Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES).

INTRODUCTION: Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. METHODS: The study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. RESULTS: Overall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40-1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53-1.39). Trilaciclib had a well-tolerated safety profile. CONCLUSIONS: Trilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.

Cholesterol and saturated fatty acids synergistically promote the malignant progression of prostate cancer.

The excessive accumulation of saturated fatty acids and cholesterol have been linked to prostate cancer (Pca). Here, we found that lipoproteins, apolipoproteins, triglycerides and free fatty acids are significantly higher in the peripheral blood of prostate cancer patients than in non-cancer patients. Furthermore, the expression of ACC1, FASN and HMGCR is significantly higher in prostate cancer tissues than that in non-cancer tissues, and positively correlated with the gleason score. Using genetically engineered mouse models, we found that in a mouse model of high grade prostatic intraneoplasia (HGPIN), a combination of fatty acid synthase (FASN) overexpression and cholesterol efflux pump (Abca1) knockout resulted in the progression of prostatic intraneoplasia (PIN) to invasive PCa with 100% penetrance, as well as an increase in prostate cancer stem cell (PCSC)population, accompanied by activation of PGE2 and TGF-ß signaling pathway. Our study suggests that the steady rise in prostate cancer incidence and mortality among Chinese population during the last several decades may be attribute to a combinational effect of fatty acid and cholesterol, and reduction in dietary fat and cholesterol intake could slow down the progression from occult lesions to prostate cancer.

Nutritional statuses before and after chemotherapy predict the prognosis of Chinese patients after gastrectomy for gastric cancer.

BACKGROUND AND OBJECTIVES: Nutritional parameters may predict the prognosis of patients with gastric cancer. This study investigated whether changes in nutritional parameters before and after chemotherapy were associated with survival among patients who underwent gastrectomy for gastric cancer. METHODS AND STUDY DESIGN: We retrospectively reviewed data from 77 Chinese patients who had undergone gastrectomy for stage III gastric cancer at a single center. Laboratory data from before and after chemotherapy were collected regarding peripheral albumin, prealbumin, total protein, hemoglobin, and total cholesterol concentrations. The prognostic nutritional index (PNI) values were calculated and compared before and after chemotherapy. The relationships between survival and the pre-chemotherapy and post-chemotherapy nutritional statuses were evaluated. RESULTS: Among the 77 patients, survival was associated with the staging, the pre-chemotherapy PNI values, and the postchemotherapy body mass index (BMI) values. Significantly better overall survival was associated with a high pre-chemotherapy PNI value (hazard ratio [HR]: 0.485, 95% confidence interval (CI): 0.255-0.920) and a normal post-chemotherapy BMI value (HR: 0.475, 95% CI: 0.249-0.907). Even better survival was associated with the co-existence of a high pre-chemotherapy PNI value and a normal post-chemotherapy BMI value (vs. one or more abnormal parameter, HR: 0.337, 95% CI: 0.167-0.679). CONCLUSIONS: Chinese patients who underwent gastrectomy for gastric cancer had nutritional statuses that deteriorated after adjuvant chemotherapy. High prechemotherapy PNI values and normal post-chemotherapy BMI values were associated with better survival outcomes. Thus, low pre-chemotherapy PNI values and/or low post-chemotherapy BMI values may predict poor outcomes among these patients.

Clinical significance and prognosis of supraclavicular lymph node metastasis in patients with thoracic esophageal cancer.

BACKGROUND: Although most studies proved that thoracic esophageal cancer surgery with supraclavicular lymph nodes (SCLNs) metastasis could benefit, less than 30% of the 5-year survival rate remained controversy on its surgical treatment. In this study, we aimed to analyze the prognosis of SCLNs on the different segments of thoracic esophageal cancer, which will supply a reference for the treatment of this disease. METHODS: Retrospectively collected the clinical data of 163 patients with thoracic esophageal squamous cancer (ESCC) and compared the effects of SCLNs on prognosis in different segments. RESULTS: Patients with SCLNs metastasis had a worse prognosis than the negative group (P<0.001). In the upper thoracic group, there was no significant difference in OS between SCLNs positive group and negative group (P=0.077); however, in the middle and lower thoracic group, SCLNs positive group had a worse prognosis than the negative group (P<0.001) and lymph nodes positive in other sites (except for SCLNs) (P=0.039). Multivariate analysis found that SCLNs metastasis was an independent risk factor affecting the prognosis of ESCC in the middle and lower thoracic segments (P=0.007). CONCLUSIONS: For patients with upper thoracic ESCC, SCLNs appear to be regional nodes. For the middle and lower thoracic ESCC, SCLNs should be defined as distant metastasis, and neoadjuvant therapy first may be an available therapy.

Gut Microbiota Functional Biomolecules With Immune-Lipid Metabolism for a Prognostic Compound Score in Epstein-Barr Virus-Associated Gastric Adenocarcinoma: A Pilot Study.

OBJECTIVE: Increasing evidence has indicated an association between gut microbiota in gastrointestinal cancer and clinical outcome. Herein, we aim to develop a prognosis-prediction tool based on an immune-lipid metabolism signature, tumor cell-associated immune microenvironment, and lipid metabolism proteins inferred from the function of gut microbiota. METHODS: 16S gene ribosomal RNA sequencing was performed on 10 fecal samples obtained after tumor resection but before chemotherapy (EBVaGC = 4 and EBVnGC = 6). Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screening for highly accurate marker proteins. A compound score based on the fraction of screened markers was then constructed using a LASSO logistic regression model. RESULTS: The Tax4Fun analysis based on Kyoto Encyclopedia of Genes and Genomes data indicated differentially expressed tumor pathway between EBVnGC and EBVaGC. Using the LASSO logistic model, a compound score was established consisting of 14 types of immune microenvironment and lipid metabolism proteins. In the training set (378 patients), significant differences were found between high- and low-compound score groups in overall survival across and within subpopulations with an identical EBV. Multivariable analysis revealed that the compound score was an independent prognostic factor (hazard ratio, 2.26; 95% confidence interval = 2.28-3.36). The prognostic value ;of the compound score was also confirmed in the validation (162 patients) and entire (540 patients) sets. DISCUSSION: The proposed compound score is a promising signature for estimating overall survival in patients with gastric cancer having EBVaGCs or EBVnGCs.

Anticancer effects of plant derived Anacardic acid on human breast cancer MDA-MB-231 cells.

Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers. It is a heterogeneous disease, characterized by early relapse, aggressive behavior, and poor prognosis, when compared to other breast cancer subtypes. Interestingly, most of the heat shock protein 90 (Hsp90) client proteins are oncoproteins, and some are closely related to the key factors that promote the progression of TNBC. Anacardic acid (AA), which is commonly seen in natural plants of Anacardiaceae, exhibits potent Hsp90 ATPase inhibition activity. In this study, the anticancer effects of AA on TNBC MDA-MB-231 cells were investigated. The results of our study showed that AA inhibited cell proliferation, induced G0/G1-phase cell cycle arrest, suppressed cell invasion and migration, and induced apoptosis in the MDA-MB-231 cells. Regulation of the key Hsp90-dependent tumor-related molecules or endoplasmic reticulum stress (ERS) related molecules, such as GRP78, Hsp70, CDK-4, MMP-9, Bcl-2, and Mcl-1 by AA may be related to these effects. Taken together, our results suggest that AA shows potential as a possible new drug for therapy of TNBC.

Clinical correlation of B7-H3 and B3GALT4 with the prognosis of colorectal cancer.

AIM: To investigate the expression and clinical significance of B7 homolog 3 (B7-H3) and ß-1,3-galactosyltransferase-4 (B3GALT4) in colorectal cancer (CRC) patients. METHODS: Using tissue microarray, we identified the expression of B7-H3 and B3GALT4 in 223 CRC patient samples by immunohistochemistry and evaluated the possible correlation between B7-H3 and B3GALT4 and clinical outcomes. Further, the mRNA and protein expression were identified to establish the regulatory relationship of B7-H3 with B3GALT4 in vitro. RESULTS: A significant positive correlation between B7-H3 and B3GALT4 was observed in CRC specimens (r = 0.219, P = 0.001). High expression of B7-H3 was identified as a significant independent predictor of poor overall survival (OS) [hazard ratio (HR) = 1.781; 95%CI: 1.027-3.089; P = 0.040]. Moreover, high expression of B3GALT4 was also recognized as an independent predictor of inferior OS (HR = 1.597; 95%CI: 1.007-2.533; P = 0.047). Additionally, CRC patients expressing both high B7-H3 and high B3GALT4 contributed to a significant decrease in OS (HR = 2.283; 95%CI: 1.289-4.042; P = 0.005). In CRC cell lines with stable expression of high B7-H3, the mRNA and protein expressions of B3GALT4 were significantly upregulated. Similarly, the expression of B3GALT4 was significantly reduced when expression of B7-H3 was knocked down. CONCLUSION: The expression of B3GALT4 in CRC is positively correlated with B7-H3 expression in vitro. B7-H3/B3GLAT4 may be used as dual prognostic biomarkers for CRC.

MicroRNA-142-3p Promotes Cellular Invasion of Colorectal Cancer Cells by Activation of RAC1.

BACKGROUND: Colorectal cancer has been proved more difficult to treat owing to potently malignant metastasis. The present study was aimed to explore the functional role of miR-142-3p in cell migration and invasion of colorectal cancer cells, as well as its underlying mechanism. MATERIALS AND METHODS: Expressions of miR-142-3p were analyzed in colorectal cancer tissues and cell lines. Ras-related C3 botulinum toxin substrate 1 (RAC1) was predicted as a target of miR-142-3p using software and network resources. SW480 cells were transfected with miR-142-3p expression plasmid and miR-142-3p silencer plasmid, and the expression of RAC1 and the cellular invasion were measured. RESULTS: In colorectal cancer cells transfected with miR-142-3p expression plasmid, RAC1 was specifically upregulated and invasiveness of cells was downregulated. Moreover, RAC1 was significantly associated with tumor stage ( P = .029) and tumor metastasis ( P = .012). CONCLUSION: miR-142-3p promotes cellular invasion in colorectal cancer cells by activating RAC1. Thereby, miR-142-3p is a potential candidate for molecular targeted therapy of colorectal cancer.

Correlation of IDH1 and B7H3 expression with prognosis of CRC patients.

BACKGROUND: B7H3 is an immuno-stimulatory glycoprotein that is overexpressed in cancer. However, its functional contributions to cancer development and progression are not well understood. In several reports, it was demonstrated that B7H3 reprograms lipid metabolism and regulates glucose metabolism. Isocitrate dehydrogenase 1 (IDH1), a metabolic enzyme in the TCA cycle, its reaction product is involved in lipid synthesis. Thus, we aimed to identify a novel marker to predict the prognosis of CRC patients and to investigate the relationship between IDH1 and B7H3. METHODS: We analyzed IDH1 and B7H3 expression levels in 225 CRC specimens by immunochemistry. Moreover, in vitro studies were performed to demonstrate the correlation between IDH1 and B7H3. RESULTS: Among 225 tissues, the positive rates of IDH1 and B7H3 were 37.8% (85/225) and 87.6% (197/225), respectively. In CRC samples, IDH1 significantly correlated with B7H3 expression (P = 0.044). Moreover, multivariate analyses revealed that high expression of both B7H3 and IDH1 and a high tumor grade were related to the prognosis of CRC patients. Kaplan-Meier survival analysis revealed that patients with co-expression of IDH1 and B7H3 had a poor overall survival. In SW480B7H3-EGFP cells, which highly express B7H3, IDH1 was up-regulated. Similarly, knockdown of B7H3 expression in Caco-2-shB7-H3 contributed to reduced IDH1 levels. CONCLUSIONS: Although IDH1 and B7H3 cannot be used as independent prognostic factors, co-expression of IDH1 and B7H3 significantly correlated with the prognosis of CRC patients and may serve as a combined predictive marker. Thus, the correlation between IDH1 and B7H3 has been proven in vivo and in vitro.

Lower serum CA125 level, negative vascular invasion, and wild BRAF were strongly associated with better 2-year disease-free survival in patients with stage III colorectal cancer who received adjuvant chemotherapy.

BACKGROUND: Adjuvant chemotherapy plays important role in the comprehensive treatment of patients with stage III colorectal cancer. However, there is few molecular markers for predicting the therapeutic effect. OBJECTIVE: To identify factors that could predict adjuvant chemotherapy benefits in patients with stage III colorectal cancer. METHODS: The medical records of 294 patients were reviewed and analyzed using the Kaplan-Meier method and Cox analysis. RESULTS: Lower CA125 (⩽ 35 u/ml, P= 0.0015) serum levels, stage IIIa (P= 0.0027), 1-3 positive lymph nodes (P= 0.0256), negative vascular invasion (P= 0.0215), lower CA199 (⩽ 27 u/ml, P= 0.0038) serum levels, and wild-type BRAF status (P= 0.0125) were significantly associated with a higher 2-year DFS rate in patients with stage III colorectal cancer. However, in multivariate COX analysis, the association remained significant only for CA125 levels (vs. ⩽ 35 u/ml group, HR 3.341; 95% CI, 1.198-9.316; P= 0.0212), vascular invasion (vs. negative vascular invasion, HR, 2.349; 95% CI, 1.227-4.499; P= 0.01), and BRAF (V600E) (vs. wild Braf, HR, 7.794; 95% CI, 1.867-32.531; P= 0.0049). CONCLUSION: Lower CA125 serum levels, negative vascular invasion, and wild-type BRAF status were significantly associated with improved 2-year DFS rates among patient with stage III disease who received adjuvant chemotherapy.

ACOT1 expression is associated with poor prognosis in gastric adenocarcinoma.

Acyl-CoA thioesterase 1 (ACOT1) is an important isoform of the ACOT family that catalyzes the reaction of fatty acyl-CoAs to CoA-SH and free fatty acids. Recent studies of gastrointestinal tumor metabolism suggest that there is abnormal metabolism of lipids and fatty acids during tumor progression. However, the function and contribution of ACOT1 in gastric cancer development are still poorly understood. In addition, GLI3 is a major transcription factor in the regulation of hedgehog signaling. GLI3 mutations induce glandular expansion and intestinal metaplasia in gastric cancer, which indicates a role for GLI3 in the preneoplastic process. Thus, we investigated the relationship between ACOT1 expression and GLI3 in gastric adenocarcinoma. A tissue microarray was constructed from 280 cases of gastric adenocarcinoma. The immunohistochemistry method was performed on tissue sections of 4 µm from each tissue microarray block. We found a significant correlation between ACOT1 expression and poor histologic grade, a lower T category, TNM stage, and increased GLI3 expression. In addition, the survival analysis revealed that the ACOT1-positive group had significantly decreased overall survival rates compared with the ACOT1-negative group. Furthermore, GLI3 expression had a significant positive correlation with ACOT1 expression in gastric adenocarcinoma cells. In summary, these findings demonstrate that increased expression of ACOT1 is correlated with pivotal clinicopathological parameters and poor prognosis in gastric adenocarcinoma through increased expression of the potential tumor-promoting protein GLI3.

Long non-coding RNA expression profiles reveals AK098783 is a biomarker to predict poor prognosis in patients with colorectal cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) have essential regulatory function, yet their roles in colorectal cancer (CRC) are not well understood. MATERIALS AND METHODS: Microarray was applied to detect lncRNAs expression profiles in tumor tissues, liver metastasis and paired adjacent normal tissues of CRC. And using RT-PCR to verify chip results. RESULTS: A total of 10 680 lncRNAs demonstrated differential expressions (fold change ≥2) between tumor tissues and adjacent normal tissues; furthermore there were 2970 lncRNAs, which showed different expression level between CRC tissues with liver metastasis and adjacent normal tissues. Especially, lncRNA-AK098783 expression level was frequently higher in cancerous tissues than corresponding noncancerous tissue. Higher AK098783 expression was significantly correlated with shortened overall survival (P < 0.001) and distant metastasis (P < 0.001). CONCLUSIONS: Our results suggest that AK098783 is involved in distant metastasis and dramatically associated with poor prognosis in patients with CRC.

High expression of AMPD2 and obesity are associated with poor prognosis in colorectal cancer.

The protein-coding gene adenosine monophosphate deaminase (AMPD) 2 plays a critical role in energy metabolism by converting adenosine-5-monophosphate (AMP) to iosine inosine-5-monophosphate (IMP). Obesity affects metabolic abnormalities in tumor cells and has been associated with high expression levels of AMPD2 and colorectal cancer (CRC). In this study, we performed immunohistochemical analysis of AMPD2 expression in 158 patients with CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine AMPD2 mRNA expression levels, which were validated by The Cancer Genome Atlas (TCGA) datasets. Chi-square test and Fisher's exact test were used to evaluate the correlation between the expression of AMPD2 and clinicopathological parameters of CRC. Overall survival (OS) rates of the CRC patients were calculated using Kaplan-Meier survival analysis and a Cox proportional regression model was performed for univariate and multivariate analysis. A logistic regression model was used to plot the receiver operating characteristic (ROC) curve and to evaluate the predictive effect of multivariate studies on prognosis outcomes of CRC. We found a significant increase in AMPD2 expression in tumor tissue (91.8%, 146/158) compared to adjacent normal tissue (52.5%, 83/158, P < 0.01). The positive rate of AMPD2 expression was 72.7% (39/54) in overweight individuals versus 51.9% (54/104) in individuals with a normal weight (P = 0.014). AMPD2 mRNA levels as determined by qRT-PCR elevated levels of AMPD2 transcripts were higher in CRC samples compared to adjacent normal tissues (P < 0.05). In both the TCGA colon adenocarcinoma and rectal adenocarcinoma dataset, the number of CRC patients with increased levels of AMPD2 in tumor tissues was significantly higher compared to patients with adjacent normal tissue (P < 0.001). High expression of AMPD2 was associated with TNM stage, higher histological grade, obesity, and lower OS rates in patients with CRC. Obesity and high expression of AMPD2 in patients are with poor prognosis. Moreover, multivariate analysis indicated that AMPD2 levels and TNM stage were significant independent prognostic factors in CRC patients. The logistic regression predictive effect of the area under the curve (AUC) was 0.821 (P < 0.001). In conclusion, high levels of AMPD2 and obesity are associated with poor prognosis in patients with CRC.

Cancer cell-expressed B7-H3 regulates the differentiation of tumor-associated macrophages in human colorectal carcinoma.

Co-stimulatory molecule B7 homolog 3 protein (B7-H3) has been described as an important tumor antigen in various human tumors. The exact role of B7-H3 in tumor progression and its receptor are still ambiguous. The phenotype and the function of tumor-associated macrophages (TAMs) in human solid tumors are complicated and could contribute to the shaping of the tumor microenvironment. In the present study, B7-H3 expression and lymphocyte infiltration were investigated by immunohistochemistry in 117 colorectal carcinoma (CRC) patients. B7-H3 expression was positively associated with the infiltrating density of macrophage in CRC tissues, and B7-H3 expression and the infiltrating density of macrophages were negatively associated with the overall survival rate of patients. The putative B7-H3 receptor was found on activated monocytes and macrophages, indicating the direct function of B7-H3 signal on macrophages. Additional results revealed that during the differentiation of TAMs, B7-H3 promoted the polarization of type 2 macrophages (M2s) and switch of the M1 phenotype to the M2 phenotype. Thus, B7-H3 signaling promotes M2 differentiation via the putative receptor on monocytes and macrophages. Targeting the manipulation of TAMs through the B7-H3 pathway may be valuable for the development of novel immunotherapeutic strategies against human CRC.

Noninvasive detection of nasopharyngeal carcinoma based on saliva proteins using surface-enhanced Raman spectroscopy.

The present study evaluated the capability of saliva analysis combining membrane protein purification with surface-enhanced Raman spectroscopy (SERS) for noninvasive detection of nasopharyngeal carcinoma (NPC). A rapid and convenient protein purification method based on cellulose acetate membrane was developed. A total of 659 high-quality SERS spectra were acquired from purified proteins extracted from the saliva samples of 170 patients with pathologically confirmed NPC and 71 healthy volunteers. Spectral analysis of those saliva protein SERS spectra revealed specific changes in some biochemical compositions, which were possibly associated with NPC transformation. Furthermore, principal component analysis combined with linear discriminant analysis (PCA-LDA) was utilized to analyze and classify the saliva protein SERS spectra from NPC and healthy subjects. Diagnostic sensitivity of 70.7%, specificity of 70.3%, and diagnostic accuracy of 70.5% could be achieved by PCA-LDA for NPC identification. These results show that this assay based on saliva protein SERS analysis holds promising potential for developing a rapid, noninvasive, and convenient clinical tool for NPC screening.

CD61+ and CAF+ were found to be good prognosis factors for invasive breast cancer patients.

BACKGROUND: During the epithelial tumor development process, changes in tumor cell genes are an important driving factor for tumorigenesis. Recently, however, studies have shown that the tumor microenvironment, especially for cancer-associated fibroblasts (CAFs) and the infiltration of platelets into tumors, plays an essential role in the progression of human malignant disease. METHODS: In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs (CAF+), the infiltration of platelets into tumors (CD61+) and platelet count before surgery in a large sample of patients with breast cancer. Podoplanin expression and platelet infiltration were evaluated by immunohistochemistry in 164 patients with breast cancer. RESULTS: Seventy-two patients (44%) showed CAF+, while fifty-seven patients (35%) showed CD61+. Several strong positive correlations were found, including CD61+ with blood platelet count before surgery (P=0.004), and CAF+ with CD61+ (P=0.048). Patients with CAF+, CD61+ or platelet count >280×109/L before surgery had a significantly shorter disease-free survival according to univariate analysis. Multivariable analysis showed that CAF+ was an independent prognostic factor (Hazard ratio=3.928; p=0.005). CONCLUSIONS: CAF+ and CD61+ were found to be good negative prognosis factors for invasive breast cancer patients. CD61+ also had strong positive correlation with blood platelet count before surgery. These targets may be used as strategies for the treatment of breast cancer in the future.

MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited therapeutic options. Temozolomide (TMZ) is a novel cytotoxic agent used as first-line chemotherapy for GBM, however, some individual cells can't be isolated for surgical resection and show treatment-resistance, thus inducing poor prognosis. By using the HiSeq sequencing and bioinformatics methods, we identified lncRNAs showing different expression levels in TMZ-resistant and non-resistant patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MALAT1 was finally identified to show considerable discriminating potential to identify responding patients from non-responding patients. Moreover, high serum MALAT1 expression was associated with poor chemoresponse and survival in GBM patients receiving TMZ treatment. Subsequently, the TMZ resistant cell lines were established, and the CCK8 assay showed that lncRNA MALAT1 knockdown significantly reversed TMZ resistance in GBM cells. The gain and loss-function experiments revealed that miR-203 was down-regulated by MALAT1 and this interaction has reciprocal effects. Besides, thymidylate synthase (TS) mRNA was identified as a direct target of miR-203. LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR-203 and down-regulating TS expression. On the other hand, MALAT1 overexpression promoted resistance by suppressing miR-203 and promoting TS expression. In conclusion, our integrated approach demonstrates that enhanced expression of lncRNA MALAT1 confers a potent poor therapeutic efficacy and inhibition of MALAT1 levels could be a future direction to develop a novel therapeutic strategy to overcome TMZ resistance in GBM patients.

Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

[Advances in Raman Spectroscopy for Nasopharyngeal Carcinoma Tissue].

Nasopharyngeal carcinoma is a unique malignant tumor that has a distinct geographic and racial distribution, with a high incidence in southeast Asia and southern China. High degree of malignancy, poor prognosis and difficulty in early diagnosis remain a problem in nasopharyngeal carcinoma. Raman spectroscopy technique based on inelastic scattering is a rapid and nonivasive detection method, which is capable of providing the information of biochemical components at molecular vibration level.This article reviewed the recent research progress of nasopharyngeal carcinoma based on Raman spectroscopy. It mainly introduces the study of detecting nasopharyngeal carcinoma tissue by using Raman spectroscopy as well as surface-enhanced Raman scattering spectroscopy (SERS). The emphasis is put on the latest works by our research group, including high wavenumber Raman spectroscopy of tissue, Raman spectroscopy of tissue smears, and a specially designed endoscopic device combined with Raman spectroscopy for in vivo nasopharyngeal cancerous tissue detection, which was firstly developed by our group. Finally, the prospects of the development of Raman spectroscopy for nasopharyngeal carcinoma were discussed.

Zoledronate can promote apoptosis and inhibit the proliferation of colorectal cancer cells.

Zoledronate (ZOL) is a third-generation bisphosphonate (BP), clinically used to treat lytic bone lesions caused by malignancies or bone resorption disorders. Mechanistically, ZOL was recently shown to have direct pro-apoptotic effects on tumor cells and to inhibit cancer cell invasion, adhesion, proliferation, and angiogenesis. The molecular mechanism of ZOL-induced apoptosis remains unknown. In this study, we observed that ZOL induced apoptosis in colorectal cancer cells HCT116 and Caco-2. After HCT116 and Caco-2 cells were treated with ZOL, decreased fluorescence of JC-1 aggregates (590 nm) was seen in mitochondria. Western blotting analysis showed that cytochrome c was decreased in the mitochondria and increased in the cytosol, respectively. The effects were dependent on the concentration and treatment time by ZOL. In vivo experiments showed that ZOL inhibited the growth of xenograft tumor in mice. Hematoxylin and eosin (H&E) staining of tissue samples showed a significantly increased apoptosis body in the ZOL-treated xenografts compared to control. Taken together, our data demonstrated that ZOL inhibits growth of HCT116 cells both in vitro and in vivo and induce apoptosis through the mitochondria pathway.