A Retrospective Paired Study: Efficacy and Safety of Nimotuzumab Combined with Radiochemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Objective: To evaluate the efficacy and safety of nimotuzumab in combination with radiochemotherapy as the primary treatment in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: We retrospectively reviewed patients with locoregionally advanced nasopharyngeal carcinoma from September 2012 to December 2016. 188 newly diagnosed patients with stage III–IVB nasopharyngeal carcinoma were treated with at least 1-2 cycles of chemotherapy concurrently with planned IMRT. 88 patients received nimotuzumab 200 mg/week. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group. Results: After 3 months of treatment, the complete response rates of nasopharyngeal tumors in the study group and the control group were 78.4% and 65.5%, respectively (?2=4.070, P=0.044). The total complete response rates of cervical lymph nodes in the study group and the control group were 80.7% and 67.6% respectively (?2=4.022, P=0.045).The median cycle for nimotuzumab addition was 6.3 weeks. With a median follow-up of 36.3 months (range, 12–72 months), the estimated 3-year progression failure-free survival and overall survival rates for the study group and the control group were 85.24% vs 81.97% and 96.67% vs 90.0%, respectively. The 3-year local recurrence-free survival rates for the study group and the control group were 96.67% vs 83.60%, respectively (P=0.047). Grade 3 radiation-induced mucositis accounted for 36.4% of treated patients. No skin rash and infusion reaction were observed, distinctly from what is reported in control patients. Conclusion: Nimotuzumab plus chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma showed promising outcomes in terms of locoregional control, without increasing the incidence of radiation-related toxicities for patients

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Background: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo. Findings: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund: Grants of NSF, NIH, and PAPD. Keywords: Fatty acid 2-hydroxylation, Gastric cancer, Lipid metabolism, mTOR, Chemotherapy, Hedgehog pathwa

The spatial and temporal contribution of glacier runoff to watershed discharge in the Yarkant River Basin, Northwest China

In this paper, a glacial module based on an enhanced temperature-index approach was successfully introduced into the Soil and Water Assessment Tool (SWAT) model to simulate the glacier runoff and water balance of a glacierized watershed, the mountainous region of the Yarkant River Basin (YRB) in Karakoram. Calibration and validation of the SWAT model were based on comparisons between the simulated and observed discharge with a monthly temporal resolution from 1961 to 2011 for the Kaqun hydrological station. The results reaffirmed the viability of the approach for simulating glacier runoff, as evidenced by a Nash–Sutcliff Efficiency (NSE) of 0.82–0.86 as well as a percentage bias (PBIAS) of −4.5% to 2.4%, for the calibration and validation periods, respectively. Over the last 50 years, the total discharge and glacier runoff both exhibited increasing trends with 0.031 × 109 m3·a−1 and 0.011 × 109 m3·a−1. The annual glacier runoff contribution to the streamflow was between 42.3% and 64.5%, with an average of 51.6%, although the glaciers accounted for only 12.6% of the watershed drainage area in the mountainous YRB. The monthly contribution of the glacier runoff ranged from 11.0% in April to 62.1% in August, and the glacier runoff from June to September accounted for about 86.3% of the annual glacier runoff. Runoff from the mountainous regions above 5000 m a.s.l. accounted for 70.5% of the total discharge, with glacier runoff contributions being approximately 46.4%

Land Surface Snow Phenology Based on an Improved Downscaling Method in the Southern Gansu Plateau, China

Snow is involved in and influences water–energy processes at multiple scales. Studies on land surface snow phenology are an important part of cryosphere science and are a hot spot in the hydrological community. In this study, we improved a statistical downscaling method by introducing a spatial probability distribution function to obtain regional snow depth data with higher spatial resolution. Based on this, the southern Gansu Plateau (SGP), an important water source region in the upper reaches of the Yellow River, was taken as a study area to quantify regional land surface snow phenology variation, together with a discussion of their responses to land surface terrain and local climate, during the period from 2003 to 2018. The results revealed that the improved downscaling method was satisfactory for snow depth data reprocessing according to comparisons with gauge-based data. The downscaled snow depth data were used to conduct spatial analysis and it was found that snow depth was on average larger and maintained longer in areas with higher altitudes, varying and decreasing with a shortened persistence time. Snow was also found more on steeper terrain, although it was indistinguishable among various aspects. The former is mostly located at high altitudes in the SGP, where lower temperatures and higher precipitation provide favorable conditions for snow accumulation. Climatically, factors such as precipitation, solar radiation, and air temperature had significantly singular effectiveness on land surface snow phenology. Precipitation was positively correlated with snow accumulation and maintenance, while solar radiation and air temperature functioned negatively. Comparatively, the quantity of snow was more sensitive to solar radiation, while its persistence was more sensitive to air temperature, especially extremely low temperatures. This study presents an example of data and methods to analyze regional land surface snow phenology dynamics, and the results may provide references for better understanding water formation, distribution, and evolution in alpine water source areas

Celecoxib Alleviates Radiation-Induced Brain Injury in Rats by Maintaining the Integrity of Blood-Brain Barrier

The underlying mechanisms of radiation-induced brain injury are poorly understood, although COX-2 inhibitors have been shown to reduce brain injury after irradiation. In the present study, the effect of celecoxib (a selective COX-2 inhibitor) pretreatment on radiation-induced injury to rat brain was studied by means of histopathological staining, evaluation of integrity of blood-brain barrier and detection of the expressions of inflammation-associated genes. The protective effect of celecoxib on human brain microvascular endothelial cells (HBMECs) against irradiation was examined and the potential mechanisms were explored. Colony formation assay and apoptosis assay were undertaken to evaluate the effect of celecoxib on the radiosensitivity of the HBMECs. ELISA was used to measure 6-keto-prostaglandin F1α (6-keto-PGF1α) and thromboxane B2 (TXB2) secretion. Western blot was employed to examine apoptosis-related proteins expressions. It was found that celecoxib protected rat from radiation-induced brain injury by maintaining the integrity of the blood-brain barrier and reducing inflammation in rat brain tissues. In addition, celecoxib showed a significant protective effect on HBMECs against irradiation, which involves inhibited apoptosis and decreased TXB2/6-keto-PGF1α ratio in brain vascular endothelial cells. In conclusion, celecoxib could alleviate radiation-induced brain injury in rats, which may be partially due to the protective effect on brain vascular endothelial cells from radiation-induced apoptosis

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancerResearch in context

Background: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo. Findings: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund: Grants of NSF, NIH, and PAPD. Keywords: Fatty acid 2-hydroxylation, Gastric cancer, Lipid metabolism, mTOR, Chemotherapy, Hedgehog pathwa

Fatty acid receptor GPR120 promotes breast cancer chemoresistance by upregulating ABC transporters expression and fatty acid synthesisResearch in context

Background: Chemoresistance is the major cause of neoadjuvant treatment failure in breast cancer patients. Despite recent progress, the mechanism underlying chemoresistance remains to be further defined. Methods: Expression of G protein-coupled receptor 120 (GPR120) was analyzed by immunohistochemistry in the biopsies of primary breast cancer who subsequently underwent preoperative neoadjuvant chemotherapy. In vitro and in vivo loss- and gain-of -function studies were performed to reveal the effects and related mechanism of GPR120 signaling pathway in the chemoresistance of breast cancer cells. Findings: We identified that GPR120, a receptor for long-chain fatty acids, was important for the acquisition of chemoresistance in breast cancer cells. We showed that GPR120 expression was positively associated with clinical response to neoadjuvant chemotherapy in patients. In breast cancer cells, GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism. Upregulated GPR120 signaling rendered cells resistant to epirubicin-induced cell death by upregulating ABC transporters expression and thus decreasing the intracellular accumulation of epirubicin. Akt/NF-κB pathway was responsible for the GPR120-mediated expression of ABC transporters leading to modulation of the concentration of chemotherapeutic drugs in cells. The functional importance of GPR120 in chemoresistance was further validated using epirubicin-treated tumor xenografts, in which we showed that blockade of GPR120 signaling with AH7614 or GPR120-siRNA significantly compromised chemoresistance. Interpretation: Our results highlight that GPR120 might be a promising therapeutic target for breast cancer chemoresistance. Fund: National Natural Science Foundation of China, Ministry of Science and Technology of China, Program of Science and Technology Commission of Shanghai Municipality. Keywords: GPR120, Chemoresistance, ABC transporters, Fatty acid synthesis, Breast cance

Aberrant fatty acid profile and FFAR4 signaling confer endocrine resistance in breast cancer

Abstract Background Evidence suggests that fatty acid receptor FFAR4 plays a tumor-promoting role in adipose tissue-adjacent malignancies, but its clinical relevance remains unexplored. Here, we investigated the clinical significance and underlying mechanisms of FFAR4 in hormone receptor-positive breast cancer (HRPBC). Methods FFAR4 expression was assessed by immunohistochemistry in an exploration cohort of 307 breast cancer cases collected from two independent institutes. Two public breast cancer microarray datasets served as validation cohorts. Gas chromatography-mass spectrometry was employed to identify FFAR4 ligands in normal and cancerous breast tissues. Survival analyses were performed in all cohorts and designated molecular subgroups. Mechanistic studies were performed in vitro in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D. Results Aberrant FFAR4 expression and endogenous FFAR4 ligands were identified in breast cancer tissues, five FFAR4 ligands showed significantly elevated proportions in cancerous versus normal tissues. In the exploration cohort, FFAR4 was demonstrated as an independent prognostic factor for recurrences (HR: 2.183, 95% CI: 1.360–3.504, P = 0.001) and breast cancer-specific deaths (HR: 2.102, 95% CI: 1.173–3.766, P = 0.013) in HRPBC cases. In contrast, FFAR4 expression was not associated with prognosis in hormone receptor-negative cases. In the validation cohorts, FFAR4 mRNA levels were also observed to be associated with disease recurrence in estrogen receptor-positive cases, but not so in estrogen receptor-negative cases. FFAR4 activation by endogenous ligands and a synthetic ligand TUG891 significantly dampened tamoxifen’s efficacy on HRPBC cells, whereas FFAR4 knockdown or antagonist AH7614 abrogated this effect. Furthermore, FFAR4-induced tamoxifen resistance was dependent on ERK and AKT pathways in HRPBC. Conclusions Our results establish a novel role of FFAR4 and its ligands in the complicated interactions between tissue lipid profile and cancer biology. FFAR4 signaling confers tamoxifen resistance in HRPBC cell line and FFAR4 expression can serve as a prognostic biomarker for tamoxifen-treated HRPBC patients. FFAR4 may serve as a potential target for anti-breast cancer therapies, especially in endocrine resistant cases

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Increasing evidence indicates that elevated expression of enhancer of zeste homolog 2 gene (EZH2) in many human malignant tumors acts a significant role in the oncogenic process. However, the underlying molecular mechanism is still unclarified. It is evident that apoptosis and autophagy of tumor cells is crucial for the tumorigenesis and progression of cancer, however, the exact role of EZH2 plays in apoptosis and autophagy has not been fully elucidated in colorectal cancer (CRC). Our previous study found that the expression level of EZH2 was higher in CRC tumor tissues than in the paired normal tissues using immunohistochemical analysis. We also recently found that the autophagy‐related gene‐related protein Ambra1 plays an important role in the autophagy pathway in CRC cells. In this study, mRNA and protein expression of EZH2 in four CRC cell lines were tested at first and RKO and HCT116 cells showed the highest levels among them. Here we transfected with EZH2‐shRNA, or added DZNep (an EZH2 inhibitor) to RKO and HCT116 cells in order to detect the effect of EZH2 on autophagy via determining the change of the protein expression of LC3 and Ambra1. The outcome indicated an obvious decrease of autophagy level in cells transfected with EZH2‐shRNA or DZNep. We also found the apoptotic rate of cells was elevated significantly after downregulation of EZH2. In addition, compared to control group, CRC cells transfected with EZH2‐shRNA or added DZNep revealed a significantly increased G1 cell cycle rate and an obvious decrease in the G2 cell cycle rate. Further analysis showed that knockdown of EZH2 induced cell-cycle arrest in CRC cells. Meanwhile, downregulation of EZH2 in CRC cells induces autophagy and apoptosis. Taken together, our results suggest that EZH2 plays a critical role in autophagy and apoptosis in the progression of CRC, which potentially facilitates the development of an ideal strategy for combating colorectal cancer