Enhancing paranasal sinus disease detection with AutoML: efficient AI development and evaluation via magnetic resonance imaging.

PURPOSE: Artificial intelligence (AI) in the form of automated machine learning (AutoML) offers a new potential breakthrough to overcome the barrier of entry for non-technically trained physicians. A Clinical Decision Support System (CDSS) for screening purposes using AutoML could be beneficial to ease the clinical burden in the radiological workflow for paranasal sinus diseases. METHODS: The main target of this work was the usage of automated evaluation of model performance and the feasibility of the Vertex AI image classification model on the Google Cloud AutoML platform to be trained to automatically classify the presence or absence of sinonasal disease. The dataset is a consensus labelled Open Access Series of Imaging Studies (OASIS-3) MRI head dataset by three specialised head and neck consultant radiologists. A total of 1313 unique non-TSE T2w MRI head sessions were used from the OASIS-3 repository. RESULTS: The best-performing image classification model achieved a precision of 0.928. Demonstrating the feasibility and high performance of the Vertex AI image classification model to automatically detect the presence or absence of sinonasal disease on MRI. CONCLUSION: AutoML allows for potential deployment to optimise diagnostic radiology workflows and lay the foundation for further AI research in radiology and otolaryngology. The usage of AutoML could serve as a formal requirement for a feasibility study.

[Effects of RPA1 down-regulation on the invasion and migration and cell cycle of human nasopharyngeal carcinoma CNE-2R cells with radio resistance].

Objective: To investigate the effects of RPA1 silencing on the invasion, migration and cell cycle of human nasopharyngeal carcinoma CNE-2R cells. Methods: shRNA technology was used to construct CNE-2R cell lines with RPA1 low-expression, which were verified by RT-PCR and Western blotting. The following assays were performed using the three 3 groups: control group(CNE-2),negative control group(NC-shRNA) and RPA1 down-regulation group(RPA1-shRNA). The effects of RPA silence on the proliferation, invasion, migration, and cell cycle of CNE-2R cells were detected using Cell Counting Kit-8, clone formation experiment, Transwell, scratch test and flow cytometry, respectively. The expressions of Chk2, p-Chk2, Cdc 25c and p-cdc25c were tested by Western blot assay. Results: The expressions of RPA1 mRNA and protein in the RPA1-shRNA group were lower than those in the CNE-2 and NC-shRNA groups significantly (P＜0.01 and 0.05). Compared with CNE-2 and NC-shRNA groups, the abilities of proliferation, invasion and migration of RPA1-shRNA group were decreased and the cell cycle in the RPA1-shRNA group was blocked in the G2/M phase (P＜0.01). The expressions of Chk2 and Cdc25c in RPA1-shRNA group cells were lower than those in CNE-2R and NC-shRNA group cells (P＜0.05), while the expressions of p-Chk2 and p-cdc25c were higher than those in the other groups (P＜0.05). Conclusion: After RPA1 silenced, the proliferation and migration of radio resistant human nasopharyngeal carcinoma CNE-2R cells was inhibited, resulting in cell cycle arrested in the G2/M phase.

TNFAIP8 drives metabolic reprogramming to promote prostate cancer cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PCa cell proliferation/migration/spheroid formation by enhancing cell metabolic activities. Mechanistically, TNFAIP8 activated the PI3K-AKT pathway and up-regulated PCa cell survival. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with a glycolysis inhibitor, 2-deoxyglucose (2-DG), reduced TNFAIP8 mediated glucose consumption, ATP production, spheroid formation, and PCa cell migration. By maintaining mitochondrial membrane potential, TNFAIP8 increased OXPHOS and glycolysis. Moreover, TNFAIP8 modulates the production of glycolytic metabolites in PCa cells. Collectively, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells. Therefore, TNFAIP8 may be a biomarker associated with prostate cancer and indicate a potential therapeutic target.

Interaction Between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Environment with Susceptibility to Ischemic Stroke in Chinese Population.

AIMS: To investigate the association of several single-nucleotide polymorphisms (SNPs) within methylenetetrahydrofolate reductase (MTHFR) gene, and additional gene-environment interaction with ischemic stroke (IS) risk. METHODS: Testing for Hardy-Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among four SNPs within MTHFR gene and smoking or alcohol drinking. RESULTS: The frequency of the rs4846049-A allele was 28.6% in IS patients and 19.1% in normal controls, in addition, the frequency of the rs3737967-T allele was 27.9% in IS patients and 20.3% in normal controls, which was also indicating a statistically significant difference. The rs4846049-A and rs3737967-T were associated with an increased risk of IS risk; adjusted odds ratios (ORs) (95% confidence interval [CI]) were 1.76 (1.28-2.13) and 1.51 (1.13-1.97), respectively. GMDR model found significant gene-alcohol drinking interaction combination, but no significant gene-tobacco smoking interaction combinations. In order to obtain the odds ratios and 95% CI for the joint effects of gene-alcohol drinking on IS, we conducted stratified analysis for interaction effect using logistic regression. We found that alcohol drinkers with rs4846049-CA/AA genotype also have the highest IS risk, compared with never drinkers with rs4846049-CC genotype, OR (95% CI) = 3.12 (1.83-4.45), after adjustment for age, smoke, and smoking status. CONCLUSIONS: The rs4846049-A and rs3737967-T, gene-environment interaction between rs1764391 and rs918592, gene-environment interaction between rs4846049 and alcohol drinking were all associated with increased IS risk.

Prognostic Value of Combined Analysis of CTLA-4 and PLR in Esophageal Squamous Cell Carcinoma (ESCC) Patients.

OBJECTIVE: The purpose of this study was to evaluate the prognostic role of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expression level and the platelet lymphocyte ratio (PLR) level in esophageal squamous cell carcinoma (ESCC) patients. METHODS: 84 ESCC patients who received surgical treatment in our hospital were enrolled in the study. The correlation of each biomarker's level with ESCC patients' clinicopathological characteristics and overall survival (OS) was assessed. RESULTS: The elevated expression rate of T-CTLA-4 (tumor cell CTLA-4) and I-CTLA-4 (interstitial lymphocyte CTLA-4) was 48.8% and 44.0%, respectively. The number of enrolled patients with a higher PLR level (≥119) was 48. The prognostic value of T-CTLA-4, I-CTLA-4, and PLR in ESCC patients was not detected. However, patients with both a low T-CTLA-4 expression level and a low PLR level that had longer OS (p = 0.023) were found. The prognostic role of T-CTLA-4(-) +PLR (-) status in ESCC patients was also confirmed in multivariate analyses (p = 0.027). CONCLUSION: These results demonstrated the potential prognostic value of combined analysis of CTLA-4 and PLR in ESCC patients.

Cooperative impact of thiazolidinedione and fatty acid synthase on human osteogenesis.

Previous, we found that the small molecules capable of inhibiting the expression and the pro-adipogenic activity of ZNF521 might improve the osteogenic performance of aging human bone marrow MSCs (bmMSCs), and that fatty acid synthase (FASN) was a critical effector of ZNF521's pro-adipogenic activity. Here, by characterizing the netoglitazone (MCC-555), one of the thiazolidinediones known as adipogenic enhancers, as an inhibitor of ZNF521 expression, we found that MCC-555 indeed also harbored pro-osteoblastic effect. Investigation revealed that MCC-555 might function as a GSK3ß inhibitor to promote osteoblastogenesis and bone formation. Importantly, combination of MCC-555 with FASN knockdown, but not with GW9662 (a PPARγ2 antagonist), blocked the pro-adipogenic but retained the pro-osteoblastic effect of MCC-555. Using a 3-dimentional culture system, we showed that MCC-555 facilitated the FASN-knockdown of aging human bmMSCs to form cell clusters in scaffolds, and to promote osteoblastic differentiation and biomineralization in cell clusters. These data indicated that MCC-555 promoted bmMSCs to produce bone-like tissues. Our data narrate a thiazolidinedione-based novel strategy to improve the osteogenic performance of aging bmMSCs to support the application of autologous aging bmMSCs in cell therapy and in producing bone-like tissues for repairing bone injury in the elderly.

Decreased expression of nemo-like kinase in melanoma is correlated with increased vascularity and metastasis.

Melanoma is a highly metastatic cancer, and its incidence has increased over the past several decades. Angiogenesis is associated with melanoma metastasis and a poor prognosis. Many genetic and epigenetic factors affecting tumour vascularization and metastasis have been investigated, despite the heterogeneity of cancer cells and the complicated mechanisms involved in melanoma. Nemo-like kinase (NLK) is a serine/threonine kinase regulating the transcription factor by negatively regulating Wnt and downstream vascular endothelial growth factor receptor 2 (VEGFR2) signalling. This study aimed to investigate whether NLK expression in melanoma correlates with VEGFR2-related angiogenesis and melanoma metastasis. Immunohistochemistry analysis using 175 biopsied tissues of melanoma patients showed that NLK is expressed in 73.7% of melanoma tissues, whereas 26.3% of the samples showed absent expression of NLK. In metastatic melanoma, the expression of NLK was significantly lower than that in primary melanoma (P = 0.002). Furthermore, tissues with a lower expression of NLK showed a higher microvessel density as detected by VEGFR2 expression compared with tissues showing higher NLK expression. These data suggest that reduced expression of NLK in melanoma correlates with VEGFR2-related microvessel formation and melanoma metastasis. This study showed that NLK may serve as a novel prognosis marker and revealed new mechanisms in melanoma metastasis.

Thalidomide (THD) alleviates radiation induced lung fibrosis (RILF) via down-regulation of TGF-ß/Smad3 signaling pathway in an Nrf2-dependent manner.

Radiation-induced lung fibrosis (RILF) is a complication of radiotherapy in thoracic cancer patients. Thalidomide (THD) has a therapeutic effect on fibrotic and inflammatory disorders. The purpose of the current study was to investigate the therapeutic effect of THD on RILF in mice and better understand the underlying regulatory mechanisms of the therapeutic effect. We found that THD mitigated the fibrosis caused by irradiation in mice. The action of THD on RILF was related to the elevation of low levels reactive oxygen species (ROS), which inhibited the transforming growth factor­ß (TGF­ß)/Smad3 signaling pathway through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Analysis of the therapeutic effect of THD using Nrf2-/- mouse model confirmed the role of Nrf2 in vivo. In addition, no radioprotective effect of THD on thoracic cancer cell lines was observed. In conclusion, these data showed that THD attenuated RILF in mice, which was mediated by Nrf2-dependent down-regulation of the TGF-ß/Smad3 pathway, suggesting THD as a potential novel agent for RILF prevention.

Nrf2-Mediated Metabolic Reprogramming in Cancer.

Metabolic reprogramming is one of the hallmarks of cancer. Nrf2 pathway is one of the critical signaling cascades involved in cell defense and survival against oxidative stress. The significance of Nrf2 in cancer metabolism begins to be recognized. In this minireview, we focus on the Nrf2-mediated cancer metabolic reprogramming and intend to highlight the role of Nrf2 in the regulation of malignant transformation, cancer proliferation, and the development of treatment resistance via metabolic adaptations. We hope for the development of noninvasive biomarkers and novel therapeutic approaches for cancer based on Nrf2-directed cancer metabolic reprogramming in the near future.

FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting ß-catenin through mRNA demethylation.

The role of N6 -methyladenosine (m6 A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of ß-catenin by reducing m6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on ß-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m6 A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.

Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer.

Brain metastases occur in 20% to 40% of lung cancer patients. Whole-brain radiotherapy (WBRT) has long been considered the treatment of choice for many patients with lung cancer, because of its wide availability, ease of delivery, and effectiveness in prolonging survival. However, WBRT is also associated with several side effects, such as decline in memory and other cognitive functions. There exists significant preclinical and clinical evidence that radiation-induced injury to the hippocampus correlates with neurocognitive decline of patients who receive WBRT. Technological advances in treatment planning and delivery facilitate the use of hippocampal-sparing (HS) WBRT as prophylactic cranial irradiation or the primary treatment modality for lung cancer patients with brain metastases. In this review, we provide a detailed and comprehensive discussion of the safety profile, techniques for hippocampus-sparing, and the clinical evidence of HS-WBRT for lung cancer patients.

AT-101 enhances gefitinib sensitivity in non-small cell lung cancer with EGFR T790M mutations.

BACKGROUND: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard care of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), development of acquired resistance is inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. Strategies or agents to overcome this type of resistance are still limited. In this study, enhanced antitumor effect of AT-101, a-pan-Bcl-2 inhibitor, on gefitinib was explored in NSCLC with T790M mutation. METHODS: The effect of cotreatment with AT-101 and gefitinib on the viability of NSCLC cell lines harboring acquired T790M mutation was investigated using the MTT assay. The cellular apoptosis of NSCLC cells after cotreatment with AT-101 and gefitinib was assessed by FITC-annexin V/PI assay and Western blots analysis. The potential underlying mechanisms of the enhanced therapeutic effect for AT-101 was also studied using Western blots analysis. The in vivo anti-cancer efficacy of the combination with AT-101 and gefitinib was examined in a mouse xenograft model. RESULTS: In this study, we found that treatment with AT-101 in combination with gefitinib significantly inhibited cell proliferation, as well as promoted apoptosis of EGFR TKIs resistant lung cancer cells. The apoptotic effects of the use of AT-101 was related to the blocking of antiapoptotic protein: Bcl-2, Bcl-xl, and Mcl-1 and downregrulation of the molecules in EGFR pathway. The observed enhancements of tumor growth suppression in xenografts supported the reverse effect of AT-101 in NSCLC with T790M mutation, which has been found in in vitro studies before. CONCLUSIONS: AT-101 enhances gefitinib sensitivity in NSCLC with EGFR T790M mutations. The addition of AT-101 to gefitinib is a promising strategy to overcome EGFR TKIs resistance in NSCLC with EGFR T790M mutations.

The therapeutic response of CDDO-Me in the esophageal squamous cell carcinoma (ESCC) cells is mediated by CaMKIIα.

CDDO-Me has exhibited a potent anticancer effect in human esophageal squamous cell carcinoma (ESCC) cells in our previous study, but the molecular interactome remains elusive. We applied the approach of stable-isotope labeling by amino acids in cell culture (SILAC) to assess the proteomic responses of CDDO-Me treatment in human ESCC Ec109 cells. The data were subsequently validated using Western blot assay. The results of our study revealed that CDDO-Me increased the expression level of 543 protein molecules, but decreased the expression level of 709 protein molecules in Ec109 cells. Among these modulated protein molecules, calcium/calmodulin-dependent protein kinase type II subunit α (CaMKIIα) was highly expressed in all tested ESCC cell lines, whereas its expression levels were substantially lower in normal control cell line. Its silencing by small interfering RNA inhibited CDDO-Me induced apoptosis and autophagy in ESCC cells. Collectively, these data demonstrate that the therapeutic response of CDDO-Me in the human ESCC cells is mediated by CaMKIIα.

Prognostic Value of Neutrophil-Related Factors in Locally Advanced Cervical Squamous Cell Carcinoma Patients Treated with Cisplatin-Based Concurrent Chemoradiotherapy.

The aim of this study was to explore the relationship between neutrophil-related factors, including neutrophil-lymphocyte ratio (NLR) and the responses of neutrophil to granulocyte colony-stimulating factors (RNG), and the prognosis of patients with locally advanced cervical squamous cell carcinoma (LACSCC) undergoing cisplatin-based concurrent chemoradiotherapy (CCCRT). A total of sixty LACSCC patients were enrolled in this study. We analyzed the association of NLR or RNG with clinicopathologic characteristics of these patients. The prognostic factors were evaluated by univariate and multivariate survival analysis. The optimal cut-off value of the NLR was determined to be 2.0 for the overall survival (OS). A higher level of the NLR was associated with younger age (P = 0.017) and higher baseline platelet count (P = 0.040). NLR was identified to be the only independent prognostic factor for OS by multivariate analysis (P = 0.037). The median RNG was 3.01, with a range of 1.19-16.84. RNG level was significantly associated with lymph node metastasis of these patients (P = 0.023). And higher RNG was identified as being a closely independent poor prognostic factor for OS (P = 0.055). This study showed that NLR and RNG may be used as potential biomarkers for survival prediction in patients with LACSCC receiving CCCRT.

Therapeutic effects of C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me; bardoxolone methyl) on radiation-induced lung inflammation and fibrosis in mice.

The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), one of the synthetic triterpenoids, has been found to have potent anti-inflammatory and anticancer properties in vitro and in vivo. However, its usefulness in mitigating radiation-induced lung injury (RILI), including radiation-induced lung inflammation and fibrosis, has not been tested. The aim of this study was to explore the therapeutic effect of CDDO-Me on RILI in mice and the underlying mechanisms. Herein, we found that administration of CDDO-Me improved the histopathological score, reduced the number of inflammatory cells and concentrations of total protein in bronchoalveolar lavage fluid, suppressed secretion and expression of proinflammatory cytokines, including transforming growth factor-ß and interleukin-6, elevated expression of the anti-inflammatory cytokine interleukin-10, and downregulated the mRNA level of profibrotic genes, including for fibronectin, α-smooth muscle actin, and collagen I. CDDO-Me attenuated radiation-induced lung inflammation. CDDO-Me also decreased the Masson's trichrome stain score, hydroxyproline content, and mRNA level of profibrotic genes, and blocked radiation-induced collagen accumulation and fibrosis. Collectively, these findings suggest that CDDO-Me ameliorates radiation-induced lung inflammation and fibrosis, and this synthetic triterpenoid is a promising novel therapeutic agent for RILI. Further mechanistic, efficacy, and safety studies are warranted to elucidate the role of CDDO-Me in the management of RILI.

The emerging role of CaMKII in cancer.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinases best known for its critical role in learning and memory. Recent studies suggested that high levels of CaMKII also expressed in variety of malignant diseases. In this review, we focus on the structure and biology properties of CaMKII, including the role of CaMKII in the regulation of cancer progression and therapy response. We also describe the role of CaMKII in the diagnosis of different kinds of cancer and recent progress in the development of CaMKII inhibitors. These data establishes CaMKII as a novel target whose modulation presents new opportunities for cancer diagnosis and treatment.

Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells.

Natural and synthetic triterpenoids have been shown to kill cancer cells via multiple mechanisms. The therapeutic effect and underlying mechanism of the synthetic triterpenoid bardoxolone methyl (C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO-Me) on esophageal cancer are unclear. Herein, we aimed to investigate the anticancer effects and underlying mechanisms of CDDO-Me in human esophageal squamous cell carcinoma (ESCC) cells. Our study showed that CDDO-Me suppressed the proliferation and arrested cells in G2/M phase, and induced apoptosis in human ESCC Ec109 and KYSE70 cells. The G2/M arrest was accompanied with upregulated p21Waf1/Cip1 and p53 expression. CDDO-Me significantly decreased B-cell lymphoma-extra large (Bcl-xl), B-cell lymphoma 2 (Bcl-2), cleaved caspase-9, and cleaved poly ADP ribose polymerase (PARP) levels but increased the expression level of Bcl-2-associated X (Bax). Furthermore, CDDO-Me induced autophagy in both Ec109 and KYSE70 cells via suppression of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. There were interactions between the autophagic and apoptotic pathways in Ec109 and KYSE70 cells subject to CDDO-Me treatment. CDDO-Me also scavenged reactive oxygen species through activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway in Ec109 and KYSE70 cells. CDDO-Me inhibited cell invasion, epithelial-mesenchymal transition, and stemness in Ec109 and KYSE70 cells. CDDO-Me significantly downregulated E-cadherin but upregulated Snail, Slug, and zinc finger E-box-binding homeobox 1 (TCF-8/ZEB1) in Ec109 and KYSE70 cells. CDDO-Me significantly decreased the expression of octamer-4, sex determining region Y-box 2 (Sox-2), Nanog, and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), all markers of cancer cell stemness, in Ec109 and KYSE70 cells. Taken together, these results indicate that CDDO-Me is a promising anticancer agent against ESCC. Further studies are warranted to explore the molecular targets, efficacy and safety of CDDO-Me in the treatment of ESCC.

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains α,ß-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600-1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease associated with type 2 diabetes. CDDO-Me has shown a promising anticancer effect in a Phase I trial. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension.

VMAT planning study in rectal cancer patients.

BACKGROUND: To compare the dosimetric differences among fixed field intensity-modulated radiation therapy (IMRT), single-arc volumetric-modulated arc therapy (SA-VMAT) and double-arc volumetric-modulated arc therapy (DA-VMAT) plans in rectal cancer. METHOD: Fifteen patients with rectal cancer previously treated with IMRT in our institution were selected for this study. For each patient, three plans were generated with the planning CT scan: one using a fixed beam IMRT, and two plans using the VMAT technique: SA-VMAT and DA-VMAT. Dose prescription to the PTV was 50 Gy in 2 Gy per fraction. Dose volume histograms (DVH) for the target volume and the organs at risk (small bowel, bladder, femoral heads and healthy tissue) were compared for these different techniques. Monitor units (MU) and delivery treatment time were also reported. RESULTS: DA-VMAT achieved the highest minimum planning target volume (PTV) dose and the lowest maximal dose, resulting in the most homogeneous PTV dose distribution. DA-VMAT also yielded the best CI, although the difference was not statistically significant. Between SA-VMAT and IMRT, the target dose coverage was largely comparable; however, SA-VMAT was able to achieve a better V95 and V107. VMAT showed to be inferior to IMRT in terms of organ at risk sparing, especially for the small bowel. Compared with IMRT, DA-VMAT increased the V15 of small bowel nearly 55 cc. The MU and treatment delivery time were significantly reduced by the use of VMAT techniques. CONCLUSION: VMAT is a new radiation technique that combines the ability to achieve highly conformal dose distributions with highly efficient treatment delivery. Considering the inferior role of normal tissue sparing, especially for small bowel, VMAT need further investigation in rectal cancer treatment.

Detection of esophageal squamous cell carcinoma by cathepsin B activity in nude mice.

BACKGROUND AND OBJECTIVE: Despite great progress in treatment, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) remains poor, highlighting the importance of early detection. Although upper endoscopy can be used for the screening of esophagus, it has limited sensitivity for early stage disease. Thus, development of new diagnosis approach to improve diagnostic capabilities for early detection of ESCC is an important need. The aim of this study was to assess the feasibility of using cathepsin B (CB) as a novel imaging target for the detection of human ESCC by near-infrared optical imaging in nude mice. METHODS: Initially, we examined specimens from normal human esophageal tissue, intraepithelial neoplasia lesions, tumor in situ, ESCC and two cell lines including one human ESCC cell line (Eca-109) and one normal human esophageal epithelial cell line (HET-1A) for CB expression by immunohistochemistry and western blot, respectively. Next, the ability of a novel CB activatable near-infrared fluorescence (NIRF) probe detecting CB activity presented in Eca-109 cells was confirmed by immunocytochemistry. We also performed in vivo imaging of tumor bearing mice injected with the CB probe and ex vivo imaging of resected tumor xenografts and visceral organs using a living imaging system. Finally, the sources of fluorescence signals in tumor tissue and CB expression in visceral organs were identified by histology. RESULTS: CB was absent in normal human esophageal mucosa, but it was overexpressed in ESCC and its precursor lesions. The novel probe for CB activity specifically detected ESCC xenografts in vivo and in vitro. CONCLUSIONS: CB was highly upregulated in human ESCC and its precursor lesions. The elevated CB expression in ESCC allowed in vivo and in vitro detection of ESCC xenografts in nude mice. Our results support the usefulness of CB activity as a potential imaging target for the detection of human ESCC.