Clinical characteristics and prognosis of bloodstream infections with carbapenem-resistant Gram-negative organisms in patients with hematological malignancies: a multicenter case-control study in China.

OBJECTIVE: To investigate clinical characteristics of hematological malignancy (HM) patients with carbapenem-resistant gram-negative organism (CRO) bloodstream infections (BSI) in China, and to elucidate the prognostic risk factors of CRO BSI. METHODS: We conducted a multicenter case-control study of 201 HM patients with CRO BSI between 2018-2020. Antimicrobial susceptibility testing and whole genome sequencing were performed for CRO isolates. Independent risk factors for 28-day crude mortality of were analyzed using Cox proportional hazards regression models. The subgroups of major species were also evaluated. RESULTS: The pathogens responsible for CRO BSI in HM patients dominated by ST11 CRKP, ST167 CREC and ST463 CRPA. Most isolates produced carbapenemases with KPC and NDM being the main. CRO isolates had resistance rates to conventional antimicrobials ranging from 55%-100% and poor susceptibility to novel antimicrobials related to carbapenemases and species. The 28-day crude mortality was 24.2%. Non-Hodgkin lymphoma, heart disease, blaKPC-2 positive, empirical antibiotic therapy with linezolid, Pitt bacteremia score >3.5 were risk factors for 28-day mortality and appropriate definitive antibiotic therapy, tigecycline-containing therapy and aminoglycoside-containing therapy were protective factors. blaKPC-2 positive in CRKP and ST463 in CRPA were associated with Pitt bacteremia score > 3.5. Solid tumor and other site infections before BSI were risk factors for ST463 CRPA BSI and Pulmonary infection before BSI was risk factor for KPC-KP BSI. CONCLUSIONS: The antimicrobial resistance of CRO isolates for BSI in HM patients is critical. HM patients with CRO BSI should be treated with appropriate definitive antibiotic therapy based on early clarification of pathology and their antimicrobial susceptibility.

The effect of multi-directional sprint training on change-of-direction speed and reactive agility of collegiate tennis players.

Objective: The aim of this study was to evaluate the effect of random route multi-directional sprint training (MDST) compared to fixed route MDST on change-of-direction speed (CODS) and reactive agility (RA), and to investigate the correlation between CODS, RA and short-distance straight sprint speed (SDSS). Method: A total of 19 collegiate tennis players from Beijing Sport University were randomly assigned to either the random route MDST group (RR group, N = 9, age: 22.22 ± 2.22 years) or the fixed route MDST group (FR group, N = 10, age: 21.90 ± 1.66 years). Both groups completed a progressive load intervention training for 3 weeks, three times a week. The RR group's random route, mirroring the distance and number of change-of-direction (COD) in the FR group's fixed route, was specifically designed. The spider run, T-drill, RA test and 5-m straight line sprint test were performed before and after the intervention. Results: Both groups showed improved performance in the spider run (p < 0.05), T-drill (p < 0.01) and 5-m straight (p < 0.001) line sprint test after the intervention. Additionally, there was no significant difference in the improvement of CODS and SDSS between the two groups (p > 0.05). The RA of the RR and FR groups after the intervention was significantly higher than before intervention (p < 0.001), and RR group showed greater improvement in RA compared to the FR group. There was a moderate correlation between spider run and T-drill (r = 0.523), RA (r = 0.388), and no significant correlation between spider run and 5-m straight sprint (p > 0.05). T-drill was moderately correlated with RA (r = 0.347) and 5-m straight sprint (r = 0.321). RA was moderately correlated with 5-m straight sprint (r = 0.551). Conclusion: Three-week multi-directional sprint training can effectively improve the change-of-direction speed, reactive agility and short-distance straight sprint speed of collegiate tennis players. And random route multi-directional sprint training has better effect on improving reactive agility.

High prevalence of carbapenem-resistant Enterobacter cloacae complex in a tertiary hospital over a decade.

The aim of this study was to explore the mechanisms and molecular epidemiology of carbapenem resistance in the carbapenem-resistant Enterobacter cloacae complex (CRECC) over a decade in a tertiary hospital in Zhejiang, China. From January 2011 to December 2021, we collected a total of 931 Enterobacter cloacae complex (ECC) isolates from a tertiary hospital in Zhejiang, China. Antimicrobial susceptibility tests were performed. Whole-genome sequencing was used to analyze the molecular characteristics of the CRECC isolates. For carbapenem-resistant strains, efflux inhibitor assay and quantitative real-time PCR (qRT-PCR) were performed to evaluate the function of efflux pumps. A total of 82 CRECC isolates were detected, and the rate of resistance for carbapenems was 8.8%, increasing from 5.5% in 2011 to 18.3% in 2019, with an overall increasing trend, with Enterobacter hormaechei subsp. hoffmannii being the predominant species. Among the CRECC, 24 (24/931) isolates were found to produce carbapenemases, including NDM-1, NDM-5, IMP-4, and KPC-2. Among all carbapenemases, NDM-1 was the most prevalent, accounting for 62.5% (15/24) of carbapenemases, followed by NDM-5 (5/24). Genes encoding extended-spectrum beta-lactamases (47/82) and AmpC (76/82) were also identified, with blaSHV-12 and blaACT being the predominant ones, respectively. Multilocus sequence typing revealed 28 different sequence types, among which ST78 was the predominant, followed by ST93 and ST177. IncFIB was the most common type of plasmid replicon. Efflux inhibitor assay and qRT-PCR indicated that the overexpression of efflux pumps was involved in carbapenem resistance mechanisms. Additionally, disrupted outer membrane proteins also contribute to carbapenem resistance. The detection rate of CRECC was rising in the tertiary hospital. BlaNDM-1 and blaNDM-5 were the main carbapenem resistance genes. Our study revealed the presence of carbapenem-resistant ECC strains, emphasizing the need for effective infection prevention approaches to reduce the prevalence of CRECC. IMPORTANCE: The emergence and spread of the carbapenem-resistant Enterobacter cloacae complex (CRECC) have become a significant public health problem. CRECC strains frequently harbor multiple drug resistance genes and can be epidemic within healthcare facilities. The study explored the characteristics and prevalence of CRECC strains in the same hospital over a decade, which provides a theoretical basis for epidemiologic surveillance and clinical treatment.

Role of CD86 on granulocyte in mediating the effect of Genus Roseburia on periodontitis.

OBJECTIVES: This study aimed to explore the causal link between the gut microbiota and periodontitis, and to delineate and quantify the intermediary role of immune cells, so as to provide new insights into the pathogenesis, prevention and treatment of periodontitis. MATERIALS AND METHODS: We employed a two-sample Mendelian randomization (MR) approach to analyze the genetic predictors of gut microbiota composition (covering 412 gut microbiota taxa and functions) and periodontitis (involving 4,784 cases and 272,252 controls) derived from genome-wide association study (GWAS) datasets. A subsequent two-step MR analysis was conducted to evaluate the extent to which immune cell traits (encompassing 731 immune cell characteristics) mediate the influence of gut microbiota on periodontitis risk. RESULTS: Our analysis implicated nine gut microbiota taxa as causal factors in periodontitis susceptibility (p < 0.05). Notably, the Genus Roseburia was identified as exerting a protective effect against periodontitis, partially mediated through the upregulation of CD86 expression on granulocytes, with an 8.15% mediation effect observed. CONCLUSIONS: Our findings establish a causal relationship between the gut microbiota and periodontitis, highlighting the protective role of Roseburia against this condition. A notable proportion of this protective effect is mediated via the upregulation of CD86 on granulocytes. CLINICAL RELEVANCE: It can provide new ideas for the pathogenesis, prevention and treatment for periodontitis through exploring the causal link between the gut microbiota and periodontitis, and describing and quantifying the intermediary role of immune cells.

MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer.

Colorectal carcinogenesis and progression are associated with aberrant alternative splicing, yet its molecular mechanisms remain largely unexplored. Here, we find that Microrchidia family CW-type zinc finger 2 (MORC2) binds to RRM1 domain of RNA binding motif protein 39 (RBM39), and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, resulting in a splicing switch of cyclin-dependent kinase 5 regulatory subunit associated protein 2 (CDK5RAP2) L to CDK5RAP2 S. CDK5RAP2 S promotes invasion of colorectal cancer cells in vitro and metastasis in vivo. Mechanistically, CDK5RAP2 S specifically recruits the PHD finger protein 8 to promote Slug transcription by removing repressive histone marks at the Slug promoter. Moreover, CDK5RAP2 S, but not CDK5RAP2 L, is essential for the promotion of epithelial-mesenchymal transition induced by MORC2 or RBM39. Importantly, high protein levels of MORC2, RBM39 and Slug are strongly associated with metastasis and poor clinical outcomes of colorectal cancer patients. Taken together, our findings uncover a novel mechanism by which MORC2 promotes colorectal cancer metastasis, through RBM39-mediated pre-CDK5RAP2 alternative splicing and highlight the MORC2/RBM39/CDK5RAP2 axis as a potential therapeutic target for colorectal cancer.

Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway.

BACKGROUND: With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PURPOSE: The objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. METHODS: An in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. RESULTS: Mice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. CONCLUSION: HAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.

Effects of aquatic and land high intensity interval training on hemodynamics and vascular function of middle-aged men.

Objective: To investigate the effects of 8-week aquatic and land high intensity interval training (HIIT) on hemodynamics and vascular function in middle-aged men. Methods: Thirty middle-aged men with low physical activity were selected and divided into 15 men (52.43 ± 4.11) in aquatic group and 15 men (52.74 ± 5.62) in land group by random number table. They performed HIIT exercise in aquatic and land 3 times a week for 8 weeks. Pre-test, inter-test and post-test respectively measure hemodynamics and blood vessel function. Results: (1) Body composition: After 8 weeks of exercise, weight, body mass index (BMI) and body fat rate (BF) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of BF in the aquatic group was better than that in the land group (p < 0.05); (2) Cardiac function: After 8 weeks of exercise, stroke volume (SV), left ventricular end-diastolic volume (EDV), cardiac output (CO), and left ventricular fractional shortening (FS), were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05), heart rate (HR) and left ventricular end-systolic volume (ESV) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SV, HR, EDV, ESV, CO and FS in the aquatic group was better than that in the land group (p < 0.05); (3) Hemodynamics: After 8 weeks of exercise, systolic blood pressure (SBP), diastolic blood pressure (DBP) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05), wall shear stress (WSS) and peak systolic velocity (PSV) were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SBP, WSS and PSV in the aquatic group was better than that in the land group (p < 0.05); (4) Vascular function: basal diameter and brachial artery flow-mediated dilatation (FMD) level in aquatic group and land group was higher than before exercise, pulse wave velocity (PWV) level was lower than before exercise (aquatic and land group: p < 0.05). The improvement of FMD in the aquatic group was better than that in the land group. Conclusion: The body composition, hemodynamics and vascular function of middle-aged men were improved by 8-week aquatic and land HIIT. Aquatic HIIT has better effect on body fat rate, hemodynamics and vascular endothelial function in middle-aged men due to the effect of aquatic pressure and temperature.

New polyketides and cytotoxic alkaloids from the mangrove endophytic fungus Talaromyces sp. SAF14.

Investigation of secondary metabolites from the mangrove endophytic fungus Talaromyces sp. SAF14 led to the isolation of two new polyketides, methyl (R)-3-(6,8-dihydroxy-7-methoxy-1-oxoisochroman-3-yl)propanoate (1), (R)-3-(5,8- dihydroxy-1-oxoisochroman-3-yl)propanoic acid (2), together with four known alkaloids (3-6). The planar structures of new compounds were elucidated by comprehensive analysis of HR-ESI-MS and NMR data. The absolute configurations were determined by comparison of the calculated ECD spectrum with the measured one. All the isolated compounds were tested for cytotoxic activities against three human cancer cell lines. The known beauvericin (3) exhibited strong cytotoxic activity against A549, MCF-7, and KB cell lines with IC50 values of 5.36 ± 2.49, 1.96 ± 1.09 and 4.46 ± 0.68 µM, respectively.

TTYH3 promotes the malignant progression of oral squamous cell carcinoma SCC-9 cells by regulating tumor-associated macrophage polarization.

OBJECTIVE: This study was designed to investigate the biological role and the reaction mechanism of Tweety family member 3 (TTYH3) in oral squamous cell carcinoma (OSCC). DESIGN: The mRNA and protein expressions of TTYH3 were assessed with RT-qPCR and western blot. After silencing TTYH3 expression, the proliferation of OSCC cells were detected using cell counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining and colony formation assay. Cell migration and invasion were detected using wound healing and transwell. Gelatin zymography protease assay was used to detect matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-2 (MMP9) activity and western blot was used to detect the expressions of proteins associated with proliferation and epithelial-mesenchymal transition (EMT). The mRNA expression of TTYH3 in THP-1-derived macrophage was detected using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). The number of CD86-positive cells and CD206-positive cells was detected using immunofluorescence assay. RT-qPCR was used to detect the expressions of M2 markers arginase 1 (ARG1), chitinase-like 3 (YM1) and mannose receptor C-type 1 (MRC1). RESULTS: In this study, it was found that TTYH3 expression was upregulated in OSCC cell lines and TTYH3 knockdown could inhibit the proliferation, migration, invasion and EMT process in OSCC via suppressing M2 polarization of tumor-associated macrophages. CONCLUSIONS: Collectively, TTYH3 facilitated the progression of OSCC through the regulation of tumor-associated macrophages polarization.

[Retracted] STK39, overexpressed in osteosarcoma, regulates osteosarcoma cell invasion and proliferation.

[This retracts the article DOI: 10.3892/ol.2017.6728.].

A panel of genotypically and phenotypically diverse clinical Acinetobacter baumannii strains for novel antibiotic development.

Acinetobacter baumannii is one of the most important pathogens worldwide. The intrinsic and acquired resistance of A. baumannii, coupled with the slow pace of novel antimicrobial drug development, poses an unprecedented and enormous challenge to clinical anti-infective therapy of A. baumannii. Recent studies in the field of pathogenicity, antibiotic resistance, and biofilms of A. baumannii have focused on the model strains, including ATCC 17978, ATCC 19606, and AB5075. However, these model strains represent only a limited portion of the heterogeneity in A. baumannii. Furthermore, variants of these model strains have emerged that show significant diversity not only at the genotypic level but also reflected in differences at the phenotypic levels of capsule, virulence, pathogenicity, and antibiotic resistance. Research on A. baumannii, a key pathogen, would benefit from a standardized approach, which characterizes heterogeneous strains in order to facilitate rapid diagnosis, discovery of new therapeutic targets, and efficacy assessment. Our study provides and describes a standardized, genomically and phenotypically heterogeneous panel of 45 different A. baumannii strains for the research community. In addition, we performed comparative analyses of several phenotypes of this panel. We found that the sequence type 2 (ST2) group showed significantly higher rates of resistance, lower fitness cost for adaptation, and yet less biofilm formation. The Macrocolony type E (MTE, flat center and wavy edge phenotype reported in the literature) group showed a less clear correlation of resistance rates and growth rate, but was observed to produce more biofilms. Our study sheds light on the complex interplay of resistance fitness and biofilm formation within distinct strains, offering insights crucial for combating A. baumannii infection. IMPORTANCE: Acinetobacter baumannii is globally notorious, and in an effort to combat the spread of such pathogens, several emerging candidate therapies have already surfaced. However, the strains used to test these therapies vary across studies (the sources and numbers of test strains are varied and often very large, with little heterogeneity). The variation complicates the studies. Furthermore, the limited standardized resources of A. baumannii strains have greatly restricted the research on the physiology, pathogenicity, and antibiotic resistance. Therefore, it is crucial for the research community to acquire a standardized and heterogeneous panel of A. baumannii. Our study meticulously selected 45 diverse A. baumannii strains from a total of 2,197 clinical isolates collected from 64 different hospitals across 27 provinces in China, providing a scientific reference for the research community. This assistance will significantly facilitate scientific exchange in academic research.

Pyrrole-containing hybrids as potential anticancer agents: An insight into current developments and structure-activity relationships.

Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.

The correlation between intestinal colonization and infection of carbapenem-resistant Klebsiella pneumoniae: A systematic review.

As a widely spread Gram-negative bacteria, Klebsiella pneumoniae (KP) mainly causes acquired infections in hospitals, such as lung infections, urinary tract infections, and bloodstream infections. In recent years, the number of multidrug-resistant KP strains has increased dramatically, posing a great threat to human health. Carbapenem-resistant KP (CRKP) can be colonized in human body, especially in gastrointestinal tract, and some colonized patients can be infected during hospitalization, among which invasive operation, underlying disease, admission to intensive care unit, antibiotic use, severity of the primary disease, advanced age, operation, coma, and renal failure are common risk factors for secondary infection. Active screening and preventive measures can effectively prevent the occurrence of CRKP infection. Based on the epidemiological status, this study aims to discuss the correlation between colonization and secondary infection induced by CRKP and risk factors for their happening and provide some reference for nosocomial infection prevention and control.

Objective Evaluation of Pulse Width Using an Array Pulse Diagram.

BACKGROUND: Pulse width, which can reflect qi, blood excess, and deficiency, has been used for diagnosing diseases and determining the prognosis in traditional Chinese medicine (TCM). This study aimed to devise an objective method to measure the pulse width based on an array pulse diagram for objective diagnosis. METHODS: The channel 6, the region wherein the pulse wave signal is the strongest, is located in the middle of the pulse sensor array and at the guan position of cunkou during data collection. Therefore, the main wave (h1) time of the pulse wave was collected from the channel 6 through calculation. The left h1 time was collected from the remaining 11 channels. The amplitudes at these time points were extracted as the h1 amplitudes for each channel. However, the pulse width could not be calculated accurately at 12 points. Consequently, a bioharmonic spline interpolation algorithm was used to interpolate the h1 amplitude data obtained from the horizontal and vertical points, yielding 651 (31 × 21) h1 amplitude data. The 651 data points were converted into a heat map to intuitively calculate the pulse width. The pulse width was calculated by multiplying the number of grids on the vertical axis with the unit length of the grid. The pulse width was determined by TCM doctors to verify the pulse width measurement accuracy. Meanwhile, a color Doppler ultrasound examination of the volunteers' radial arteries was performed and the intravascular meridian widths of the radial artery compared with the calculated pulse widths to determine the reliability. RESULTS: The pulse width determined using the maximal h1 amplitude method was comparable with the radial artery intravascular meridian widths measured using color Doppler ultrasound. The h1 amplitude was higher in the high blood pressure group and the pulse width was greater. CONCLUSIONS: The pulse width determined using the maximal h1 amplitude was objective and accurate. Comparison between the pulse widths of the normal and high blood pressure groups verified the reliability of the method.

Impact of early rehabilitation therapy on functional outcomes in patients post distal radius fracture surgery: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aims to investigate the efficacy of early rehabilitation on patients who have undergone surgery for distal radius fractures (DRFs) with palmar plating, focusing on multiple outcome measures including upper limb function, wrist function, back extension mobility, pain levels, and complications. METHODS: A rigorous search strategy adhering to the PRISMA guidelines was employed across four major databases, including PubMed, Embase, Web of Science, and the Cochrane Library. Studies were included based on stringent criteria, and data extraction was performed independently by two reviewers. Meta-analysis was conducted employing both fixed-effect and random-effects models as dictated by heterogeneity, assessed by the I2 statistic and chi-square tests. A total of 7 studies, encompassing diverse demographic groups and timelines, were included for the final analysis. RESULTS: The meta-analysis disclosed that early rehabilitation yielded a statistically significant improvement in upper limb function (SMD -0.27; 95% CI -0.48 to -0.07; P < 0.0001) and back extension mobility (SMD 0.26; 95% CI 0.04 to 0.48; P = 0.021). A notable reduction in pain levels was observed in the early rehabilitation group (SMD -0.28; 95% CI -0.53 to -0.02; P = 0.03). However, there were no significant differences in wrist function (SMD -0.13; 95% CI -0.38 to 0.12; P = 0.36) and complications (OR 0.99; 95% CI 0.61 to 1.61; P = 0.96). CONCLUSIONS: Early rehabilitation post-DRF surgery with palmar plating has been found to be beneficial in enhancing upper limb functionality and back extension mobility, and in reducing pain levels. Nevertheless, no significant impact was observed regarding wrist function and complications.

FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation.

FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3-FBXO31-SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.

Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer.

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFRT790M/C797S , several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFRDel19/T790M/C797S and H1975-EGFRL858R/T790M cells, with an IC50 of 0.22 ± 0.07 and 0.52 ± 0.03 µM, respectively. Meanwhile, the kinase activity of A23 against EGFRL858R/T790M and EGFRDel19/T790M/C797S was also evaluated, with an IC50 of 0.33 and 0.133 µM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFRDel19/T790M/C797S inhibitor.

Targeting the PD-L1 cytoplasmic domain and its regulatory pathways to enhance cancer immunotherapy.

As a significant member of the immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy. Clinically approved drugs mainly target the extracellular domain of PD-L1. Recently, the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways. Therefore, the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy, expanding available strategies for combined immunotherapy. Here, we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways. The conserved motifs, homodimerization, and posttranslational modifications of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring, degradation, nuclear translocation, and glycosylation of PD-L1, etc. This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.

Genetically incorporated crosslinkers identify regulators of membrane protein PD-L1 in mammalian cells.

Profiling membrane proteins' interacting networks is crucial for understanding their regulatory mechanisms and functional characteristics, but it remains a challenging task. Here, by combining genetic incorporation of crosslinkers, tandem denatured purification, and proteomics, we added interaction partners for PD-L1, a cancer cell surface protein that inhibits T cell activity. The site-specifically incorporated crosslinker mediates the covalent capture of interactions under physiological conditions and enabled the PD-L1 complexes to withstand the harsh extraction conditions of membrane proteins. Subsequent experiments led to the identification of potential PD-L1 interaction candidates and verified membrane-associated progesterone receptor component 1 as a novel PD-L1 interaction partner in mammalian cells. Importantly, we demonstrated that PGRMC1 positively regulates PD-L1 expression by regulating GSK3ß-mediated PD-L1 degradation in cancer cells. Furthermore, PGRMC1 knockdown results in dramatically enhanced T cell-mediated cytotoxicity in cancer cells. In conclusion, our study elucidated the interactome of PD-L1 and uncovered a new player in the PD-L1 regulation mechanism.

Bacterial effector restricts liquid-liquid phase separation of ZPR1 to antagonize host UPRER.

How pathogens manipulate host UPRER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.