Integrating Traditional Machine Learning and Deep Learning for Precision Screening of Anticancer Peptides: A Novel Approach for Efficient Drug Discovery.

The rapid and effective identification of anticancer peptides (ACPs) by computer technology provides a new perspective for cancer treatment. In the identification process of ACPs, accurate sequence encoding and effective classification models are crucial for predicting their biological activity. Traditional machine learning methods have been widely applied in sequence analysis, but deep learning provides a new approach to capture sequence complexity. In this study, a two-stage ACPs classification model was innovatively proposed. Three novel coding strategies were explored; two mainstream Natural Language Processing (NLP) models and 11 machine learning models were fused to identify ACPs, which significantly improved the prediction accuracy of ACPs. We analyzed the correlation between peptide chain amino acids and evaluated the relevant performance of the model by the ROC curve and t-SNE dimensionality reduction technique. The results indicated that the deep learning and machine learning fusion models of M3E-base and KNeighborsDist models, especially when considering the semantic information on amino acid sequences, achieved the highest average accuracy (AvgAcc) of 0.939, with an AUC value as high as 0.97. Then, in vitro cell experiments were used to verify that the two ACPs predicted by the model had antitumor efficacy. This study provides a convenient and effective method for screening ACPs. With further optimization and testing, these strategies have the potential to play an important role in drug discovery and design.

Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study.

Although serum iron status and sarcopenia are closely linked, the presence of comprehensive evidence to establish a causal relationship between them remains insufficient. The objective of this study is to employ Mendelian randomization techniques to clarify the association between serum iron status and sarcopenia. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationship between iron status and sarcopenia. MR analyses were performed using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were conducted to verify the reliability of the causal association results. Then, we harvested a combination of SNPs as an integrated proxy for iron status to perform a MVMR analysis based on IVW MVMR model. UVMR analyses based on IVW method identified causal effect of ferritin on appendicular lean mass (ALM, ß = - 0.051, 95% CI - 0.072, - 0.031, p = 7.325 × 10-07). Sensitivity analyses did not detect pleiotropic effects or result fluctuation by outlying SNPs in the effect estimates of four iron status on sarcopenia-related traits. After adjusting for PA, the analysis still revealed that each standard deviation higher genetically predicted ferritin was associated with lower ALM (ß = - 0.054, 95% CI - 0.092, - 0.015, p = 0.006). Further, MVMR analyses determined a predominant role of ferritin (ß = - 0.068, 95% CI - 0.12, - 0.017, p = 9.658 × 10-03) in the associations of iron status with ALM. Our study revealed a causal association between serum iron status and sarcopenia, with ferritin playing a key role in this relationship. These findings contribute to our understanding of the complex interplay between iron metabolism and muscle health.

An immune sandwich electrochemical biosensor based on triple-modified zirconium derivatives for detection of CD146 in serum.

CD146, also known as melanoma cell adhesion molecule (MCAM), is overexpressed in various cancer patients, making it a valuable predictor for early diagnosis. In this work, an immune sandwich electrochemical biosensor is proposed for sensitive and non-invasive quantitative detection of CD146 in serum. Zirconium-based MOF (UIO-66) was modified by simultaneous copper atom doping, in situ growth carbon-based support and physical embedding of platinum nanoparticles (PtNPs). Triple-modified Cu-UIO-66@SWCNT/PtNPs nanocomposites with high stability and excellent electrochemical properties, serve as surface modification materials for glassy carbon electrodes. Anti-CD146 antibody (Ab1) was grafted onto the electrode surface via Pt-S bond. Meanwhile, the secondary antibody (Ab2) was conjugated with silver nanoparticles (AgNPs) to cooperate for CD146 capture and achieve secondary electrical signal amplification. Under optimal conditions, square wave voltammetry was employed to determine CD146 in the concentration range of 10-9-10-4 mg/mL and a limit of detection of 12 fg/mL was obtained. Finally, it was successfully applied to the analysis of CD146 in lung and liver cancer patients' serum samples.

Joint association and interaction of birth weight and lifestyle with hypertension: A cohort study in UK Biobank.

Low birth weight and unhealthy lifestyle are both associated with an increased risk of hypertension. The authors aimed to assess the joint association and interaction of birth weight and lifestyle with incident hypertension. The authors included 205 522 participants free of hypertension at baseline from UK Biobank. A healthy lifestyle score was constructed using information on body mass index, physical activity, diet, smoking status and alcohol intake. Cox proportional hazard models were used to investigate the impact of birth weight, healthy lifestyle score and their joint effect on hypertension. The authors documented 13 548 (6.59%) incident hypertension cases during a median of 8.6 years of follow-up. The multivariate adjusted hazard ratios and 95% confidence intervals were 1.12 (1.09, 1.15) per kg lower birth weight and 0.76 (0.75, 0.77) per score increment in healthy lifestyle score. Healthy lifestyle reduced the risk of hypertension in any category of different birth weight groups. The preventive effect of healthy lifestyle on hypertension was the most pronounced at lower birth weight with <2500 g and 2500-2999 g, respectively. Addictive interaction between birth weight and healthy lifestyle score was observed with the relative excess risk due to interaction of 0.04 (0.03, 0.05). Our findings emphasized the importance of healthy lifestyle for hypertension prevention, especially among the high-risk population with lower birth weight.

Immunological profile of lactylation-related genes in Crohn's disease: a comprehensive analysis based on bulk and single-cell RNA sequencing data.

BACKGROUND: Crohn's disease (CD) is a disease characterized by intestinal immune dysfunction, often accompanied by metabolic abnormalities. Disturbances in lactate metabolism have been found in the intestine of patients with CD, but studies on the role of lactate and related Lactylation in the pathogenesis of CD are still unknown. METHODS: We identified the core genes associated with Lactylation by downloading and merging three CD-related datasets (GSE16879, GSE75214, and GSE112366) from the GEO database, and analyzed the functions associated with the hub genes and the correlation between their expression levels and immune infiltration through comprehensive analysis. We explored the Lactylation levels of different immune cells using single-cell data and further analyzed the differences in Lactylation levels between inflammatory and non-inflammatory sites. RESULTS: We identified six Lactylation-related hub genes that are highly associated with CD. Further analysis revealed that these six hub genes were highly correlated with the level of immune cell infiltration. To further clarify the effect of Lactylation on immune cells, we analyzed single-cell sequencing data of immune cells from inflammatory and non-inflammatory sites in CD patients and found that there were significant differences in the levels of Lactylation between different types of immune cells, and that the levels of Lactylation were significantly higher in immune cells from inflammatory sites. CONCLUSIONS: These results suggest that Lactylation-related genes and their functions are closely associated with changes in inflammatory cells in CD patients.

OH2 oncolytic virus: A novel approach to glioblastoma intervention through direct targeting of tumor cells and augmentation of anti-tumor immune responses.

Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.

Decoding gene regulatory circuitry underlying TNBC chemoresistance reveals biomarkers for therapy response and therapeutic targets.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterised by extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, leveraging single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we unravel distinct cell subpopulations intricately associated with chemoresistance and the signature genes defining these populations. Notably, using genome-wide mapping of the H3K27ac mark, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and associated transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells, and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed epigenetic and transcription factor networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.

Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice.

BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.

Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. METHODS AND RESULTS: Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS". CONCLUSIONS: Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.

Dual action of macrophage miR-204 confines cyclosporine A-induced atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA-204 (miR-204) transcription. We therefore hypothesised that miR-204 is involved in the development of CsA-induced atherosclerosis. EXPERIMENTAL APPROACH: ApoE-/- mice with macrophage-miR-204 overexpression were generated to determine the effects of miR-204 on CsA-induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR-204 effects. KEY RESULTS: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high-fat diet-induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE-/- mice, respectively. miR-204 levels decreased in circulating monocytes and plaque lesions during CsA-induced atherosclerosis. The upregulation of miR-204 in macrophages inhibited CsA-induced atherosclerotic plaque formation but did not affect serum lipid levels. miR-204 limited the CsA-induced foam cell formation by reducing the expression of the scavenger receptors SR-BII and CD36. SR-BII was post-transcriptionally regulated by mature miR-204-5p via 3'-UTR targeting. Additionally, nuclear-localised miR-204-3p prevented the CsA-induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR-BII or CD36 expression restoration dampened the beneficial effects of miR-204 on CsA-induced atherosclerosis. CONCLUSION AND IMPLICATIONS: Macrophage miR-204 ameliorates CsA-induced atherosclerosis, suggesting that miR-204 may be a potential target for the prevention and treatment of CsA-related atherosclerotic side effects.

Caffeine Impaired Acupuncture Analgesia in Inflammatory Pain by Blocking Adenosine A1 Receptor.

Caffeine consumption inhibits acupuncture analgesic effects by blocking adenosine signaling. However, existing evidence remains controversial. Hence, this study aimed to examine the adenosine A1 receptor (A1R) role in moderate-dose caffeine-induced abolishing effect on acupuncture analgesia using A1R knockout mice (A1R-/-). We assessed the role of A1R in physiological sensory perception and its interaction with caffeine by measuring mechanical and thermal pain thresholds and administering A1R and adenosine 2A receptor antagonists in wild-type (WT) and A1R-/- mice. Formalin- and complete Freund's adjuvant (CFA)-induced inflammatory pain models were recruited to explore moderate-dose caffeine effect on pain perception and acupuncture analgesia in WT and A1R-/- mice. Moreover, a C-fiber reflex electromyogram in the biceps femoris was conducted to validate the role of A1R in the caffeine-induced blockade of acupuncture analgesia. We found that A1R was dispensable for physiological sensory perception and formalin- and CFA-induced hypersensitivity. However, genetic deletion of A1R impaired the antinociceptive effect of acupuncture in A1R-/- mice under physiological or inflammatory pain conditions. Acute moderate-dose caffeine administration induced mechanical and thermal hyperalgesia under physiological conditions but not in formalin- and CFA-induced inflammatory pain. Moreover, caffeine significantly inhibited electroacupuncture (EA) analgesia in physiological and inflammatory pain in WT mice, comparable to that of A1R antagonists. Conversely, A1R deletion impaired the EA analgesic effect and decreased the caffeine-induced inhibitory effect on EA analgesia in physiological conditions and inflammatory pain. Moderate-dose caffeine administration diminished the EA-induced antinociceptive effect by blocking A1R. Overall, our study suggested that caffeine consumption should be avoided during acupuncture treatment. PERSPECTIVE: Moderate-dose caffeine injection attenuated EA-induced antinociceptive effect in formalin- and CFA-induced inflammatory pain mice models by blocking A1R. This highlights the importance of monitoring caffeine intake during acupuncture treatment.

Neuronal MeCP2 in the dentate gyrus regulates mossy fiber sprouting of mice with temporal lobe epilepsy.

Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system.

Phosphorylcholine-grafted graphene oxide loaded with irinotecan for potential oncology therapy.

2-Methacryloyloxyethyl phosphorylcholine (MPC) zwitterions were modified onto self-made graphene oxide (GO) through the atom transfer radical polymerization method. The chemical structures of the products were verified using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, nuclear magnetic resonance spectroscopy (NMR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), etc. It was found that the modified GO (GO-PCn) is well dispersed in water with an average hydrodynamic diameter of about 170 nm. By utilizing the 2D planar structure of this modified graphene, the irinotecan@GO-PCn composite can be loaded with about 20% of irinotecan via π-π stacking interaction and exhibit pH-sensitive drug release performance, releasing faster in the acidic environment. The in vitro cytotoxicity assessments confirmed that GO-PCn composed of phosphorylcholine moiety represented low cytotoxicity and acted as a certain effect on reducing the acute toxicity of irinotecan, which established a foundation for further studies of the system in oncology therapy.

Toxic effects of combined exposure to cadmium and nitrate on intestinal morphology, immune response, and microbiota in juvenile Japanese flounder (Paralichthys olivaceus).

Cadmium (Cd2+) and nitrate (NO3-) are important environmental pollutants in the offshore marine ecological environment. However, limited research has explored their combined effects, particularly regarding their impact on the microbiota and intestinal health of marine fish. In this study, juvenile Japanese flounders (P. olivaceus) were immersed in seawater samples with different combinations of Cd2+ (0, 0.2, and 2 mg/L) and NO3- (0 and 80 mg/L NO3N) for 30 days to explore their toxic impacts on intestinal morphology, tight junction (TJ) barrier, immune response, and microbiota. Our results showed that Cd2+ or NO3- exposure alone led to histopathological damage of the gut, while their co-exposure aggravated intestinal damage. Moreover, co-exposure substantially decreased TJ-related gene expression, including occludin, claudin-10, and ZO-2, suggesting increased TJ permeability in the gut. Regarding the immune response, we observed upregulated expression of immune-related markers such as HSP40, IL-1ß, TNF-α, and MT, suggesting the onset of intestinal inflammation. Furthermore, Cd2+ and NO3- exposure led to changes in intestinal microflora, characterized by decreased the abundance of Sediminibacterium and NS3a_marine_group while increasing the prevalence of pathogens or opportunistic pathogens such as Ralstonia, Proteus, and Staphylococcus. This alteration in microbiota composition increased network complexity and α-diversity, ultimately causing dysbiosis in the fish gut. Additionally, combined exposure resulted in metabolic disorders that affected the predicted functions of the intestinal microbiota. Overall, our study demonstrates that Cd2+-NO3- co-exposure amplifies the deleterious effects compared to single exposure. These findings enhance our understanding of the ecological risks posed by Cd2+-NO3- co-exposure in marine ecosystems.

APOE ε4 Gene Carriers Demonstrate Reduced Retinal Capillary Densities in Asymptomatic Older Adults.

Early identification of Apolipoprotein E (APOE)-related microvascular pathology will help to study the microangiopathic contribution to Alzheimer's disease and provide a therapeutic target for early intervention. To evaluate the differences in retinal microvasculature parameters between APOE ε4 carriers and non-carriers, asymptomatic older adults aged ≥ 55 years underwent APOE ε4 genotype analysis, neuropsychological examination, and optical coherence tomography angiography (OCTA) imaging. One hundred sixty-three older adults were included in the data analysis. Participants were also defined as cognitively impaired (CI) and non-cognitively impaired (NCI) according to their MoCA scores and educational years. APOE ε4 carriers demonstrated reduced SVC (p = 0.023) compared to APOE ε4 non-carriers. Compared to NCI, CI participants showed reduced SVC density (p = 0.006). In the NCI group, no significant differences (p > 0.05) were observed in the microvascular densities between APOE ε4 carriers and non-carriers. In the CI group, APOE ε4 carriers displayed reduced microvascular densities compared to non-carriers (SVC, p = 0.006; DVC, p = 0.048). We showed that CI and APOE ε4 affect retinal microvasculature in older adults. Quantitative measures of the retinal microvasculature could serve as surrogates for brain microcirculation, providing an opportunity to study microvascular contributions to AD.

Expression of p53 as a biomarker in determining response to apatinib for advanced gastric cancer.

Background: Apatinib has shown outstanding value in the treatment of advanced gastric cancer (AGC). However, no biomarkers are available to select AGC patients who will benefit from apatinib. The aim of the present study was to investigate the association between p53 and Ki67 expression of and the outcome in AGC patients treated with apatinib. Methods: From December 2015 to December 2020, 92 AGC patients were enrolled and was retrospectively evaluated. They were given apatinib at a daily dose of 500 or 250 mg every 4 weeks to monitor clinical efficacy and adverse events (AEs). Kaplan-Meier method was used for survival analysis. Expression of p53 and Ki67 was detected by immunohistochemistry (IHC) and correlated with survival. Results: Among 92 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 17.4% and 79.3%, respectively, and none of them achieved a CR, 16 achieved a PR (17.4%) (95% CI 9.8%-26.1%). Stable disease (SD) was observed in 57.6% of patients (95% CI 49.2%-69.9%) and PD in 21.7% of patients (95% CI 13.6%-31.3%). The median progression free survival (mPFS) was 122.7 ± 8.2 days, and the median overall survival (mOS) was 203.4 ± 11.9 days. P53 expression was observed in 35 patients (38.0%) and high expression of Ki67 was detected in 34 patients (37.0%). There was a statistically significant inverse relationship between p53 and Ki67 expression (P=0.014). Moreover, p53 was significantly correlated with the OS (P=0.018), but Ki67 had no significant influence on OS. Conclusions: Apatinib showed promising efficiency and was well tolerated as a second-line treatment for AGC patients. AGC patients with p53-negative were likely to benefit from apatinib treatment; however, the expression of Ki67 proteins has no significant impact on the outcome of AGC patients.

Supramolecular immunotherapy on diversiform immune cells.

Supramolecular immunotherapy employs supramolecular materials to stimulate the immune system for inhibiting tumor cell growth and metastasis, reducing the cancer recurrence rate, and improving the quality of the patient's life. Additionally, it can lessen patient suffering and the deterioration of their illness, as well as increase their survival rate. This paper will outline the fundamentals of tumor immunotherapy based on supramolecular materials as well as its current state of development and potential applications. To be more specific, we will first introduce the basic principles of supramolecular immunotherapy, including the processes, advantages and limitations of immunotherapy, the construction of supramolecular material structures, and its benefits in treatment. Second, considering the targeting of supramolecular drugs to immune cells, we comprehensively discuss the unique advantages of applying supramolecular drugs with different types of immune cells in tumor immunotherapy. The current research advances in supramolecular immunotherapy, including laboratory research and clinical applications, are also described in detail. Finally, we reveal the tremendous promise of supramolecular materials in tumor immunotherapy, as well as discuss the opportunities and challenges that may be faced in future development.

Efficacy and safety of using aminocaproic acid and tranexamic acid during the perioperative period for treating trochanteric fractures in elderly femurs.

BACKGROUND: Tranexamic acid (TXA) has long been the antifibrinolytic hemostatic drug of choice for orthopedic surgery. In recent years, the hemostatic effect of epsilon aminocaproic acid (EACA) has gradually been recognized by orthopedic surgeons and has begun to be used in hip and knee arthroplasty with little mention of the comparison of these two drugs; Therefore, this study compared the efficacy and safety of EACA and TXA in the perioperative period of elderly patients with trochanteric fractures to verify whether EAC could be a "qualified alternative" to TXA and to provide theoretical support for the clinical application of TXA. METHODS: Two hundred and forty-three patients who received proximal femoral nail antirotation (PFNA) for trochanteric fractures from January 2021 to March 2022 at our institution were included and divided into the EACA group (n = 146) and the TXA group. (n = 97) determined by the drugs used in the perioperative period The main observations were blood loss and blood transfusion.The second second outcome was blood routine, coagulation, Hospital complications and complications after discharge. RESULTS: The perioperative EACA patients had significantly lower significant blood loss (DBL) than the TXA group (p < 0.0001) and statistically significant lower C-reactive protein in the EACA group than in the TXA group on postoperative day 1 (p = 0.022). Patients on perioperative TXA had better postoperative day one (p = 0.002) and postoperative day five erythrocyte width than the EACA group (p = 0.004). However, there was no statistically significant difference between the two groups in the remaining indicators in both drugs: blood items, coagulation indicators, blood loss, blood transfusion, length of hospital(LOH), total hospital expense, and postoperative complications (p > 0.05). CONCLUSION: The hemostatic effects and safety of EACA and TXA in the perioperative application of trochanteric fractures in the elderly are essentially similar, and EACA can be considered for use as an alternative to TXA, increasing the flexibility of physicians to use it in the clinical setting. However, the limited sample size included necessitated a high-quality, large sample of clinical studies and long-term follow-up.

Effects of primers, PCR approaches and sample preservation methods on diversity studies of myxobacteria.

Myxobacteria have potential application value in developing new antibiotics and environmental protection. In this study, in order to establish a more suitable method for diversity studies of myxobacteria, the effects of primers, polymerase chain reaction (PCR) approaches and sample preservation methods on the results were compared by Illumina high-throughput sequencing. The results showed that the relative abundance and operational taxonomic unit (OTU) ratio of myxobacteria amplified by the universal primers accounted for 0.91-1.85% and 2.82-4.10% of total bacteria, indicating that myxobacteria were the dominant bacteria both in population and species numbers. The relative abundance and OTU number and ratio of myxobacteria amplified by the myxobacteria semi-specific primers were significantly higher than those amplified by the universal primers, of which the primer pair W2/802R specifically amplified myxobacteria of suborder Cystobacterineae, while the primer pair W5/802R mainly amplified myxobacteria of suborder Sorangineae and also amplified more species of suborder Nannocystineae at the same time. Among three PCR approaches, the relative abundance and OTU ratio of myxobacteria amplified by the touch-down PCR were the highest. More myxobacterial OTUs were detected in most dried samples. In conclusion, the combination of the myxobacteria semi-specific primer pairs W2/802R and W5/802R, touch-down PCR, and dry preservation of samples were more conducive to diversity studies of myxobacteria.

Association between GLS Gene Polymorphisms and the Susceptibility to Lung Cancer in the Chinese Han Population.

BACKGROUND: Lung cancer is one of the most serious malignant tumors endangering human health and life. This study focused on evaluating the association between single nucleotide polymorphisms (SNPs) of the glutaminase (GLS) and lung cancer susceptibility in the Chinese Han population. METHODS: A total of 684 lung cancer patients and 684 healthy individuals were enrolled. Five GLS SNPs (rs143584207 C/A, rs117985587 T/C, rs74271715 G/T, rs2355570 G/A, and rs6713444 A/G) were screened as candidate genetic loci. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the association between GLS SNPs and lung cancer susceptibility. False-positive report probability (FPRP) analysis further verified whether the positive results deserved attention. Finally, the multi-factor dimensionality reduction (MDR) method was applied to analyze the interactions between SNPs. RESULTS: The overall analysis revealed that GLS rs143584207 and rs6713444 were significantly associated with lung cancer susceptibility. The subgroup and clinical information analyses further revealed that GLS rs143584207 and rs6713444 could remarkably reduce lung cancer susceptibility in different subgroups (age >60, females, body mass index (BMI) <24, and lung adenocarcinoma). Rs143584207 could significantly reduce lung cancer susceptibility in non-smokers. Additionally, rs6713444 also had a protective effect on patients with advanced lung cancer. CONCLUSIONS: Our study indicated that GLS rs143584207 and rs6713444 could strikingly reduce lung cancer susceptibility in the Chinese Han population, which will give a new direction for the timely treatment of lung cancer.