Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer.

We have investigated the prognostic value of two novel interim 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUVNTO ). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUVNTO ) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUVNTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUVNTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUVNTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.

Confirmation of the prognostic value of pretherapeutic tumor SUR and MTV in patients with esophageal squamous cell carcinoma.

PURPOSE: The prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. In a recent publication, we were able to show that PET can provide independent prognostic information in such a patient group and that the tumor-to-blood standard uptake ratio (SUR) can improve the prognostic value of tracer uptake values. The present investigation addresses the question of whether the distinctly improved prognostic value of SUR can be confirmed in a similar patient group that was examined and treated at a different site. METHODS: 18F-FDG PET/CT was performed in 147 consecutive patients (115 male, 32 female, mean age: 62 years) with newly diagnosed esophageal squamous cell carcinoma prior to definitive radiochemotherapy. In the PET images, the metabolic active volume (MTV) of the primary tumor was delineated with an adaptive threshold method. For the resulting ROIs, SUVmax and total lesion glycolysis (TLG = MTV × SUVmean) were computed. The blood SUV was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as ratio of tumor SUV and blood SUV. Univariate Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), distant-metastases-free survival (DM), and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. RESULTS: Univariate Cox regression revealed MTV, TLG, and SURmax as significant prognostic factors for OS. MTV as well as TLG were significant prognostic factors for LRC while SURmax showed only a trend for significance. None of the PET parameters was prognostic for DM. In univariate analysis, SUVmax was not prognostic for any of the investigated clinical endpoints. In multivariate analysis (T-stage, N-stage, MTV, and SURmax), MTV was an independent prognostic factor for OS and showed a trend for significance for LRC. SURmax was not an independent predictor for OS or LRC. When including the PET parameters separately in multivariate analysis, MTV as well as SURmax were prognostic factors for OS indicating that SURmax is independent from the clinical parameters but not from MTV. In addition, MTV was an independent prognostic factor for LRC in this separate analysis. CONCLUSIONS: Our study revealed a clearly improved prognostic value of tumor SUR compared to tumor SUV and confirms our previously published findings regarding OS. Furthermore, SUR delivers prognostic information beyond that provided by the clinical parameters alone, but does not add prognostic information beyond that provided by MTV in this patient group. Therefore, our results suggest that pretherapeutic MTV is the parameter of choice for PET-based risk stratification in the considered setting but further investigations are necessary to demonstrate that this suggestion is correct.

Increased evidence for the prognostic value of FDG uptake on late-treatment PET in non-tumour-affected oesophagus in irradiated patients with oesophageal carcinoma.

PURPOSE: 18F-FDG uptake in irradiated non-tumour-affected oesophagus (NTO) on restaging PET is a potential surrogate for the measurement of radiation-induced inflammation. Radiation-induced inflammation itself has been shown to be of high prognostic relevance in patients undergoing preoperative radiochemotherapy (RCT) for locally advanced oesophageal cancer. We assessed the prognostic relevance of FDG uptake in the NTO in an independent cohort of patients treated with definitive RCT. METHODS: This retrospective evaluation included 72 patients with oesophageal squamous cell carcinoma treated with definitive RCT with curative intent. All patients underwent pretreatment and restaging FDG PET after receiving a radiation dose of 40-50 Gy. Standardized uptake values (SUVmax/SUVmean), metabolic tumour volume (MTV) and relative changes from pretreatment to restaging PET (∆SUVmax/∆SUVmean) were determined within the tumour and NTO. Univariate Cox regression with respect to overall survival (OS), local control (LC), distant metastases (DM) and treatment failure (TF) was performed. Independence of parameters was tested by multivariate Cox regression. RESULTS: ∆SUVmax NTO and MTV were prognostic factors for all investigated clinical endpoints (OS, LC, DM, TF). Inclusion of clinical and PET tumour parameters in multivariate analysis showed that ∆SUVmax NTO was an independent prognostic factor. Furthermore, multivariate analysis of ∆SUVmax NTO using previously published cut-off values from preoperatively treated patients revealed that ∆SUVmax NTO was independent prognostic factor for OS (HR = 1.88, p = 0.038), TF (HR = 2.11, p = 0.048) and DM (HR = 3.02, p = 0.047). CONCLUSION: NTO-related tracer uptake during the course of treatment in patients with oesophageal carcinoma was shown to be of high prognostic relevance. Thus, metabolically activity of NTO measured in terms of ∆SUVmax NTO is a potential candidate for future treatment individualization (i.e. organ preservation).

Astragaloside IV plays a role in reducing radiation-induced liver inflammation in mice by inhibiting thioredoxin-interacting protein/nod-like receptor protein 3 signaling pathway.

OBJECTIVE: To investigate the efficacy of Astragaloside IV (AS-IV) on radiation-induced liver inflammation in mice. METHODS: The mice were divided into normal group, dimethyl sulfoxide solvent group, irradiation group (IR), irradiation + AS-IV (20 mg/kg) group (IR+AS-20) and irradiation + AS-IV (40 mg/kg) group (IR+AS-40). One month after intraperitoneal injection of AS-IV, the mice were irradiated with 8Gry Co60γ, the blood was collected for biochemical analysis, and the liver was collected for hematoxylin-eosin staining, immunofluorescence and electron microscopic observation, oxidative stress, and Western blot analysis. RESULTS: The AS-IV treatment significantly ameliorated the pathological morphology of liver and reduced the alanine aminotransferase and aspertate amino-transferase levels in serum induced by radiation; AS-IV treatment also significantly reduced the expression of inflammatory factors tumor necrosis factor alpha and interleukin 6 and antagonized malonaldehyde content and superoxide dismutase activity in liver caused by radiation; in addition, AS-IV treatment can significantly inhibited the positive expression of thioredoxin-interacting protein (TXNIP) and nod-like receptor protein 3 (NLRP3) inflammasome in liver tissue after radiation; The expression of TXNIP, NLRP3 inflammasome, apoptosis-associated speck-like protein containing a CARD, cysteinyl aspartate-specific proteinase 1 and interleukin 1beta in the AS-IV prevention group decreased significantly compared to the radiation group. CONCLUSIONS: These findings suggested that Co60γ radiation can cause structural and functional damage to the liver, which may be related to the NLRP3 mediated inflammatory pathway; AS-IV may play a protective role by inhibiting the TXNIP/NLRP3 inflammasome signaling pathway in the radiation-induced liver injury model.

Graphene oxide disrupted mitochondrial homeostasis through inducing intracellular redox deviation and autophagy-lysosomal network dysfunction in SH-SY5Y cells.

Graphene oxide (GO) nanomaterials have significant advantages for drug delivery and electrode materials in neural science, however, their exposure risks to the central nervous system (CNS) and toxicity concerns are also increased. The current studies of GO-induced neurotoxicity remain still ambiguous, let alone the mechanism of how complicated GO chemistry affects its biological behavior with neural cells. In this study, we characterized the commercially available GO in detail and investigated its biological adverse effects using cultured SH-SY5Y cells. We found that ultrasonic processing in medium changed the oxidation status and surface reactivity on the planar surface of GO due to its hydration activity, causing lipid peroxidation and cell membrane damage. Subsequently, ROS-disrupted mitochondrial homeostasis, resulting from the activation of NOX2 signaling, was observed following GO internalization. The autophagy-lysosomal network was initiated as a defensive reaction to obliterate oxidative damaged mitochondria and foreign nanomaterials, which was ineffective due to reduced lysosomal degradation capacity. These sequential cellular responses exacerbated mitochondrial stress, leading to apoptotic cell death. These data highlight the importance of the structure-related activity of GO on its biological properties and provide an in-depth understanding of how GO-derived cellular redox signaling induces mitochondrion-related cascades that modulate cell functionality and survival.

MicroRNA miR-92a-3p regulates breast cancer cell proliferation and metastasis via regulating B-cell translocation gene 2 (BTG2).

MicroRNAs (miRNAs) dysregulation contributes to tumorigenesis, and it is reported that abnormal miR-92a-3p expression participates in multiple cancers' occurrence and progression. This study focuses on miR-92a-3p's functions and regulatory mechanism in breast cancer (BC). The current study proved miR-92a-3p expression was enhanced in BC tissues and cells, and its high expression was related to increased TNM stage and larger tumor size of BC patients. Functionally, transfection of miR-92a-3p mimics facilitated BC cell proliferation and metastasis, yet transfection of miR-92a-3p inhibitors functioned oppositely. In addition, BTG2 was verified as a direct miR-92a-3p target in BC cells. This research indicated that miR-92a-3p facilitates BC cell proliferation and metastasis through repressing BTG2 expression.

A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation.

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment.

Lipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-1beta, TNF-alpha and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS.

Lipopolysaccharide (LPS) derived from the periodontal pathogen Porphyromonas gingivalis has been shown to differ from enterobacterial LPS in structure and function; therefore, the Toll-like receptors (TLRs) and the intracellular inflammatory signaling pathways are accordingly different. To elucidate the signal transduction pathway of P. gingivalis, LPS-induced pro-inflammatory cytokine production in the human monocytic cell line THP-1 was measured by ELISA, and the TLRs were determined by the blocking test using anti-TLRs antibodies. In addition, specific inhibitors as well as Phospho-ELISA kits were used to analyze the intracellular signaling pathways. Escherichia coli LPS was used as the control. In this study, P. gingivalis LPS showed the ability to induce cytokine production in THP-1 cells and its induction was significantly (P < 0.05) suppressed by anti-TLR2 antibody or JNK inhibitor, and the phosphorylation level of JNK was significantly increased (P < 0.05). These results indicate that TLR2-JNK is the main signaling pathway of P. gingivalis LPS-induced cytokine production, while the cytokine induction by E. coli LPS was mainly via TLR4-NF-kappaB and TLR4-p38MAPK. This suggests that P. gingivalis LPS differs from E. coli LPS in its signaling pathway in THP-1 cells, and that the TLR2-JNK pathway might play a significant role in P. gingivalis LPS-induced chronic inflammatory periodontal disease.