First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

CXCL16 Promotes Ly6Chigh Monocyte Infiltration and Impairs Heart Function after Acute Myocardial Infarction.

High CXCL16 levels during acute cardiovascular events increase long-term mortality. However, the mechanistic role of CXCL16 in myocardial infarction (MI) is unknown. Here we investigated the role of CXCL16 in mice with MI injury. CXCL16 deficiency increased the survival of mice after MI injury, and inactivation of CXCL16 resulted in improved cardiac function and decreased infarct size. Hearts from CXCL16 inactive mice exhibited decreased infiltration of Ly6Chigh monocytes. In addition, CXCL16 promoted the macrophage expression of CCL4 and CCL5. Both CCL4 and CCL5 stimulated Ly6Chigh monocyte migration, and CXCL16 inactive mice had a reduced expression of CCL4 and CCL5 in the heart after MI. Mechanistically, CXCL16 promoted CCL4 and CCL5 expression by activating the NF-κB and p38 MAPK signaling pathways. Anti-CXCL16 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Additionally, anti-CCL4 and anti-CCL5 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Thus, CXCL16 aggravated cardiac injury in MI mice by facilitating Ly6Chigh monocyte infiltration.

SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway.

Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study used APP/PS1 mice as an animal model of AD and amyloid-ß (Aß)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aß deposition in mice and apoptosis, respectively. Protein expression was assessed by Western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of Sirt4. Subsequently, the binding of transcription factors to Sirt4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aß-treated HT-22 cells compared with their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased Aß deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.NEW & NOTEWORTHY The study reveals that in Alzheimer's disease models, SIRT4 expression increases, contributing to neuronal apoptosis and amyloid-ß deposition. Reducing SIRT4 lessens apoptosis and amyloid-ß accumulation, improving memory in mice. This process involves the mTOR pathway, regulated by STAT2 transcription factor. These findings suggest targeting the STAT2-SIRT4-mTOR axis as a potential Alzheimer's treatment strategy.

ER-α36 is involved in calycosin inhibition of IL-6 production in macrophages.

The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour-associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL-6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali, has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL-6 production in peripheral blood mononuclear cell (PBMC)- and THP-1-derived macrophages and explore its potential mechanisms using co-immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER-α36, a variant of the ER, and reduced IL-6 production in macrophages. Mechanistically, ER-α36 physically interacted with NF-κBp65 and retained p65 in the cytoplasm to attenuate NF-κB function as an IL-6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL-6 production by enhancing ER-α36 expression and its interaction with p65, which attenuated NF-κB function as an IL-6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.

KDM1A, a potent and selective target, for the treatment of DNMT3A-deficient non-small cell lung cancer.

BACKGROUND: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies. METHODS: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction. RESULTS: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level. CONCLUSION: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.

Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

Dnttip2 is one of the components of the small subunit (SSU) processome. In yeast, depletion of dnttip2 leads to an inefficient processing of pre-rRNA and a decrease in synthesis of the mature 18S rRNA. However, the biological roles of Dnttip2 in higher organisms are poorly defined. In this study, we demonstrate that dnttip2 is a maternal gene in zebrafish. Depletion of Dnttip2 leads to embryonic lethal with severe digestive organs hypoplasia. The loss of function of Dnttip2 also leads to partial defects in cleavage at the A0-site and E-site during 18S rRNA processing. In conclusion, Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

An Organic-Inorganic Hydrogel with Exceptional Mechanical Properties via Anion-Induced Synergistic Toughening for Accelerating Osteogenic Differentiation.

Mineralized bio-tissues achieve exceptional mechanical properties through the assembly of rigid inorganic minerals and soft organic matrices, providing abundant inspiration for synthetic materials. Hydrogels, serving as an ideal candidate to mimic the organic matrix in bio-tissues, can be strengthened by the direct introduction of minerals. However, this enhancement often comes at the expense of toughness due to interfacial mismatch. This study reveals that extreme toughening of hydrogels can be realized through simultaneous in situ mineralization and salting-out, without the need for special chemical modification or additional reinforcements. The key to this strategy lies in harnessing the kosmotropic and precipitation behavior of specific anions as they penetrate a hydrogel system containing both anion-sensitive polymers and multivalent cations. The resulting mineralized hydrogels demonstrate significant improvements in fracture stress, fracture energy, and fatigue threshold due to a multiscale energy dissipation mechanism, with optimal values reaching 12 MPa, 49 kJ m-2, and 2.98 kJ m-2. This simple strategy also proves to be generalizable to other anions, resulting in tough hydrogels with osteoconductivity for promoting in vitro mineralization of human adipose-derived mesenchymal stem cells. This work introduces a universal route to toughen hydrogels without compromising other parameters, holding promise for biological applications demanding integrated mechanical properties.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group.

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms.

Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, regardless of patient's sex, age, or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.

Molecular and genetic regulation of petal number variation.

Floral forms with an increased number of petals, also known as double-flower phenotypes, have been selected and conserved in many domesticated plants, particularly in ornamentals, because of their great economic value. The molecular and genetic mechanisms that control this trait are therefore of great interest, not only for scientists, but also for breeders. In this review, we summarize current knowledge of the gene regulatory networks of flower initiation and development and known mutations that lead to variation of petal number in many species. In addition to the well-accepted miR172/AP2-like module, for which many questions remain unanswered, we also discuss other pathways in which mutations also lead to the formation of extra petals, such as those involved in meristem maintenance, hormone signalling, epigenetic regulation, and responses to environmental signals. We discuss how the concept of 'natural mutants' and recent advances in genomics and genome editing make it possible to explore the molecular mechanisms underlying double-flower formation, and how such knowledge could contribute to the future breeding and selection of this trait in more crops.

ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT.

N6-methyladenosine (m6A) is the most prevalent mRNA modification, and it is verified to be closely correlated with cancer occurrence and progression. The m6A demethylase ALKBH5 (alkB homolog 5) is dysregulated in various cancers. However, the role and underlying mechanism of ALKBH5 in the pathogenesis and especially the chemo-resistance of non-small cell lung cancer (NSCLC) is poorly elucidated. The current study shows that ALKBH5 expression is reduced in paclitaxel (PTX) resistant NSCLC cells and down-regulation of ALKBH5 usually implies poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells can suppress cell proliferation and enhance chemo-sensitivity, while knockdown of ALKBH5 exerts the opposite effect, which further supports the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 can also reverse the epithelial-mesenchymal transition (EMT) process in PTX-resistant cancer cells. Mechanistically, data from RNA-seq, real-time PCR and western blotting indicate that CEMIP (cell migration inducing hyaluronidase 1), also known as KIAA1199, may be the downstream target of ALKBH5. Furthermore, ALKBH5 negatively regulates the CEMIP level by reducing the stability of CEMIP mRNA. Collectively, the current data demonstrate that the ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates the chemo-sensitivity of cancer cells to PTX.

Zeptojoule detection of terahertz pulses by parametric frequency upconversion.

We combine parametric frequency upconversion with the single-photon counting technology to achieve terahertz (THz) detection sensitivity down to the zeptojoule (zJ) pulse energy level. Our detection scheme employs a near-infrared ultrafast source, a GaP nonlinear crystal, optical filters, and a single-photon avalanche diode. This configuration is able to resolve 1.4 zJ (1.4 × 10-21 J) THz pulse energy, corresponding to 1.5 photons per pulse, when the signal is averaged within only 1 s (or 50,000 pulses). A single THz pulse can also be detected when its energy is above 1185 zJ. These numbers correspond to the noise-equivalent power and THz-to-NIR photon detection efficiency of 1.3 × 10-16 W/Hz1/2 and 5.8 × 10-2%, respectively. To test our scheme, we perform spectroscopy of the water vapor between 1 and 3.7 THz and obtain results that are in agreement with those acquired with a standard electro-optic sampling (EOS) method. Our technique provides a 0.2 THz spectral resolution offering a fast alternative to EOS THz detection for monitoring specific spectral components in spectroscopy, imaging, and communication applications.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.

Superhydrophobic Tensile Designability of Silicone Rubber Composites.

Silicone rubber has broad applications in the field of industrial engineering due to its stable physical and chemical properties. However, the superhydrophobic properties, of silicone rubber, especially large deformation superhydrophobic properties, were not satisfactory for many harsh application environments and complex engineering structures. Here, we report the preparation of superhydrophobic tensile designable silicone rubber composites by a mixed deposition process that included powder deposition and smoke deposition. The infrared test showed that the deposited powder from silicone rubber combustion was mainly composed of SiO2 and short chain siloxane. The mixed deposited surface with a rich micro-nanostructure, which was the key to the formation of superhydrophobic properties. The water contact angle (WCA) and sliding angle (SA) of coating surface could reach 157.6° and 5° ± 1°, respectively, and the tensile designability of superhydrophobic surface is closely related to the prestretched process. In addition, bounce tests, high temperature tests, and solvent resistance tests showed the application potential of modified silicone rubber composites in the field of engineering.

Kinetic Analysis of the Reaction of Micrometer-Sized Al-Mg Alloy Particles in a Water Vapor Atmosphere.

This study investigated the reaction mechanism of aluminum-magnesium (Al-Mg) alloy particles with water (Al-Mg/H2O) through thermogravimetric analysis-differential scanning calorimetry experiments and kinetic analysis using isoconversional methods and the master plot technique to determine the reaction mechanism function, with the aim of providing insights to support metal powder/water ramjet engine design and combustion characteristics. The results showed that the Al-Mg/H2O reaction occurred in two distinct stages, with stage 1 primarily involving the reaction of Mg elements in the L(Al-Mg) alloy with water while Al played a leading role in stage 2. Notably, the reaction temperatures of Al-Mg particles were significantly lower than those for either Al or Mg particles alone in a water vapor environment. Additionally, the activation energy of stage 1 was lower than that for the individual Al and Mg particles and decreased with increasing Mg content in stage 2. Furthermore, the concentration of Mg in the alloy was found to have a major influence on the reaction mechanism, which followed a random nucleation and growth model. Overall, this work elucidated an alternating endothermic and exothermic staged reaction process for Al-Mg/H2O dominated first by Mg and then Al with kinetic insights providing theoretical support for optimizing Al-Mg alloy compositions for improved ignition and combustion performance in metal powder/water ramjet engines.

A novel real-time model for predicting acute kidney injury in critically ill patients within 12 hours.

BACKGROUND: A major challenge in prevention and early treatment of acute kidney injury (AKI) is the lack of high-performance predictors in critically ill patients. Therefore, we innovatively constructed U-AKIpredTM for predicting AKI in critically ill patients within 12 h of panel measurement. METHODS: The prospective cohort study included 680 patients in the training set and 249 patients in the validation set. After performing inclusion and exclusion criteria, 417 patients were enrolled in the training set and 164 patients were enrolled in the validation set finally. AKI was diagnosed by Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Twelve urinary kidney injury biomarkers (mALB, IgG, TRF, α1MG, NAG, NGAL, KIM-1, L-FABP, TIMP2, IGFBP7, CAF22 and IL-18) exhibited good predictive performance for AKI within 12 h in critically ill patients. U-AKIpredTM, combined with three crucial biomarkers (α1MG, L-FABP and IGFBP7) by multivariate logistic regression analysis, exhibited better predictive performance for AKI in critically ill patients within 12 h than the other twelve kidney injury biomarkers. The area under the curve (AUC) of the U-AKIpredTM, as a predictor of AKI within 12 h, was 0.802 (95% CI: 0.771-0.833, P < 0.001) in the training set and 0.844 (95% CI: 0.792-0.896, P < 0.001) in validation cohort. A nomogram based on the results of the training and validation sets of U-AKIpredTM was developed which showed optimal predictive performance for AKI. The fitting effect and prediction accuracy of U-AKIpredTM was evaluated by multiple statistical indicators. To provide a more flexible predictive tool, the dynamic nomogram (https://www.xsmartanalysis.com/model/U-AKIpredTM) was constructed using a web-calculator. Decision curve analysis (DCA) and a clinical impact curve were used to reveal that U-AKIpredTM with the three crucial biomarkers had a higher net benefit than these twelve kidney injury biomarkers respectively. The net reclassification index (NRI) and integrated discrimination index (IDI) were used to improve the significant risk reclassification of AKI compared with the 12 kidney injury biomarkers. The predictive efficiency of U-AKIpredTM was better than the NephroCheck® when testing for AKI and severe AKI. CONCLUSION: U-AKIpredTM is an excellent predictive model of AKI in critically ill patients within 12 h and would assist clinicians in identifying those at high risk of AKI.

Intraventricular or intrathecal polymyxin B for treatment of post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria: a 8-year retrospective study.

PURPOSE: Post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a life-threatening complication. This study aimed to assess the current practices and clinical outcomes of intravenous (IV) combined with intraventricular (IVT)/intrathecal (ITH) polymyxin B in treating CRGNB intracranial infection. METHODS: A retrospective study was conducted on patients with post-neurosurgical intracranial infection due to CRGNB from January 2013 to December 2020. Clinical characteristics and treatment outcomes were collected and described. Kaplan-Meier survival and multivariate logistic regression analyses were performed. RESULTS: The study included 114 patients, of which 72 received systemic antimicrobial therapy combined with IVT/ITH polymyxin B, and 42 received IV administration alone. Most infections were caused by carbapenem-resistant Acinetobacter baumannii (CRAB, 63.2%), followed by carbapenem-resistant Klebsiella pneumoniae (CRKP, 31.6%). Compared with the IV group, the IVT/ITH group had a higher cerebrospinal fluid (CSF) sterilization rate in 7 days (p < 0.001) and lower 30-day mortality (p = 0.032). In the IVT/ITH group, patients with CRKP infection had a higher initial fever (p = 0.014), higher incidence of bloodstream infection (p = 0.040), lower CSF sterilization in 7 days (p < 0.001), and higher 30-day mortality (p = 0.005) than those with CRAB infection. Multivariate logistic regression analysis revealed that the duration of IVT/ITH polymyxin B (p = 0.021) was independently associated with 30-day mortality. CONCLUSIONS: Intravenous combined with IVT/ITH polymyxin B increased CSF microbiological eradication and improved clinical outcomes. CRKP intracranial infections may lead to more difficult treatment and thus warrant attention and further optimized treatment.