Endothelial cell specific molecule 1 promotes epithelial-mesenchymal transition of cervical cancer via the E-box binding homeobox 1.

OBJECTIVE: To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger E-box binding homeobox 1 (ZEB1)/EMT pathway. METHODS: The correlation between ESM1 expression and prognosis of cervical cancer patients was analyzed by bioinformatics. SiHa, HeLa cell lines and corresponding control cell lines with stable ESM1 expression were obtained. Cell proliferation ability was detected by CCK-8 assay. The invasion and migration ability of Hela and SiHa cells were detected by Transwell assay and scratch closure assay. Expressions of EMT-related markers E-cadherin and Vimentin were detected by real-time PCR. The ability of silenced ESM1 to tumor formation in vivo was detected by tumor formation in nude mice. The effects of aloe-emodin on inhibit ESM1 expression and its inhibitory effect on cervical cancer cells in vitro and in vivo were analyzed by the same method. RESULTS: ESM1 was highly expressed in cervical cancer, and the high expression of ESM1 was associated with poor prognosis of cervical cancer patients. CCK-8 results showed that the proliferation, invasion and migration of Hela and SiHa cells were significantly reduced after siRNA interfered with ESM1 expression. Overexpression of ESM1 promoted the proliferation and migration of cervical cancer cells. Mechanism studies have shown that the oncogenic effect of ESM1 is realized through the ZEB1/PI3K/AKT pathway. High throughput drug screening found that aloe-emodin can target ESM1. Inhibitory effect of aloe emodin on ESM1/ZEB1/EMT signaling pathway and cervical cancer cells. CONCLUSION: The silencing of ESM1 expression may inhibit the proliferation, invasion, metastasis and epithelial-mesenchymal transformation of cervical cancer cells by inhibiting ZEB1/PI3K/AKT. Aloe-emodin is a potential treatment for cervical cancer, which can play an anti-tumor role by inhibiting ESM1/ZEB1.

Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Effects of Saponins on Lipid Metabolism: The Gut-Liver Axis Plays a Key Role.

Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut-liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives-short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut-liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.

Evaluating the use of three-dimensional reconstruction visualization technology for precise laparoscopic resection in gastroesophageal junction cancer.

BACKGROUND: Laparoscopic gastrectomy for esophagogastric junction (EGJ) carcinoma enables the removal of the carcinoma at the junction between the stomach and esophagus while preserving the gastric function, thereby providing patients with better treatment outcomes and quality of life. Nonetheless, this surgical technique also presents some challenges and limitations. Therefore, three-dimensional reconstruction visualization technology (3D RVT) has been introduced into the procedure, providing doctors with more comprehensive and intuitive anatomical information that helps with surgical planning, navigation, and outcome evaluation. AIM: To discuss the application and advantages of 3D RVT in precise laparoscopic resection of EGJ carcinomas. METHODS: Data were obtained from the electronic or paper-based medical records at The First Affiliated Hospital of Hebei North University from January 2020 to June 2022. A total of 120 patients diagnosed with EGJ carcinoma were included in the study. Of these, 68 underwent laparoscopic resection after computed tomography (CT)-enhanced scanning and were categorized into the 2D group, whereas 52 underwent laparoscopic resection after CT-enhanced scanning and 3D RVT and were categorized into the 3D group. This study had two outcome measures: the deviation between tumor-related factors (such as maximum tumor diameter and infiltration length) in 3D RVT and clinical reality, and surgical outcome indicators (such as operative time, intraoperative blood loss, number of lymph node dissections, R0 resection rate, postoperative hospital stay, postoperative gas discharge time, drainage tube removal time, and related complications) between the 2D and 3D groups. RESULTS: Among patients included in the 3D group, 27 had a maximum tumor diameter of less than 3 cm, whereas 25 had a diameter of 3 cm or more. In actual surgical observations, 24 had a diameter of less than 3 cm, whereas 28 had a diameter of 3 cm or more. The findings were consistent between the two methods (χ2 = 0.346, P = 0.556), with a kappa consistency coefficient of 0.808. With respect to infiltration length, in the 3D group, 23 patients had a length of less than 5 cm, whereas 29 had a length of 5 cm or more. In actual surgical observations, 20 cases had a length of less than 5 cm, whereas 32 had a length of 5 cm or more. The findings were consistent between the two methods (χ2 = 0.357, P = 0.550), with a kappa consistency coefficient of 0.486. Pearson correlation analysis showed that the maximum tumor diameter and infiltration length measured using 3D RVT were positively correlated with clinical observations during surgery (r = 0.814 and 0.490, both P < 0.05). The 3D group had a shorter operative time (157.02 ± 8.38 vs 183.16 ± 23.87), less intraoperative blood loss (83.65 ± 14.22 vs 110.94 ± 22.05), and higher number of lymph node dissections (28.98 ± 2.82 vs 23.56 ± 2.77) and R0 resection rate (80.77% vs 61.64%) than the 2D group. Furthermore, the 3D group had shorter hospital stay [8 (8, 9) vs 13 (14, 16)], time to gas passage [3 (3, 4) vs 4 (5, 5)], and drainage tube removal time [4 (4, 5) vs 6 (6, 7)] than the 2D group. The complication rate was lower in the 3D group (11.54%) than in the 2D group (26.47%) (χ2 = 4.106, P < 0.05). CONCLUSION: Using 3D RVT, doctors can gain a more comprehensive and intuitive understanding of the anatomy and related lesions of EGJ carcinomas, thus enabling more accurate surgical planning.

Dual­regulated oncolytic adenovirus carrying ERCC1­siRNA gene possesses potent antitumor effect on ovarian cancer cells.

Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying ERCC1 short interfering (si)RNA, regulated by hTERT and HIF promoters, termed Ad­siERCC1. The findings demonstrated that this oncolytic adenovirus effectively inhibits the proliferation, migration and invasion of ovarian cancer cells. Furthermore, the downregulation of ERCC1 expression by siRNA ameliorates drug resistance to cisplatin (DDP) chemotherapy. It was found that Ad­siERCC1 blocks the cell cycle in the G1 phase and enhances apoptosis through the PI3K/AKT­caspase­3 signaling pathways in SKOV3 cells. The results of the present study highlighted the critical effect of oncolytic virus Ad­siERCC1 in inhibiting the survival of ovarian cancer cells and increasing chemotherapy sensitivity to DDP. These findings underscore the potent antitumor effect of Ad­siERCC1 on ovarian cancers in vivo.

Association of circulating long-chain free fatty acids and incident diabetes risk among normoglycemic Chinese adults: a prospective nested case-control study.

BACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking. OBJECTIVES: Our study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18-26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

TMBstable: a variant caller controls performance variation across heterogeneous sequencing samples.

In cancer genomics, variant calling has advanced, but traditional mean accuracy evaluations are inadequate for biomarkers like tumor mutation burden, which vary significantly across samples, affecting immunotherapy patient selection and threshold settings. In this study, we introduce TMBstable, an innovative method that dynamically selects optimal variant calling strategies for specific genomic regions using a meta-learning framework, distinguishing it from traditional callers with uniform sample-wide strategies. The process begins with segmenting the sample into windows and extracting meta-features for clustering, followed by using a pre-trained meta-model to select suitable algorithms for each cluster, thereby addressing strategy-sample mismatches, reducing performance fluctuations and ensuring consistent performance across various samples. We evaluated TMBstable using both simulated and real non-small cell lung cancer and nasopharyngeal carcinoma samples, comparing it with advanced callers. The assessment, focusing on stability measures, such as the variance and coefficient of variation in false positive rate, false negative rate, precision and recall, involved 300 simulated and 106 real tumor samples. Benchmark results showed TMBstable's superior stability with the lowest variance and coefficient of variation across performance metrics, highlighting its effectiveness in analyzing the counting-based biomarker. The TMBstable algorithm can be accessed at https://github.com/hello-json/TMBstable for academic usage only.

DeepLION2: deep multi-instance contrastive learning framework enhancing the prediction of cancer-associated T cell receptors by attention strategy on motifs.

Introduction: T cell receptor (TCR) repertoires provide valuable insights into complex human diseases, including cancers. Recent advancements in immune sequencing technology have significantly improved our understanding of TCR repertoire. Some computational methods have been devised to identify cancer-associated TCRs and enable cancer detection using TCR sequencing data. However, the existing methods are often limited by their inadequate consideration of the correlations among TCRs within a repertoire, hindering the identification of crucial TCRs. Additionally, the sparsity of cancer-associated TCR distribution presents a challenge in accurate prediction. Methods: To address these issues, we presented DeepLION2, an innovative deep multi-instance contrastive learning framework specifically designed to enhance cancer-associated TCR prediction. DeepLION2 leveraged content-based sparse self-attention, focusing on the top k related TCRs for each TCR, to effectively model inter-TCR correlations. Furthermore, it adopted a contrastive learning strategy for bootstrapping parameter updates of the attention matrix, preventing the model from fixating on non-cancer-associated TCRs. Results: Extensive experimentation on diverse patient cohorts, encompassing over ten cancer types, demonstrated that DeepLION2 significantly outperformed current state-of-the-art methods in terms of accuracy, sensitivity, specificity, Matthews correlation coefficient, and area under the curve (AUC). Notably, DeepLION2 achieved impressive AUC values of 0.933, 0.880, and 0.763 on thyroid, lung, and gastrointestinal cancer cohorts, respectively. Furthermore, it effectively identified cancer-associated TCRs along with their key motifs, highlighting the amino acids that play a crucial role in TCR-peptide binding. Conclusion: These compelling results underscore DeepLION2's potential for enhancing cancer detection and facilitating personalized cancer immunotherapy. DeepLION2 is publicly available on GitHub, at https://github.com/Bioinformatics7181/DeepLION2, for academic use only.

Surgical stress induced tumor immune suppressive environment.

Despite significant advances in cancer treatment over the decades, surgical resection remains a prominent management approach for solid neoplasms. Unfortunately, accumulating evidence suggests that surgical stress caused by tumor resection may potentially trigger postoperative metastatic niche formation. Surgical stress not only activates the sympathetic-adrenomedullary axis and hypothalamic-pituitary-adrenocortical axis but also induces hypoxia and hypercoagulable state. These adverse factors can negatively impact the immune system by downregulating immune effector cells and upregulating immune suppressor cells, which contribute to the colonization and progression of postoperative tumor metastatic niche. This review summarizes the effects of surgical stress on four types of immune effector cells (neutrophils, macrophages, natural killer cells and cytotoxic T lymphocytes) and two types of immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells), and discusses the immune mechanisms of postoperative tumor relapse and progression. Additionally, relevant therapeutic strategies to minimize the pro-tumorigenic effects of surgical stress are elucidated.

Learning from circadian rhythm to transform cancer prevention, prognosis, and survivorship care.

Circadian timekeeping mechanisms and cell cycle regulation share thematic biological principles in responding to signals, repairing cellular damage, coordinating metabolism, and allocating cellular resources for optimal function. Recent studies show interactions between cell cycle regulators and circadian clock components, offering insights into potential cancer treatment approaches. Understanding circadian control of metabolism informs timing for therapies to reduce adverse effects and enhance treatment efficacy. Circadian adaptability to lifestyle factors, such as activity, sleep, and nutrition sheds light on their impact on cancer. Leveraging circadian regulatory mechanisms for cancer prevention and care is vital, as most risk stems from modifiable lifestyles. Monitoring circadian factors aids risk assessment and targeted interventions across the cancer care continuum.

Hydrogen sulfide inhibits alveolar type II cell senescence and limits pulmonary fibrosis via promoting MDM2-mediated p53 degradation.

AIM: Senescence of alveolar type II (AT2) cells is an important driver of pulmonary fibrosis. This study aimed to investigate whether and how dysregulation of hydrogen sulfide (H2 S) production affected AT2 cell senescence, and then explored the effect of H2 S on the communication between AT2 and fibroblasts. METHODS: ICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 µmol/kg/d) was intraperitoneally injected for 2 weeks. The H2 S-generating enzyme cystathionine-ß-synthase (CBS) knockout heterozygous (CBS+/- ) mice were used as a low H2 S production model. RESULTS: Analysis of microarray datasets revealed downregulation of H2 S-generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H2 S production was correlated with higher levels of cell senescence markers p53 and p21 in bleomycin-induced lung fibrosis. CBS+/- mice exhibited increased levels of p53 and p21. The numbers of AT2 cells positive for p53 and p21 were increased in CBS+/- mice as compared to control mice. H2 S donor NaHS attenuated bleomycin-induced AT2 cell senescence both in vivo and in vitro. H2 S donor suppressed bleomycin-induced senescence-associated secretory phenotype (SASP) of AT2 cells via inhibiting p53/p21 pathway, consequently suppressing proliferation and myofibroblast transdifferentiation of fibroblasts. Mechanically, H2 S suppressed p53 expression by enhancing the mouse double-minute 2 homologue (MDM2)-mediated ubiquitination and degradation of p53. CONCLUSION: H2 S inactivated p53-p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H2 S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts.

Long-lasting complete response to SHR-1701 plus famitinib in refractory advanced gallbladder cancer: A case report.

Biliary tract cancer (BTC) is an aggressive malignancy with few options for advanced-stage treatment. The combination of PD-1/PD-L1 inhibitors with famitinib, a receptor tyrosine kinase (RTK) inhibitor, has demonstrated improved clinical outcomes in several clinical trials. We herein reported a case of a gallbladder cancer (GBC) patient with liver metastases, previously resistant to traditional chemotherapy. Remarkably, the patient achieved a complete response (CR) with a long-lasting survival benefit exceeding 3 years. This was achieved using a novel regimen combining SHR-1701, an anti-PD-L1/TGF-ßR fusion protein, and famitinib, even though the patient had proficient mismatch repair (pMMR) and tested negative for PD-L1. Adverse events were limited and manageable. This is the first report of such a treatment regimen being applied in a clinical setting, suggesting that the SHR-1701 and famitinib combination may be a promising immunotherapeutic approach for patients with refractory advanced GBC.

Alfalfa leaf meal as a new protein feedstuff improves meat quality by modulating lipid metabolism and antioxidant capacity of finishing pigs.

The effects of alfalfa leaf meal (ALM) on the meat quality of finishing pigs are largely unknown. Here, we investigated the effects of ALM diet on meat quality by replacing 0%, 25%, 50%, and 75% of soybean meal in the diet of finishing pigs, respectively. The findings showed that 25% ALM diet increased the IMF, cooked meat rate, a* and antioxidant capacity of longissimus dorsi (LD), improved amino acid composition, increased MUFA content, and increased LD lipid synthesis and mRNA expression of antioxidation-related genes. At the same time, ALM diet altered serum lipid metabolism (TG, FFA). Correlation analysis showed that antioxidant capacity was positively correlated with meat quality. In addition, metabolomic analysis of LD showed that the main metabolites of 25% ALM diet altered stachydrine and l-carnitine were associated with meat quality and antioxidant capacity. In conclusion, ALM replacing 25% soybean meal diet can improve the meat quality of pigs.

Pachymic acid suppresses the inflammatory response of chondrocytes and alleviates the progression of osteoarthritis via regulating the Sirtuin 6/NF-κB signal axis.

Articular cartilage degeneration is a characteristic pathological change of osteoarthritis (OA). Pachymic acid (PA) is an active ingredient found in Poria cocos. Previous studies have shown that PA has anti-inflammatory effects on a variety of diseases. However, the role of PA in OA and its underlying mechanisms has not been clearly elucidated. In this study, we investigated potential protective effect of PA on OA through cell experiments in vitro and animal experiments in vivo. PA inhibited interleukin-1ß-induced inflammatory mediator production in chondrocytes, which includes nitric oxide, inducible nitric oxide synthase, prostaglandin E2, cyclooxygenase-2, tumor necrosis factor alpha and interleukin-6. Meanwhile, PA also reversed the up-regulation of matrix metalloproteinase-3 and thrombospondin motifs 5, and the down-regulation of collagen type II and aggrecan in IL-1ß-treated chondrocytes. Mechanistically, our findings revealed that PA-mediated overexpression of SIRT6 inhibited the NF-κB signaling pathway. In vivo, PA contributes to improve cartilage damage in the mouse OA model. In summary, PA inhibited IL-1ß-induced inflammation and extracellular matrix degeneration by promoting SIRT6 expression and inhibiting the NF-κB signaling pathway, which indicates that PA is beneficial for the treatment of OA.

Elastic modulus-reflected liver lesion stiffness relates to worse prognosis in pancreatic cancer patients with liver metastasis.

BACKGROUND: Liver stiffness relates to more advanced tumor status and poor outcomes in primary liver cancer, while its prognostic role in pancreatic cancer with liver metastasis is unclear. Therefore, the current study aimed to explore the correlation of elastic modulus (EM)-reflected liver lesion stiffness with clinical characteristics, tumor markers, and survival among pancreatic cancer patients with liver metastasis. METHODS: Fifty-four pancreatic cancer patients with liver metastasis were enrolled, and the EM of liver metastasis and peripheral liver tissue was measured by two-dimensional shear wave elastography. Relative EM was calculated as the ratio of EM in liver metastasis to that in peripheral liver tissue, which reflected the relative liver lesion stiffness. RESULTS: The median relative EM of liver metastasis was 7.8 (interquartile range: 4.8-10.7) folds. Relative EM of liver metastasis was correlated with primary pancreatic cancer location (P = 0.048), the presence of extra lung metastasis (P = 0.040), liver metastasis ≥ 3 cm (P = 0.007), and the absence of extraskeletal metastasis (P = 0.036); but it was not correlated with tumor markers such as CA199, CA125, or CEA (all P > 0.05). Encouragingly, high relative EM of liver metastasis (cut off by median value) was correlated with poor progression-free survival (PFS) (P = 0.032) but not overall survival (OS) (P = 0.285). Multivariable Cox analysis showed that high relative EM of liver metastasis (hazard ratio (HR) = 1.768, P = 0.048) and multiple metastases (HR = 2.262, P = 0.036) independently predicted decreased PFS, but only abnormal CEA independently forecasted decreased OS (HR = 2.390, P = 0.027). CONCLUSION: Elastic modulus reflected liver lesion stiffness may predict a worse prognosis in pancreatic cancer patients with liver metastasis.

An independent evaluation in a CRC patient cohort of microbiome 16S rRNA sequence analysis methods: OTU clustering, DADA2, and Deblur.

16S rRNA is the universal gene of microbes, and it is often used as a target gene to obtain profiles of microbial communities via next-generation sequencing (NGS) technology. Traditionally, sequences are clustered into operational taxonomic units (OTUs) at a 97% threshold based on the taxonomic standard using 16S rRNA, and methods for the reduction of sequencing errors are bypassed, which may lead to false classification units. Several denoising algorithms have been published to solve this problem, such as DADA2 and Deblur, which can correct sequencing errors at single-nucleotide resolution by generating amplicon sequence variants (ASVs). As high-resolution ASVs are becoming more popular than OTUs and only one analysis method is usually selected in a particular study, there is a need for a thorough comparison of OTU clustering and denoising pipelines. In this study, three of the most widely used 16S rRNA methods (two denoising algorithms, DADA2 and Deblur, along with de novo OTU clustering) were thoroughly compared using 16S rRNA amplification sequencing data generated from 358 clinical stool samples from the Colorectal Cancer (CRC) Screening Cohort. Our findings indicated that all approaches led to similar taxonomic profiles (with P > 0.05 in PERMNAOVA and P <0.001 in the Mantel test), although the number of ASVs/OTUs and the alpha-diversity indices varied considerably. Despite considerable differences in disease-related markers identified, disease-related analysis showed that all methods could result in similar conclusions. Fusobacterium, Streptococcus, Peptostreptococcus, Parvimonas, Gemella, and Haemophilus were identified by all three methods as enriched in the CRC group, while Roseburia, Faecalibacterium, Butyricicoccus, and Blautia were identified by all three methods as enriched in the healthy group. In addition, disease-diagnostic models generated using machine learning algorithms based on the data from these different methods all achieved good diagnostic efficiency (AUC: 0.87-0.89), with the model based on DADA2 producing the highest AUC (0.8944 and 0.8907 in the training set and test set, respectively). However, there was no significant difference in performance between the models (P >0.05). In conclusion, this study demonstrates that DADA2, Deblur, and de novo OTU clustering display similar power levels in taxa assignment and can produce similar conclusions in the case of the CRC cohort.

Application of Surface Landmarks Combined with Image-Guided Sinus Location in the Retrosigmoid Approach and Their Clinic-Image Relationship Analysis.

Objectives During craniotomy for cerebellopontine angle (CPA) lesions, the exact exposure of the margin of the venous sinuses complex remains an essential but risky part of the procedure. Here, we revealed the exact position of the asterion and sinus complex by combining preoperative image information and intraoperative cranial landmarks, and analyzed their clinic-image relationship. Methods Ninety-four patients who underwent removal of vestibular schwannoma (VS) through retrosigmoid craniotomies were enrolled in the series. To determine the exact location of the sigmoid sinus and the transverse sinus and sigmoid sinus junction (TSSJ), we used preoperative images, such as computed tomography (CT) and/or magnetic resonance imaging (MRI) combined with intraoperative anatomical landmarks. The distance between the asterion and the sigmoid sinus was measured using MRI T1 sequences with gadolinium and/or the CT bone window. Results In 94 cases of retrosigmoid craniotomies, the asterion lay an average of 12.71 mm on the posterior to the body surface projection to the TSSJ. Intraoperative cranial surface landmarks were used in combination with preoperative image information to identify the distance from the asterion to the sigmoid sinus at the transverse sinus level, allowing for an appropriate initial burr hole (the margin of the TSSJ). Conclusion By combining intraoperative anatomical landmarks and preoperative image information, the margin of the TSSJ, in particular, the inferior margin of the transverse sinus, can be well and thoroughly identified in the retrosigmoid approach.

Tissue kallikrein-related peptidase8 accentuates cardiac fibrosis after myocardial ischemia-reperfusion injury via regulation of cardiac fibroblasts.

AIMS: Tissue kallikrein-related peptidase8 (KLK8) has been found to mitigate acute myocardial ischemia-reperfusion (IR) injury. However, the effect of KLK8 on cardiac remodeling in response to IR injury has not been determined. MATERIALS AND METHODS: KLK8 overexpressing transgenic rat (KLK8-TG) was used as the animal model. IR injury was induced by ligating the left anterior descending coronary artery for 1 h and subsequent reperfusion. The functional and morphological changes of the heart were examined 14 days after the injury. Neonatal rat cardiac fibroblasts (CFs) were used to investigate the molecular mechanisms in vitro. KEY FINDINGS: KLK8 overexpression enhanced cardiac diastolic dysfunction, fibrosis, and hypertrophy after IR injury, indicating that KLK8 accentuated cardiac remodeling in response to IR injury. Moreover, KLK8 overexpression increased epidermal growth factor (EGF) release and promoted the phosphorylation of EGF receptor (EGFR) and ERK1/2 in the heart after IR injury. It was interesting to find that both EGFR antagonist (AG 1478) and MEK inhibitor (PD98059) attenuated the KLK8-induced proliferation and activation of CFs in vitro, indicating that EGFR signaling might mediate the pro-fibrotic action of KLK8. SIGNIFICANCE: KLK8 plays a crucial role in cardiac remodeling after myocardial infarction. KLK8 accentuates cardiac fibrosis after IR injury, possibly mediated by EGFR signaling in CFs.