Establishment and validation of a predictive model for peripherally inserted central catheter-related thrombosis in patients with liver cancer.

BACKGROUND: Peripherally inserted central catheters (PICCs) are commonly used in hospitalized patients with liver cancer for the administration of chemotherapy, nutrition, and other medications. However, PICC-related thrombosis is a serious complication that can lead to morbidity and mortality in this patient population. Several risk factors have been identified for the development of PICC-related thrombosis, including cancer type, stage, comorbidities, and catheter characteristics. Understanding these risk factors and developing a predictive model can help healthcare providers identify high-risk patients and implement preventive measures to reduce the incidence of thrombosis. AIM: To analyze the influencing factors of PICC-related thrombosis in hospitalized patients with liver cancer, construct a predictive model, and validate it. METHODS: Clinical data of hospitalized patients with liver cancer admitted from January 2020 to December 2023 were collected. Thirty-five cases of PICC-related thrombosis in hospitalized patients with liver cancer were collected, and 220 patients who underwent PICC placement during the same period but did not develop PICC-related thrombosis were randomly selected as controls. A total of 255 samples were collected and used as the training set, and 77 cases were collected as the validation set in a 7:3 ratio. General patient information, case data, catheterization data, coagulation indicators, and Autar Thrombosis Risk Assessment Scale scores were analyzed. Univariate and multivariate unconditional logistic regression analyses were performed on relevant factors, and the value of combined indicators in predicting PICC-related thrombosis in hospitalized patients with liver cancer was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Univariate analysis showed statistically significant differences (P < 0.05) in age, sex, Karnofsky performance status score (KPS), bedridden time, activities of daily living impairment, parenteral nutrition, catheter duration, distant metastasis, and bone marrow suppression between the thrombosis group and the non-thrombosis group. Other aspects had no statistically significant differences (P > 0.05). Multivariate regression analysis showed that age ≥ 60 years, KPS score ≤ 50 points, parenteral nutrition, stage III to IV, distant metastasis, bone marrow suppression, and activities of daily living impairment were independent risk factors for PICC-related thrombosis in hospitalized patients with liver cancer (P < 0.05). Catheter duration of 1-6 months and catheter duration > 6 months were protective factors for PICC-related thrombosis (P < 0.05). The predictive model for PICC-related thrombosis was obtained as follows: P predictive probability = [exp (Logit P)]/[1 + exp (Logit P)], where Logit P = age × 1.907 + KPS score × 2.045 + parenteral nutrition × 9.467 + catheter duration × 0.506 + tumor-node-metastasis (TNM) staging × 2.844 + distant metastasis × 2.065 + bone marrow suppression × 2.082 + activities of daily living impairment × 13.926. ROC curve analysis showed an area under the curve (AUC) of 0.827 (95%CI: 0.724-0.929, P < 0.001), with a corresponding optimal cut-off value of 0.612, sensitivity of 0.755, and specificity of 0.857. Calibration curve analysis showed good consistency between the predicted occurrence of PICC-related thrombosis and actual occurrence (P > 0.05). ROC analysis showed AUCs of 0.888 and 0.729 for the training and validation sets, respectively. CONCLUSION: Age, KPS score, parenteral nutrition, TNM staging, distant metastasis, bone marrow suppression, and activities of daily living impairment are independent risk factors for PICC-related thrombosis in hospitalized patients with liver cancer, while catheter duration is a protective factor for the disease. The predictive model has an AUC of 0.827, indicating high predictive accuracy and clinical value.

CircUBA2 promotes the cancer stem cell-like properties of gastric cancer through upregulating STC1 via sponging miR-144-5p.

BACKGROUND: Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. METHODS: We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. RESULTS: CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. CONCLUSIONS: Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC.

Global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035.

OBJECTIVE: To study the historical global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. METHODS: Incidence data were retrieved from the Cancer Incidence in Five Continents (CI5) volumes I-XI, and mortality data were obtained from the latest update of the World Health Organization (WHO) mortality database. We used join-point regression analysis to examine historical incidence and mortality trends and used the package NORDPRED in R to predict the number of deaths and mortality rates by 2035 by country and sex. RESULTS: More than 1,089,000 new cases of gastric cancer and 769,000 related deaths were reported in 2020. The average annual percent change (AAPC) in the incidence of gastric cancer from 2003 to 2012 among the male population, South Korea, Japan, Malta, Canada, Cyprus, and Switzerland showed an increasing trend (P > 0.05); among the female population, Canada [AAPC, 1.2; (95%Cl, 0.5-2), P < 0.05] showed an increasing trend; and South Korea, Ecuador, Thailand, and Cyprus showed an increasing trend (P > 0.05). AAPC in the mortality of gastric cancer from 2006 to 2015 among the male population, Thailand [3.5 (95%cl, 1.6-5.4), P < 0.05] showed an increasing trend; Malta Island, New Zealand, Turkey, Switzerland, and Cyprus had an increasing trend (P > 0.05); among the male population aged 20-44, Thailand [AAPC, 3.4; (95%cl, 1.3-5.4), P < 0.05] showed an increasing trend; Norway, New Zealand, The Netherlands, Slovakia, France, Colombia, Lithuania, and the USA showed an increasing trend (P > 0.05). It is predicted that the mortality rate in Slovenia and France's female population will show an increasing trend by 2035. It is predicted that the absolute number of deaths in the Israeli male population and in Chile, France, and Canada female population will increase by 2035. CONCLUSION: In the past decade, the incidence and mortality of gastric cancer have shown a decreasing trend; however, there are still some countries showing an increasing trend, especially among populations younger than 45 years. Although mortality in most countries is predicted to decline by 2035, the absolute number of deaths due to gastric cancer may further increase due to population growth.

N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway.

BACKGROUND: Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori-induced HIF-1α expression and carcinogenesis remain unclear. AIM: To explore the underlying mechanism of H. pylori-induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1). METHODS: The study was conducted with human GES-1 cells in vitro. Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively. RESULTS: H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect. CONCLUSION: H. pylori-induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.

The association between heparin sensitivity index and postoperative blood loss in Chinese patients undergoing elective off-pump coronary artery bypass grafting: a single center retrospective study.

BACKGROUND: The heparin sensitivity index (HSI) is closely associated with perioperative ischemic events and increased blood loss in cardiac surgery. Previous studies have produced conflicting results. Therefore, this study aimed to investigate the relationship between HSI and postoperative blood loss specifically in Chinese patients undergoing elective off-pump coronary artery bypass grafting (OPCAB). METHODS: Patients underwent OPCAB between March 2021 and July 2022 were retrospectively included. Enrolled patients were classified into Low-HSI (HSILOW; HSI < 1.3) and Normal-HSI (HSINORM; HSI ≥ 1.3) groups. HSI = [(activated clotting time (ACT) after heparin) - (baseline ACT)] / [loading dose of heparin (IU/kg)]. Primary outcome included postoperative blood loss at 24 h. Secondary outcomes were total postoperative blood loss, transfusion requirement of red blood cell (RBC), fresh frozen plasma (FFP), platelet concentrates (PC), and other complications. RESULTS: We retrospectively analyzed 303 Chinese OPCAB patients. HSILOW group had higher preoperative platelet (PLT) count (221 × 109/L vs. 202 × 109/L; P = 0.041) and platelet crit (PCT) value (0.23% vs. 0.22%; P = 0.040) compared to HSINORM group. Two groups showed no significant differences in postoperative blood loss at 24 h (460 mL vs. 470 mL; P = 0.252), total blood loss (920 mL vs. 980 mL; P = 0.063), RBC transfusion requirement (3.4% vs. 3.1%; P = 1.000), FFP transfusion requirement (3.4% vs. 6.2%; P = 0.380), and other complications. Preoperative high PLT count was associated with low intraoperative HSI value (odds ratio: 1.006; 95% confidence interval: 1.002, 1.011; P = 0.008). CONCLUSIONS: Intraoperative HSI value was not associated with postoperative blood loss in Chinese patients undergoing OPCAB. Preoperative high PLT count was an independent predictor of low intraoperative HSI value.

Acute treatment of bilateral rTMS combined with antidepressants on the plasma fatty acids for major depressive episodes.

Bilateral repetitive transcranial magnetic stimulation (B-rTMS) has been largely used in the treatment of major depressive disorder (MDD). Nonetheless, information on the acute treatment by B-rTMS combined with antidepressants (ADs) on the plasma fatty acids in MDD is limited. The present study focused on depressive symptoms; Plasma was obtained from 27 adult patients with MDD at baselinephase (MDD), after 2 weeks of treatment (MDD-2w), and 27 healthy controls (HC). Meanwhile, we evaluated the composition of short-chain fatty acids (SCFAs) and medium-and long-chain fatty acids (MLCFAs) in the plasma. Consequently, the levels of Isobutyric acid, Caproic acid, and Propionic acid were low both in the MDD and MDD-2w groups and negatively correlated with the scores of HAMD and HAMA. Besides, minimal changes were observed between the MDD and HC groups, whereas significant MLCFA levels were high in the MDD-2w group. Moreover, we developed combined panels that could effectively differentiate MDD from HCs (AUC=0.99), MDD-2w from HC (AUC=0.983), and MDD from MDD-2w (AUC=0.852). These findings may provide a reference for the use of B-rTMS combined with ADs against the acute phase of depressive episodes and shed light on the relationship between plasma FAs and MDD.

Synthesis and Characterization of Negative-Tone Photosensitive Polyimides with Low Coefficient of Thermal Expansion for Packaging Applications.

Negative-tone photosensitive polyimides (PSPIs) with a low coefficient of thermal expansion (CTE) were prepared by dissolving polyimide precursor-poly(amide ester) (PAE) resins, photoinitiators, photocrosslinkers and other additives in organic solvents. Using triamine as a monomer and dianhydride and diamine as polycondensates, tri-branched structure PAE resins with different molecular weights named PAE-1~5 were prepared. A series of corresponding PSPI films named PSPI-1~5 were prepared from PAE-1~5 resins with the same formulation, respectively. The PSPI-1~5 films prepared from resins of this structure have excellent mechanical, thermal and electrical properties after being thermally cured at 350 °C/2 h in nitrogen. The PSPI-1~5 films' coating solution also show good photolithographic performance and are able to obtain photolithographic patterns with a resolution of about 10 µm after homogenization, exposure and development. Among the PSPI-1~5 films, PSPI-2 has the most excellent lithographic properties with a weight average molecular weight (Mw) of 2.9 × 104 g/mol, a CTE of 41 ppk/°C, a glass transition temperature (Tg) of 343 °C and a 5% weight loss temperature (Td5) of 520 °C, making it suitable for industrial scale-up. The mechanical properties of elongation at breakage of 42.4%, tensile moduli of 3.4 GPa and tensile strength of 153.7 MPa were also measured.

The Role of Ferroptosis in Atrial Fibrillation: A Promising Future.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, with its diagnosis being closely tied to higher rates of cardiovascular morbidity and mortality. AF is associated with a range of dangerous complications including stroke and heart failure, making it a key driver of healthcare spending and a major threat to global public health. The precise mechanisms that govern AF incidence and the onset of related complications, however, remain uncertain. Ferroptotic cell death has been the focus of rising interest in the cardiac arrhythmias, and there is recent evidence supporting a role for atrial ferroptosis as a mediator of AF development. Interventional strategies focused on ferroptotic activity, such as novel ferroptosis inhibitors, have also shown promise as a means of protecting against AF through their ability to reduce iron overload. In this review, we provide a summary of the proposed mechanisms whereby ferroptosis contributes to the pathophysiology of AF and their therapeutic implications.

Drug-coated balloon angioplasty for the treatment of intracranial arterial stenosis in a young stroke patient: A case report.

BACKGROUND: Intracranial arterial narrowing is a significant factor leading to brief episodes of reduced blood flow to the brain, known as transient ischemic attacks, or full-blown strokes. While atherosclerosis is commonly associated with intracranial arterial narrowing, it is frequently of a non-atherosclerotic nature in younger patients. CASE SUMMARY: Here, we present the case of a young stroke patient with narrowing of the middle cerebral artery (MCA), characterized as non-atherosclerotic lesions, who experienced an ischemic stroke despite receiving standard drug therapy. The patient underwent digital subtraction angiography (DSA) to assess the entire network of blood vessels in the brain, revealing significant narrowing (approximately 80%) in the M1 segment of the right MCA. Subsequently, the patient underwent Drug-Coated Balloon Angioplasty to treat the stenosis in the right MCA's M1 segment. Follow-up DSA confirmed the resolution of stenosis in this segment. Although the remaining branches showed satisfactory blood flow, the vessel wall exhibited irregularities. A review of DSA conducted six months later showed no evident stenosis in the right MCA, with a smooth vessel wall. CONCLUSION: The use of drug-coated balloon angioplasty demonstrated favorable outcomes in repairing and reshaping the blood vessel wall in young patients. Therefore, it may be considered a promising treatment option for similar cases.

Viral shedding pattern of severe fever with thrombocytopenia syndrome virus in severely ill patients: A prospective, Multicenter cohort study.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is spreading rapidly in Asia. The pathway of SFTS virus shedding from patient and specific use of personal protective equipments (PPEs) against viral transmission have rarely been reported. The study was to determine SFTS virus (SFTSV) shedding pattern from the respiratory, digestive and urinary tract to outside in patients. Methods: Patients were divided into mild and severe groups in three sentinel hospitals for SFTS in Anhui province from April 2020 to October 2022. SFTSV level from blood, throat swabs, fecal/anal swabs, urine and bedside environment swabs of SFTS patients were detected by qRT-PCR. Specific PPEs were applied in healthcare workers contacting with the patients who had oropharyngeal virus shedding and hemorrhagic signs. Results: A total of 189 SFTSV-confirmed patients were included in the study, 54 patients died (case fatality rate, 28.57 %). Positive SFTSV in throat swabs (T-SFTSV), fecal/anal swabs (F-SFTSV) and urine (U-SFTSV) were detected in 121 (64.02 %), 91 (48.15 %) and 65 (34.4 %) severely ill patients, respectively. The levels of T-SFTSV, F-SFTSV and U-SFTSV were positively correlated with the load of SFTSV in blood. We firstly revealed that SFTSV positive rate of throat swabs were correlated with occurrence of pneumonia and case fatality rate of patients (P < 0.0001). Specific precaution measures were applied by healthcare workers in participating cardiopulmonary resuscitation and orotracheal intubation for severely ill patients with positive T-SFTSV, no event of SFTSV human-to-human transmission occurred after application of effective PPEs. Conclusions: Our research demonstrated SFTSV could shed out from blood, oropharynx, feces and urine in severely ill patients. The excretion of SFTSV from these parts was positively correlated with viral load in the blood. Effective prevention measures against SFTSV human-to-human transmission are needed.

Efficient Chemical Synthesis of Multi-Monoubiquitylated and Diubiquitylated Histones by the α-Halogen Ketone-Mediated Strategy.

The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones. We were surprised to find that the synthetic efficiencies of multi-monoubiquitylated histones were comparable to those of single-monoubiquitylated ones, suggesting that this strategy is highly tolerant to the number of ubiquitin monomers installed onto histones. The facile generation of a series of single-, dual-, and triple-monoubiquitylated H3 proteins enabled us to evaluate the influence of ubiquitylation patterns on the binding of DNA methyltransferase 1 (DNMT1) to nucleosomes. Our study highlights the potential of site-specific conjugation chemistry to generate chemically defined histones for epigenetic studies.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis.

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

Therapeutic potential of salidroside in type I diabetic erectile dysfunction: Attenuation of oxidative stress and apoptosis via the Nrf2/HO-1 pathway.

The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in Sprague‒Dawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue.

Enantioselective synthesis of chiral amides by carbene insertion into amide N-H bond.

Chiral amides are important structure in many natural products and pharmaceuticals, yet their efficient synthesis from simple amide feedstock remains challenge due to its weak Lewis basicity. Herein, we describe our study of the enantioselective synthesis of chiral amides by N-alkylation of primary amides taking advantage of an achiral rhodium and chiral squaramide co-catalyzed carbene N-H insertion reaction. This method features mild condition, rapid reaction rate (in all cases 1 min) and a wide substrate scope with high yield and excellent enantioselectivity. Further product transformations show the synthetic potential of this reaction. Mechanistic studies reveal that the non-covalent interactions between the catalyst and reaction intermediate play a critical role in enantiocontrol.

Structural and mechanistic basis for nucleosomal H2AK119 deubiquitination by single-subunit deubiquitinase USP16.

Epigenetic regulators have a crucial effect on gene expression based on their manipulation of histone modifications. Histone H2AK119 monoubiquitination (H2AK119Ub), a well-established hallmark in transcription repression, is dynamically regulated by the opposing activities of Polycomb repressive complex 1 (PRC1) and nucleosome deubiquitinases including the primary human USP16 and Polycomb repressive deubiquitinase (PR-DUB) complex. Recently, the catalytic mechanism for the multi-subunit PR-DUB complex has been described, but how the single-subunit USP16 recognizes the H2AK119Ub nucleosome and cleaves the ubiquitin (Ub) remains unknown. Here we report the cryo-EM structure of USP16-H2AK119Ub nucleosome complex, which unveils a fundamentally distinct mode of H2AK119Ub deubiquitination compared to PR-DUB, encompassing the nucleosome recognition pattern independent of the H2A-H2B acidic patch and the conformational heterogeneity in the Ub motif and the histone H2A C-terminal tail. Our work highlights the mechanism diversity of H2AK119Ub deubiquitination and provides a structural framework for understanding the disease-causing mutations of USP16.

Endogenous Retroviruses Unveiled: A Comprehensive Review of Inflammatory Signaling/Senescence-Related Pathways and Therapeutic Strategies.

Endogenous retroviruses (ERVs), a subset of genomic transposable elements (TEs) in a broader sense, have remained latent within mammalian genomes for tens of millions of years. These genetic elements are typically in a silenced state due to stringent regulatory mechanisms. However, under specific conditions, they can become activated, triggering inflammatory responses through diverse mechanisms. This activation has been shown to play a potential role in various neurological disorders, tumors, and cellular senescence. Consequently, the regulation of ERV expression through various methods holds promise for clinical applications in disease treatment. ERVs also engage in interactions with a variety of exogenous viruses, thereby influencing the outcomes of viral infectious diseases. This article comprehensively reviews the pathogenic cascade of ERVs, encompassing activation, inflammation, associated diseases, senescence, and interplay with viruses. Additionally, it outlines therapeutic strategies targeting ERVs with the aim of offering novel research directions for understanding the relationship between ERVs and diseases, along with corresponding treatment modalities.

Cynanchum paniculatum (Bunge) Kitag. ex H.Hara inhibits pancreatic cancer progression by inducing caspase-dependent apoptosis and suppressing TGF-ß-mediated epithelial-mesenchymal transition.

Background: Cynanchum paniculatum (Bunge) Kitag. ex H.Hara, a member of the Asclepiadaceae family, has a rich history as a traditional Chinese medicinal plant used to treat digestive disorders. However, its potential anti-cancer effects in pancreatic cancer remain largely unexplored. Aim: This study delves into the intricate anti-pancreatic cancer mechanisms of C. paniculatum (Bunge) Kitag. ex H.Hara aqueous extract (CPAE) by elucidating its role in apoptosis induction and the inhibition of invasion and migration. Methods: A comprehensive set of methodologies was employed to assess CPAE's impact, including cell viability analyses using MTT and colony formation assays, flow cytometry for cell cycle distribution and apoptosis assessment, scratch-wound and Matrigel invasion assays for migration and invasion capabilities, and immunoblotting to measure the expression levels of key proteins involved in apoptosis and metastasis. Additionally, a murine xenograft model was established to investigate CPAE's in vivo anti-cancer potential. Results: CPAE exhibited time- and dose-dependent suppression of proliferation and colony formation in pancreatic cancer cells. Notably, CPAE induced apoptosis and G2/M phase arrest, effectively activating the caspase-dependent PARP pathway. At non-cytotoxic doses, CPAE significantly curtailed the metastatic abilities of pancreatic cells, effectively suppressing epithelial-mesenchymal transition (EMT) and downregulating the TGF-ß1/Smad2/3 pathway. In vivo experiments underscored CPAE's ability to inhibit tumor proliferation. Conclusion: This study illuminates the multifaceted anti-proliferative, pro-apoptotic, anti-invasive, and anti-migratory effects of CPAE, both in vitro and in vivo. CPAE emerges as a promising herbal medicine for pancreatic cancer treatment, with its potential mediated through apoptosis induction via the caspase-dependent PARP pathway and MET suppression via the TGF-ß1/Smad2/3 signaling pathway at non-cytotoxic doses. These findings advocate for further exploration of CPAE's therapeutic potential in pancreatic cancer.

Copper-Catalyzed Enantioselective Synthesis of Spirohydroindoles by Ethoxyformylmethylene Oxindole and Iminoester 1,3-Dipole Cycloaddition: An Examination of Associated Biological Activities.

A highly enantioselective 1,3-dipolar cycloaddition of ethoxyformylmethylene oxindole with iminoesters has been achieved using the Cu(I)-(S,Sp)-Ph Phosferrox catalytic system, generating a series of chiral spiro[pyrrolidin-3,3'-oxindole] compounds with four consecutive stereocenters, including a spirocycle quaternary center (71%-99% yield, up to >20:1 dr and 95:5 er). The compounds exhibited good inhibitory activity against Valsa mali (V.m.), Fusarium oxysporium (F.o.), and Alternaria brassicae (A.b.).

Robotic versus laparoscopic distal gastrectomy for resectable gastric cancer: a randomized phase 2 trial.

Robotic surgery may be an alternative to laparoscopic surgery for gastric cancer (GC). However, randomized controlled trials (RCTs) reporting the differences in survival between these two approaches are currently lacking. From September 2017 to January 2020, 300 patients with cT1-4a and N0/+ were enrolled and randomized to either the robotic (RDG) or laparoscopic distal gastrectomy (LDG) group (NCT03313700). The primary endpoint was 3-year disease-free survival (DFS); secondary endpoints reported here are the 3-year overall survival (OS) and recurrence patterns. The remaining secondary outcomes include intraoperative outcomes, postoperative recovery, quality of lymphadenectomy, and cost differences, which have previously been reported. There were 283 patients in the modified intention-to-treat analysis (RDG group: n = 141; LDG group: n = 142). The trial has met pre-specified endpoints. The 3-year DFS rates were 85.8% and 73.2% in the RDG and LDG groups, respectively (p = 0.011). Multivariable Cox regression model including age, tumor size, sex, ECOG PS, lymphovascular invasion, histology, pT stage, and pN stage showed that RDG was associated with better 3-year DFS (HR: 0.541; 95% CI: 0.314-0.932). The RDG also improved the 3-year cumulative recurrence rate (RDG vs. LDG: 12.1% vs. 21.1%; HR: 0.546, 95% CI: 0.302-0.990). Compared to LDG, RDG demonstrated non-inferiority in 3-year DFS rate.