B7-H3 immune checkpoint expression is a poor prognostic factor in colorectal carcinoma.

Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p < 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.

A clinical model to predict the risk of synchronous bone metastasis in newly diagnosed colorectal cancer: a population-based study.

BACKGROUND: The early detection of synchronous bone metastasis (BM) in newly diagnosed colorectal cancer (CRC) affects its initial management and prognosis. A clinical model to individually predict the risk of developing BM would be attractive in current clinical practice. METHODS: A total of 55,869 CRC patients were identified from Surveillance, Epidemiology, and End Results (SEER) database, of whom 317 patients were diagnosed with synchronous BM. Risk factors for BM in CRC patients was identified using multivariable logistic regression. A weighted scoring system was built with beta-coefficients (P < 0.05). A random sample of 75% of the CRC patients was used to establish the risk model, and the remaining 25% was used to validate its accuracy of this model. The performance of risk model was estimated by receiver operating curve (ROC) analysis. RESULTS: The risk model consisted of 8 risk factors including rectal cancer, poorly-undifferentiation, signet-ring cell carcinoma, CEA positive, lymph node metastasis, brain metastasis, liver metastasis and lung metastasis. The areas under the receiver operating curve (AUROC) were 0.903 and 0.889 in the development and validation cohort. Patients with scores from 0 to 4 points had about 0.1% risk of developing BM, and the risk increased to about 30% in patients with scores ≥15 points. CONCLUSIONS: This clinical risk model is accurate enough to identify the CRC patients with high risk of synchronous BM and to further provide more individualized clinical decision.

Current practice patterns of preoperative bowel preparation in colorectal surgery: a nation-wide survey by the Chinese Society of Colorectal Cancer.

BACKGROUND: The optimal preoperative bowel preparation for colorectal surgery remains controversial. However, recent studies have established that bowel preparation varies significantly among countries and even surgeons at the same institution. This survey aimed to obtain information on the current practice patterns of bowel preparation for colorectal surgery in China. METHODS: A paper-based survey was circulated to the members of the Chinese Society of Colorectal Cancer (CSCC). The survey responses were collected and analyzed. Statistical analysis was performed for all the categorical variables according to the responses to individual questions. RESULTS: Three hundred forty-one members completed the questionnaire. Regarding surgical practice, 203 (59.5%) performed > 50% of the colorectal operations laparoscopically or robotically; the use of mechanical bowel preparation (MBP) alone was significantly higher (63.5 vs 31.9%; P < 0.001). The respondents who performed > 200 colonic or rectal resections provided significantly more MBP alone (79.6 vs 39.1%, P < 0.001; 76.6 vs 43.2%, P < 0.001; respectively). Among hospitals with fewer than 500 beds, 52.4% of the respondents used MBP + oral antibiotics preparation (OAP) + enema, a significantly higher percentage than the respondents of hospitals with more than 500 beds (P < 0.001). Nearly 40% of the respondents prescribed OAP in regimens; meanwhile, 74.8% prescribed preoperative intravenous antibiotics. CONCLUSIONS: The study demonstrates considerable variation among members from the CSCC. These findings should be considered when developing multicenter trials and to provide more definitive answers.

Controllable Structures Designed with Multiple-Dielectric Responses in Hybrid Perovskite-Type Molecular Crystals.

In this report, two new hybrid organic-inorganic perovskite-type compounds, (IBA)CdBr3 (1; IBA = isobutylammonium cation, i-C4H9-NH3) and (IBA)2CdBr4 (2), have been successfully synthesized by reasonable modulation of the ratio of the reactants. 1 with a one-dimensional (1D) chained structure presents sequential solid-state phase transitions, and 2 with a two-dimensional (2D) layered structure undergoes triple structural phase transitions. The phase transitions are attributable to the stepwise ordering process of the organic IBA cation of the title compounds, which also exhibit temperature-dependent dielectric transitions and dielectric anisotropies. Among the different structural environments, the dynamic motions of organic cations show distinct differences, driving the variation of physical properties.

LncRNA HOXC-AS3 overexpression inhibits TGF-ß2-induced colorectal cancer cell migration and invasion by sponging miR-1269.

OBJECTIVE: Long non-coding RNA (lncRNA) HOXC-AS3 has been characterized as a cancer-related lncRNA in many types of cancer, while its role in colorectal cancer (CRC) is unknown. METHODS: The expression of HOXC-AS3 and TGF-ß2 were detected by RT-qPCR. Overexpression assays were performed to explore the interaction between HOXC-AS3 and TGF-ß2. A follow-up study was performed to explore the prognostic value of HOXC-AS3 for CRC. The direct interaction between HOXC-AS3 and miR-1269 was assessed with RNA-RNA pulldown assay. Transwell assays were performed to determine the role of HOXC-AS3 and TGF-ß2 in regulating CRC cell invasion and migration. RESULTS: HOXC-AS3 was significantly downregulated in CRC tissues, while TGF-ß2 was significantly upregulated in CRC tissues compared to that in adjacent non-cancer tissues of CRC patients. The follow-up study showed that low expression levels of HOXC-AS3 in CRC tissues were closely correlated with poor survival. Correlation analysis showed that HOXC-AS3 and TGF-ß2 were inversely correlated across CRC tissues but not non-cancer tissues. Overexpression of HOXC-AS3 in the two cell lines resulted in downregulation of TGF-ß2, while the expression of HOXC-AS3 was not affected by TGF-ß2. Transwell migration and invasion assay showed that overexpression of TGF-ß2 increased cell invasion and migration, while overexpression of HOXC-AS3 decreased cell migration and invasion. In addition, overexpression of HOXC-AS3 attenuated the effects of overexpression of TGF-ß2. MiR-1269 increased the expression of TGF-ß2. HOXC-AS3 directly interacted with miR-1269 in CRC cells. CONCLUSIONS: Upregulation of HOXC-AS3 inhibited TGF-ß2-induced colorectal cancer (CRC) cell migration and invasion possibly by sponging miR-1269.

A Deep Learning Based Framework for Diagnosing Multiple Skin Diseases in a Clinical Environment.

Background: Numerous studies have attempted to apply artificial intelligence (AI) in the dermatological field, mainly on the classification and segmentation of various dermatoses. However, researches under real clinical settings are scarce. Objectives: This study was aimed to construct a novel framework based on deep learning trained by a dataset that represented the real clinical environment in a tertiary class hospital in China, for better adaptation of the AI application in clinical practice among Asian patients. Methods: Our dataset was composed of 13,603 dermatologist-labeled dermoscopic images, containing 14 categories of diseases, namely lichen planus (LP), rosacea (Rosa), viral warts (VW), acne vulgaris (AV), keloid and hypertrophic scar (KAHS), eczema and dermatitis (EAD), dermatofibroma (DF), seborrheic dermatitis (SD), seborrheic keratosis (SK), melanocytic nevus (MN), hemangioma (Hem), psoriasis (Pso), port wine stain (PWS), and basal cell carcinoma (BCC). In this study, we applied Google's EfficientNet-b4 with pre-trained weights on ImageNet as the backbone of our CNN architecture. The final fully-connected classification layer was replaced with 14 output neurons. We added seven auxiliary classifiers to each of the intermediate layer groups. The modified model was retrained with our dataset and implemented using Pytorch. We constructed saliency maps to visualize our network's attention area of input images for its prediction. To explore the visual characteristics of different clinical classes, we also examined the internal image features learned by the proposed framework using t-SNE (t-distributed Stochastic Neighbor Embedding). Results: Test results showed that the proposed framework achieved a high level of classification performance with an overall accuracy of 0.948, a sensitivity of 0.934 and a specificity of 0.950. We also compared the performance of our algorithm with three most widely used CNN models which showed our model outperformed existing models with the highest area under curve (AUC) of 0.985. We further compared this model with 280 board-certificated dermatologists, and results showed a comparable performance level in an 8-class diagnostic task. Conclusions: The proposed framework retrained by the dataset that represented the real clinical environment in our department could accurately classify most common dermatoses that we encountered during outpatient practice including infectious and inflammatory dermatoses, benign and malignant cutaneous tumors.

Evaluation of clinical significance of claudin 7 and construction of prognostic grading system for stage II colorectal cancer.

BACKGROUND: Claudin 7 is often abnormally expressed in cancers and promotes the progression of some malignancies. However, the role of claudin 7 in stage II colorectal cancer (CRC) has not been studied. AIM: To assess the expression and prognostic value of claudin 7 in stage II CRC. METHODS: We retrospectively studied 231 stage II CRC patients who underwent radical surgery at our hospital from 2013 to 2014. The protein expression level of claudin 7 was assessed and its relationship with clinicopathological features and prognosis was statistically analyzed. The independent prognostic factors were identified by Cox proportional hazards models. A prognostic grading system was constructed to stratify the survival of CRC patients. RESULTS: The expression of claudin 7 was significantly reduced in cancer tissues compared with normal tissues (P < 0.001), and its low expression was closely related to recurrence of the disease (P = 0.017). Multivariate analysis confirmed that claudin 7 low expression (claudin 7-low) (P = 0.028) and perineural invasion positivity (PNI+) (P = 0.026) were independent predictors of poor disease-free survival (DFS). A prognostic grading system based on the status of claudin 7 and PNI classified the patients into three prognostic grades: grade A (claudin 7-high and PNI-), grade B (claudin 7-low and PNI-, claudin 7-high and PNI+), and grade C (claudin 7-low and PNI+). The DFS was significantly different among the three grades (grade B vs grade A, P = 0.032; grade C vs grade A, P < 0.001; grade C vs grade B, P = 0.040). CONCLUSION: Claudin 7 can be used as a new prognostic marker to predict the DFS of patients with stage II CRC. The prognostic grading system with the addition of claudin 7 can further improve prognosis stratification of patients.

A prognostic index model to individually predict clinical outcomes for colorectal cancer with synchronous bone metastasis.

Background: The prognosis of synchronous bone metastasis (BM) in colorectal cancer (CRC) is poor and rarely concerned. A clinical tool to evaluate the prognosis and clinical outcomes for BM would be attractive in current clinical practice. Methods: A total of 342 CRC patients with synchronous BM were identified from Surveillance, Epidemiology, and End Results (SEER) database. The cancer specific survival (CSS) was estimated with the Kaplan-Meier method. Prognostic factors were identified from multivariate Cox model, and the final clinical nomogram was developed to predict the CSS. The concordance index (C-index) was used to assess the discriminative ability. Calibration curves were provided to internally validate the performance of the nomogram. Results: The nomogram finally consisted of 6 prognostic factors including age, tumor grade, AJCC N stage, carcinoembryonic antigen (CEA) levels, primary tumor resection and chemotherapy, which translated the effects of prognostic factors into certain scores to predict the 1-, 2- and 3-year CSS for the synchronous BM in CRC patients. The nomogram presented a good accuracy for predicting the CSS with the C-index of 0.742. The calibration of the nomogram predictions was also accurate. Conclusions: This nomogram was accurate enough to predict the CSS of CRC patients with synchronous BM using readily available clinicopathologic factors and could provide individualized clinical decisions for both physicians and patients.

The Distinction of Clinicopathological Characteristics, Treatment Strategy and Outcome in Colorectal Cancer Patients With Synchronous vs. Metachronous Bone Metastasis.

Background: The impact of the timing of bone metastasis (BM) diagnosis on colorectal cancer (CRC) patients is unclear. Our study aimed to explore the differences in clinicopathological characteristics, treatments and prognosis between synchronous BM (SBM) and metachronous BM (MBM) from CRC. Methods: We retrospectively investigated clinical data of CRC patients with SBM or MBM from 2008 to 2017 at Chinese National Cancer Center. Cancer specific survival (CSS) after BM diagnosis was estimated using the Kaplan-Meier method. The multivariable COX regression model identified the prognostic factors of CSS. Results: Finally, 63 CRC patients with SBM and 138 CRC patients with MBM were identified. Compared to SBM from CRC, MBM significantly was more involving multiple bone lesions (63.0 vs. 7.9%; p < 0.001), and more frequently originated from rectal cancer (60.9 vs. 41.3%; p = 0.033). The therapeutic strategies in SBM and MBM group were contrasted including systemic treatment, bisphosphonates, radiotherapy and metastasectomy for BM. 85.5% of patients in MBM group and 25.4% of patients in SBM group underwent primary tumor resection at initial diagnosis (p < 0.001). The median CSS was 11 months in both SBM and MBM group (p = 0.556), yet MBM patients developed from CRC in early AJCC stage presented obviously longer survival than those from advanced stage. Furthermore, patients could have improved CSS from primary tumor resection while there might be no survival benefit from targeted therapy in both SBM and MBM groups. Bisphosphonates was associated with a better CSS for patients with SBM, while radiotherapy for BM was related to a better CSS for patients with MBM. Conclusion: The CRC patients in SBM and MBM group represented different clinicopathological characteristics and treatment modalities, which affected the prognosis in different ways. Distinct consideration for CRC patients with SBM and MBM in clinical decision making is required.

Dynamic modeling and characteristic analysis of piezoelectric rudder actuator.

In this note, dynamic equations of the piezoelectric rudder actuator are established using a numerical method, and the dynamic characteristics are analyzed. A simulation is performed using finite element software to verify the validity of the theory. The results show that an increase in axial force has significant amplification effects on the static displacement output of the bimorph and its rudder actuator, and the axial stiffness of the piezoelectric bimorph is evidently nonlinear against larger axial force. The response time of the rudder actuator is less affected by the axial force and remains in the order of milliseconds under the axial force of 0.85 times the buckling critical load.

GGN Promotes Tumorigenesis by Regulating Proliferation and Apoptosis in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. GGN is a germ cell-specific gene, but its function in CRC has been rarely reported to date. The aim of this study was to investigate the potential role of GGN in CRC tumorigenesis. Therefore, in this study, we examined the expression of GGN in CRC cell lines and tissues and its effects on cellular proliferation and apoptosis. We then explored the underlying mechanism. Our results showed that GGN was significantly overexpressed in both CRC cell lines and tissues. Silencing GGN robustly inhibited proliferation of CRC cells, and it also promoted apoptosis of CRC cells. Moreover, knockdown of GGN inhibited the expression of p-Akt in CRC cells. Taken together, these results showed that knockdown of GGN inhibits proliferation and promotes apoptosis of CRC cells through the PI3K/Akt signaling pathway. Our findings revealed for the first time a potential oncogenic role for GGN in CRC progress. This finding may provide a unique perspective on how a germ cell-specific gene might serve as a biomarker, or even as a therapeutic target, for CRC.

Tunable dielectric transitions in layered organic-inorganic hybrid perovskite-type compounds: [NH3(CH2)2Cl]2[CdCl4-4xBr4x] (x = 0, 1/4, 1).

Molecular bistable dielectric switches represent a class of highly desirable intelligent materials due to their sensitive switchable responses, simple and environmentally friendly processing, light weights, and mechanical flexibility. However, most of these switches can only work at a very low temperature, extremely limiting their potential applications. Herein, three layered organic-inorganic hybrid perovskite-type compounds of the general formula A2BX4, [NH3(CH2)2Cl]2[CdCl3Br] (1), [NH3(CH2)2Cl]2[CdCl4] (2) and [NH3(CH2)2Cl]2[CdBr4] (3), which display sensitive dielectric switching reversibility and remarkable switching anti-fatigue, have been successfully designed. Differential scanning calorimetry and dielectric measurements for 1 confirm its reversible phase transition at around 166 K. Through anion modulation, the phase transition temperatures of 2 and 3 can be greatly improved up to 237 K and 254 K, respectively. Structural analysis discloses that the phase transition temperature's shifts may result from the differences among the inorganic frameworks. Moreover, due to the significant order-disorder transitions of ammonium cations, the permittivities of 1, 2 and 3 change abruptly at around the phase transition points, making them excellent stimuli-responsive electrical switches. Such an anion-modulated method will open up new possibilities of highly efficiently tuning the phase transition temperature of molecular bistable dielectric switches.

Sequential dielectric phase transitions induced by the vibrations of water molecules in an organic-inorganic hybrid halide (N-(2-ammoniumethyl)piperazinium) CuCl5·2H2O.

Organic-inorganic hybrids represent a new type of material showing promising properties. In this report, sequential dielectric transitions have been studied in an organic-inorganic hybrid halide, (N-2-AP)CuCl5·2H2O (N-2-AP = N-(2-ammoniumethyl)piperazinium) (1). The packing structure of 1 displays discrete [CuCl5]3- rectangular pyramids and N-2-AP cations, which are linked by two water molecules, forming infinite hydrogen bond networks with inorganic and organic components along the b-axis. Characterization studies containing differential scanning calorimetry (DSC) measurements, variable-temperature X-ray diffraction and dielectric measurements were performed to investigate the phase transitions in 1. The deuterated sample of 1 (named 2) also exhibits a similar behavior to that in 1, but shows different phase transition temperatures in dielectric transitions. The arresting deuterated effect strongly confirms that the phase transitions in 1 are attributable to the local vibrations of water molecules resulting from the variation of hydrogen-bonding interactions.

High-temperature structural phase transition coupled with dielectric switching in an organic-inorganic hybrid crystal: [NH3(CH2)2Br]3CdBr5.

Molecular bistable switches (electrical switches "ON" and "OFF") represent a class of highly desirable intelligent materials due to their sensitive switchable responses, simple and environmentally friendly processing, light weight, and mechanical flexibility. In particular, these switches above room temperature with potential practical application are rarely reported. In this work, a new zigzag chained organic-inorganic hybrid compound [NH3(CH2)2Br]3CdBr5 (1), which displays rapidly sensitive dielectric switching reversibility and remarkable switching antifatigue, has been successfully synthesized. Systematic characterization including differential scanning calorimetry measurements (DSC), dielectric measurements, and variable-temperature structural analyses was performed to reveal the phase transition of 1. A couple of reversible heat anomaly peaks at 335.6/323.8 K with a large hysteresis (ca. 11.8 K) were observed in the DSC curve, indicating the first-order type of phase transition. 1 exhibits an obvious dielectric switching at around 327 K, which makes 1 a potential switchable dielectric material. Variable-temperature structural analyses show that the cationic order-disorder motion is the main attribution for the phase transition of 1.

MicroRNA-186 promotes macrophage lipid accumulation and secretion of pro-inflammatory cytokines by targeting cystathionine γ-lyase in THP-1 macrophages.

BACKGROUND AND AIMS: Several studies suggest that cardiomyocyte-enriched miR-186 is involved in cardiac injury and myocardial infarction, and also plays an important role in atherosclerotic diseases, but the underlying mechanism is unknown. Cystathionine-γ-lyase (CSE) is the predominant enzyme to produce H2S in the cardiovascular system. Here, miR-186 was identified to bind to the 3'UTR of CSE. In this study, we aimed at exploring whether miR-186 affects lipid accumulation and secretion of pro-inflammatory cytokines by targeting CSE and its underlying mechanism in human THP-1 macrophages and peripheral blood monocyte-derived macrophages (PBMDM). PBMDM just as a control group for the comparison with the THP-1 macrophages. METHODS: MiR-186 target genes, CSE 3'UTR sequence and free energy were predicted and analyzed by bioinformatics analyses and dual-luciferase reporter assays. The expression of CSE mRNA and protein were measured by real-time quantitative PCR and western blot analyses. The lipid accumulation in THP-1 macrophages was detected by high performance liquid chromatography (HPLC). The effects of miR-186 on secretion of IL-6, IL-1ß and TNF-α were examined by ELISA. Endogenous H2S was detected by spectrophotometry. Using small interfering RNA (siRNA) approach to decrease the expression of CSE protein and mRNA. RESULTS: We found that miR-186 directly inhibited CSE protein and mRNA expression through targeting CSE 3'UTR by bioinformatics analyses and dual-luciferase reporter assays. HPLC assays showed that miR-186 increased the lipid accumulation in human THP-1 macrophages. We also showed that miR-186 enhanced secretion of pro-inflammatory cytokines in human THP-1 macrophages. Using siRNA approach, we found that CSE siRNA could inhibit the miR-186 inhibitor-induced decrease in the expression of LPL protein and mRNA in human THP-1 macrophages, which was accompanied a decrease in the level of H2S. CONCLUSIONS: MicroRNA-186 promotes macrophage lipid accumulation and pro-inflammatory cytokine secretion by targeting cystathionine γ-lyase in THP-1 macrophages.