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BACKGROUND AND OBJECTIVE: Patients who undergo gross total resection (GTR) of Central Nervous System World Health Organization (WHO) grade 1 meningioma constitute a "low-risk" group, but some low-risk meningiomas can recur despite reassuring clinical and histological features. In this study, gene expression values in newly diagnosed WHO grade 1 meningiomas that had undergone GTR were evaluated for their association with recurrence. METHODS: This was a retrospective, international, multicenter cohort study that included WHO grade 1 meningiomas that underwent GTR, as first treatment, based on postoperative magnetic resonance imaging. Normalized gene expression values from a previously validated 34-gene panel were evaluated for their association with recurrence. Kaplan-Meier, multivariable Cox proportional hazard analyses, and K-means clustering were performed to assess the association of genes of interest with recurrence and identify molecular subgroups among clinically and histologically low-risk meningiomas. RESULTS: In total, 442 patients with WHO grade 1 meningiomas that underwent GTR and had available gene expression profiling data were included in the study. The median follow-up was 5.0 years (interquartile range 2.6-7.7 years), local recurrence occurred in 36 patients (8.1%), 5-year local freedom from recurrence was 90.5%, and median time to recurrence was 2.9 years (range 0.5-10.7 years). Eleven genes were associated with local recurrence, including lower expression of ARID1B, ESR1, LINC02593, PGR, and TMEM30B and higher expression of CDK6, CDKN2C, CKS2, KIF20A, PGK1, and TAGLN. Of these genes, PGK1 had the largest effect size. K-means clustering based on these 11 genes distinguished 2 molecular groups of clinically and histologically low-risk meningiomas with significant differences in local freedom from recurrence (hazard ratio 2.5, 95% CI 1.2-5.1, P = .016). CONCLUSION: Gene expression profiling may help to identify newly diagnosed WHO grade 1 meningiomas that have an elevated risk of recurrence despite GTR.
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BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. CONCLUSIONS: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.
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PURPOSE: Patients undergoing radiation therapy may terminate treatment for any number of reasons. The incidence of treatment termination (TT) during radiation therapy has not been studied. Herein, we present a cohort of TT at a large multicenter radiation oncology department over 10 years. METHODS AND MATERIALS: TTs between January 2013 and January 2023 were prospectively analyzed as part of an ongoing departmental quality and safety program. TT was defined as any premature discontinuation of therapy after initiating radiation planning. The rate of TT was calculated as a percentage of all patients starting radiation planning. All cases were presented at monthly morbidity and mortality conferences with a root cause reviewed. RESULTS: A total of 1448 TTs were identified out of 31,199 planned courses of care (4.6%). Six hundred eighty-six (47.4%) involved patients treated with curative intent, whereas 753 (52.0%) were treated with palliative intent, and 9 (0.6%) were treated for benign disease. The rate of TT decreased from 8.49% in 2013 to 3.02% in 2022, with rates decreasing yearly. The most common disease sites for TT were central nervous system (21.7%), head and neck (19.3%), thorax (17.5%), and bone (14.2%). The most common causes of TT were hospice and/or patient expiration (35.9%), patient choice unrelated to toxicity (35.2%), and clinician choice unrelated to toxicity (11.5%). CONCLUSIONS: This 10-year prospective review of TTs identified a year-over-year decrease in TTs as a percentage of planned patients. This decrease may be associated with the addition of root cause reviews for TTs and discussions monthly at morbidity and mortality rounds, coupled with departmental upstream quality initiatives implemented over time. Understanding the reasons behind TTs may help decrease preventable TTs. Although some TTs may be unavoidable, open discourse and quality improvement changes effectively reduce TT incidents over time.
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Background: There have been few articles on the vertical dimension of the Asian upper eyelid, the eyelid crease segment, and the upper palpebral segment. The eyelid crease height manifests differently depending on whether it is closed (on extreme downgaze), open, or on upward gaze. This study will investigate a ratio practical for use in Asian blepharoplasty (external incisional method). Methods: The central vertical dimensions of Asian upper eyelids were measured, together with the upper palpebral segment and eyelid crease height when present. These parameters were recorded preoperatively and following double-eyelid surgery, and remeasured at 1 week and 2 months postoperative with eyelids closed and with eyes open looking straight ahead. The ratios of anatomic upper/lower segments and apparent (eyes opened) upper/lower ratio were tabulated for each case. Results: The mean vertical height of upper eyelid skin among Asian women 30 years of age and younger was 23.4 mm, and between 31 and 50 years of age was 25.4 mm. The design of Asian upper eyelid crease and determination of skin tissues that can be safely removed include designing crease height to be 7 mm or slightly less and leaving an upper eyelid segment of at least a length 2 times or more of the crease height, to yield an aesthetically desirable double-eyelid segments ratio. Conclusions: The study confirms the practical application of the upper/lower segments ratio at surgery and at full recovery (2 mo) using such technique and shows its progression to a desirable range of double-eyelid segments ratio. It has proven effective and useful for patients seeking Asian blepharoplasty.
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Background: To compare tumor margins and surgical outcomes between transanal minimally invasive surgery (TAMIS) and endoscopic submucosal dissection (ESD) for large or malignant rectal adenomatous polyps. Methods: Single institution retrospective analysis of patients who underwent TAMIS or ESD surgery. Results: In total, 30 consecutive patients with similar demographics who underwent either TAMIS (n = 19) or ESD (n = 11) were included. The median (interquartile range, IQR) tumor distances from the anal verge for TAMIS and ESD were 5 cm (3.5-8) and 3 cm (2-4.25) (P = 0.016). Four in TAMIS and two in ESD occupied more than half of the circumference of the bowel lumen. Five (four in situ and one stage 1) in TAMIS and two (one in situ and one stage 1) in ESD were malignant. The median specimen length, width, and height were 3.2 cm, 2.6 cm, and 1.0 cm and 3.5 cm, 2.0 cm, and 0.3 cm for TAMIS and ESD, respectively. There were no statistically significant differences in tumor circumference, malignant ratios, or specimen sizes. Resection margins were involved in two of the ESD, while none of the TAMIS were involved (P = 0.041). The median (IQR) operative time was 72 (62-89) minutes and 120 (90-180) minutes for TAMIS and ESD (P = 0.005). The median (IQR) follow-up time was 3.3 (0.3-11.7) and 0.9 (0.3-15.4) months for TAMIS and ESD. There were no morbidities, no mortalities, or local recurrences among the two groups. Conclusions: Both TAMIS and ESD were found to be feasible and safe in community hospital practice. Operative time was shorter, and there were no involved margins in TAMIS (versus ESD).
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The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically "cold" microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an â¼50â¯% complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.
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Antígenos de Neoplasias , Neoplasias Colorretais , Instabilidade de Microssatélites , Animais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Humanos , Camundongos , Feminino , Linhagem Celular Tumoral , Linfócitos T/imunologia , MasculinoRESUMO
Age-related structural and functional changes in the kidney can eventually lead to development of chronic kidney disease, which is one of the leading causes of mortality among elderly people. For effective management of age-related kidney complications, it is important to identify new therapeutic interventions with minimal side-effects. The present study was designed to evaluate the synergistic effect of a traditional Chinese herb, Alpinate Oxyphyllae Fructus (AOF), and adipose-derived mesenchymal stem cells (ADMSCs) in ameliorating D-galactose (D-gal)-induced renal aging phenotypes in WKY rats. The study findings showed that D-gal-induced alteration in the kidney morphology was partly recovered by the AOF and ADMSC co-treatment. Moreover, the AOF and ADMSC co-treatment reduced the expression of proinflammatory mediators (NFkB, IL-6, and Cox2) and increased the expression of redox regulators (Nrf2 and HO-1) in the kidney, which were otherwise augmented by the D-gal treatment. Regarding kidney cell death, the AOF and ADMSC co-treatment was found to abolish the proapoptotic effects of D-gal by downregulating Bax and Bad expressions and inhibiting caspase 3 activation. Taken together, the study findings indicate that the AOF and ADMSC co-treatment protect the kidney from D-gal-induced aging by reducing cellular inflammation and oxidative stress and inhibiting renal cell death. This study can open up a new path toward developing novel therapeutic interventions using both AOF and ADMSC to effectively manage age-related renal deterioration.
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Medicamentos de Ervas Chinesas , Galactose , Rim , Células-Tronco Mesenquimais , Animais , Galactose/efeitos adversos , Ratos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
INTRODUCTION: The key outcome of joint registries is revision events, which inform clinical practice and identify poor-performing implants. Registries record revision events and reasons, but accuracy may be limited by a lack of standardized definitions of revision. Our study aims to assess the accuracy and completeness of unicompartmental knee arthroplasty (UKA) revision and indications reported to the New Zealand Joint Registry (NZJR) with independent clinical review. METHODS: Case record review of 2272 patients undergoing primary UKA at four large tertiary hospitals between 2000 and 2017 was performed, identifying 158 patients who underwent revision. Detailed review of clinical findings, radiographs and operative data was performed to identify revision cases and the reasons for revision using a standardized protocol. These were compared to NZJR data using chi-squared and Fisher exact tests. RESULTS: The NZJR recorded 150 (95%) of all UKA revisions. Osteoarthritis progression was the most common reason on the systematic clinical review (35%), however, this was underreported to the registry (8%, P < 0.001). A larger proportion of revisions reported to the registry were for 'pain' (30% of cases vs. 5% on clinical review, P < 0.001). A reason for revision was not reported to the registry for 10% of cases. CONCLUSION: The NZJR had good capture of UKA revisions, but had significant differences in registry-reported revision reasons compared to our independent systematic clinical review. These included over-reporting of 'pain', under-reporting of osteoarthritis progression, and failing to identify a revision reason. Efforts to improve registry capture of revision reasons for UKA could be addressed through more standardized definitions of revision and tailored revision options for UKA on registry forms.
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Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.
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Heterogeneidade Genética , Neoplasias Meníngeas , Meningioma , Meningioma/genética , Meningioma/patologia , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Análise de Célula Única , Proliferação de Células/genética , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genética , Linhagem Celular Tumoral , TranscriptomaRESUMO
BACKGROUND: There are few available studies that compare the feasibility, efficacy, and safety of robotic pelvic lateral lymph node dissection compared to laparoscopic pelvic lateral lymph node dissection (LPLND) in advanced rectal cancer. This meta-analysis aims to compare perioperative outcomes between robotic and LPLND. METHODS: We performed a systemic literature review of PubMed, Embase, and Web of Science databases. Perioperative parameters were extracted and pooled for analysis. This meta-analysis provided an analysis of heterogeneity and prediction intervals. RESULTS: Five studies were included: 567 patients divided between 266 robotic and 301 LPLND. Overall operation time was longer in the robotic group than laparoscopic group (difference in means = 67.11, 95% CI [30.80, 103.42], p < 0.001) but the difference in the pelvic lateral lymph dissection time was not statistically significant (difference in means = - 1.212, 95% CI [ - 11.594, 9.171], p = 0.819). There were fewer overall complications in the robotic than in the laparoscopic group (OR = 1.589, 95% CI [1.009, 2.503], p = 0.046), especially with respect to urinary retention (OR = 2.23, 95% CI [1.277, 3.894], p = 0.005). More pelvic lateral lymph nodes were harvested by robotic surgery than by laparoscopy (differences in means = - 1.992, 95% CI [ - 2.421, 1.563], p < 0.001). CONCLUSIONS: In this meta-analysis, robotic pelvic lateral lymph node dissection was associated with more pelvic lateral lymph nodes harvested and lower overall complications, especially urinary retention when compared to LPLND. Further studies are needed to reinforce these findings.
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Laparoscopia , Excisão de Linfonodo , Pelve , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Humanos , Excisão de Linfonodo/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Laparoscopia/métodos , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.
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Neoplasias Meníngeas , Meningioma , Transcriptoma , Meningioma/genética , Meningioma/patologia , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Algoritmos , Perfilação da Expressão Gênica/métodosRESUMO
Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.
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Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival.
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It's been long thought that CD8+ cytotoxic T cells play a major role in T cell-mediated antitumor responses, whereas CD4+ T cells merely provide some assistance to CD8+ T cells as the "helpers." In recent years, numerous studies support the notion that CD4+ T cells play an indispensable role in antitumor responses. Here, we summarize and discuss the current knowledge regarding the roles of CD4+ T cells in antitumor responses and immunotherapy, with a focus on the molecular and cellular mechanisms behind these observations. These new insights on CD4+ T cells may pave the way to further optimize cancer immunotherapy.
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Linfócitos T CD4-Positivos , Imunoterapia , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/patologia , Linfócitos T CD4-Positivos/imunologia , Animais , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologiaRESUMO
BACKGROUND: Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC. METHODS: Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNß1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq. RESULTS: Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8+ immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNß1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models. CONCLUSION: Our results support that increasing cancer-intrinsic IFNß1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.
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Neoplasias Colorretais , Interferon Tipo I , Interferon beta , RNA de Cadeia Dupla , Humanos , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/imunologia , Interferon beta/metabolismo , Camundongos , Animais , Interferon Tipo I/metabolismo , Transdução de Sinais , Feminino , MasculinoRESUMO
Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.
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Camptotecina/análogos & derivados , Neoplasias Colorretais , Inibidores da Topoisomerase I , Humanos , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Neoplasias Colorretais/terapia , Citosol , Microambiente TumoralRESUMO
Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.
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Apoptose , Proliferação de Células , Duocarmicinas , Leucemia Mieloide Aguda , Humanos , Apoptose/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Proliferação de Células/efeitos dos fármacos , Duocarmicinas/farmacologia , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Células HL-60 , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacosRESUMO
Background: Patients with metastatic colorectal cancer (mCRC) who are refractory to two or more lines of systemic chemotherapy have limited therapeutic options. The aim of this study was to evaluate the effect of autologous dendritic cell cytokine-induced killer (DC-CIK) transfer on the survival of patients with mCRC who are refractory or intolerant to at least two lines of systemic chemotherapies. Methods: A matched case-control comparative study was conducted with patients who received DC-CIK immunotherapy in addition to standard chemotherapy (cases) and those with standard chemotherapy alone (controls). The primary objective was to compare the duration of oncologic survival, including overall survival (OS) and progression-free survival (PFS), between the two groups. Results: A total of 27 cases and 27 controls were included. The median OS in the DC-CIK case group was 18.73 ± 5.48 months, which was significantly longer than that in the control group (14.23 ± 1.90 months, p = 0.045). However, there was no significant difference in PFS between the two groups (p = 0.086). Subgroup analysis showed that in patients with liver or extra-regional lymph node metastasis, DC-CIK cases had longer OS than controls (17.0 vs. 11.87 months, p = 0.019; not match vs. 6.93 months, p = 0.002, respectively). In patients with Eastern Cooperative Oncology Group (ECOG) scale 0 or wild RAS/BRAF, DC-CIK cases showed a significant increase in OS duration compared to controls (28.03 vs. 14.53 months, p = 0.038; 18.73 vs. 11.87 months, p = 0.013, respectively). Conclusions: The addition of autologous DC-CIK to standard chemotherapy had a positive effect on OS of patients with refractory mCRC, especially those with liver or extra-regional lymph node metastasis, ECOG = 0, and wild RAS/BRAF status.