Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer.

Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer.

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

The Machine Learning Model for Predicting Inadequate Bowel Preparation Before Colonoscopy: A Multicenter Prospective Study.

INTRODUCTION: Colonoscopy is a critical diagnostic tool for colorectal diseases; however, its effectiveness depends on adequate bowel preparation (BP). This study aimed to develop a machine learning predictive model based on Chinese adults for inadequate BP. METHODS: A multicenter prospective study was conducted on adult outpatients undergoing colonoscopy from January 2021 to May 2023. Data on patient characteristics, comorbidities, medication use, and BP quality were collected. Logistic regression and 4 machine learning models (support vector machines, decision trees, extreme gradient boosting, and bidirectional projection network) were used to identify risk factors and predict inadequate BP. RESULTS: Of 3,217 patients, 21.14% had inadequate BP. The decision trees model demonstrated the best predictive capacity with an area under the receiver operating characteristic curve of 0.80 in the validation cohort. The risk factors at the nodes included body mass index, education grade, use of simethicone, diabetes, age, history of inadequate BP, and longer interval. DISCUSSION: The decision trees model we created and the identified risk factors can be used to identify patients at higher risk of inadequate BP before colonoscopy, for whom more polyethylene glycol or auxiliary medication should be used.

Biochar and zero-valent iron alleviated sulfamethoxazole and tetracycline co-stress on the long-term system performance of bioretention cells: Insights into microbial community, antibiotic resistance genes and functional genes.

Antibiotics and antibiotic resistance genes (ARGs), known as emerging contaminants, have raised widespread concern due to their potential environmental and human health risks. In this study, a conventional bioretention cell (C-BRC) and three modified bioretention cells with biochar (BC-BRC), microbial fuel cell coupled/biochar (EBC-BRC) and zero-valent iron/biochar (Fe/BC-BRC) were established and two antibiotics, namely sulfamethoxazole (SMX) and tetracycline (TC), were introduced into the systems in order to thoroughly investigate the co-stress associated with the long-term removal of pollutants, dynamics of microbial community, ARGs and functional genes in wastewater treatment. The results demonstrated that the SMX and TC co-stress significantly inhibited the removal of total nitrogen (TN) (C-BRC: 37.46%; BC-BRC: 41.64%; EBC-BRC: 55.60%) and total phosphorous (TP) (C-BRC: 53.11%; BC-BRC: 55.36%; EBC-BRC: 62.87%) in C-BRC, BC-BRC and EBC-BRC, respectively, while Fe/BC-BRC exhibited profoundly stable and high removal efficiencies (TN: 89.33%; TP: 98.36%). Remarkably, greater than 99% removals of SMX and TC were achieved in three modified BRCs compared with C-BRC (SMX: 30.86 %; TC: 59.29%). The decreasing absolute abundances of denitrifying bacteria and the low denitrification functional genes (nirK: 2.80 × 105-5.97 × 105 copies/g; nirS: 7.22 × 105-1.69 × 106 copies/g) were responsible for the lower TN removals in C-BRC, BC-BRC and EBC-BRC. The amendment of Fe/BC successfully detoxified SMX and TC to functional bacteria. Furthermore, the co-stress of antibiotics stimulated the propagation of ARGs (sulI, sulII, tetA and tetC) in substrates of all BRCs and only Fe/BC-BRC effectively reduced all the ARGs in effluent by an order of magnitude. The findings contribute to developing robust ecological wastewater treatment technologies to simultaneously remove nutrients and multiple antibiotics.

Risk of papillary thyroid carcinoma and nodular goiter associated with exposure to semi-volatile organic compounds: A multi-pollutant assessment based on machine learning algorithms.

BACKGROUND: Exposure to semi-volatile organic compounds (SVOCs) may link to thyroid nodule risk, but studies of mixed-SVOCs exposure effects are lacking. Traditional analytical methods are inadequate for dealing with mixed exposures, while machine learning (ML) seems to be a good way to fill the gaps in the field of environmental epidemiology research. OBJECTIVES: Different ML algorithms were used to explore the relationship between mixed-SVOCs exposure and thyroid nodule. METHODS: A 1:1:1 age- and gender-matched case-control study was conducted in which 96 serum SVOCs were measured in 50 papillary thyroid carcinoma (PTC), 50 nodular goiters (NG), and 50 controls. Different ML techniques such as Random Forest, AdaBoost were selected based on their predictive power, and variables were selected based on their weights in the models. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the mixed effects of the SVOCs exposure on thyroid nodule. RESULTS: Forty-three of 96 SVOCs with detection rate >80 % were included in the analysis. ML algorithms showed a consistent selection of SVOCs associated with thyroid nodule. Fluazifop-butyl and fenpropathrin are positively associated with PTC and NG in single compound models (all P < 0.05). WQS model shows that exposure to mixed-SVOCs was associated with an increased risk of PTC and NG, with the mixture dominated by fenpropathrin, followed by fluazifop-butyl and propham. In the BKMR model, mixtures showed a significant positive association with thyroid nodule risk at high exposure levels, and fluazifop-butyl showed positive effects associated with PTC and NG. CONCLUSION: This study confirms the feasibility of ML methods for variable selection in high-dimensional complex data and showed that mixed exposure to SVOCs was associated with increased risk of PTC and NG. The observed association was primarily driven by fluazifop-butyl and fenpropathrin. The findings warranted further investigation.

Characterization of the immune cell function landscape in head and neck squamous carcinoma to assist in prognosis prediction and immunotherapy.

BACKGROUND: The malignant characteristics of cancer depend not only on intrinsic properties of cancer cells but also on the functions of infiltrating immune cells. In this study, we aimed to investigate the functional landscape of immune cells in head and neck squamous cell carcinoma (HNSCC). METHODS: We employed single-sample gene set enrichment analysis to examine the immunophenotypes of HNSCC based on 29 immune cell functions (ICFs) in TCGA and GSE65858 datasets. We analyzed the clinical features, immune microenvironment, molecular profiles, and biological processes. Additionally, we developed and validated an ICF-based risk score for personalized prognosis prediction. We confirmed the value of the ICF score in our cohort using qRT-PCR and immunohistochemistry. Molecular docking was used to predict potential compounds for immunotherapy. RESULTS: Three immunophenotypes (Immune-L, Immune-M, and Immune-H) were identified in 769 HNSCC samples. The characteristics of Immune-H were consistent with a "Hot" tumor, Immune-L was similar to a "Cold" tumor, and Immune-M exhibited intermediate features. The ICF risk score was associated with immune checkpoints, infiltrating immune cells, tumor mutation burden, and sensitivities to targeted/chemotherapeutic agents. Gene set variation analysis implicated the involvement of metabolic reprogramming pathways in the high-risk group. The combination of "Tumor Immune Dysfunction and Exclusion" and "Immunophenoscore" algorithms indicated that the low-risk group had a higher likelihood of benefiting from immunotherapy. Finally, we identified Eltrombopag and other compounds that may be beneficial for HNSCC immunotherapy. CONCLUSION: Our study provides a novel perspective on the tumor microenvironment of HNSCC, aiding in the understanding of HNSCC heterogeneity and the development of personalized/precision medicine.

Comparative study on the clinical efficacy of small plate assisted anatomic plate and traditional double plate in the treatment of Rüedi and Allgöwer II - III pilon fracture.

OBJECTIVE: The aim of this study was to investigate the clinical efficacy of small plate assisted anatomical plate and traditional double plate in the treatment of Rüedi and Allgöwer II - III pilon fracture. METHODS AND MATERIALS: The data of 68 patients with pilon fracture admitted to Hospital from June 2017 to June 2020 were retrospectively analyzed. Study group and control group were divided according to different operation methods, with 34 cases in each group. There were 28 cases of Rüedi and Allgöwer II type and 40 cases of Rüedi and Allgöwer III type. Perioperative period data, Ankle joint function score, visual analog scale (VAS) scores and the incidence of incision complications were analyzed between these two groups. RESULTS: There were no significant differences in full load time, fracture healing time between these two groups (P > 0.05). The operation time, intraoperative blood loss, length of hospital stay, Ankle joint function score and postoperative incision complication rate in observation group were lower than those in control group (P < 0.05). CONCLUSION: Small plate assisted anatomic plate is comparable to traditional double plate in the treatment of pilon fracture in terms of complete loading time, fracture healing time, but the former can shorten the operation time, reduce intraoperative blood loss and effectively reduce the incidence of postoperative complications.

Impact of progesterone concentration on human chorionic gonadotropin trigger day on clinical outcomes with one top-quality cleavage-stage embryo or blastocyst transfer in fresh in vitro fertilization cycles.

Objective: To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol. Methods: The retrospective cohort study included a total of 1,550 fresh autologous ART cycles with one top-quality embryo transfer. Multivariate regression analysis, curve fitting, and threshold effect analysis were performed. Results: A significant association was found between the progesterone concentration and clinical pregnancy rate (adjusted OR, 0.77; 95% CI, 0.62-0.97; P = 0.0234), especially in blastocyst transfer (adjusted OR, 0.56; 95% CI, 0.39-0.78; P = 0.0008). The association between the progesterone concentration and the ongoing pregnancy rate was insignificant. The clinical pregnancy rate showed a linear relationship with an increased progesterone concentration in cleavage-stage embryo transfer. In blastocyst transfer, as the progesterone concentration increased, the clinical and ongoing pregnancy rates showed a parabolic reverse-U curve; the curve initially increased before declining at high progesterone concentrations. The clinical pregnancy rate increased with a progesterone concentration up to 0.80 ng/mL rather than tended to be stable. The clinical pregnancy rate significantly decreased when the progesterone concentration was ≥0.80 ng/mL. Conclusion: The progesterone concentration on the hCG trigger day exhibits a curvilinear relationship with pregnancy outcomes in blastocyst transfer cycles, and the optimal threshold of the progesterone concentration is 0.80 ng/mL.

Hypoxia-induced reprogramming of glucose-dependent metabolic pathways maintains the stemness of human bone marrow-derived endothelial progenitor cells.

The benefits of hypoxia for maintaining the stemness of cultured human bone marrow-derived endothelial progenitor cells (BM EPCs) have previously been demonstrated but the mechanisms responsible remain unclear. Growing evidences suggest that cellular metabolism plays an important role in regulating stem cell fate and self-renewal. Here we aimed to detect the changes of glucose metabolism and to explore its role on maintaining the stemness of BM EPCs under hypoxia. We identified the metabolic status of BM EPCs by using extracellular flux analysis, LC-MS/MS, and 13C tracing HPLC-QE-MS, and found that hypoxia induced glucose metabolic reprogramming, which manifested as increased glycolysis and pentose phosphate pathway (PPP), decreased tricarboxylic acid (TCA) and mitochondrial respiration. We further pharmacologically altered the metabolic status of cells by employing various of inhibitors of key enzymes of glycolysis, PPP, TCA cycle and mitochondria electron transport chain (ETC). We found that inhibiting glycolysis or PPP impaired cell proliferation either under normoxia or hypoxia. On the contrary, inhibiting pyruvate oxidation, TCA or ETC promoted cell proliferation under normoxia mimicking hypoxic conditions. Moreover, promoting pyruvate oxidation reverses the maintenance effect of hypoxia on cell stemness. Taken together, our data suggest that hypoxia induced glucose metabolic reprogramming maintains the stemness of BM EPCs, and artificial manipulation of cell metabolism can be an effective way for regulating the stemness of BM EPCs, thereby improving the efficiency of cell expansion in vitro.

Novel Aggregation-Induced Emission Fluorescent Molecule for Platinum(IV) Ion-Selective Recognition and Imaging of Controlled Release in Cells.

The loading, delivery, and release of Pt(IV) precursors in living organisms are important aspects of exploring the development of platinum drugs. In recent years, the biological application of the fluorescent sensors to platinum drugs has been insufficient to meet the study of Pt(IV) precursors. It is urgent to design and develop a biocompatible, multifunctional fluorescent sensor for the study of loading, transport, and release of Pt(IV) ions. Herein, we report a fluorescent molecule (E)-6-(diethylamino)-N'-(4-(diphenylamino) benzylidene)-2-oxo-2H-chromene-3 carbohydrazide (CHTPA). CHTPA has good sensitivity and selectivity to Pt(IV) when the water content is 5%, and significant increase of the fluorescence emission intensity of CHTPA is observed with Pt(IV) concentration. The sensing mechanism is attributed to photo-induced electron transfer, which is verified by X-ray absorption near edge spectroscopy spectra, UV-vis absorption spectroscopy, 1H NMR spectra, and Fourier transform infrared spectra. Furthermore, the CHTPA-Pt(IV) complex is able to release Pt(IV) in aqueous solution, and the green fluorescence of CHTPA based on the aggregation-induced emission effect can be observed. Inspired by these, the amphiphilic block copolymer poly(ethyloxide)-block-polystyrene (PEO-b-PS) is used to prepare the nonconjugated polymer dots (Pdots). The experimental results show that Pdots can effectively slow down the release speed of Pt(IV) in aqueous solution and it has a great monodispersity in aqueous solution. Meanwhile, Pdots show low cytotoxicity, and this is favorable for intracellular applications. The investigation of cellular imaging indicates that these Pdots can act as a carrier to deliver Pt(IV) into MCF-7 cells for visualized delivery and sustained release of platinum(IV) ions. Therefore, this study provides a new avenue to design and develop a biocompatible multifunctional fluorescent sensor for studying the loading, delivery, and release of Pt(IV) in cells.

Endoscopic and clinicopathologic features of early gastric signet ring cell carcinoma ≤20 mm: a retrospective observational study.

OBJECTIVES: Limited literature exists on the characteristics of early gastric signet ring cell carcinoma (GSRCC) within 20 mm. This study aimed to explore this type of cancer from several aspects, to provide guidance for early detection and intervention of GSRCC. METHODS: We retrospectively collected data from 24 patients diagnosed with early GSRCC ≤20 mm in Beijing Friendship Hospital from 2016 to 2021. According to tumor size, those lesions were divided into three groups: diminutive group (1-5 mm, n = 4), small group (6-10 mm, n = 12) and intermediate group (11-20 mm, n = 8). The clinicopathologic and endoscopic characteristics of GSRCC were compared among the three groups. RESULTS: Treatment strategies for lesions differed according to the size (p<.05). There were no significant differences among the three groups with regard to age, sex, Helicobacter pylori infection, tumor location and macroscopic type. Lesions were often flat type and more likely to present with discoloration, uneven color, ulceration and submucosal invasion with the increase of diameter. Almost all cases showed abnormal intervening part (IP) under magnifying endoscopy. CONCLUSIONS: The location of early signet ring cell carcinoma is not specific, and the diminutive lesions are often flat. Abnormal IP may be the early endoscopic feature of early GSRCC.

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells.

Haematopoietic stem cells (HSCs) home to the bone marrow via, in part, interactions with vascular cell adhesion molecule-1 (VCAM1)1-3. Once in the bone marrow, HSCs are vetted by perivascular phagocytes to ensure their self-integrity. Here we show that VCAM1 is also expressed on healthy HSCs and upregulated on leukaemic stem cells (LSCs), where it serves as a quality-control checkpoint for entry into bone marrow by providing 'don't-eat-me' stamping in the context of major histocompatibility complex class-I (MHC-I) presentation. Although haplotype-mismatched HSCs can engraft, Vcam1 deletion, in the setting of haplotype mismatch, leads to impaired haematopoietic recovery due to HSC clearance by mononuclear phagocytes. Mechanistically, VCAM1 'don't-eat-me' activity is regulated by ß2-microglobulin MHC presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. VCAM1 is also used by cancer cells to escape immune detection as its expression is upregulated in multiple cancers, including acute myeloid leukaemia (AML), where high expression associates with poor prognosis. In AML, VCAM1 promotes disease progression, whereas VCAM1 inhibition or deletion reduces leukaemia burden and extends survival. These results suggest that VCAM1 engagement regulates a critical immune-checkpoint gate in the bone marrow, and offers an alternative strategy to eliminate cancer cells via modulation of the innate immune tolerance.

Classification and Diagnosis of Residual Thyroid Tissue in SPECT Images Based on Fine-Tuning Deep Convolutional Neural Network.

Patients with thyroid cancer will take a small dose of 131I after undergoing a total thyroidectomy. Single-photon emission computed tomography (SPECT) is used to diagnose whether thyroid tissue remains in the body. However, it is difficult for human eyes to observe the specificity of SPECT images in different categories, and it is difficult for doctors to accurately diagnose the residual thyroid tissue in patients based on SPECT images. At present, the research on the classification of thyroid tissue residues after thyroidectomy is still in a blank state. This paper proposes a ResNet-18 fine-tuning method based on the convolutional neural network model. First, preprocess the SPECT images to improve the image quality and remove background interference. Secondly, use the preprocessed image samples to fine-tune the pretrained ResNet-18 model to obtain better features and finally use the Softmax classifier to diagnose the residual thyroid tissue. The method has been tested on SPECT images of 446 patients collected by local hospital and compared with the widely used lightweight network SqueezeNet model and ShuffleNetV2 model. Due to the small data set, this paper conducted 10 random grouping experiments. Each experiment divided the data set into training set and test set at a ratio of 3:1. The accuracy and sensitivity rates of the model proposed in this paper are 96.69% and 94.75%, which are significantly higher than other models (p < 0.05). The specificity and precision rates are 99.6% and 99.96%, respectively, and there is no significant difference compared with other models. (p > 0.05). The area under the curve of the proposed model, SqueezeNet, and ShuffleNetv2 are 0.988 (95% CI, 0.941-1.000), 0.898 (95% CI, 0.819-0.951) (p = 0.0257), and 0.885 (95% CI, 0.803-0.941) (p = 0.0057) (p < 0.05). We prove that this thyroid tissue residue classification system can be used as a computer-aided diagnosis method to effectively improve the diagnostic accuracy of thyroid tissue residues. While more accurately diagnosing patients with residual thyroid tissue in the body, we try our best to avoid the occurrence of overtreatment, which reflects its potential clinical application value.

Circ_0058106 promotes proliferation, metastasis and EMT process by regulating Wnt2b/ß-catenin/c-Myc pathway through miR-185-3p in hypopharyngeal squamous cell carcinoma.

Hypopharyngeal squamous cell carcinoma (HSCC) accounts 95% of hypopharyngeal cancer, which is characterized by high early metastasis rate and poor prognosis. It is reported that circular RNA is involved in the occurrence and development of cancer; however, the role of circRNA in hypopharyngeal cancer has little been investigated. We performed hypopharyngeal carcinoma circRNA microarray and qRT-PCR verification. The results showed circ_0058106 expression level was significantly upregulated in tumor tissues than in corresponding normal tissues. We found that circ_0058106 upregulation promoted proliferation, migration and invasion of HSCC cells, while knockdown of circ_0058106 inhibited proliferation, migration and invasion of HSCC cells both in vitro and in vivo. Bioinformatics predicted circ_0058106 may interact with miR-185-3p. We verified circ_0058106 directly bound miR-185-3p and downregulated miR-185-3p expression by using dual-luciferase reporter assay and qRT-PCR. Moreover, we proved circ_0058106 promoted HSCC cells tumorigenesis and EMT process by regulating Wnt2b/ß-catenin/c-Myc pathway via miR-185-3p. In conclusion, our findings firstly confirmed the carcinogenic effect of circ_0058106 in promoting HSCC cells tumorigenesis, metastasis, invasion and EMT process by regulating Wnt2b/ß-catenin/c-Myc pathway through sponging miR-185-3p, indicating that circ_0058106 may be a new therapeutic target and prognostic marker for HSCC.

MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells.

Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. The mechanisms by which these critical activities are balanced are still unclear. Here, we report that Macrophage-Erythroblast Attacher (MAEA, also known as EMP), a receptor thus far only identified in erythroblastic island, is a membrane-associated E3 ubiquitin ligase subunit essential for HSC maintenance and lymphoid potential. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and leads to a lethal myeloproliferative syndrome. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in the absence of Maea, thereby prolonging their intracellular signalling. This is associated with impaired autophagy flux in HSCs but not in mature haematopoietic cells. Administration of receptor kinase inhibitor or autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. Our results suggest that MAEA provides E3 ubiquitin ligase activity, guarding HSC function by restricting cytokine receptor signalling via autophagy.

Long noncoding RNA LINC01296 plays an oncogenic role in colorectal cancer by suppressing p15 expression.

OBJECTIVE: To examine the role of the long noncoding RNA LINC01296 in colorectal carcinoma (CRC) and to explore the underlying mechanism. METHODS: We detected LINC01296 expression levels in a cohort of 51 paired CRC and normal tissues. We also assessed the effects of LINC01296 on cell proliferation and apoptosis in CRC cells in vitro, and measured its effect on tumor growth in an in vivo mouse model. We identified the potential downstream targets of LINC01296 and assessed its regulatory effects. RESULTS: Expression levels of LINC01296 were elevated in 37/51 CRC tissues compared with the corresponding normal tissues and were significantly associated with tumor stage, lymph node metastasis, and distant metastasis. Knockdown of LINC01296 using antisense oligonucleotides inhibited cell proliferation and promoted apoptosis of colon cancer cells in vitro and inhibited tumor growth in vivo. Knockdown of LINC01296 also significantly increased the gene expression of p15 in colon cancer cells. LINC01296-specific suppression of p15 was validated by the interaction between enhancer of zeste homolog 2 and LINC01296. CONCLUSION: Overexpression of LINC01296 suppressed the expression of p15 leading to CRC carcinogenesis. These findings may provide the basis for novel future CRC-targeted therapies.

The profiling of elements and pesticides in surface water in Nanjing, China with global comparisons.

The study on high-throughput determination covering various kinds of elements and pesticides in surface water is rarely reported. The surface water samples were collected from the Yangtze River, the Qinhuai River and the Xuanwu Lake in Nanjing which is a large and populous city in eastern China, and elementome (47 elements) and pesticide exposome (60 pesticides) were profiled, which were characterized by univariate and multivariate statistical analysis, literature comparison, and risk assessment. A total of 47 elements and 47 pesticides were detectable. By combining the results of univariate and multivariate statistical analysis, we consistently found that the levels of elements in the Qinhuai River were relatively higher than those in the Yangtze River and the Xuanwu Lake, mainly including rare earth elements and macroelements. The concentrations of isoprocarb, profenofos and simazine in the Yangtze River were relatively higher than those in the Qinhuai River and the Xuanwu Lake. Based on literature search and our data, the results about global element and pesticide concentrations in surface water were summarized. The surface water in Nanjing showed notably higher aluminum level when compared to the level around the world. The risk assessment suggested that arsenic posed a considerable carcinogenic risk. This study provided a large volume of first-hand information about the profiles of elements and pesticides in surface water, which can be used for warning of surface water pollution and preventing potential hazardous effect on public health.

The Effects of Endometrial Thickness on Pregnancy Outcomes of Fresh IVF/ICSI Embryo Transfer Cycles: An Analysis of Over 40,000 Cycles Among Five Reproductive Centers in China.

Objective: To investigate the effects of endometrial thickness (EMT) on pregnancy outcomes on hCG trigger day in fresh in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. Methods: A total of 42,132 fresh cycles between 1 January 2013 and 31 December 2019 were included in this retrospective cohort study. Data were collected from five reproductive centers of large academic or university hospitals in China. All patients were divided into different groups according to their endometrial thickness on hCG trigger day. Multivariate regression analysis, curve fitting and threshold effect analysis were performed. Results: After adjusting for age, body mass index, infertility type, number of embryos transferred, number of retrieved oocytes and COS (controlled ovarian stimulation) protocols, significant associations were found between endometrial thickness and clinical pregnancy rate (adjusted odds ratio [aOR]: 1.05; 95% confidence interval [CI]: 1.06-1.08, P < 0.0001), live birth rate (aOR: 1.04; 95% CI: 1.03-1.05, P < 0.0001) as well as miscarriage rate(aOR: 0.96; 95% CI: 0.94 - 0.98, P < 0.0001). When the endometrial thickness was less than 12mm, the clinical pregnancy rate and live birth rate were increased significantly by 10% and 9%(OR:1.10; 95%CI: 1.08-1.12, OR:1.09; 95%CI: 1.07-1.11), respectively, along with the increase of each millimeter increment of endometrial thickness. However, when the EMT ranged from 12-15 mm, were stable at the ideal level, that were not significantly associated with EMT growth. Additionally, clinical pregnancy rate and live birth rate were slightly reduced by 6% and 4% when EMT was ≥15mm. Meanwhile, the miscarriage rate was significantly declined by 8% (OR:0.92; 95%CI: 0.90-0.95)with each millimeter increment of EMT. And when EMT was thicker than 12mm, the miscarriage rate didn't change any more significantly. Conclusions: Endometrial thickness exhibits a curvilinear relationship with pregnancy outcomes in fresh embryo transfer cycles. Clinical pregnancy rate, live birth rate and miscarriage rate may achieve their optimal level when EMT ≥ 12 mm, but some adverse pregnancy outcomes would be observed when EMT ≥15 mm especially for clinical pregnancy.

Lymphocyte-activated gene-3 (LAG3) protein expressed in tumor-infiltrating lymphocytes of colorectal cancer.

Immunotherapy can reverse tumor immune escape by suppressing immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an important checkpoint and its role in colorectal cancer is not clear. In this study, we investigated LAG3 protein expression and its correlation with clinicopathologic parameters. The expression of LAG3 protein was assessed in 150 surgically resected colorectal cancer tissue samples by immunohistochemistry. The relationship between LAG3 expression and clinicopathological parameters, MSI status and survival was statistically analyzed. LAG3 protein was not expressed in colorectal cancer cells, and was expressed on the tumor-infiltrating lymphocytes (TILs) in 31 out of 150 (20.7%) colorectal cancer samples. Positive expression of LAG3 in TILs is associated with lymph node metastasis (p < 0.001), TNM stage (p = 0.024) and MSI-H (p = 0.035). No significant relationship was found between LAG3 expression and gender, age, tumor location, tumor invasion depth, and differentiation. LAG3 expression is associated with longer overall survival (p = 0.045). Our data show LAG3 expression on TILs in parts of CRC tissue. Positive expression of LAG3 was associated with advanced tumor stage, MSI-H and a poor prognosis. We conclude that LAG3 is an important checkpoint gene in CRC and may be a potential marker for prognosis of CRC.