ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation.

The nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a critical mediator of the innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that a cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation. NLRP3 is post-translationally palmitoylated by zinc-finger and aspartate-histidine-histidine-cysteine 5 (ZDHHC5) at the LRR domain, which promotes NLRP3 inflammasome assembly and activation. Silencing ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1ß/18 release, and GSDMD cleavage, both in human cells and in mice. ABHD17A depalmitoylates NLRP3, and one human-heritable disease-associated mutation in NLRP3 was found to be associated with defective ABHD17A binding and hyper-palmitoylation. Furthermore, Zdhhc5-/- mice showed defective NLRP3 inflammasome activation in vivo. Taken together, our data reveal an endogenous mechanism of inflammasome assembly and activation and suggest NLRP3 palmitoylation as a potential target for the treatment of NLRP3 inflammasome-driven diseases.

Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.

BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.

A Treg-related riskscore model may improve the prognosis evaluation of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) poses a significant health challenge. This study aims to investigate the prognostic value of a regulatory T cell (Treg)-related gene signature in CRC. METHODS: We extracted the gene expression and clinical data on CRC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The gene module related to Treg was identified by weighted gene co-expression network analysis (WGCNA). The genes in the significant module were filtered by univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. A riskscore model was established in terms of the key Treg-related genes. The reliability of this riskscore model was validated using the external GEO dataset. The association of riskscore with clinical features, mutation patterns and signaling pathways was explored. RESULTS: Genes in the blue module showed the strongest association with Tregs. After a series of filtering cycles, seven Treg-related key genes, GDE1, GSR, HSPB1, AOC2, TBX19, TAMM41 and TIGD6, were selected to construct a riskscore model. This model performed well in evaluating the patients' survival in TCGA cohort, and was further affirmed by the GSE17536 validation cohort. For precise evaluation of the patients' survival, we established a nomogram in light of riskscore and clinical factors. Patients in different risk groups had distinct clinical features, mutation patterns and signaling pathway activities. The expression of five key genes was significantly associated with Treg infiltration in the CRC samples. CONCLUSION: We established a useful riskscore model in light of seven Treg-related genes. This model may contribute to the prognosis evaluation, direct tailored treatment, and hopefully improve clinical outcomes of the CRC patients.

The proportion of tumour stroma predicts response to treatment of immune checkpoint inhibitor in combination with chemotherapy in patients with stage IIIB-IV non-small cell lung cancer.

AIMS: Immunotherapy has brought a new era to cancer treatment, yet we lack dependable predictors for its effectiveness. This study explores the predictive significance of intratumour stroma proportion (iTSP) for treatment success and prognosis in non-small cell lung cancer (NSCLC) patients undergoing treatment with immune check-point inhibitors (ICIs) together with chemotherapy. METHODS AND RESULTS: We retrospectively collected data from patients with unresectable stage IIIB-IV NSCLC who were treated with first-line ICIs and chemotherapy. Each patient received a confirmed pathological diagnosis, and the pathologist evaluated the iTSP on haematoxylin and eosin (H&E)-stained sections of diagnostic tissue slides. Among the 102 H&E-stained biopsy samples, 61 (59.8%) were categorised as stroma-L (less than 50% iTSP), while 41 (40.2%) were classified as stroma-H (more than 50% iTSP). We observed that the stroma-L group exhibited a significantly better objective response rate (ORR) (72.1 versus 51.2%, P = 0.031) and deeper response depth (DpR) (-50.49 ± 28.79% versus -35.83 ± 29.91%, P = 0.015) compared to the stroma-H group. Furthermore, the stroma-L group showed longer median progression-free survival (PFS) (9.6 versus 6.0 months, P = 0.011) and overall survival (OS) (24.0 versus 12.2 months, P = 0.001) compared to the stroma-H group. Multivariate Cox proportional hazards regression analysis indicated that iTSP was a highly significant prognostic factor for both PFS [hazard ratio (HR) = 1.713; P = 0.030] and OS (HR = 2.225; P = 0.003). CONCLUSION: Our findings indicate that a lower iTSP corresponds to improved clinical outcomes and greater DpR in individuals with stage IIIB-IV NSCLC treated with first-line ICIs and chemotherapy. The iTSP could potentially serve as a predictive biomarker for ICIs therapy response.

FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis.

AIMS: Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance. METHODS: By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma. RESULTS: FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients. CONCLUSION: Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.

Accurate and Convenient Lung Cancer Diagnosis through Detection of Extracellular Vesicle Membrane Proteins via Förster Resonance Energy Transfer.

Tumor-derived extracellular vesicles (EVs) are promising to monitor early stage cancer. Unfortunately, isolating and analyzing EVs from a patient's liquid biopsy are challenging. For this, we devised an EV membrane proteins detection system (EV-MPDS) based on Förster resonance energy transfer (FRET) signals between aptamer quantum dots and AIEgen dye, which eliminated the EV extraction and purification to conveniently diagnose lung cancer. In a cohort of 80 clinical samples, this system showed enhanced accuracy (100% versus 65%) and sensitivity (100% versus 55%) in cancer diagnosis as compared to the ELISA detection method. Improved accuracy of early screening (from 96.4% to 100%) was achieved by comprehensively profiling five biomarkers using a machine learning analysis system. FRET-based tumor EV-MPDS is thus an isolation-free, low-volume (1 µL), and highly accurate approach, providing the potential to aid lung cancer diagnosis and early screening.

Comprehensive analyses of a CD8+ T cell infiltration related gene signature with regard to the prediction of prognosis and immunotherapy response in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is associated with a worse prognosis than other histological subtypes of non-small cell lung cancer. Due to the vital role of CD8+ T cells in anti-tumor immunity, the characterization of CD8+ T cell infiltration-related (CTLIR) gene signature in LUSC is worthy of in-depth exploration. In our study, tumor tissues of LUSC patients from Renmin Hospital of Wuhan University were stained by multiplex immunohistochemistry to evaluate the density of infiltrated CD8+ T cells and explore the correlation with immunotherapy response. We found that the proportion of LUSC patients who responded to immunotherapy was higher in the high density of CD8+ T cell infiltration group than in the low density of CD8+ T cell infiltration group. Subsequently, we collected bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) database. The abundance of infiltrating immune cells in LUSC patients was analyzed by using CIBERSORT algorithm, and weighted correlation network analysis was performed to identify the co-expressed gene modules related to CD8+ T cells. We then developed a prognostic gene signature based on CD8+ T cell co-expressed genes and calculated the CTLIR risk score, which stratified LUSC patients into high-risk and low-risk groups. With univariate and multivariate analyses, the gene signature was identified as an independent prognostic factor in LUSC patients. The overall survival of LUSC patients in the high-risk group was significantly shorter than that of the low-risk group in the TCGA cohort, which was validated in Gene Expression Omnibus datasets. We analyzed immune cell infiltration in the tumor microenviroment and found fewer CD8+ T cells and more regulatory T cell infiltration in the high-risk group, which is characterized as an immunosuppressive phenotype. Furthermore, the LUSC patients in the high-risk group were predicted to have a better response to immunotherapy than those in the low-risk group when treated with PD-1 and CTLA4 inhibitors. In conclusion, we performed a comprehensive molecular analysis of the CTLIR gene signature in LUSC and constructed a risk model for LUSC patients to predict prognosis and immunotherapy response.

Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Primary tumor resection benefited the survival of patients with distant metastatic gastric cancer.

BACKGROUND: The role of surgery in the treatment of patients with distant metastatic (M1) gastric cancer (GC) remains controversial currently. This study aimed to clarify the impact of primary tumor resection (PTR) on the survival of such patients. MATERIALS AND METHODS: The surveillance, epidemiology, and end results database was adopted to extract eligible patients. We designed a retrospective case-control study. The patients were divided into two groups according to whether they received PTR. The 1:1 propensity score matching (PSM) analysis was performed to balance the confounding factors between no-surgery and surgery groups. The categorical variables were described with Chi-square tests. Cancer-specific survival (CSS) and overall survival (OS) were evaluated by Kaplan-Meier method with log-rank test. Cox proportional hazard models were utilized to identify prognostic factors of CSS. RESULTS: A total of 1716 patients were included, including 1108 (64.6%) patients without surgery and 608 (35.4%) patients with surgery. After PSM, most confounders were well balanced between the two comparison groups. Survival analysis in matched cohorts indicated that surgery exerted significant survival advantages in both CSS and OS curves. The median CSS was 11.0 (9.8-12.2) months in the surgery group versus 9.0 (8.0-10.0) months in the no-surgery group (P < 0.001). Multivariable Cox regression analysis identified surgery as an independent prognostic factor for favorable prognosis (hazard ratio: 0.689, 95% confidence interval: 0.538-0.881, P = 0.003). CONCLUSION: Surgery showed significant survival benefits for the patients with M1 stage GC. Our study has provided additional evidence to support PTR for these patients.

CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city.

OBJECTIVES: To characterize the chest computed tomography (CT) findings of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to clinical severity. We compared the CT features of common cases and severe cases, symptomatic patients and asymptomatic patients, and febrile and afebrile patients. METHODS: This was a retrospective analysis of the clinical and thoracic CT features of 120 consecutive patients with confirmed SARS-CoV-2 pneumonia admitted to a tertiary university hospital between January 10 and February 10, 2020, in Wuhan city, China. RESULTS: On admission, the patients generally complained of fever, cough, shortness of breath, and myalgia or fatigue, with diarrhea often present in severe cases. Severe patients were 20 years older on average and had comorbidities and an elevated lactate dehydrogenase (LDH) level. There were no differences in the CT findings between asymptomatic and symptomatic common type patients or between afebrile and febrile patients, defined according to Chinese National Health Commission guidelines. CONCLUSIONS: The clinical and CT features at admission may enable clinicians to promptly evaluate the prognosis of patients with SARS-CoV-2 pneumonia. Clinicians should be aware that clinically silent cases may present with CT features similar to those of symptomatic common patients. KEY POINTS: • The clinical features and predominant patterns of abnormalities on CT for asymptomatic, typic common, and severe cases were summarized. These findings may help clinicians to identify severe patients quickly at admission. • Clinicians should be cautious that CT findings of afebrile/asymptomatic patients are not better than the findings of other types of patients. These patients should also be quarantined. • The use of chest CT as the main screening method in epidemic areas is recommended.

Prognostic nomogram for predicting survival in patients with high grade endometrial stromal sarcoma: a Surveillance Epidemiology, and End Results database analysis.

OBJECTIVE: High grade endometrial stromal sarcoma is a rare and highly malignant tumor that lacks a prognostic model. The aim of this study was to develop a prognostic nomogram predicting the overall survival of patients with high grade endometrial stromal sarcoma. METHODS: Clinical data for patients were derived from the Surveillance Epidemiology, and End Results database. Cox analysis and Akaike's information criterion were used to construct the nomogram. The concordance index, time dependent receiver operating characteristic curve, and calibration plot were used to evaluate the discriminative and calibrating capability. The net reclassification index, integrated discrimination improvement, and concordance index change were also compared between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO) stage. Clinical benefit was evaluated using decision curve analysis. The patients were separated into groups with low and high nomogram risk scores. Kaplan-Meier curve analysis and Cox analysis were used to investigate the survival difference between the two groups. RESULTS: The training and validation cohorts had 461 and 195 patients, respectively. A nomogram that incorporated disease stage, age, surgery, lymph node status, radiotherapy, and chemotherapy for predicting overall survival was established and validated. The concordance index of the nomogram was 0.734 (0.708-0.761) in the training cohort and 0.705 (0.659-0.751) in the validation cohort. The calibration plots showed a favorable calibrating ability of the nomogram. The 1 year and 3 year time dependent receiver operating characteristic curves showed the better discriminative ability of the nomogram than the staging system. The concordance index change, net reclassification index, and integrated discrimination improvement also indicated a significantly (p<0.05) better predictive power of the nomogram over disease stage. Furthermore, decision curve analysis suggested that the nomogram was clinically useful and had a larger clinical net benefit than disease stage alone. Patients with a high risk score had distinctly poorer survival than those with low risk scores. CONCLUSIONS: A prognostic nomogram in patients with high grade endometrial stromal sarcoma exhibited favorable prognostic discrimination and survival prediction ability compared with FIGO stage.

Potentiality of forkhead box Q1 as a biomarker for monitoring tumor features and predicting prognosis in non-small cell lung cancer.

BACKGROUND: This study aimed to explore the correlation of forkhead box Q1 (FOXQ1) with clinicopathological features and survival profiles in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 238 NSCLC patients with TNM stage I-III who underwent surgical resection were reviewed, and the expression of FOXQ1 in tumor and paired adjacent tissue was detected using immunohistochemistry assays. The clinical data and survival data of patients with NSCLC were retrieved and calculated. RESULTS: FOXQ1 expression was increased in tumor tissue (61.3% high expression and 38.7% low expression) compared with paired adjacent tissue (37.8% high expression and 62.2% low expression) (P < .001). In addition, high FOXQ1 expression was associated with larger tumor size (P = .042), lymph node metastasis (P = .040), and advanced TNM stage (P = .002). Disease-free survival (DFS) (P = .016) and overall survival (OS) (P = .008) were both reduced in patients with high FOXQ1 expression compared with patients with low FOXQ1 expression. Additionally, high FOXQ1 expression (P = .043), poor pathological differentiation (P = .003), and lymph node metastasis (P < .001) were independent risk factors for DFS, and high FOXQ1 expression (P = .021), tumor size (>5 cm) (P = .014), and lymph node metastasis (P < .001) were independent risk factors for OS. CONCLUSION: High FOXQ1 expression is associated with advanced tumor features as well as undesirable survival profiles in patients with NSCLC, implying the potential prognostic value of FOXQ1 for NSCLC.

Surgery to the primary tumor is associated with improved survival of patients with metastatic esophageal cancer: propensity score-matched analyses of a large retrospective cohort.

The survival advantage of surgery to the primary tumor for patients with distant metastatic esophageal cancer has not been adequately evaluated. This study aims to investigate the role of surgery to the primary tumor in distant metastatic esophageal cancer and to evaluate possible different effects of surgery on survival of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). This study included a cohort of 4,367 metastatic esophageal cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, registered from January 2004 to December 2014. Kaplan-Meier and Cox proportional hazardous models were used to evaluate the overall survival (OS) and corresponding 95% confidence interval (CI). Propensity score matching (PSM) was used to adjust for potential baseline confounding. Both EAC (median OS for surgery group vs. no-surgery group-14.0 vs. 9.0 months, P < 0.001) and ESCC (median OS for surgery vs. no-surgery group-11.0 vs. 7.0 months, P = 0.002) experienced survival benefits from surgery. We found that surgery to the primary tumor, when combined with chemotherapy, was associated with improved survival for patients with M1b disease, both EAC and ESCC, with a greater benefit observed in younger patients, and those with EAC. While the present data indicate a potential survival benefit from surgery for some patients with metastatic esophageal cancer, it is possible that performance status and metastatic disease burden impacted patient selection, influencing these results. Further studies are needed to determine the role of surgery for patients with metastatic esophageal cancer.

Comparison of geometrical uncertainties in the radiotherapy for various treatment sites with two different immobilization marking methods.

OBJECTIVE: The skin marking method (SMM) and bow-form-ruler marking method (BFRM) are two commonly used patient marking methods in mainland China. This study aims to evaluate SMM and BFRM by comparing the inter-fraction setup errors from using these two methods together with vacuum cushion immobilization in patients underwent radiotherapy for different treatment sites. MATERIALS AND METHODS: Eighteen patients diagnosed with pelvic, abdominal and thoracic malignant tumors (with 6 patients per treatment site) were enrolled in this prospective study. All patients were immobilized with vacuum cushion. Each patient was marked by both SMM and BFRM before computed tomography (CT) simulation. Target location was verified by cone beam CT images with displacements assessed prior to each sampled treatment session. The localization errors in three translational and three rotational directions were recorded and analyzed. RESULTS: Images from 108 fractions in 18 patients produced 324 translational and 324 rotational comparisons for SMM and BFRM. The setup errors of all treatment sites showed no difference in two marking methods in any directions (p > 0.05). In subgroups of treatment site analysis, SMM significantly lessened the lateral and yaw setup errors compared to BFRM in the pelvic sites (0.39±1.85 mm vs -1.28±1.13 mm, p < 0.01 and -0.19±0.59° vs -0.61±0.59°, p < 0.05). However, in the abdominal subgroup, BFRM was superior to SMM for reduced vertical errors (0.17±2.73 mm vs 2.28±3.16 mm, p < 0.05). For the underweight or obese patients (with Body Mass Index, BMI < 18.5 or BMI≥24), SMM resulted in less yaw errors compared to BFRM (-0.05±0.38° vs -0.43±0.48°, p < 0.05). No significant difference between SMM and BFRM in setup errors of normal weighted patients (18.5≤BMI < 24) was observed for all three studied treatment sites. CONCLUSIONS: This study shows no significant difference in patient setup errors for various treatment sites between SMM and BFRM in general. SMM may be suitable for the pelvic tumor and patients with BMI < 18.5 or BMI≥24, while BFRM is recommended for the abdominal tumor sites.

Naringenin Ameliorates Radiation-Induced Lung Injury by Lowering IL-1ß Level.

Radiation-induced lung injury (RILI) is the main complication of radiotherapy for thoracic malignancies. Since naringenin, a potent immune-modulator, has been found to relieve bleomycin-induced lung fibrosis by restoring the balance of disordered cytokines, we sought to determine whether naringenin would mitigate RILI and to investigate the underlying mechanism. Animals received fractionated irradiation in the thoracic area to induce RILI. Enzyme-linked immunosorbent assay and MILLIPLEX assays were used for serum and bronchoalveolar lavage fluid for cytokine analyses, hematoxylin and eosin staining for pathologic changes, and Masson trichrome staining for determination of lung fibrosis. Interleukin (IL)-1ß was found significantly elevated after thoracic irradiation and it triggered production of profibrotic tumor growth factor ß both in vivo and in vitro, suggesting the vital role of in IL-1ß in the development of RILI. Furthermore, we found that naringenin was able to ameliorate RILI through downregulation of IL-1ß and restoration of the homeostasis of inflammatory factors. Our results demonstrated that naringenin could serve as a potent immune-modulator to ameliorate RILI. More importantly, we suggest that a new complementary strategy of maintaining the homeostasis of inflammatory factors combined with radiation could improve the efficacy of thoracic radiotherapy.

Radiotherapy Improves the Survival of Patients With Metastatic Cervical Cancer: A Propensity-Matched Analysis of SEER Database.

OBJECTIVE: To demonstrate whether radiotherapy has an effect on the survival of patients with stage IVb (M1) cervical cancer, as it has not been adequately clarified. METHODS: We analyzed International Federation of Gynecology and Obstetrics (FIGO) stage M1 cervical cancer diagnosed in patients between 1992 and 2013 using population-based data from the Surveillance, Epidemiology, and End Results registry. Propensity score (PS) analysis with 1:1 matching and the nearest neighbor matching method was performed to ensure well-balanced characteristics of comparison groups. Data were analyzed by Kaplan-Meier and Cox proportional hazards regression models to evaluate the overall survival (OS) and cancer-specific survival (CSS) months with corresponding 95% confidence intervals (95% CIs). RESULTS: In general, receiving radiotherapy significantly improved OS and CSS both before and after PS matching (PSM) (P < 0.001), with significantly improved OS (hazard ratio, 0.69; 95% CI, 0.62-0.76) and CSS (hazard ratio, 0.79; 95% CI, 0.70-0.89) after PSM in patients with stage M1 cervical cancer. Before PSM, radiotherapy was found to be associated with improved survival even for the patients with stage M1 cervical cancer with extensive metastasis (≥2 metastatic sites) (P < 0.001). Although P value was not significant for brain metastasis, the survival month was numerically improved before PSM (OS and CSS, 1 month vs 4 months). Overall, radiotherapy still significantly improved survival for patients with one metastatic site (ie, oligometastases) either before or after PSM (P < 0.05), with the survival month improved more than 6 months. CONCLUSIONS: The large Surveillance, Epidemiology, and End Results results support that radiotherapy might improve the survival of patients with metastatic cervical cancer. It might be prudent to carefully select suitable patients for radiation therapy for metastatic cervical cancer.

Insulin promotes progression of colon cancer by upregulation of ACAT1.

BACKGROUND: Insulin resistant and the progression of cancer is closely related. The aim of this study was to  investigate the effect of insulin on the proliferation and migration of colon cancer cells and its underlying mechanism. METHODS: Colon carcinoma tissues from the 80 cases of colon cancer patients were collected. Immunohistochemistry was used to detect the expression of acyl coenzyme A: cholesterol acyltransferase1 (ACAT1), and we analyzed the correlation between hyperglycemia and ACAT1, hyperglycemia and metastasis. CCK8 assay and transwell assay were used to investigate the effect of different concentrations of insulin and ACAT1siRNA on human colon cancer cell line HT-29. ACAT1 mRNA expression and protein level in HT-29 cells were determined by real-time quantitative PCR and western blotting, respectively. RESULTS: Biopsies from patients with colon carcinoma showed hyperglycemia links ACAT1, lymph nodes metastasis and distant metastasis. Insulin markedly promoted cell proliferation and migration in human colon cancer HT-29 cells. Moreover, ACAT1mRNA expression and protein level were increased by insulin. ACAT1siRNA resulted in a complete inhibition of the ACAT1 mRNA expression. Consequently insulin-triggered cell proliferation and migration on colon cancer cells were inhibited. CONCLUSION: The progression of colon cancer has a positive correlation with hyperinsulinemia. Insulin-triggered cell proliferation and metastatic effects on colorectal cancer cells are mediated by ACAT1. Therefore, insulin could promote colon cancer progression by upregulation of ACAT1, which maybe is a potential therapeutic target for colon cancer.

Synergy of Dendritic Cell Vaccines and Avasimibe in Treatment of Head and Neck Cancer in Mice.

BACKGROUND The main purpose of this study was to explore the antitumor effect and mechanisms of ACAT1 inhibitor combined with CSCs-DC vaccine. MATERIAL AND METHODS We isolated HNSCC CSCs and gained CSCs antigens, then used CSCs antigens to load dendritic cells (DC) and generated a CSCs-DC vaccine. We treated mice after surgical excision of established SCC7 tumors with CSCs-DC vaccine and/or ACAT1 inhibitor, and recorded local tumor relapse and host survival. T cells and B cells were harvested from mice treated with CSCs-DC vaccine and/or ACAT1 inhibitor. We tested antibody production and the death rate of CSCs killed by T cells. RESULTS The tumors in the combined treatment group were smaller than in all other groups (P<0.01). The average survival time of the combined treatment group was 82 days and was the longest of all groups. Analysis of IgG levels secreted by B cell and CTL activity in spleens of mice found that results of the combined treatment group were the highest, and the results of the CSCs-DC group were lower than in the combined treatment group. The ACAT1 inhibitor group results were lower than in the CSCs-DC group and the combined treatment group results, but higher than in the PBS group, and the difference was statistically significant. CONCLUSIONS ACAT1 inhibitor enhanced the therapeutic effect of CSCs-DC vaccine in the treatment of the mouse HNSCC postoperative recurrence model. ACAT1 may play an important role in cancer immunotherapy.