Hemicyanine-Based Highly Water-soluble Probe for Extracellular Nitroreductase.

Nitroreductase (NTR) has long been a target of interest for its important role involved in the nitro compounds metabolism. Various probes have been reported for NTR analysis, but rarely able to distinguish the extracellular NTR from intracellular ones. Herein we reported a new NTR sensor, HCyS-NO2, which was a hemicyanine molecule with one nitro and two sulfo groups attached. The nitro group acted as the reporting group to respond NTR reduction. Direct linkage of nitro group into the hemicyanine π conjugate system facilitated the intramolecular electron transfer (IET) process and thus quenched the fluorescence of hemicyanine core. Upon reduction with NTR, the nitro group was rapidly converted into the hydroxylamino and then the amino group, eliminating IET process and thus restoring the fluorescence. The sulfo groups installed significantly increased the hydrophilicity of the molecule, and introduced negative charges at physiological pH, preventing the diffusion into bacteria. Both gram-negative and gram-positive bacteria were able to turn on the fluorescence of HCyS-NO2, without detectable diffusion into cells, providing a useful tool to probe the extracellular reduction process.

A novel circPIK3C2A/miR­31­5p/TFRC axis drives ferroptosis and accelerates myocardial injury.

Iron overload is common in cardiovascular disease, it is also the factor that drives ferroptosis. Noncoding RNAs play an important role in heart disease; however, their regulatory role in iron overload-mediated ferroptosis remains much unknown. In our study, the iron overload model in mice was constructed through a high-iron diet, and ammonium iron citrate  treatment was used to mimic iron overload in vitro. We found iron overload induced ferroptosis in cardiomyocytes, which was dependent on the high expression of transferrin receptor (TFRC). MiR-31-5p was downregulated during iron overload; it inhibited cardiomyocyte ferroptosis by targeting TFRC. CircPIK3C2A, a highly expressed circRNA in the heart, was upregulated when iron was overloaded. CircPIK3C2A enhanced the expression of TFRC by sponging miR-31-5p and promoted ferroptosis during iron overload. Our results reveal a novel mechanistic insight into noncoding RNA-based ferroptosis and identify the circPIK3C2A/miR-31-5p/TFRC axis as a promising therapeutic target for myocardial damage.

Coverage of the Combined DTaP-IPV/Hib Vaccine Among Children Aged 2-18 Months - 9 PLADs, China, 2019-2021.

What is already known on this topic?: In China, there is limited data available on the use and coverage of the non-program, combined diphtheria, tetanus toxoid, acellular pertussis adsorbed, inactivated poliovirus and haemophilus influenzae type b (DTaP-IPV/Hib) pentavalent vaccine, and its role as a substitute for the separately administered standalone program vaccines. What is added by this report?: We evaluated the use and coverage of the pentavalent vaccine in nine provincial-level administrative divisions (PLADs) spanning eastern, central, and western China from 2019 to 2021. Initial use and coverage were low, but demonstrated annual growth albeit with regional and urban-rural discrepancies. The pentavalent vaccine was increasingly substituted for standalone vaccines over the course of this period. What are the implications for public health practice?: Parents in China are increasingly opting to replace the standard program vaccines with voluntarily purchased combination vaccines, particularly the pentavalent vaccine. The development of combination vaccines should thus be promoted in China, as it could enhance utilization and coverage rates, and decrease the economic burden.

Correlation between geriatric nutritional risk index and intradialytic hypotension in elderly patients undergoing maintenance hemodialysis: a case-control study.

BACKGROUND: There is a correlation between nutritional status and treatment outcomes and long-term survival in MHD patients but there is limited research on the relationship between GNRI and IDH. This case-control study aimed to investigate the correlation between Geriatric Nutritional Risk Index (GNRI) and intradialytic hypotension (IDH) in elderly patients undergoing maintenance hemodialysis (MHD). METHODS: This study was carried out on 129 cases of MHD patients with IDH and 258 non-IDH-controls in Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China, between June 2020 and May 2022. Professional researchers collected patients' general information on gender, primary disease, dialysis-related indicators, anthropometric measures, laboratory biochemicals, and GNRI. Logistic regression analysis was used to evaluate the correlation between GNRI and IDH. RESULTS: A total of 385 elderly MHD patients were included. Compared with GNRI Q4 group, the odds ratios for the risk of IDH in GNRI Q3 group, GNRI Q2 group, and GNRI Q1 group of elderly MHD patients were 1.227, 2.196, and 8.350, respectively, showing a significant downward trend (P-trend < 0.05). The area under the curve of GNRI for predicting IDH was 0.839 (95% CI: 0.799-0.879). Between different genders, a decrease in GNRI was closely related to an increase in IDH risk (P for trend < 0.05). CONCLUSIONS: This research shows a significant association between GNRI and the incidence of IDH among elderly MHD patients and has an important warning effect. Encouraging the incorporation of GNRI assessment into the clinical assessment protocols of older patients with MHD may help to improve the nutritional status of those suffering from it and reduce the risk of IDH.

Comprehensive evaluation of the water-fertilizer coupling effects on pumpkin under different irrigation volumes.

Compared to conventional irrigation and fertilization, the Water-fertilizer coupling can significantly enhance the efficiency of water and fertilizer utilization, thereby promoting crop growth and increasing yield. Targeting the challenges of poor crop growth, low yield, and inefficient water and fertilizer utilization in the arid region of northwest China under conventional irrigation and fertilization practices. Therefore, a two-year on-farm experiment in 2022 and 2023 was conducted to study the effects of water-fertilizer coupling regulation on pumpkin growth, yield, water consumption (ET), and water and fertilizer use efficiency. Simultaneously the comprehensive evaluation of multiple objectives was carried out using principal component analysis (PCA) methods, so as to propose an suitable water-fertilizer coupling regulation scheme for the region. The experiment was set up as a two-factor trial using water-fertilizer integration technology under three irrigation volume (W1 = 37.5 mm, W2 = 45.5 mm, W3 = 52.5mm) and three organic fertilizer application amounts (F1 = 3900-300 kg ha-1, F2 = 4800-450 kg·ha-1, F3 = 5700-600 kg·ha-1), with the traditional irrigation and fertilization scheme from local farmers as control treatments (CK). The results indicated that irrigation volume and organic fertilizer application significantly affected pumpkin growth, yield, and water and fertilizer use efficiency (P<0.05). Pumpkin yield increased with increasing irrigation volume. Increasing organic fertilizer levels within a certain range benefited pumpkin plant growth, dry matter accumulation, and yield, however, excessive application beyond a certain level had inhibited effects on those. The increased fertilizer application under the same irrigation volume enhanced the efficiency of water and fertilizer utilization. However excessive irrigation only resulted in inefficient water consumption, reducing the water and fertilizer use efficiency. The Comprehensive evaluation by PCA revealed that the F2W3 treatment outperformed all the others, effectively addressing the triple objectives of increasing production, improving efficiency, and promoting green production. Therefore, F2W3 (Irrigation volume: 52.5 mm; Fertilizer application amounts: 4800-450 kg/ha-1) as a water and fertilizer management scheme for efficient pumpkin production in the arid region of northwest China.

Efficacy of hypertonic dextrose proliferation therapy in the treatment of rotator cuff lesions: a meta-analysis.

BACKGROUND: One of the most prevalent illnesses of the shoulder is rotator cuff tendinosis, which is also a major contributor to shoulder discomfort and shoulder joint dysfunction. According to statistics, rotator cuff tendinosis occurs in 0.3-5.5% of cases and affects 0.5-7.4% of people annually. It will be necessary to conduct a meta-analysis to evaluate the efficacy of hypertonic glucose proliferation therapy in the treatment of rotator cuff problems. METHODS: The databases Cochrane PubMed, Library, Web of Science and EMbase, are retrieved by the computer. Individuals with rotator cuff lesions in the intervention group were treated with hypertonic dextrose proliferation therapy, whereas individuals in the control condition were treated with a placebo. Outcome markers for rotator cuff lesions patients; Pursuant to studies, the visual analogue scale (VAS) score, the shoulder pain & disability index (SPADI), & other metrics are used to evaluate the effects of hypertonic dextrose proliferation treatment on individuals with rotator cuff diseases. After carefully evaluating the calibre of the literature, data analysis was performed utilising the RevMan 5.3 programme. RESULTS: Meta-analysis finally contained 6 papers. In six investigations, the test & control group's VAS scores improved, with the test team's score considerably outperforming the control team [standardized mean difference (SMD): 1.10; 95% Cl: 0.37,1.83; P < 0.01], shoulder pain and disability index (SPADI) score (SMD:8.13; 95% Cl: 5.34,10.91; P < 0.01), Flexion (SMD:5.73; 95% Cl: 0.99,10.47; P < 0.05), Abduction (SMD:6.49; 95% Cl: 0.66,12.31; P < 0.05), Internal rotation (SMD:-1.74; 95% Cl: -4.25,0.78; P = 0.176) and External rotation (SMD:2.78; 95% Cl: -0.13,5.69; P = 0.062). CONCLUSION: The findings of this study suggest that individuals with rotator cuff injuries may benefit from hypertonic dextrose proliferation treatment based on the visual analogue scale (VAS) score, the Shoulder Pain and Disability Index (SPADI) score, Flexion, & Abduction. These results must, nevertheless, be supported by high-caliber follow-up research.

Recovery of Ag(I) from Wastewater by Adsorption: Status and Challenges.

Untreated or inadequately treated silver-containing wastewater may pose adverse effects on hu-man health and the ecological environment. Currently, significant progress has been made in the treatment of Ag(I) in wastewater using adsorption methods, with adsorbents playing a pivotal role in this process. This paper provides a systematic review of various adsorbents for the recovery and treatment of Ag(I) in wastewater, including MOFs, COFs, transition metal sulfides, metal oxides, biomass materials, and other polymeric materials. The adsorption mechanisms of these materials for Ag(I) are elaborated upon, along with the challenges currently faced. Furthermore, insights into optimizing adsorbents and developing novel adsorbents are proposed in this study.

Platelet-mediated circulating tumor cell evasion from natural killer cell killing via immune checkpoint CD155-TIGIT.

BACKGROUND AIMS: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. APPROACH RESULTS: We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from natural killer (NK) cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. CONCLUSIONS: Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.

Effects of electrolyte balance on intestinal barrier, amino acid metabolism, and mTORC1 signaling pathway in piglets fed low-protein diets.

A proper dietary electrolyte balance (dEB) is essential to ensure optimal growth performance of piglets. In the low-protein diet, this balance may be affected by the reduction of soybean meal and the inclusion of high levels of synthetic amino acids. The objective of this experiment was to evaluate the optimal dEB of low-protein diets and its impact on the growth performance of piglets. A total of 108 piglets (initial age of 35 d) were randomly divided into 3 groups with 6 replicates of 6 pigs each as follows: low electrolyte diet (LE group; dEB = 150 milliequivalents [mEq]/kg); medium electrolyte diet (ME group; dEB = 250 mEq/kg); high electrolyte diet (HE group; dEB = 350 mEq/kg). Results indicated that the LE and HE diet significantly decreased the average daily gain, average daily feed intake, and crude protein digestibility (P < 0.05) in piglets. Meanwhile, LE diets disrupted the structural integrity of the piglets' intestines and decreased jejunal tight junction protein (occludin and claudin-1) expression (P < 0.05). Additionally, the pH and HCO3- in the arterial blood of piglets in the LE group were lower than those in the ME and HE groups (P < 0.05). Interestingly, the LE diet significantly increased lysine content in piglet serum (P < 0.05), decreased the levels of arginine, leucine, glutamic acid, and alanine (P < 0.05), and inhibited the mammalian target of rapamycin complex 1 (mTORC1) pathway by decreasing the phosphorylation abundance of key proteins. In summary, the dietary electrolyte imbalance could inhibit the activation of the mTORC1 signaling pathway, which might be a key factor in the influence of the dEB on piglet growth performance and intestinal health. Moreover, second-order polynomial (quadratic) regression analysis showed that the optimal dEB of piglets in the low-protein diet was 250 to 265 mEq/kg.

An In-Situ-Tag-Generation Proximity Labeling Technology for Recording Cellular Interactions.

Obtaining information about cellular interactions is fundamental to the elucidation of physiological and pathological processes. Proximity labeling technologies have been widely used to report cellular interactions in situ; however, the reliance on addition of tag molecules typically restricts their application to regions where tags can readily diffuse, while the application in, for example, solid tissues, is susceptible. Here, we propose an "in-situ-tag-generation mechanism" and develop the GalTag technology based on galactose oxidase (GAO) for recording cellular interactions within three-dimensional biological solid regions. GAO mounted on bait cells can in situ generate bio-orthogonal aldehyde tags as interaction reporters on prey cells. Using GalTag, we monitored the dynamics of cellular interactions and assessed the targeting ability of engineered cells. In particular, we recorded, for the first time, the footprints of Bacillus Calmette-Guérin (BCG) invasion into the bladder tissue of living mice, providing a valuable perspective to elucidate the anti-tumor mechanism of BCG.

[Bupleuri Radix-Paeoniae Radix Alba medicated plasma exerts effects on HepG2 hepatoma cells by regulating miR-1297/PTEN signaling axis].

The present study aimed to investigate the effect and mechanism of Bupleuri Radix-Paeoniae Radix Alba medicated plasma on HepG2 hepatoma cells by regulating the microRNA-1297(miR-1297)/phosphatase and tensin homologue deleted on chromosome 10(PTEN) signaling axis. Real-time quantitative PCR(RT-qPCR) was carried out to determine the mRNA levels of miR-1297 and PTEN in different hepatoma cell lines. The dual luciferase reporter assay was employed to verify the targeted interaction between miR-1297 and PTEN. The cell counting kit-8(CCK-8) was used to detect cell proliferation, and the optimal concentration and intervention time of the medicated plasma were determined. The cell invasion and migration were examined by Transwell assay and wound healing assay. Cell cycle distribution was detected by PI staining, and the apoptosis of cells was detected by Annexin V-FITC/PI double staining. The mRNA levels of miR-1297, PTEN, protein kinase B(Akt), and phosphatidylinositol 3-kinase(PI3K) were determined by RT-qPCR. Western blot was employed to determine the protein levels of PTEN, Akt, p-Akt, caspase-3, caspase-9, B-cell lymphoma-2(Bcl-2), and Bcl-2-associated X protein(Bax). The results showed that HepG2 cells were the best cell line for subsequent experiments. The dual luciferase reporter assay confirmed that miR-1297 could bind to the 3'-untranslated region(3'UTR) in the mRNA of PTEN. The medicated plasma inhibited the proliferation of HepG2 cells, and the optimal intervention concentration and time were 20% and 72 h. Compared with the blank plasma, the Bupleuri Radix-Paeoniae Radix Alba medicated plasma, miR-1297 inhibitor, miR-1297 inhibitor + medicated plasma all inhibited the proliferation, invasion, and migration of HepG2 cells, increased the proportion of cells in the G_0/G_1 phase, decreased the proportion of cells in the S phase, and increased the apoptosis rate. The medicated plasma down-regulated the mRNA levels of miR-1297, PI3K, and Akt and up-regulated the mRNA level of PTEN. In addition, it up-regulated the protein levels of PTEN, Bax, caspase-3, and caspsae-9 and down-regulated the protein levels of p-Akt, p-PI3K, and Bcl-2. In conclusion, Bupleuri Radix-Paeoniae Radix Alba medicated plasma can inhibit the expression of miR-1297 in HepG2 hepatoma cells, promote the expression of PTEN, and negatively regulate PI3K/Akt signaling pathway, thereby inhibiting the proliferation and inducing the apoptosis of HepG2 cells.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

Novel CRISPR/SpRY system for rapid detection of CRISPR/Cas-mediated gene editing in rice.

The gene editing technology represented by clustered rule-interspersed short palindromic repeats (CRISPR)/Cas9 has developed as a common tool in the field of biotechnology. Many gene-edited products in plant varieties have recently been commercialized. However, the rapid on-site visual detection of gene-edited products without instrumentation remains challenging. This study aimed to develop a novel and efficient method, termed the CRISPR/SpRY detection platform, for the rapid screening of CRISPR/Cas9-induced mutants based on CRISPR/SpRY-mediated in vitro cleavage using rice (Oryza sativa L.) samples genetically edited at the TGW locus as an example. We designed the workflow of the CRISPR/SpRY detection platform and conducted a feasibility assessment. Subsequently, we optimized the reaction system of CRISPR/SpRY, and developed a one-pot CRISPR/SpRY assay by integrating recombinase polymerase amplification (RPA). The sensitivity of the method was further verified using recombinant plasmids. The proposed method successfully identified various types of mutations, including insertions, deletions (indels), and nucleotide substitutions, with excellent sensitivity. Finally, the applicability of this method was validated using different rice samples. The entire process was completed in less than an hour, with a limit of detection as low as 1%. Compared with previous methods, our approach is simple to operate, instrumentation-free, cost-effective, and time-efficient. The primary significance lies in the liberation of our developed system from the limitations imposed using protospacer adjacent motif sequences. This expands the scope and versatility of the CRISPR-based detection platform, making it a promising and groundbreaking platform for detecting mutations induced by gene editing.

Anti-pancreatic cancer activity of cassane diterpenoids isolated from the seeds of Caesalpinia sappan mediated by autophagy activation via ROS/AMPK/mTORC1 pathway.

Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC50 value of 18.13 ± 0.63 µM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.

Chromium immobilization from wastewater via iron-modified hydrochar: Different iron fabricants and practicality assessment.

The recycling of industrial solid by-products such as red mud (RM) has become an urgent priority, due to their large quantities and lack of reutilization methods can lead to resource wastage. In this work, RM was employed to fabricate green hydrochar (HC) to prepare zero-valent iron (ZVI) modified carbonous materials, and conventional iron salts (IS, FeCl3) was applied as comparison, fabricated HC labeled as RM/HC and IS/HC, respectively. The physicochemical properties of these HC were comprehensively characterized. Further, hexavalent chromium (Cr(VI)) removal performance was assessed (375.66 and 337.19 mg/g for RM/HC and IS/HC, respectively). The influence of dosage and initial pH were evaluated, while isotherms, kinetics, and thermodynamics analysis were also conducted, to mimic the surface interactions. The stability and recyclability of adsorbents also verified, while the practical feasibility was assessed by bok choy-planting experiment. This work revealed that RM can be used as a high value and green fabricant for HC the effective removal of chromium contaminants from the wastewater.

Constructing polynomial libraries for reservoir computing in nonlinear dynamical system forecasting.

Reservoir computing is an effective model for learning and predicting nonlinear and chaotic dynamical systems; however, there remains a challenge in achieving a more dependable evolution for such systems. Based on the foundation of Koopman operator theory, considering the effectiveness of the sparse identification of nonlinear dynamics algorithm to construct candidate nonlinear libraries in the application of nonlinear data, an alternative reservoir computing method is proposed, which creates the linear Hilbert space of the nonlinear system by including nonlinear terms in the optimization process of reservoir computing, allowing for the application of linear optimization. We introduce an implementation that incorporates a polynomial transformation of arbitrary order when fitting the readout matrix. Constructing polynomial libraries with reservoir-state vectors as elements enhances the nonlinear representation of reservoir states and more easily captures the complexity of nonlinear systems. The Lorenz-63 system, the Lorenz-96 system, and the Kuramoto-Sivashinsky equation are used to validate the effectiveness of constructing polynomial libraries for reservoir states in the field of state-evolution prediction of nonlinear and chaotic dynamical systems. This study not only promotes the theoretical study of reservoir computing, but also provides a theoretical and practical method for the prediction of nonlinear and chaotic dynamical system evolution.

In Situ Glycan Analysis and Editing in Living Systems.

Besides proteins and nucleic acids, carbohydrates are also ubiquitous building blocks of living systems. Approximately 70% of mammalian proteins are glycosylated. Glycans not only provide structural support for living systems but also act as crucial regulators of cellular functions. As a result, they are considered essential pieces of the life science puzzle. However, research on glycans has lagged far behind that on proteins and nucleic acids. The main reason is that glycans are not direct products of gene coding, and their synthesis is nontemplated. In addition, the diversity of monosaccharide species and their linkage patterns contribute to the complexity of the glycan structures, which is the molecular basis for their diverse functions. Research in glycobiology is extremely challenging, especially for the in situ elucidation of glycan structures and functions. There is an urgent need to develop highly specific glycan labeling tools and imaging methods and devise glycan editing strategies. This Perspective focuses on the challenges of in situ analysis of glycans in living systems at three spatial levels (i.e., cell, tissue, and in vivo) and highlights recent advances and directions in glycan labeling, imaging, and editing tools. We believe that examining the current development landscape and the existing bottlenecks can drive the evolution of in situ glycan analysis and intervention strategies and provide glycan-based insights for clinical diagnosis and therapeutics.

Efficacy and safety of terlipressin infusion during liver surgery: a protocol for systematic review and meta-analysis.

INTRODUCTION: Liver disease causes 2 million deaths annually, accounting for 4% of all deaths worldwide. Liver surgery is one of the effective therapeutic options. Bleeding is a major complication during liver surgery. Perioperative bleeding and allogeneic blood transfusion may deteriorate the prognosis. Terlipressin (TP), a synthetic analogue of the antidiuretic hormone, may reduceblood loss during abdominal surgery. Several clinical centres have attempted to use TP during liver surgery, but the evidence for its effectiveness in reducing blood loss and the need for allogeneic blood transfusion, as well as its safety during the perioperative period, remains unclear. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of TP in reducing blood loss and allogeneic blood transfusion needs during liver surgery. METHODS AND ANALYSIS: We will search PubMed, EMBASE, the Cochrane Library and Web of Science for studies on perioperative use of TP during liver surgery from inception to July 2023. We will limit the language to English, and two reviewers will independently screen and select articles. The primary study outcomes are estimated blood loss and the need for allogeneic blood transfusion. Secondary outcomes include operating time, intensive care unit stay, length of stay, intraoperative urine output, acute kidney injury rate, postoperative complications, hepatic and renal function during follow-up, and TP-related adverse effects. We will include studies that met the following criteria: (1) randomised controlled trials (RCTs), cohort studies or case-control studies; (2) the publication time was till July 2023; (3) adult patients (≥18 years old) undergoing elective liver surgery; (4) comparison of TP with other treatments and (5) the study includes at least one outcome. We will exclude animal studies, case reports, case series, non-original articles, reviews, paediatric articles, non-controlled trials, unpublished articles, non-English articles and other studies that are duplicates. We will use Review Manager V.5.3 software for meta-analysis and perform stratification analysis for the study quality of RCTs based on the Jadad score. For cohort or case-control studies, the study quality will be analysed based on Newcastle-Ottawa Scale scores. Grading of Recommendations, Assessment, Development and Evaluation will be used to assess confidence in the cumulative evidence. For primary outcomes, we will conduct subgroup analyses based on meta-regression. We will also perform leave-one-out sensitivity analyses to evaluate the effect of each individual study on the combined results by removing the individual studies one by one for outcomes with significant heterogeneity. The protocol follows the Cochrane Handbook for Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines. ETHICS AND DISSEMINATION: This study is a secondary analysis of existing data; therefore, it does not require ethical approval. We will disseminate the results through peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42023450333.

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

The effect of ß-cell dysfunction on reproductive outcomes of PCOS undergoing IVF or ICSI embryo transfer cycles: a retrospective cohort study.

Objective: To investigate the effects of ß-cell dysfunction on IVF outcomes in women with PCOS. Methods: This retrospective cohort study includes 1,212 women with PCOS undergoing their first IVF cycle between September 2010 and December 2019. Beta-cell dysfunction was measured by homeostasis model assessment of ß-cell function (HOMA-ß) index. Results: In quartiles of HOMA-ß, the incidence of miscarriage dramatically increased from 10.2% (Q1) to 31.1% (Q4) (P for trend <0.001). Likewise, the incidence of miscarriage in quartiles of HOMA-ß also showed a similar trend (P for trend <0.001). After adjusting for confounding factors, logistic regression analyses showed that high HOMA-IR values were independently associated with a high risk of miscarriage, with the odds ratios (OR) and 95% confidence intervals for quartiles 2-4 versus quartile 1 were 1.30 (0.69-2.46), 1.82 (0.97-3.43), and 3.57 (1.86-6.85), respectively (P for trend <0.001). When analyzed jointly, women in the highest HOMA-IR and highest HOMA-ß group exhibited the highest risk for miscarriage compared with all other groups. Furthermore, higher HOMA-IR values were associated with higher risks of miscarriage among PCOS women regardless of HOMA-ß values. Conclusions: ß-cell dysfunction is independently associated with increased miscarriage rate and decreased live birth rate in women with PCOS. It also plays a synergistic role with IR in terms of the reproductive outcomes, while the influence of IR overweighs that of ß-cell dysfunction.