Palladium-Catalyzed Domino Conversion of Aryl-Thianthreniums with Anhydrides: Rapidly Building Highly Functionalized Fluorenones.

As a class of rising electrophilic coupling reagents, aryl-thianthreniums (aryl-TTs) have been gaining immense attention. Herein, a novel palladium-catalyzed domino annulation of aryl-TTs with anhydrides is proposed to rapidly assemble a collection of highly functionalized fluorenones. This finding presents an innovative reaction pattern of aryl-TTs wherein the domino annulation version is first involved. Heavily compared with the existing conversions with aryl-TTs, this identified process successively functions as four aryl C-H bonds.

Exploration of Molecular Nanoparticles as Soft Structural Materials and Their Structure-Property Relationship.

The search for alternative chemical systems other than polymers with chain topologies for soft structural materials raises general interests in fundamental materials and chemical sciences. It is also appealing from an engineering perspective for the urgent need to resolve the typical trade-offs of polymer systems. Herein, a subnanometer molecular cluster, polyhedral oligomeric silsesquioxanes, is assembled into molecular nanoparticles (MNPs) with star topology. Broadly tunable viscoelasticity can be realized by fine-tuning the MNPs' deformability. Being analogous to polymeric systems, the hierarchical structural relaxation dynamics can be observed, and their relaxation time and temperature dependence are dominated by the linker flexibilities. This not only provides microscopic understanding on MNP's unique viscoelasticity but also offers enormous opportunities for modulating their mechanical properties via linker engineering. Our work proves the possibility of applying structural units with particle topologies for the design of soft structural materials.

Advancements in research on the effects of panax notoginseng saponin constituents in ameliorating learning and memory disorders.

Learning and memory disorder is a cluster of symptoms caused by neuronal aging and other diseases of the central nervous system (CNS). Panax notoginseng saponins (PNS) are a series of saponins derived from the natural active ingredients of traditional Chinese medicine (TCM) that have neuroprotective effects on the central nervous system. In this paper, we review the ameliorative effects and mechanisms of Panax notoginseng saponin-like components on learning and memory disorders to provide valuable references and insights for the development of new drugs for the treatment of learning and memory disorders. Our summary results suggest that Panax ginseng saponins have significant effects on improving learning and memory disorders, and these effects and potential mechanisms are mediated by their anti-inflammatory, anti-apoptotic, antioxidant, ß-amyloid lowering, mitochondrial homeostasis in vivo, neuronal structure and function improving, neurogenesis promoting, neurotransmitter release regulating, and probiotic homeostasis in vivo activities. These findings suggest the potential of Panax notoginseng saponin-like constituents as drug candidates for improving learning and memory disorders.

Silver-palladium bimetallic nanoparticles stabilized by elm pod polysaccharide with peroxidase-like properties for glutathione detection and photothermal anti-tumor ability.

Noble metal nanoparticles show good application prospects in biosensors and anti-tumor drug research. Herein, the near-spherical silver­palladium bimetallic nanoparticles supported by elm pod polysaccharide (EPP-AgPd1.5 NPs) were prepared by using the elm pod polysaccharide (EPP). EPP acts as a stabilizer and reducing agent due to its water solubility and weak reducing ability. The particle size of EPP-AgPd1.5 NPs was 33.6 ± 5.5 nm. In addition, EPP-AgPd1.5 NPs had peroxidase-like activity to catalyze 3,3',5,5'-tetramethylbenzidine (TMB) to oxidized TMB by catalyzing H2O2 to OH. Based on the peroxidase-like activity of EPP-AgPd1.5 NPs, a method for detecting glutathione was established, and the detection limit and linear range of glutathione concentration were 0.279 µM and 0-400 µM, respectively. More importantly, the photothermal conversion efficiency of EPP-AgPd1.5 NPs reached 39.7 %, and their inhibition rate in HeLa cells reached 69.9 %. Silver­palladium bimetallic nanoparticles stabilized by EPP had good performance in glutathione detection and anti-tumor drugs.

Constructing copper Phthalocyanine/Molybdenum disulfide (CuPc/MoS2) S-scheme heterojunction with S-rich vacancies for enhanced Visible-Light photocatalytic CO2 reduction.

Constructing a heterojunction by combining two semiconductors with similar band structures is a successful approach to obtaining photocatalysts with high efficiency. Herein, a CuPc/DR-MoS2 heterojunction involving copper phthalocyanine (CuPc) and molybdenum disulfide with S-rich vacancies (13.66%) is successfully prepared by the facile hydrothermal method. Experimental results and theoretical calculations firmly demonstrated that photoelectrons exhibit an S-scheme charge transfer mechanism in the CuPc/DR-MoS2 heterojunction. The S-scheme heterojunction system has proven significant advantages in promoting the charge separation and transfer of photogenerated carriers, enhancing visible-light responsiveness, and achieving robust photoredox capability. As a result, the optimized 3CuPc/DR-MoS2 S-scheme heterojunction exhibits photocatalytic yields of CO and CH4 at 200 and 111.6 µmol g-1h-1, respectively. These values are four times and 4.5 times greater than the photocatalytic yields of pure DR-MoS2. This study offers novel perspectives on the advancement of innovative and highly effective heterojunction photocatalysts.

Unique Viscoelasticity and Hierarchical Relaxation Dynamics of Molecular Granular Materials.

Resulting from the dense packing of subnanometer molecular clusters, molecular granular materials (MGMs) are shown to maintain high elasticity far above their apparent glass transition temperature (Tg*). However, our microscopic understanding of their structure-property relationship is still poor. Herein, 1 nm polyhedral oligomeric silsesquioxanes (POSSs) are appended to a backbone chain in a brush configuration with different flexible linker chains. Assemblies of these brush polymers exhibit hierarchical relaxation dynamics with the glass transition arising from the cooperative dynamics of packed POSSs. The interaction among the assemblies can be strengthened by increasing the rigidity of linkers with the MGM relaxation modes changing from colloid- to polymer chain-like behavior, rendering their tunable viscoelasticity. This finally contributes to the decoupling of mechanical and thermal properties by showing elasticity dominant mechanical properties at a temperature 150 K above the Tg*.

CGRP attenuates pulmonary vascular remodeling by inhibiting the cGAS-STING-NFκB pathway in pulmonary arterial hypertension.

BACKGROUND: Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. METHODS: The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. RESULTS: Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. CONCLUSION: This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.

Impact of Polarity Mismatch in Infinite-Layer Nickelates.

The recent discovery of superconductivity in infinite-layer Sr-doped NdNiO2 grown on SrTiO3(001) provides a new platform to explore the conducting mechanism of unconventional superconductors. However, the electronic structure of infinite-layer nickelates remains controversial. In this paper, we systematically compare the structural and electronic properties of NdNiO2 films grown on SrTiO3 and LaAlO3 substrates using first-principles calculations. Our results show that the lattice reconstruction accompanied by electronic reconstruction occurs in nickelate films on both substrates. Although both heterostructures (HSs) are conducting at the interface, the SrTiO3-based HS shows distinct atomic displacement in the interfacial TiO2 layer and significant electron accumulation deep into three SrTiO3 layers below the interface, while the LaAlO3-based HS shows negligible atomic displacement and electron localization in the interfacial AlO2 layer, reflecting the impact of polarity mismatch on the electronic structure. Further, Wannier function calculations reveal that the interface stress has no obvious effect on the splitting energy and hopping integral between Ni 3d and Nd-layer orbitals. Although the hybridization between Ni 3dx2-y2 and Nd 5d orbitals is tiny, the hybridization between the Ni 3dx2-y2 orbital and an itinerant interstitial s (IIS) orbital is significantly strong in both cases, suggesting that the IIS orbital may play a critical role in the superconductivity of nickelates.

Predicting preterm birth using auto-ML frameworks: a large observational study using electronic inpatient discharge data.

Background: To develop and compare different AutoML frameworks and machine learning models to predict premature birth. Methods: The study used a large electronic medical record database to include 715,962 participants who had the principal diagnosis code of childbirth. Three Automatic Machine Learning (AutoML) were used to construct machine learning models including tree-based models, ensembled models, and deep neural networks on the training sample (N = 536,971). The area under the curve (AUC) and training times were used to assess the performance of the prediction models, and feature importance was computed via permutation-shuffling. Results: The H2O AutoML framework had the highest median AUC of 0.846, followed by AutoGluon (median AUC: 0.840) and Auto-sklearn (median AUC: 0.820), and the median training time was the lowest for H2O AutoML (0.14 min), followed by AutoGluon (0.16 min) and Auto-sklearn (4.33 min). Among different types of machine learning models, the Gradient Boosting Machines (GBM) or Extreme Gradient Boosting (XGBoost), stacked ensemble, and random forrest models had better predictive performance, with median AUC scores being 0.846, 0.846, and 0.842, respectively. Important features related to preterm birth included premature rupture of membrane (PROM), incompetent cervix, occupation, and preeclampsia. Conclusions: Our study highlights the potential of machine learning models in predicting the risk of preterm birth using readily available electronic medical record data, which have significant implications for improving prenatal care and outcomes.

Design, synthesis, and evaluation of n-butylphthalide and ligustrazine hybrids as potent neuroprotective agents for the treatment of ischemic stroke in vitro and in vivo.

A series of novel NBP-TMP hybrids with neuroprotective effects were designed and synthesized for the treatment of ischemic stroke. The anti-cerebral ischemic activity of these compounds was screened by evaluating their neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell injury model in vitro. Nine compounds 7e, 7h-7i, 7k, 7m-7p and 7r showed better activities on cell viability and LDH levels compared to NBP at the concentration of 6.25 µM. Among them, compound 7m showed the best potency with a percentage of protection 90.2 % compared to NBP (69.2 %) and other compounds. Preliminary structure-activity analysis revealed that the introduction of iodine and N-methylpiperazine groups could significantly improve the neuroprotective effect. Further mechanism research showed that compound 7m could reduce the damage to neuronal mitochondria caused by OGD/R by reducing ROS and increasing mitochondrial membrane potential (MMP), and reduce the apoptosis and necrosis of neurons to play a neuroprotective role. In addition, 7m could regulate the levels of mitochondrial apoptosis pathway-related proteins Bcl-2, Bax, and caspase 3. Finally, in vivo experiments showed that the compound 7m significantly inhibited ischemia-reperfusion injury and cerebral blood flow in rats, and showed a more significant neuroprotective effect than the positive drug NBP at a dose concentration of 20 mg/kg. In conclusion, our results suggest that 7m may be used as a novel lead compound for the future development of anti-cerebral ischemic agents.

Ab Initio Molecular Dynamics Study of Electron Excitation Effects on UO2 and U3Si.

In this study, an ab initio molecular dynamics method is employed to investigate how the microstructures of UO2 and U3Si evolve under electron excitation. It is found that the U3Si is more resistant to electron excitation than UO2 at room temperature. UO2 undergoes a crystalline-to-amorphous structural transition with an electronic excitation concentration of 3.6%, whereas U3Si maintains a crystalline structure until an electronic excitation concentration reaches up to 6%. Such discrepancy is mainly due to their different electronic structures. For insulator UO2, once valence U 5f electrons receive enough energy, they are excited to the conduction bands, which induces charge redistribution. Anion disordering is then driven by cation disordering, eventually resulting in structural amorphization. As for metallic U3Si, the U 5f electrons are relatively more difficult to excite, and the electron excitation leads to cation disordering, which eventually drives the crystalline-to-amorphous phase transition. This study reveals that U3Si is more resistant to electron excitation than UO2 under an irradiation environment, which may advance the understanding of related experimental and theoretical investigations to design radiation-resistant nuclear fuel uranium materials.

Zwitterionic dendrimer self-assembled nanodrugs with high drug loading for enhanced anti-tumor ability.

Zwitterionic dendrimers have been used to construct many nanomedicines due to their ability to achieve controlled drug release, but their low drug loading content limits their application in nanodrug delivery. To solve this problem, the surface of second generation polypropylimine (G2 PPI) was modified with mercapturized paclitaxel (PTX-SH) and zwitterionic groups to prepare zwitterionic prodrug molecule (PPIMPC), and then zwitterionic dendrimer self-assembled nanodrugs (PPIMPC-DOX micelles) were prepared by incorporating doxorubicin (DOX) into the micelles. The DOX loading and paclitaxel (PTX) loading in PPIMPC-DOX micelles was 6.7% and 26.2%, respectively, and the total drug loading of PPIMPC-DOX was high to 32.9%. In addition, PPIMPC-DOX micelles showed enhanced cytotoxicity due to improved cell uptake of DOX. More importantly, the inhibition rate of tumor was much higher than free DOX. The zwitterionic property and high drug loading of PPIMPC-DOX micelles enhanced anti-tumor ability of chemotherapeutic drugs. The method of preparation of zwitterionic and high drug loading of nanodrugs shows good application prospects in the future.

The effect of fission products Xe and Cs on the thermal conductivity of the U3Si2lattice: a first-principles study.

In the past decades, uranium silicide (U3Si2) as a promising accident tolerant fuel (ATF) has drawn considerable attention in the field of nuclear physics. In comparison with traditional nuclear fuel (UO2), the U3Si2has higher thermal conductivity and uranium density, thereby resulting in lower centerline temperatures and better fuel economy. However, during the nuclear fission reaction, some unexpected fission products, such as Xe and Cs, are released and form the defective states. In this study, we explore the influence of Xe and Cs on the thermal conductivity of the U3Si2lattice from 200 to 1500 K using density functional theory calculations combined with Boltzmann transport equation. Our results reveal that the lattice and electronic thermal conductivities of defective U3Si2are reduced at a constant temperature, as compared with that of ideal system, thus resulting in a decrease of the total thermal conductivity. In the case of Cs occupation at U1 site, the total thermal conductivity (4.42 W mK-1) is decreased by ∼56% at 300 K, as compared with the value of 9.99 W mK-1for ideal system. With U1 and Si sites being occupied by Xe, the total thermal conductivities (4.45 and 6.52 W mK-1) are decreased by ∼55% and 35% at 300 K, respectively. The presented results suggest that the U3Si2has potential as a promising ATF at high temperatures.

Analysis of risk factors for non-alcoholic fatty liver disease in hospitalized children with obesity before the late puberty stage.

Objective: This study aimed to determine the clinical characteristics of obese pediatric non-alcoholic fatty liver disease (NAFLD) in central China and verify the applicability of some known risk factors for pediatric NAFLD before late puberty. Methods: This was a retrospective case-control study. A total of 1,029 inpatients at Wuhan Children's Hospital before the late puberty stage were enrolled in the study, including 815 children with obesity (non-NAFLD group) and 214 children with obesity and NAFLD (NAFLD group) diagnosed by liver ultrasound. Subgroup analyses were performed according to sex and puberty. The anthropometric indices and laboratory test data of these 1,029 children were sorted. After intergroup comparison, a logistic regression model was used to determine the risk factors for pediatric NAFLD. Significant risk factors for NAFLD were further tested using receiver operating characteristic (ROC) curves to evaluate their ability to predict an early diagnosis of NAFLD. Results: The NAFLD group had a mean age of 11.03 ± 1.66, with 11.18 ± 1.66 and 10.27 ± 1.45 years for male and female children, respectively (p < 0.05 and p < 0.01, respectively). Even subdivided by both sex and puberty, raised body mass index (BMI), homeostatic model-insulin resistance, triglycerides, alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (γ-GT) were still found in the non-NAFLD and NAFLD groups (p < 0.05 and p < 0.01, respectively). The results of logistic regression analysis showed that BMI (odds ratio [OR], 1.468;95% confidence interval [CI], 1.356-1.590; p<0.001) and ALT (OR, 1.073;95%CI, 1.060-1.087; P<0.001) were two most independent risk factors for NAFLD. The maximal OR for BMI was 1.721 (95% CI, 1.336-2.217). In the female group, the maximal OR of ALT was found to be 1.104 (95% CI, 1.061-1.148). Age and thyroid-stimulating hormone (TSH) and γ-GT levels were also risk factors, but they appeared only in some groups. The results of the ROC analysis showed that ALT was a better predictor of pediatric NAFLD than BMI. The maximum area under the ROC curve in six of the nine groups belongs to ALT. Conclusions: BMI, ALT, and age are risk factors for NAFLD in children with obesity before late puberty. BMI had the greatest exposure risk for NAFLD, and ALT had the highest predictive value for the diagnosis of NAFLD. At the stratified level, for exposure risk, age was specific to the male sex, TSH was specific to the early puberty stage, and γ-GT was specific to the female sex plus the prepuberty stage. On a stratified level, for the female sex, even with age stratification, BMI rather than ALT has a better ability for the diagnosis of NAFLD.

HOXD9 is a potential prognostic biomarker involved in immune microenvironment of glioma.

BACKGROUND: Glioma is the prevailing malignant tumor affecting the brain and central nervous system, constituting over 80% of all malignant brain tumors. HOXD9 has been implicated in the development of glioma, but the specific mechanism of its influence on glioma pathogenesis remains incompletely understood. The purpose of this study was to investigate the role of HOXD9 in glioma and examine the changes in HOXD9 expression during the progression of glioma, thus contributing new insights into the pathogenesis of glioma. METHODS: Glioma samples from the Cancer Gene Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets were included in this study. Variations in HOXD9 expression in gliomas between different subgroups of multiple clinical characteristics were explored, and the expression was validated in glioma samples using qRT-PCR and western blotting. Next, the impact of HOXD9 on the prognosis of gliomas was explored by survival analysis, receiver operating characteristic curve, and nomogram plots. Subsequently, the association between HOXD9 and the tumor immune microenvironment was explored using the ssGSEA algorithm and the ESTIMATE algorithm. Then, immune-related pathways associated with HOXD9 were determined by differential express analysis and GSEA. Finally, HOXD9-related genomic alterations were identified. RESULTS: HOXD9 expression is upregulated and correlated with malignant properties in glioma. Similarly, our validation results showed significantly upregulated protein and mRNA levels of HOXD9 in glioma brain tissues. In addition, high HOXD9 expression was indicative of a poor prognosis for glioma patients. Additionally, elevated HOXD9 levels were associated with reduced tumor purity and higher levels of immune invasion. Finally, HOXD9 was significantly associated with genomic alterations. CONCLUSION: Overall, this study has unveiled a significant association between HOXD9 and the prognosis and survival of glioma patients. Our findings highlight the potential of HOXD9 as a prognostic biomarker, implicating its role in influencing the glioma immune microenvironment.

Inducible Rbpms-CreERT2 Mouse Line for Studying Gene Function in Retinal Ganglion Cell Physiology and Disease.

Retinal ganglion cells (RGCs) are the sole output neurons conveying visual stimuli from the retina to the brain, and dysfunction or loss of RGCs is the primary determinant of visual loss in traumatic and degenerative ocular conditions. Currently, there is a lack of RGC-specific Cre mouse lines that serve as invaluable tools for manipulating genes in RGCs and studying the genetic basis of RGC diseases. The RNA-binding protein with multiple splicing (RBPMS) is identified as the specific marker of all RGCs. Here, we report the generation and characterization of a knock-in mouse line in which a P2A-CreERT2 coding sequence is fused in-frame to the C-terminus of endogenous RBPMS, allowing for the co-expression of RBPMS and CreERT2. The inducible Rbpms-CreERT2 mice exhibited a high recombination efficiency in activating the expression of the tdTomato reporter gene in nearly all adult RGCs as well as in differentiated RGCs starting at E13.5. Additionally, both heterozygous and homozygous Rbpms-CreERT2 knock-in mice showed no detectable defect in the retinal structure, visual function, and transcriptome. Together, these results demonstrated that the Rbpms-CreERT2 knock-in mouse can serve as a powerful and highly desired genetic tool for lineage tracing, genetic manipulation, retinal physiology study, and ocular disease modeling in RGCs.

Evaluation of the role of Sigma 1 receptor and Cullin3 in retinal photoreceptor cells.

Sigma 1 receptor (Sig1R), a pluripotent modulator of cell survival, is neuroprotective in models of retinal degeneration when activated by the high-affinity, high-specificity ligand (+)-pentazocine ((+)-PTZ). The molecular mechanisms of Sig1R-mediated retinal neuroprotection are under investigation. We previously reported that the antioxidant regulatory transcription factor Nrf2 may be involved in Sig1R-mediated retinal photoreceptor cell (PRC) rescue. Cullin 3 (Cul3) is a component of the Nrf2-Keap1 antioxidant pathway and facilitates Nrf2 ubiquitination. Our earlier transcriptome analysis revealed decreased Cul3 in retinas lacking Sig1R. Here, we asked whether Sig1R activation can modulate Cul3 expression in 661 W cone PRCs. Proximity ligation and co-immunoprecipitation (co-IP) showed that Cul3 resides closely to and co-IPs with Sig1R. Activation of Sig1R using (+)-PTZ significantly increased Cul3 at the gene/protein level; silencing Sig1R decreased Cul3 gene/protein levels. Experiments in which Cul3 was silenced in cells exposed to tBHP resulted in increased oxidative stress, which was not attenuated with Sig1R activation by (+)-PTZ, whereas cells transfected with scrambled siRNA (and incubated with tBHP) responded to (+)-PTZ treatment by decreasing levels of oxidative stress. Assessment of mitochondrial respiration and glycolysis revealed significantly improved maximal respiration, spare capacity and glycolytic capacity in oxidatively-stressed cells transfected with scrambled siRNA and treated with (+)-PTZ, but not in (+)-PTZ treated, oxidatively-stressed cells in which Cul3 had been silenced. The data provide the first evidence that Sig1R co-localizes/interacts with Cul3, a key player in the Nrf2-Keap1 antioxidant pathway. The data suggest that the preservation of mitochondrial respiration/glycolytic function and reduction of oxidative stress observed upon activation of Sig1R occur in part in a Cul3-dependent manner.

Comparing Arsenic-Containing Qinghuang Powder and Low-Intensity Chemotherapy in Elderly Patients with Acute Myeloid Leukemia.

OBJECTIVE: To compare the clinical effect of arsenic-containing Qinghuang Powder (QHP) and low-intensity chemotherapy (LIC) in treatment of elderly acute myeloid leukemia (eAML) patients. METHODS: Clinical data of 80 eAML patients treated at Xiyuan Hospital of China Academy of Chinese Medical Sciences from January 2015 to December 2020 were retrospectively analyzed. The treatment scheme was designed by real world study according to patients' preference, and patients were divided into a QHP group (35 cases) and a LIC group (45 cases). The median overall survival (mOS), 1-, 2-, and 3-year OS rates, and incidence of adverse events were compared between the two groups. RESULTS: The mOS of 80 patients was 11 months, and the 1-, 2-, and 3-year OS rates were 45.51%, 17.96%, and 11.05%, respectively. The QHP and LIC groups demonstrated no significant difference in mOS (12 months vs. 10 months), 1- (48.57% vs. 39.65%), 2- (11.43% vs. 20.04%), and 3-year OS rates (5.71% vs. 13.27%, all P>0.05). Moreover, the related factors of mOS demonstrated no significant difference in patients with age>75 years (11 months vs. 8 months), secondary AML (11 months vs. 8 months), poor genetic prognosis (9 months vs. 7 months), Eastern Cooperative Oncology Group performance status score ⩾ 3 (10 months vs. 7 months) and hematopoietic stem cell transplant comorbidity index ⩾ 4 (11 months vs. 7 months) between the QHP and LIC groups (all P>0.05). However, the incidence of myelosuppression was significantly lower in the QHP group than that in the LIC group (28.57% vs. 73.33%, P<0.01). CONCLUSIONS: QHP and LIC had similar survival rates in eAML patients, but QHP had a lower myelosuppression incidence. Hence, QHP can be an alternative for eAML patients who do not tolerate LIC.

Sigma 1 receptor activation improves retinal structure and function in the RhoP23H/+ mouse model of autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of devastating inherited retinal diseases that leads to visual impairment and oftentimes complete blindness. Currently no cure exists for RP thus research into prolonging vision is imperative. Sigma 1 receptor (Sig1R) is a promising small molecule target that has neuroprotective benefits in retinas of rapidly-degenerating mouse models. It is not clear whether Sig1R activation can provide similar neuroprotective benefits in more slowly-progressing RP models. Here, we examined Sig1R-mediated effects in the slowly-progressing RhoP23H/+ mouse, a model of autosomal dominant RP. We characterized the retinal degeneration of the RhoP23H/+ mouse over a 10 month period using three in vivo methods: Optomotor Response (OMR), Electroretinogram (ERG), and Spectral Domain-Optical Coherence Tomography (SD-OCT). A slow retinal degeneration was observed in both male and female RhoP23H/+ mice when compared to wild type. The OMR, which reflects visual acuity, showed a gradual decline through 10 months. Interestingly, female mice had more reduction in visual acuity than males. ERG assessment showed a gradual decline in scotopic and photopic responses in RhoP23H/+ mice. To investigate the neuroprotective benefits of Sig1R activation in the RhoP23H/+ mouse model, mutant mice were treated with a high-specificity Sig1R ligand (+)-pentazocine ((+)-PTZ) 3x/week at 0.5 mg/kg and examined using OMR, ERG, SD-OCT. A significant retention of visual function was observed in males and females at 10 months of age, with treated females retaining ∼50% greater visual acuity than non-treated mutant females. ERG revealed significant retention of scotopic and photopic b-wave amplitudes at 6 months in male and female RhoP23H/+ mice treated with (+)-PTZ. Further, in vivo analysis by SD-OCT revealed a significant retention of outer nuclear layer (ONL) thickness in male and female treated RhoP23H/+ mice. Histological studies showed significant retention of IS/OS length (∼50%), ONL thickness, and number of rows of photoreceptor cell nuclei at 6 months in (+)-PTZ-treated mutant mice. Interestingly, electron microscopy revealed preservation of OS discs in (+)-PTZ treated mutant mice compared to non-treated. Taken collectively, the in vivo and in vitro data provide the first evidence that targeting Sig1R can rescue visual function and structure in the RhoP23H/+ mouse. These results are promising and provide a framework for future studies to investigate Sig1R as a potential therapeutic target in retinal degenerative disease.

GRN is a prognostic biomarker and correlated with immune infiltration in glioma: A study based on TCGA data.

Background: Among primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) database. Methods: First, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry. Results: Increased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM. Conclusion: GRN is a prognostic biomarker and correlated with immune infiltrates in GBM.