Deltex E3 ubiquitin ligase 3 inhibits colorectal cancer cell growth and regulates cell cycle progression via upregulating E2F transcription factor 1.

BACKGROUND: The mortality rate of colorectal cancer (CRC) remains high in developing countries. Interventions that can inhibit the proliferation of tumor cells represent promising strategies in CRC treatment. Deltex E3 ubiquitin ligase 3 (DTX3) plays an essential role in tumor development and may predict the outcome of cancer patients. This study aimed to investigate the regulatory mechanisms of DTX3 in CRC progression. METHODS AND RESULTS: The expression of DTX3 was significantly downregulated in CRC tissues relative to normal colorectal tissues. DTX3 overexpression inhibited, while DTX3 knockout promoted the colony-forming capacity and proliferation of CRC cells. E2F transcription factor 1 (E2F1) is a key mediator of cell cycle progression that participates in the progression, metastasis, and chemoresistance of CRC. Further analysis revealed that DTX3 regulated the transcriptional activity of E2F1 in CRC cells. The transcription by E2F1 was significantly reduced with the increase in the cellular level of DTX3, while DTX3 knockout exerted an opposite effect. DTX3 knockout also increased the expression of E2F1 target genes involved in cell cycle progression, CDC2 and Cyclin D3, while PD 0332991, an inhibitor of E2F1 transcription, inhibited the expression of both proteins. CONCLUSIONS: In conclusion, DTX3 regulated CRC cell growth via regulating E2F1 and its downstream genes. These findings support further exploration of DTX3 as a potential therapeutic target for CRC.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

The dual role of complement in cancers, from destroying tumors to promoting tumor development.

Complement is an important branch of innate immunity; however, its biological significance goes far beyond the scope of simple nonspecific defense and involves a variety of physiological functions, including the adaptive immune response. In this review, to unravel the complex relationship between complement and tumors, we reviewed the high diversity of complement components in cancer and the heterogeneity of their production and activation pathways. In the tumor microenvironment, complement plays a dual regulatory role in the occurrence and development of tumors, affecting the outcomes of the immune response. We explored the differential expression levels of various complement components in human cancers via the Oncomine database. The gene expression profiling interactive analysis (GEPIA) tool and Kaplan-Meier plotter (K-M plotter) confirmed the correlation between differentially expressed complement genes and tumor prognosis. The tumor immune estimation resource (TIMER) database was used to statistically analyze the effect of complement on tumor immune infiltration. Finally, with a view to the role of complement in regulating T cell metabolism, complement could be a potential target for immunotherapies. Targeting complement to regulate the antitumor immune response seems to have potential for future treatment strategies. However, there are still many complex problems, such as who will benefit from this therapy and how to select the right therapeutic target and determine the appropriate drug concentration. The solutions to these problems depend on a deeper understanding of complement generation, activation, and regulatory and control mechanisms.

Serum interleukin-6 is an indicator for severity in 901 patients with SARS-CoV-2 infection: a cohort study.

BACKGROUND: Interleukin-6 (IL-6) was proposed to be associated with the severity of coronavirus disease 2019 (COVID-19). The present study aimed to explore the kinetics of IL-6 levels, validate this association in COVID-19 patients, and report preliminary data on the efficacy of IL-6 receptor blockade. METHODS: We conducted a retrospective single-institutional study of 901 consecutive confirmed cases. Serum IL-6 concentrations were tested on admission and/or during hospital stay. Tocilizumab was given to 16 patients with elevated IL-6 concentration. RESULTS: 366 patients were defined as common cases, 411 patients as severe, and 124 patients as critical according to the Chinese guideline on diagnosis and treatment of COVID-19. The median concentration of IL-6 was < 1.5 pg/ml (IQR < 1.50-2.15), 1.85 pg/ml (IQR < 1.50-5.21), and 21.55 pg/ml (IQR 6.47-94.66) for the common, severe, and critical groups respectively (P < 0.001). The follow-up kinetics revealed serum IL-6 remained high in critical patients even when cured. An IL-6 concentration higher than 37.65 pg/ml was predictive of in-hospital death (AUC 0.97 [95% CI 0.95-0.99], P < 0.001) with a sensitivity of 91.7% and a specificity of 95.7%. In the 16 patients who received tocilizumab, IL-6 concentrations were significantly increased after administration, and survival outcome was not significantly different from that of propensity-score matched counterparts (n = 53, P = 0.12). CONCLUSION: Serum IL-6 should be included in diagnostic work-up to stratify disease severity, but the benefit of tocilizumab needs further confirmation. Trial registration retrospectively registered.

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage.

Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-ß (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3Cpro). SVV 3Cpro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-ß. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules.IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3Cpro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for the Toll-like receptor 3 (TLR3)-mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-ß. These findings increase our understanding of the interaction between SVV and host innate immunity.

DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses.

Radiotherapy resistance is one of the major factors limiting the efficacy of radiotherapy in lung cancer patients. The extensive investigations indicate the diversity in the mechanisms underlying radioresistance. Here, we revealed that DNA damage binding protein 2 (DDB2) is a potential regulator in the radiosensitivity of non-small cell lung cancer (NSCLC) cells. DDB2, originally identified as a DNA damage recognition factor in the nucleotide excision repair, promotes the survival and inhibits the apoptosis of NSCLC cell lines upon ionizing radiation (IR). Mechanistic investigations demonstrated that DDB2 is able to facilitate IR-induced phosphorylation of Chk1, which plays a critical role in the cell cycle arrest and DNA repair in response to IR-induced DNA double-strand breaks (DSBs). Indeed, knockdown of DDB2 compromised the G2 arrest in the p53-proficient A549 cell line and reduced the efficiency of homologous recombination (HR) repair. Taken together, our data indicate that the expression of DDB2 in NSCLC could be used as a biomarker to predict radiosensitivity of the patients. Targeting Chk1 can be used to increase the efficacy of radiotherapy in patients of NSCLC possessing high levels of DDB2.

The dose-response effect of physical activity on cancer mortality: findings from 71 prospective cohort studies.

BACKGROUND: The WHO recommends moderate physical activity to combat the increasing risk of death from chronic diseases. We conducted a meta-analysis to assess the association between physical activity and cancer mortality and the WHO recommendations to reduce the latter. METHODS: MEDLINE and EMBASE were searched up until May 2014 for cohort studies examining physical activity and cancer mortality in the general population and cancer survivors. Combined HRs were estimated using fixed-effect or random-effect meta-analysis of binary analysis. Associated HRs with defined increments and recommended levels of recreational physical activity were estimated by two-stage random-effects dose-response meta-analysis. RESULTS: A total of 71 cohort studies met the inclusion criteria and were analysed. Binary analyses determined that individuals who participated in the most physical activity had an HR of 0.83 (95% CI 0.79 to 0.87) and 0.78 (95% CI 0.74 to 0.84) for cancer mortality in the general population and among cancer survivors, respectively. There was an inverse non-linear dose-response between the effects of physical activity and cancer mortality. In the general population, a minimum of 2.5 h/week of moderate-intensity activity led to a significant 13% reduction in cancer mortality. Cancer survivors who completed 15 metabolic equivalents of task (MET)-h/week of physical activity had a 27% lower risk of cancer mortality. A greater protective effect occurred in cancer survivors undertaking physical activity postdiagnosis versus prediagnosis, where 15 MET-h/week decreased the risk by 35% and 21%, respectively. CONCLUSIONS: Our meta-analysis supports that current physical activity recommendations from WHO reduce cancer mortality in both the general population and cancer survivors. We infer that physical activity after a cancer diagnosis may result in significant protection among cancer survivors.

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.

Immunohistochemistry as a quick screening method for clinical detection of BRAF(V600E) mutation in melanoma patients.

With the increased uses of targeted therapeutics, diagnostic detection of target mutations becomes essential for the effective clinical applications of targeted therapeutics. Currently, there are two types of methods detecting target mutations in clinics: one is based on DNA sequence and the other uses the newly developed mutation-specific antibodies recognizing mutated proteins. Each method has its own advantages and disadvantages. Here, we explored the sensitivity and specificity of a new commercially available BRAF(V600E) mutation-specific mouse monoclonal antibody. Using routine manual immunohistochemistry (IHC), we tested tumor tissues from 38 melanoma patients. For those melanoma tissues with abundant endogenous melanin, we pretreated the tumor tissues with 3 % hydrogen peroxide to remove melanin for reliable signal detection. We also performed DNA sequencing and ARMS-PCR analyses for these 38 tumor samples. Comparing to the results from DNA-based detection methods, the IHC method with this BRAF(V600E) mutation-specific antibody displayed 100 % sensitivity and 92.9 % specificity. Hence, this IHC detection is sensitive for clinic uses as a simple, fast, inexpensive, and reliable method to screen cancer patients for the BRAF(V600E) mutation and could be easily adapted for use in most hospital pathology laboratories.

Sparing functional anatomical structures during intensity-modulated radiotherapy: an old problem, a new solution.

During intensity-modulated radiotherapy, an organ is usually assumed to be functionally homogeneous and, generally, its anatomical and spatial heterogeneity with respect to radiation response are not taken into consideration. However, advances in imaging and radiation techniques as well as an improved understanding of the radiobiological response of organs have raised the possibility of sparing the critical functional structures within various organs at risk during intensity-modulated radiotherapy. Here, we discuss these structures, which include the critical brain structure, or neural nuclei, and the nerve fiber tracts in the CNS, head and neck structures related to radiation-induced salivary and swallowing dysfunction, and functional structures in the heart and lung. We suggest that these structures can be used as potential surrogate organs at risk in order to minimize their radiation dose and/or irradiated volume without compromising the dose coverage of the target volume during radiation treatment.

Two new compounds from biotransformation of glycyrrhetinic acid.

Glycyrrhetinic acid may undergo biotransformation to obtain derivatives with stronger pharmacological activity and fewer side effects. This study used 19 fungi to biotransform glycyrrhetinic acid and yielded two compounds namely bicyclo(14.15.27)glycyrrhetinic acid (1) and 2-ene-glycyrrhetinic acid (2) from the glycyrrhetinic acid metabolites of two fungi, Botrytis cinerea B05.10 ATCC 11542 and Aspergillus ochraceopetaliformis ATCC 12066. Compound 1 inhibited HMEC-1 cell proliferation in a concentration-dependent manner (IC50=239.1 µ M), but showed no significant cytotoxicity to A549 cells.

Whole transcriptome sequencing identifies a competitive endogenous RNA network that regulates the immunity of bladder cancer.

Several types of non-coding RNAs such as circRNAs, lncRNAs, and miRNAs have been identified to regulate mRNAs through the mechanism known as the competitive endogenous RNA (ceRNA) network. To explore the role of the ceRNA regulatory network in the immune microenvironment of bladder cancer, whole-transcriptome sequencing of bladder tumor and its peritumoral tissues from 38 bladder cancer patients, with a total of 63 samples, was performed to screen differentially expressed circ-, lnc-, mi-, and mRNAs to construct a circ/lnc-mi-mRNA regulatory network with pruning algorithms. We excavated a key immune-related gene BDNF to build the final ceRNA network as hsa-miR-107 sponged by hsa-circ-000211, AC108488.1, and LINC00163. Finally, a meta-analysis of 7 public datasets demonstrated that low expression of BDNF and high expression of hsa-miR-107 were associated with longer survival. Our study identified a ceRNA regulatory network as a potentially new prognostic marker and molecular therapeutic target of bladder cancer.

Suicide among lymphoma patients.

BACKGROUND: Higher suicide rates were observed in patients diagnosed with lymphoma. In this study, we accurately identified patients with high-risk lymphoma for suicide by constructing a nomogram with a view to effective interventions and reducing the risk of suicide. METHODS: 235,806 patients diagnosed with lymphoma between 2000 and 2020 were picked from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training (N = 165,064) and validation set (N = 70,742). A combination of the Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression identified the predictors that constructed the nomogram. To assess the discrimination, calibration, clinical applicability, and generalization of this nomogram, we implemented receiver operating characteristic curves (ROC), calibration curves, decision curve analysis (DCA), and internal validation. The robustness of the results was assessed by the competing risks regression model. RESULTS: Age at diagnosis, gender, ethnicity, marital status, stage, surgery, radiotherapy, and annual household income were key predictors of suicide in lymphoma patients. A nomogram was created to visualize the risk of suicide after a lymphoma diagnosis. The c-index for the training set was 0.773, and the validation set was 0.777. The calibration curve for the nomogram fitted well with the diagonal and the clinical decision curve indicated its clinical benefit. LIMITATION: The effects of unmeasured and unnoticed biases and confounders were difficult to eliminate due to retrospective studies. CONCLUSION: A convenient and reliable model has been constructed that will help to individualize and accurately quantify the risk of suicide in patients diagnosed with lymphoma.

Oxymatrine induces apoptosis in non-small cell lung cancer cells by downregulating TRIM46.

Sophora flavescens Aiton, a traditional Chinese medicine that was supposed to predominantly play an anti-inflammatory role, has been used to treat multiple diseases, including cancer, for over two thousand years. Recently, it has attracted increasing attention due to the anti-tumor properties of Oxymatrine, one of the most active alkaloids extracted from S. flavescens. This study aims to explore it's anti-tumor effects in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We first investigated the effects of oxymatrine on cell apoptosis in lung cancer cell lines A549 and PC9 as well as explored related genes in regulating the apoptosis by transcriptome analysis. Subsequently, to further study the role of TRIM46, we constructed two types of TRIM46 over-expression cells (A549TRIM46+ and PC9TRIM46+ cells) and then investigated the effect of TRIM46 on oxymatrine-induced apoptosis. Moreover, we explored the effect of TRIM46 on downstream signaling pathways. Transcriptome analysis suggested that shared differentially expressed genes (DEGs) in A549 and PC9 cells treated with oxymatrine were CACNA1I, PADI2, and TRIM46. According to TCGA database analysis, the abundance of TRIM46 expression was higher than CACNA1I, and PADI2 in lung cancer tissues, then was selected as the final DEG for subsequent studies. We observed that oxymatrine resulted in down-expression of TRIM46 as well as induced the apoptosis of the cancer cells in a dose- and time-dependent manner. Meanwhile, we found that apoptosis induced by oxymatrine was inhibited by over-expressing TRIM46. Furthermore, our study indicated that the NF-κB signaling pathway was involved in apoptosis suppressed by TRIM46. We conclude that TRIM46 is the direct target of oxymatrine to induce anti-tumor apoptosis and may activate the downstream NF-κB signaling pathway.

Black rice diet alleviates colorectal cancer development through modulating tryptophan metabolism and activating AHR pathway.

Consumption of dietary fiber and anthocyanin has been linked to a lower incidence of colorectal cancer (CRC). This study scrutinizes the potential antitumorigenic attributes of a black rice diet (BRD), abundantly rich in dietary fiber and anthocyanin. Our results demonstrate notable antitumorigenic effects in mice on BRD, indicated by a reduction in both the size and number of intestinal tumors and a consequent extension in life span, compared to control diet-fed counterparts. Furthermore, fecal transplants from BRD-fed mice to germ-free mice led to a decrease in colonic cell proliferation, coupled with maintained integrity of the intestinal barrier. The BRD was associated with significant shifts in gut microbiota composition, specifically an augmentation in probiotic strains Bacteroides uniformis and Lactobacillus. Noteworthy changes in gut metabolites were also documented, including the upregulation of indole-3-lactic acid and indole. These metabolites have been identified to stimulate the intestinal aryl hydrocarbon receptor pathway, inhibiting CRC cell proliferation and colorectal tumorigenesis. In summary, these findings propose that a BRD may modulate the progression of intestinal tumors by fostering protective gut microbiota and metabolite profiles. The study accentuates the potential health advantages of whole-grain foods, emphasizing the potential utility of black rice in promoting health.

A terpenoids database with the chemical content as a novel agronomic trait.

Natural products play a pivotal role in drug discovery, and the richness of natural products, albeit significantly influenced by various environmental factors, is predominantly determined by intrinsic genetics of a series of enzymatic reactions and produced as secondary metabolites of organisms. Heretofore, few natural product-related databases take the chemical content into consideration as a prominent property. To gain unique insights into the quantitative diversity of natural products, we have developed the first TerPenoids database embedded with Content information (TPCN) with features such as compound browsing, structural search, scaffold analysis, similarity analysis and data download. This database can be accessed through a web-based computational toolkit available at http://www.tpcn.pro/. By conducting meticulous manual searches and analyzing over 10 000 reference papers, the TPCN database has successfully integrated 6383 terpenoids obtained from 1254 distinct plant species. The database encompasses exhaustive details including isolation parts, comprehensive molecule structures, chemical abstracts service registry number (CAS number) and 7508 content descriptions. The TPCN database accentuates both the qualitative and quantitative dimensions as invaluable phenotypic characteristics of natural products that have undergone genetic evolution. By acting as an indispensable criterion, the TPCN database facilitates the discovery of drug alternatives with high content and the selection of high-yield medicinal plant species or phylogenetic alternatives, thereby fostering sustainable, cost-effective and environmentally friendly drug discovery in pharmaceutical farming. Database URL: http://www.tpcn.pro/.

Combine thermal processing with polyvalent phage LPEK22 to prevent the Escherichia coli and Salmonella enterica contamination in food.

Thermal processing is the most frequently used method to destruct bacteria in food processing. However, insufficient thermal processing may lead to the outbreak of foodborne illness. This study combined thermal processing with thermostable phage to prevent food contamination. The thermostable phages were screened which can retain activity at 70 °C for 1 h. Among them, the polyvalent phage LPEK22 was obtained to lyse Escherichia coli and Salmonella enterica, especially several multi-drug resistant bacteria. In milk (liquid food matrix), LPEK22 significantly reduced the E. coli by 5.00 ± 0.18 log10 CFU/mL and S. enterica by 4.20 ± 0.23 log10 CFU/mL after thermal processing at 63 °C for 30 min. For beef sausage (solid food matrix), LPEK22 significantly reduced the E. coli by 2.34 ± 0.17 log10 CFU/cm2 and S. enterica by 1.54 ± 0.13 log10 CFU/cm2 after thermal processing at 66 °C for 90 s. Genome analysis revealed that LPEK22 was a novel phage with a unique tail spike protein belonging to the family of Ackermannviridae. LPEK22 did not contain lysogenic, drug-resistant, and virulent genes that may compromise the safety of food application. These results determined that LPEK22, a novel polyvalent Ackermannviridae phage, could combine with thermal processing to prevent drug-resistant E. coli and S. enterica both in vitro and in foods.

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.

Models Based on Dynamic Clinicopathological Indices for Predicting Prognosis During the Perioperative Period for Patients with Colorectal Cancer.

BACKGROUND: Recent studies have found that clinicopathological indices, such as inflammatory and biochemical indices, play a significant role in the prognosis of colorectal cancer (CRC) patients. However, few studies have focused on the effect of dynamic changes in these indicators. In our study, we studied the influence of dynamic changes in inflammatory and biochemical indices on patient outcomes during the perioperative period. METHODS: We enrolled 551 patients from Hubei Cancer Hospital who had undergone radical resection of CRC and collected the results of laboratory examinations performed within 1 week before surgery and at the first admission after surgery. The whole population was randomly divided into the training (386) and testing (185) cohorts. We used postoperative inflammatory and biochemical indices/preoperative inflammatory and biochemical indices (ΔX) to reflect the dynamic changes. Chi-square tests, Kaplan-Meier survival analyses, and univariate and multivariate Cox regression analyses were used to evaluate the prognosis. The prediction accuracies of models for overall survival (OS) and disease-free survival (DFS) were estimated through Harrell's concordance index (the C-index) and Brier scores. Nomograms of the prognostic models were plotted for evaluations of individualized outcomes. RESULTS: The median follow-up time of the 551 patients was 35.6 (range: 1.1-73.8) months. Ultimately, the prognostic models based on age, sex, TNM stage, pathological conditions, inflammatory and biochemical indices, CEA, and CA199 were found to have exceptional performance for OS and DFS. The C-index of the nomogram for OS was 0.806 (95% CI, 0.75-0.86) in the training cohort and 0.921 (95% CI, 0.87-0.96) in the testing cohort. The C-index of the nomogram for DFS was 0.781 (95% CI, 0.74-0.82) in the training cohort and 0.835 (95% CI, 0.78-0.88) in the testing cohort. CONCLUSION: We successfully established a novel model based on inflammatory and biochemical indices to guide clinical decision-making for CRC.