QTL detection for grain shape and fine mapping of two novel locus qGL4 and qGL6 in rice.

Rice grain size and grain weight, which have a great influence on rice quality and yield, are complex quantitative traits that are mediated by grain length (GL), grain width (GW), length-to-width ratio (LWR), and grain thickness (GT). In this study, the BC1F2 and BC1F2:3 populations derived from a cross between two indica rice varieties, Guangzhan 63-4S (GZ63-4S) and Dodda, were used to locate quantitative trait loci (QTL) related to grain size. A total of 30 QTL associated with GL, GW and LWR were detected, of which six QTL were scanned repeatedly in both populations. Two QTL, qGL4 and qGL6, were selected for genetic effect validation and were subsequently fine mapped to 2.359 kb and 176 kb, respectively. LOC_Os04g52240 (known as OsKS2/OsKSL2), which encoding an ent-beyerene synthase and as the only gene found in 2.359 kb interval, was proposed to be the candidate for qGL4. Moreover, the grains of qGL4 homozygous mutant plants generated by the CRISPR-Cas9 system became shorter and wider. In addition, the qGL4 allele from GZ63-4S contributes to the increase of yield per plant. Our study not only laid the foundation for further functional study of qGL4 and map-based cloning of qGL6, but also provided genetic resources for the development of high yield and good quality rice varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01502-8.

Vein distensibility is superior to vein diameter for predicting unassisted maturation of arteriovenous fistulae.

BACKGROUND: A mature arteriovenous fistula (AVF) is the preferred hemodialysis access owing to its durability and lower risk of complications. Various factors have been implicated as predictors for maturation, including vein diameter and access type. Vein distensibility, which refers to the ability of the vein to dilate in response to changes in blood flow and pressure, has been proposed as a potential predictor for maturation, but its utility remains poorly studied. METHODS: This is a single-institution retrospective study of AVFs performed under regional anesthesia. Vein distensibility was defined as the absolute and relative difference in target vein diameter (TVD) between the preoperative ultrasound vein mapping performed with tourniquet and a repeat ultrasound examination after a regional block before AVF creation and without a tourniquet. RESULTS: There were 46 patients who underwent first-time AVF surgery and had distensibility captured in a prospectively maintained database. The mean initial preoperative TVD was 2.7 mm and after the block 3.4 mm. The unassisted maturation rate for the entire cohort was 76%. In patients with an absolute change of TVD of <0.5 mm (Δ<0.5), the unassisted maturation rate was 63% (12/19), even though 95% of the group had a preoperative TVD of >3 mm. In those with ≥0.5 mm, the unassisted maturation rate was 85% (23/27; P = .08), even though the preoperative vein map TVD was 2.3 mm and 75% had a vein map TVD of <3 mm. For radiocephalic AVFs (n = 26), the unassisted maturation rate was 75% for Δ<0.5 vs 94% for Δ≥0.5 (P = .16), despite a preoperative vein map TVD of >3 mm in 92% vs 75%, respectively. The receiver operatring characteristic area under the curve for unassisted maturation with a Δ≥0.5 mm was 0.68 (P = .26). CONCLUSIONS: Quality in dialysis access surgery requires optimizing the unassisted maturation rate. A physiological measure that accounts for the dynamic process of maturation may be more informative than anatomic measurements alone. The results shown here demonstrate that vein distensibility may be a better predictor than absolute vein diameter on standard vein mapping ultrasound examinations.

The Effect of Cuproptosis-Related Proteins on Macrophage Polarization in Mesothelioma is Revealed by scRNA-seq.

High invasiveness mesothelioma is a malignant tumor of the peritoneum or pleura. The effect of cuproptosis on mesothelioma (MESO) is still unknown, though. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets were used to identify differential genes linked to cuproptosis in mesothelioma. Multigene features were then created to assess the course of the disease. Use single-cell data and in vitro validation to uncover crucial gene regulation mechanisms. In MESO, we found nine differentially expressed genes linked to cuproptosis. Using univariate Cox and LASSO regression techniques, a 3-gene feature (P < 0.05) was created, showing a good predictive potential for survival time. According to the risk score, patients in the low-risk subset had a considerably greater survival rate than those in the high-risk subset (P = 0). The similar survival pattern and prediction performance are also seen in the validation queue. The findings of the drug sensitivity research indicate that in high-risk patients, vinblastine, paclitaxel, gefitinib, and erlotinib are sensitive medications (P < 0.05). Classical monocytes were identified as core cells connected to cuproptosis by the CellChat results. SLC31A1 is implicated in the positive regulation of M2 macrophage polarization, according to cell subtype analysis and in vitro confirmation. Genes linked to cuproptosis have a major influence on tumor immunity and can predict how MESO will progress.

The ß-d-manno-heptoses are immune agonists across kingdoms.

Bacterial small molecule metabolites such as adenosine-diphosphate-d-glycero-ß-d-manno-heptose (ADP-heptose) and their derivatives act as effective innate immune agonists in mammals. We show that functional nucleotide-diphosphate-heptose biosynthetic enzymes (HBEs) are distributed widely in bacteria, archaea, eukaryotes, and viruses. We identified a conserved STTR5 motif as a hallmark of heptose nucleotidyltransferases that can synthesize not only ADP-heptose but also cytidine-diphosphate (CDP)- and uridine-diphosphate (UDP)-heptose. Both CDP- and UDP-heptoses are agonists that trigger stronger alpha-protein kinase 1 (ALPK1)-dependent immune responses than ADP-heptose in human and mouse cells and mice. We also produced ADP-heptose in archaea and verified its innate immune agonist functions. Hence, the ß-d-manno-heptoses are cross-kingdom, small-molecule, pathogen-associated molecular patterns that activate the ALPK1-dependent innate immune signaling cascade.

Fractionated plasma separation and adsorption integrated with continuous veno-venous hemofiltration in patients with acute bipyridine herbicide poisoning.

OBJECTIVE: To evaluate the clinical efficacy and safety of fractionated plasma separation and adsorption combined with continuous veno-venous hemofiltration (FPSA-CVVH) treatment in patients with acute bipyridine herbicide poisoning. METHODS: A retrospective analysis of 18 patients with acute bipyridine herbicide poisoning was conducted, of which 9 patients were poisoned by diquat and 9 patients by paraquat. All patients underwent FPSA-CVVH treatment. The serum cytokine levels in pesticide-poisoned patients were assessed. The efficacy of FPSA-CVVH in eliminating cytokines, the 90-d survival rate of poisoned patients, and adverse reactions to the treatment were observed. RESULTS: Fourteen patients (77.8%) had acute kidney injuries and 10 (55.6%) had acute liver injuries. The serum cytokine levels of high mobility group protein B-1 (HMGB-1), interleukin-6 (IL-6), IL-8, interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1ß (MIP-1ß) were significantly elevated. A total of 41 FPSA-CVVH treatment sessions were administered. After a single 8-h FPSA-CVVH treatment, the decreases in HMGB-1, IL-6, IL-8, IP-10, MCP-1, and MIP-1ß were 66.0%, 63.5%, 73.3%, 63.7%, 53.9%, and 54.1%, respectively. During FPSA-CVVH treatment, one patient required a filter change due to coagulation in the plasma component separator, and one experienced a bleeding adverse reaction. The 90-d patient survival rate was 50%, with 4 patients with diquat poisoning and 5 patients with paraquat poisoning, and both liver and kidney functions were restored to normal. CONCLUSION: Cytokine storms may play a significant role in the progression of multiorgan dysfunction in patients with acute bipyridine herbicide poisoning. FPSA-CVVH can effectively reduce cytokine levels, increase the survival rate of patients with acute bipyridine herbicide poisoning, and decrease the incidence of adverse events.

Final analysis of a phase II trial of neoadjuvant chemoimmunotherapy for locoregionally advanced head and neck squamous cell carcinoma.

OBJECTIVES: Neoadjuvant chemoimmunotherapy has shown promising results for resectable, locoregionally advanced (LA) head and neck squamous cell carcinoma (L/A HNSCC). We published the first phase II trial of neoadjuvant camrelizumab combined with chemotherapy in resectable, L/A HNSCC, demonstrating it was safe and feasible with favorable pathological complete response (pCR). Here, we report the final analysis results for neoadjuvant chemoimmunotherapy in L/A HNSCC (minimum 2.0 years of follow-up). MATERIALS AND METHODS: Three cycles of chemoimmunotherapy were administered before surgery to patients with L/A HNSCC. Two-year disease-free survival (DFS), overall survival (OS) and quality of life (QOL) were reported. RESULTS: The overall two-year DFS and OS rates were 90 % and 100 %, respectively. With a median follow-up of 33.7 months, 9 of 10 (90 %) patients with pCR were alive and disease free. Patients with TNM stage (II/III) or < 20 % of residual viable tumor trended toward improved DFS; hazard ratio (HR), 0.44 [95 % confidence interval (CI), 0.04-5.28] and HR, 0.26 (95 % CI, 0.03-2.36), respectively. All QLQ-C30 functioning and symptom scales other than nausea and vomiting were resolved at 2 years after the completion of radiotherapy. CONCLUSION: Neoadjuvant camrelizumab in combination with chemotherapy provided encouraging clinical outcomes for patients with L/A HNSCC. Further studies with longer follow-up and larger samples are warranted. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR1900025303. Registered Aug 22, 2019. https://www.chictr.org.cn/showproj.html?proj=41380.

Protective Role of MerTK in Diabetic Peripheral Neuropathy via Inhibition of the NF-κB Signaling Pathway.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) impacts patient quality of life. In such patients, increased expression of mer tyrosine kinase (MerTK) has been demonstrated; however, its mechanism of action remains unclear. In this study, type 2 diabetes mellitus (T2DM) and DPN models were established in Sprague Dawley rats via low-dose streptozotocin and a high-fat diet and the mode of action of MerTK was examined. METHODS: MerTK-specific inhibitors were administered by gavage once daily for 2 weeks. Sciatic nerve conduction velocity and nerve structure were measured. The levels of MerTK, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and relevant biochemical indexes were detected. RESULTS: The study revealed upregulation of MerTK expression in T2DM and more so in DPN groups. Inhibiting MerTK led to reduced nerve conduction velocity and further deterioration of sciatic nerve structure, as evidenced by structural morphology. Concurrently, serum levels of total cholesterol, glycated hemoglobin, and triglyceride significantly increased. Moreover, levels of NF-κB increased in both serum and nerve tissue, alongside a significant rise in TNF-α and IL-1ß expressions. MerTK could bind to the inhibitor of kappa B kinase beta (Ikbkb) in Schwann cells, establishing Ikbkb as a precursor to NF-κB activation. DISCUSSION: Inhibition of MerTK exacerbates neuropathy, indicating its protective role in DPN by suppressing the NF-κB pathway, highlighting a potential new target for its diagnosis and treatment.

Computational Enzyme Redesign Enhances Tolerance to Denaturants for Peptide C-Terminal Amidation.

The escalating demand for biocatalysts in pharmaceutical and biochemical applications underscores the critical imperative to enhance enzyme activity and durability under high denaturant concentrations. Nevertheless, the development of a practical computational redesign protocol for improving enzyme tolerance to denaturants is challenging due to the limitations of relying solely on model-driven approaches to adequately capture denaturant-enzyme interactions. In this study, we introduce an enzyme redesign strategy termed GRAPE_DA, which integrates multiple data-driven and model-driven computational methods to mitigate the sampling biases inherent in a single approach and comprehensively predict beneficial mutations on both the protein surface and backbone. To illustrate the methodology's effectiveness, we applied it to engineer a peptidylamidoglycolate lyase, resulting in a variant exhibiting up to a 24-fold increase in peptide C-terminal amidation activity under 2.5 M guanidine hydrochloride. We anticipate that this integrated engineering strategy will facilitate the development of enzymatic peptide synthesis and functionalization under denaturing conditions and highlight the role of engineering surface residues in governing protein stability.

Unveiling the repressive mechanism of a PPS-like regulator (PspR) in polyhydroxyalkanoates biosynthesis network.

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is a type of polyhydroxyalkanoates (PHA) that exhibits numerous outstanding properties and is naturally synthesized and elaborately regulated in various microorganisms. However, the regulatory mechanism involving the specific regulator PhaR in Haloferax mediterranei, a major PHBV production model among Haloarchaea, is not well understood. In our previous study, we showed that deletion of the phosphoenolpyruvate (PEP) synthetase-like (pps-like) gene activates the cryptic phaC genes in H. mediterranei, resulting in enhanced PHBV accumulation. In this study, we demonstrated the specific function of the PPS-like protein as a negative regulator of phaR gene expression and PHBV synthesis. Chromatin immunoprecipitation (ChIP), in situ fluorescence reporting system, and in vitro electrophoretic mobility shift assay (EMSA) showed that the PPS-like protein can bind to the promoter region of phaRP. Computational modeling revealed a high structural similarity between the rifampin phosphotransferase (RPH) protein and the PPS-like protein, which has a conserved ATP-binding domain, a His domain, and a predicted DNA-binding domain. Key residues within this unique DNA-binding domain were subsequently validated through point mutation and functional evaluations. Based on these findings, we concluded that PPS-like protein, which we now renamed as PspR, has evolved into a repressor capable of regulating the key regulator PhaR, and thereby modulating PHBV synthesis. This regulatory network (PspR-PhaR) for PHA biosynthesis is likely widespread among haloarchaea, providing a novel approach to manipulate haloarchaea as a production platform for high-yielding PHA. KEY POINTS: • The repressive mechanism of a novel inhibitor PspR in the PHBV biosynthesis was demonstrated • PspR is widespread among the PHA accumulating haloarchaea • It is the first report of functional conversion from an enzyme to a trans-acting regulator in haloarchaea.

[Structure motif guided mining of MHET hydrolase and development of a two-enzyme cascade for plastics depolymerization at mild temperature].

The utilization of polyethylene terephthalate (PET) has caused significant and prolonged ecological repercussions. Enzymatic degradation is an environmentally friendly approach to addressing PET contamination. Hydrolysis of mono(2-hydroxyethyl) terephthalate (MHET), a competitively inhibited intermediate in PET degradation, is catalyzed by MHET degrading enzymes. Herein, we employed bioinformatic methods that combined with sequence and structural information to discover an MHET hydrolase, BurkMHETase. Enzymatic characterization showed that the enzyme was relatively stable at pH 7.5-10.0 and 30-45 ℃. The kinetic parameters kcat and Km on MHET were (24.2±0.5)/s and (1.8±0.2) µmol/L, respectively, which were similar to that of the well-known IsMHETase with higher substrate affinity. BurkMHETase coupled with PET degradation enzymes improved the degradation of PET films. Structural analysis and mutation experiments indicated that BurkMHETase may have evolved specific structural features to hydrolyze MHET. For MHET degrading enzymes, aromatic amino acids at position 495 and the synergistic interactions between active sites or distal amino acids appear to be required for MHET hydrolytic activity. Therefore, BurkMHETase may have substantial potential in a dual-enzyme PET degradation system while the bioinformatic methods can be used to broaden the scope of applicable MHETase enzymes.

Abnormal upregulation of NUBP2 contributes to cancer progression in colorectal cancer.

Colorectal cancer (CRC), a digestive tract malignancy with high mortality and morbidity, lacks effective biomarkers for clinical prognosis due to its complex molecular pathogenesis. Nucleotide binding protein 2 (NUBP2) plays a vital role in the assembly of cytosolic Fe/S protein and has been implicated in cancer progression. In this study, we found that NUBP2 was highly expressed in CRC by TCGA database analysis. Subsequently, we verified the expression of NUBP2 in CRC tumor tissues and para-carcinoma tissues using IHC staining, and further investigated its association with clinicopathological parameters. In vitro cell experiments were conducted to assess the role of NUBP2 in CRC by evaluating cell proliferation, migration, and apoptosis upon NUBP2 dysregulation. Furthermore, we established a subcutaneous CRC model to evaluate the impact of NUBP2 on tumor growth in vivo. Additionally, we performed mechanistic exploration using a Human Phospho-Kinase Array-Membrane. Our results showed higher expression of NUBP2 in CRC tissues, which positively correlated with the pathological stage, indicating its involvement in tumor malignancy. Functional studies demonstrated that NUBP2 knockdown reduced cell proliferation, increased apoptosis, and impaired migration ability. Moreover, NUBP2 knockdown inhibited tumor growth in mice. We also observed significant changes in the phosphorylation level of GSK3ß upon NUBP2 knockdown or overexpression. Additionally, treatment with CHIR-99021 HCl, an inhibitor of GSK3ß, reversed the malignant phenotype induced by NUBP2 overexpression. Overall, this study elucidated the functional role of NUBP2 in CRC progression both in vitro and in vivo, providing insights into the molecular mechanisms underlying CRC and potential implications for targeted therapeutic strategies.

Computational redesign of a hydrolase for nearly complete PET depolymerization at industrially relevant high-solids loading.

Biotechnological plastic recycling has emerged as a suitable option for addressing the pollution crisis. A major breakthrough in the biodegradation of poly(ethylene terephthalate) (PET) is achieved by using a LCC variant, which permits 90% conversion at an industrial level. Despite the achievements, its applications have been hampered by the remaining 10% of nonbiodegradable PET. Herein, we address current challenges by employing a computational strategy to engineer a hydrolase from the bacterium HR29. The redesigned variant, TurboPETase, outperforms other well-known PET hydrolases. Nearly complete depolymerization is accomplished in 8 h at a solids loading of 200 g kg-1. Kinetic and structural analysis suggest that the improved performance may be attributed to a more flexible PET-binding groove that facilitates the targeting of more specific attack sites. Collectively, our results constitute a significant advance in understanding and engineering of industrially applicable polyester hydrolases, and provide guidance for further efforts on other polymer types.

Efficient production of peptidylglycine α-hydroxylating monooxygenase in yeast for protein C-terminal functionalization.

Peptidylglycine α-hydroxylating monooxygenase (PHM) is pivotal for C-terminal amidation of bioactive peptides in animals, offering substantial potential for customized protein synthesis. However, efficient PHM production has been hindered by the complexity of animal cell culture and the absence of glycosylation in bacterial hosts. Here, we demonstrate the recombinant expression of Caenorhabditis elegans PHM in the yeast Pichia pastoris, achieving a remarkable space-time yield of 28.8 U/L/day. This breakthrough surpasses prior PHM production rates and eliminates the need for specialized cultivation equipment or complex transfection steps. Mass spectrometry revealed N-glycosylation at residue N182 of recombinant CePHM, which impacts the enzyme's activity as indicated by biochemical experiments. To showcase the utility of CePHM, we performed C-terminal amidation on ubiquitin at a substrate loading of 30 g/L, a concentration meeting the requirements for pharmaceutical peptide production. Overall, this work establishes an efficient PHM production method, promising advancements in scalable manufacturing of C-terminally modified bioactive peptides and probe proteins.

Re-injection off-axis integrated cavity output spectroscopy for the simultaneous detection of N2O, H2O and CO with a mid-infrared QCL laser.

Off-axis integrated cavity output spectroscopy (OA-ICOS) has attracted much interest because it potentially allows highly sensitive field measurements with robust optical alignment. In this paper, a novel instrument that employs a high-finesse optical cavity as an absorption cell has been developed for sensitive measurements of multi-component gases N2O, H2O and CO in the atmosphere based on a mid-infrared quantum cascade laser (QCL) and OA-ICOS. In order to improve the energy utilization and increase the signal-to-noise ratio (SNR) of the signal, a new type of optical path structure of the laser re-injection method is adopted. Furthermore, the system performance can be effectively improved by using a new intervention method of injecting radio frequency (RF) white noise into a laser driver to suppress cavity mode noise and combining the wavelength modulation method (WMS). We compared the sensitivity of the second harmonic signal demodulation between the re-injection method and the standard OA-ICOS, and the SNR increased by 2.68 times compared to the latter. Analysis of the spectral measurements with Allan variance indicates that within an integration time of 1 s, the measurement accuracy of N2O, H2O, and CO is 6.71 ppb, 13.945 ppm, and 1.81 ppb, respectively, and within an integration time of 820 s, the measurement accuracy of N2O, H2O, and CO can be further improved to 1.26 ppb, 2.089 ppm, and 172 ppt, respectively. Our approach represents an underlying analytical method that provides guidelines for monitoring of representative gases in the atmosphere, industrial processes, emergency safety, etc.

Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis.

BACKGROUND: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. It is an aggressive tumor characterized by rapid proliferation, diffuse tumor morphology, and poor prognosis. Unfortunately, current treatments, such as surgery, radiotherapy, and chemotherapy, are unable to achieve good outcomes. Therefore, there is an urgent need to explore new treatment targets. A detailed mechanistic exploration of the role of the nuclear pore transporter KPNB1 in GBM is lacking. This study demonstrated that KPNB1 regulated GBM progression through a transcription factor YBX1 to promote the expression of post-protrusion membrane protein NLGN3. This regulation was mediated by the deubiquitinating enzyme USP7. METHODS: A tissue microarray was used to measure the expression of KPNB1 and USP7 in glioma tissues. The effects of KPNB1 knockdown on the tumorigenic properties of glioma cells were characterized by colony formation assays, Transwell migration assay, EdU proliferation assays, CCK-8 viability assays, and apoptosis analysis using flow cytometry. Transcriptome sequencing identified NLGN3 as a downstream molecule that is regulated by KPNB1. Mass spectrometry and immunoprecipitation were performed to analyze the potential interaction between KPNB1 and YBX1. Moreover, the nuclear translocation of YBX1 was determined with nuclear-cytoplasmic fractionation and immunofluorescence staining, and chromatin immunoprecipitation assays were conducted to study DNA binding with YBX1. Ubiquitination assays were performed to determine the effects of USP7 on KPNB1 stability. The intracranial orthotopic tumor model was used to detect the efficacy in vivo. RESULTS: In this study, we found that the nuclear receptor KPNB1 was highly expressed in GBM and could mediate the nuclear translocation of macromolecules to promote GBM progression. Knockdown of KPNB1 inhibited the progression of GBM, both in vitro and in vivo. In addition, we found that KPNB1 could regulate the downstream expression of Neuroligin-3 (NLGN3) by mediating the nuclear import of transcription factor YBX1, which could bind to the NLGN3 promoter. NLGN3 was necessary and sufficient to promote glioma cell growth. Furthermore, we found that deubiquitinase USP7 played a critical role in stabilizing KPNB1 through deubiquitination. Knockdown of USP7 expression or inhibition of its activity could effectively impair GBM progression. In vivo experiments also demonstrated the promoting effects of USP7, KPNB1, and NLGN3 on GBM progression. Overall, our results suggested that KPNB1 stability was enhanced by USP7-mediated deubiquitination, and the overexpression of KPNB1 could promote GBM progression via the nuclear translocation of YBX1 and the subsequent increase in NLGN3 expression. CONCLUSION: This study identified a novel and targetable USP7/KPNB1/YBX1/NLGN3 signaling axis in GBM cells.

Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis.

Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.

Fractionated plasma separation and adsorption integrated with continuous veno-venous hemofiltration in patients with acute liver failure: A single center experience from China.

OBJECTIVE: To evaluate the clinical efficacy and safety of fractionated plasma separation and adsorption integrated with continuous veno-venous hemofiltration (FPSA-CVVH) treatment in patients with acute liver failure (ALF). METHODS: In this retrospective study, we enrolled patients with ALF (serum total bilirubin >10 mg/dL or Model for End-Stage Liver Disease [MELD] Score >18) hospitalized between August 2017 and August 2022. All patients had at least two sessions of FPSA-CVVH. The primary measure of treatment efficacy was the reduction ratios (RRs) of bilirubin after each session of FPSA-CVVH. RESULTS: Seventy-eight patients with ALF were enrolled. The MELD score at baseline was 22.9 ± 7.5. The mean total bilirubin was 22.05 ± 5.94 mg/dL, direct bilirubin was 16.33 ± 4.60 mg/dL and indirect bilirubin was 3.43 ± 1.60 mg/dL. One hundred and eighty seven sessions of FPSA-CVVH treatment lasting 8 hours each were performed. After a single session, serum total bilirubin, direct bilirubin and indirect bilirubin were significantly decreased. RRs were 52.0% ± 7.6% for total bilirubin, 59.4% ± 13.0% for direct bilirubin and 36.9% ± 15.4% for indirect bilirubin. Twenty nine patients (37.2%) survived and were discharged from the hospital, 12 of them recovered their liver function while the remaining 17 patients needed intermittent artificial liver support therapy. CONCLUSION: FPSA-CVVH therapy is an effective artificial liver support therapy in patients with ALF. It may be considered as a "bridge technique" to the recovery of liver function in critical ill patients with ALF.

Irradiated engineered tumor cell-derived microparticles remodel the tumor immune microenvironment and enhance antitumor immunity.

Radiotherapy (RT), administered to roughly half of all cancer patients, occupies a crucial role in the landscape of cancer treatment. However, expanding the clinical indications of RT remains challenging. Inspired by the radiation-induced bystander effect (RIBE), we used the mediators of RIBE to mimic RT. Specifically, we discovered that irradiated tumor cell-released microparticles (RT-MPs) mediated the RIBE and had immune activation effects. To further boost the immune activation effect of RT-MPs to achieve cancer remission, even in advanced stages, we engineered RT-MPs with different cytokine and chemokine combinations by modifying their production method. After comparing the therapeutic effect of the engineered RT-MPs in vitro and in vivo, we demonstrated that tIL-15/tCCL19-RT-MPs effectively activated antitumor immune responses, significantly prolonged the survival of mice with malignant pleural effusion (MPE), and even achieved complete cancer remission. When tIL-15/tCCL19-RT-MPs were combined with PD-1 monoclonal antibody (mAb), a cure rate of up to 60% was achieved. This combination therapy relied on the activation of CD8+ T cells and macrophages, resulting in the inhibition of tumor growth and the establishment of immunological memory against tumor cells. Hence, our research may provide an alternative and promising strategy for cancers that are not amenable to conventional RT.

Care intervention on psychological outcomes among patients admitted to intensive care unit: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Numerous studies have explored care interventions to improve the psychological outcome of intensive care unit (ICU) patients, but inconclusive evidence makes it difficult for decision-makers, managers, and clinicians to get familiar with all available literature and find appropriate interventions. This umbrella review aimed to analyze the relationship between care intervention and psychological outcomes of ICU patients based on existing systematic reviews. METHODS: An umbrella review of evidence across systematic reviews and meta-analyses published between 1987 and 2023 was undertaken. We systematically searched reviews that examined the association between care intervention and the improvement of adverse psychological outcomes in ICU patients using PubMed, EMBASE, Web of Science, Cochrane Library, and manual reference screening. The measurement tool (AMSTAR 2) was applied to evaluate the methodological quality of included studies. The excess significance bias, between-study heterogeneity expressed by I2, small-study effect, and evidence class were estimated. RESULTS: A total of 5110 articles were initially identified from the search databases and nine of them were included in the analysis. By applying standardized criteria, only weak evidence was observed in 13 associations, even though most included reviews were of moderate to high methodological quality. These associations pertained to eight interventions (music therapy, early rehabilitation, post-ICU follow-up, ICU diary, information intervention, preoperative education, communication and psychological support, surrogate decision-making) and five psychological outcomes (post-intensive care syndrome, transfer anxiety, post-traumatic stress disorder, anxiety, and depression). Weak or null association was shown among the rest of the associations (e.g., weak association between music therapy and maternal anxiety or stress level). CONCLUSIONS: The evidence of these eight supporting interventions to improve the adverse psychological outcomes of ICU patients and caregivers was weak. Data from more and better-designed studies with larger sample sizes are needed to establish robust evidence.