A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria.

The bacterial ribonuclease RNase E plays a key role in RNA metabolism. Yet, with a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known, limiting our understanding on posttranscriptional regulatory mechanisms in bacteria. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested substrates. Consistent with the inhibitory function of RebA on RNase E, depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, potentially conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

A c-di-GMP binding effector controls cell size in a cyanobacterium.

Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial signaling molecule. It is also a critical player in the regulation of cell size and cell behaviors such as cell aggregation and phototaxis in cyanobacteria, which constitute an important group of prokaryotes for their roles in the ecology and evolution of the Earth. However, c-di-GMP receptors have never been revealed in cyanobacteria. Here, we report the identification of a c-di-GMP receptor, CdgR, from the filamentous cyanobacterium Anabaena PCC 7120. Crystal structural analysis and genetic studies demonstrate that CdgR binds c-di-GMP at the dimer interface and this binding is required for the control of cell size in a c-di-GMP-dependent manner. Different functions of CdgR, in ligand binding and signal transmission, could be separated genetically, allowing us to dissect its molecular signaling functions. The presence of the apo-form of CdgR triggers cell size reduction, consistent with the similar effects observed with a decrease of c-di-GMP levels in cells. Furthermore, we found that CdgR exerts its function by interacting with a global transcription factor DevH, and this interaction was inhibited by c-di-GMP. The lethal effect triggered by conditional depletion of DevH or by the production of several point-mutant proteins of CdgR in cells indicates that this signaling pathway plays critical functions in Anabaena. Our studies revealed a mechanism of c-di-GMP signaling in the control of cell size, an important and complex trait for bacteria. CdgR is highly conserved in cyanobacteria, which will greatly expand our understanding of the roles of c-di-GMP signaling in these organisms.

A proteolytic pathway coordinates cell division and heterocyst differentiation in the cyanobacterium Anabaena sp. PCC 7120.

The filamentous, multicellular cyanobacterium Anabaena sp. PCC 7120 (Anabaena) is a prokaryotic model for the study of cell differentiation and cell-cell interactions. Upon combined-nitrogen deprivation, Anabaena forms a particular cell type, heterocyst, for aerobic nitrogen fixation. Heterocysts are semiregularly spaced among vegetative cells. Heterocyst differentiation is coupled to cell division, but the underlying mechanism remains unclear. This mechanism could be mediated by the putative protease HetF, which is a divisome component and is necessary for heterocyst differentiation. In this study, by suppressor screening, we identified PatU3, as a negative regulator acting downstream of HetF for cell division and heterocyst development. The inactivation of patU3 restored the capacity of cell division and heterocyst differentiation in the ΔhetF mutant, and overexpression of patU3 inhibited both processes in the wild-type background. We demonstrated that PatU3 was a specific substrate of the protease activity of HetF. Consequently, PatU3 accumulated in the hetF-deficient mutant, which was responsible for the resultant mutant phenotype. The cleavage site of PatU3 by HetF was mapped after the Arg117 residue, whose mutation made PatU3 resistant to HetF processing, and mimicked the effect of hetF deletion. Our results provided evidence that HetF regulated cell division and heterocyst differentiation by controlling the inhibitory effects of PatU3. This proteolytic pathway constituted a mechanism for the coordination between cell division and differentiation in a prokaryotic model used for studies on developmental biology and multicellularity.

Severity Identification of Graves Orbitopathy via Random Forest Algorithm.

This study aims to establish a random forest model for detecting the severity of Graves Orbitopathy (GO) and identify significant classification factors. This is a hospital-based study of 199 patients with GO that were collected between December 2019 and February 2022. Clinical information was collected from medical records. The severity of GO can be categorized as mild, moderate-to-severe, and sight-threatening GO based on guidelines of the European Group on Graves' orbitopathy. A random forest model was constructed according to the risk factors of GO and the main ocular symptoms of patients to differentiate mild GO from severe GO and finally was compared with logistic regression analysis, Support Vector Machine (SVM), and Naive Bayes. A random forest model with 15 variables was constructed. Blurred vision, disease course, thyroid-stimulating hormone receptor antibodies, and age ranked high both in mini-decreased gini and mini decrease accuracy. The accuracy, positive predictive value, negative predictive value, and the F1 Score of the random forest model are 0.83, 0.82, 0.86, and 0.82, respectively. Compared to the three other models, our random forest model showed a more reliable performance based on AUC (0.85 vs. 0.83 vs. 0.80 vs. 0.76) and accuracy (0.83 vs. 0.78 vs. 0.77 vs. 0.70). In conclusion, this study shows the potential for applying a random forest model as a complementary tool to differentiate GO severity.

Dysfunctional iron metabolism in pressure injuries is related to aberrant CD163 and Homx-1 signal transduction.

Dysregulation of iron metabolism has been associated with impaired chronic wound healing. However, changes in iron metabolism have yet to be reported in pressure injuries, a type of chronic wound. In this study, we aimed to investigate changes in iron metabolism and associated regulatory mechanisms in pressure injuries. We collected tissue biopsies and data from 20 consenting stage IV-pressure injuries patients and 5 non-pressure injuries patients hospitalised at the Affiliated Hospital of Qingdao University between March 2021 and June 2021. In addition, we measured the iron content by inductively coupled plasma mass spectrometry and Prussian blue staining in deep tissue pressure injury mouse models. An Enzyme-linked immune sorbent assay measured the expression of ferritin, ferroportin-1 and transferrin. Immunofluorescence staining, high-throughput transcriptome sequencing, Western blot and RT-qPCR further analysed the fundamental mechanisms regulating iron metabolism. In this study, we observed numerous inflammatory cells infiltrating the marginal tissues of stage IV pressure injury patients and in deep tissue pressure injury models. The expression levels of pro-inflammatory factors, such as inducible nitric oxide synthase and interleukin-6, were significantly increased (p < 0.05). The iron level was proportional to the degree of progression, with the most significant change appearing on the third day in deep tissue pressure injury models (p < 0.05). Enzyme-linked immune sorbent assay results suggested abnormal gene expression was related to iron metabolism, including a substantial increase in ferritin and a significant decrease in the expression of ferroportin-1 (p < 0.05). In addition, immunofluorescence staining and Western blot showed that the expression of macrophage membrane receptor CD163 was abnormally elevated (p < 0.05). Both high-throughput transcriptome sequencing and qRT-PCR results suggested aberrant expression of the CD163/Homx-1-mediated signalling pathway. Dysfunctional iron metabolism was suggested to be related to the aberrant CD163/Homx-1 signalling pathway in deep tissue pressure injury models.

The intake of solid fat and cheese may be associated with a reduced risk of Helicobacter pylori infection status: a cross-sectional study based on NHANES 1999-2000.

BACKGROUND: Diet plays an important role in Helicobacter pylori (HP) infection, and our objective was to investigate potential connections between dietary patterns, specific food groups, and HP infection status in U.S. adults. METHODS: The data for this study was obtained from the NHANES (National Health and Nutrition Survey) database for the year 1999-2000. This cross-sectional study involved the selection of adults aged 20 years and older who had undergone dietary surveys and HP testing. Factor analysis was employed to identify dietary patterns, and logistic regression models were utilized to assess the association between these dietary patterns and specific food groups with HP infection status. RESULT: Based on the inclusion and exclusion criteria, our final analysis included 2,952 individuals. The median age of participants was 51.0 years, and 48.7% were male. In the study population, the overall prevalence of HP infection was 44.9%. Factor analysis revealed three distinct dietary patterns: High-fat and high-sugar pattern (including solid fats, refined grains, cheese, and added sugars); Vegetarian pattern (comprising fruits, juices, and whole grains); Healthy pattern (encompassing vegetables, nuts and seeds, and oils). Adjusted results showed that the high-fat and high-sugar pattern (OR = 0.689, 95% CI: 0.688-0.690), vegetarian pattern (OR = 0.802, 95% CI: 0.801-0.803), and healthy pattern (OR = 0.717, 95% CI: 0.716-0.718) were all linked to a lower likelihood of HP infection. Further analysis of the high-fat and high-sugar pattern revealed that solid fats (OR = 0.717, 95% CI: 0.716-0.718) and cheese (OR = 0.863, 95% CI: 0.862-0.864) were protective factors against HP infection, while refined grains (OR = 1.045, 95% CI: 1.044-1.046) and added sugars (OR = 1.014, 95% CI: 1.013-1.015) were identified as risk factors for HP infection. CONCLUSION: Both the Vegetarian pattern and the Healthy pattern are associated with a reduced risk of HP infection. Interestingly, the High-fat and High-sugar pattern, which is initially considered a risk factor for HP infection when the score is low, becomes a protective factor as the intake increases. Within this pattern, animal foods like solid fats and cheese play a protective role, while the consumption of refined grains and added sugars increases the likelihood of HP infection.

LDLR c.89_92dup: a novel frameshift variation in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing. OBJECTIVE: The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants. METHODS: Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members. RESULTS: A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance. CONCLUSION: This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.

Prussian-Blue-Analogue-Derived Ultrathin Co2P-Fe2P Nanosheets for Universal-pH Overall Water Splitting.

The great interest in large-scale electrochemical water splitting toward clean hydrogen has spurred large numbers of studies on developing cost-efficient and high-performance bifunctional electrocatalysts. Here, a Prussian-blue-analogue-derived method is proposed to prepare honeycomb-like ultrathin and heterogeneous Co2P-Fe2P nanosheets on nickel foam, showing low overpotentials of 0.080, 0.088, and 0.109 V for the hydrogen evolution reaction (HER) at 10 mA cm-2 as well as 0.290, 0.370, and 0.730 V for the oxygen evolution reaction (OER) at 50 mA cm-2 in alkaline, acidic, and neutral electrolytes, respectively. When directly applied for universal-pH water electrolysis, excellent performances are achieved especially at ultralow voltages of 1.45 V at 10 mA cm-2, 1.66 V at 100 mA cm-2, and 1.79 V at 500 mA cm-2 under alkaline conditions. In situ Raman spectroscopy measurements demonstrate that the excellent HER performance can be attributed to heterogeneous Co2P-Fe2P while the ultrahigh alkaline OER performance originates from reconstruction-induced oxyhydroxides.

The Mediating Role of Self-efficacy and Coping Mode Between Powerlessness and Quality of Life in Patients with Venous Leg Ulcers.

OBJECTIVE: To explore the mediating effect of self-efficacy and coping mode between powerlessness and quality of life in patients with a venous leg ulcer (VLU). METHODS: The authors used a convenience sampling method to select 208 patients with a VLU in four tertiary grade A hospitals in Qingdao and Tianjin from June 2021 to August 2022. Instruments included the Powerlessness Assessment Tool, Venous Leg Ulcer Self-efficacy Tool, Medical Coping Modes Questionnaire, and Venous Leg Ulcer Quality of Life Questionnaire. The authors used descriptive statistics, Pearson correlation, and PROCESS macros for data analysis. RESULTS: The powerlessness score was significantly negatively associated with self-efficacy and confrontation coping mode scores and positively associated with patients' quality-of-life scores. In addition, self-efficacy and confrontation coping modes separately and sequentially mediated the relationship between powerlessness and quality of life. CONCLUSIONS: Self-efficacy and confrontation coping mode play important mediating roles between powerlessness and quality of life in patients with VLUs. By decreasing patients' sense of powerlessness, boosting their self-efficacy, and encouraging them to adopt confrontation coping mode, health professionals can improve patients' quality of life.

Dendritic epidermal T cell hydrogel induces the polarization of M2 macrophages to promote the healing of deep tissue pressure injury.

Dendritic epidermal T cells (DETCs) have been shown to promote wound healing. However, the mechanisms involved need to be better understood. In the present study, we investigated the role and mechanism of DETCs in deep tissue pressure injury (DTPI). We established the DTPI model using C57BL/6 mice. Then, DTPI was evaluated and analyzed by histological staining, immunohistochemistry, real-time PCR, Western blotting, and flow cytometry in different treatment groups (DETCs, DETCs/gel, Matrigel, Saline, and Normal group). The results showed that insulin-like growth factor 1 and vascular endothelial growth factor-A expression increased after local DETCs and DETCs/gel implantation in DTPI on days 3 and 7. M1 (inducible nitric oxide synthas-marked) macrophages were predominant at 3 days after DTPI. At 7 days, M1 macrophages were decreased, and M2 (CD206-marked) macrophages were increased in the DETCs and DETCs/gel groups. In vitro, in the co-culture of DETCs and RAW264.7, CD206 expression was significantly increased in M2 macrophages. In addition, Interleukin-17A initially inhibited wound healing 1 day after injury. However, it promoted wound healing at 7, 14, and 21 days after treatment with DETCs and DETCs/gel, respectively. In conclusion, our data suggest that exogenous DETCs improve DTPI wound healing by regulating M1 to M2 macrophage polarization.

Self-Adaptive Aromatic Cation-π Driven Dimensional Polymorphism in Supramolecular Polymers for the Photocatalytic Oxidation and Separation of Aromatic/Cyclic Aliphatic Compounds.

The phenomenon of polymorphism is ubiquitous in nature, the controlled manipulation of which not only increases our ontological understanding of nature but also facilitates the conceptualization and realization of novel functional materials. However, achieving targeted polymorphism in supramolecular assemblies (SAs) remains a formidable challenge, largely because of the constraints inherent in controlling the specific binding motifs of noncovalent interactions. Herein, we propose self-adaptive aromatic cation-π binding motifs to construct polymorphic SAs in both the solid and solution states. Using distinct discrete cation-π-cation and long-range cation-π binding motifs enables control of the self-assembly directionality of a C2h-symmetric bifunctional monomer, resulting in the successful formation of both two-dimensional and three-dimensional crystalline SAs (2D-CSA and 3D-CSA). The differences in the molecular packing of 3D-CSA compared with that of 2D-CSA significantly improve the charge separation and carrier mobility, leading to enhanced photocatalytic activity for the aerobic oxidation of thioanisole to methyl phenyl sulfoxide (yield of 99 % vs 57 %). 2D-CSA, which has a vertical extended structure with favorable stronger interaction with toluene though face-to-face cation-π interactions than methylcyclohexane, shows higher toluene/methylcyclohexane separation efficiency than 3D-CSA (96.9 % for 2D-CSA vs 56.3 % for 3D-CSA).

Triply Interlocked [2]catenanes: Rational Synthesis, Reversible Conversion Studies and Unprecedented Application in Photothermal Responsive Elastomer.

Triply interlocked [2]catenane complexes featuring two identical, mechanically interlocked units are extraordinarily rare chemical compounds, whose properties and applications remain open to detailed studies. Herein, we introduce the rational design of a new ligand precursor, L1, suitable for the synthesis of six triply interlocked [2]catenanes by coordination-driven self-assembly. The interlocked compounds can be reversibly converted into the corresponding simple triangular prism metallacage by addition of H2O or DMF solvents to their CH3OH solutions, thereby demonstrating the importance of π···π stacking and hydrogen bonding interactions in the formation of triply interlocked [2]catenanes. Moreover, extensive studies have been conducted to assess the remarkable photothermal conversion performance. Complex 6a, exhibiting outstanding photothermal conversion performance (conversion efficiency in solution : 31.82%), is used to prepare novel photoresponsive elastomer in combination with thermally activated liquid crystal elastomer. The resultant material displays robust response to near-infrared (NIR) laser and the capability of completely reforming the shape and reversible actuation, paving the way for the application of half-sandwich organometallic units in photo-responsive smart materials.

Kinesin family member 11 promotes progression of hepatocellular carcinoma via the OCT4 pathway.

Hepatocellular carcinoma (HCC) is the tumor with the second highest mortality rate worldwide. Recent research data show that KIF11, a member of the kinesin family (KIF), plays an important role in the progression of various tumors. However, its expression and molecular mechanism in HCC remain elusive. Here, we evaluated the potential role of KIF11 in HCC. The effect of KIF11 was evaluated using the hepatocellular carcinoma cell lines, LM3 and Huh7, after genetic or pharmacological treatment. Evaluating the role of KIF11 in the xenograft animal models using its specific inhibitor. The role of KIF11 was systematically evaluated using specimens obtained from the aforementioned animal and cell models after various in vivo and in vitro experiments. The clinicopathological analysis showed that KIF11 was expressed at high levels in patients with hepatocellular carcinoma. Cell experiments in vitro showed that KIF11 deficiency significantly slowed the proliferation of liver tumor cells. And in the experiment using liver cancer cells overexpressing OCT4, overexpression of OCT4 substantially increased the proliferation of tumor cells compared with tumor cells with KIF11 knockdown alone. Both in vitro cell experiment and in vivo xenotransplantation tumor experiment showed that monastrol, an inhibitor of KIF11, could effectively delay the proliferation and migration of tumor cells. Based on these results, KIF11 is expressed at high levels in hepatocellular carcinoma and promotes tumor proliferation in an OCT4-dependent manner. KIF11 may become a therapeutic target for hepatocellular carcinoma, and its inhibitor monastrol may become a clinical antitumor drug.

Integrated pan-cancer analysis of centromere protein F and experimental verification of its role and clinical significance in cholangiocarcinoma.

Centromere protein F (CENPF), a protein related to the cell cycle, is a key part of the kinetochore-centromere complex involved in cell division, differentiation, and proliferation. CENPF expression is upregulated in various types of cancer and plays a role in oncogenesis and tumor progression. However, the expression pattern, prognostic significance, and biological role of CENPF in these cancer types are poorly understood. Therefore, in this study, we conducted a pan-cancer analysis of the role of CENPF, which we considered a cut point, to investigate its utility as a prognostic and immunological indicator for malignancies, especially cholangiocarcinoma (CCA). Using systematic bioinformatics analysis, we investigated the expression patterns, prognostic relevance, molecular function, signaling pathways, and immune infiltration patterns of CENPF in the pan-cancer analysis. Western blot and immunohistochemistry staining assays were performed to evaluate the expression profiles of CENPF in CCA tissues and cell lines. Furthermore, Cell Counting Kit-8, colony formation, wound healing, and Transwell assays, as well as CCA xenograft mouse models, were employed to determine the role and function of CENPF in CCA. The results showed that CENPF expression was upregulated and strongly linked to a worse prognosis in most cancer types. CENPF expression was substantially associated with immune cell infiltration, tumor microenvironment, genes related to immune checkpoints, tumor mutational burden, microsatellite instability, and immunotherapy response in diverse malignancies. CENPF was considerably overexpressed in CCA tissues and cells. Functionally, inhibiting CENPF expression significantly reduced the proliferating, migrating, and invading abilities of CCA cells. CENPF expression also affects the prognosis of multiple malignancies, which is highly associated with immunotherapy response and tumor immune cell infiltration. In conclusion, CENPF may act as an oncogene and an immune infiltration-related biomarker and can accelerate tumor development in CCA.

Alterations of conjunctival microbiota associated with orthokeratology lens wearing in myopic children.

BACKGROUND: Orthokeratology (OK) lens wear increases the risk of bacterial infection, but little is known about the microbiota of the conjunctival sac in myopic children wearing OK lenses. This study aimed to investigate the changes of conjunctival microbiota in children after treatment with OK lenses using 16 S rDNA sequencing. METHODS: Twenty-eight myopic children who had been continuously wearing OK lenses for 12 to 13 months were enrolled in this prospective study. Twenty-two gender- and age-matched myopic children who had not worn OK lenses or discontinued OK lens wear at least 1 year ago were recruited as controls. Conjunctival swabs from each participant were collected for exploration of the microbiota profiles, targeting the V3-V4 regions of the 16 S rRNA gene by MiSeq sequencing. The differences in the microbial community structure and diversity were also compared between groups. RESULTS: The bacterial alpha diversity indices in the OK lens group were not different from those in the non-wearer group (P > 0.05, Wilcoxon test), while beta diversity examined using principle coordinate analysis of unweighted UniFrac divided the two groups into different clusters. Proteobacteria, Bacteroidetes, and Firmicutes were the abundant phyla in the conjunctival sac microbiota in both groups (P < 0.05, Mann-Whitney U test). Among children in the OK lens group, the Linear discriminant analysis Effect Size identified the compositional changes in OK lens-associated bacteria. Key functional genera such as Blautia, Parasutterella, and Muribaculum were enriched, whereas Brevundimonas, Acinetobacter, Proteus, and Agathobacter decreased significantly (P < 0.05, Mann-Whitney U test). Phylogenetic investigation of communities by reconstruction of unobserved states also showed altered bacterial metabolic pathways in OK lens-associated microbiota. Moreover, using receiver operating characteristic curves, Brevundimonas, Acinetobacter, Proteus, and Agathobacter alone (the area under the curve was all > 0.7500) or in combination (the area under the curve was 0.9058) were revealed to discriminate OK lens wearers from controls. CONCLUSIONS: The relative abundance of the microbial community in the conjunctival sac of myopic children can alter after OK lens wear. Brevundimonas, Acinetobacter, Proteus, and Agathobacter may be candidate biomarkers to distinguish between OK lens wearers and non-wearers.

MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials.

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0 mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing chemotherapy-induced-neutropenia in early-stage breast cancer patients.

BACKGROUND: To compare the clinical value of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and pegylated rhG-CSF(PEG-rhG-CSF) in early-stage breast cancer (EBC) patients receiving adjuvant chemotherapy, compare the efficacy of PEG-rhG-CSF with different dose and explore the timing of rhG-CSF rescue treatment. METHODS: Patients in two PEG-rhG-CSF subgroups were given 3 mg or 6 mg PEG-rhG-CSF within 24 ~ 48 h after chemotherapy for preventing myelosuppression, while patients in the rhG-CSF group were given rhG-CSF. Observation indicators include the incidence of febrile neutropenia (FN) and grade 3/4 chemotherapy-induced-neutropenia (CIN), the overall levels and nadir values of white blood cells (WBC) and absolute neutrophil count (ANC), comparison of WBC and ANC curves over time, the incidence of CIN-related complications, the incidence of adverse events in each group and the timing of rescue treatment for rhG-CSF. RESULTS: There was no significant difference in the incidence of FN in the first cycle among the groups (P = 0.203). But the incidence of ≥ 3 grade CIN in two PEG-rhG-CSF subgroups was significantly lower than that in the rhG-CSF group (P < 0.001). The overall WBC and ANC levels in the PEG-rhG-CSF group were significantly higher than those in the rhG-CSF group (P < 0.001). In terms of CIN-related complications, less chemotherapy delay rate (1.1 vs. 7.5%, P = 0.092), less dose reduction rate (6.9 vs. 7.5%, P = 1.000), less antibiotic use rate (3.4 vs. 17.5%, P = 0.011) and less proportion of rhG-CSF rescue therapy (24.1 vs. 85.0%, P < 0.001) in the PEG-rhG-CSF group, and there were no significant differences between PEG-rhG-CSF subgroups. In the incidence of adverse events among the groups, there were no statistical differences. All patients undergoing rhG-CSF rescue treatment were mainly 4 grade (63.6%) and 3 grade (25.5%) CIN, and 10.9% of patients with 1 ~ 2 grade CIN who had high infection risk or had been infected. CONCLUSION: PEG-rhG-CSF has better efficacy and equal tolerance compared with rhG-CSF in preventing CIN in EBC patients receiving EC regimen. Moreover, a half-dose 3 mg PEG-rhG-CSF also had good efficacy. Last, patients with ≥ 3 grade CIN and others who have been assessed to be at high risk of infection or have co-infection should consider rhG-CSF or even antibiotic rescue treatment.

Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress has been reported to be transmitted from tumor cells to immune cells via exosome and implicated in immune escape. However, the influence of ER stress on monocytes in chronic lymphocytic leukemia (CLL) cells is largely unknown. Here, we observed the expression of ER stress markers (GRP78, ATF6, PERK, IRE1a, and XBP1s) in CLL cells. The increasing mRNA expression of these ER stress response components was positively correlated with more aggressive disease. Exosome from ER stress inducer tunicamycin (TM)-primed CLL cells (ERS-exo) up-regulated the expression of ER stress marker on monocytes, indicating ER stress is transmissible in vitro via exosome. Treatment with ERS-exo promoted the survival of monocytes and induced phenotypic changes with a significantly larger percentage of CD14+ CD16+ monocytes. Finally, we identified exosome-mediated transfer of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) from ER stressed CLL cells into monocytes as a novel mechanism through which ERS-exo regulated monocytes. Exosomal eNAMPT up-regulated nicotinamide adenine dinucleotide (NAD+ ) production which subsequently activated SIRT1-C/EBPß signaling pathway in monocytes. Our results suggest the role of ER stress in mediating immunological dysfunction in CLL.

Noninvasive Evaluation of the Notch Signaling Pathway via Radiomic Signatures Based on Multiparametric MRI in Association With Biological Functions of Patients With Glioma: A Multi-institutional Study.

BACKGROUND: Noninvasive determination of Notch signaling is important for prognostic evaluation and therapeutic intervention in glioma. PURPOSE: To predict Notch signaling using multiparametric (mp) MRI radiomics and correlate with biological characteristics in gliomas. STUDY TYPE: Retrospective. POPULATION: A total of 63 patients for model construction and 47 patients from two public databases for external testing. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T, T1-weighted imaging (T1WI), T2WI, T2 fluid attenuated inversion recovery (FLAIR), contrast-enhanced (CE)-T1WI. ASSESSMENT: Radiomic features were extracted from CE-T1WI, T1WI, T2WI, and T2FLAIR and imaging signatures were selected using a least absolute shrinkage and selection operator. Diagnostic performance was compared between single modality and a combined mpMRI radiomics model. A radiomic-clinical nomogram was constructed incorporating the mpMRI radiomic signature and Karnofsky Performance score. The performance was validated in the test set. The radiomic signatures were correlated with immunohistochemistry (IHC) analysis of downstream Notch pathway components. STATISTICAL TESTS: Receiver operating characteristic curve, decision curve analysis (DCA), Pearson correlation, and Hosmer-Lemeshow test. A P value < 0.05 was considered statistically significant. RESULTS: The radiomic signature derived from the combination of all sequences numerically showed highest area under the curve (AUC) in both training and external test sets (AUCs of 0.857 and 0.823). The radiomics nomogram that incorporated the mpMRI radiomic signature and KPS status resulted in AUCs of 0.891 and 0.859 in the training and test sets. The calibration curves showed good agreement between prediction and observation in both sets (P= 0.279 and 0.170, respectively). DCA confirmed the clinical usefulness of the nomogram. IHC identified Notch pathway inactivation and the expression levels of Hes1 correlated with higher combined radiomic scores (r = -0.711) in Notch1 mutant tumors. DATA CONCLUSION: The mpMRI-based radiomics nomogram may reflect the intratumor heterogeneity associated with downstream biofunction that predicts Notch signaling in a noninvasive manner. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Blood virome of patients with traumatic sepsis.

Sepsis is one of the possible outcomes of severe trauma, and it poses a dire threat to human life, particularly in immunocompromised people. The most prevalent pathogens are bacteria and fungi, but viruses should not be overlooked. For viral metagenomic analysis, we collected blood samples from eight patients with post-traumatic sepsis before and seven days after treatment. The results demonstrated that Anellovirus predominated the viral community, followed by Siphoviridae and Myoviridae, and that the variations in viral community and viral load before and after treatment were not statistically significant. This study allows us to investigate methods for establishing NGS-based viral diagnostic instruments for detecting viral infections in the blood of sepsis patients so that antiviral therapy can be administered quickly.