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Chronic kidney disease (CKD) is a serious public health problem. Due to a high variability in the speed of CKD progression to end-stage renal disease (ESRD) and the critical involvement of Wnt/β-catenin signaling in CKD, we investigated the role of the Wnt antagonist Dickkopf-1 (DKK1) in CKD progression. Our data revealed that patients with CKD stages 4–5 had higher DKK1 levels in their serum and renal tissues than the control subjects. In an 8-year follow-up, the serum DKK1-high group in the enrolled CKD patients showed a faster progression to ESRD than the serum DKK1-low group. Using a rat model of 5/6 nephrectomy (Nx)-induced CKD, we consistently detected elevated serum levels and renal production of DKK1 in 5/6 Nx rats compared to sham-operated rats. Importantly, the knockdown of the DKK1 levels in the 5/6 Nx rats markedly attenuated the CKD-associated phenotypes. Mechanistically, we demonstrated that the treatment of mouse mesangial cells with recombinant DKK1 protein induced not only the production of multiple fibrogenic proteins, but also the expression of endogenous DKK1. Collectively, our findings suggest that DKK1 acts as a profibrotic mediator in CKD, and elevated levels of serum DKK1 may be an independent predictor of faster disease progression to ESRD in patients with advanced CKD.

Supplementary Figure 4. Effects of Calcitriol on IL-6/STAT3 signaling in esophageal SCC

Supplementary Figure 6. Effect of Calcitriol treatments on the function and recruitment of MDSC in vivo.

Supplementary methods and legends for supplementary Figures

The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)–induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial–mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO–induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO–induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC. Mol Cancer Ther; 14(6); 1365–75. ©2015 AACR.

Supplementary Figure 1. Effects of Calcitriol on tumor cell proliferation in vitro

Supplementary Figure 5. IL-6 levels in 4-NQO-treated mice with or without Calcitriol or IL-6 injection were measured using ELISA

Supplementary Figure 3. Effects of blocking IL-6 on tumor growth and EMT in vitro

Locoregional control is a significant prognostic factor for hepatocellular carcinoma (HCC). Historically, the use of radiotherapy (RT) for HCC was limited owing to the low radiotolerance of the liver and the need for high RT doses for disease control. We aimed to examine if 1α,25-dihydroxyvitamin D3 (calcitriol) has a role in the tumor inhibition and the radiation response of HCC in vitro and in vivo, and explore the underlying mechanisms. The human and murine liver cancer cell lines were selected for cellular and animal experiments to investigate the changes in tumor characteristics and the radiation response after calcitriol supplementation. The effects induced by calcitriol supplementation on interleukin-6 (IL-6) signaling and the tumor immune microenvironment following RT were also examined. Our data revealed that calcitriol supplementation attenuated tumor aggressive behavior, decrease IL-6 expression, and augmented radiation-induced tumor inhibition. The biological changes following calcitriol treatment included suppressed epithelial-mesenchymal transition, attenuated cancer stem cell-like properties and increased radiation-induced reactive oxygen species and cell death in vitro. Regarding immune microenvironment, calcitriol attenuated the recruitment of myeloid-derived suppressor cell (MDSC) recruitment and increased the infiltration of cytotoxic T cells in tumor following RT. Furthermore, When the primary liver tumor was irradiated with larger dose per fraction, calcitriol induced a smaller size of synchronous unirradiated tumor in mice, which linked with attenuated IL-6 signaling and MDSC recruitment. In conclusion, calcitriol treatment reduced tumor aggressiveness and enhanced the radiation response. The inhibited IL-6 signaling and subsequently enhanced antitumor immunity might be responsible to augment radiation-induced tumoricidal effect induced by calcitriol. Based on our results, we suggest that calcitriol could exert the antitumor and radiosensitization effects for HCC, especially for multifocal tumors.

Acoustic levitation is considered one of the most effective noncontact particle manipulation methods, along with aerodynamic, ferromagnetic, and optical levitation techniques. It is not restricted by the material properties of the target. However, existing acoustic levitation techniques have some drawbacks that limit their potential applications. Therefore, in this article, an innovative approach is proposed to manipulate objects more intuitively and freely. By taking advantage of the transition periods between the acoustic pulse trains and electrical driving signals, acoustic traps can be created by switching the acoustic focal spots rapidly. Since the high-energy-density points are not formed simultaneously, the computation of the acoustic field distribution with complicated mutual interference can be eliminated. Therefore, compared to the existing approaches that created acoustic traps by solving pressure distributions using iterative methods, the proposed method simplifies the computation of time delay and makes it possible to be solved even with a microcontroller. In this work, three experiments have been demonstrated successfully to prove the capability of the proposed method including lifting a Styrofoam sphere, transportation of a single target, and suspending two objects. Besides, simulations of the distributions of acoustic pressure, radiation force, and Gor'kov potential were conducted to confirm the presence of acoustic traps in the scenarios of lifting one and two objects. The proposed tactic should be considered effective since the results of the practical experiments and simulations support each other.

Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1β, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD.

Depression is a common comorbid disorder associated with breast cancer, and it can have considerable physical and psychological impacts. Circulating cytokines have been proposed as a potential tool to predict depression in various diseases; however, limited studies have specifically examined it in breast cancer. In this study, we examined and compared the prediction ability of various circulating cytokines for depression in patients with breast cancer. Eighty-three patients with a new diagnosis of breast cancer not receiving chemotherapy were recruited; among them, 15 patients had depression and 68 did not have depression. Depression was evaluated using the Patient Health Questionnaire 9 (PHQ-9). Cytokine levels in the serum were measured using an immunology multiplex assay. Two types of cytokines were assayed: (1) proinflammatory cytokines (interleukin [IL]-1β, IL-2, IL-6, IL-12, IL-17A, interferon [IFN]γ, and tumor necrosis factor [TNF]α) and (2) anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). Receiver operating characteristic (ROC) analysis was performed to calculate the area under the curves (AUCs), sensitivities, and specificities of circulating cytokines for predicting depression. As a result, IL-2 (AUC = 0.78) and IL-5 (AUC = 0.76) demonstrated good predictability for depression, even after controlling for the covariates (i.e. age, education, stage of cancer, surgery, radiation therapy, and hormone therapy). The optimal cut-off value of IL-2 for predicting depression was 1.06 pg/mL with a sensitivity of 86.7% and a specificity of 52.9%; this cytokine also had the best prediction ability in this study. Owing to the prediction ability and practical feasibility of circulating cytokines, they may be used as a valid laboratory diagnostic tool for depression in breast cancer.

Previous findings regarding declines in cognitive functioning among patients with breast cancer (BC) before and after chemotherapy have been inconsistent. The present study explored the effect of BC and cancer-related chemotherapies on cognitive functioning. A cross-sectional design was adopted to compare BC patients before their chemotherapy treatment, BC patients 3 ~ 9 months after the completion of chemotherapy, and noncancer controls. Evaluations of cognitive functioning included subjective and objective dimensions, with focus on memory, executive functioning, attention, and language. ANCOVA and Pearson’s correlation analysis were used to examine the relationship among cancer, chemotherapy, cognitive performance, and psychological distress. After adjustment for intelligence quotient, anxiety, and depression, we found significant differences in the Semantic Association of Verbal Fluency between post-chemotherapy (C/T) patients and noncancer controls. Specifically, post-C/T patients scored lower than controls (p = 0.03, η2 = 0.07). No significant differences were found in other objective cognitive measures. However, both subjective and objective cognitive scores were significantly associated with depression, anxiety, and fatigue. In BC patients, levels of anxiety were positively correlated with measures of executive function. Among pre-C/T patients, self-perceived interference by fatigue was positively associated with better performances in some of the objective cognitive measures. Our findings suggest cognitive impairments in the domain of executive functioning among patients with BC who received chemotherapy. Providing relevant suggestions or strategies of managements for these negative consequences may help increase the long-term quality of life of patients with BC.

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.

Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. In non-stressed conditions, NRF2 maintains the hemostasis of redox with housekeeping work. It expresses constitutively with basal activity, maintained by Kelch-like-ECH-associated protein 1 (KEAP1)-associated ubiquitination and degradation. When encountering stress, it can be up-regulated by several mechanisms to exert its anti-oxidative ability in diseases or inflammatory processes to protect tissues and organs from further damage. From acute kidney injury to chronic kidney diseases, such as diabetic nephropathy or glomerular disease, many results of studies have suggested that, as a master of regulating redox, NRF2 is a therapeutic option. It was not until the early termination of the clinical phase 3 trial of diabetic nephropathy due to heart failure as an unexpected side effect that we renewed our understanding of NRF2. NRF2 is not just a simple antioxidant capacity but has pleiotropic activities, harmful or helpful, depending on the conditions and backgrounds.

Background Type 1 diabetes is an inflammatory state. Myeloid-derived suppressive cells (MDSCs) originate from immature myeloid cells and quickly expand to control host immunity during infection, inflammation, trauma, and cancer. Immunotherapy is a method of disease treatment that involves stimulating or suppressing an immune response. Although the spleens and blood of tumor-bearing mice are the most common MDSC source for immunotherapy, many safety precautions must be considered. Methods Cytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-1β. Arginase-1 and inducible NO synthase (iNOS) expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Diabetes was diagnosed as a sustained blood sugar level > 350 mg/dL. The immunized T cells harvested from the spleens of nonobese diabetic (NOD) mice cotransplanted with cMDSCs were injected intravenously to the NOD mice with severe combined immune deficiency (SCID), twice a week for 5 consecutive weeks. Diabetes-free survival of NOD–SCID mice was measured. Fibronectin expressions of the renal glomerulus and insulin production of the pancreas were analyzed using immunohistochemistry studies. Results This study presents an ex vivo procedure to develop MDSCs from bone marrow cells propagated from GM-CSF, IL-6, and IL-1β cytokines expressing less costimulatory and more inhibitory surface markers as well as considerably high levels of the iNOS enzyme through the signal transducer and activator of transcription 1 (STAT1) signaling pathway. In addition, the MDSCs also displayed immature morphology and strong immunosuppression of T cell proliferation. The adoptive transfer of cMDSCs improved the hyperglycemic state in and prolonged the diabetes-free survival of NOD-SCID mice induced by reactive splenic T cells harvested from NOD mice. In addition, cMDSC use reduced fibronectin production in the renal glomeruli and improved pancreatic insulitis in the NOD–SCID mice. Conclusions The administration of cMDSCs propagated from GM-CSF, IL-6, and IL-1β cytokines provides an alternative immunotherapy protocol for the treatment of diabetic pancreatic insulitis and renal nephropathy.

Undernourishment is reported to impair treatment response, further leading to poor prognosis for cancer patients. We aimed to investigate the role of nutritional status on the prognosis of squamous cell carcinoma (SCC) of the esophagus, and its correlation with anticancer immune responsiveness. We retrospectively reviewed 340 esophageal-SCC patients who completed curative treatment and received a nutrition evaluation by the Patient-Generated Subjective Global Assessment (PGSGA) score at the beginning and completion of neoadjuvant treatment at our hospital. The correlation between the nutritional status and various clinicopathological parameters and prognosis were examined. In addition, the role of nutritional status in the regulation of the anticancer immune response was also assessed in cancer patients and in a 4-nitroquinoline 1-oxide (4NQO)-induced esophageal tumor model. Our data revealed that malnutrition (patients with a high PGSGA score) was associated with advanced stage and reduced survival rate. Patients in the group with a high PGSGA score were correlated with the higher neutrophil-to-lymphocyte ratio, higher proportion of myeloid-derived-suppressor cells (MDSC) and increased IL-6 level. Furthermore, surgical resection brought the survival benefit to patients in the low PGSGA group, but not for the malnourished patients after neoadjuvant treatment. Using a 4NQO-induced tumor model, we found that nutrition supplementation decreased the rate of invasive tumor formation and attenuated the immune-suppressive microenvironment. In conclusion, malnutrition was associated with poor prognosis in esophageal-SCC patients. Nutritional status evaluated by PGSGA may be useful to guide treatment decisions in clinical practice. Nutritional supplementation is suggested to improve prognosis, and it might be related to augmented anticancer immune response.

Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERKs in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed a higher mRNA expression of Bruton’s tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably diminish the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.—Keshari, S., Sipayung, A. D., Hsieh, C.-C., Su, L.-J., Chiang, Y.-R., Chang, H.-C., Yang, W.-C., Chuang, T.-H., Chen, C.-L., Huang, C.-M. IL-6/p-BTK/p-ERK signaling mediates calcium phosphate–induced pruritus.

Background: Malnutrition in patients with tuberculosis (TB) is associated with poor outcomes. This study assessed the validity of the patient-generated subjective global assessment (PG-SGA) in adult TB patients and examined the association of the PG-SGA score with adverse outcomes. Methods: This is a retrospective chart review study compared with the well-nourished and malnourished TB patients. The nutritional status was determined using the PG-SGA for adult patients (n = 128). Clinical outcomes included liver injury and mortality. Adverse outcomes included hepatitis during anti-tuberculosis therapy. Results: By comparing nutritional status using global assessment, well-nourished patients had a significantly higher body weight index (p = 0.002), a lower PG-SGA score (p &lt, 0.001), and lower diabetic rate (p = 0.029). Malnourishment was a risk factor (p = 0.022) for liver injury and fatal outcomes (p &lt, 0.001). A higher PG-SGA score was a risk factor for liver injury (p = 0.002) and an independent risk factor for fatal outcomes (p = 0.031). ROC analysis for outcome prediction showed that a PG-SGA score of 5.5 points yielded the most appropriate sensitivity (61.5%) and specificity (64.7%). Conclusion: Both global assessment and the total PG-SGA score were related to tuberculosis outcome and liver injury during anti-TB treatment.

Increasing evidence indicates that the microbiome may influence tumor growth and modulate the tumor microenvironment of gastrointestinal cancers. However, the role of oral bacteria in the development of esophageal squamous cell carcinoma (EsoSCC) has remained unclear. Herein, we investigated the relationship between the periodontal pathogen Porphyromonas gingivalis and EsoSCC.To identify bacterial biomarkers associated with EsoSCC, we analyzed microbiomes in oral biofilms. The presence of P. gingivalis in esophageal tissues and relationships of P. gingivalis infection with clinicopathologic characteristics in 156 patients with EsoSCC were assessed using immunohistochemistry. The role of P. gingivalis infection in in vitro and in vivo EsoSCC progression was also assessed.Microbiota profiles in oral biofilms revealed that P. gingivalis abundance was associated with an increased risk of EsoSCC development. In total, 57% of patients with EsoSCC were found to be infected with P. gingivalis. The presence of P. gingivalis was found to be associated with advanced clinical stages and a poor prognosis. It was also found to be associated with an elevated esophageal cancer incidence in a 4-nitroquinoline 1-oxide-induced mouse model and with an increased xenograft tumor growth. P. gingivalis infection increased interleukin (IL)-6 production and it promoted epithelial-mesenchymal transition and the recruitment of myeloid-derived suppressor cells. Furthermore, inhibited IL-6 signaling attenuated the tumor-promoting effects of P. gingivalis in 4-nitroquinoline 1-oxide-treated mice and xenograft mouse models.Our data indicate that P. gingivalis may promote esophageal cancer development and progression. Direct targeting of P. gingivalis or concomitant IL-6 signaling may be a promising strategy to prevent and/or treat EsoSCC associated with P. gingivalis infection.

Acoustic pyrometer is expected to be a useful noninvasive method for monitoring gas temperature distribution inside a steel-making furnace. On the superficial layer above the burden of a blast furnace, most of the high-temperature gas is concentrated near the center, and tracking the position of the hotspot is critical for productivity. However, most of the existing acoustic temperature distribution reconstruction algorithms are developed with relatively uniform temperature distribution environments. Besides, their capabilities of tracking the pinnacle of temperature distribution in the region of interest (ROI) are rarely discussed. In this research, a reconstruction method of acoustic temperature tomography dedicated for highly centralized gas temperature distribution is proposed and demonstrated. The key metrics include the reproducibility of 2-D temperature distribution, the sensitivity of hotspot shift, and the accuracy of point-to-point (P2P)/peak temperature. To optimize the result of each metric, previous approaches of acoustic temperature tomography have been first evaluated. Then, the investigation of effects from the shape and size of meshes is proceeded to improve the performance. After that, a novel method to address convergence issues while using the iterative method is introduced. Consequently, the reconstruction method proposed in this article could effectively visualize the temperature map while hotspot moves to different locations. It could also sense the occurrence of a hotspot (2.56% of ROI) traveled from center to 1% of ROI’s diameter. Moreover, a competitive accuracy with 5.89% and 1.46% error at P2P root-mean-square (rms) and peak temperature is achieved, respectively. Finally, a practical acoustic 2-D pyrometer consisted of 12 ultrasonic transducers arranged in a circular pattern with a 1-m width of ROI successfully detected the shift of a hotspot when the displacement of a heater reaches 5 cm.

Chia-Hsin Chen,1 Ching-Chuan Hsieh,2 Chih-Shen Chang,1 Miao-Fen Chen1,3 1Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 3Chang Gung University College of Medicine, Taoyuan City, TaiwanCorrespondence: Miao-Fen ChenDepartment of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi, TaiwanEmail miaofen@adm.cgmh.org.twBackground: A better understanding of the organs-at-risk (OAR) dose metrics and the related toxicity induced by radiotherapy (RT) for left breast cancer (BC) will improve the quality of life. This study addressed the issue for left-BC patients treated with intensity-modulated radiotherapy (IMRT) compared to three-dimensional conformal radiotherapy (3D-CRT).Patients and Methods: Between 2012 and 2018, 308 left-BC patients underwent adjuvant RT at our hospital. Before June 2015, 134 patients were treated with 3D-CRT. Thereafter, 174 patients underwent IMRT. The patient’s characteristics in the IMRT group did not significantly different compared to those in the 3D-CRT group.Results: Among the total study population, the incidence of ≥grade 2 radiation dermatitis (RID) was 17.3%. Higher volumes receiving 105% (≥ 5.7%) and 107% (≥ 1%) of prescribed dose and 3D-CRT technique were associated with a higher risk of RID. Regarding lung toxicity, the mean lung dose (≥ 10.2Gy) and V20 (≥ 20%) of ipsilateral lung were significantly associated with the incidence of RT-induced pulmonary changes. By dosimetry analysis, IMRT achieved better dose conformity and delivered lower mean doses to heart and ipsilateral lung compared to 3D-CRT. Furthermore, propensity sore and multivariate analysis showed that IMRT technique helped to reduce RT-induced dermatitis and lung toxicity.Conclusion: Our data suggest that the volume of OAR exposed to higher doses is a predictor of RT-induced toxicity. Adjuvant RT with IMRT technique offered better dose conformity and spared high-dose levels to OARs to reduce radiation-related morbidity for BC patients.Keywords: breast cancer, IMRT, 3D-CRT, OAR, toxicity

The acoustic tomographic (AT) approach aims to obtain information in a non-invasive way. Multidimensional and comprehensive information about temperature distribution can be used to optimize the performance of industrial processes. AT is a promising method for visualizing the 2D temperature field. The key challenge is to improve the accuracy of the relative spatial distribution and the absolute temperature value. Thus, this paper presents an alternative way to improve the reconstruction of the temperature field distribution by analyzing the effect of the grid structure and acoustic paths. In order to achieve this spatial moving average technique (MAT) have been studied and implemented across different grid structures (hexagon, square, and polar). Several numerical simulations were conducted to analyze the accuracy of the reconstructed temperature field using these three grid shapes. The effect of grid size was also analyzed. It was found that the hexagonal grid is more sensitive to the shift of hot spots and more accurate in the peak temperature. A hexagonal grid whose radius of the circumscribed circle is equal to 7 % of the sample diameter could efficiently detect a 3 % shift of the hotspot with less than 5 % error in the peak temperature. This simulation result was supported experimentally by 12 ultrasonic transceivers arranged in a circular pattern with 1 m in diameter.

Background In this study, we examined the differential associations of various proinflammatory and anti-inflammatory cytokines with depression severity from the development of breast cancer to subsequent chemotherapy treatment. Methods A cross-sectional study was conducted on a sample of 116 women: 29 controls without cancer, 55 patients with breast cancer who were not receiving chemotherapy, and 32 patients with breast cancer who were receiving chemotherapy. Blood samples were assayed to evaluate serum levels of the following cytokines: interferon-γ, interleukin (IL)-12 (p70), IL-1β, IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-10, IL-13, IL-6, and IL-17A. Depression severity was assessed using the Patient Health Questionnaire. Results After adjustment for sociodemographics, consistent patterns of the association between cytokine and depression were noted in the different groups. No significant associations were observed in the controls. Inverse associations were observed between cytokines levels and depression severity in patients with breast cancer who were not receiving chemotherapy, whereas positive associations were noted in patients with breast cancer who were receiving chemotherapy. Specific differential relationships between IL-5 levels and depression severity were found between patients with breast cancer who were receiving and not receiving chemotherapy. Conclusions Our study revealed differential relationships between cytokine levels and depression severity with the development of cancer. Immunostimulation and immunosuppression in breast cancer and cancer treatment may account for the differential responses with the development of breast cancer.

Background The microbiota is reported to affect tumor growth and the microenvironment of gastrointestinal cancers. However, the possible role of keystone bacterial infection in the development of esophageal squamous cell carcinoma (EsoSCC) remains unclear. In the present study, we studied the relationship between the oral microbiome, the periodontal pathogen Porphyromonas gingivalis (PG), and EsoSCC and elucidated the underlying mechanisms.Methods The microbiota in oral biofilms from patients was studied to identify bacterial biomarkers associated with EsoSCC by bioinformatics analyses. We then performed immunohistochemistry to examine the presence of PG in the esophageal tissues and analyze its relationship with the clinicopathologic characteristics in 156 EsoSCC patients. Furthermore, we investigated the role of PG infection in the progression of EsoSCC and its relationship with tumor microenvironment.Results The microbiota profiles from oral biofilms revealed that the abundance of PG was associated with a higher risk of developing EsoSCC. The presence of PG was detected immunohistochemically in 57% of cancerous tissues and was associated with a higher clinical stage and poor prognosis. Using cellular experiments and a 4-nitroquinoline 1-oxide (4NQO)-induced tumor animal model, the presence of PG was found to be associated with a higher risk of esophageal cancer. Increased IL-6 expression associated with an augmented epithelial-mesenchymal transition and recruitment of myeloid-derived suppressor cells were possible underlying mechanisms. Furthermore, in animal model including 4NQO-induced tumor and xenograft tumor model, we showed that the increased vitamin D3 induced by UVB light treatment obviously down-regulated IL-6 signaling and subsequently attenuated the increased risk of esophageal cancer induced by PG infection.Conclusions Our findings suggested that the presence of PG played an important role in the progression of esophageal cancer. Directly targeting PG or increasing vitamin D3 could be a promising strategy for the treatment of EsoSCC patients with PG infection noted by oral microbiota screening.

Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative and absolute quantitation (iTRAQ), a human plasma proteome database, and public Oncomine datasets to search for aberrantly expressed oncogene-associated proteins in GC tissues and plasma. One of the most significantly upregulated biomarkers, DEK, was selected and its expression validated. Our immunohistochemistry (IHC) (n = 92) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 72) analyses disclosed a marked increase in DEK expression in tumor tissue, compared with paired nontumor mucosa. Importantly, significantly higher preoperative plasma DEK levels were detected in GC patients than in healthy controls via enzyme-linked immunosorbent assay (ELISA). In clinicopathological analysis, higher expression of DEK in both tissue and plasma was significantly associated with advanced stage and poorer survival outcomes of GC patients. Data from receiver operating characteristic (ROC) curve analysis disclosed a better diagnostic accuracy of plasma DEK than carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), and C-reactive protein (CRP), highlighting its potential as an effective plasma biomarker for GC. Plasma DEK is also more sensitive in tumor detection than the other three biomarkers. Knockdown of DEK resulted in inhibition of GC cell migration via a mechanism involving modulation of matrix metalloproteinase MMP-2/MMP-9 level and vice versa. Our results collectively support plasma DEK as a useful biomarker for making diagnosis and prognosis of GC patients.

The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.

Malnutrition is common among patients who have oral cavity squamous cell carcinoma (OSCC), but its effect on the incidence of postoperative complications remains uncertain. Validated nutrition and complication assessment tools were used to evaluate the effects of nutrition on the likelihood of postoperative complications after curative surgery for OSCC. A retrospective study that spanned January 2014 to December 2018 enrolled 70 patients who received curative surgery for OSCC. Nutritional status before surgery was evaluated with the scored Patient-Generated Subjective Global Assessment (PG-SGA), and patients were classified as either well-nourished (rating A) or malnourished (ratings B and C). Complications 30 days after the operation were graded using Clavien-Dindo classification. The perioperative clinicopathological characteristics of the groups were compared, and risk factors for postoperative complications were identified through logistic regression. A total of 44 (62.8%) patients formed the malnourished group, and they tended to be older (P = .03), weigh less (P = .001), have lower Body Mass Index (P = .003), higher PG-SGA scores (P

The aim of this study was to analyze the nutritional risk factors for postoperative complications following hepatic resection for hepatocellular carcinoma (HCC).The preoperative nutritional status of patients with HCC who underwent hepatic resection was evaluated using the scored Patient-Generated Subjective Global Assessment (PG-SGA). The perioperative variables were compared between well-nourished and malnourished patients. Regression analysis was employed to identify the risk factors for postoperative complications.The overall operative mortality and morbidity of 287 patients who underwent resection for HCC were 1.7% and 44.3%, respectively. Upon admission, 96 (33.4%) study participants were malnourished, which was associated with a significantly higher PG-SGA score (P 0.001), higher frequency of comorbidity (P 0.001), more postoperative complications (P 0.001) and a longer length of hospital stay (P 0.001). In addition, major complications (Clavien-Dindo classification ≥ IIIa) occurred significantly more frequently in the malnourished group (P 0.01). Age ≥70 years (risk ratio [RR] = 2.50, P = 0.008) and PG-SGA score ≥ 4 ([RR] = 9.85, P 0.001) were significant risk factors for postoperative complications.The PG-SGA score is an effective tool for predicting postoperative complications in patients with HCC following hepatic resection.

Background Diabetes is a proinflammatory state. Fibrosis of the renal glomerulus is the most common cause of end-stage renal disease. Glomerulosclerosis is caused by the accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space. Mesangial cells are unique stromal cells in the renal glomerulus that form the vascular pole of the renal corpuscle along with the mesangial matrix. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that rapidly expand to regulate host immunity during inflammation, infection, and cancer. High concentrations of granulocyte–macrophage colony-stimulating factor (GM-CSF) alone or in combination with other molecules represent the most common ex-vivo protocol for differentiating MDSCs from bone marrow or from peripheral blood mononuclear cells. In this study, we analyzed and characterized the functions of MDSCs under the influence of mouse mesangial cells (MMCs) in a hyperglycemic environment and investigated whether cytokine-induced MDSCs ameliorated renal glomerulosclerosis in diabetic mice. Methods Cytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant GM-CSF, IL-6, and IL-1β. Diabetic mice were induced with streptozotocin (STZ) and maintained at a blood glucose concentration exceeding 350 mg/dl. The ECM of the renal cortex and fibronectin expression of MMCs were analyzed through immunohistochemistry and western blotting. Arginase 1 and inducible NO synthase expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Cytokines released from MMCs were examined using a cytokine array assay. Results MDSCs in the diabetic mice were redistributed from the bone marrow into peripheral organs. An increase in fibronectin production was also observed in the renal glomerulus. MMCs in vitro produced more fibronectin and proinflammatory cytokines, such as macrophage inflammatory protein-2, RANTES, and stromal-cell-derived factor-1, under hyperglycemic conditions. The adoptive transfer of cytokine-induced MDSCs into STZ-induced mice normalized the glomerular filtration rate to reduce the kidney to body weight ratio and decrease fibronectin production in the renal glomerulus, ameliorating renal fibrosis. These results demonstrate the anti-inflammatory properties of cytokine-induced MDSCs and offer an alternative immunotherapy protocol for the management of diabetic nephropathy. Conclusions The application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy. Electronic supplementary material The online version of this article (10.1186/s13287-018-0915-0) contains supplementary material, which is available to authorized users.

Figure S3. mRNA expression of arginase 1 and iNOS in cytokine-induced MDSCs. Expression of arginase 1 and iNOS mRNA from MDSCs derived from BM cells propagated for 7 days in presence of GM-CSF alone, GM-CSF + IL-1β, GM-CSF + IL6, and GM-CSF+ IL-1β + IL6 determined through qPCR (*P

Figure S4. Glucose, not d-mannitol, reduced MDSC production. BM cells from femur and tibia of B6 mice were cultured in presence of mouse recombinant GM-CSF (10Â ng/ml) under normal or high glucose conditions with or without 20Â mM of d-mannitol. Cells isolated for examination 7Â days later. Isolated cells two-color stained with specific mAbs against CD11b and Gr-1 for flow analyses (PDF 111 kb)

Figure S2. MDSCs isolated from STZ-treated mice inhibit less T-cell proliferative responses. CFSE-labeled B6 mice spleen T cells were cultured with splenic MDSCs isolated from STZ-treated mice or untreated mice at ratio of 10:1, 20:1, or 40:1 in presence of 1Â Îźg/ml of CD3/CD28 for 3Â days. Proliferation of T cells determined by CFSE dilution (PDF 120 kb)