Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

STAT3 as a target for sensitizing prostate cancer cells to irradiation.

Radioresistance of prostate cancer (PCa) is a major factor leading to local failure of radiotherapy. STAT3 is an oncogenic protein that was recently found to be activated in PCa tumors. This study aimed to investigate the radiosensitization effect of targeting STAT3 in PCa tumors. Here, the radiosensitization effect of STAT3 blockade was investigated by clonogenic assay, flow cytometry and western blot analysis in human PCa cells in vitro and in vivo. We demonstrated that STAT3 blockade with a STAT3 inhibitor or siRNA increased the radiosensitivity of PCa cells and that radiation together with STAT3 blockade induced more apoptosis and double-strand breaks (DSBs) than radiation alone in LNCaP cells. In addition, radiation induced STAT3 activation and survivin expression in PCa cells, which was inhibited by STAT3 blockade. Transfection with survivin cDNA attenuated the radiosensitization effect of STAT3 blockade. These effects were further confirmed by in vivo studies, which showed that the STAT3 inhibitor enhanced the treatment efficacy of radiation on LNCaP xenografts with decreased STAT3 activation and survivin expression. These findings suggest that STAT3 blockade radiosensitizes PCa cells through regulation of survivin. Thus, our study has revealed STAT3 as a potential sensitizer for irradiation in PCa cells. Its clinical application as an adjuvant in radiotherapy of PCa should be explored in the future.

Inflammation-Immunity-Nutrition Score: A Novel Prognostic Score for Patients with Resectable Colorectal Cancer.

PURPOSE: This study was designed to investigate the prognostic value of the combination of high-sensitivity C-reactive protein, lymphocyte, and albumin in patients with resectable colorectal cancer. PATIENTS AND METHODS: Seven-hundred-and-nineteen patients who underwent colorectal cancer resection in Hubei Cancer Hospital were included. Inflammation-Immunity-Nutrition score (0-6) was constructed based on preoperative high-sensitivity C-reactive protein, lymphocyte, and albumin. Time-dependent receiver operating characteristic curve, decision curve, Kaplan-Meier survival curve, Cox regression, and C-index were conducted to detect the prognostic values of inflammation-immunity-nutrition score. The prognostic values of inflammation-immunity-nutrition score in different subgroups by sex, location of tumor, pathologic stage, and KRAS mutation were also explored. The prognostic performance of inflammation-immunity-nutrition score was further compared with that of other traditional prognostic indicators. RESULTS: The median follow-up time was 40 months. High inflammation-immunity-nutrition score (>2 scores) presented worse survival, with the adjusted hazard ratios (95% confidence intervals) of 3.106 (2.202-4.380) for overall survival and 2.105 (1.604-2.764) for disease-free survival. Besides, the associations of high inflammation-immunity-nutrition score with overall survival were even stronger in cases with wild type KRAS, with the adjusted hazard ratios (95% confidence intervals) of 4.018 (2.355-6.854). Considering the AUCs, C-indices, and hazard ratios estimates, inflammation-immunity-nutrition score presented better prognostic performance than high-sensitivity modified Glasgow prognostic score, high-sensitivity C-reactive protein to albumin ratio, prognostic nutrition index, carcinoembryonic antigen, and carbohydrate antigen 19-9 for overall survival. CONCLUSION: Inflammation-immunity-nutrition score might serve as a powerful prognostic score in patients with colorectal cancer for overall survival, particularly in patients with wild type KRAS.

Chinese expert consensus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies.

Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis (PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of < 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases I, II and III clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.

Formation and determination of the oxidation products of 5-methylcytosine in RNA.

Similar to the reversible epigenetic modifications on DNA, dynamic RNA modifications were recently considered to constitute another realm for biological regulation in the form of "RNA epigenetics". 5-Methylcytosine (5-mC) has long been known to be present in RNA from all three kingdoms of life. However, the functions of 5-mC in RNA have not been fully understood, especially for the RNA demethylation mechanism. The discovery of 5-hydroxymethylcytosine (5-hmC) in RNA together with our recently reported 5-formylcytosine (5-foC) in RNA indicated that 5-mC in RNA may undergo the same cytosine oxidation demethylation pathway with generating intermediates 5-hmC, 5-foC, and 5-carboxylcytosine (5-caC) by ten-eleven translocation (Tet) proteins as that in DNA. However, endogenous 5-caC in RNA has not been observed so far. In the current study, we established a method using chemical labeling coupled with liquid chromatography-mass spectrometry analysis for the sensitive and simultaneous determination of the oxidative products of 5-mC. Our results demonstrated that the detection sensitivities of 5-mC, 5-hmC, 5-foC and 5-caC in RNA increased by 70-313 folds upon 2-bromo-1-(4-diethylaminophenyl)-ethanone (BDEPE) labeling. Using this method, we discovered the existence of 5-caC in the RNA of mammals. In addition, we found the 5-mC occurs in all RNA species including mRNA, 28S rRNA, 18S rRNA and small RNA (<200 nt). However, 5-hmC, 5-foC and 5-caC mainly occur in mRNA, and barely detected in other types of RNA. Furthermore, we found that the content of 5-hmC in the RNA of human colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC) tissues significantly decreased compared to tumor adjacent normal tissues, suggesting that 5-hmC in RNA may play certain functional roles in the regulation of cancer development and formation.

Laparoscopic TME associated with neoadjuvant chemoradiation towards aggressive colorectal cancer.

OBJECTIVE: This study aims to investigate the clinical synchronization of the neoadjuvant chemoradiation (NC) and the laparoscopic total mesorectal excision (TME) in the treatment of locally aggressive colorectal cancer (LACC). METHODS: 92 LACC patients were selected for the research, among who 46 cases, who were performed the synchronized NC, were divided into the treatment group, after having rest for 4-6 weeks after the treatment, the 40 patients of the treatment group, who were performed the laparoscopic surgery, formed the laparoscopy group. The rest 46 patients were divided into the control group, who were performed the conventional treatment. The intraoperative conditions, postoperative recoveries, postoperative complications and recurrence rates of the two groups were compared. RESULTS: The stage-declining rate of the treatment group was 67.3%, and the surgical resection rate, anal preservation rate and postoperative complications were 86.9%, 69.6% and 26%, respectively, which were significantly higher than the control group; while the long-term recurrence rate significantly decreased to 21.7%, and the difference was statistically significant (P<0.05). CONCLUSION: The NC could effectively achieve the stage-declining purpose against the LACC, improve the resection rate and reduce the postoperative recurrence rate.

High SIPA-1 expression in proximal tubules of human kidneys under pathological conditions.

Systemic lupus erythematosus (SLE) and clear cell renal cell carcinoma (CC-RCC) are serious disorders and usually fatal, and always accompanied with pathological changes in the kidney. Signal-induced proliferation-associated protein 1 (SIPA-1) is a Rap1GTPase activating protein (Rap1GAP) expressed in the normal distal and collecting tubules of the murine kidney. Lupus-like autoimmune disease and leukemia have been observed in SIPA-1 deficient mice, suggesting a pathological relevance of SIPA-1 to SLE and carcinoma in human being. The expression pattern of SIPA-1 is as yet undefined and the pathogenesis of these diseases in humans remains elusive. In this study, we used both immunohistochemistry and quantum dot (QD)-based immunofluorescence staining to investigate the expression of SIPA-1 in renal specimens from SLE and CC-RCC patients. MTT assay and Western blotting were employed to evaluate the effects of SIPA-1 overexpression on the proliferation and apoptosis of renal cell lines. Semi-quantitative reverse transcriptase-PCR (RT-PCR) was applied to examine the changes of hypoxia-inducible factor-1α (HIF-1α) mRNA level. Results showed that SIPA-1 was highly expressed in the proximal and collecting tubules of nephrons in SLE patients compared to normal ones, and similar results were obtained in the specimens of CC-RCC patients. Although SIPA-1 overexpression did not affect cellular proliferation and apoptosis of both human 786-O renal cell carcinoma cells and rat NRK-52E renal epithelial cell lines, RT-PCR results showed that HIF-1α mRNA level was down-regulated by SIPA-1 overexpression in 786-O cells. These findings suggest that SIPA-1 may play critical roles in the pathological changes in kidney, and might provide a new biomarker to aid in the diagnosis of SLE and CC-RCC.

Quick-response magnetic nanospheres for rapid, efficient capture and sensitive detection of circulating tumor cells.

The study on circulating tumor cells (CTCs) has great significance for cancer prognosis, treatment monitoring, and metastasis diagnosis, in which isolation and enrichment of CTCs are key steps due to their extremely low concentration in peripheral blood. Herein, magnetic nanospheres (MNs) were fabricated by a convenient and highly controllable layer-by-layer assembly method. The MNs were nanosized with fast magnetic response, and nearly all of the MNs could be captured by 1 min attraction with a commercial magnetic scaffold. In addition, the MNs were very stable without aggregation or precipitation in whole blood and could be re-collected nearly at 100% in a monodisperse state. Modified with anti-epithelial-cell-adhesion-molecule (EpCAM) antibody, the obtained immunomagnetic nanospheres (IMNs) successfully captured extremely rare tumor cells in whole blood with an efficiency of more than 94% via only a 5 min incubation. Moreover, the isolated cells remained viable at 90.5 ± 1.2%, and they could be directly used for culture, reverse transcription-polymerase chain reaction (RT-PCR), and immunocytochemistry (ICC) identification. ICC identification and enumeration of the tumor cells in the same blood samples showed high sensitivity and good reproducibility. Furthermore, the IMNs were successfully applied to the isolation and detection of CTCs in cancer patient peripheral blood samples, and even one CTC in the whole blood sample was able to be detected, which suggested they would be a promising tool for CTC enrichment and detection.

Sensory denervation reduces visceral hypersensitivity in adult rats exposed to chronic unpredictable stress: evidences of neurogenic inflammation.

The purpose of this study is to provide evidence of neurogenic inflammation in chronic unpredictable stressed rats with the changes of visceral sensitivity, number of mast cells, and close proximity among mast cell-nerve-blood vessels. We found that (1) capsaicin denervation blocked stress-induced increase of visceral sensitivity, while doxantrazole presented a partial blocking; (2) capsaicin denervation blocked stress-induced enhancement of the proximity of mast cell-nerve fiber-blood vessels and blood vessel damage, while doxantrazole showed no effects on these; (3) doxantrazole blocked stress-induced increases of the MPO activity, the number and the degranulation of mast cells in the colon; (4) sensory denervation and doxantrazole had no effects on stress-induced behavioral inhibition. These results suggest that capsaicin-sensitive sensory fibers play a key role in stress-induced visceral hypersensitivity and the ultrastructural changes, mast cells play an important role in the generation of stress-induced colon inflammation.