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Photothermal therapy is an alternative cancer therapy that uses a photothermal agent with light irradiation to induce fatal hyperthermia in cancer cells. In a previous study, we found that ex vivo photothermal (PT) treatment induced expression of heat shock proteins (HSPs), such as HSP70, HSP27, and HSP90, in cancer cells; moreover, immunization with lysates from PT-treated tumor cells resulted in significant tumor growth inhibition in tumor-bearing mice. In this study, we hypothesized that sublethal PT treatment of antigen-presenting cells regulates their immunogenicity. We observed the upregulation of expression of intracellular HSP70 and surface activation markers, such as CD40, CD80, CD86, and MHC class II, in sublethal PT-treated cells. The protumoral activity of myeloid-derived suppressor cells (MDSCs) was reduced by sublethal hyperthermia. Furthermore, poorly immunogenic MDSCs were converted into immunogenic antigen-presenting cells by PT treatment. The differences in immunogenicity between MDSCs untreated or treated with the PT technique were evaluated using the Student's t-test or Mann-Whitney rank sum test. Collectively, direct hyperthermic treatment resulted in phenotypic changes and the functional regulation of immune cells.
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Respuesta al Choque Térmico , Células Supresoras de Origen Mieloide , Terapia Fototérmica , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Animales , Ratones , Terapia Fototérmica/métodos , Línea Celular Tumoral , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Hipertermia Inducida/métodos , Ratones Endogámicos C57BL , Femenino , HumanosRESUMEN
Arabidopsis PSEUDO RESPONSE REGULATOR7 (PRR7) is a core component of the circadian oscillator which also plays a crucial role in freezing tolerance. PRR7 undergoes proteasome-dependent degradation to discretely phase maximal expression in early evening. While its transcriptional repressive activity on downstream genes is integral to cold regulation, the mechanism of the conditional regulation of the PRR7 protein activity is unknown. We used double mutant analysis, protein interaction and ubiquitylation assays to establish that the ubiquitin ligase adaptor, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 15 (HOS15), controls the protein accumulation pattern of PRR7 through direct protein-protein interactions. Freezing tolerance and electrolyte leakage assays show that PRR7 enhances cold temperature sensitivity, supported by ChIP-qPCR at C-REPEAT BINDING FACTOR (CBF) and COLD REGULATED 15A (COR15A) promoters where PRR7 levels were higher in hos15 mutants. We establish that HOS15 mediates PRR7 protein turnover through enhanced ubiquitylation at low temperature in the dark. Under the same conditions, increased PRR7 association with the promoter regions of CBFs and COR15A in hos15 correlates with decreased CBF1 and COR15A transcription and enhanced freezing sensitivity. We propose a novel mechanism whereby HOS15-mediated regulation of PRR7 provides an intersection between the circadian system and other cold acclimation pathways leading to freezing tolerance through upregulation of CBF1 and COR15A.
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BACKGROUND: Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants. METHODS: Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis. RESULTS: Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively. CONCLUSIONS: Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.
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Proteínas de Ciclo Celular , Demencia Frontotemporal , Proteínas de Transporte de Membrana , Proteínas Serina-Treonina Quinasas , Factor de Transcripción TFIIIA , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Ciclo Celular/genética , China/epidemiología , Pueblos del Este de Asia/genética , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Transporte de Membrana/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Factor de Transcripción TFIIIA/genéticaRESUMEN
Phospholipase C (PLC) is a key enzyme that regulates physiological processes via lipid and calcium signaling. Despite advances in protein engineering, no tools are available for direct PLC control. Here, we developed a novel optogenetic tool, light-controlled PLCß (opto-PLCß). Opto-PLCß uses a light-induced dimer module, which directs an engineered PLC to the plasma membrane in a light-dependent manner. Our design includes an autoinhibitory capacity, ensuring stringent control over PLC activity. Opto-PLCß triggers reversible calcium responses and lipid dynamics in a restricted region, allowing precise spatiotemporal control of PLC signaling. Using our system, we discovered that phospholipase D-mediated phosphatidic acid contributes to diacylglycerol clearance on the plasma membrane. Moreover, we extended its applicability in vivo, demonstrating that opto-PLCß can enhance amygdala synaptic plasticity and associative fear learning in mice. Thus, opto-PLCß offers precise spatiotemporal control, enabling comprehensive investigation of PLC-mediated signaling pathways, lipid dynamics, and their physiological consequences in vivo.
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Luz , Plasticidad Neuronal , Animales , Ratones , Humanos , Fosfolipasa C beta/metabolismo , Ratones Endogámicos C57BL , Optogenética , Fosfolipasas de Tipo C/metabolismo , Membrana Celular/metabolismo , Masculino , Células HEK293 , Diglicéridos/metabolismo , Diglicéridos/química , Calcio/metabolismo , Ácidos Fosfatidicos/metabolismo , Ácidos Fosfatidicos/químicaRESUMEN
Background: Patients with chronic obstructive pulmonary disease (COPD) have a high risk of developing lung cancer. Due to the high rates of complications from invasive diagnostic procedures in this population, detecting circulating tumor DNA (ctDNA) as a non-invasive method might be useful. However, clinical characteristics that are predictive of ctDNA mutation detection remain incompletely understood. This study aimed to investigate factors associated with ctDNA detection in COPD patients with lung cancer. Methods: Herein, 177 patients with COPD and lung cancer were prospectively recruited. Plasma ctDNA was genotyped using targeted deep sequencing. Comprehensive clinical variables were collected, including the emphysema index (EI), using chest computed tomography. Machine learning models were constructed to predict ctDNA detection. Results: At least one ctDNA mutation was detected in 54 (30.5%) patients. After adjustment for potential confounders, tumor stage, C-reactive protein (CRP) level, and milder emphysema were independently associated with ctDNA detection. An increase of 1% in the EI was associated with a 7% decrease in the odds of ctDNA detection (adjusted odds ratio =0.933; 95% confidence interval: 0.857-0.999; P=0.047). Machine learning models composed of multiple clinical factors predicted individuals with ctDNA mutations at high performance (AUC =0.774). Conclusions: ctDNA mutations were likely to be observed in COPD patients with lung cancer who had an advanced clinical stage, high CRP level, or milder emphysema. This was validated in machine learning models with high accuracy. Further prospective studies are required to validate the clinical utility of our findings.
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PURPOSE: This study aims to determine the association between pre- and postoperative radiotherapy (PORT) circulating tumor DNA (ctDNA) dynamics and oncological outcomes in patients with residual triple-negative breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Between March 2019 and July 2020, 11 nonmetastatic patients with residual disease who underwent surgery after NAC were prospectively enrolled. In each patient, tumor specimens obtained during surgery and blood samples collected at three time points during PORT (T0: pre-PORT, T1: 3 weeks after PORT, T2: 1 month after PORT) were sequenced, targeting 38 cancer-related genes. Disease-free survival (DFS) was evaluated and the association between DFS and ctDNA dynamics was analyzed. RESULTS: At T0, ctDNA was detected in three (27.2%) patients. The ctDNA dynamics were as follows: two showed a decreasing ctDNA variant allele frequency (VAF) and reached zero VAF at T2, while one patient exhibited an increasing VAF during PORT and maintained an elevated VAF at T2. After a median follow-up of 48 months, two patients experienced distant metastasis without any locoregional failures. All failures occurred in patients with ctDNA positivity at T0 and a decreased VAF after PORT. The 4-year DFS rates according to the T0 ctDNA status were 67% (positive ctDNA) and 100% (negative ctDNA) (p=0.032). CONCLUSION: More than a quarter of the patients with residual disease after post-NAC surgery exhibited pre-PORT ctDNA positivity, and ctDNA positivity was associated with poor DFS. For patients with pre-PORT ctDNA positivity, the administration of a more effective systemic treatment should be considered.
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ADN Tumoral Circulante , Neoplasias de la Mama Triple Negativas , Humanos , Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/radioterapia , Resultado del Tratamiento , ADN Tumoral Circulante/genética , Estudios Prospectivos , Recurrencia Local de Neoplasia/patología , Biomarcadores de Tumor/genéticaRESUMEN
Photothermal therapy is an anti-cancer strategy that induce cell death by converting light energy into heat energy. During photothermal therapy, cancer cells were treated with photothermal agents, such as indocyanine green, and irradiated with a laser. Heat stress in cancer cells results in cellular death and inflammatory responses. In the present study, we demonstrated how ex vivo photothermal (PT)-treated cells underwent immunogenic cell death. PT treatment caused significant expression of heat shock protein (HSP) 27, HSP70, and HSP90 in murine tumor cells. To evaluate the immunogenicity of heat-stressed cells, lysate from PT-treated tumor cells or water-based heated cells was pulsed to syngeneic bone-marrow-derived dendritic cells (DCs) to generate a DC-based vaccine. Administration with PT-treated tumor lysates-pulsed DC vaccine resulted in significant inhibition of tumor growth in BALB/c and C57BL/6 syngeneic tumor-bearing mice. The immunogenicity of PT-treated cancer cells was reduced in the presence of HSP inhibitors, J2, VER-155008 or 17-AAG. Our study elucidates how PT techniques have distinct mechanisms from water-based heating and might be a potentially robust and efficient solution to developing an anti-cancer vaccine.
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Vacunas contra el Cáncer , Neoplasias , Vacunas , Animales , Ratones , Ratones Endogámicos C57BL , Muerte Celular Inmunogénica , Neoplasias/terapia , Neoplasias/patología , Agua , Células Dendríticas , Línea Celular TumoralRESUMEN
Green synthesis strategies have been widely applied for the preparation of versatile nanomaterials. Gold nanospheres with an average size of 6.95 ± 2.25 nm were green synthesized by using a 70% ethanol extract of Korean red ginseng (Panax ginseng Meyer) root as a reducing agent. A seed-mediated synthesis was conducted to prepare Au-Ag bimetallic nanoparticles using gold nanospheres as seeds. Remarkably, Au-Ag bimetallic nanoparticles with an average size of 80.4 ± 11.9 nm were synthesized. Scanning transmission electron microscopy, energy dispersive X-ray spectroscopy and elemental mappings revealed bimetallic nanoparticles with Au-Ag alloy core and Au-rich shells. A face-centered cubic structure of Au-Ag bimetallic nanoparticles was confirmed by X-ray diffraction analysis. For Au-Ag bimetallic nanoparticles, the ratio of Ag/Au was 0.20 which was detected and analyzed by inductively coupled plasma-mass spectrometry. Gold nanospheres and Au-Ag bimetallic nanoparticles were functionalized by PEGylation, folic acid conjugation and grafting onto graphene oxide. Finally, docetaxel was loaded for evaluating the in vitro cell viability on cancer cells. Successful functionalization was confirmed by Fourier-transform infrared spectra. The anticancer activity of the docetaxel-loaded nanoparticles was higher than that of their non-docetaxel-loaded counterparts. The highest anticancer activity on human gastric adenocarcinoma cells (AGS) was observed in the docetaxel-loaded gold nanospheres that were functionalized by PEGylation, folic acid conjugation and grafting onto graphene oxide. Additionally, grafting onto graphene oxide and docetaxel loading induced high intracellular reactive oxygen species generation. For chemo-photothermal (PTT) anticancer therapy, cell viability was investigated using near-infrared laser irradiation at 808 nm. The highest chemo-PTT anticancer activity on AGS cells was observed in the docetaxel-loaded Au-Ag bimetallic nanoparticles. Therefore, the newly prepared docetaxel-loaded Au-Ag bimetallic nanoparticles in the current report have potential applications in chemo-PTT anticancer therapy.
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Amphiphysin (AMPH) autoimmunity is associated with a variety of neurological complications, including encephalitis, peripheral neuropathy, myelopathy, and cerebellar syndrome. Its diagnosis is based on clinical neurological deficits and the presence of serum anti-AMPH antibodies. Active immunotherapy, such as intravenous immunoglobulins, steroids, and other immunosuppressive therapies, has been reported to be effective in most patients. However, the extent of recovery varies depending on the case. Herein, we report the case of a 75-year-old woman with semi-rapidly progressive systemic tremors, visual hallucinations, and irritability. Upon hospitalization, she developed a mild fever and cognitive impairment. Brain magnetic resonance imaging (MRI) showed semi-rapidly progressive diffuse cerebral atrophy (DCA) over 3 months, while no clear abnormal intensities were observed. The nerve conduction study revealed sensory and motor neuropathy in the limbs. The fixed tissue-based assay (TBA) failed to detect antineuronal antibodies; however, based on commercial immunoblots, the presence of anti-AMPH antibodies was suspected. Therefore, serum immunoprecipitation was performed, which confirmed the presence of anti-AMPH antibodies. The patient also had gastric adenocarcinoma. High-dose methylprednisolone, and intravenous immunoglobulin were administered and tumor resection was performed, resulting in resolution of the cognitive impairment and improvement in the DCA on the post-treatment MRI. After immunotherapy and tumor resection, the patient's serum was analyzed using immunoprecipitation, which showed a decrease in the level of anti-AMPH antibodies. This case is noteworthy because the DCA showed improvement after immunotherapy and tumor resection. Additionally, this case demonstrates that negative TBA with positive commercial immunoblots do not necessarily indicate false positive results.
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INTRODUCTION: For patients with early stage EGFR-mutant-positive (EGFR-M+) NSCLC, curative surgery followed by adjuvant chemotherapy is considered the standard of care. This study evaluated the feasibility and efficacy of longitudinal monitoring of circulating tumor DNA (ctDNA) as a valuable biomarker for early detection of minimal residual disease (MRD) and provides identification of the group at high risk for recurrence in resected stages I to IIIA EGFR-M+ NSCLC. METHODS: Between August 2015 and October 2017, a total of 278 patients with curative resected, stages I to IIIA (American Joint Committee on Cancer seventh version) common EGFR-M+ NSCLC were analyzed. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet-digital polymerase chain reaction from baseline (preoperative), 4 weeks after curative surgery, and follow-up per protocol until 5 years. The primary outcomes were disease-free survival (DFS) according to the status of ctDNA positivity at landmark points and the sensitivity of longitudinal monitoring of ctDNA. RESULTS: Among 278 patients, preoperative baseline ctDNA was detected in 67 (24%) patients: 23% (stage IA), 18% (IB), 18% (IIA), 50% (IIB), and 42% (IIIA) (p = 0.06). Of patients with baseline ctDNA, 76% (51 of 67) had clearance at 4 weeks after surgery (postoperative). Patients were classified into the following three groups; group A, baseline ctDNA negative (n = 211) versus group B, baseline ctDNA positive but postoperative MRD negative (n = 51) versus group C, baseline ctDNA positive and postoperative MRD positive (n = 16). The 3-year DFS rate was significantly different among the three groups (84% for group A, 78% for group B, and 50% for group C, p = 0.02). After adjusting for clinicopathologic variables, ctDNA still remains an independent risk factor for DFS along with stage (p < 0.001) and micropapillary subtype (p = 0.02). With longitudinal monitoring of ctDNA, MRD was detected before radiological recurrence in 69% of patients with exon 19 deletion and in 20% with L858R mutation. CONCLUSIONS: These results suggest that patients with baseline ctDNA-positive or MRD-positive status were associated with poor DFS in curative resected stages I to IIIA EGFR-M+ NSCLC and that longitudinal monitoring of ctDNA, a noninvasive method, might be useful to detect early recurrence before radiological recurrence.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Supervivencia sin Enfermedad , Mutación , Receptores ErbB/uso terapéuticoRESUMEN
Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes (PDGFRB, AHNAK, OBSCN, RBM10, CACNA1E, and OR5P3), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.
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Aneurisma Intracraneal , FN-kappa B , Animales , Ratones , Aneurisma Intracraneal/genética , Mutación/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/genética , HumanosRESUMEN
The COVID-19 pandemic has increased demand for safe and effective vaccines. Research to develop vaccines against diseases including Middle East respiratory syndrome, Ebolavirus, human immunodeficiency virus, and various cancers would also contribute to global well-being. For successful vaccine development, the advancement of technologies such as antigen (Ag) screening, Ag delivery systems and adjuvants, and manufacturing processes is essential. Ag delivery systems are required not only to deliver a sufficient amount of Ag for vaccination, but also to enhance immune response. In addition, Ag types and their delivery systems determine the manufacturing processes of the vaccine product. Here, we analyze the characteristics of various Ag delivery systems: plasmids, viral vectors, bacterial vectors, nanoparticles, self-assembled particles, natural and artificial cells, and extracellular vesicles. This review provides insight into the current vaccine landscape and highlights promising avenues of research for the development and improvement of Ag delivery systems.
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BACKGROUND: Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from normal tissues adjacent to tumors (NATs) are better predictors of relapse. RESULTS: Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models-NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. CONCLUSIONS: Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.
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Neoplasias Colorrectales , Transcriptoma , Humanos , Transcriptoma/genética , Estudios Retrospectivos , Neoplasias Colorrectales/patología , Recurrencia Local de Neoplasia/genética , Perfilación de la Expresión Génica , PronósticoRESUMEN
Variant callers typically produce massive numbers of false positives for structural variations, such as cancer-relevant copy-number alterations and fusion genes resulting from genome rearrangements. Here we describe an ultrafast and accurate detector of somatic structural variations that reduces read-mapping costs by filtering out reads matched to pan-genome k-mer sets. The detector, which we named ETCHING (for efficient detection of chromosomal rearrangements and fusion genes), reduces the number of false positives by leveraging machine-learning classifiers trained with six breakend-related features (clipped-read count, split-reads count, supporting paired-end read count, average mapping quality, depth difference and total length of clipped bases). When benchmarked against six callers on reference cell-free DNA, validated biomarkers of structural variants, matched tumour and normal whole genomes, and tumour-only targeted sequencing datasets, ETCHING was 11-fold faster than the second-fastest structural-variant caller at comparable performance and memory use. The speed and accuracy of ETCHING may aid large-scale genome projects and facilitate practical implementations in precision medicine.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Genoma , Análisis de Secuencia de ADN/métodosRESUMEN
PURPOSE: Plasma circulating tumor DNA (ctDNA) could reflect the genetic alterations present in tumor tissues. However, there is little information about the clinical relevance of cell-free DNA genotyping in peripheral T-cell lymphoma (PTCL). MATERIALS AND METHODS: After targeted sequencing plasma cell-free DNA of patients with various subtypes of PTCL (n=94), we analyzed the mutation profiles of plasma ctDNA samples and their predictive value of dynamic ctDNA monitoring for treatment outcomes. RESULTS: Plasma ctDNA mutations were detected in 53 patients (56%, 53/94), and the detection rate of somatic mutations was highest in angioimmunoblastic T-cell lymphoma (24/31, 77%) and PTCL, not otherwise specified (18/29, 62.1%). Somatic mutations were detected in 51 of 66 genes that were sequenced, including the following top 10 ranked genes: RHOA, CREBBP, KMT2D, TP53, IDH2, ALK, MEF2B, SOCS1, CARD11, and KRAS. In the longitudinal assessment of ctDNA mutation, the difference in ctDNA mutation volume after treatment showed a significant correlation with disease relapse or progression. Thus, a ≥ 1.5-log decrease in genome equivalent (GE) between baseline and the end of treatment showed a significant association with better survival outcomes than a < 1.5-log decrease in GE. CONCLUSION: Our results suggest the clinical relevance of plasma ctDNA analysis in patients with PTCL. However, our findings should be validated by a subsequent study with a larger study population and using a broader gene panel.
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ADN Tumoral Circulante , Linfoma de Células T Periférico , Humanos , ADN Tumoral Circulante/genética , Linfoma de Células T Periférico/genética , Genotipo , Biomarcadores de Tumor/genética , Recurrencia Local de Neoplasia , MutaciónRESUMEN
BACKGROUND & AIMS: International guidelines recommend physical activity for subjects with nonalcoholic fatty liver disease (NAFLD). This study investigated the association of physical activity with risk of liver fibrosis, sarcopenia, and cardiovascular disease (CVD) in NAFLD. METHODS: In this multicenter, retrospective study, 11,690 NAFLD subjects who underwent a health screening program and were assessed for physical activity (metabolic equivalent task [MET]-min/week) between 2014 and 2020 were recruited. Liver fibrosis was assessed by using the fibrosis-4 index, NAFLD fibrosis score, and FibroScan-AST score, sarcopenia by using multi-frequency bioelectric impedance analysis, and CVD risk by using atherosclerotic CVD (ASCVD) risk score, and coronary artery calcium (CAC) score were calculated. RESULTS: The prevalence of fibrosis, sarcopenia, high probability of ASCVD, and high CAC score significantly decreased with increasing quartiles of physical activity (all P for trend <.001). In a fully adjusted model, physical activity above 600 MET-min/week (≥third quartile) was independently associated with a reduced risk of fibrosis (adjusted odds ratio [aOR] = 0.59; 95% confidence interval [CI], 0.40-0.86), sarcopenia (aOR = 0.72; 95% CI, 0.58-0.88), high probability of ASCVD (aOR = 0.58; 95% CI, 0.46-0.73), and high CAC score (aOR = 0.32; 95% CI, 0.13-0.83; all P <.05). In addition, increasing amounts of physical activity were significantly associated with risk reduction between fibrosis, sarcopenia, and high probability of ASCVD (all P for trend <.001). In subjects with sarcopenic obesity or lean NAFLD, physical activity was also independently associated with reduced risk of fibrosis and high probability of ASCVD (all P <.05). CONCLUSIONS: Physical activity showed a protective effect against fibrosis, sarcopenia, and CVD in NAFLD.
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Enfermedades Cardiovasculares , Enfermedad del Hígado Graso no Alcohólico , Sarcopenia , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Sarcopenia/epidemiología , Sarcopenia/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios Retrospectivos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Cirrosis Hepática/diagnóstico , Fibrosis , Ejercicio FísicoRESUMEN
Although the combination of radiotherapy and immunotherapy has proven to be effective in lung cancer treatment, it may not be sufficient to fully activate the antitumor immune response. Here, we investigated whether entinostat, a histone deacetylase inhibitor, could improve the efficacy of radiotherapy and anti-PD-1 in a murine syngeneic LL/2 tumor model. A total of 12 Gy of X-rays administered in two fractions significantly delayed tumor growth in mice, which was further enhanced by oral entinostat administration. Flow cytometry-aided immune cell profiling revealed that entinostat increased radiation-induced infiltration of myeloid-derived suppressor cells and CD8+ T cells with decreased regulatory T-cells (Tregs). Transcriptomics-based immune phenotype prediction showed that entinostat potentiated radiation-activated pathways, such as JAK/STAT3/interferon-gamma (IFN-γ) and PD-1/PD-L1 signaling. Entinostat augmented the antitumor efficacy of radiation and anti-PD-1, which may be related to an increase in IFN-γ-producing CD8+ T-cells with a decrease in Treg cells. Comparative transcriptomic profiling predicted that entinostat increased the number of dendritic cells, B cells, and T cells in tumors treated with radiation and anti-PD-1 by inducing MHC-II genes. In conclusion, our findings provided insights into how entinostat improves the efficacy of ionizing radiation plus anti-PD-1 therapy and offered clues for developing new strategies for clinical trials.
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Carcinoma Pulmonar de Lewis , Inhibidores de Histona Desacetilasas , Animales , Ratones , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Linfocitos T CD8-positivos , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Inmunomodulación , Inmunidad , Interferón gamma/farmacología , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Predicting colorectal cancer recurrence after tumor resection is crucial because it promotes the administration of proper subsequent treatment or management to improve the clinical outcomes of patients. Several clinical or molecular factors, including tumor stage, metastasis, and microsatellite instability status, have been used to assess the risk of recurrence, although their predictive ability is limited. Here, we predicted colorectal cancer recurrence based on cellular deconvolution of bulk tumors into two distinct immune cell states: cancer-associated (tumor-infiltrating immune cell-like) and noncancer-associated (peripheral blood mononuclear cell-like). Prediction model performed significantly better when immune cells were deconvoluted into two states rather than a single state, suggesting that the difference in cancer recurrence was better explained by distinct states of immune cells. It indicates the importance of distinguishing immune cell states using cellular deconvolution to improve the prediction of colorectal cancer recurrence.
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BACKGROUND: Based on specific epigenetic mutation in AITL such as TET2, DNMT3A, IDH2, and RHOA, hypomethylating agents are emerging as a promising treatment option for AITL. METHOD: The efficacy and safety of 5-azacytidine as salvage chemotherapy were retrospectively analyzed in 15 patients with RR-AITL from 2019 to 2022. RESULTS: During the median 6.0 months of follow-up, the overall response rate (ORR) was 40% (n = 6/15) with 2 CRs and 4 PRs. The patients who previously had received ≤2 prior chemotherapies showed higher ORR than subjects with >2 prior chemotherapies (80% vs. 20%). The 10 patients who received 5-azacitidine at the late chemotherapy lines (>2 prior chemotherapy lines) usually received less dose 5-azacitidine. And these patients discontinued treatment due to disease progression (n = 6/10, 60%) or neutropenic fever (n = 4/10, 40%). The patients who received a full dose (75 mg/m2 for 7 days) of 5-azacitidine seemed to show better ORR than subjects (100 mg for 7 days) who did not receive an optimal dose (60.0% vs. 30.0%). The median progression-free survival (PFS) was 1.6 months, and the patients who previously had undergone ≤2 chemotherapies had better PFS compared with subjects who previously received >2 chemotherapies (P-value = .04). CONCLUSION: 5-azacitidine shows reasonable efficacy and manageable toxicities for patients with RR-AITL, especially those who previously received ≤2 chemotherapy lines.