The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms.

UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.

A common variant in PIK3CG gene associated with the prognosis of heart failure.

Phosphoinositide 3-kinase γ (PI3Kγ) is G-protein-coupled receptor-activated lipid kinase with both kinase-dependent and kinase-independent activity. Plenty of evidence have demonstrated that PI3Kγ participated in TAC and I/R-induced myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in the PI3Kγ gene (PIK3CG) were associated with the prognosis of HF in the Chinese Han population. Through re-sequencing and genotyping, we finally identified a common variant in the 3'UTR of PIK3CG strongly associated with the prognosis of HF in two-stage population: adjusted p = 0.007, hazard ratio = 0.56 (0.36-0.85) in the first cohort and adjusted p = 0.024, hazard ratio = 0.39 (0.17-0.88) in the replicated cohort. A series of functional assays revealed that rs10215499-A allele suppressed PIK3CG translation by facilitating has-miR-133a-3p binding, but not the G allele. Subjects carrying the GG genotype showed higher mRNA and protein level than those with AA and AG genotype. Furthermore, overexpression of PIK3CG could protect AC16 from hypoxia/reoxygenation (H/R)-induced apoptosis, while the case was opposite for PIK3CG silencing. In conclusion, common variant rs10215499 in the 3'-UTR of PIK3CG might affect the prognosis of HF by interfering with miR-133a-3p binding and PIK3CG is a promising target for HF treatment in the future.

Integrated multi-omics analysis and machine learning to refine molecular subtypes, prognosis, and immunotherapy in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) has a malignant characteristic that is highly aggressive and prone to metastasis. There is still a lack of suitable biomarkers to facilitate the refinement of precision-based therapeutic regimens. We used a combination of 10 known clustering algorithms and the omics data from 4 dimensions to identify high-resolution molecular subtypes of LUAD. Subsequently, consensus machine learning-related prognostic signature (CMRS) was developed based on subtypes related genes and an integrated program framework containing 10 machine learning algorithms. The efficiency of CMRS was analyzed from the perspectives of tumor microenvironment, genomic landscape, immunotherapy, drug sensitivity, and single-cell analysis. In terms of results, through multi-omics clustering, we identified 2 comprehensive omics subtypes (CSs) in which CS1 patients had worse survival outcomes, higher aggressiveness, mRNAsi and mutation frequency. Subsequently, we developed CMRS based on 13 key genes up-regulated in CS1. The prognostic predictive efficiency of CMRS was superior to most established LUAD prognostic signatures. CMRS demonstrated a strong correlation with tumor microenvironmental feature variants and genomic instability generation. Regarding clinical performance, patients in the high CMRS group were more likely to benefit from immunotherapy, whereas low CMRS were more likely to benefit from chemotherapy and targeted drug therapy. In addition, we evaluated that drugs such as neratinib, oligomycin A, and others may be candidates for patients in the high CMRS group. Single-cell analysis revealed that CMRS-related genes were mainly expressed in epithelial cells. The novel molecular subtypes identified in this study based on multi-omics data could provide new insights into the stratified treatment of LUAD, while the development of CMRS could serve as a candidate indicator of the degree of benefit of precision therapy and immunotherapy for LUAD.

Integrating bulk-RNA sequencing and single-cell sequencing analyses to characterize adenosine-enriched tumor microenvironment landscape and develop an adenosine-related prognostic signature predicting immunotherapy in lung adenocarcinoma.

The adenosine-signaling axis has been recognized as an important immunomodulatory pathway in tumor immunity. However, the biological role of the adenosine-signaling axis in the remodeling of the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Here, we quantified adenosine signaling (ado_sig) in LUAD samples using the GSVA method and assessed the prognostic value of adenosine in LUAD. Afterward, we explored the heterogeneity of the tumor-immune microenvironment at different adenosine levels. In addition, we analyzed the potential biological pathways engaged by adenosine. Next, we established single-cell transcriptional profiles of LUAD and analyzed cellular composition and cell-cell communication analysis under different adenosine microenvironments. Moreover, we established adenosine-related prognostic signatures (ARS) based on comprehensive bioinformatics analysis and evaluated the efficacy of ARS in predicting immunotherapy. The results demonstrated that adenosine signaling adversely impacted the survival of immune-enriched LUAD. The high-adenosine microenvironment exhibited elevated pro-tumor-immune infiltration, including M2 macrophages and displayed notably increased epithelial-mesenchymal transition (EMT) transformation. Furthermore, adenosine signaling displayed significant associations with the expression patterns and prognostic value of immunomodulators within the TME. Single-cell sequencing data revealed increased fibroblast occupancy and a prominent activation of the SPP1 signaling pathway in the high adenosine-signaling microenvironment. The ARS exhibited promising effectiveness in prognostication and predicting immunotherapy response in LUAD. In summary, overexpression of adenosine can cause a worsened prognosis in the LUAD with abundant immune infiltration. Moreover, increased adenosine levels are associated with pro-tumor-immune infiltration, active EMT transformation, pro-tumor angiogenesis, and other factors promoting cancer progression, which collectively contribute to the formation of an immunosuppressive microenvironment. Importantly, the ARS developed in this study demonstrate high efficacy in evaluating the response to immunotherapy.

CDC45 promotes the stemness and metastasis in lung adenocarcinoma by affecting the cell cycle.

OBJECTIVE: This study aimed to assess the functions of cell division cycle protein 45 (CDC45) in Non-small cell lung cancer (NSCLC) cancer and its effects on stemness and metastasis. METHODS: Firstly, differentially expressed genes related to lung cancer metastasis and stemness were screened by differential analysis and lasso regression. Then, in vitro, experiments such as colony formation assay, scratch assay, and transwell assay were conducted to evaluate the impact of CDC45 knockdown on the proliferation and migration abilities of lung cancer cells. Western blotting was used to measure the expression levels of related proteins and investigate the regulation of CDC45 on the cell cycle. Finally, in vivo model with subcutaneous injection of lung cancer cells was performed to verify the effect of CDC45 on tumor growth. RESULTS: This study identified CDC45 as a key gene potentially influencing tumor stemness and lymph node metastasis. Knockdown of CDC45 not only suppressed the proliferation and migration abilities of lung cancer cells but also caused cell cycle arrest at the G2/M phase. Further analysis revealed a negative correlation between CDC45 and cell cycle-related proteins, stemness-related markers, and tumor mutations. Mouse experiments confirmed that CDC45 knockdown inhibited tumor growth. CONCLUSION: As a novel regulator of stemness, CDC45 plays a role in regulating lung cancer cell proliferation, migration, and cell cycle. Therefore, CDC45 may serve as a potential target for lung cancer treatment and provide a reference for further mechanistic research and therapeutic development.

Activation of Cryptic Donor Splice Sites within the UDP-Glucuronosyltransferase (UGT)1A First-Exon Region Generates Variant Transcripts That Encode UGT1A Proteins with Truncated Aglycone-Binding Domains.

The human UDP-glucuronosyltransferases (UGTs) have crucial roles in metabolizing and clearing numerous small lipophilic compounds. The UGT1A locus generates nine UGT1A mRNAs, 65 spliced transcripts, and 34 circular RNAs. In this study, our analysis of published UGT-RNA capture sequencing (CaptureSeq) datasets identified novel splice junctions that predict 24 variant UGT1A transcripts derived from ligation of exon 2 to unique sequences within the UGT1A first-exon region using cryptic donor splice sites. Of these variants, seven (1A1_n1, 1A3_n3, 1A4_n4, 1A5_n1, 1A8_n2, 1A9_n2, 1A10_n7) are predicted to encode UGT1A proteins with truncated aglycone-binding domains. We assessed their expression profiles and deregulation in cancer using four RNA sequencing (RNA-Seq) datasets of paired normal and cancerous drug-metabolizing tissues from large patient cohorts. Variants were generally coexpressed with their canonical counterparts with a higher relative abundance in tumor than in normal tissues. Variants showed tissue-specific expression with high interindividual variability but overall low abundance. However, 1A8_n2 showed high abundance in normal and cancerous colorectal tissues, with levels that approached or surpassed canonical 1A8 mRNA levels in many samples. We cloned 1A8_n2 and showed expression of the predicted protein (1A8_i3) in human embryonic kidney (HEK)293T cells. Glucuronidation assays with 4-methylumbelliferone (4MU) showed that 1A8_i3 had no activity and was unable to inhibit the activity of 1A8_i1 protein. In summary, the activation of cryptic donor splice sites within the UGT1A first-exon region expands the UGT1A transcriptome and proteome. The 1A8_n2 cryptic donor splice site is highly active in colorectal tissues, representing an important cis-regulatory element that negatively regulates the function of the UGT1A8 gene through pre-mRNA splicing. SIGNIFICANT STATEMENT: The UGT1A locus generates nine canonical mRNAs, 65 alternately spliced transcripts, and 34 different circular RNAs. The present study reports a series of novel UDP-glucuronosyltransferase (UGT)1A variants resulting from use of cryptic donor splice sites in both normal and cancerous tissues, several of which are predicted to encode variant UGT1A proteins with truncated aglycone-binding domains. Of these, 1A8_n2 shows exceptionally high abundance in colorectal tissues, highlighting its potential role in the first-pass metabolism in gut through the glucuronidation pathway.

RACGAP1 promotes the progression and poor prognosis of lung adenocarcinoma through its effects on the cell cycle and tumor stemness.

OBJECTION: Investigating the key genes and mechanisms that influence stemness in lung adenocarcinoma. METHODS: First, consistent clustering analysis was performed on lung adenocarcinoma patients using stemness scoring to classify them. Subsequently, WGCNA was utilized to identify key modules and hub genes. Then, machine learning methods were employed to screen and identify the key genes within these modules. Lastly, functional analysis of the key genes was conducted through cell scratch assays, colony formation assays, transwell migration assays, flow cytometry cell cycle analysis, and xenograft tumor models. RESULTS: First, two groups of patients with different stemness scores were obtained, where the high stemness score group exhibited poor prognosis and immunotherapy efficacy. Next, LASSO regression analysis and random forest regression were employed to identify genes (PBK, RACGAP1) associated with high stemness scores. RACGAP1 was significantly upregulated in the high stemness score group of lung adenocarcinoma and closely correlated with clinical pathological features, poor overall survival (OS), recurrence-free survival (RFS), and unfavorable prognosis in lung adenocarcinoma patients. Knockdown of RACGAP1 suppressed the migration, proliferation, and tumor growth of cancer cells. CONCLUSION: RACGAP1 not only indicates poor prognosis and limited immunotherapy benefits but also serves as a potential targeted biomarker influencing tumor stemness.

Schwann cells transplantation improves nerve injury and alleviates neuropathic pain in rats.

The mechanism of neuropathic pain induced by nerve injury is complex and there are no effective treatment methods. P2X4 receptor expression is closely related to the occurrence of pain. Schwann cells (SCs) play a key protective role in the repair of peripheral nerve injury and myelin sheath regeneration. However, whether SCs can affect the expression of P2X4 receptor and play a role in pathological pain is still unclear. Therefore, this study investigated the effect of SCs on whether they can down regulate the expression of P2X4 receptor to affect pain. The results showed that in the neuropathic pain induced by sciatic nerve injury model, the expression of P2X4 receptor in spinal cord tissue was significantly increased and the pain sensation of rats was increased. While SCs transplantation could down regulate the expression of P2X4 receptors in spinal cord and increase the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats. These data indicate that SCs can reduce the expression of P2X4 receptors to alleviate neuropathic pain, indicating that SCs can mediate P2X4 receptor signalling as a new target for pain treatment.

Discovery of Palbociclib as a potent c-Myc G4 stabilizer for lung cancer treatment using molecular docking, molecular dynamics simulation, and in vitro activity evaluation.

Despite significant progress in lung cancer treatment, this disease remains a prevalent and serious global malignancy, leading to high rates of illness and death. Urgent research is needed to discover new or alternative therapies that can improve clinical outcomes for lung cancer patients. In our study, we successfully demonstrated the effectiveness of Palbociclib, a CDK4/6 inhibitor, in suppressing the growth of lung cancer cells. The IC50 values obtained were 11.00 µM and 11.74 µM for H1299 and A549 cells, respectively. Furthermore, our findings indicate that Palbociclib may possess strong c-Myc G4 stabilizing properties by significantly reducing both protein and mRNA expression levels of c-Myc. Additionally, Palbociclib induces apoptosis and causes cell cycle arrest at the G2/M phase in two cells. Through circular dichroism (CD), molecular docking, and molecular dynamics (MD) simulation, we have provided evidence that Palbociclib enhances the structural stability of c-Myc G4 while exhibiting a high binding affinity to its ligand's binding site on c-Myc G4. These results suggest that Palbociclib holds promise as a novel c-Myc G4 stabilizer for treating cancers associated with abnormal c-Myc activity; further optimization and development are warranted.

Celastrol-Ligustrazine compound proven to be a novel drug candidate for idiopathic pulmonary fibrosis by intervening in the TGF-ß1 mediated pathways-an experimental in vitro and vivo study.

Idiopathic Pulmonary Fibrosis (IPF) is a disease characterized by pulmonary interstitial fibrosis and collagen proliferation, currently lacking effective therapeutic options. The combined use of Celastrol and Ligustrazine has been proved to synergistically improve the pathological processes of inflammation and fibrosis. In earlier studies, we designed and synthesized a Celastrol-Ligustrazine compound CL-001, though its role in IPF remains unclear. Here, the effects and mechanisms of CL-001 in bleomycin (BLM)-induced IPF were investigated. In vivo, CL-001 significantly improved lung function, reduced pulmonary inflammation, and decreased collagen deposition, thereby preventing the progression of IPF. In vitro, CL-001 concurrently inhibited both Smad-dependent and Smad-independent pathways, thereby suppressing TGF-ß1-induced epithelial-mesenchymal transition (EMT) and epithelial cell migration. This inhibitory effect was superior to that of Celastrol or Ligustrazine administered alone. Additionally, CL-001 significantly increased the level of apoptosis and promoted the expression of apoptosis-related proteins (Caspase-8 and PARP), ultimately leading to widespread apoptosis in activated lung epithelial cells. In summary, CL-001 exhibits excellent anti-IPF effects both in vitro and in vivo, suggesting its potential as a novel candidate drug for IPF, warranting further development.

Differential performance regarding the relationship of C3-epi-25(OH)D3 levels and %C3-epi-25(OH)D3 with common pediatric diseases: a case control study.

BACKGROUND: Recently, the C3-epimer of 25-hydroxyvitamin D [C3-epi-25(OH)D] has become a topic of interest among 25-hydroxyvitamin D [25(OH)D] metabolites. Although it can lead to an overestimation of vitamin D storage, its relationship with disease occurrence remains controversial, possibly related to the great extent of tracking of 25(OH)D by C3-epi-25(OH)D over time. This study aimed to investigate the differential performance of C3-epi-25(OH)D3 and its percentage [%C3-epi-25(OH)D3] with respect to 20 common paediatric diseases. METHODS: This study involved 805 healthy children and adolescents and 2962 patients with common paediatric diseases. We investigated sex, age, and seasonal differences in C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 levels; their variations on 20 common paediatric diseases; and their degree of correlation with 25(OH)D3 levels and various diseases. RESULTS: Among the healthy underage participants, C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 changed similarly, with no sex differences. Moreover, their levels were higher in the infant period than in the other periods (t = 5.329-5.833, t = 4.640-5.711, all Padj < 0.001), and in spring and summer than in autumn and winter (t = 3.495-6.061, t = 3.495-5.658, all Padj < 0.01). Under healthy and disease conditions, C3-epi-25(OH)D3 was positively correlated with 25(OH)D3 (ρ = 0.318 ~ 0.678, all P < 0.017), whereas %C3-epi-25(OH)D3 was not, except in patients with nephrotic syndrome (ρ=-0.393, P = 0.001). Before and after adjusting for 25(OH)D3, the relationship of C3-epi-25(OH)D3 with the diseases was notably different. However, it was almost consistent for %C3-epi-25(OH)D3. Our results indicated that %C3-epi-25(OH)D3 was associated with short stature, nephrotic syndrome, lymphocytic leukaemia, rickets, paediatric malnutrition, and hypovitaminosis D (OR = 0.80 ~ 1.21, all P < 0.05). CONCLUSIONS: The %C3-epi-25(OH)D3 can correct the properties of C3-epi-25(OH)D3 to better track 25(OH)D3 and may be more suitable for exploring its pathological relevance. Further detailed studies of each disease should be conducted.

Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts.

Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-ß) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.

Magnetic resonance imaging-based classification of the myodural bridge complex and its influencing factors.

Cerebrospinal fluid (CSF) circulation is considered the third circulation of the human body. Recently, some scholars have proposed the myodural bridge (MDB) as a novel power source for CSF flow. Moreover, the suboccipital muscles can exert a driving force on the CSF via the MDB. This hypothesis is directly supported by head rotation and nodding movements, which can affect CSF circulation. The MDB has been validated as a normal structure in humans and mammals. In addition, the fusion of MDB fibers of different origins that act in concert with each other forms the MDB complex (MDBC). The MDBC may be associated with several CSF disorder-related neurological disorders in clinical practice. Therefore, the morphology of the MDBC and its influencing factors must be determined. In this study, T2-weighted imaging sagittal images of the cervical region were analyzed retrospectively in 1085 patients, and magnetic resonance imaging (MRI) typing of the MDBC was performed according to the imaging features of the MDBC in the posterior atlanto-occipital interspace (PAOiS) and posterior atlanto-axial interspace (PAAiS). The effects of age and age-related degenerative changes in the cervical spine on MRI staging of the MDBC were also determined. The results revealed four MRI types of the MDBC: type A (no MDBC hyposignal shadow connected to the dura mater in either the PAOiS or PAAiS), type B (MDBC hyposignal shadow connected to the dura mater in the PAOiS only), type C (MDBC hyposignal shadow connected to the dura mater in the PAAiS only), and type D (MDBC hyposignal shadow connected to the dura mater in both the PAOiS and PAAiS). The influencing factors for the MDBC typing were age (group), degree of intervertebral space stenosis, dorsal osteophytosis, and degenerative changes in the cervical spine (P < 0.05). With increasing age (10-year interval), the incidence of type B MDBC markedly decreased, whereas that of type A MDBC increased considerably. With the deepening of the degree of intervertebral space stenosis, the incidence of type C MDBC increased significantly, whereas that of type A MDBC decreased. In the presence of dorsal osteophytosis, the incidence of type C and D MDBCs significantly decreased, whereas that of type A increased. In the presence of protrusion of the intervertebral disc, the incidence of type B, C, and D MDBCs increased markedly, whereas that of type A MDBC decreased considerably, with cervical degenerative changes combined with spinal canal stenosis. Moreover, the incidence of both type C and D MDBCs increased, whereas that of type A MDBC decreased. Based on the MRI signal characteristics of the dural side of the MDBC, four types of the MDBC were identified. MDBC typing varies dynamically according to population distribution, depending on age and cervical degeneration (degree of intervertebral space stenosis, vertebral dorsal osteophytosis formation, simple protrusion of intervertebral disc, and cervical degeneration changes combined with spinal canal stenosis, except for the degree of protrusion of the intervertebral disc and the degree of spinal canal stenosis); however, it is not influenced by sex.

AKT/GSK-3beta/VEGF signaling is involved in P2RY2 activation-induced the proliferation and metastasis of gastric cancer.

Studies have revealed the contribution of ATP-G-protein-coupled P2Y2 receptor (P2RY2) in tumor progression, but the role of P2RY2 in regulating the progression of gastric cancer (GC) and related molecular mechanisms are relatively lacking. Therefore, this study investigates the effects of P2RY2 on the proliferation and migration of GC through in vivo and in vitro experiments. The results showed that P2RY2 was expressed in GC tissues and GC cell lines. Adenosine triphosphate (ATP) increased the calcium influx in AGS and HGC-27 cells, and was dose-dependent with ATP concentration. ATP and UTP increased the intracellular glycogen content, enhanced the actin fiber stress response, and promoted the proliferation and migration of GC cells, while P2RY2 competitive antagonist AR-C118925XX reversed the changes induced by ATP. Knockdown of P2RY2 expression by shRNA inhibited the proliferation of GC cells. Activation of P2RY2 increased the expression of Snail, Vimentin, and ß-catenin in GC cells, and down-regulated the expression of E-cadherin, while AR-C118925XX decreased the expression of these genes induced by ATP. Activation of P2RY2 activated AKT/GSK-3beta/VEGF signal to promote the proliferation of GC cells, and the P13/AKT signaling pathway LY294002 reversed the corresponding phenomenon, but no synergistic pharmacological properties of AR-C118925XX and LY294002 have been found. In vivo experiments showed that ATP-induced tumor growth, while AR-C118925XX inhibited ATP-induced tumor growth. Our conclusion is that P2RY2 activated the AKT/GSK-3beta/VEGF signal to promote the proliferation and migration of GC, suggesting that P2RY2 may be a new potential target for the treatment of GC.

Identification of a signature based on non-apoptotic regulatory cell death to improve prognosis prediction in acute myeloid leukaemia.

Although anti-apoptotic cell death is a common feature of cancer and non-apoptotic regulatory cell death (RCD) is highly correlated with cancer progression and response to therapy, its prognostic role in patients with acute myeloid leukaemia (AML) is unknown. The RNA sequence and clinical data from AML patients were downloaded from the TCGA and GEO databases. The prognostic characteristics of non-apoptotic RCD-related genes (NRGs) were determined by Cox and LASSO regression analysis. Thirteen NRG signatures were identified as independent prognostic parameters in patients with AML that outperformed other prognostic models. Higher NRG scores were associated with shorter survival and less retention of tumour mutations. Although patients with high NRG risk have abundant signalling pathways for cell adhesion, cytokine upregulation, and cellular defence responses, patients with low NRG risk may benefit the most from immunotherapy. Specifically, patients with high NRG score may benefit from treatment with anti-EGFR and CDK2 inhibitors, including erlotinib and roscovitine. The NPM1 and FLT3 mutant cell lines undergo alterations after multiple drug treatments. Our established NRG signature and scoring highlight its vital clinical significance, emphasize the inevitability of stratifying treatment for different mutation subtypes and provide new ideas to guide personalized immunotherapy strategies for AML patients.

SPOCK1, as a potential prognostic and therapeutic biomarker for lung adenocarcinoma, is associated with epithelial-mesenchymal transition and immune evasion.

BACKGROUND: The occurrence of epithelial-mesenchymal transition (EMT) and immune evasion is considered to contribute to poor prognosis in lung adenocarcinoma (LUAD). Therefore, this study aims to explore the key oncogenes that promote EMT and immune evasion and reveal the expression patterns, prognostic value, and potential biological functions. METHODS: Firstly, we identified gene modules associated with EMT and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Next, we utilized differential analysis and machine learning to identify the key genes and validate them. Moreover, we analyzed the correlation between key genes and tumor microenvironment remodeling, drug sensitivity, as well as mutation frequency. Furthermore, we explored and validated their malignant biological characteristics through in vitro experiments and clinical samples. Finally, potential drugs for LUAD were screened based on CMap and validated through experiments. RESULTS: Firstly, WGCNA analysis revealed that red and green modules were highly correlated with EMT and TIDE. Among them, upregulated expression of SPOCK1 was observed in lung adenocarcinoma tissues and was associated with poor prognosis. Additionally, patients in the high SPOCK1 group showed more activation of malignant oncogenic pathways, higher infiltration of immunosuppressive components, and a higher frequency of mutations. The knockdown of SPOCK1 suppressed invasion and metastasis capabilities of lung adenocarcinoma cells, and the high expression of SPOCK1 was associated with low infiltration of CD8+ T cells. Therapeutic aspects, SPOCK1 can be a candidate indicator for drug sensitivity and CMap showed that VER-155008 was the drug candidate with the largest perturbation effect on the SPOCK1 expression profile. In vitro and in vivo experiments validated the cancer-inhibitory effect of VER-155008 in LUAD. CONCLUSION: This study revealed through comprehensive bioinformatics analysis and experimental analysis that SPOCK1 can promote EMT and immune escape in LUAD, and it may serve as a promising candidate prognostic biomarker and therapeutic target for LUAD.

Robust shortcut for controlling Bloch states in optical lattices.

The ability to manipulate quantum states with robustness is crucial for various quantum applications, including quantum computation, quantum simulation, and quantum precision measurement. While pulsed shortcut techniques have proven effective for controlling bands and orbits in optical lattices, their robustness has not been extensively studied. In this paper, we present an improved shortcut design scheme that retains the advantages of high speed and high fidelity, while ensuring exceptional robustness. We conduct comprehensive experimental verifications to demonstrate the effectiveness of this new robust shortcut and its application in quantum gate design. The proposed scheme is expected to enhance the robustness of optical lattice orbit-based interferometry, quantum gates, and other processes.

Washed microbiota transplantation improves haemoglobin levels in anaemia of chronic disease.

BACKGROUND: Anaemia of chronic disease (ACD) is the second most common type of anaemia and lacks an effective treatment. Patients with anaemia are reported to have altered gut microbial profiles, which may affect erythropoiesis. Here, we investigated the gut microbial features of patients with ACD and determined whether regulating gut microbiota using washed microbiota transplantation (WMT) was effective in treating ACD. METHODS: We compared the gut microbiota profile of patients with ACD and healthy controls, evaluated the efficacy of WMT on haematological parameters in the patients, and analysed the alterations in gut microbiota after WMT treatment. RESULTS: Patients with ACD had lower gut microbial richness, and differences in microbial composition and function, relative to healthy controls. Additionally, the relative abundances of two butyrate-producing genera Lachnospiraceae NK4A136 group and Butyricicoccus, were positively correlated with the haemoglobin (HGB) level and lower in patients with ACD than controls. WMT significantly increased HGB levels in patients with ACD. After the first, second and third WMT rounds, normal HGB levels were restored in 27.02%, 27.78% and 36.37% (all p < .05) of patients with ACD, respectively. Moreover, WMT significantly increased the abundance of butyrate-producing genera and downregulated gut microbial functions that were upregulated in patients with ACD. CONCLUSIONS: Patients with ACD exhibited differences in gut microbial composition and function relative to healthy controls. WMT is an effective treatment for ACD that reshapes gut microbial composition, restores butyrate-producing bacteria and regulates the functions of gut microbiota.

Applications of optical property measurement for quality evaluation of agri-food products: a review.

Spectroscopic techniques coupled with chemometric approaches have been widely used for quality evaluation of agricultural and food (agri-food) products due to the nondestructive, simple, fast, and easy characters. However, these techniques face the issues or challenges of relatively weak robustness, generalizability, and applicability in modeling and prediction because they measure the aggregate amount of light interaction with tissues, resulting in the combined effect of absorption and scattering of photons. Optical property measurement could separate absorption from scattering, providing new insights into more reliable prediction performance in quality evaluation, which is attracting increasing attention. In this review, a brief overview of the currently popular measurement techniques, in terms of light transfer principles and data analysis algorithms, is first presented. Then, the emphases are put on the recent advances of these techniques for measuring optical properties of agri-food products since 2000. Corresponding applications on qualitative and quantitative analyses of quality evaluation, as well as light transfer simulations within tissues, were reviewed. Furthermore, the leading groups working on optical property measurement worldwide are highlighted, which is the first summary to the best of our knowledge. Finally, challenges for optical property measurement are discussed, and some viewpoints on future research directions are also given.

HighlightsEmerging techniques for measuring optical properties are briefly introducedQualitative analyses of maturity evaluation and defect detection are reviewedQuantitative analyses of attribute prediction and microstructure estimation are presentedLight transfer simulations based on optical properties are comprehensively discussedLeading groups are summarized for the first time, to the best of our knowledgeChallenges and prospects for optical property measurement are given.

Construction and Validation of a Novel Immune-Related Gene Pairs-Based Prognostic Model in Lung Adenocarcinoma.

OBJECT: Focus on immune-related gene pairs (IRGPs) and develop a prognostic model to predict the prognosis of patients with lung adenocarcinoma (LUAD). METHODS: First, the LUAD patient dataset was downloaded from The Cancer Genome Atlas database, and paired analysis of immune-related genes was subsequently conducted. Then, LASSO regression was used to screen prognostic IRGPs for building a risk prediction model. Meanwhile, the Gene Expression Omnibus database was used for external validation of the model. Next, the clinical predictive power of IRGPs features was assessed by uni-multivariate Cox regression analysis, the infiltration of key immune cells in high and low IRGPs risk groups was analyzed with CIBERSORT, quanTIseq, and Timer, and the key pathways enriched for IRGPs were assessed using the Kyoto Encyclopedia of Genes and Genomes. Finally, the expression and related functions of key immune cells and genes were verified by immunofluorescence and cell experiments of tissue samples. RESULTS: It was revealed that the risk score of 19 IRGPs could be used as accurate indicators to evaluate the prognosis of LUAD patients, and the risk score was mainly related to T cell infiltration based on CIBERSORT analysis. Two genes of IRGPs, IL6, and CCL2, were found to be closely associated with the expression of PD-1/PD-L1 and the function of T-cells. Depending on the results of tissue immunofluorescence, IL6, CCL2, and T cells were highly expressed in the LUAD tissues of patients. Furthermore, IL6 and CCL2 were positively correlated with the expression of T cells. Besides, qRT-PCR assay in four different LUAD cells proved that IL6 and CCL2 were positively correlated with the expression of PD-L1 (P < .001). CONCLUSIONS: Based on 19 IRGPs, an effective prognosis model was established to predict the prognosis of LUAD patients. In addition, IL6 and CCL2 are closely related to the function of T-cells.