optimization and ensemble approach, and conducted a retrospective data simulated prospective study using ultrasound images of breast masses for precise diagnoses. We extracted 629 breast masses and 2235 images from 561 cases in the institution to train the model in six stages to diagnose benign and malignant tumors, pathological types, and diseases. We randomly selected 180 out of 3098 cases from two external institutions. The CLS was tested with seven independent datasets and compared with 21 physicians, and the system's diagnostic ability exceeded 20 physicians by training stage six. The optimal integrated method we developed is expected accurately diagnose breast masses. This method can also be extended to the intelligent diagnosis of masses in other organs. Overall, our findings have potential value in further promoting the application of AI diagnosis in precision medicine.
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The aim of this study was to investigate the anticancer mechanisms of white genius mushroom (WGM). WGM is a popular edible mushroom in Taiwan and has been demonstrated to mediate potent antiproliferation effects against human Hep3B liver cancer cells in our previous study. According to next generation sequencing technology and KEGG pathway enrichment analysis, mTOR and MAPK signaling pathways were markedly changed during treatment with WGM extracts in Hep3B cells. Therefore, this study examined the effects of WGM extracts on the expression of mTOR and MAPK signaling pathway-related proteins, such as PI3K, Akt, mTOR, Ras, Raf, MEK, ERK, p38 and JNK in Hep3B cells. According to the results of immunoblotting, we demonstrated that the protein expression of the members of PI3K/Akt/mTOR and MAPK signaling pathways were involved in WGM extracts-induced cell death. Furthermore, the inhibitors of PI3K/Akt/mTOR and MAPK signaling pathways such as rapamycin, MK2206, LY3214996 and SB202190, blocked the induction of cell death and vacuoles formation induced by WGM extracts. This study also demonstrated that WGM extracts is able to inhibit Hep3B cell migration and colony formation in a dose-dependent manner. In addition to being a very popular food, WGM should be a pharmacologically safe natural agent for cancer treatment. Therefore, WGM might be designed to develop into a dietary chemopreventive agent for the cancer treatment.
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As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson's disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.
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Apoptose , Cobre , Doenças Neurodegenerativas , Humanos , Morte Celular , Homeostase/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Estresse OxidativoRESUMO
CD19 chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the cytokine release syndrome (CRS) was presented in most patients as common toxicity and severe CRS (sCRS) characterized by the sharp increase in interleukin-6 (IL-6) could be life-threatening. We conducted a phase II clinical trial of ssCAR-T-19 cells, anti-CD19 CAR-T cells with shRNA targeting IL-6, in 61 patients with r/r B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT03275493. Fifty-two patients achieved CR while nine patients were considered NR. The median duration of response (DOR) and overall survival (OS) were not reached (>50 months). CRS developed in 81.97% of patients, including 54.10% with grades 1 to 2 (grade 1, 31.15%; grade 2, 22.95%) and 27.87% with grades 3 to 4 (grade 3, 26.23%; grade 4, 1.64%). sCRS occurs earlier than mild CRS (mCRS). A multivariable analysis of baseline characteristics identified high bone marrow disease burden and poor genetic risk before infusion as independent risk factors for sCRS. After infusion, patients with sCRS exhibited larger expansion of ssCAR-T-19 cells, higher peak levels of IL-6, IL-10, and IFN-γ, and suffered more severe hematological and non-hematological toxicities compared with those with mCRS.
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Linfoma Folicular , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos , Síndrome da Liberação de Citocina/etiologia , Humanos , Interleucina-6/genética , Linfoma Folicular/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Fatores de RiscoRESUMO
Background: 3D organoid cultures of hair follicles (HFs) are powerful models that mimic native HF for both in-depth study of HF disease and precision therapy. However, few studies have investigated the complete structure and properties of HF organoids. To investigate and characterize the complete HF organoids self-assembled by coculture of neonatal mouse epidermal cells (MECs) and dermal cells in Matrigel. Methods: Fresh epidermal and dermal cells from newborn mice (n=4) were isolated, and cocultured (1:1 ratio) in Matrigel using DMEM/F12 medium for 1 week. During the culture, an inverted microscope was used to observe the morphology of the 3D constructs. After 1 week, hematoxylin-eosin (HE) and immunofluorescence (IF) staining of HF-related markers (K5, K73, AE13, and K10), HF stem cell markers (K15, CD34, CD49f), skin-derived precursor-related marker (Nestin), and dermal papillae (DP)-specific markers (SOX2 and ALP) was performed in the harvested constructs to identify the HF organoids. Results: Epidermal and dermal cells self-assembled into HF organoids comprising an infundibular cyst-like structure, a lower segment-like structure, and a bulb-like structure from tail to root. The HF organoid had multiple, well-defined compartments similar to native anagen HF. Of the three segments, K73 was expressed in the inner root sheath-like layer, AE13 was localized in the hair shaft-like structure, K5, K15, CD34, and CD49f were present in the outer root sheath-like layer, Nestin labeled the connective tissue sheath-like layer, and SOX2 and ALP were expressed in the DP-like structure. Furthermore, K10 and K73 were expressed in the infundibular cyst-like structure. The expression of these molecular proteins was consistent with native anagen HF. Conclusions: The complete HF organoid regenerated in Matrigel has specific compartments and is an excellent model to study HF disease and precision therapy.
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White strain of Hypsizygus marmoreus is named as white genius mushroom (WGM) and is a popular food in Taiwan. We have confirmed the cytotoxicity of WGM extracts on human Hep3B liver cancer cells. A total of 8711 significantly differential genes were identified through large-scale transcriptome sequencing. According to the KEGG pathway enrichment analysis, autophagy, mitophagy and apoptosis pathways were identified as significant in WGM extracts-treated cells. WGM extracts induced a dose-dependent generation of reactive oxygen species (ROS) and membrane-enclosed vacuoles in Hep3B cells. The inhibition of ROS by the ROS scavengers blocked the induction of cell death and vacuoles formation. We suggested that the cell death and membrane-enclosed vacuoles induced by WGM extracts are dependent on ROS production in Hep3B cells. (2E,6E)-3,7,11,15,19,23,27,31,35-Nonamethylhexatriaconta-2,6,34-triene-1,11,15,19,23,27,31-heptol and (18:2) lysophosphatidylcholine were identified in WGM extracts. In addition to being a very popular edible mushrooms, WGM may be developed into a dietary supplement or dietary chemopreventive agent for the cancer treatment.
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Lysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, respectively, demonstrated a lysoptosis phenotype distinct from other cell death pathways. Like in C. elegans, this pathway depended on LMP and released cathepsins, predominantly cathepsin L. These studies suggested that lysoptosis is an evolutionarily-conserved eukaryotic LDCD that predominates in the absence of neutralizing endogenous inhibitors.
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Antígenos de Neoplasias/genética , Morte Celular , Células Epiteliais/fisiologia , Serpinas/genética , Animais , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Serpinas/metabolismoRESUMO
The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, with biochemical and cellular features of lysoptosis. Rescue with wild-type SERPINB3 or a reactive site loop mutant indicates that protease inhibitory activity is required to protect cervical tumor cells from radiation-induced death. Transcriptomics analysis of primary cervix tumor samples and genetic knock out demonstrates a role for the lysosomal protease cathepsin L in radiation-induced cell death in SERPINB3 knock-out cells. These data support targeting of SERPINB3 and lysoptosis to treat radioresistant cervical cancers.
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Antígenos de Neoplasias/genética , Catepsina L/antagonistas & inibidores , Morte Celular , Radiação Ionizante , Serpinas/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Células Neoplásicas Circulantes/efeitos dos fármacos , Serpinas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.
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Analgésicos Opioides/farmacologia , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Leucemia Mieloide Aguda/patologia , Receptores Opioides mu/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Loperamida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides mu/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia. METHODS: A clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen. RESULTS: Thirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others. CONCLUSION: The double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier:NCT03985007.
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Protein acetylation is a central event in orchestrating diverse cellular processes. However, current strategies to investigate protein acetylation in cells are often nonspecific or lack temporal and magnitude control. Here, we developed an acetylation tagging system, AceTAG, to induce acetylation of targeted proteins. The AceTAG system utilizes bifunctional molecules to direct the lysine acetyltransferase p300/CBP to proteins fused with the small protein tag FKBP12F36V, resulting in their induced acetylation. Using AceTAG, we induced targeted acetylation of a diverse array of proteins in cells, specifically histone H3.3, the NF-κB subunit p65/RelA, and the tumor suppressor p53. We demonstrate that targeted acetylation with the AceTAG system is rapid, selective, reversible and can be controlled in a dose-dependent fashion. AceTAG represents a useful strategy to modulate protein acetylation and should enable the exploration of targeted acetylation in basic biological and therapeutic contexts.
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Fator de Transcrição RelARESUMO
Computed tomography (CT) screening is essential for early lung cancer detection. With the development of artificial intelligence techniques, it is particularly desirable to explore the ability of current state-of-the-art methods and to analyze nodule features in terms of a large population. In this paper, we present an artificial-intelligence lung image analysis system (ALIAS) for nodule detection and segmentation. And after segmenting the nodules, the locations, sizes, as well as imaging features are computed at the population level for studying the differences between benign and malignant nodules. The results provide better understanding of the underlying imaging features and their ability for early lung cancer diagnosis.