Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function.

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure-function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

A novel prognostic classification integrating lipid metabolism and immune co-related genes in acute myeloid leukemia.

Background: As a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML. Methods: First, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored. Results: Eight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs. Conclusions: This study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

Multimode microdimer robot for crossing tissue morphological barrier.

Swimming microrobot energized by magnetic fields exhibits remotely propulsion and modulation in complex biological experiment with high precision. However, achieving high environment adaptability and multiple tasking capability in one configuration is still challenging. Here, we present a strategy that use oriented magnetized Janus spheres to assemble the microdimer robots with two magnetic distribution configurations of head-to-side configuration (HTS-config) and head-to-head configuration (HTH-config), achieving performance of multiple tasks through multimode transformation and locomotion. Modulating the magnetic frequency enables multimode motion transformation between tumbling, rolling, and swing motion with different velocities. The dual-asynchronization mechanisms of HTS-config and HTH-config robot dependent on magnetic dipole-dipole angle are investigated by molecular dynamic simulation. In addition, the microdimer robot can transport cell crossing morphological rugae or complete drug delivery on tissues by switching motion modes. This microdimer robot can provide versatile motion modes to address environmental variations or multitasking requirements.

Small molecular inhibitors for KRAS-mutant cancers.

Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered "undruggable", recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.

The emerging role of copper in depression.

Copper (Cu) is an essential trace element in the brain and serves as an important cofactor for numerous enzymes involved in a wide range of biochemical processes including neurobehavioral, mitochondrial respiration, and antioxidant effects. Recent studies have demonstrated that copper dyshomeostasis is tightly associated with the development of depression by inducing oxidative stress and inflammatory responses. However, these findings have remained controversial so far. Cumulative studies have shown a positive association, while some other studies showed no association and even a negative association between serum/plasma copper level and depression. Based on these conflicted results, the association was speculated to be due to the clinical features of the population, stages of the disease, severity of copper excess, and types of specimens detected in these studies. In addition, there was an inverse association between dietary copper intake and depression. Furthermore, increasing copper intake could influence dietary zinc and iron intake to prevent and treat depression. Thus, copper supplementation may be a good measure to manage depression. This review provided a deeper understanding of the potential applicability of copper in the prevention and treatment of depression.

ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2.

This study aims to elucidate the effect of ARHGAP9 on lung adenocarcinoma (LUAD) metastasis, and preliminarily explore its molecular mechanism. As a result, we found that ARHGAP9 was downregulated and correlated with poor prognosis of LUAD. ARHGAP9 knockdown promoted LUAD cell proliferation, migration and invasion, inhibited cell apoptosis and reduced G0G1 cell cycle arrest, in contrast to the results of ARHGAP9 overexpression. Further RNA sequencing analysis demonstrated that ARHGAP9 knockdown in H1299 cells significantly reduced DKK2 (dickkopf related protein 2) expression. Silencing ARHGAP9 in H1299 cells while overexpressing DKK2, DKK2 reversed the promoted effects of ARHGAP9 knockdown on LUAD cell proliferation, migration and invasion. Meanwhile, the activity of Wnt/ß-catenin signaling pathway was also reduced. Taken together, these data indicated that ARHGAP9 knockdown promoted LUAD metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2. This may provide a new strategy for LUAD treatment.

Tumor necrosis factor-related lncRNAs predict prognosis and immunotherapy response for patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) has become one of the most lethal cancers, for which the recurrence and survival rates remain unfavorable. The tumor necrosis factor (TNF) family is involved in tumorigenesis and tumor progression. Various long non-coding RNAs (lncRNAs) play important roles by mediating the TNF family in cancer. Therefore, this study aimed to construct a TNF-related lncRNA signature to predict prognosis and immunotherapy response in LUAD. Methods: The expression of TNF family members and their related lncRNAs in a total of 500 enrolled LUAD patients was collected from The Cancer Genome Atlas (TCGA). Univariate Cox and the least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to construct a TNF family-related lncRNA prognostic signature. Kaplan-Meier (KM) survival analysis was used to evaluate survival status. The time-dependent area under the receiver operating characteristic (ROC) curve (AUC) values were used to assess the predictive value of the signature to 1-, 2-, and 3-year overall survival (OS). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify the signature-related biological pathways. Furthermore, tumor immune dysfunction and exclusion (TIDE) analysis was employed to evaluate immunotherapy response. Results: A total of 8 TNF-related lncRNAs significantly associated with OS of LUAD patients were used to construct a TNF family-related lncRNA prognostic signature. According to risk score, these patients were divided into high- and low-risk subgroups. The KM survival analysis indicated that patients in the high-risk group showed significantly less favorable OS than that of low-risk group. The AUC values in predicting 1-, 2-, and 3-year OS were 0.740, 0.738, and 0.758, respectively. Moreover, the GO and KEGG pathway analyses demonstrated that these lncRNAs were closely involved in immune-related signaling pathways. The further TIDE analysis indicated that high-risk patients had a lower TIDE score than that of low-risk patients, indicating that high-risk patients may be appropriate candidates for immunotherapy. Conclusions: For the first time, this study constructed and validated a prognostic predictive signature of LUAD patients based on TNF-related lncRNAs, and the signature showed good performance to predict immunotherapy response. Therefore, this signature may provide new strategies for individualized treatment of LUAD patients.

Amoeba-Inspired Magnetic Venom Microrobots.

Nature provides a successful evolutionary direction for single-celled organisms to solve complex problems and complete survival tasks - pseudopodium. Amoeba, a unicellular protozoan, can produce temporary pseudopods in any direction by controlling the directional flow of protoplasm to perform important life activities such as environmental sensing, motility, predation, and excretion. However, creating robotic systems with pseudopodia to emulate environmental adaptability and tasking capabilities of natural amoeba or amoeboid cells remains challenging. Here, this work presents a strategy that uses alternating magnetic fields to reconfigure magnetic droplet into Amoeba-like microrobot, and the mechanisms of pseudopodia generation and locomotion are analyzed. By simply adjusting the field direction, microrobots switch in monopodia, bipodia, and locomotion modes, performing all pseudopod operations such as active contraction, extension, bending, and amoeboid movement. The pseudopodia endow droplet robots with excellent maneuverability to adapt to environmental variations, including spanning 3D terrains and swimming in bulk liquids. Inspired by the "Venom," the phagocytosis and parasitic behaviors have also been investigated. Parasitic droplets inherit all the capabilities of amoeboid robot, expanding their applicable scenarios such as reagent analysis, microchemical reactions, calculi removal, and drug-mediated thrombolysis. This microrobot may provide fundamental understanding of single-celled livings, and potential applications in biotechnology and biomedicine.

Metabolomics Identifies a Panel of Diagnostic Biomarkers for Early Human Embryonic Development Arrest.

Early embryonic development arrest (EEDA) is a unique form of early spontaneous abortion in pregnant women, which is previously suggested to be associated with metabolic abnormalities. Noninvasive biomarkers would significantly improve its diagnosis and clinical outcome. Here, we performed a targeted metabolomics study in plasma from EEDA patients (n = 27) and normal pregnant women (NPW, n = 27) using liquid chromatography coupled with mass spectrometry (LC-MS) to identify potential diagnostic marker metabolites. Our results showed significantly different plasma metabolic profiles between EEDA patients and NPW. Particularly, EEDA patients showed significant alterations in amino acid, carbohydrate, and vitamin metabolism, which were characterized by 21 significantly increased metabolites and five decreased metabolites in plasma. Further receiver operating characteristic analysis showed that an optimal combination of S-methyl-5'-thioadenosine, kynurenine, leucine, and malate could be used as a panel of metabolites for EEDA diagnosis. The area under the curve of the metabolite panel was 0.941, suggesting a better performance than any single metabolite for the diagnosis of EEDA. In summary, our study identifies a panel of differential metabolites in plasma that could act as potential biomarkers for the diagnosis of EEDA in clinical settings.

Breaking through Barriers: Ultrafast Microbullet Based on Cavitation Bubble.

Micromotors hold great promise for extensive practical applications such as those in biomedical domains and reservoir exploration. However, insufficient propulsion of the micromotor limits its application in crossing biological barriers and breaking reservoir boundaries. In this study, an ultrafast microbullet based on laser cavitation that can utilize the energy of a cavitation bubble and realize its own hurtling motion is reported. The experiments are performed using high-speed photography. A boundary integral method is adopted to reveal the motion mechanism of a polystyrene (PS)/magnetic nanoparticle (MNP) microbullet under the action of laser cavitation. Furthermore, the influence of certain factors (including laser intensity, microbullet size, and ambient temperature) on the motion of the microbullet was explored. For the PS/MNP microbullet driven by laser cavitation, the instantaneous velocity obtained can reach 5.23 m s-1 . This strategy of driving the PS/MNP microbullet provides strong penetration ability and targeted motion. It is believed that the reported propulsion mechanism opens up new possibilities for micromotors in a wide range of engineering applications.

Association of genetic polymorphisms with mercapturic acids in the urine of young healthy subjects before and after exposure to outdoor air pollution.

We aimed to identify the relationship between variations in metabolic genes and human urinary changes in mercapturic acids (MAs), including CEMA, HMPMA, SPMA, HPMA and HEMA, before and after air pollution exposure. Genotype detection for 47 relevant single nucleotide polymorphisms (SNPs) collected by literature research was performed. Five MAs expression levels in the urinary samples of 50 young healthy individuals with short-term exposure to clean, polluted and purified air at five time points were detected by targeted online solid-phase extraction liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS), followed with associations of SNPs with MAs changes. Difference in MAs between polluted and clean/purified air was significantly associated with 21 SNPs mapped into 9 genes. Five SNPs in GSTP1 showed the most prominent association with the changes in SPMA expression, indicating that those SNPs in GSTP1 and SPMA might serve as biomarkers for susceptibility and the prognosis of lung cancer.

Prognostic value and immune regulatory role of dynamin 1-like in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC), with poor treatment outcomes worldwide. Dynamin-related protein 1 (DRP1), which is encoded by the dynamin 1-like (DNM1L) gene, acts as a regulator of mitochondrial fission and plays crucial roles in tumor initiation and progression. However, the clinical value and immune regulation of DNM1L in LUAD have not been explored. Methods: We comprehensively analyzed the expression of DNM1L in the LUAD cohort of the Human Protein Atlas (HPA) and the University of The ALabama at Birmingham CANcer data analysis Portal (UALCAN) databases. Kaplan-Meier plotter, in addition to the PrognoScan database, was used to estimate the correlation between DNM1L expression and survival outcome of LUAD patients. The association between the immune tumor microenvironment (TME) and DNM1L expression in LUAD was evaluated based on the Tumor IMmune Estimation Resource (TIMER)2.0 database. Finally, the functions of DNM1L were validated in vitro experiments, including reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot, wound healing assays, and transwell assays. Results: DNM1L was overexpressed in LUAD compared to healthy control tissues and was regarded as an independent prognostic factor. Overexpression of DNM1L was significantly related to clinical variables and poor survival outcomes of LUAD patients. Moreover, DNM1L expression was positively associated with the expression of key genes involved in the regulation of immune cell subsets, including T helper (Th)2 cells, Th cells, B cells, CD8 T cells, dendritic cells, and mast cells. In contrast, DNM1L was negatively correlated with the infiltrating levels of myeloid dendritic cells and B cells. Furthermore, DNM1L may play a role in regulating immune cell infiltration and have prognostic value in LUAD patients. Finally, the in vitro experiments showed that increased DNM1L significantly promoted the proliferation and migration of LUAD cells. Conclusions: This study suggested that DNM1L may play an important role in regulating the proliferation and migration of LUAD cells as well as the infiltration of tumor-related immune cells, which suggests DNM1L was a potential therapeutic target in LUAD. Further studies are however warranted to define its exact mechanism of action and potential therapeutic significance in LUAD patients.

Chaetoglobosin E inhibits tumor growth and promotes the anti-tumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma by targeting PLK1.

Background: Currently, there is no satisfactory treatment available for esophageal squamous cell carcinoma (ESCC), and thus, there is a pressing need to develop effective drugs. Chaetoglobosin E, a cytochalasan alkaloid derived from metabolites of Chaetomium madrasense 375, is a chaetoglobosin with intense anti-tumor activity. Therefore, revealing its anti-tumor mechanism for the application of cytochalasans is crucial. Methods: The cytotoxic effect of chaetoglobosin E and cisplatin on esophageal cancer KYSE-30, KYSE-150, and TE-1 cells was detected using cell viability or colony formation assays. The cell cycle, apoptosis, autophagy, invasion, and metastasis were assayed by flow cytometry or western blot. The potential target of chaetoglobosin E was assayed by RNA sequencing (RNA-seq) and large loop prediction software analysis and was assessed by western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of its target on cell pyroptosis was assayed using overexpression and silence experiments. Results: Chaetoglobosin E significantly inhibited the proliferation of KYSE-30, KYSE-150, and TE-1 cells, especially KYSE-30 cells. Our results showed that chaetoglobosin E induced the G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and up-regulation of p21. Moreover, chaetoglobosin E also decreased the anti-apoptotic protein expression of Bcl-2, increased apoptotic expression of Bax, increased autophagy protein expressions of beclin1 and LC3, decreased invasion and metastasis protein expression of E-cadherin, and increased expression of vimentin. The RNA-seq and large loop prediction software analysis results indicated that its potential target might be polo-like kinase 1 (PLK1). Moreover, results also showed that chaetoglobosin E can reverse the PLK1 overexpression plasmid-induced up-regulation of the PLK1 protein. Furthermore, we found that chaetoglobosin E induced pyroptosis via the activation of the gasdermin E (GSDME) protein. Further studies showed that the high expression of PLK1 inactivated the GSDME protein, while the knockdown of PLK1 expression activated the GSDME protein, indicating that chaetoglobosin E induced cell pyroptosis by inhibiting PLK1. Conclusions: This study suggested that chaetoglobosin E may be a novel lead compound to the treatment of ESCC patients by targeting PLK1, and elucidated for the first time that PLK1 was involved in a new pyroptosis mechanism.

Clinical significance and immune landscape of cuproptosis-related lncRNAs in kidney renal clear cell carcinoma: a bioinformatical analysis.

Background: Kidney renal clear cell carcinoma (KIRC) is considered an immunogenic tumor. Cuproptosis is a newly identified copper-induced regulated cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) have emerged as significant players in tumorigenesis and metastasis. However, there is a huge knowledge gap on the prognostic role of cuproptosis-related lncRNAs in KIRC. And, the clinical value of them is still unknown. Here, we aimed to develop a cuproptosis-related lncRNA prognostic signature in KIRC. Methods: The messenger RNA (mRNA)/lncRNA expression profiles and the clinical information including age, gender, tumor stage, grade, and overall survival (OS) were acquired from The Cancer Genome Atlas (TCGA) database. The included KIRC samples were further randomly assigned into training (n=258) or testing (n=257) data sets. We performed Pearson correlation analysis to identify the cuproptosis-related lncRNAs and then constructed the prognostic signature using Cox regression analysis and LASSO algorithm. Subsequently, Kaplan-Meier survival analysis, a nomogram, and receiver operating characteristic (ROC) curve were performed to assess the predictive performance of the signature. Moreover, the immune characteristics and drug sensitivity related to the signature were also explored. Results: The signature comprised 7 cuproptosis-related lncRNAs. The patients with a low-risk score had superior OS compared with those with a high-risk score. The survival rates of the high- and low-risk groups were 44.96% and 83.72% (P<0.001). The area under the curve (AUC) value for 1-, 3-, 5-year survival rate reached 0.814, 0.762 and 0.825, respectively. In addition, a nomogram was also generated; the AUC was 0.785 for risk score, higher than that for age (0.593), gender (0.489), grade (0.679), and stage (0.721). The high-risk group had more enriched immune- and tumor-related genes. Patients with low-risk scores were more sensitive to immunotherapy and the small molecular drugs GSK1904529A, tipifarnib, BX-912, FR-180204, and GSK1070916. Meanwhile, the high-risk group tended to be more sensitive to pyrimethamine, MS-275, and CGP-60474. Conclusions: Collectively, we constructed a cuproptosis-related lncRNA prognostic signature with a higher predictive accuracy compared to multiple clinicopathological parameters, which may provide vital guidance for therapeutic strategies in KIRC. Combination of more prognostic biomarkers may further improve the accuracy.

A reporting quality evaluation of the clinical practice guidelines for bladder cancer based on the RIGHT checklist.

Background: The Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist was developed to improve the reporting quality in clinical practice guidelines (CPGs). CPGs could provide the recommendations for key clinical issues with alternative care options and adherence to them could improve the outcomes. And, high reporting quality CPGs can assist health workers to incorporate the best evidence into the individual practice. There is no evaluation study on the reporting quality of CPGs in bladder cancer (BLCA). This study assessed the reporting quality of CPGs on BLCA and provided new insights for the development of CPGs in this disease. Methods: We conducted a systematic search in multiple literature databases, including PubMed, Wanfang, China National Knowledge Infrastructure (CNKI) and China Biology Medicine (CBM) as well as the medical associations and websites of guideline development organizations. Relevant CPGs published between January 2017 and December 2021 were identified. Four trained investigators independently screened the extracted documents to include all eligible CPGs and evaluated whether the items in the RIGHT checklist were reported in each CPG. Subsequently, the reporting rate of each CPG and item, as well as the mean reporting rate of each domain in the RIGHT checklist was calculated. Results: A total of 23 CPGs related to BLCA were finally included, of which, 22 guidelines were written in English and 1 was published in Chinese. The mean reporting rate of the included CPGs was approximately 65%. The reporting rates of the items in each RIGHT domain were 77% for basic information domain, 75% for recommendations domain, 72% for evidence domain, 69% for background domain, 43% for funding and declaration and management of interest domain, 35% for review and quality assurance domain, and 41% for other information domain. The reporting rate was determined as the mean value in Office Excel 2019. Conclusions: The reporting quality of BLCA CPGs related to the domains of funding and declaration and management of interest domain, review and quality assurance domain, and other information domain is poor and warrants improvement in the future.

An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms.

Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.

Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer.

The continuous emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses new challenges in the fight against the coronavirus disease 2019 (COVID-19) pandemic. The newly emerging Omicron strain caused serious immune escape and raised unprecedented concern all over the world. The development of an antibody targeting a conserved and universal epitope is urgently needed. A subset of neutralizing antibodies (NAbs) against COVID-19 from convalescent patients were isolated in our previous study. In this study, we investigated the accommodation of these NAbs to SARS-CoV-2 variants of concern (VOCs), revealing that IgG 553-49 neutralizes pseudovirus of the SARS-CoV-2 Omicron variant. In addition, we determined the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike (S) protein complexed with three monoclonal antibodies targeting different epitopes, including 553-49, 553-15, and 553-60. Notably, 553-49 targets a novel conserved epitope and neutralizes the virus by disassembling S trimers. IgG 553-15, an antibody that neutralizes all of the VOCs except Omicron, cross-links two S trimers to form a trimer dimer, demonstrating that 553-15 neutralizes the virus by steric hindrance and virion aggregation. These findings suggest the potential to develop 553-49 and other antibodies targeting this highly conserved epitope as promising therapeutic reagents for COVID-19. IMPORTANCE The emergence of the Omicron strain of SARS-CoV-2 caused higher immune escape, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. In this study, we identified a SARS-CoV-2 neutralizing antibody, 553-49, which neutralizes all variants by targeting a completely conserved novel epitope. In addition, we revealed that IgG 553-15 neutralizes SARS-CoV-2 by cross-linking virions and that 553-60 functions by blocking receptor binding. Comparison of different receptor binding domain (RBD) epitopes revealed that the 553-49 epitope is hidden in the S trimer and keeps a high degree of conservation during SARS-CoV-2 evolution, making 553-49 a promising therapeutic reagent against the emerging Omicron and future variants of SARS-CoV-2.

Sushi-Repeat-Containing Protein X-Linked 2: A Potential Therapeutic Target for Inflammation and Cancer Therapy.

Accumulating evidence has showed that sushi-repeat-containing protein X-linked 2 (SRPX2) is an abnormal expression in a variety of cancers and involved in cancer carcinogenesis, chemosensitivity, and prognosis, which mainly promote cancer cell metastasis, invasion, and migration by regulating the uPAR/integrins/FAK signaling pathway, epithelial-mesenchymal transition (EMT), angiogenesis, and glycosylation. Inflammation has been regarded as a key role in regulating cancer initiation, progression, EMT, and therapeutics. Furthermore, SRPX2 exhibited excellent antifibrosis effect via the TGFßR1/SMAD3/SRPX2/AP1/SMAD7 signaling pathway. Therefore, this review provides compelling evidence that SRPX2 might be a therapeutic target for inflammation and cancer-related inflammation for future cancer therapeutics.

A distinct lipid metabolism signature of acute myeloid leukemia with prognostic value.

Background: Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by extensive genetic abnormalities that might affect the prognosis and provide potential drug targets for treatment. Reprogramming of lipid metabolism plays important roles in tumorigenesis and progression and has been newly recognized a new hallmark of malignancy, and some related molecules in the signal pathways could be prognostic biomarkers and potential therapeutic targets for cancer treatment. However, the clinical value of lipid metabolism reprogramming in AML has not been systematically explored. In this study, we aim to explore the clinical value of lipid metabolism reprogramming and develop a prognostic risk signature for AML. Methods: We implemented univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO analysis to develop the risk signature with six lipid metabolism-related genes (LDLRAP1, PNPLA6, DGKA, PLA2G4A, CBR1, and EBP). The risk scores of samples were calculated and divided into low- and high-risk groups by the median risk score. Results: Survival analysis showed the high-risk group hold the significantly poorer outcomes than the low-risk group. The signature was validated in the GEO datasets and displayed a robust prognostic value in the stratification analysis. Multivariate analysis revealed the signature was an independent prognostic factor for AML patients and could serve as a potential prognostic biomarker in clinical evaluation. Furthermore, the risk signature was also found to be closely related to immune landscape and immunotherapy response in AML. Conclusions: Overall, we conducted a comprehensive analysis of lipid metabolism in AML and constructed a risk signature with six genes related to lipid metabolism for the malignancy, prognosis, and immune landscape of AML, and our study might contribute to better understanding in the use of metabolites and metabolic pathways as the potential prognostic biomarkers and therapeutic targets for AML.