Spermatogenesis associated serine rich 2 like plays a prognostic factor and therapeutic target in acute myeloid leukemia by regulating the JAK2/STAT3/STAT5 axis.

BACKGROUND: Spermatogenesis associated serine rich 2 like (SPATS2L) was highly expressed in homoharringtonine (HHT) resistant acute myeloid leukemia (AML) cell lines. However, its role is little known in AML. The present study aimed to investigate the function of SPATS2L in AML pathogenesis and elucidate the underlying molecular mechanisms. METHODS: Overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) were used to evaluate the prognostic impact of SPATS2L for AML from TCGA database and ourcohort. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. The changes of proteins were assessed by Western blot(WB). A xenotransplantation mice model was used to evaluate in vivo growth and survival. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML. RESULTS: SPATS2L expression increased with increasing resistance indexes(RI) in HHT-resistant cell lines we had constructed. Higher SPATS2L expression was observed in intermediate/high-risk patients than in favorable patients. Meanwhile, decreased SPATS2L expression was observed in AML patients achieving complete remission (CR). Multivariate analysis showed high SPATS2L expression was an independent poor predictor of OS, EFS, RFS in AML. SPATS2L knock down (KD) suppressed cell growth, induced apoptosis, and suppressed key proteins of JAK/STAT pathway, such as JAK2, STAT3, STAT5 in AML cells. Inhibiting SPATS2L expression markedly enhanced the pro-apoptotic effects of traditional chemotherapeutics (Ara-c, IDA, and HHT). CONCLUSIONS: High expression of SPATS2L is a poor prognostic factor in AML, and targeting SPATS2L may be a promising therapeutic strategy for AML patients.

The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent subtype of leukemia in Western countries, causing a substantial health burden on patients and society. Comprehensive evaluation of the epidemiological characteristics of CLL is warranted, especially in the current context of global population aging. The main objective of this study is evaluating the disease burden of CLL at global, regional, and national levels from 1990 to 2019. As secondary objectives, we studied the influence of demographic factors and performed risk factor analysis. We hope this study could provide evidence for the evaluation of the effectiveness of previous prevention strategies and the formulation of future global health policies. RESULTS: Based on data of CLL between 1990 to 2019 from the Global Burden of Disease (GBD) study 2019, we depicted the age, gender, and regional structure of the CLL burden population and described the impact of social development on the disease burden of CLL. The distribution and changing trends of attributable risk factors were also investigated. The global burden of CLL has increased dramatically. A high incidence has been achieved in males and elder people. Countries and territories with high social-demographic index (SDI) tended to have higher global burden than low-SDI region. Of risk factors, high body mass index and smoking were the major contributors for CLL-related mortality and disability adjusted life-years (DALYs). CONCLUSION: In summary, the global CLL burden continues to rise over the past 30 years. The relocation of medical resource should be considered on a global scale.

Fixation stability comparison of bone screws based on thread design: buttress thread, triangle thread, and square thread.

BACKGROUND: The influence of thread profile on the fixation stability of bone screws remains unclear. This study aimed to compare the fixation stability of screws with different thread profiles under several loading conditions. METHODS: Bone screws that differed in thread profile (buttress, triangle, and square thread) only were made of stainless steel. Their fixation stabilities were evaluated individually by the axial pullout test and lateral migration test, besides, they were also evaluated in pairs together with a dynamic compression plate and a locking plate in polyurethane foam blocks under cyclic craniocaudal and torsional loadings. RESULTS: The triangle-threaded and square-threaded screws had the highest pullout forces and lateral migration resistance. When being applied to a dynamic compression plate, higher forces and more cycles were required for both triangle- and square-threaded screws to reach the same displacement under cyclic craniocaudal loading. On the other hand, the triangle-threaded screws required a higher torque and more cycles to reach the same angular displacement under cyclic torsional loading. When being applied to a locking plate, the square-threaded screws needed higher load, torque, and more cycles to reach the same displacement under both cyclic craniocaudal and torsion loadings. CONCLUSIONS: The triangle-threaded screws had superior pullout strength, while square-threaded screws demonstrated the highest lateral migration resistance. Moreover, dynamic compression plate fixation with triangle- and square-threaded screws achieved more favorable fixation stability under craniocaudal loading, while triangle-threaded screws demonstrated superior fixation stability under torsional loading. Locking plate fixation with a square-threaded screw achieved better fixation stability under both loading types.

Using sternal angle as anatomic landmark for right internal jugular vein catheterization in pediatrics.

BACKGROUND: Many formulas based on the patient's height, weight and/or age exist to determine central venous catheter (CVC) depth in children. However, this information is unavailable in some emergency conditions. Therefore, direct methods should be developed to guide catheter position in children. METHODS: Eighty patients aged 1-10 y were enrolled from July 2015 to August 2016 and seventy-five were completed; fifty were male, and twenty-five were female. The exclusion criteria were inability to identify the sternal angle or failure to use the right internal jugular vein approach. The catheter was inserted using the right internal jugular vein approach, the distance from the skin puncture point to the midpoint of the sternal angle plane was measured, and the catheter tip was positioned to this distance minus 1 cm. Chest radiography were performed for those children after catheter insertion. The relative position between the catheter tip and carina was confirmed and the longitudinal distance from the catheter tip to the carina was calculated on radiographic images, and related complications were recorded. RESULTS: All catheter tips were above the carina, and the average distance from the catheter tip to the carina was 9.8 mm. No patients experienced serious complications. CONCLUSION: The sternal angle is a useful and reliable anatomic landmark for guiding CVC position in children. Using this landmark, the catheter can be quickly and conveniently placed at a safety position in right internal jugular vein, especially in some emergency conditions.

Lidocaine Attenuates Cognitive Impairment After Isoflurane Anesthesia by Reducing Mitochondrial Damage.

Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in isoflurane-induced neuronal damage. Lidocaine has been demonstrated to attenuate the impairment of cognition in aged rats induced by isoflurane in our previous study. In this study, we hypothesized that lidocaine could attenuate isoflurane anesthesia-induced cognitive impairment by reducing mitochondrial damage. H4 human neuroglioma cells and 18-month-old male Fischer 344 rats were exposed to isoflurane or isoflurane plus lidocaine. Cognitive function was tested at 14 days after treatment by the Barnes Maze test in male Fischer 344 rats. Morphology was observed under electron microscope, and mitochondrial transmembrane potential, electron transfer chain (ETC) enzyme activity, complex-I-IV activity, immunofluorescence and flow cytometry of annexin V-FITC binding, TUNEL assay, and Western blot analyses were applied. Lidocaine attenuated cognitive impairment caused by isoflurane in aged Fischer 344 rat. Lidocaine was effective in reducing mitochondrial damage, mitigating the decrease in mitochondrial membrane potential (ΔΨm), reversing isoflurane-induced changes in complex activity in the mitochondrial electron transfer chain and inhibiting the apoptotic activities induced by isoflurane in H4 cells and Fischer 344 rats. Additionally, lidocaine suppressed the ratio of Bax (the apoptosis-promoting protein) to Bcl-2 (the apoptosis-inhibiting protein) caused by isoflurane in H4 cells. Lidocaine proved effective in attenuating isoflurane-induced POCD by reducing mitochondrial damage.

Understanding How the Suppression of Insertion-Induced Phase Transitions Leads to Fast Charging in Nanoscale LixMoO2.

Fast-charging Li-ion batteries are technologically important for the electrification of transportation and the implementation of grid-scale storage, and additional fundamental understanding of high-rate insertion reactions is necessary to overcome current rate limitations. In particular, phase transformations during ion insertion have been hypothesized to slow charging. Nanoscale materials with modified transformation behavior often show much faster kinetics, but the mechanism for these changes and their specific contribution to fast-charging remain poorly understood. In this work, we combine operando synchrotron X-ray diffraction with electrochemical kinetics analyses to illustrate how nanoscale crystal size leads to suppression of first-order insertion-induced phase transitions and their negative kinetic effects in MoO2, a tunnel structure host material. In electrodes made with micrometer-scale particles, large first-order phase transitions during cycling lower capacity, slow charge storage, and decrease cycle life. In medium-sized nanoporous MoO2, the phase transitions remain first-order, but show a considerably smaller miscibility gap and shorter two-phase coexistence region. Finally, in small MoO2 nanocrystals, the structural evolution during lithiation becomes entirely single-phase/solid-solution. For all nanostructured materials, the changes to the phase transition dynamics lead to dramatic improvements in capacity, rate capability, and cycle life. This work highlights the continuous evolution from a kinetically hindered battery material in bulk form to a fast-charging, pseudocapacitive material through nanoscale size effects. As such, it provides key insight into how phase transitions can be effectively controlled using nanoscale size and emphasizes the importance of these structural dynamics to the fast rate capability observed in nanostructured electrode materials.

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia.

Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

Global research trends of nanotechnology for pain management.

Background: Nanotechnology has been increasingly used in healthcare during recent years. However, the systematic evaluation of research on nanotechnology for pain management is lacking. In this study, we employed a bibliometric approach to examine the status of the research and global trends of nanotechnology in relation to pain management. Methods: We selected relevant papers published in the Web of Science Core Collection database between 2013 and 2022 using search terms related to nanotechnology and pain management. Subsequently, the following bibliographic information was collected: publication year, originating country/region, affiliated authors and institutions, published journal, references cited, citation frequency, and keywords. The bibliometric software programs VOSViewer and CiteSpace were employed to obtain bibliometric statistics and perform visual analysis. Results: A total of 2680 papers were retrieved. The number of publications in the field of nanotechnology for pain management has been increasing annually since 2013. China had the highest number of published papers, whereas the United States led in total citations. The Chinese Academy of Sciences was the most prolific institution, while the Tehran University of Medical Sciences had the highest overall citations. Furthermore, De Paula was the most prolific author. Papers associated with nanotechnology for pain management were mainly published in the International Journal of Pharmaceutics, Pharmaceutics, and the International Journal of Nanomedicine. Keyword analysis showed that "in-vitro" and "drug-delivery" appeared most frequently, with the top 10 common keywords comprising nanoparticles, pain, in-vitro, drug-delivery, delivery, release, inflammation, neuropathic pain, formulation, and expression. Lastly, the latest emerging keyword was "electrochemical sensor". Conclusion: Research on applying nanotechnology for pain management is growing steadily. China is the top country in terms of number of publications, with institutions under the Chinese Academy of Sciences making significant contributions to this field. "In-vitro" and "drug-delivery" are the current hotspots in this area, with "electrochemical sensor" as the latest topic at the research forefront. However, national and inter-institutional collaborations should be strengthened to enable patients with pain disorders to benefit from nanotechnology implementation in pain management.

Identification of a novel NPM1 mutation in acute myeloid leukemia.

Nucleophosmin (NPM1) is a widely expressed nucleocytoplasmic shuttling protein with prominent nucleolar localization. It is estimated that 25-35% of adult patients with acute myeloid leukemia (AML) carry NPM1 mutations. The classic NPM1 type A mutation occurs in exon 12, which accounts for 75-80% of adult patients with NPM1-mutated AML. It produces an additional leucine and valine-rich nuclear export signal (NES) at the C-terminus, and causes aberrant cytoplasmic dislocation of NPM1 protein. Notably, emerging evidence indicates that besides the classic type A mutation, rare mutants occurring in other exons may also lead to the imbalance of the nucleocytoplasmic shuttle of NPM1. Identification of novel non-type A mutants is crucial for the diagnosis, prognosis, risk stratification and disease monitoring of potential target populations. Here we reported a novel NPM1 mutation in exon 5 identified from a de novo AML patient. Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is another NPM1 "born to be exported" mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novel NPM1 mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.

Activation of the Akt Attenuates Ropivacaine-Induced Myelination Impairment in Spinal Cord and Sensory Dysfunction in Neonatal Rats.

Prolonged exposure to local anesthetics (LAs) or intrathecal administration of high doses of LAs can cause spinal cord damage. Intraspinal administration of LAs is increasingly being used in children and neonates. Therefore, it is important to study LA-related spinal cord damage and the underlying mechanism in developmental models. First, neonatal Sprague-Dawley rats received three intrathecal injections of 0.5% ropivacaine, 1% ropivacaine, 2% ropivacaine or saline (90-min interval) on postnatal day 7. Electron microscopy, luxol fast blue staining and behavioral tests were performed to evaluate the spinal neurotoxicity caused by ropivacaine at different concentrations. Western blot analysis and immunostaining was performed to detect the expression changes of p-Akt, Akt, myelin gene regulatory factor (MYRF) and myelin basic protein (MBP) in the spinal cord treated with different concentrations of ropivacaine. Our results showed that 1% or 2% ropivacaine impaired myelination in the spinal cord and induced sensory dysfunction, but 0.5% ropivacaine did not. Moreover, 1% or 2% ropivacaine decreased the expression of p-Akt, MYRF and MBP in the spinal cord. Then, in order to further explore the role of these proteins in this model, the Akt-specific activator (SC79) was intraperitoneally injected 30 min before 2% ropivacaine treatment. Interestingly, SC79-mediated activation of Akt partly rescued ropivacaine-induced myelination impairments and sensory dysfunction. Overall, the results showed that ropivacaine caused spinal neurotoxicity in a dose-dependent manner in neonatal rats and that activation of the Akt partly rescued ropivacaine-induced these changes. These data provide insight into the neurotoxicity to the developing spinal cord caused by LAs.

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development.

Despite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC-BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

Sevoflurane increases intracellular calcium to induce mitochondrial injury and neuroapoptosis.

Sevoflurane is commonly used in clinical anesthesia. However, some reports indicated that Sevoflurane could induce mitochondrial injury and neuroapoptosis. Although the mechanism remains unclear, evidence points to the increase of intracellular calcium after administration of Sevoflurane. Herein, we sought whether the increment of intracellular Ca2+ caused by Sevoflurane administration could induce mitochondrial injury and apoptosis in primary neurons of the hippocampus. Fluo-4-acetoxymethyl ester Ca2+ probe was used for measuring intracellular Ca2+ concentrations. LDH assay, CCK-8 assay, and Western blotting were performed to confirm Sevoflurane-induced neuroapoptosis. ROS, mPTP, and ATP production were assayed to reveal mitochondrial injury. Our results indicated that Sevoflurane increased intracellular Ca2+ and neuronal death. Sevoflurane also elevated ROS and the opening of mPTP, and decreased ATP production in neurons. The expression of cytochrome c, cleaved caspase-9, cleaved caspase-3, and the ratio of Bax/Bcl-2 were also increased. By using calcium channel blocker Nimodipine, the increase of intracellular Ca2+ was attenuated, and the death rate of neurons, the ROS and opening of mPTP, decreased ATP production, the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3 and the ratio of Bax/Bcl-2 were alleviated. Our study suggested that Sevoflurane could increase intracellular Ca2+ to induce mitochondrial injury and mitochondria-mediated neuroapoptosis in neurons.

Targeting miR-126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells.

BACKGROUND: Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment. METHODS: We evaluated microRNA-126 (miR-126) levels in MDS patients' sample and in a NUP98-HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs' maintenance by inhibiting miR-126 expression in vitro and in vivo. Identification of miR-126 effectors was conducted using biotinylated miR-126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti-miR-126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models. RESULTS: miR-126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR-126 in NHD13 mice decreased quiescence and self-renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony-forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non-coding RNA PTTG3P as a novel miR-126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients. CONCLUSIONS: MiR-126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR-126 is a potentially novel approach in MDS.

Prognostic values of inhibitory κB kinases mRNA expression in human gastric cancer.

Background: Inhibitory κB kinases (IKKs) play a key role in modulating proinflammatory and growth stimulating signals through their regulation of the nuclear factor κB (NF-κB) cascade. Therefore, the level of expression of IKKs represents a viable prognostic predictor with regard to various pathological processes. The prognostic value of IKKs expression in gastric cancer remains unclear. Methods: We used the 'Kaplan-Meier plotter' (KM plotter) online database, to explore the predictive prognostic value of individual IKKs members' mRNA expression to overall survival (OS) in different clinical data including pathological staging, histology, and therapies employed. Results: Our results revealed that a higher mRNA expression of inhibitor of NF-κB kinase subunit α (IKKα) was correlated to better OS, whereas higher mRNA expression of IKKß, inhibitor of NF-κB kinase subunit γ (IKKγ), inhibitor of NF-κB kinase subunit ε (IKKε), and suppressor of IKKε (SIKE) were generally correlated to unfavorable OS in gastric cancer. Increased mRNA expression of IKKε also showed better outcomes in stage IV gastric cancer. Further a correlation between elevated levels of mRNA expression of both IKKε and SIKE was found to have favorable OS in diffuse type gastric cancer. It was also revealed that high expression of SIKE had favorable OS when treated with other adjuvant therapies, while worse OS when treated only with 5FU therapy. Conclusion: Our results suggest that mRNA expression of individual IKKs and SIKE are associated with unique prognostic significance and may act as valuable prognostic biomarkers and potential targets for future therapeutic interventions in gastric cancer.

Harnessing redox activity for the formation of uranium tris(imido) compounds.

Classically, late transition-metal organometallic compounds promote multielectron processes solely through the change in oxidation state of the metal centre. In contrast, uranium typically undergoes single-electron chemistry. However, using redox-active ligands can engage multielectron reactivity at this metal in analogy to transition metals. Here we show that a redox-flexible pyridine(diimine) ligand can stabilize a series of highly reduced uranium coordination complexes by storing one, two or three electrons in the ligand. These species reduce organoazides easily to form uranium-nitrogen multiple bonds with the release of dinitrogen. The extent of ligand reduction dictates the formation of uranium mono-, bis- and tris(imido) products. Spectroscopic and structural characterization of these compounds supports the idea that electrons are stored in the ligand framework and used in subsequent reactivity. Computational analyses of the uranium imido products probed their molecular and electronic structures, which facilitated a comparison between the bonding in the tris(imido) structure and its tris(oxo) analogue.