A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation.

BACKGROUND: Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models. METHODS: KTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC-MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR. RESULTS: KTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8+ T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models. CONCLUSION: KTC1101's dual mechanism of action-directly inhibiting tumor cell growth and dynamically enhancing the immune response- represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.

Comprehensive evaluation of nitrogen contamination in water ecosystems of the Miyun reservoir watershed, northern China: distribution, source apportionment and risk assessment.

Miyun Reservoir plays a vital role as a source of drinking water for Beijing, however it grapples with nitrogen contamination issues that have been poorly understood in terms of their distribution, source, and associated health risks. This study addresses this knowledge gap by employing data on nitrate nitrogen (NO3--N), chloride (Cl-), dual isotopic compositions of NO3- (δ15N-NO3- and δ18O-NO3-) data in water ecosystems, systematically exploring the distribution, source and health risk of nitrogen contaminants in Miyun reservoir watersheds. The results showed that over the past 30 years, surface water runoff has exhibited a notable decrease and periodic fluctuations due to the combined influence of climate and anthropogenic activities, while the total nitrogen (TN) concentration in aquatic ecosystems presented an annual fluctuating upward trend. The TN concentration in the wet season was predominantly elevated because a large amount of nitrogen contaminants migrated into water ecosystems through heavy rainfall or river erosion. The concentration of NO3--N, the main contaminant of the water ecosystems, showed distinct variations across different watersheds, followed as rivers over the Miyun reservoir. Moreover, NO3--N levels gradually increased from upstream to downstream in different basins. NO3--N in surface water was mainly derived from the mixture of agricultural ammonia fertilizer and sewage and manure, with a minority of samples potentially undergoing denitrification. Comparatively, the main sources of NO3--N in groundwater were soil N and sewage and manure, while the denitrification process was inactive. The carcinogenic risks caused by NO3--N in groundwater were deemed either nonexistent or minimal, while the focus should predominantly be on potential non-carcinogenic risks, particularly for infants and children. Therefore, it is crucial to perform proactive measures aimed at safeguarding water ecosystems, guided by an understanding of the distribution, sources, and associated risks of nitrogen contamination.

Dissecting the Ultrafast Stepwise Bidirectional Proton Relay in a Blue-Light Photoreceptor.

Proton relays through H-bond networks are essential in realizing the functionality of protein machines such as in photosynthesis and photoreceptors. It has been challenging to dissect the rates and energetics of individual proton-transfer steps during the proton relay. Here, we have designed a proton rocking blue light using a flavin (BLUF) domain with the flavin mononucleotide (FMN)-glutamic acid (E)-tryptophan (W) triad and have resolved the four individual proton-transfer steps kinetically using ultrafast spectroscopy. We have found that after the photo-induced charge separation forming FMN·-/E-COOH/WH·+, the proton first rapidly jumps from the bridging E-COOH to FMN- (τfPT2 = 3.8 ps; KIE = 1.0), followed by a second proton transfer from WH·+ to E-COO- (τfPT1 = 336 ps; KIE = 2.6) which immediately rocks back to W· (τrPT1 = 85 ps; KIE = 6.7), followed by a proton return from FMNH· to E-COO- (τrPT2 = 34 ps; KIE = 3.3) with the final charge recombination between FMN·- and WH·+ to close the reaction cycle. Our results revisited the Grotthuss mechanism on the ultrafast timescale using the BLUF domain as a paradigm protein.

Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese.

BACKGROUND: Genetic knowledge of gestational diabetes mellitus (GDM) in Chinese women is quite limited. This study aimed to identify the risk factors and mechanism of GDM at the genetic level in a Chinese population. METHODS: We conducted a genome-wide association study (GWAS) based on single nucleotide polymorphism (SNP) array genotyping (ASA-CHIA Bead chip, Illumina) and a case-cohort study design. Variants including SNPs, copy number variants (CNVs), and insertions-deletions (InDels) were called from genotyping data. A total of 2232 pregnant women were enrolled in their first/second trimester between February 2018 and December 2020 from Anqing Municipal Hospital in Anhui Province, China. The GWAS included 193 GDM patients and 819 subjects without a diabetes diagnosis, and risk ratios (RRs) and their 95% confidence intervals (CIs) were estimated by a regression-based method conditional on the population structure. The calling and quality control of genotyping data were performed following published guidelines. CNVs were merged into CNV regions (CNVR) to simplify analyses. To interpret the GWAS results, gene mapping and overexpression analyses (ORAs) were further performed to prioritize the candidate genes and related biological mechanisms. RESULTS: We identified 14 CNVRs (false discovery rate corrected P values < 0.05) and two suggestively significant SNPs (P value < 0.00001) associated with GDM, and a total of 19 candidate genes were mapped. Ten genes were significantly enriched in gene sets related to lipase (triglyceride lipase and lipoprotein lipase) activity (LIPF, LIPK, LIPN, and LIPJ genes), oxidoreductase activity (TPH1 and TPH2 genes), and cellular components beta-catenin destruction complex (APC and GSK3B genes), Wnt signalosome (APC and GSK3B genes), and lateral element in the Gene Ontology resource (BRCA1 and SYCP2 genes) by two ORA methods (adjusted P values < 0.05). CONCLUSIONS: Genes related to lipolysis, redox reaction, and proliferation of islet ß-cells are associated with GDM in Chinese women. Energy metabolism, particularly lipolysis, may play an important role in GDM aetiology and pathology, which needs further molecular studies to verify.

Super diffraction limit spectral imaging detection and material type identification of distant space objects.

The image information of distant objects shows a diffuse speckle pattern due to diffraction limit, non-uniform scattering, etc., which is difficult to achieve object discrimination. In this study, we have developed a staring spectral video imaging system mounted on a ground-based telescope observation platform to detect the high orbit space objects and gain their spectral images for six groups of GEO targets. The speckle remains basically the same characteristic as the projection structure of the object due to "the balloon inflation phenomenon of near parallel light during long-distance atmospheric transmission" under the premise of considering the bi-directional reflection distribution function (BRDF), Rayleigh scattering theory, and the memory effect. Based on this phenomenon, a mathematical model of remote target scattering spectrum imaging is established where the speckle can be treated as both a global speckle and speckle combination of texture blocks caused by various components of the target. The radial basis function (RBF) neural network is separately used to invert the global speckle and the speckle combination of the texture blocks on account of the typical target material database. The results show that the target materials are of relatively fewer kinds in the global inversion with only including gallium arsenide panel (GaAs) and carbon fiber (CF), for which the highest goodness of curve fitting is only 77.97. An improved algorithm makes their goodness of fit reach 90.29 and 93.33, respectively, in view of one conjecture that the target surface contains unknown materials. The spectral inversion result of the texture blocks shows that the types of materials in each target texture block increase significantly, and that the area ratio of different materials inverted in the block is different from each other. It is further confirmed that the speckle image contains the overall projection structure of distant target and the spectral image projection of each component is relatively fixed, which is the result of the comprehensive action of various mechanisms of ultra-long-haul atmospheric transmission and optical system focusing imaging after BRDF spectral scattering. The spectral image fine inversion is expected to restore the clear structure of the target. This discovery provides important support for the remote imaging and identification of distant and ultra-diffractive targets.

Co3+ -Rich Na1.95 CoP2 O7 Phosphates as Efficient Bifunctional Catalysts for Oxygen Evolution and Reduction Reactions in Alkaline Solution.

Implementing sustainable energy conversion and storage technologies is highly reliant on crucial oxygen electrocatalysis, such as the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). However, the pursuit of low cost, energetic efficient and robust bifunctional catalysts for OER and ORR remains a great challenge. Herein, the novel Na-ion-deficient Na2-x CoP2 O7 catalysts are proposed to efficiently electrocatalyze OER and ORR in alkaline solution. The engineering of Na-ion deficiency can tune the electronic structure of Co, and thus tailor the intrinsically electrocatalytic performance. Among the sodium cobalt phosphate catalysts, the Na1.95 CoP2 O7 (NCPO5) catalyst exhibits the lowest ΔE (EJ10,OER -EJ-1,ORR ) of only 0.86 V, which favorably outperforms most of the reported non-noble metal catalysts. Moreover, the Na-ion deficiency can stabilize the phase structure and morphology of NCPO5 during the OER and ORR processes. This study highlights the Na-ion deficient Na2-x CoP2 O7 as a promising class of low-cost, highly active and robust bifunctional catalysts for OER and ORR.

Comparison of weekly and triweekly cisplatin regimens during concurrent chemoradiotherapy for nasopharyngeal carcinoma.

BACKGROUND: We compared the survival outcomes and acute toxicities of weekly and triweekly cisplatin regimens during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS: Patients were treated with CCRT alone. CCRT was initiated on the first day of RT. Cisplatin 30-40 mg/m2 was infused on days 1, 8, 15, 22, 29, 36 and 43 in the Weekly Group, while cisplatin 80-100 mg/m2 was delivered on days 1, 22 and 43 in the Triweekly Group. The survival outcomes were revealed by the Kaplan-Meier method and Cox regression modelling to measure 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). RESULTS: Ninety-three (28.9%) patients received three to 7 cycles of cisplatin weekly (Weekly Group) and 229 (71.1%) patients received two to 3 cycles of cisplatin triweekly (Triweekly Group). Five-year OS (weekly vs. triweekly, 96.7% vs. 88.3%, P = 0.036) and DFS (weekly vs. triweekly, 90.7% vs. 80.5%, P = 0.028) were better in the Weekly Group than in the Triweekly Group. The weekly vs. triweekly 5-year DMFS and LRFS rates were: DMFS, 96.7% vs. 91.4%, χ2 = 2.694, P = 0.101; LRFS, 96.3% vs. 93.5%, χ2 = 1.317, P = 0.251. Cisplatin delivery regimen was not an independent prognostic factor. The incidence rate of acute toxicities was similar between the groups. CONCLUSIONS: Compared with Triweekly cisplatin regimen, Weekly regimen may be a better choice during CCRT.

Expression and purification of half-smooth tongue sole (Cynoglossus semilaevis) CSDAZL protein.

The csdazl gene is a sex related gene of half-smooth tongue sole (Cynoglossus semilaevis). Our research group have cloned full length cDNA of csdazl, and studied its expression pattern. To get the further information of csdazl, we constructed a prokaryotic expression plasmid, pET-32a-CSDAZL, expressed in Escherichia coli BL21 and purified the fusion protein by His Trap. In order to detect the biological activity of the fusion protein, we injected the protein with liposome into fish, and detected other sex-related genes' mRNA expression. The results showed that the expression levels of half-smooth tongue sole female-related genes Cyp19a and Foxl2 significantly decreased between 6 and 24 h; however, both genes' expressions returned to their normal levels 72 h after injection, indicating that recombinant CSDAZL protein could down-regulated the expression of female-related genes, Foxl2 and Cyp19a genes, implying that the fusion protein has biological activity and csdazl plays a role in sex differentiation by regulating sex related genes' expression.

Elementary Reactions in the Functional Triads of the Blue-Light Photoreceptor BLUF Domain.

The blue light using the flavin (BLUF) domain is one of the smallest photoreceptors in nature, which consists of a unique bidirectional electron-coupled proton relay process in its photoactivation reaction cycle. This perspective summarizes our recent efforts in dissecting the photocycle into three elementary processes, including proton-coupled electron transfer (PCET), proton rocking, and proton relay. Using ultrafast spectroscopy, we have determined the temporal sequence, rates, kinetic isotope effects (KIEs), and concertedness of these elementary steps. Our findings provide important implications for illuminating the photoactivation mechanism of the BLUF domain and suggest an engineering platform to characterize intricate reactions involving proton motions that are ubiquitous in nonphotosensitive protein machines.

One-Step Preparation of Magnetic Lipid Bubbles: Magnetothermal Effect Induces the Simultaneous Formation of Gas Nuclei and Self-Assembly of Phospholipids.

In recent years, enveloped micro-nanobubbles have garnered significant attention in research due to their commendable stability, biocompatibility, and other notable properties. Currently, the preparation methods of enveloped micro-nanobubbles have limitations such as complicated preparation process, large bubble size, wide distribution range, low yield, etc. There exists an urgent demand to devise a simple and efficient method for the preparation of enveloped micro-nanobubbles, ensuring both high concentration and a uniform particle size distribution. Magnetic lipid bubbles (MLBs) are a multifunctional type of enveloped micro-nanobubble combining magnetic nanoparticles with lipid-coated bubbles. In this study, MLBs are prepared simply and efficiently by a magneto internal heat bubble generation process based on the interfacial self-assembly of iron oxide nanoparticles induced by the thermogenic effect in an alternating magnetic field. The mean hydrodynamic diameter of the MLBs obtained was 384.9 ± 8.5 nm, with a polydispersity index (PDI) of 0.248 ± 0.021, a zeta potential of -30.5 ± 1.0 mV, and a concentration of (7.92 ± 0.46) × 109 bubbles/mL. Electron microscopy results show that the MLBs have a regular spherical stable core-shell structure. The superparamagnetic iron oxide nanoparticles (SPIONs) and phospholipid layers adsorbed around the spherical gas nuclei of the MLBs, leading the particles to demonstrate commendable superparamagnetic and magnetic properties. In addition, the effects of process parameters on the morphology of MLBs, including phospholipid concentration, phospholipid proportiona, current intensity, magnetothermal time, and SPION concentration, were investigated and discussed to achieve controlled preparation of MLBs. In vitro imaging results reveal that the higher the concentration of MLBs loaded with iron oxide nanoparticles, the better the in vitro ultrasound (US) imaging and magnetic resonance imaging (MRI) results. This study proves that the magneto internal heat bubble generation process is a simple and efficient technique for preparing MLBs with high concentration, regular structure, and commendable properties. These findings lay a robust foundation for the mass production and application of enveloped micro-nanobubbles, particularly in biomedical fields and other related domains.

Novel genetic variants linked to prelabor rupture of membranes among Chinese pregnant women.

INTRODUCTION: The etiology of prelabor rupture of membranes (PROM), either preterm or term PROM (PPROM or TPROM), remains largely unknown. This study aimed to investigate the association between maternal genetic variants (GVs) and PROM and further establish a GV-based prediction model for PROM. METHODS: In this case-cohort study (n = 1166), Chinese pregnant women with PPROM (n = 51), TPROM (n = 283) and controls (n = 832) were enrolled. A weighted Cox model was applied to identify the GVs (single nucleotide polymorphisms [SNPs], insertions/deletions, and copy number variants) associated with either PPROM or TPROM. Gene set enrichment analysis (GSEA) was to explore the mechanisms. The suggestively significant GVs were applied to establish a random forest (RF) model. RESULTS: PTPRT variants (rs117950601, P = 4.37 × 10-9; rs147178603, P = 8.98 × 10-9) and SNRNP40 variant (rs117573344, P = 2.13 × 10-8) were associated with PPROM. STXBP5L variant (rs10511405, P = 4.66 × 10-8) was associated with TPROM. GSEA results showed that genes associated with PPROM were enriched in cell adhesion, and TPROM in ascorbate and glucuronidation metabolism. The area under the receiver operating characteristic curve of SNP-based RF model for PPROM was 0.961, with a sensitivity of 100.0% and specificity of 83.3%. DISCUSSION: Maternal GVs in PTPRT and SNRNP40 were associated with PPROM, and GV in STXBP5L was associated with TPROM. Cell adhesion participated in PPROM, while ascorbate and glucuronidation metabolism contributed in TPROM. The PPROM might be well predicted using the SNP-based RF model.

Constructing high sensitivity thermometry with dual-emitting Nd3+/Er3+/Yb3+ codoped BaWO4 single crystal material.

Inorganic oxides doped with rear earth(RE) have attracted much interest because of their outstanding optical properties. In this paper, the BaWO4:Yb3+/Er3+/Nd3+ phosphors were successfully prepared by typical solid state method. The crystalline structure of the samples was characterized through X-ray diffraction(XRD). The morphology of that was demonstrated with field emission scanning electron microscopy(FE-SEM). Under 980 nm excitation, the BaWO4: Yb3+/Er3+/Nd3+ phosphor presented four typical emissions at green(524-550 nm, Er3+), red(∼655 nm, Er3+), near infrared(∼710 nm, ∼820 nm, Nd3+). Furthermore, the temperature sensing properties of the samples were investigated in the temperature range of 303-573 K. The fluorescence intensity ratio(FIR) technique based on thermal and non-thermal coupled levels was applied to analyse the sensing performances. For BaWO4:Yb3+/Er3+/Nd3+ phosphor, the maximum absolute sensitivity reached 0.0423 K-1 at 303 K, which is based on 2H11/2(Er3+) and 4F7/2(Nd3+) levels. The repeatability of temperature response also was proved through four cold and heat cycles. The above result indicated that the BaWO4:Yb3+/Er3+/Nd3+ phosphor would be a promising temperature sensing materials.

[The event of acute hepatitis of unknown etiology in children].

Recently, the cases of acute hepatitis of unknown etiology (AHUE) in children worldwide have been increasing continuously and rapidly, involving more than 396 cases in 26 countries, and global public health actions, including surveillance, health alerts, research, are being implemented. AHUE mainly affects immunocompetent children with typical acute hepatitis, which can be severe and require liver transplantation. There are few systematic studies at present; the risk factors are unknown, the etiology remains to be established, and the clinical features and pathogenesis remain elucidated. It is urgent to strengthen the monitoring and research of AHUE cases.

Synchrotron X-ray-induced Synthesis of Copper Hydroxide Nitrate Nanoplates on Cu Thin Films in an Ambient Atmosphere.

Synchrotron X-rays are widely used for material characterizations. However, they can also ionize atoms and molecules to damage and manipulate probed materials. We report here an X-ray-induced growth of copper hydroxide nitrate, Cu2(OH)3NO3, on copper thin films in the ambient atmosphere without solvents and thermal treatment. In situ synchrotron X-ray diffraction measurements showed that the time-dependent growth process of theCu2(OH)3NO3 is accompanied by the consumption of Cu metal and can be described by a sigmoidal model. The growth rate was reduced after the initial fast growth period. Scanning electron microscopy (SEM) images show that the isolated islands of Cu2(OH)3NO3 nanoplates formed in the beginning, which grew together with new nanoplates formed under continued X-ray irradiation. The result demonstrated that high-flux synchrotron X-rays may provide an unconventional approach to synthesizing and manipulating materials, which will inspire future investigation both experimentally and theoretically.

Investigation on the upconversion luminescence and ratiometric thermal sensing of SrWO4:Yb3+/RE3+ (RE = Ho/Er) phosphors.

SrWO4 phosphors doped with Ho3+(Er3+)/Yb3+ are successfully prepared by a high temperature solid-state reaction method. The upconversion (UC) luminescence properties of all the samples have been investigated under 980 nm excitation. Strong green emissions are obtained in the SrWO4:Yb3+/Ho3+ and SrWO4:Yb3+/Er3+ samples with the naked eyes. In a temperature range going from 303 K to 573 K, the UC emission spectra of the phosphors have been measured. Then the temperature sensing properties also have been discussed via fluorescence intensity ratio (FIR) technology. For the SrWO4:Yb3+/Ho3+ phosphor, the FIR technologies based on thermal coupling levels (TCLs)(5F4,5F5) and non-thermal coupling levels (non-TCLs)(5S2, 5F4/5F5) are used for investigating the sensitivity. The results show that the maximum absolute sensitivity reaches 0.0158 K-1 with non-TCLs. As for Yb3+/Er3+ codoped SrWO4 phosphor, the maximum absolute sensitivity reaches 0.013 K-1 with TCLs (2H11/2,4S5/2) at a temperature of 513 K. These significant results demonstrate that the SrWO4:Ho3+(Er3+)/Yb3+ phosphors are robust for optical temperature sensors.

The optimization of microbial influenced corrosion resistance of HVOF sprayed nanostructured WC-10Co-4Cr coatings by ultrasound-assisted sealing.

In this study, high-velocity oxygen-fuel (HVOF) sprayed nanostructured WC-10Co-4Cr coatings were subjected to seawater with sulfate-reducing bacteria (SRB) for different time. The effect of ultrasound-assisted sealing with aluminum phosphate on the microstructural features and microbial influenced corrosion (MIC) behavior was evaluated using scanning electron microscopy (SEM), potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The results showed that the ultrasound-assisted sealing promoted the infiltration of the sealant into as-sprayed coating, enhanced the resistance values of about one order of magnitude, and reduced the corrosion current density. During the whole immersion period, the MIC process of both unsealed and sealed coatings can be divided into two different stages, and the ultrasound-assisted sealing treatment significantly delayed the MIC process, suggesting that the ultrasound-assisted sealing with aluminum phosphate is an effective way for controlling the MIC of SRB on the WC-10Co-4Cr cermet coatings in marine environment.

Efficient upconversion emission and high-sensitivity thermometry of BaIn2O4:Yb3+/Tm3+/RE3+ (RE = Er3+, Ho3+) phosphor.

BaIn2O4:Yb3+/Tm3+/RE3+ (RE = Er3+, Ho3+) upconversion (UC) phosphors were synthesized via the sol-gel method. Rietveld refinement based on XRD data proved that In3+ ions were replaced by rare earth (RE) ions. Under 980 nm excitation, UC and optical temperature-sensing properties were investigated, and the results indicated that the samples demonstrated high UC emission efficiencies and bright emission visible to the naked eye. The luminescence intensity ratio (LIR) technology based on thermally and non-thermally coupled levels was applied to study the optical temperature-sensing properties of the RE-doped BaIn2O4 phosphors. For the BaIn2O4:Yb3+/Tm3+/Er3+ phosphor, the absolute sensitivity reached a maximum value of 0.1433 K-1 at 473 K, which was based on the non-thermally coupled levels (non-TCLs) of 1G4 (blue luminescence at 480 nm of Tm3+ ion) and 2H11/2 (green luminescence at 525 nm of Er3+ ion). For the BaIn2O4:Yb3+/Tm3+/Ho3+ phosphor, the maximum absolute sensitivity was 0.2545 K-1, which came from the non-TCLs of 3H4 (infrared luminescence at 795 nm of Tm3+ ion) and 1G4 (blue luminescence at 480 nm of Tm3+ ion). BaIn2O4:Yb3+/Tm3+/RE3+ (RE = Er3+, Ho3+) samples were proven to have excellent optical temperature-sensing properties and could be applied to design optical thermometry.

Structure and function analysis of a potent human neutralizing antibody CA521FALA against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February . There is currently no approved therapeutics for treating COVID-19. The SARS-CoV-2 Spike protein is considered a key therapeutic target by many researchers. Here we describe the identification of several monoclonal antibodies that target SARS-CoV-2 Spike protein. One human antibody, CA521FALA, demonstrated neutralization potential by immunizing human antibody transgenic mice. CA521FALA showed potent SARS-CoV-2-specific neutralization activity against SARS-CoV-2 pseudovirus and authentic SARS-CoV-2 infection in vitro. CA521FALA also demonstrated having a long half-life of 9.5 days in mice and 9.3 days in rhesus monkeys. CA521FALA inhibited SARS-CoV-2 infection in SARS-CoV-2 susceptible mice at a therapeutic setting with virus titer of the lung reduced by 4.5 logs. Structural analysis by cryo-EM revealed that CA521FALA recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 RBD in the Spike protein. CA521FALA blocks the interaction by binding all three RBDs of one SARS-CoV-2 spike trimer simultaneously. These results demonstrate the importance for antibody-based therapeutic interventions against COVID-19 and identifies CA521FALA a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity.

The prognostic value of B7-H6 in esophageal squamous cell carcinoma.

B7-H6, a member of the B7 family molecules, participates in the clearance of tumor cells by binding to NKp30 on NK cells. B7-H6 expression level in esophageal squamous cell carcinoma (ESCC) and the clinical value remain unknown. The goal of this study was to determine the expression of B7-H6 in ESCC and further explore its clinical significance. We retrospectively collected the clinical data of 145 patients diagnosed with ESCC between January 2007 and December 2008. The expression of B7-H6 of the pathological tissue samples was detected by immunohistochemistry. The chi-square (χ2) test was used to analyse the relationships of B7-H6 and clinicopathological characteristics. Survival and hazard functions were estimated using the Kaplan-Meier method, and survival between groups was compared using the two-sided log-rank test. The Cox proportional hazards regression model was used to adjust for the risk factors related to overall survival (OS). 133/145 (91.72%) of the ESCC tissue samples exhibited B7-H6 expression. The expression level of B7-H6 was correlated with T stage (P = 0.036) and lymphatic metastasis status (P = 0.044). High B7-H6 expression (P = 0.003) was associated with a significantly worse OS than low B7-H6 expression. Multivariate Cox proportional hazards regression analysis demonstrated that tumour size (P = 0.021), B7-H6 expression (P = 0.025) and lymphatic metastasis status (P = 0.049) were independent prognostic factors of OS for ESCC. Collectively, our findings suggest that B7-H6 is widely expressed in ESCC samples. And B7-H6 may represent a predictor of poor prognosis for ESCC.

The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma.

INTRODUCTION: We aimed to characterize the expression of major facilitator superfamily domain-containing protein 2A (MFSD2A) in hepatocellular carcinoma (HCC) patients and analyze its prognostic value. RESULTS: Immunohistochemistry revealed that low expression of MFSD2A was present in 37 of 79 cases (46.84%), which was significantly correlated with poor histological differentiation (P = 0.012). The plasma MFSD2A level in HCC patients was significantly lower than in healthy controls (P = 0.0079) and controls with chronic hepatitis B virus (HBV) infection (P = 0.0430). Moreover, patients with lower MFSD2A expression had shorter survival than higher expression (P = 0.021). Multivariate analysis revealed that MFSD2A was an independent prognostic predictor for HCC patients (P = 0.027). CONCLUSION: The current study indicate MFSD2A may be an optimal diagnostic and prognostic biomarker for HCC. METHODS: First, we examined MFSD2A expression in 24 paired HCC and nontumorous tissues by real-time quantitative PCR (RT-qPCR). Second, the protein levels of MFSD2A in 11 paired HCC and nontumorous tissues were investigated by western blotting (WB). Moreover, MFSD2A protein expression was evaluated by immunohistochemistry in 79 HCC patients. In addition, we detected the plasma level of MFSD2A in HCC patients and healthy individuals and investigated the relationship between MFSD2A expression and clinicopathological parameters or prognosis of HCC patients.