Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.

OBJECTIVE: The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC. DESIGN: RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9. RESULTS: MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of ß-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC. CONCLUSIONS: CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.

Drawing Inspiration from Nature: Trinitarian Strategies for Designing Polyoxometalates and Metal-Organic Framework-Based Biomimetic Microhoneycomb Electromagnetic Wave-Absorbing Materials.

Trinitarian designs in the morphology, components, and microstructure remain challenging for advanced electromagnetic wave absorption (EMWA) materials with light weight, strong absorption, and well-defined structure-function relationships. Herein, a series of X-doped MoS2/Cu9S5 with multilevel honeycomb structures (X-MoS2/Cu9S5 MHs, X = P, Si, Ge) were designed by space-confined growth and in situ sulfidation of a polyoxometalate-based metal-organic framework. X-MoS2/Cu9S5 MHs possess low density, high surface area, and abundant cation-cuprum and anion-sulfur double vacancies (VCu and VS) simultaneously that are unmatched by conventional EMWA materials. Also, the systematic investigation of the doping effect of various polyoxometalate heteroatoms on VCu and VS in the microhoneycomb has been conducted. Experimental results and density functional theory calculations reveal that the excellent EMWA performance (-56.21 dB) results from the synergistic effect of morphology design, component optimization, and vacancy regulation. This study not only provides an important opportunity to understand a morphology-component-microstructure strategy in electromagnetic wave absorption but also builds a noteworthy bridge between bioinspired engineering and microscale absorbers.

Non-radical activation of persulfate with Bi2O3/BiO1.3I0.4 for efficient degradation of propranolol under visible light.

Non-radical activation of persulfate (PS) by photocatalysts is an effective approach for removing organic pollutants from aqueous environments. In this study, a novel Bi2O3/BiO1.3I0.4 heterojunction was synthesized using a facile solvothermal approach and used for the first time for non-radical activation of PS to degrade propranolol (PRO) in the presence of visible light. The findings found that the degradation rate of PRO in the Bi2O3/BiO1.3I0.4/PS system was significantly increased from 19% to more than 90% within 90 min compared to the Bi2O3/BiO1.3I0.4 system. This indicated that the composite system exerted an excellent synergistic effect between the photocatalyst and the persulfate-based oxygenation. Quenching tests and electron paramagnetic resonance demonstrated that the non-radical pathway with singlet oxygen as the active species played a major role in the photocatalytic process. The existence of photo-generated holes during the reaction could also be directly involved in the oxidation of pollutants. Meanwhile, a possible PRO degradation pathway was also proposed. Furthermore, the impacts of pH, humic acid and common anions on the PRO degradation by the Bi2O3/BiO1.3I0.4/PS were explored, and the system's stability and reusability were also studied. This study exhibits a highly productive catalyst for PS activation via a non-radical pathway and provides a new idea for the degradation of PRO.

Immunopotentiating Activity of Fucoidans and Relevance to Cancer Immunotherapy.

Fucoidans, discovered in 1913, are fucose-rich sulfated polysaccharides extracted mainly from brown seaweed. These versatile and nontoxic marine-origin heteropolysaccharides have a wide range of favorable biological activities, including antitumor, immunomodulatory, antiviral, antithrombotic, anticoagulant, antithrombotic, antioxidant, and lipid-lowering activities. In the early 1980s, fucoidans were first recognized for their role in supporting the immune response and later, in the 1990s, their effects on immune potentiation began to emerge. In recent years, the understanding of the immunomodulatory effects of fucoidan has expanded significantly. The ability of fucoidan(s) to activate CTL-mediated cytotoxicity against cancer cells, strong antitumor property, and robust safety profile make fucoidans desirable for effective cancer immunotherapy. This review focusses on current progress and understanding of the immunopotentiation activity of various fucoidans, emphasizing their relevance to cancer immunotherapy. Here, we will discuss the action of fucoidans in different immune cells and review how fucoidans can be used as adjuvants in conjunction with immunotherapeutic products to improve cancer treatment and clinical outcome. Some key rationales for the possible combination of fucoidans with immunotherapy will be discussed. An update is provided on human clinical studies and available registered cancer clinical trials using fucoidans while highlighting future prospects and challenges.

Diagnostic and prognostic significance of miR-451a in patients with atherosclerosis.

OBJECTIVES: Atherosclerosis (AS) is a chronic inflammatory vascular disease. This study aimed to detect the expression level of miR-451a and investigate the diagnostic and prognostic values of miR-451a for AS patients. METHODS: The relative expression of miR-451a was assessed by qRT-PCR. Comparison of groups was analyzed with the t-test and chi-squared test. Pearson analysis was used to validate the correlation of miR-451 with CRP and CIMT. The receiver operating characteristic (ROC) curves, K-M analysis, and Cox regression analysis were conducted to explore the roles of miR-451a in diagnosing AS patients and predicting outcomes of AS patients. RESULTS: The expression of miR-451a was significantly decreased in the serum of AS patients. The results of Pearson analysis showed the expression of miR-451a was negatively correlated with CRP and CIMT. The data of ROC proposed miR-451a could differentiate AS patients from healthy individuals with high sensitivity and specificity. K-M analysis and Cox regression showed miR-451a might be an independent biomarker of suffering cardiovascular endpoint diseases in AS patients. The expression of miR-451a was obviously inhibited in AS patients with cardiovascular endpoint events. CONCLUSION: Deregulation of miR-451a might be associated with the development of AS. MiR-451a might be used as a promising diagnostic and prognostic biomarker for clinical treatment of AS patients.

Detection of Green Asparagus Using Improved Mask R-CNN for Automatic Harvesting.

Advancements in deep learning and computer vision have led to the discovery of numerous effective solutions to challenging problems in the field of agricultural automation. With the aim to improve the detection precision in the autonomous harvesting process of green asparagus, in this article, we proposed the DA-Mask RCNN model, which utilizes the depth information in the region proposal network. Firstly, the deep residual network and feature pyramid network were combined to form the backbone network. Secondly, the DA-Mask RCNN model added a depth filter to aid the softmax function in anchor classification. Afterwards, the region proposals were further processed by the detection head unit. The training and test images were mainly acquired from different regions in the basin of the Yangtze River. During the capturing process, various weather and illumination conditions were taken into account, including sunny weather, sunny but overshadowed conditions, cloudy weather, and daytime greenhouse conditions as well as nighttime greenhouse conditions. Performance experiments, comparison experiments, and ablation experiments were carried out using the five constructed datasets to verify the effectiveness of the proposed model. Precision, recall, and F1-score values were applied to evaluate the performances of different approaches. The overall experimental results demonstrate that the balance of the precision and speed of the proposed DA-Mask RCNN model outperform those of existing algorithms.

Effects of process water obtained from hydrothermal carbonization of poultry litter on soil microbial community, nitrogen transformation, and plant nitrogen uptake.

Process water (PW) obtained from hydrothermal carbonization of nitrogen-rich (N-rich) biowaste is proposed to be a renewable resource utilized as a liquid N fertilizer. However, its effects on soil microbial community, N transformation, and plant N uptake are unclear or controversial. In this study, fertilizers were prepared with different percentages of PW (poultry litter, 220 °C 1 or 8 h, PW-S or -L) and urea to supply 160 mg kg-1 total N in a barren alkali soil. Results showed that the addition of PW relative to pure urea decreased organic N mineralization by low bio-accessibility, increased N loss by high soil pH, and decreased NO3--N by low nitrification substrate. It supported the lettuce in health but decreased plant N uptake by low NO3--N. It significantly increased the gram-positive bacteria that responded to resistant organic matter, changed the bacterial community to enhance decomposition, detoxification, ureolysis, and denitrification, and to decrease nitrification. Its inhibition effect on nitrification activity was stronger than that on nitrifiers growth. Different from PW-S, the addition of PW-L seriously and significantly decreased seed germination index and fungal biomass that responded to N retaining capacity, respectively. The best fertilizer was 50% urea +50% PW-S that supported the seed germination and seedling growth, and mildly affected microbial community.

A prediction model for xerostomia in locoregionally advanced nasopharyngeal carcinoma patients receiving radical radiotherapy.

BACKGROUND: This study was to evaluate the predictors of xerostomia and Grade 3 xerostomia in locoregionally advanced nasopharyngeal carcinoma (NPC) patients receiving radical radiotherapy and establish prediction models for xerostomia and Grade 3 xerostomia based on the predictors. METHODS: Totally, 365 patients with locoregionally advanced NPC who underwent radical radiotherapy were randomly divided into the training set (n = 255) and the testing set (n = 110) at a ratio of 7:3. All variables were included in the least absolute shrinkage and selection operator regression to screen out the potential predictors for xerostomia as well as the Grade 3 xerostomia in locoregionally advanced NPC patients receiving radical radiotherapy. The random forest (RF), a decision tree classifier (DTC), and extreme-gradient boosting (XGB) models were constructed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC) and accuracy were analyzed to evaluate the predictive performance of the models. RESULTS: In the RF model for predicting xerostomia, the sensitivity was 1.000 (95%CI 1.000-1.000), the PPV was 0.990 (95%CI 0.975-1.000), the NPV was 1.000 (95%CI 1.000-1.000), the AUC was 0.999 (95%CI 0.997-1.000) and the accuracy was 0.992 (95%CI 0.981-1.000) in the training set. The sensitivity was 0.933 (95%CI 0.880-0.985), the PPV was 0.933 (95%CI 0.880-0.985), and the AUC was 0.915 (95%CI 0.860-0.970) in the testing set. Hypertension, age, total radiotherapy dose, dose at 50% of the left parotid volume, mean dose to right parotid gland, mean dose to oral cavity, and course of induction chemotherapy were important variables associated with the risk of xerostomia in locoregionally advanced NPC patients receiving radical radiotherapy. The AUC of DTC model for predicting xerostomia was 0.769 (95%CI 0.666-0.872) in the testing set. The AUC of the XGB model for predicting xerostomia was 0.834 (0.753-0.916) in the testing set. The RF model showed the good predictive ability with the AUC of 0.986 (95%CI 0.972-1.000) in the training set, and 0.766 (95%CI 0.626-0.905) in the testing set for identifying patients who at high risk of Grade 3 xerostomia in those with high risk of xerostomia. CONCLUSIONS: An RF model for predicting xerostomia in locoregionally advanced NPC patients receiving radical radiotherapy and an RF model for predicting Grade 3 xerostomia in those with high risk of xerostomia showed good predictive ability.

Proteome of Saccharomyces cerevisiae under paraquat stress regulated by therapeutic concentration of copper ions.

Paraquat (PQ) is a non-selective herbicide with strong toxicity to humans and mammals. However, the proteome regulation of cells by PQ is still unclear, limiting the development of effective antidotes. Studies have shown that a slight excess of intracellular copper levels could be beneficial to the survival under exposure to PQ. In this study, Saccharomyces cerevisiae was used as a model to explore the regulation effect of copper ions on PQ poisoning by the approach of date independent acquisition proteomics. The results showed that toxic effect of PQ was primarily induced by oxidative damage in the mitochondria and the disorder of gene expression. The addition of Cu2+ involved a series of favorable reactions to cell survival under PQ stress, including activation of the mitogen-activated protein kinase signaling pathway, regulation of processes such as sulfur metabolism, carbon metabolism and gene expression in cells. The generation of glutathione, heme and steroids advantageous to cell growth under stress was also increased. These findings inferred that therapeutic concentration of copper ions could prolong the survival of cells under PQ stress.

Selection of Aptamers Specific for DEHP Based on ssDNA Library Immobilized SELEX and Development of Electrochemical Impedance Spectroscopy Aptasensor.

A selection of aptamers specific for di(2-ethylhexyl) phthalate (DEHP) and development of electrochemical impedance spectroscopy (EIS) aptasensor are described in this paper. The aptamers were selected from an immobilized ssDNA library using the systematic evolution of ligands by exponential enrichment (SELEX). The enrichment was monitored using real-time quantitative PCR (Q-PCR), and the aptamers were identified by high-throughput sequencing (HTS), gold nanoparticles (AuNPs) colorimetric assay, and localized surface plasmon resonance (LSPR). The EIS aptasensor was developed to detect DEHP in water samples. After eight rounds of enrichment, HTS, AuNPs colorimetric assay, and LSPR analysis indicated that four aptamers had higher binding activity, and aptamer 31 had the highest affinity (Kd = 2.26 ± 0.06 nM). The EIS aptasensor had a limit of detection (LOD) of 0.103 pg/mL with no cross-reactivity to DEHP analogs and a mean recovery of 76.07% to 141.32% for detection of DEHP in water samples. This aptamer is novel with the highest affinity and sensitivity.

Forensic evaluation and population genetic study of 30 insertion/deletion polymorphisms in a Chinese Yi group.

Insertion/deletion polymorphisms have become a research hot spot in forensic science due to their tremendous potential in recent years. In the present study, we investigated 30 indel loci in a Chinese Yi ethnic group. The allele frequencies of the short allele of the 30 indel loci were in the range of 0.1025-0.9221. The power of discrimination values were observed ranging from to 0.2630 (HLD111 locus) to 0.6607 (HLD70 locus) and probability of exclusion values ranged from 0.0189 (HLD111 locus) to 0.2343 (HLD56 locus). The combined power of discrimination and power of exclusion for 30 loci in the studied Yi group were 0.99999999995713 and 0.97746, respectively, which showed tremendous potential for forensic personal identification in the Yi group. Moreover, the DA distances, phylogenetic tree, principal component analysis, and cluster analysis showed the Yi group had close genetic relationships with the Tibetan, South Korean, Chinese Han, and She groups.

Mechanism study of peptide GMBP1 and its receptor GRP78 in modulating gastric cancer MDR by iTRAQ-based proteomic analysis.

BACKGROUND: Multidrug resistance (MDR) is a major obstacle to the treatment of gastric cancer (GC). Using a phage display approach, we previously obtained the peptide GMBP1, which specifically binds to the surface of MDR gastric cancer cells and is subsequently internalized. Furthermore, GMBP1 was shown to have the potential to reverse the MDR phenotype of gastric cancer cells, and GRP78 was identified as the receptor for this peptide. The present study aimed to investigate the mechanism of peptide GMBP1 and its receptor GRP78 in modulating gastric cancer MDR. METHODS: Fluorescence-activated cell sorting (FACS) and immunofluorescence staining were used to investigate the subcellular location and mechanism of GMBP1 internalization. iTRAQ was used to identify the MDR-associated downstream targets of GMBP1. Differentially expressed proteins were identified in GMBP1-treated compared to untreated SGC7901/ADR and SGC7901/VCR cells. GO and KEGG pathway analyses of the differentially expressed proteins revealed the interconnection of these proteins, the majority of which are involved in MDR. Two differentially expressed proteins were selected and validated by western blotting. RESULTS: GMBP1 and its receptor GRP78 were found to be localized in the cytoplasm of GC cells, and GRP78 can mediate the internalization of GMBP1 into MDR cells through the transferrin-related pathway. In total, 3,752 and 3,749 proteins were affected in GMBP1-treated SGC7901/ADR and SGC7901/VCR cells, respectively, involving 38 and 79 KEGG pathways. Two differentially expressed proteins, CTBP2 and EIF4E, were selected and validated by western blotting. CONCLUSION: This study explored the role and downstream mechanism of GMBP1 in GC MDR, providing insight into the role of endoplasmic reticulum stress protein GRP78 in the MDR of cancer cells.

Natural variation in paternal behavior is associated with central estrogen receptor alpha and oxytocin levels.

In monogamous mammals paternal care plays an important role in the neural and behavioral development of offspring. However, the neuroendocrine mechanisms underlying paternal behavior remain poorly understood. Here, we investigate the association between natural variation in paternal responsiveness and central levels of oxytocin (OT) and estrogen receptor alpha (ERα). We used the frequency of licking and grooming behavior to distinguish low paternal responsiveness and high paternal responsiveness in virgin mandarin voles (Microtus mandarinus). Males that engaged in high paternal behavior had elevated levels of OT immunoreactive neurons in the paraventricular nuclei of the hypothalamus and supraoptic nuclei of the hypothalamus compared with males that displayed low paternal behavior. Likewise, males of high paternal responsiveness had more ERα immunoreactive neurons in the medial preoptic area, bed nucleus of the stria terminalis, arcuate nucleus of the hypothalamus and medial amygdaloid nucleus compared to low responsive males. The level of ERα immunoreactive neurons in the ventromedial hypothalamic nucleus was lower in highly paternal males compared to less paternal males. These results suggest that natural variation in paternal responsiveness may be directly related to variation in central OT and ERα.

Behavioral responses to pups in males with different reproductive experiences are associated with changes in central OT, TH and OTR, D1R, D2R mRNA expression in mandarin voles.

Male rodents behave differently toward pups because of different sexual and/or paternal experiences; however, the mechanisms underlying these responses are not well understood. Using socially monogamous mandarin voles (Microtus mandarinus) we investigated the behavioral responses of males with different reproductive experiences (virgin males, paired males and new fathers) to new born pups. Central levels of neuropeptide oxytocin (OT), tyrosine hydroxylase (TH), as well as oxytocin receptor (OTR), dopamine 1-type receptor (D1R) and dopamine 2-type receptor (D2R) mRNA expression in the nucleus accumbens and medial amygdala were also measured in these males. Our data showed that new fathers exhibited more approaching behavior and contained more OT-immunoreactive and TH-immunoreactive neurons. In addition to increased OTR mRNA expression in the nucleus accumbens and medial amygdala, new fathers had higher D1R and D2R mRNA expression in the nucleus accumbens, and less D1R and D2R mRNA expression in the medial amygdala than paired males. These results demonstrate that males with different reproductive experiences display different behavioral responses to pups and that these differences are associated with altered OT and dopamine, and their receptors in specific brain regions.

Effects of drying process of yuanzhi (Radix Palygalae) on its bioactive ingredients.

OBJECTIVE: To study the effects of the drying processing in terms operational parameters on the bioactive constituents of six Yuanzhi (Radix Palygalae) samples across China. METHODS: Six Yuanzhi (Radix Palygalae) samples were investigated using thermogravimetry analysis. The heating courses were set in two ways: the temperature-programmed process from room temperature to 150 degrees C, and the constant-temperature course at 50 degrees C, 70 degrees C and 90 degrees C. RESULTS: The peak temperature of six Yuanzhi (Radix Palygalae) samples ranged from 78 degrees C to 88 degrees C. The mass loss rate of Yuanzhi (Radix Palygalae) alcohol-soluble extract was significantly increased when heated at 90 degrees C. Four types of bioactive ingredients were detected in volatile oils of Yuanzhi (Radix Palygalae) sample from Shanxi province by Gas Chromatography-mass spectrometry analysis. Fourier Transform Infrared Spectroscopy results showed that the drying temperature exerted a great influence on types and amount of ingredients of Yuanzhi (Radix Palygalae). The kinetic study showed that the constant-temperature drying process of Yuanzhi Radix Palygalae) samples could be well described by the Page Model, especially for the drying process at 50 degrees C, in which R2 and SD values were more than 0.98 and less than 0.04, respectively. The drying constant k of three Yuanzhi (Radix Palygalae) samples from Shanxi, Gansu and Shaanxi provinces in China was corresponding to the Arrhenius equation, and their activation energies were 28.07, 25.38 and 21.48 kJ/mol, respectively. CONCLUSION: The drying process of Yuanzhi (Radix Palygalae) was very important for bioactive ingredients improvement in Yuanzhi (Radix Palygalae). Temperature was a thermodynamic property significantly affecting the process.

Case report: Clinical complete response in advanced ALK-positive lung squamous cell carcinoma: a case study of successful anti-PD-1 immunotherapy post ALK-TKIs failure.

In patients with advanced lung adenocarcinoma (LADC) harboring the echinoderm microtubule-associated protein-like 4 (EML4) -anaplastic lymphoma kinase (ALK) rearrangement, targeted therapy typically demonstrates superior efficacy as an initial treatment compared to chemotherapy. Following resistance to ALK-tyrosine kinase inhibitors (TKIs), regimens incorporating platinum-based dual agents or combined with bevacizumab often show effectiveness. However, therapeutic alternatives become constrained after resistance develops to both TKIs and platinum-based therapies. Given that the majority of ALK-positive non-small cell lung carcinomas (NSCLC) are LADC, the benefits of TKIs for patients with ALK-positive lung squamous cell carcinoma (LSCC) and the optimal treatment strategy for these patients remain a subject of debate. In this case study, we report on a patient with advanced LSCC, in whom the EML4-ALK rearrangement was identified via ARMS-PCR (Amplification Refractory Mutation System-Polymerase Chain Reaction). The patient underwent oral treatment with crizotinib and alectinib, showing effectiveness in both first-line and second-line ALK-TKI therapies, albeit with limited progression-free survival (PFS). Subsequent resistance to second-generation TKI was followed by the detection of tumors in the left neck region via computed tomography (CT). Biopsy pathology revealed non-squamous cell carcinoma, and subsequent treatment with platinum-based double-drug therapy proved ineffective. Further analysis through next-generation sequencing (NGS) indicated ALK negativity but a high expression of programmed death-ligand 1 (PD-L1). Immunotherapy was then initiated, resulting in a PFS of over 29 months and clinical complete remission (cCR). This case underscores the potential benefit of ALK-TKIs in patients with ALK-positive LSCC. Resistance to second-generation TKIs may lead to ALK negativity and histological transformation, highlighting the necessity of repeated biopsies post-TKI resistance for informed treatment decision-making. As of November 2023, imaging studies continue to indicate cCR in the patient, with a survival time exceeding 47 months.

New insights from bidirectional Mendelian randomization: causal relationships between telomere length and mitochondrial DNA copy number in aging biomarkers.

Mitochondrial DNA (mtDNA) copy number and telomere length (TL) are dynamic factors that have been linked to the aging process in organisms. However, the causal relationship between these variables remains uncertain. In this research, instrumental variables (IVs) related to mtDNA copy number and TL were obtained from publicly available genome-wide association studies (GWAS). Through bidirectional Mendelian randomization (MR) analysis, we examined the potential causal relationship between these factors. The forward analysis, with mtDNA copy number as the exposure and TL as the outcome, did not reveal a significant effect (B=-0.004, P>0.05). On the contrary, upon conducting a reverse analysis, it was found that there exists a positive causal relationship (B=0.054, P<0.05). Sensitivity analyses further confirmed the reliability of these results. The outcomes of this study indicate a one-way positive causal relationship, indicating that telomere shortening in the aging process may lead to a decrease in mtDNA copy number, providing new perspectives on their biological mechanisms.

Clinical characteristics of acute non-varicose upper gastrointestinal bleeding and the effect of endoscopic hemostasis.

BACKGROUND: Acute non-variceal upper gastrointestinal bleeding (ANVUGIB) constitutes a prevalent emergency within Gastroenterology, encompassing 80%-90% of all gastrointestinal hemorrhage incidents. This condition is distinguished by its abrupt onset, swift progression, and notably elevated mortality rate. AIM: To gather clinical data from patients with ANVUGIB at our hospital in order to elucidate the clinical characteristics specific to our institution and analyze the therapeutic effectiveness of endoscopic hemostasis. METHODS: We retrospectively retrieved the records of 532 patients diagnosed with ANVUGIB by endoscopy at our hospital between March 2021 and March 2023, utilizing our medical record system. Data pertaining to general patient information, etiological factors, disease outcomes, and other relevant variables were meticulously collected and analyzed. RESULTS: Among the 532 patients diagnosed with ANVUGIB, the male-to-female ratio was 2.91:1, with a higher prevalence among males. Notably, 43.6% of patients presented with black stool as their primary complaint, while 27.4% had hematemesis as their initial symptom. Upon admission, 17% of patients exhibited both hematemesis and black stool, while most ANVUGIB patients primarily complained of overt gastrointestinal bleeding. Urgent routine blood examinations at admission revealed that 75.8% of patients had anemia, with 63.4% experiencing moderate to severe anemia, and 1.5% having extremely severe anemia (hemoglobin < 30 g/L). With regard to etiology, 53.2% of patients experienced bleeding without a definitive trigger, 24.2% had a history of using gastric mucosa-irritating medications, 24.2% developed bleeding after alcohol consumption, 2.8% attributed it to improper diet, 1.7% to emotional excitement, and 2.3% to fatigue preceding the bleeding episode. Drug-induced ANVUGIB was more prevalent in the elderly than middle-aged and young individuals, while bleeding due to alcohol consumption showed the opposite trend. Additionally, diet-related bleeding was more common among the young age group compared to the middle-aged group. Gastrointestinal endoscopy identified peptic ulcers as the most frequent cause of ANVUGIB (73.3%), followed by gastrointestinal malignancies (10.9%), acute gastric mucous lesions (9.8%), and androgenic upper gastrointestinal bleeding (1.5%) among inpatients with ANVUGIB. Of the 532 patients with gastrointestinal bleeding, 68 underwent endoscopic hemostasis, resulting in an endoscopic treatment rate of 12.8%, with a high immediate hemostasis success rate of 94.1%. CONCLUSION: ANVUGIB patients exhibit diverse characteristics across different age groups, and endoscopic hemostatic treatments have demonstrated remarkable efficacy.

Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma.

Timely liver function recovery (LFR) is crucial for postoperative hepatocellular carcinoma (HCC) patients. Here, we established the significance of LFR on patient long-term survival through retrospective and prospective cohorts and identified a key gut microbe, Bifidobacterium longum, depleted in patients with delayed recovery. Fecal microbiota transfer from HCC patients with delayed recovery to mice similarly impacted recovery time post hepatectomy. However, oral gavage of B. longum improved liver function and repair in these mice. In a clinical trial of HCC patients, orally administering a probiotic bacteria cocktail containing B. longum reduced the rates of delayed recovery, shortened hospital stays, and improved overall 1-year survival. These benefits, attributed to diminished liver inflammation, reduced liver fibrosis, and hepatocyte proliferation, were associated with changes in key metabolic pathways, including 5-hydroxytryptamine, secondary bile acids, and short-chain fatty acids. Our findings propose that gut microbiota modulation can enhance LFR, thereby improving postoperative outcomes for HCC patients.

CInQ-03, a novel allosteric MEK inhibitor, suppresses cancer growth in vitro and in vivo.

The mitogen-activated protein kinase kinase 1 and 2 signaling pathway is a major component of the RAS (Rat sarcoma)/RAF (Radpidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERKs (Extracellular signal-regulated kinases) signaling axis that regulates tumorigenesis and cancer cell growth. MEK is frequently activated in various cancers that have mutations in the KRAS and BRAF oncogenes. Therefore, MEK has been suggested as a therapeutic target for inhibitor development against tumors that are dependent on the activating mutations in mitogen-activated protein kinase signaling. Herein, we report the discovery of three novel MEK inhibitors, herein referred to as CInQ-01, CInQ-03 and CInQ-06. All three inhibitors were highly effective in suppressing MEK1 and MEK2 in vitro kinase activity as well as anchorage-dependent and anchorage-independent cell growth. The inhibitory activity was associated with markedly reduced phosphorylation of ERKs and ribosomal S6 kinases. Furthermore, administration of CInQ-03 inhibited colon cancer cell growth in an in vivo xenograft mouse model and showed no skin toxicity. Overall, these results suggest that these novel MEK inhibitors might be used for chemotherapy or prevention.