JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex.

Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.

Tuning Fe3O4 for sustainable cathodic heterogeneous electro-Fenton catalysis by acetylated chitosan.

Peroxidase-like catalysts are safe and low-cost candidates to tackle the dilemma in constructing sustainable cathodic heterogeneous electro-Fenton (CHEF) catalysts for water purification, but the elusive structure-property relationship of enzyme-like catalysts constitutes a pressing challenge for the advancement of CHEF processes in practically relevant water and wastewater treatment. Herein, we probe the origins of catalytic efficiency in the CHEF process by artificially tailoring the peroxidase-like activity of Fe3O4 through a series of acetylated chitosan-based hydrogels, which serve as ecofriendly alternatives to traditional carbon shells. The optimized acetylated chitosan wrapping Fe3O4 hydrogel on the cathode shows an impressive activity and stability in CHEF process, overcoming the complicated and environmentally unfavored procedures in the electro-Fenton-related processes. Structural characterizations and theoretical calculations reveal that the amide group in chitosan can modulate the intrinsic redox capacity of surficial Fe sites on Fe3O4 toward CHEF catalysis via the neutral hydrogen bond. This work provides a sustainable path and molecule-level insight for the rational design of high-efficiency CHEF catalysts and beyond.

Delta-band Activity Underlies Referential Meaning Representation during Pronoun Resolution.

Human language offers a variety of ways to create meaning, one of which is referring to entities, objects, or events in the world. One such meaning maker is understanding to whom or to what a pronoun in a discourse refers to. To understand a pronoun, the brain must access matching entities or concepts that have been encoded in memory from previous linguistic context. Models of language processing propose that internally stored linguistic concepts, accessed via exogenous cues such as phonological input of a word, are represented as (a)synchronous activities across a population of neurons active at specific frequency bands. Converging evidence suggests that delta band activity (1-3 Hz) is involved in temporal and representational integration during sentence processing. Moreover, recent advances in the neurobiology of memory suggest that recollection engages neural dynamics similar to those which occurred during memory encoding. Integrating from these two research lines, we here tested the hypothesis that neural dynamic patterns, especially in delta frequency range, underlying referential meaning representation, would be reinstated during pronoun resolution. By leveraging neural decoding techniques (i.e., representational similarity analysis) on a magnetoencephalogram data set acquired during a naturalistic story-listening task, we provide evidence that delta-band activity underlies referential meaning representation. Our findings suggest that, during spoken language comprehension, endogenous linguistic representations such as referential concepts may be proactively retrieved and represented via activation of their underlying dynamic neural patterns.

Electrocatalytic Coenhancement of Bimetallic Polyphthalocyanine-Anchored Ru Nanoclusters Enabling Efficient Overall Water Splitting at Ampere-Level Current Densities.

Efficient electrocatalysts capable of operating continuously at industrial ampere-level current densities are crucial for large-scale applications of electrocatalytic water decomposition for hydrogen production. However, long-term industrial overall water splitting using a single electrocatalyst remains a major challenge. Here, bimetallic polyphthalocyanine (FeCoPPc)-anchored Ru nanoclusters, an innovative electrocatalyst comprising the hydrogen evolution reaction (HER) active Ru and the oxygen evolution reaction (OER) active FeCoPPc, engineered for efficient overall water splitting are demonstrated. By density functional theory calculations and systematic experiments, the electrocatalytic coenhancement effect resulting from unique charge redistribution, which synergistically boosts the HER activity of Ru and the OER activity of FeCoPPc by optimizing the adsorption energy of intermediates, is unveiled. As a result, even at a large current density of 2.0 A cm-2 , the catalyst exhibits low overpotentials of 220 and 308 mV, respectively, for HER and OER. It exhibits excellent stability, requiring only 1.88 V of cell voltage to achieve a current density of 2.0 A cm-2 in a 6.0 m KOH electrolyte at 70 °C, with a remarkable operational stability of over 100 h. This work provides a new electrocatalytic coenhancement strategy for the design and synthesis of electrocatalyst, paving the way for industrial-scale overall water splitting applications.

Efficacy and Safety of Huangqi Guizhi Wuwu Decoction for Oxaliplatin-Induced Peripheral Neurotoxicity: A Systematic Review and Meta-Analysis.

Objective: Oxaliplatin is a first-line chemotherapy drug for the treatment of colorectal cancer, but its induced oxaliplatin-induced peripheral neurotoxicity (OIPN) affect the chemotherapy process and quality of life of tumor patients. OIPN is a serious and potentially permanent side effect of cancer treatment. Currently, no unified standard has been established for preventing and treating OIPN in Western medicine. Therefore, it is very important to seek effective prevention and treatment measures. Many clinical trials have reported that Huangqi Guizhi Wuwu decoction can effectively prevent OIPN, but substantial evidence base to support this treatment is lacking. We collected existing literature and evaluated the clinical efficacy and safety of Huangqi Guizhi Wuwu decoction for OIPN by performing a meta-analysis. Methods: We systematically searched China National Knowledge Internet (CNKI), VIP, Wan Fang Database, Pubmed, EMBASE, and Cochrane Library from inception through to Oct 2022 to identify only randomized controlled trials examining the prevention of OIPN using Huangqi Guizhi Wuwu decoction. This search was supplemented by manual retrieval, including dissertations and conference papers. All data were analyzed using RevMan 5.3 software. Results: A total of 18 papers involving 564 patients in the treatment group and 523 patients in the control group were included. A total of 17 articles reported the overall incidence of peripheral neurotoxicity (I² = 0%), and the overall incidence of peripheral neurotoxicity in the treatment group was 0.27 times higher than in the control group (95% CI: 0.20-0.36). A total of 16 articles reported the incidence of level III-IV severe peripheral neurotoxicity (I² = 0%), which was 0.16 times higher in the treatment group than in the control group (95% CI: 0.09-0.32). In the Huangqi Guizhi Wuwu VS no-interference subgroup, it showed that the incidence of severe peripheral neurotoxicity in the treat group was significantly lower than in the control group (OR:0.13, 95% CI:0.06-0.28). But in the Huangqi Guizhi Wuwu VS west medicine therapy subgroup, no significant difference between Huangqi Quizhi Wuwu and conventional Western medicine was observed for the prevention and treatment of severe OIPN (OR:0.37, 95% CI:0.09-1.53). A total of 2 articles were reported median nerve conduction velocity (I² = 51.2%); and no significant difference was found between the treatment and control groups (SMD: 1.43; 95% CI: 0.80-2.08); 4 studies showed Huangqi Guizhi Wuwu decoction did not increase the incidence of chemotherapy-related adverse reactions and was safe. Conclusions: Our current findings support the application of Huangqi Guizhi Wuwu decoction for the clinical prevention and treatment of patients with OIPN. However, high-quality RCT research is still needed to further exploration. The potential impact of Huangqi Guizhi Wuwu decoction on the quality of life or treatment compliance of cancer patients needs further research.

Comprehensive Profiling of Amine-Containing Metabolite Isomers with Chiral Phosphorus Reagents.

Metabolite isomers play diverse and crucial roles in various metabolic processes. However, in untargeted metabolomics analysis, it remains a great challenge to distinguish between the constitutional isomers and enantiomers of amine-containing metabolites due to their similar chemical structures and physicochemical properties. In this work, the triplex stable isotope N-phosphoryl amino acids labeling (SIPAL) is developed to identify and relatively quantify the amine-containing metabolites and their isomers by using chiral phosphorus reagents coupled with high-resolution tandem mass spectroscopy. The constitutional isomers could be effectively distinguished with stereo isomers by using the diagnosis ions in MS/MS spectra. The in-house software MS-Isomerism has been parallelly developed for high-throughput screening and quantification. The proposed strategy enables the unbiased detection and relative quantification of isomers of amine-containing metabolites. Based on the characteristic triplet peaks with SIPAL tags, a total of 854 feature peaks with 154 isomer groups are successfully recognized as amine-containing metabolites in liver cells, in which 37 amine-containing metabolites, including amino acids, polyamines, and small peptides, are found to be significantly different between liver cancer cells and normal cells. Notably, it is the first time to identify S-acetyl-glutathione as an endogenous metabolite in liver cells. The SIPAL strategy could provide spectacular insight into the chemical structures and biological functions of the fascinating amine-containing metabolite isomers. The feasibility of SIPAL in isomeric metabolomics analysis may reach a deeper understanding of the mirror-chemistry in life and further advance the discovery of novel biomarkers for disease diagnosis.

Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability.

BACKGROUND: The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40-45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC. METHODS: The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1ß and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry. RESULTS: Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1ß-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC. CONCLUSIONS: CD8+ T cells and IL-1ß were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1ß-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1ß antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.

A One-Step Self-Flowering Method toward Programmable Ultrathin Porous Carbon-Based Materials for Microwave Absorption and Hydrogen Evolution.

Ultrathin 2D porous carbon-based materials offer numerous fascinating electrical, catalytic, and mechanical properties, which hold great promise in various applications. However, it remains a formidable challenge to fabricate these materials with tunable morphology and composition by a simple synthesis strategy. Here, a facile one-step self-flowering method without purification and harsh conditions is reported for large-scale fabrication of high-quality ultrathin (≈1.5 nm) N-doped porous carbon nanosheets (NPC) and their composites. It is demonstrated that the layered tannic/oxamide (TA/oxamide) hybrid is spontaneously blown, exfoliated, bloomed, in situ pore-formed, and aromatized during pyrolysis to form flower-like aggregated NPC. This universal one-step self-flowering system is compatible with various precursors to construct multiscale NPC-based composites (Ru@NPC, ZnO@NPC, MoS2 @NPC, Co@NPC, rGO@NPC, etc.). Notably, the programmable architecture enables NPC-based materials with excellent multifunctional performances, such as microwave absorption and hydrogen evolution. This work provides a facile, universal, scalable, and eco-friendly avenue to fabricate functional ultrathin porous carbon-based materials with programmability.

Magnifying image-enhanced endoscopy-only mode boosted early cancer diagnostic efficiency: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Magnifying image-enhanced endoscopy (MIEE) is an advanced endoscopy with image enhancement and magnification used in preoperative examination. However, its impact on the detection rate is unknown. METHODS: We conducted an open-label, randomized, parallel (1:1:1), controlled trial in 6 hospitals in China. Patients were recruited between February 14, 2022 and July 30, 2022. Eligible patients were aged ≥18 years and undergoing gastroscopy in outpatient departments. Participants were randomly assigned to the MIEE-only mode (o-MIEE) group, white-light endoscopy-only mode (o-WLE) group, and MIEE when necessary mode (n-MIEE) group (initial WLE followed by switching to another endoscope with MIEE if necessary). Biopsy sampling of suspicious lesions of the lesser curvature of the gastric antrum was performed. Primary and secondary aims were to compare detection rates and positive predictive value (PPV) of early cancer and precancerous lesions in these 3 modes, respectively. RESULTS: A total of 5100 recruited patients were randomly assigned to the o-MIEE (n = 1700), o-WLE (n = 1700), and n-MIEE (n = 1700) groups. In the o-MIEE, o-WLE, and n-MIEE groups, 29 (1.51%; 95% confidence interval [CI], 1.05-2.16), 4 (.21%; 95% CI, .08-.54), and 8 (.43%; 95% CI, .22-.85) early cancers were found, respectively (P < .001). The PPV for early cancer was higher in the o-MIEE group compared with the o-WLE and n-MIEE groups (63.04%, 33.33%, and 38.1%, respectively; P = .062). The same trend was seen for precancerous lesions (36.67%, 10.00%, and 21.74%, respectively). CONCLUSIONS: The o-MIEE mode resulted in a significant improvement in diagnosing early upper GI cancer and precancerous lesions; thus, it could be used for opportunistic screening. (Clinical trial registration number: ChiCTR2200064174.).

Association between vitamin D supplementation and cancer incidence and mortality: A trial sequential meta-analysis of randomized controlled trials.

Observational studies and clinical trials have evaluated the associations between vitamin D supplementation and cancer incidence/mortality and obtained mixed results. Previous meta-analyses have also yielded inconsistent conclusions. In this paper, we conduct an updated meta-analysis by including current randomized clinical trials (RCTs) to assess the association between vitamin D supplementation and cancer incidence and mortality. The PubMed, Scopus and Embase databases were systematically searched from their inception to 6 February 2022. Fixed-effects meta-analyses were conducted. Trial sequential analyses were performed using a risk ratio reduction threshold of 10% for cancer incidence and mortality. Twenty-six RCTs were eligible, and pooled results indicated that vitamin D supplementation, compared to placebo with/without calcium, was not associated with a reduction in total cancer incidence (risk ratio: 0.98, 95% CI: 0.94, 1.02; I2 = 0%). In contrast, vitamin D supplementation significantly reduced total cancer mortality (risk ratio: 0.88, 95% CI: 0.8, 0.96; I2 = 0%). Moreover, trial sequential analysis provided reliable evidence that supplementation with vitamin D lowered the relative risk of total cancer mortality by 10%. Our updated meta-analysis suggested that vitamin D supplementation did not reduce total cancer incidence but significantly lowered total cancer mortality.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2056574 .

Apocarotenoids from Equisetum debile Roxb. ex Vaucher regulate the lipid metabolism via the activation of the AMPK/ACC/SREBP-1c signaling pathway.

Sixteen undescribed apocarotenoids (1-16), along with 22 known analogues, were isolated from the aerial parts of Equisetum debile. Their structures, including absolute configurations, were elucidated by NMR, HRESIMS, X-ray diffraction analysis, the modified Mosher's method and the quantum-chemical calculation of electronic circular dichroism (ECD) spectra. Compounds 1-9, 11-12 are the first example of C16-apocarotenoids appeared in nature. The plausible biosynthetic pathway of 1-16 was proposed. Moreover, the isolates were evaluated for their lipid-lowering activity, and the results showed that 13, 14, 15, 22, 31, 32 and 33 could remarkably decrease the levels of both TC and TG in FFA induced HepG2 cells at 20 µM. The oil red staining assay further demonstrated the lipid-lowering effects of 13, 14 and 15. The western blot results indicated that compounds 13, 14 and 15 could regulate the lipid metabolism via the activation of the AMPK/ACC/SREBP-1c signaling pathway. A preliminary structure-activity relationship (SAR) study of the isolates indicated that the apocarotenoids with 6/5 ring system displayed more potent lipid-lowering effects.

Synthesis of Low-Cost and High-Performance Dual-Atom Doped Carbon-Based Materials with a Simple Green Route as Anodes for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) are promising alternatives to replace lithium-ion batteries as future energy storage batteries because of their abundant sodium resources, low cost, and high charging efficiency. In order to match the high energy capacity and density, designing an atomically doped carbonous material as the anode is presently one of the important strategies to commercialize SIBs. In this work, we report the preparation of high-performance dual-atom-doped carbon (C) materials using low-cost corn starch and thiourea (CH4N2S) as the precursors. The electronegativity and radii of the doped atoms and C are different, which can vary the embedding properties of sodium ions (Na+) into/on C. As sulfur (S) can effectively expand the layer spacing, it provides more channels for embedding and de-embedding Na+. The synergistic effect of N and S co-doping can remarkably boost the performance of SIBs. The capacity is preserved at 400 mAh g -1 after 200 cycles at 500 mA g-1; more notably, the initial Coulombic efficiency is 81%. Even at a high rate of high current of 10 A g-1, the cell capacity can still reach 170 mAh g-1. More importantly, after 3000 cycles at 1 A g-1, the capacity decay is less than 0.003% per cycle, which demonstrates its excellent electrochemical performance. These results indicate that high-performance carbon materials can be prepared using low-cost corn starch and thiourea.

[The impact of anxiety levels in male soldiers with infertility on stress coping strategies and the quality of fertility life].

OBJECTIVE: To explore and analyze the correlation between anxiety levels, coping strategies, and fertility quality of life in male soldiers with infertility. METHODS: A questionnaire survey was conducted on 480 male soldiers with infertility who visited the Reproductive Medicine Department of the Eastern Theater Command General Hospital from June 2022 to February 2023, analyze the impact of anxiety levels on stress coping strategies and fertility quality of life in male officers and soldiers with infertility. RESULTS: Self evaluation scale score is (43.06 ± 15.02), Fertility Quality of Life Scale score is （52.11 ± 36.68）, Trait Coping Style Questionnaire score is (48.45 ± 23.15). The relevant analysis results show that there is a negative correlation between the scores of the Self Rating Anxiety Scale and the Reproductive Quality of Life Scale, a positive correlation between the scores of the Self Rating Anxiety Scale and the Trait Coping Style Questionnaire, and a positive correlation between the scores of the Reproductive Quality of Life Scale and the Trait Coping Style Questionnaire. The results of multiple regression analysis showed that years of infertility, history of childbirth, anxiety level, and coping strategies entered the regression equation. The anxiety level of male officers and soldiers with infertility has a mediating effect on the relationship between stress coping styles and quality of life during childbirth. CONCLUSION: The mental health status of male officers and soldiers with infertility is poor, and their coping strategies and quality of life during childbirth are at a moderate to low level. This indicates that more attention should be paid to the special group of male officers and soldiers with infertility, and psychological intervention should be strengthened in routine treatment. Provide support from different perspectives to address concerns and enhance the combat effectiveness of the military.

Isobaric Stable Isotope N-Phosphorylation Labeling (iSIPL) for Ultrasensitive Proteome Quantification.

Stable isotope chemical labeling methods have been widely used for high-throughput mass spectrometry (MS)-based quantitative proteomics in biological and clinical applications. However, the existing methods are far from meeting the requirements for high sensitivity detection. In the present study, a novel isobaric stable isotope N-phosphorylation labeling (iSIPL) strategy was developed for quantitative proteome analysis. The tryptic peptides were selectively labeled with iSIPL tag to generate the novel reporter ions containing phosphoramidate P-N bond with high intensities under lower collision energies. iSIPL strategy are suitable for peptide sequencing and quantitative analysis with high sensitivity and accuracy even for samples of limited quantity. Furthermore, iSIPL coupled with affinity purification and mass spectrometry was applied to measure the dynamics of cyclin dependent kinase 9 (CDK9) interactomes during transactivation of the HIV-1 provirus. The interaction of CDK9 with PARP13 was found to significantly decrease during Tat-induced activation of HIV-1 gene transcription, suggesting the effectiveness of iSIPL strategy in dynamic analysis of protein-protein interaction in vivo. More than that, the proposed iSIPL strategy would facilitate large-scale accurate quantitative proteomics by increasing multiplexing capability.

MS-IDF: A Software Tool for Nontargeted Identification of Endogenous Metabolites after Chemical Isotope Labeling Based on a Narrow Mass Defect Filter.

Chemical isotope labeling liquid chromatography mass spectrometry (LC-MS) is an emerging metabolomic strategy for the quantification and characterization of small molecular compounds in biological samples. However, its subsequent data analysis is not straightforward due to a large amount of data produced and interference of biological matrices. In order to improve the efficiency of searching and identification of target endogenous metabolites, a new software tool for nontargeted metabolomics data processing called MS-IDF was developed based on the principle of a narrow mass defect filter. The developed tool provided two function modules, including IsoFinder and MDFinder. The IsoFinder function module applied a conventional peak extraction method by using a fixed mass differences between the heavy and light labels and by the alignment of chromatographic retention time (RT). On the other hand, MDFinder was designed to incorporate the accurate mass defect differences between or among stable isotopes in the peak extraction process. By setting an appropriate filter interval, the target metabolites can be efficiently screened out while eliminating interference. Notably, the present results showed that the efficiency in compound identification using the new MDFinder module was nearly doubled as compared to the conventional IsoFinder method (an increase from 259 to 423 compounds). The Matlab codes of the developed MS-IDF software are available from github at https://github.com/jydong2018/MS_IDF. Based on the MS-IDF software tool, a novel and effective approach from nontargeted to targeted metabolomics research was developed and applied to the exploration of potential primary amine biomarkers in patients with schizophrenia. With this approach, potential biomarkers, including N,N-dimethylglycine, S-adenosine-l-methionine, dl-homocysteine, and spermidine, were discovered.

Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization.

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

The protective effects of propofol against renal ischemia-reperfusion injury are potentiated by norisoboldine treatment via inhibition of oxidative stress pathways.

Acute kidney injury (AKI) is a significant worldwide health problem. The protective effects of norisoboldine (NOR) against ischemia/reperfusion (I/R) induced renal injury in a rat model were evaluated. AKI was induced in rats by I/R. Animals were treated with 20 mg/kg/h propofol, intraperitoneally administered and 10 mg/kg NOR 30 min before inducing renal ischemia. Biomarkers of kidney function, including cytokines and oxidative stress parameters, were measured in serum. The serum levels of creatinine and blood urea nitrogen in propofol- and NOR-treated rats were lower compared to the untreated I/R group. Moreover, treatment with propofol or NOR, alone and in combination, decreased the levels of cytokines and oxidative stress in rats with kidney injury. In conclusion, this study suggested that treatment with NOR potentiated the nephroprotective effects of propofol in rats with I/R-induced renal injury by ameliorating oxidative stress and apoptosis pathway.

Efficacy and safety of the "watch-and-wait" approach for rectal cancer with clinical complete response after neoadjuvant chemoradiotherapy: a meta-analysis.

BACKGROUND: Watch-and-Wait (WW) approach is positioned at the cutting edge of non-invasive approach for rectal cancer patients who achieve clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT). This meta-analysis aimed to compare the clinical, oncologic, and survival outcomes of WW versus radical surgery (RS) and to evaluate the efficacy, safety, and possible superiority of WW. METHODS: A systematic search for studies comparing WW with RS was conducted on MEDLINE, Ovid, Embase, Cochrane Library, and Web of Science databases. After screening for inclusion, data extraction, and quality assessment, statistical analysis was performed using Stata/SE14.0 software. Permanent colostomy (PC), local recurrence (LR), distant metastasis (DM), cancer-related death (CRD), 2-, 3-, and 5-year disease-free survival (DFS), and overall survival (OS) were analyzed using fixed effects or random-effects models depending on the heterogeneity. RESULTS: Fourteen studies with moderate-high quality involving 1254 patients were included. Of these, 513 patients were managed with WW and 741 patients were subjected to RS. Compared to RS group, WW group had higher rate of LR (odds ratio OR = 11.09, 95% confidence interval CI = 5.30-23.20, P = 0.000), 2-year OS, and 3-year OS and had lower rate of PC (OR = 0.12, 95% CI = 0.05-0.29, P = 0.000). There were no significant between-group differences with respect to DM, CRD, 2-, 3-, and 5-year DFS (OR = 0.92, 95% CI = 0.81-1.03, P = 0.153), or 5-year OS (OR = 1.01, 95% CI = 0.28-3.63, P = 0.988). CONCLUSION: The WW is a promising treatment approach and is a relatively safe alternative to RS for managing patients with rectal cancer who achieve cCR after nCRT. However, this modality requires rigorous screening criteria and standardized follow-up. Large-scale, multicenter prospective randomized controlled trials are warranted to further verify the outcomes of WW approach.

Identification of candidate targets and mechanisms involved in miRNA regulation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a complex disease affected by many factors. The recognition of miRNA networks is helpful for specific detection and personalised treatment. METHODS: mRNA expression profiles were obtained from GSE39754 and GSE87830, and differentially expressed mRNAs (DEmRs) between MM and controls were identified. The intersection of the two sets of DEmRs in GSE39754 and GSE87830 was identified as common mRNAs, and enrichment analysis was subsequently performed. Moreover, we analysed differentially expressed miRNAs (DEmiRs) between MM and controls in GSE87830. A regulatory network of target mRNAs related to the overall survival of MM patients was then constructed. RESULTS: In this study, a total of 356 common mRNAs were identified that were significantly enriched in neutrophil-mediated immunity, Th17 cell differentiation and PI3K-Akt signalling pathways. Moreover, we identified 103 DEmiRs and predicted 91 differentially expressed mRNAs as target mRNAs. Cox regression analysis was used to screen 14 target mRNAs that significantly affected the survival of MM patients. In the constructed integrated regulatory network, HIF1A and THBS1 were found to participate in Th17 cell differentiation and PI3K-Akt signalling pathways. CONCLUSION: These findings improve the understanding of the regulatory mechanisms of MM. Genes that are part of integrated regulatory networks may represent candidate targets for MM treatment.

Lipskynoids A-G, New Acyclic Diterpenes from the Flowers of Carpesium lipskyi.

Seven new acyclic diterpenes, namely lipskynoids A-G (1-7), were isolated from the flowers of Carpesium lipskyi, a traditional Tibetan herbal medicine with anti-inflammatory and antipyretic-analgesic effects. These new compounds were elucidated by analysis of extensive spectroscopic data including ESI-MS, 1D, 2D NMR, and DP4+ analyses. Biological assays showed that 1-7 display significant inhibitory effects against the NO production in LPS-induced RAW264.7 cells with its IC50 values from 9.9 to 18.47 µM, however, no cytotoxicity effect was observed of these isolates against the growth of HePG2, PC3, DU145, and A549 cells.