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Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.
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Glicoesfingolípidos , Inhibidores de Puntos de Control Inmunológico , Pirrolidinas , Humanos , Femenino , Persona de Mediana Edad , Masculino , Anciano , Glicoesfingolípidos/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacología , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Ratones , Glucosiltransferasas/antagonistas & inhibidores , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
DNA methyltransferase inhibitor decitabine plus anti-PD-1 (DP) combination therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine and anti-PD-1 camrelizumab (CDP) in 52 patients with relapsed/refractory cHL who had previously received DP therapy (NCT04233294). CDP treatment was well-tolerate and resulted in an objective response rate of 94% (95% CI, 84-99%), with 50% (95% CI, 36-64%) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses following CDP therapy, although their CR rate was lower compared to patients responsive to prior DP. Overall, the median progression-free survival following CDP therapy was 29.4 months. Through single-cell RNA sequencing of pre-treatment and on-treatment cHL tumor biopsies, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with the abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. In contrast, the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance.
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The potential of automated radiology report generation in alleviating the time-consuming tasks of radiologists is increasingly being recognized in medical practice. Existing report generation methods have evolved from using image-level features to the latest approach of utilizing anatomical regions, significantly enhancing interpretability. However, directly and simplistically using region features for report generation compromises the capability of relation reasoning and overlooks the common attributes potentially shared across regions. To address these limitations, we propose a novel region-based Attribute Prototype-guided Iterative Scene Graph generation framework (AP-ISG) for report generation, utilizing scene graph generation as an auxiliary task to further enhance interpretability and relational reasoning capability. The core components of AP-ISG are the Iterative Scene Graph Generation (ISGG) module and the Attribute Prototype-guided Learning (APL) module. Specifically, ISSG employs an autoregressive scheme for structural edge reasoning and a contextualization mechanism for relational reasoning. APL enhances intra-prototype matching and reduces inter-prototype semantic overlap in the visual space to fully model the potential attribute commonalities among regions. Extensive experiments on the MIMIC-CXR with Chest ImaGenome datasets demonstrate the superiority of AP-ISG across multiple metrics.
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Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC.
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Neoplasias Colorrectales , Péptidos y Proteínas de Señalización Intracelular , Activación de Macrófagos , Macrófagos , Ratones Noqueados , Factor de Transcripción STAT1 , Transducción de Señal , Proteínas de Motivos Tripartitos , Animales , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Activación de Macrófagos/genética , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Ratones , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Macrófagos/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
PURPOSE: Our study aimed to evaluate the impact of concomitant medications on the response and survival of patients with advanced digestive tract cancer receiving an immunotherapy-antiangiogenesis combination. METHODS: We conducted a three-center observational retrospective study of patients with advanced digestive tract cancer who received programmed death-1 (PD-1) inhibitors plus antiangiogenic agents between March 2019 and July 2022 in China. The patients had one of the three types of primary tumors: hepatocellular carcinoma (HCC), colorectal cancer (CRC), and gastric cancer (GC). RESULTS: The study included 352 patients. The most frequently prescribed co-medications were nonsteroidal anti-inflammatory drugs (NSAIDs) (46.3%), proton pump inhibitors (PPIs) (38.0%), systemic antibiotics (33.8%), and corticosteroids (30.1%). Probiotics had a direct correlation with a higher objective response rate (ORR) (OR 2.4, 95% CI 1.2 to 4.7, p = 0.013). Patients who received PPIs for gastritis/gastroesophageal reflux disease (GERD) (HR 0.7, 95% CI 0.5 to 1.0, p = 0.045), anticoagulants (HR 0.5, 95% CI 0.3 to 0.9, p = 0.009), and probiotics (HR 0.7, 95% CI 0.5 to 1.0, p = 0.034) had longer progression-free survival (PFS). Patients who received PPIs for gastritis/GERD (HR 0.6, 95% CI 0.4 to 0.9; p = 0.009) had longer overall survival (OS), while patients receiving opioids (HR 1.5, 95% CI 1.1 to 2.0, p = 0.010) had a significantly higher risk of death. CONCLUSION: Patients with advanced digestive tract cancer who were administered PPIs for gastritis/GERD indication, anticoagulants, or probiotics in combination with PD-1 inhibitors and antiangiogenic agents experienced improved clinical outcomes. However, opioid administration was linked to reduced OS in patients receiving combined therapy.
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Medical image reporting focused on automatically generating the diagnostic reports from medical images has garnered growing research attention. In this task, learning cross-modal alignment between images and reports is crucial. However, the exposure bias problem in autoregressive text generation poses a notable challenge, as the model is optimized by a word-level loss function using the teacher-forcing strategy. To this end, we propose a novel Token-Mixer framework that learns to bind image and text in one embedding space for medical image reporting. Concretely, Token-Mixer enhances the cross-modal alignment by matching image-to-text generation with text-to-text generation that suffers less from exposure bias. The framework contains an image encoder, a text encoder and a text decoder. In training, images and paired reports are first encoded into image tokens and text tokens, and these tokens are randomly mixed to form the mixed tokens. Then, the text decoder accepts image tokens, text tokens or mixed tokens as prompt tokens and conducts text generation for network optimization. Furthermore, we introduce a tailored text decoder and an alternative training strategy that well integrate with our Token-Mixer framework. Extensive experiments across three publicly available datasets demonstrate Token-Mixer successfully enhances the image-text alignment and thereby attains a state-of-the-art performance. Related codes are available at https://github.com/yangyan22/Token-Mixer.
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BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.
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Neoplasias , Receptores de Factores de Crecimiento Transformadores beta , Adulto , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Criterios de Evaluación de Respuesta en Tumores Sólidos , Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidoresRESUMEN
BACKGROUND: Chronic wounds refer to those that can't reconstruct anatomical and physical functional integrity, and are usually associated with signs of microbial infection. Current therapies include debridement and dressing change, local or systemic application of antibiotics, and medical dressing care, which are not ideal for the healing of chronic wounds. OBJECTIVE: To explore the efficacy and safety of photodynamic therapy (ALA-PDT) for the treatment of chronic infectious wounds. MATERIALS AND METHODS: ALA-PDT was used in ten patients with persistent wound infections and systemic complications who did not respond to conventional treatment. 5 % ALA solution was applied to the wound surface after debridement, incubated for 3 h with light protection, and then irradiated with red light for 20 min. This procedure was repeated every two weeks, and any adverse reactions were recorded. After the end of three treatments, the patients were followed up for 3 months. RESULTS: Patients who exhibit resistance to traditional therapies demonstrate a favorable therapeutic outcome with ALA-PDT, although complications may impede wound healing. All participants successfully underwent ALA-PDT treatment and subsequent monitoring, with 90 % achieving complete healing. Common adverse reactions to ALA-PDT encompass treatment-related pain, temporary erythema, and swelling, all of which are well-tolerated by patients without enduring severe consequences. CONCLUSIONS: ALA-PDT proves to be an efficacious intervention for managing chronic wounds, irrespective of the presence of localized infections or systemic complications.
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Ácido Aminolevulínico , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Fotoquimioterapia/métodos , Masculino , Femenino , Fármacos Fotosensibilizantes/uso terapéutico , Persona de Mediana Edad , Anciano , Ácido Aminolevulínico/uso terapéutico , Enfermedad Crónica , Cicatrización de Heridas/efectos de los fármacos , Adulto , Infección de Heridas/tratamiento farmacológico , Anciano de 80 o más AñosRESUMEN
The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding.
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Anticuerpos Monoclonales Humanizados , Síndromes de Neurotoxicidad , Receptores Quiméricos de Antígenos , Humanos , Síndrome de Liberación de Citoquinas/terapia , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T , Intercambio Plasmático , Estudios Prospectivos , Estudios Retrospectivos , Inmunoterapia Adoptiva/métodos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Corticoesteroides/uso terapéuticoRESUMEN
Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.
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Arginina , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Nucleotidiltransferasas , Proteína-Arginina N-Metiltransferasas , Proteína-Arginina N-Metiltransferasas/metabolismo , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Nucleotidiltransferasas/metabolismo , Arginina/metabolismo , Metilación/efectos de los fármacos , Animales , Ratones , Interferón Tipo I/metabolismo , Daño del ADN , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacosRESUMEN
Cancer survivors are vulnerable to frailty. While few studies have focused on the association of frailty with mortality risk among cancer survivors, the current study aimed to reveal this association. In this cohort study, 4723 cancer survivors were enrolled from the National Health and Nutrition Examination Surveys (NHANES, 1999-2018). Frailty status was quantified using the 53-item frailty index. Death outcomes were linked to National Death Index mortality data (as of December 31, 2019). Cox proportional hazard models were used to estimate HRs (95% CIs). The median (IQR) frailty score was 0.190 (0.132, 0.277). During the median follow-up of 6.7 years, 1775 all-cause deaths (including 581 cancer deaths and 385 cardiac deaths) were documented. Compared to the lowest tertile of frailty scores, the adjusted HRs (95% CIs) for the highest tertile were 2.698 (2.224, 3.272) for all-cause mortality (P trend < 0.001), 2.145 (1.547, 2.973) for cancer mortality (P trend < 0.001), and 3.735 (2.231, 6.251) for cardiac mortality (P trend < 0.001). Moreover, a positive doseâresponse association between the frailty score and mortality risk was determined. Each per-unit increase in the frailty score (natural logarithm transformed) was found to increase all-cause mortality by 159% (P < 0.001), cancer mortality by 103% (P < 0.001), and cardiac mortality by 256% (P < 0.001). A consistent result was shown when stratifying by age, sex, race, body mass index, and type of cancer. This study suggested that the frailty index was positively associated with all-cause mortality and cause-specific mortality (including cancer and cardiac deaths) among cancer survivors.
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Supervivientes de Cáncer , Fragilidad , Neoplasias , Humanos , Estudios de Cohortes , Encuestas NutricionalesRESUMEN
Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.
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Neoplasias Colorrectales , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Transcriptoma/genética , Estudio de Asociación del Genoma Completo , Neoplasias Colorrectales/metabolismo , Células HCT116 , Regulación Neoplásica de la Expresión Génica/genética , Proliferación Celular/genéticaRESUMEN
ABBREVIATIONS: A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.
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Neoplasias Asociadas a Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Autofagia/fisiología , Fosfatidilinositol 3-Quinasas , Endorribonucleasas , Proteínas Serina-Treonina Quinasas , Escherichia coli , ADN Helicasas , Proteínas Nucleares , Factores de Transcripción , Proteínas Activadoras de GTPasaRESUMEN
Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving inflammatory responses have primarily focused on pattern recognition by myeloid cells and subsequent transcriptional events, it is crucial to note that post-transcriptional regulation plays a pivotal role in this process. In addition to the transcriptional regulation of innate immune responses, additional layers of intricate network of post-transcriptional mechanisms critically determine the quantity and duration of key inflammatory products and thus the outcome of immune responses. A multitude of mechanisms governing post-transcriptional regulation in innate immunity have been uncovered, encompassing RNA alternative splicing, mRNA stability, and translational regulation. This review encapsulates the current insights into the post-transcriptional regulation of inflammatory genes within myeloid cells, with particular emphasis on translational regulation during inflammation. While acknowledging the advancements, we also shed light on the existing gaps in immunological research pertaining to post-transcriptional levels and propose perspectives that controlling post-transcriptional process may serve as potential targets for therapeutic interventions in inflammatory diseases.
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Inmunidad Innata , Inflamación , Humanos , Inmunidad Innata/genética , Inflamación/genética , Células Mieloides , Macrófagos , Empalme AlternativoAsunto(s)
Neoplasias , Humanos , Neoplasias/terapia , Células Presentadoras de Antígenos , Linfocitos T , InmunidadRESUMEN
BACKGROUND: Little was known on infection and mortality rates, still less the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant in B-cell lymphoma patients following CD19 targeted chimeric antigen receptor T cell (CAR-T). AIMS: We performed a retrospective multicenter study and analyzed the details of relapsed/refractory (R/R) B-cell lymphoma patients who received CD19 targeted CAR-T heretofore in five cellular immunotherapy centers in China during the omicron wave. MATERIALS & METHODS: One hundred fifty-four patients were enrolled in this study. RESULTS: Among them, 52 patients (33.8%) were uninfected, 74 patients (48.1) had ambulatory mild disease (including nine patients of asymptomatic infection), 22 patients (14.3%) had moderate disease and six patients (3.9%) had severe disease when data collected up. Three patients with severe disease died from COVID-19, the death rate was 1.9% for all enrolled patients, and 2.9% for infected patients. We also found that patients over 60 years old or with diabetes mellitus (DM) tend to develop severe disease (p = 0.0057 and p = 0.0497, respectively). Patients had CAR-T infusion within 6 months also tend to have severe disease (p = 0.0011). In multivariate logistic regression model, CAR-T infusion within 6 months (relative risk (RR) 40.92; confidence interval (CI) 4.03-415.89; p = 0.002) were associated with significantly higher risk of severe disease. CONCLUSION: Through this study, we conclude that the outcome for B-cell lymphoma patients following CD19 targeted CAR-T therapy when facing omicron infection was improved, but aggressive precautionary measures were particularly crucial for patients with high risk factors.
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COVID-19 , Linfoma de Células B , Receptores Quiméricos de Antígenos , Humanos , Persona de Mediana Edad , SARS-CoV-2 , Linfocitos T , COVID-19/epidemiología , COVID-19/terapia , COVID-19/etiología , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19 , Factores de Riesgo , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.
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Although chimeric antigen receptor (CAR) T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies, more than 60% of patients with diffuse large B-cell lymphoma (DLBCL) treated with CAR-T cell therapies fail to achieve a durable response. To reveal changes in CAR-T cell therapy and identify response biomarkers, we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy. We performed bulk RNA-Seq, single-cell RNA-Seq, and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients. We note that a CD8+ stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response. By analysing autologously-derived, pre-manufacture T cells, our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL. The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression, coupled with increased expression of activation- and inhibitor-related genes in the CD8+ naïve-T cell populations among the apheresis T cells from patients with a poor molecular response. These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos TRESUMEN
OBJECTIVE: To construct a clinical prediction nomogram model using the 1-min IOF osteoporosis risk test as an evaluation tool for male osteoporosis. METHODS: The 1-min test results and the incidence of osteoporosis were collected from 354 patients in the osteoporotic clinic of our hospital. LASSO regression model and multi-factor logistic regression were used to analyze the risk factors of osteoporosis in patients, and the risk prediction model of osteoporosis was established. Verify with an additional 140 objects. RESULTS: We used logistic regression to construct a nomogram model. According to the model, the AUC value of the training set was 0.760 (0.704-0.817). The validation set has an AUC value of 0.806 (0.733-0.879). The test set AUC value is 0.714 (0.609-0.818). The calibration curve shows that its advantage is that the deviation correction curve of the nomogram model can maintain a good consistency with the ideal curve. In terms of clinical applicability, compared with the "total intervention" and "no intervention" schemes, the clinical net return rate of the nomogram model showed certain advantages. CONCLUSION: Using the 1-min osteoporosis risk test provided by IOF, we built a male osteoporosis risk prediction model with good prediction effect, which can provide greater reference and help for clinicians.