Efficacy and safety of robotic vs. laparoscopic gastrectomy for patients with gastric cancer: systematic review and meta-analysis.

BACKGROUND: The emergence of robotic surgical systems compensated for the technological shortcomings of laparoscopic approaches. However, whether robotic gastrectomy (RG) has better perioperative outcomes and survival than laparoscopic gastrectomy (LG) for gastric cancer is still unclear but increasingly drawing attention. MATERIALS AND METHODS: In this systematic review and meta-analysis, we searched the PubMed, EMBASE, Web of Science, and Cochrane Library as of January 20, 2024 and referenced list of eligible articles for all published studies comparing RG and LG for patients with gastric cancer, Data on study characteristics, individual characteristics, and outcome parameters were extracted. The quality of studies was assessed using the Revised Cochrane risk-of-bias 2 tool and the risk of bias in non-randomized studies of interventions tool. The main outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS: We identified 3641 articles, of which 72 studies (30081 patients) were included in the meta-analysis. Compared with LG, RG was associated with higher OS [hazard ratio (HR)=0.89, 95% CI=0.83 to 0.96), lower rate of overall postoperative complications [odds ratio (OR)=0.77, 95% CI=0.71 to 0.84], longer operating time [mean difference (MD)=35.53, 95% CI=29.23 to 41.83], less estimated blood loss (MD=-37.45, 95% CI=-46.24 to -28.67), a higher number of retrieved lymph nodes (MD=1.88, 95% CI=0.77 to 3.00), faster postoperative recovery, and lower rate of conversion (OR=0.44, 95% CI=0.36 to 0.55). Mortality and DFS were not significantly different between the two groups. The subgroup of meta-analysis results also showed the advantages of robotic surgery over laparoscopic surgery in intracorporeal reconstruction, total gastrectomy, Ⅰ/Ⅱ stage, and BMI≥25, especially for patients with stage Ⅰ/Ⅱ, there is better overall survival and disease-free survival. CONCLUSION: Our findings point to robotic surgery having great benefits compared with laparoscopic surgery in gastric cancer. Our study may help inform decision-making in applying robotic surgical systems to clinical treatment.

CRISPR/Cas13a-based supersensitive circulating tumor DNA assay for detecting EGFR mutations in plasma.

Despite recent technological advancements in cell tumor DNA (ctDNA) mutation detection, challenges persist in identifying low-frequency mutations due to inadequate sensitivity and coverage of current procedures. Herein, we introduce a super-sensitivity and specificity technique for detecting ctDNA mutations, named HiCASE. The method utilizes PCR-based CRISPR, coupled with the restriction enzyme. In this work, HiCASE focuses on testing a series of EGFR mutations to provide enhanced detection technology for non-small cell lung cancer (NSCLC), enabling a detection sensitivity of 0.01% with 40 ng cell free DNA standard. When applied to a panel of 140 plasma samples from 120 NSCLC patients, HiCASE exhibits 88.1% clinical sensitivity and 100% specificity with 40 µL of plasma, higher than ddPCR and Super-ARMS assay. In addition, HiCASE can also clearly distinguish T790M/C797S mutations in different positions at a 1% variant allele frequency, offering valuable guidance for drug utilization. Indeed, the established HiCASE assay shows potential for clinical applications.

Prognostic value of dynamic changes of pre- and post-operative tumor markers in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) prognosis assessment is vital for personalized treatment plans. This study investigates the prognostic value of dynamic changes of tumor markers CEA, CA19-9, CA125, and AFP before and after surgery and constructs prediction models based on these indicators. METHODS: A retrospective clinical study of 2599 CRC patients who underwent radical surgery was conducted. Patients were randomly divided into training (70%) and validation (30%) datasets. Univariate and multivariate Cox regression analyses identified independent prognostic factors, and nomograms were constructed. RESULTS: A total of 2599 CRC patients were included in the study. Patients were divided into training (70%, n = 1819) and validation (30%, n = 780) sets. Univariate and multivariate Cox regression analyses identified age, total number of resected lymph nodes, T stage, N stage, the preoperative and postoperative changes in the levels of CEA, CA19-9, and CA125 as independent prognostic factors. When their postoperative levels are normal, patients with elevated preoperative levels have significantly worse overall survival. However, when the postoperative levels of CEA/CA19-9/CA125 are elevated, whether their preoperative levels are elevated or not has no significance for prognosis. Two nomogram models were developed, and Model I, which included CEA, CA19-9, and CA125 groups, demonstrated the best performance in both training and validation sets. CONCLUSION: This study highlights the significant predictive value of dynamic changes in tumor markers CEA, CA19-9, and CA125 before and after CRC surgery. Incorporating these markers into a nomogram prediction model improves prognostic accuracy, enabling clinicians to better assess patients' conditions and develop personalized treatment plans.

Computational analysis of PD-L1 dimerization mechanism induced by small molecules and potential dynamical properties.

The design of small molecule inhibitors that target the programmed death ligand-1 (PD-L1) is a forefront issue in immune checkpoint blocking therapy. Small-molecule inhibitors have been shown to exert therapeutic effects by inducing dimerization of the PD-L1 protein, however, the specific mechanisms underlying this dimerization process remain largely unexplored. Furthermore, there is a notable lack of comparative studies examining the binding modes of structurally diverse inhibitors. In view of the research gaps, this work employed molecular dynamics simulations to meticulously examine the interactions between two distinct types of inhibitors and PD-L1 in both monomeric and dimeric forms, and predicted the dimerization mechanism. The results revealed that inhibitors initially bind to a PD-L1 monomer, subsequently attracting another monomer to form a dimer. Notably, symmetric inhibitors observed superior binding efficiency compared to other inhibitors. Key residues, including Ile54, Tyr56, Met115 and Tyr123 played a leading role in binding. Structurally, symmetric inhibitors were capable of thoroughly engaging the binding pocket, promoting a more symmetrical formation of PD-L1 dimers. Furthermore, symmetric inhibitors formed more extensive hydrophobic interactions with protein residues. The insights garnered from this research are expected to significantly contribute to the rational design and optimization of small molecule inhibitors targeting PD-L1.

[99mTc]Tc-HYNIC-ALUG SPECT/CT in the initial staging of 227 consecutive patients with newly diagnosed prostate cancer: a 5-year monocentric retrospective study.

Purpose: The purpose of this study was to assess the effectiveness of [99mTc]Tc-HYNIC-ALUG SPECT/CT in the initial staging of patients with newly diagnosed PCa. Methods: A retrospective analysis was conducted on 227 consecutive patients who underwent [99mTc]Tc-HYNIC-ALUG SPECT/CT imaging for the primary staging of newly diagnosed PCa. The presence and location of PSMA-positive lesions were determined, and the maximum standardized uptake values (SUVmax) of the primary prostate tumor were also measured. The metastatic findings and SUVmax were stratified according to International Society of Urological Pathology (ISUP) grade, prostate-specific antigen (PSA) levels, and D'Amico classification. Furthermore, the [99mTc]Tc-HYNIC-ALUG SPECT/CT findings were compared to the histopathological findings in patients who had undergone radical prostatectomy with pelvic lymph node dissection (PLND). Results: Of the 227 patients, 92.1% (209/227) had positive [99mTc]Tc-HYNIC-ALUG SPECT/CT findings. Advanced disease was detected in 38.8% (88/227) of the patients and was positively correlated with increasing ISUP grade and PSA levels. Lymph node metastases (both pelvic and extrapelvic), bone metastases, and visceral metastases were detected in 30.0% (68/227), 25.6% (58/227), and 3.1% (7/227) of the patients, respectively. For the 129 patients who underwent radical prostatectomy with PLND, the sensitivity of [99mTc]Tc-HYNIC-ALUG SPECT/CT in the evaluation of PCa was 90.7% (117/129). The sensitivity, specificity, accuracy, and positive and negative predictive values for detecting pelvic lymph node metastases on [99mTc]Tc-HYNIC-ALUG SPECT/CT were 23.5% (12/51), 93.6% (73/78), 65.9% (85/129), 70.6% (12/17), and 65.2% (73/112), respectively. Among the 209 patients with PSMA-avid primary prostate disease, the SUVmax of the primary prostate tumor was significantly associated with ISUP grade (p<0.0001), PSA levels (p<0.0001), D'Amico classification (p<0.0001), and advanced disease (p<0.0001). Receiver operating characteristic (ROC) analysis revealed that a PSA level >19.8 ng/ml and SUVmax of the primary prostate tumor >7.4 had a sensitivity of 71.6% and 71.6% and specificity of 76.9% and 82.6%, respectively, for detecting metastatic disease. Conclusions: [99mTc]Tc-HYNIC-ALUG SPECT/CT emerges as a valuable imaging tool for the initial staging of newly diagnosed PCa. The presence of advanced disease and the SUVmax of the primary prostate tumor were positively correlated with ISUP grade and PSA levels.

Targeted disruption of the BCR-ABL fusion gene by Cas9/dual-sgRNA inhibits proliferation and induces apoptosis in chronic myeloid leukemia cells.

The BCR-ABL fusion gene, formed by the fusion of the breakpoint cluster region protein ( BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase ( ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. Current therapies have limited efficacy in patients with chronic myeloid leukemia (CML) because of drug resistance or disease relapse. Identification of novel strategies to treat CML is essential. This study aims to explore the efficiency of novel CRISPR-associated protein 9 (Cas9)/dual-single guide RNA (sgRNA)-mediated disruption of the BCR-ABL fusion gene by targeting BCR and cABL introns. A co-expression vector for Cas9 green fluorescent protein (GFP)/dual-BA-sgRNA targeting BCR and cABL introns is constructed to produce lentivirus to affect BCR-ABL expression in CML cells. The effects of dual-sgRNA virus-mediated disruption of BCR-ABL are analyzed via the use of a genomic sequence and at the protein expression level. Cell proliferation, cell clonogenic ability, and cell apoptosis are assessed after dual sgRNA virus infection, and phosphorylated BCR-ABL and its downstream signaling molecules are detected. These effects are further confirmed in a CML mouse model via tail vein injection of Cas9-GFP/dual-BA-sgRNA virus-infected cells and in primary cells isolated from patients with CML. Cas9-GFP/dual-BA-sgRNA efficiently disrupts BCR-ABL at the genomic sequence and gene expression levels in leukemia cells, leading to blockade of the BCR-ABL tyrosine kinase signaling pathway and disruption of its downstream molecules, followed by cell proliferation inhibition and cell apoptosis induction. This method prolongs the lifespan of CML model mice. Furthermore, the effect is confirmed in primary cells derived from patients with CML.

Vitamin K: Infection, Inflammation, and Auto-Immunity.

Vitamin K (VK) comprises a group of substances with chlorophyll quinone bioactivity and exists in nature in the form of VK1 and VK2. As its initial recognition originated from the ability to promote blood coagulation, it is known as the coagulation vitamin. However, based on extensive research, VK has shown potential for the prevention and treatment of various diseases. Studies demonstrating the beneficial effects of VK on immunity, antioxidant capacity, intestinal microbiota regulation, epithelial development, and bone protection have drawn growing interest in recent years. This review article focuses on the mechanism of action of VK and its potential preventive and therapeutic effects on infections (eg, asthma, COVID-19), inflammation (eg, in type 2 diabetes mellitus, Alzheimer's disease, Parkinson's disease, cancer, aging, atherosclerosis) and autoimmune disorders (eg, inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis). In addition, VK-dependent proteins (VKDPs) are another crucial mechanism by which VK exerts anti-inflammatory and immunomodulatory effects. This review explores the potential role of VK in preventing aging, combating neurological abnormalities, and treating diseases such as cancer and diabetes. Although current research appoints VK as a therapeutic tool for practical clinical applications in infections, inflammation, and autoimmune diseases, future research is necessary to elucidate the mechanism of action in more detail and overcome current limitations.

CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Small extracellular vesicles-mediated cellular interactions between tumor cells and tumor-associated macrophages: Implication for immunotherapy.

The tumor microenvironment consists of cancer cells and various stromal cells, including macrophages, which exhibit diverse phenotypes with either pro-inflammatory (M1) or anti-inflammatory (M2) effects. The interaction between cancer cells and macrophages plays a crucial role in tumor progression. Small extracellular vesicles (sEVs), which facilitate intercellular communication, are known to play a vital role in this process. This review provides a comprehensive summary of how sEVs derived from cancer cells, containing miRNAs, lncRNAs, proteins, and lipids, can influence macrophage polarization. Additionally, we discuss the impact of macrophage-secreted sEVs on tumor malignant transformation, including effects on proliferation, metastasis, angiogenesis, chemoresistance, and immune escape. Furthermore, we address the therapeutic advancements and current challenges associated with macrophage-associated sEVs, along with potential solutions.

Prognostic value of normal levels of preoperative tumor markers in colorectal cancer.

Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and alpha-fetoprotein (AFP) are widely used tumor markers for colorectal cancer (CRC), but their clinical significance is unknown when the levels of these tumor markers were within the normal range. This retrospective study included 2145 CRC patients. The entire cohort was randomly divided into training and validation datasets. The optimal cut-off values of tumor markers were calculated using X-tile software, and univariate and multivariate analyses were performed to assess its association with overall survival (OS). The nomogram model was constructed and validated. The entire cohort was randomly divided into a training dataset (1502 cases, 70%) and a validation dataset (643 cases,30%). Calculated from the training dataset, the optimal cut-off value was 2.9 ng/mL for CEA, 10.1 ng/mL for CA19-9, 13.4 U/mL for CA125, and 1.8 ng/mL for AFP, respectively. Multivariate analysis revealed that age, tumor location, T stage, N stage, preoperative CA19-9, and CA125 levels were independent prognostic predictors. Even within the normal range, CRC patients with relatively high levels of CA19-9 or CA125 worse OS compared to those with relatively low levels. Then, based on the independent prognostic predictors from multivariate analysis, two models with/without (model I/II) CA19-9 and CA125 were built, model I showed better prediction and reliability than model II. Within the normal range, relatively high levels of preoperative CA19-9 and CA125 were significantly associated with poor OS in CRC patients. The nomogram based on CA19-9 and CA125 levels showed improved predictive accuracy ability for CRC.

Analysis of the clinical factors affecting excellent response of Iodine-131 treatment for pulmonary metastases from differentiated thyroid cancer.

Background: Iodiene-131 (131I) treatment is the primary therapeutic approach for imaging 131I-avid pulmonary metastases. The response to radioiodine (RAI) treatment is an important prognostic factor in patients with pulmonary metastases from differentiated thyroid cancer (DTC). Patients who achieve an excellent response (ER) to 131I treatment show significantly reduced disease-related mortality. This study aimed to retrospectively analyse the clinical data and therapeutic effects of 131I treatment in patients with DTC and pulmonary metastases and to screen out the clinical factors affecting ER. Materials and methods: The study included a total of 75 patients with exclusively Iodine-131 avid (131I-avid) pulmonary metastases who underwent 131I treatment. Relevant clinical data for these patients were collected. Following treatment, the status of DTC metastatic lesions was categorized as follows: excellent response (ER), biochemical incomplete response (BIR), structural incomplete response (SIR), or indeterminate response (IDR). Gender, age at diagnosis, pathological type, stages (TNM), stimulated thyroglobulin (sTg) value before initial 131I treatment, metastatic nodule size, and type of post-treatment whole body scan (Rx-WBS) were recorded. Mono-factor analysis and binary logistic regression analyses were used to identify the factors that might affect the ER in DTC pulmonary metastases. The receiver operating characteristic (ROC) curve of the sTg value was used to predict the ER of 131I treatment. Results: All 75 patients with exclusively 131I-avid pulmonary metastases received 131I treatment and underwent follow-up. Out of the 75 patients, 26 achieved ER, resulting in an excellent response rate of 34.7 % (26/75). Among them, 25 (25/26, 96.2 %) achieved an ER after undergoing two rounds of 131I treatment. Binary logistic regression analysis showed that the factors influencing DTC pulmonary metastases excellent response were lower sTg levels [odds ratio (OR) = 0.998, P < 0.001], micronodular metastases (OR = 0.349, P = 0.001) and focal distribution on Rx-WBS imaging (OR = 0.113, P = 0.001). The area under the ROC curve for sTg value predicting ER was 0.876, and the cut-off value was 26.84 ng/mL, with a sensitivity and specificity of 87.9 % and 80.3 %, respectively. Conclusions: 131I treatment is effective for 131I-avid pulmonary metastases of DTC. Some patients who underwent 131I treatment achieved ER. Most patients with ER were obtained after two rounds of 131I treatments. Patients with sTg values before initial 131I treatment lower than 26.84 ng/mL, micronodular metastases, and focal distribution on Rx-WBS imaging were more likely to achieve ER.

Negative regulation of tobacco cold stress tolerance by NtPhyA.

Cold stress is a non-biological stressor that adversely affects tobacco yield and leaf quality. Plant photoreceptor proteins, which function as dual light-temperature sensors, play a vital role in temperature changes, making them crucial for responses to non-biological stressors. However, the regulatory mechanisms of PhyA in tobacco remain poorly understood. Therefore, in this study, we aimed to clone the NtPhyA gene from tobacco and generate overexpression (OE-NtPhyA) and mutant (KO-NtPhyA) constructs of NtPhyA. By assessing the physiological and biochemical responses of the mutants under cold stress and performing transcriptome sequencing, we determined the signalling mechanism of NtPhyA under cold stress. Comparative analysis with wild-type (WT) NtPhyA revealed that KO-NtPhyA exhibited increased seed germination rates and reduced wilting under cold stress. In additional, the degree of damage to leaf cells, cell membranes, and stomatal structures was mitigated, and the levels of reactive oxygen species (ROS) were significantly decreased. Antioxidant enzyme activity, net photosynthetic rate, and Fv/Fm were significantly enhanced in KO-NtPhyA, whereas the opposite effects were observed in OE-NtPhyA. These findings indicate that KO-NtPhyA augments tobacco tolerance to cold stress, implying a negative regulatory role of NtPhyA in tobacco during cold stress. Transcriptome analysis revealed that NtPhyA governs the expression of a cascade of genes involved in the response to oxygen-containing compounds, hydrogen peroxide (H2O2), ROS, temperature stimuli, photosystem II oxygen-evolving complex assembly, water channel activity, calcium channel activity, and carbohydrate transport. Collectively, our findings indicate that NtPhyA activates downstream gene expression to enhance the resilience of tobacco to cold stress.

The NtDEGP5 gene improves drought tolerance in tobacco (Nicotiana tabacum L.) by dampening plastid extracellular Ca2+ and flagellin signaling and thereby reducing ROS production.

Tobacco is an essential cash crop, but drought has become a major factor in the decline of global tobacco production as a result of changes in the global climate. The HtrA protease is an oligomeric serine endopeptidase that responds to stress in plants. DEGP5 is a member of the gene family that encodes HtrA protease, which promotes plant adaptation to adversity. The aim of this study was to investigate the role and mechanism employed by the DEGP5 gene in response to drought stress in tobacco. NtDEGP5-overexpression lines were obtained by genetic transformation and the phenotypes and transcriptomes of NtDEGP5-overexpression lines and wild-type (K326) tobacco seedlings were compared under drought stress. The results demonstrated that plants overexpressing NtDEGP5 exhibited greater drought tolerance. The differentially expressed genes involved in the regulation of drought tolerance by DEGP5 were enriched in metabolic pathways, such as plant-pathogen interaction and glutathione metabolism, with the plant-pathogen interaction pathway having the most differentially expressed genes. An analysis of the plant-pathogen interaction pathway revealed that these genes contributed to the suppression of plastid extracellular Ca2+ signaling and flagellin signaling to inhibit reactive oxygen species production, and that lower levels of reactive oxygen species act as a signal to regulate the activation of the antioxidant system, further balancing the production and removal of reactive oxygen species in tobacco seedlings under drought stress. These findings suggest that the NtDEGP5 gene can enhance the drought tolerance of tobacco by regulating the homeostasis of reactive oxygen species by inhibiting extracellular plastids.

Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.

The role of mast cells (MCs) in colorectal cancer (CRC) remains unclear, and a comprehensive single-cell study on CRC MCs has not been conducted. This study used a multi-omics approach, integrating single-cell sequencing, spatial transcriptomics, and bulk tissue sequencing data to investigate the heterogeneity and impact of MCs in CRC. Five MC signature genes (TPSAB1, TPSB2, CPA3, HPGDS, and MS4A2) were identified, and their average expression was used as a marker of MCs. The MC density was found to be lower in CRC compared to normal tissue, but MCs in CRC demonstrated distinct activation features. Activated MCs were defined by high expression of receptors and MC mediators, while resting MCs had low expression. Most genes, including the five MC signature genes, were expressed at higher levels in activated MCs. The MC signature was linked to a better prognosis in both CRC and pan-cancer patient cohorts. Elevated KITLG expression was observed in fibroblasts and endothelial cells in CRC samples compared to normal tissue, and co-localization of MCs with these cell types was revealed by spatial transcriptome analysis. In conclusion, this study finds decreased MC density in CRC compared to normal tissue, but highlights a shift in MC phenotype from CMA1high resting cells to activated TPSAB1high, CPA3high, and KIThigh cells. The elevated KITLG expression in the tumor microenvironment's fibroblasts and endothelial cells may activate MCs through the KITLG-KIT axis, potentially suppressing tumor progression.

A nomogram was developed using clinicopathological features to predict postoperative liver metastasis in patients with colorectal cancer.

PURPOSE: The objective of this study is to examine the risk factors that contribute to the development of liver metastasis (LM) in patients who have suffered radical resection for colorectal cancer (CRC), and to establish a nomogram model that can be used to predict the occurrence of the LM. METHODS: The present study enrolled 1377 patients diagnosed with CRC between January 2010 and July 2021. The datasets were allocated to training (n = 965) and validation (n = 412) sets in a randomly stratified manner. The study utilized univariate and multivariate logistic regression analyses to establish a nomogram for predicting LM in patients with CRC. RESULTS: Multivariate analysis revealed that T stage, N stage, number of harvested lymph nodes (LNH), mismatch repair (MMR) status, neutrophil count, monocyte count, postoperative carcinoembryonic antigen (CEA) levels, postoperative cancer antigen 125 (CA125) levels, and postoperative carbohydrate antigen 19-9 (CA19-9) levels were independent predictive factors for LM after radical resection. These factors were then utilized to construct a comprehensive nomogram for predicting LM. The nomogram demonstrated great discrimination, with an area under the curve (AUC) of 0.782 for the training set and 0.768 for the validation set. Additionally, the nomogram exhibited excellent calibration and significant clinical benefit as confirmed by the calibration curves and the decision curve analysis, respectively. CONCLUSION: This nomogram has the potential to support clinicians in identifying high-risk patients who may develop LM post-surgery. Clinicians can devise personalized treatment and follow-up plans, ultimately leading to an improved prognosis for patients.

Comprehensive analysis unveils altered binding kinetics of 5-/6-methylCytosine/adenine modifications in R2R3-DNA system.

Recent studies have shown that DNA methylation is an important epigenetic marker. Two prominent forms are methylation of the C5 position of cytosine and methylation of the C6 position of adenine. Given the vital significance of DNA methylation, investigating the mechanisms that influence protein binding remains a compelling pursuit. This study used molecular dynamics simulations to investigate the binding patterns of R2R3 protein and four differentially methylated DNAs. The alanine scanning combined with interaction entropy method was used to identify key residues that respond to different methylation patterns. The order of protein binding ability to DNA is as follows: unmethylated DNA > A11 methylation (5'-A6mAC-3') (6m2A system) > A10 methylation (5'-6mAAC-3') (6m1A system) > both A10 and A11 methylation (5'-6mA6mAC-3') (6mAA system) > C12 methylation (5'-AA5mC-3') (5mC system). All methylation systems lead to the sixth α helix (H6) (residues D105 to L116) moving away from the binding interface, and in the 5mC and 6m1A systems, the third α helix (H3) (residues G54 to L65) exhibits a similar trend. When the positively charged amino acids in H3 and H6 move away from the binding interface, their electrostatic and van der Waals interactions with the negatively charged DNA are weakened. Structural changes induced by methylation contributed to the destabilization of the hydrogen bond network near the original binding site, except for the 6m2A system. Moreover, there is a positive correlation between the number of methylated sites and the probability of distorting the DNA structure. Our study explores how different methylation patterns affect binding and structural adaptability, and have implications for drug discovery and understanding diseases related to abnormal methylation.

Diagnostic accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting osteomalacia-associated tumors.

Objectives: Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) SPECT/CT in detecting TIO. Methods: 99mTc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The 99mTc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results. Results: Using 99mTc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the 99mTc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of 99mTc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25). Conclusions: The 99mTc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.

HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2.

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl4-induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.

Identification of a novel MSI-related ceRNA network for predicting the prognosis and immunotherapy response of gastric cancer.

BACKGROUND: Mounting evidence has underscored the pivotal role of the competitive endogenous RNA (ceRNA) regulatory networks among various cancers. However, the behavior characteristics and complexity of the ceRNA network in Gastric cancer (GC) remains unclear. In this study, we aimed to clarify a Microsatellite instability (MSI)-related ceRNA regulatory network and identify potential prognostic markers associated with GC. METHODS AND RESULTS: We extracted transcriptome data of GC patients from The Cancer Genome Atlas (TCGA) and identified differentially expressed lncRNAs, miRNAs and mRNAs based on MSI status. A hub ceRNA network including 1 lncRNAs (MIR99AHG), 2 miRNAs and 26 mRNAs specific to MSI was established in GC. We further constructed a prognostic model with seven target mRNAs by Lasso Cox regression, which yielded AUC values of 0.76. The prognostic model was further validated in an external independent dataset that integrated three GEO datasets. The characterization of immune cell infiltration and immunotherapy effects between high-risk and low-risk groups were then analyzed. Immune cell infiltration was significantly different between high- and low-risk groups based on risk scores. GC patients with lower risk scores correlated with better immune checkpoint inhibitor therapy (ICI) response. We further validated the expression and regulatory relationship of the ceRNA network in vitro experiments, and also confirmed the relationship between MIR99AHG and PD-L1. CONCLUSIONS: Our research provides in-depth insights on the role of MSI-related ceRNA in GC and the prognosis and ICIs therapy response of GC patients can be assessed by the risk model based on MSI-related ceRNA network.