RESUMEN
Microplastics ï¼MPsï¼ are ubiquitous in the marine environment and have become an emerging pollutant that is attracting great attention. To reveal the pollution characteristics of MPs in surface seawater of coastal waters in Guangdong Province, nine bays ï¼estuariesï¼ were selected from Jiangmen to Shantou. The distribution and compositional characteristics of MPs were investigated through field sampling, oxidation digestion, and visual and compositional identification, and their potential sources were analyzed. The ecological risks were assessed by combining the pollution load index and the polymer risk index. The results showed that MPs were detected in all 30 surface seawater samples from the coastal waters of Guangdong Province, with an abundance range of 70-920 n·m-3 and an average abundance of ï¼295.3 ±175.3ï¼ n·m-3. The highest MPs abundance was found in the Pearl River estuary, and the lowest abundance was found in Shenquan bay. The distribution patterns were mainly influenced by human activities and ocean currents. The dominant polymer types included polypropylene ï¼31.2%ï¼, phenol resin ï¼16.0%ï¼, polyethylene terephthalate ï¼15.3%ï¼, and polyethylene ï¼10.9%ï¼. The main shape, color, and size categories of MPs were fiber ï¼57.5%ï¼, transparent ï¼72.0%ï¼, and 0.5-1 mm ï¼32.8%ï¼, respectively. The possible sources of MPs mainly included aquaculture, fishing, navigation, tourism, municipal sewage discharge, and ocean current transportation. The model assessment results showed that the pollution load risk of MPs was relatively low, but the polymer risk was at a medium-high level. This study provides a data basis for the action plan of plastic pollution control in Guangdong Province and supports the prevention and control of marine MPs pollution.
RESUMEN
BACKGROUND: This study aimed to compare the diagnostic value of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT imaging for primary lesions and metastatic lymph nodes in patients with tonsil cancer. METHOD: Twenty-one tonsil cancer patients who underwent [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT scans within two weeks in our centre were retrospectively enrolled. The maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR) of the two tracers were compared by using the MannâWhitney U test. In addition, the sensitivity, specificity, and accuracy of the two methods for diagnosing metastatic lymph nodes were analysed. RESULTS: In detecting primary lesions, the efficiency was higher for [68 Ga]Ga-DOTA-FAPI-04 PET/CT (20/22) than for [18F]FDG PET/CT (9/22). Although [68 Ga]Ga-DOTA-FAPI-04 uptake (SUVmax, 5.03 ± 4.06) was lower than [18F]FDG uptake (SUVmax, 7.90 ± 4.84, P = 0.006), [68 Ga]Ga-DOTA-FAPI-04 improved the distinction between the primary tumor and contralateral normal tonsillar tissue. The TBR was significantly higher for [68 Ga]Ga-DOTA-FAPI-04 PET/CT (3.19 ± 2.06) than for [18F]FDG PET/CT (1.89 ± 1.80) (p < 0.001). In lymph node analysis, SUVmax and TBR were not significantly different between [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT (7.67 ± 5.88 vs. 8.36 ± 6.15, P = 0.498 and 5.56 ± 4.02 vs. 4.26 ± 3.16, P = 0.123, respectively). The specificity and accuracy of [68 Ga]Ga-DOTA-FAPI-04 PET/CT were higher than those of [18F]FDG PET/CT in diagnosing metastatic cervical lymph nodes (all P < 0.05). CONCLUSION: The availability of [68 Ga]Ga-DOTA-FAPI-04 complements the diagnostic results of [18F]FDG by improving the detection rate of primary lesions and the diagnostic accuracy of cervical metastatic lymph nodes in tonsil cancer compared to [18F]FDG.
Asunto(s)
Fluorodesoxiglucosa F18 , Metástasis Linfática , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias Tonsilares , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Masculino , Femenino , Estudios Retrospectivos , Metástasis Linfática/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Neoplasias Tonsilares/diagnóstico por imagen , Neoplasias Tonsilares/patología , Adulto , Radioisótopos de Galio , Compuestos Organometálicos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patologíaRESUMEN
OBJECTIVE: To explore the effects of Huxin formula (HXF) in curtailing atherosclerosis and its underlying mechanism. METHODS: According to random number table method, 24 specific pathogen free male ApoE-/- mice were randomly divided into model group, HXF low-dose (HXF-L) group (8.4 g/kg daily), HXF high-dose (HXF-H) group (16.8 g/kg daily), and pravastatin (8 mg/kg daily) group in Experiment I (n=6 per group). C57BL/6J mice served as the control group (n=6). ApoE-/- mice in HXF-L, HXF-H, pravastatin groups were fed a Western diet and administered continuously by gavage for 12 weeks, while C57BL/6J mice in the control group were fed conventional lab mouse chow for 12 weeks. Further, Tregs were depleted by weekly intraperitoneal injection of purified anti-mouse CD25 antibody (PC61, 250 µg per mouse) for 4 weeks in Experiment II (n=6 per group). Oil Red O and Masson staining were used to evaluate the plaque area and aortic root fibrosis. The CD4+CD25+Foxp3+Treg counts in the lymph nodes and spleen cells were detected using flow cytometric analysis. The transforming growth factor-ß1 (TGF-ß1), interleukin (IL)-10, and IL-6 serum levels were examined by MILLIPLEX® MAP technology. Quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot were utilized to assess the expression of TGF-ß mRNA and protein in the aorta. The expression of CD4+T lymphocytes, macrophages and smooth muscle cells in the aortic root were detected by immunofluorescence staining. RESULTS: HXF reduced plaque area in ApoE-/- mice (P<0.01). HXF increased the Treg counts in the lymph nodes and spleen cells (P<0.05 or P<0.01). Moreover, HXF alleviated inflammatory response via elevating IL-10 and TGF-ß 1 serum levels (P<0.05), while decreasing the IL-6 serum levels in ApoE-/- mice (P>0.05). Also, HXF upregulated the expression of TGF-ß mRNA and protein in the aorta (P<0.05). Additionally, HXF attenuated CD4+T lymphocytes, macrophages and smooth muscle cells in aortic root plaque (P<0.01). Furthermore, the depletion of Tregs with CD25 antibody (PC61) curtailed the reduction in plaque area and aortic root fibrosis by HXF (P<0.01). CONCLUSION: HXF relieved atherosclerosis, probably by restraining inflammatory response, reducing inflammatory cell infiltration and attenuating aortic root fibrosis by increasing Treg counts.
RESUMEN
Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/ß-catenin signaling pathway. PICK1 restrained the nuclear accumulation of ß-catenin and accelerated the degradation of ß-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/ß-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC.
Asunto(s)
Biomarcadores de Tumor , Proteínas Portadoras , Proliferación Celular , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteínas Nucleares , Vía de Señalización Wnt , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/metabolismo , Pronóstico , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Animales , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , beta Catenina/metabolismo , Ratones Desnudos , Masculino , Femenino , Ratones , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Mutación/genéticaRESUMEN
BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma is limited because of their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in locally recurrent nasopharyngeal carcinoma. METHODS: This multicenter, retrospective study included 921 patients with locally recurrent nasopharyngeal carcinoma. A machine learning signature and nomogram based on pretreatment magnetic resonance imaging features were developed for predicting overall survival in a training cohort and validated in 2 independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA-sequencing analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving concordance indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables statistically improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with statistically distinct overall survival rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-sequencing analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: A magnetic resonance imaging-based radiomic signature predicted overall survival more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for locally recurrent nasopharyngeal carcinoma patients.
Asunto(s)
Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Recurrencia Local de Neoplasia , Nomogramas , Radiómica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aprendizaje Automático , Imagen por Resonancia Magnética , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The present meta-analysis aimed to evaluate the efficacy and safety of adding nimotuzumab to radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Prospective randomized controlled studies at EMBASE, PubMed, and the Cochrane Library from January 1, 2010, to October 1, 2022, were searched. Data on the overall survival (OS), progress-free survival (PFS), disease-free survival (DFS), complete response rate (CRR), objective response rate (ORR), and all grade adverse events were collected from the enrolled publications. OS was the primary measurement indicator. Pooled analysis was performed with relative risks (RRs), hazard risks (HRs), and their corresponding 95% confidence intervals (CIs) in the software Stata SE 16.0. RESULTS: Six randomized controlled studies were included in the analysis of the overall pooled effect. As compared to the control group, the nimotuzumab intervention group exhibited improved OS by 21% (pooled HR=0.79,95% CI: 0.64-0.98, P=0.028), along with PFS up to 31% (HR=0.69, 95% CI: 0.55-0.86, P=0.001) and DFS up to 29% (HR=0.71, 95% CI: 0.56-0.91, P=0.006), increased CRR as 50% (RR=1.50, 95% CI:1.09-2.04; P=0.012), and ORR as 35% (RR=1.35, 95% CI:1.04-1.73; P=0.022). Regarding safety, nimotuzumab in combination with RT or CRT did not increase the incidence of all grade adverse events (pooled-RD=-1.27, 95% CI:-2.78-0.23, P=0.099). CONCLUSION: The present meta-analysis has demonstrated that nimotuzumab, in combination with RT or CRT, could provide survival benefits and increase response rates. Its safety profile has been found to be controllable.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Neoplasias de Cabeza y Cuello , Humanos , Quimioradioterapia/métodos , Quimioradioterapia/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificaciónRESUMEN
The low detection rate of primary tumors by current diagnostic techniques remains a major concern for patients with head and neck cancer of unknown primary (HNCUP). Therefore, in this study, we aimed to investigate the potential role of 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT compared with 18F-FDG PET/CT for the detection of primary tumors of HNCUP. Methods: In this prospective comparative imaging trial conducted at Fudan University Shanghai Cancer Center, 91 patients with negative or equivocal findings of a primary tumor by comprehensive clinical examination and conventional imaging were enrolled from June 2020 to September 2022. The presence of a primary tumor was recorded by 3 experienced nuclear medicine physicians. Primary lesions were validated by histopathologic analysis and a composite reference standard. Results: Of the 91 patients (18 women, 73 men; median age, 60 y; age range, 24-76 y), primary tumors were detected in 46 (51%) patients after a thorough diagnostic work-up. 68Ga-FAPI PET/CT detected more primary lesions than 18F-FDG PET/CT (46 vs. 17, P < 0.001) and showed better sensitivity, positive predictive value, and accuracy in locating primary tumors (51% vs. 25%, 98% vs. 43%, and 51% vs. 19%, respectively). Furthermore, 68Ga-FAPI PET/CT led to treatment changes in 22 of 91 (24%) patients compared with 18F-FDG PET/CT. The Kaplan-Meier curve illustrated that patients with unidentified primary tumors had a significantly worse prognosis than patients with identified primary tumors (hazard ratio, 5.77; 95% CI, 1.86-17.94; P = 0.0097). Conclusion: 68Ga-FAPI PET/CT outperforms 18F-FDG PET/CT in detecting primary lesions and could serve as a sensitive, reliable, and reproducible imaging modality for HNCUP patients.
Asunto(s)
Neoplasias de Cabeza y Cuello , Neoplasias Primarias Desconocidas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , China , Fluorodesoxiglucosa F18 , Radioisótopos de Galio , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Estudios ProspectivosRESUMEN
BACKGROUND AND IMPORTANCE: Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia commonly seen in the emergency department. Both modified Valsalva maneuver (MVM) and intravenous adenosine are the first line treatment, of which the former has e lower success rate while the latter has a higher success rate but some risks and adverse effects. Given both of these reverse rhythms quickly, combining them may achieve a better effect. OBJECTIVE: The objective of this study is to evaluate the success rate and potential risk of combining the use of intravenous adenosine while patients were doing MVM as a treatment for paroxysmal supraventricular tachycardia(pSVT). DESIGN, SETTINGS AND PARTICIPANTS: We recruited patients with pSVT from 2017 to 2022, and randomly assigned them into 3 groups, MVM group, intravenous adenosine group, and combination therapy group, in which MVM was allowed to be performed twice, while intravenous adenosine was given in a titration manner to repeat three times, recorded the success rate and side effects in each group. MAIN RESULTS: The success rate of the MVM group, adenosine group, and combination group are 42.11%, 75.00 and 86.11%, respectively. The success rate of the adenosine group and combination group is significantly higher than the n MVSM group (p < 0.01, p < 0.001), while the success rate of the combination group is higher than the adenosine group, it has no significant difference (p = 0.340). In terms of safety, the longest RR durations (asystole period) are 1.61 s, 1.60s, and 2.27 s, there is a statistical difference among the three groups (p < 0.01) and between the adenosine and combination group (0.018). CONCLUSION: Therefore, we can conclude that combination therapy has a relatively high success rate and good safety profile, but the current study failed to show its superiority to adenosine.
Asunto(s)
Taquicardia Paroxística , Taquicardia Supraventricular , Taquicardia Ventricular , Humanos , Adenosina/uso terapéutico , Taquicardia Paroxística/tratamiento farmacológico , Taquicardia Supraventricular/tratamiento farmacológico , Taquicardia Supraventricular/inducido químicamente , Taquicardia Ventricular/tratamiento farmacológico , Maniobra de ValsalvaRESUMEN
PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Hipofaríngeas , Neoplasias Laríngeas , Laringe , Humanos , Neoplasias Hipofaríngeas/tratamiento farmacológico , Neoplasias Hipofaríngeas/patología , Preservación de Órganos , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/patología , Fluorouracilo , Laringectomía , Recurrencia Local de Neoplasia/patología , Laringe/patología , Cisplatino , Quimioterapia de Inducción , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.
Asunto(s)
Neoplasias Nasofaríngeas , Recurrencia Local de Neoplasia , Humanos , Carcinoma Nasofaríngeo/genética , Estudios Retrospectivos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/genética , Pronóstico , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVE: To investigate the role of additional induction chemotherapy (IC) prior to re-irradiation in locally recurrent nasopharyngeal carcinoma (lrNPC). METHODS: A total of 480 patients from three cancer treatment centers who received re-irradiation between 2012 and 2020 were retrospectively analyzed. Overall survival (OS) was determined using the Kaplan-Meier method and compared with log-rank method. Inverse probability of treatment weighting (IPTW) was performed to match the patients in pairwise treatment groups. Multivariate analysis using the Cox proportional hazards regression method identified predictors of OS. The risk stratification model was defined by the risk score calculated with the sum of coefficients. RESULTS: In the entire cohort, the addition of IC was associated with similar OS compared with radiotherapy alone (P = 0.58) or with concomitant chemoradiation (P = 0.76). A risk stratification model was constructed and validated based on significant prognostic factors (coefficient) including male (0.6), age ≥ 60 years (0.9), volume of recurrence gross tumor volume ≥ 16 cc (0.7), and lactate dehydrogenase (LDH)-ratio ≥ 0.5 (0.4). In the intermediate-risk group (sum of coefficient: 0.9---1.6), patients with IC plus re-irradiation had a significantly better OS than those who received re-irradiation (P = 0.03). After adjustments for several potentially confounding variables with IPTW, survival benefit of IC was also observed (P = 0.031). However, no significant difference in OS for the additional IC prior to re-irradiation was demonstrated in the low- (sum of coefficient: <0.9) and high-risk group (sum of coefficient: > 1.6). CONCLUSION: Additional IC prior to re-irradiation was associated with improved OS in the intermediate-risk group of lrNPC, whereas there was no difference for the low-risk and high-risk group. Prospective validation is required to validate these findings.
RESUMEN
Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.
Asunto(s)
Proteínas de Transporte de Membrana , Proteínas de Saccharomyces cerevisiae , Proteínas de Transporte de Membrana/química , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Transporte de Proteínas , Mitocondrias/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Mitocondriales/metabolismo , Péptidos/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
BACKGROUNDS: Despite publication of international guidelines, there are notable controversial points of clinical target volume (CTV) delineation in nasopharyngeal carcinoma (NPC). Recently, scholars proposed a novel way of delineation of CTV in NPC-individualization of CTV delineation based on T classification and spread patterns, which yielded excellent long-term local control with limited late toxicities. The aim of this study was to clarify the anatomic patterns and pathways of local recurrence of NPC and provide a clinical reference for the delineation of CTV. METHODS: A total of 869 patients with non-metastatic NPC were treated with intensity-modulated radiation therapy (IMRT) at our institution between 2009 and 2010. Among the 57 cases of local/locoregional recurrence, 52 cases with traceable radiotherapy plans and magnetic resonance imaging at the time of the first diagnosis of recurrence were included. Anatomical structures and gross tumor volume of local recurrence were contoured. The incidence of relapse of each anatomic structure, route of local recurrence, and their correlation were analyzed. RESULTS: Locally advanced disease had a significantly increased risk of recurrence in the posterior nasal cavity and a trend towards higher risk of recurrence in the clivus, lateral pterygoid muscle, and hypoglossal canal. Based on the incidence of local recurrence, we constructed a high-risk map for the early and locally advanced stages. Local recurrences were classified into five routes, where anterior extension accounted for the majority (30.8%), and caudal tumor extension pathway had the lowest incidence (5.8%). There was a significant correlation between the local recurrences of neural foramina and neighboring anatomical structures along each pathway. All cases relapsed at unilateral cavernous sinus, most at the same side of primary tumor. Based on our findings, we proposed some suggestions on delineations of CTV, based on T classification and local extension pattern. CONCLUSIONS: Local recurrence of NPC varied according to T classification, followed a stepwise pattern, spread via neural foramina, and recurred at ipsilateral cavernous sinus. This provides meaningful clinical evidence for delineation of CTV, especially individualized delineation.
Asunto(s)
Neoplasias Nasofaríngeas , Radioterapia de Intensidad Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/patología , Planificación de la Radioterapia Asistida por Computador/métodos , Estadificación de NeoplasiasRESUMEN
BACKGROUND: To explore the prognostic role of FDG PET/CT maximal standard uptake values of metastatic lesions (SUVmax-M) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) following palliative chemotherapy and locoregional radiotherapy (LRRT). METHODS: We retrospectively collected the information of 86 eligible patients between Jan 2012 and Oct 2020. All the parameters involving SUVmax and serum lactate dehydrogenase (LDH) at diagnosis were evaluated and cutoff values were determined by the maximum log-rank statistic method. The multivariate analysis was performed using Cox proportional hazards regression to identify the independent prognostic factors associated with overall survival (OS). All estimated survival rates were conducted with Kaplan-Meier method. RESULTS: Median survival and progression time in the cohort were 38.2 and 13.9 months, respectively. The univariable analysis showed that male, number of metastatic sites ≥ 4, presence of liver, serum LDH ≥ 229, SUVmax-M ≥ 10, SUVmax-M-sum ≥ 10, and SUVmax-M-mean ≥ 8.8 were significant prognostic factors. Five variables were identified after LASSO regression and entered into the multivariate analysis. Furthermore, liver involvement (P = 0.039), elevated LDH (≥ 229) (P = 0.05) and higher SUVmax-M (≥ 10) (P = 0.004) were significantly associated with worse OS. CONCLUSION: The high SUVmax of metastatic lesions (≥ 10), liver involvement, and elevated serum LDH (≥ 229) at diagnosis could independently predict poor survival for de novo mNPC patients treated with palliative chemotherapy following LRRT.
Asunto(s)
Neoplasias Nasofaríngeas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Masculino , Carcinoma Nasofaríngeo , Pronóstico , Fluorodesoxiglucosa F18 , Estudios RetrospectivosRESUMEN
Human papillomavirus (HPV)-driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTL) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with a divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161- counterparts and a T cell-inflamed phenotype that could be further reinvigorated by immune-checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Virus del Papiloma Humano , Pronóstico , Linfocitos T Citotóxicos/patologíaRESUMEN
BACKGROUND: Postoperative radiotherapy (PORT) is beneficial in the improvement of local-regional control and overall survival (OS) for major salivary gland carcinomas (SGCs), and distant metastasis remained the main failure pattern. This study was designed to develop a nomogram model involving immune-inflammation index to predict distant metastasis-free survival (DMFS) of major SGCs. PATIENTS AND METHODS: A total of 418 patients with major SGCs following PORT were randomly divided into a training (n = 334) and validation set (n = 84). The pre-radiotherapy neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated and transformed as continuous variables for every patient. Associations between DMFS and variables were performed by univariate and multivariable analysis using Log-rank and Cox regression methods. A nomogram was constructed based on the prognostic factors identified by the Cox hazards model. The decision curve analysis (DCA) was conducted with the training and validation set. RESULTS: The estimated 3-, 5-, and 10-year DMFS were 79.4%, 71.8%, and 59.1%, respectively. The multivariate analysis revealed that age (p = 0.033), advanced T stage (p = 0.003), positive N stage (p < 0.001), high-risk pathology (p = 0.011), and high PLR (p = 0.001) were significantly associated with worse DMFS. The nomogram showed good calibration and discrimination in the training (AUC = 80.9) and validation set (AUC = 87.9). Furthermore, the DCA demonstrated favorable applicability, and a significant difference (p < 0.001) was observed for the DMFS between the subgroups based on the nomogram points. CONCLUSION: The nomogram incorporating clinicopathological features and PLR presented accurate individual prediction for DMFS of the patients with major SGCs following PORT. Further external validation of the model is warranted for clinical utility.
Asunto(s)
Carcinoma , Neoplasias de las Glándulas Salivales , Humanos , Nomogramas , Plaquetas , Inflamación , Glándulas SalivalesRESUMEN
BACKGROUND: The role of additional chemoradiotherapy (CRT) for distant metastasis (DM) on the resected malignancy of the major salivary gland (SGM) remained unknown. We conducted this study to externally validate a recently reported DM risk score model and compare the survival outcome between adjuvant CRT and RT alone. MATERIALS: We retrospectively reviewed the patients with SGM following postoperative radiotherapy (PORT). The cumulative incidence of DM was assessed using a competing risk method. Multivariate analysis was performed with Cox proportional-hazards regression to identify significant predictors for DM. Patients were classified as high- and low-risk subgroups with the cutoff value of the DM risk score model. The inverse probability of treatment weighting (IPTW) was conducted to minimize the bias of the groups. RESULTS: A total of 586 eligible patients were analyzed and 67 cases underwent adjuvant CRT. The 5-year incidence of DM was 19.5% (95% CI 16.0-23.0%). The model reasonably discriminated the DM risk between the high- and low-risk subgroup in our cohort, and the c-index was 0.75. No survival benefit was observed for the CRT group compared with RT alone in the entire cohort after IPTW (p = 0.095). After subgroup analysis, increased mortality was identified with the administration of CRT in the low-risk subset (p = 0.002) while no significant difference in OS was illustrated in the high-risk subgroup (p = 0.98). CONCLUSIONS: This external validation provides further exploration of the DM risk score model in major SGM. Our results demonstrated no support for the utility of additional chemotherapy to PORT in the major SGM, especially in the low-risk subgroup of patients with DM.
RESUMEN
OBJECTIVE: Patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) were assigned to dose and volume de-escalated intensity-modulated radiation therapy (IMRT) based on response to induction chemotherapy (IC) to limit treatment related toxicity while preserving efficacy. METHODS AND MATERIALS: A single-arm de-escalated phase II trial was performed in this study. Patients with LANPC received two cycles of IC with docetaxel 60 mg/m2 d1, cisplatin 25 mg/m2/day d1-3 and 5-fluorouracil 500 mg/m2/day d1-5 q21d, followed by IMRT. The gross tumor volume of the primary intracavity nasopharyngeal tumor and involved lymph nodes were delineated based on the post-IC tumor extension. Part of the prescribed doses were reduced from 70.4 Gy to 66 Gy for T3-4 diseases. The primary end point was 5-year progression-free survival (PFS) in stage III and IVA-B NPC compared with historical controls of 50% and 35%. RESULTS: Between January 2010 and November 2013, 48 and 83 eligible patients with stage III and IVA-B NPC were accrued to this trial. With a median follow-up of 92 months, the 5-year and 8-year estimated PFS were 89.6% and 76.0%, 63.9% and 58.0% for patients with stage III and IVA-B disease, which were all improved in comparison with historical controls. Grade 3 acute mucositis were developed in 27.5% patients. Cranial neuropathy and asymptomatic temporal lobe necrosis were found in 2.3% and 1.5% patients. CONCLUSION: Dose and volume de-escalated IMRT was associated with high PFS and mild late neurological toxicities for IC responders. Further exploration of de-escalation strategies in appropriate patients is needed. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT03389295.
Asunto(s)
Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Radioterapia de Intensidad Modulada , Quimioradioterapia , Cisplatino , Docetaxel/uso terapéutico , Fluorouracilo , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/radioterapia , Estadificación de Neoplasias , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodosRESUMEN
BACKGROUND: To evaluate the predicting factors associated with distant metastasis (DM) for lymphoepithelial carcinoma of salivary gland (LECSG) following postoperative radiotherapy (PORT). METHODS: We retrospectively collected 160 eligible patients from two cancer institutions. The DM rate was evaluated using competing risk method. RESULTS: The median follow-up time was 65.6 months. Elevated preradiotherapy serum LDH (ratio >0.5) (p = 0.006) and N classification (N2-3) (p = 0.001) were independently associated with DM for the LECSG. After the risk stratification, the high-risk subgroup was defined as the patients presented higher risk score (score >0), whereas 5-year cumulative incidence of DM in the high- and low-risk group was 30.9% and 6.0%, respectively (p < 0.001). Moreover, a significantly worse overall survival (OS) was observed in the high-risk patients compared with the low-risk subgroup (5-year OS: 83.9% vs. 97.8%, p = 0.006). CONCLUSION: Elevated preradiotherapy serum LDH could serve as a predictive factor for DM in the LECSG following PORT.
Asunto(s)
Carcinoma , Neoplasias de las Glándulas Salivales , Humanos , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/radioterapia , Neoplasias de las Glándulas Salivales/cirugía , Glándulas Salivales/patología , Carcinoma/radioterapia , Lactato DeshidrogenasasRESUMEN
Background: Considered an effective supplementary therapy, traditional Chinese medicine (TCM) has been widely applied in the treatment of coronary heart disease (CHD). In this study, we aim to investigate the effects and mechanisms of Huo-Tan-Chu-Shi decoction (HTCSD, an in-hospital TCM prescription) in the treatment of CHD with the phlegm-damp syndrome in mice by non-targeted metabolomics with liquid chromatography-mass spectrometry (LC-MS)/MS. Methods: A CHD with phlegm-damp syndrome model was established with ApoE-/- mice by subcutaneous injection with isoproterenol combined with high temperature, high humidity, and a high-fat diet, and divided into the HTCSD and Tanshi groups. C57BL/6 mice were set as the control group with an ordinary environment and diet. After administration, electrocardiogram (ECG), interventricular septum thickness (IVS) and left ventricular posterior wall thickness (LVPW), serum levels of creatine phosphokinase-Mb (CK-MB), cardiac troponin T (cTnT), lactic dehydrogenase (LDH) and oxidized low-density lipoprotein (oxLDL), and myocardial histopathological changes were recorded to assess myocardial damage. LC-MS/MS was applied to demonstrate the serum metabolic profile and explore potential mechanisms. Results: The obvious depressions of the ST segment and T wave presented in the ECG of Tanshi mice, while the depressions in ECG of HTCSD mice were significantly reduced. Compared with the control group, IVS, LVPW, and serum levels of CK-MB, cTnT, LDH, and oxLDL increased greatly in the Tanshi group, while these indicators decreased remarkably in the HTCSD group compared with those of the Tanshi group. Histopathology showed severe structural disorder, necrosis, and fibrosis of myocardial cells in Tanshi mice, which were alleviated in HTCSD mice. Metabonomics analysis showed obvious metabolic alterations among the experimental mice and revealed that the relevant metabolic pathways mainly included phospholipid metabolism, necroptosis, and autophagy. Conclusions: HTCSD has a certain therapeutic effect in mice with CHD with phlegm-damp syndrome via reducing myocardial ischemia, hypertrophy, and fibrosis. The underlying mechanisms involve the regulation of phospholipid metabolism, necroptosis, and autophagy.