Building evidence on safety of endovascular thrombectomy for patients under anticoagulation with vitamin K antagonists.

A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within 7 days prior to hospital admission. Through this retrospective, observational cohort study, they found prior VKA use did not increase the risk of symptomatic intracranial hemorrhage (sICH) overall. However, recent VKA use with a presenting international normalized ratio (INR) > 1.7 was associated with a significantly increased risk of sICH. Future large-scale randomized controlled trials should be conducted to further clarify the effects and feasibility of EVT therapy in ischemic stroke patients under anticoagulation.

The association between air pollutant exposure and cerebral small vessel disease imaging markers with modifying effects of PRS-defined genetic susceptibility.

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40-69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5-10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles. Three CSVD markers were used: white matter hyper-intensity (WMH), mean diffusivity (MD), and fractional anisotropy (FA). The first principal components of the MD and FA measures in the 48 white matter tracts were analysed. The sample consisted of 44,470 participants from the UK Biobank. The median (T1-T3) concentrations of pollutants were as follows: NO2, 25.5 (22.4-28.7) µg/m3; NOx, 41.3 (36.2-46.7) µg/m3; PM10, 15.9 (15.4-16.4) µg/m3; PM2.5, 9.9 (9.5-10.3) µg/m3; PM2.5 absorbance, 1.1 (1.0-1.2) per metre; and PM2.5-10, 6.1 (5.9-6.3) µg/m3. Compared with the low group, the high group's APEX, NOX, and PM2.5 levels were associated with increased WMH volumes, and the estimates (95 %CI) were 0.024 (0.003, 0.044), 0.030 (0.010, 0.050), and 0.032 (0.011, 0.053), respectively, after adjusting for potential confounders. APEX, PM10, PM2.5 absorbance, and PM2.5-10 exposure in the high group were associated with increased FA values compared to that in the low group. Sex-specific analyses revealed associations only in females. Regarding the combined associations of air pollutant exposure and PRS-defined genetic susceptibility with CSVD markers, the associations of NO2, NOX, PM2.5, and PM2.5-10 with WMH were more profound in females with low PRS-defined genetic susceptibility, and the associations of PM10, PM2.5, and PM2.5 absorbance with FA were more profound in females with higher PRS-defined genetic susceptibility. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.

Long-term outcomes and risk factors for early bacterial infection after pediatric liver transplantation: a prospective cohort study.

BACKGROUND: Liver transplantation (LT) is the most efficient treatment for pediatric patients with end-stage liver diseases, while bacterial infection is the leading reason for posttransplant mortality. The present study is to explore the outcomes and risk factors of early bacterial infection (within 1 mo) after pediatric LT. METHODS: In this prospective cohort study, 1316 pediatric recipients (median [IQR] age: 9.1 [6.3-28.0] months; male: 48.0%; median [IQR] follow-up time: 40.6 [29.1-51.4] months) who received LT from September 2018 to April 2022 were included. Bacterial culture samples such as sputum, abdominal drainage, blood and so on were collected when recipients were presented with infective symptoms. Kaplan-Meier analysis was applied to estimate the long-term survival rates and logistic regression was used to identify independent risk factors. To explore the role of pretransplant rectal swab culture (RSC) in reducing posttransplant bacterial infection rate, 188 infant LT recipients (median [IQR] age: 6.8 [5.5-8.1] months; male: 50.5%) from May 2022 to September 2023 were included. Log-binomial regression was used to measure the association of pretransplant RSC screening and posttransplant bacterial infection. The "Expectation Maximization" algorithm was used to impute the missing data. RESULTS: Bacterial infection was the primary cause for early (38.9%) and overall mortality (35.6%) after pediatric LT. Kaplan-Meier analysis revealed inferior 1- and 5-year survival rates for recipients with posttransplant bacterial infection (92.6% vs. 97.1%, 91.8% vs. 96.4% respectively; P<0.001). Among all detected bacteria, Staphylococcus spp. (34.3%) and methicillin-resistant coagulase-negative Staphylococci (43.2%) were the dominant species and multi-drug resistant organisms, respectively. Multivariable analysis revealed that infant recipients (adjusted odds ratio [aOR], 1.49; 95% CI, 1.01-2.20), male recipients (aOR, 1.43; 95% CI, 1.08-1.89), high graft-to-recipient weight ratio (aOR, 1.64; 95% CI, 1.17-2.30), positive posttransplant RSC (aOR, 1.45; 95% CI, 1.04-2.02) and nasopharyngeal swab culture (aOR 2.46; 95% CI, 1.72-3.52) were independent risk factors for early bacterial infection. Furthermore, RSC screening and antibiotic prophylaxis before transplantation could result in a relatively lower posttransplant infection rate, albeit without statistical significance (adjusted RR, 0.53; 95% CI, 0.25-1.16). CONCLUSION: In this cohort study, posttransplant bacterial infection resulted in an inferior long-term patient survival rate. The five identified independent risk factors for posttransplant bacterial infection could guide the prophylaxis strategy of posttransplant bacterial infection in the future. Additionally, pretransplant RSC might decrease posttransplant bacterial infection rate.

Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate.

We designed and developed 9MW2821, an anti-Nectin-4 antibody-drug conjugate (ADC) with an enzymatically cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) as the payload. Four bioanalytical assays for total antibodies, conjugated antibodies, conjugated payload, and free payload were then developed and validated for the comprehensive evaluation of the multiple drug forms of 9MW2821. Specific sandwich enzyme-linked immunosorbent assays were used to quantify total antibodies and conjugated antibody, showing good drug-to-antibody ratio (DAR) tolerance. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine free MMAE, and conjugated MMAE was quantified using a combination of ligand-binding assay (LBA) and LC-MS/MS. Based on these four assays, we studied the serum stability and monkey pharmacokinetic profiles of 9MW2821, and the in vivo DAR of 9MW2821 was calculated and dynamically monitored. In conclusion, we developed and validated series of bioanalytical assays to quantify multiple forms of 9MW2821, a new ADC, and used the assays to evaluate the serum stability and monkey pharmacokinetic characteristics. The results indicate good linker stability and suggest that the developed assays can be further used in clinical settings.

Automated thorax disease diagnosis using multi-branch residual attention network.

Chest X-ray (CXR) is an extensively utilized radiological modality for supporting the diagnosis of chest diseases. However, existing research approaches suffer from limitations in effectively integrating multi-scale CXR image features and are also hindered by imbalanced datasets. Therefore, there is a pressing need for further advancement in computer-aided diagnosis (CAD) of thoracic diseases. To tackle these challenges, we propose a multi-branch residual attention network (MBRANet) for thoracic disease diagnosis. MBRANet comprises three components. Firstly, to address the issue of inadequate extraction of spatial and positional information by the convolutional layer, a novel residual structure incorporating a coordinate attention (CA) module is proposed to extract features at multiple scales. Next, based on the concept of a Feature Pyramid Network (FPN), we perform multi-scale feature fusion in the following manner. Thirdly, we propose a novel Multi-Branch Feature Classifier (MFC) approach, which leverages the class-specific residual attention (CSRA) module for classification instead of relying solely on the fully connected layer. In addition, the designed BCEWithLabelSmoothing loss function improves the generalization ability and mitigates the problem of class imbalance by introducing a smoothing factor. We evaluated MBRANet on the ChestX-Ray14, CheXpert, MIMIC-CXR, and IU X-Ray datasets and achieved average AUCs of 0.841, 0.895, 0.805, and 0.745, respectively. Our method outperformed state-of-the-art baselines on these benchmark datasets.

Enhancing the Performance of Perovskite Light-Emitting Diodes via Synergistic Effect of Defect Passivation and Dielectric Screening.

Metal halide perovskites, particularly the quasi-two-dimensional perovskite subclass, have exhibited considerable potential for next-generation electroluminescent materials for lighting and display. Nevertheless, the presence of defects within these perovskites has a substantial influence on the emission efficiency and durability of the devices. In this study, we revealed a synergistic passivation mechanism on perovskite films by using a dual-functional compound of potassium bromide. The dual functional potassium bromide on the one hand can passivate the defects of halide vacancies with bromine anions and, on the other hand, can screen the charged defects at the grain boundaries with potassium cations. This approach effectively reduces the probability of carriers quenching resulting from charged defects capture and consequently enhances the radiative recombination efficiency of perovskite thin films, leading to a significant enhancement of photoluminescence quantum yield to near-unity values (95%). Meanwhile, the potassium bromide treatment promoted the growth of homogeneous and smooth film, facilitating the charge carrier injection in the devices. Consequently, the perovskite light-emitting diodes based on this strategy achieve a maximum external quantum efficiency of ~ 21% and maximum luminance of ~ 60,000 cd m-2. This work provides a deeper insight into the passivation mechanism of ionic compound additives in perovskite with the solution method.

The major histocompatibility complex participates in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and the aggregation of alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that the immune responses are involved in PD. The major histocompatibility complex (MHC) presents antigens from antigen-presenting cells (APCs) to T lymphocytes, immune responses will be induced. MHCs are expressed in microglia, astrocytes, and dopaminergic neurons. Single nucleotide polymorphisms in MHC are related to the risk of PD. The aggregated α-syn triggers the expression of MHCs by activating glia cells. CD4+ and CD8+ T lymphocytes responses and microglia activation are detected in brains of PD patients. In addiction immune responses further increase blood-brain barrier (BBB) permeability and T cell infiltration in PD. Thus, MHCs are involved in PD through participating in immune and inflammatory responses.

MCC950 attenuates plasma cell mastitis in an MDSC-dependent manner.

Plasma cell mastitis (PCM) is a sterile inflammatory condition primarily characterized by periductal inflammation and ductal ectasia. Currently, there is a lack of non-invasive or minimally invasive treatment option other than surgical intervention. The NLRP3 inflammasome has been implicated in the pathogenesis and progression of various inflammatory diseases, however, its involvement in PCM has not yet been reported. In this study, we initially observed the pronounced upregulation of NLRP3 in both human and mouse PCM tissue and elucidated the mechanism underlying the attenuation of PCM through inhibition of NLRP3. We established the PCM murine model and collected samples on day 14, when inflammation reached its peak, for subsequent research purposes. MCC950, an NLRP3 inhibitor, was utilized to effectively ameliorate PCM by significantly reducing plasma cell infiltration in mammary tissue, as well as attenuate the expression of pro-inflammatory cytokines including IL-1ß, TNF-α, IL-2, and IL-6. Mechanistically, we observed that MCC950 augmented the function of myeloid-derived suppressor cells (MDSCs), which in turn inhibited the infiltration of plasma cells. Furthermore, it was noted that depleting MDSCs greatly compromised the therapeutic efficacy of MCC950. Collectively, our findings suggest that the administration of MCC950 has the potential to impede the progression of PCM by augmenting MDSCs both numerically and functionally, ultimately treating PCM effectively. This study provides valuable insights into the utilization of pharmacological agents for PCM treatment.

Macropinocytic cups function as signal platforms for the mTORC2-AKT pathway to modulate LPS-induced cytokine expression in macrophages.

Macropinocytosis is a large-scale endocytosis process that is primarily observed in phagocytes as part of their cellular function to ingest antigens. Once phagocytes encounter gram-negative bacteria, the receptor proteins identify lipopolysaccharides (LPSs), which trigger radical membrane ruffles that gradually change to cup-like structures. The open area of the cups closes to generate vesicles called macropinosomes. The target bacteria are isolated by the cups and engulfed by the cells as the cups close. In addition to its ingestion function, macropinocytosis also regulates the AKT pathway in macrophages. In the current study, we report that macropinocytic cups are critical for LPS-induced AKT phosphorylation (pAKT) and cytokine expression in macrophages. High-resolution scanning electron microscope (SEM) observations detailed the macropinocytic cup structures induced by LPS stimulation. Confocal microscopy revealed that AKT and the kinase molecule mTORC2 were localized in the cups. The biochemical analysis showed that macropinocytosis inhibition blocked LPS-induced pAKT. RNA-Seq, qPCR, and ELISA analyses revealed that the inhibition of macropinocytosis or the AKT pathway causes a decrease in the expression of pro-inflammatory cytokines IL-6 and IL-1α. Moreover, activation of the transcription factor NF-κB, which regulates the cytokine expression downstream of the AKT/IκB pathway, was hindered when macropinocytosis or AKT were inhibited. These results indicate that LPS-induced macropinocytic cups function as signal platforms for the AKT pathway to regulate the cytokine expression by modulating NF-κB activity in LPS-stimulated macrophages. Based on these findings, we propose that macropinocytosis may be a good therapeutic target for controlling cytokine expression.

Evaluation of the effectiveness and safety of sequential vaccination with inactivated SARS-CoV-2 vaccine and Ad5-nCoV booster in pediatric liver transplant recipients.

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.

Role of the CXCR4-Gnαq-Plcß signaling pathway in the pathogenesis of collagen-induced arthritis in rats.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which immune cells and inflammatory cytokines are abnormally activated, leading to immunoregulatory dysfunction in the body and triggering systemic inflammatory responses. The interaction between CXC chemokine receptor 4 (CXCR4) and heterotrimeric G-protein α-subunit Gαq (Gnαq) activates phospholipase Cß (PLCß), which influences the expression of downstream effectors and participates widely in the onset and development of various diseases, thus suggesting the potential involvement of these molecules in RA pathogenesis. Therefore, the present study aimed to determine whether the CXCR4-Gnαq-PLCß signaling pathway participates in the onset and development of RA. Using a collagen-induced arthritis (CIA) rat model, we found that compared with the control (healthy) rat group, CIA rats exhibited highly time-dependent arthritis, with the maximum arthritis score occurring in week 3. In contrast to the splenic and joint tissue of control rats, CIA rats showed obvious hyperplasia in the lymphoid white pulp and main germination centers of the spleen, narrowing of joint cavities, and inflammatory cellular infiltration on articular surfaces. The serum levels of expression of IL-1ß, IL-4, IL-6, and TNF-α were significantly elevated (P < 0.05, P < 0.01). Core genes of the CXCR4-Gnαq-PLCß pathway, namely CXCR4, Gnαq, PLCß1, MMP1, and MMP3, also showed a significant increase in mRNA and protein expression levels (P < 0.05, P < 0.01). Proteins related to the CXCR4-Gnαq-PLCß pathway were mainly localized to the red and white pulp regions in the spleen as well as in stromal, endothelial, and subdifferentiated synovial cells in the joints. These results indicated that CXCR4 is dependent on Gnαq for inducing the expression of PLCß1 and stimulation of secretion of inflammatory cytokines by inflammatory cells. This consequently affects the expression of matrix metalloproteinases (MMPs), which serve as downstream effectors, thereby promoting RA pathogenesis. Our findings play an important role in elucidating the mechanisms of the onset and development of RA.

Study of high-pressure thermophysical properties of orthocarbonate Sr3CO5 using deep learning molecular dynamics simulations.

The exploration of the physical attributes of the recently discovered orthocarbonate Sr3CO5 is significant for comprehending the carbon cycle and storage mechanisms within the Earth's interior. In this study, first-principles calculations are initially used to examine the structural phase transitions of Sr3CO5 polymorphs within the range of lower mantle pressures. The results suggest that Sr3CO5 with the Cmcm phase exhibits a minimal enthalpy between 8.3 and 30.3 GPa. As the pressure exceeds 30.3 GPa, the Cmcm phase undergoes a transition to the I4/mcm phase, while the experimentally observed Pnma phase remains metastable under our studied pressure. Furthermore, the structural data of SrO, SrCO3, and Sr3CO5 polymorphs are utilized to develop a deep learning potential model suitable for the Sr-C-O system, and the pressure-volume relationship and elastic constants calculated using the potential model are in line with the available results. Subsequently, the elastic properties of Cmcm and I4/mcm phases in Sr3CO5 at high temperature and pressure are calculated using the molecular dynamics method. The results indicate that the I4/mcm phase exhibits higher temperature sensitivity in terms of elastic moduli and wave velocities compared to the Cmcm phase. Finally, the thermodynamic properties of the Cmcm and I4/mcm phases are predicted in the range of 0-2000 K and 10-120 GPa, revealing that the heat capacity and bulk thermal expansion coefficient of both phases increase with temperature, with the constant volume heat capacity gradually approaching the Dulong-Petit limit as the temperature rises.

A theoretical investigation on the structural stability, superconductivity, and optical and thermodynamic properties of Ir2P under pressure.

The potential applications of Ir2P are promising due to its desirable hardness, but its fundamental properties are still not fully understood. In this study, we present a systematic investigation of Ir2P's structural, electronic, superconducting, optical, and thermodynamic properties of Ir2P under pressure. Our calculations show that Ir2P has a Fm3̄m structure at ambient pressure, which matches well with experimental data obtained from high-pressure synchrotron X-ray diffraction. As pressure increases, a transition from the Fm3̄m to the I4/mmm phase occurs at 103.4 GPa. The electronic structure and electron-phonon coupling reveal that the Fm3̄m and I4/mmm phases of Ir2P are superconducting materials with superconducting transition temperatures of 2.51 and 0.89 K at 0 and 200 GPa, respectively. The optical properties of Ir2P indicate that it has optical conductivity in the infrared, visible, and ultraviolet regions. Additionally, we observed that the reflectivity R(ω) of Ir2P is higher than 76% in the 25-35 eV energy range at different pressures, which suggests that it could be used as a reflective coating. We also explored the finite-temperature thermodynamic properties of Ir2P, including the Debye temperature, the first and second pressure derivatives of the isothermal bulk modulus, and the thermal expansion coefficient up to 2000 K using the quasi-harmonic Debye model. Our findings offer valuable insights for engineers to design better devices.

GTPase-activating protein ARAP1 regulates circular dorsal ruffles as a nutrient uptake mechanism in the Hep3B hepatocellular carcinoma cell line.

Circular dorsal ruffles (CDRs), large-scale rounded membrane ruffles, function as precursors of macropinocytosis. We recently reported that CDRs are exposed in the Hep3B hepatocellular carcinoma cell line, while not in other hepatocellular carcinoma cell lines, indicating that the CDRs in Hep3B are associated with malignant potential. In this study, we investigated the cellular function of CDRs in Hep3B cells by focusing on the molecular mechanisms of the GTPase-activating protein ARAP1. ARAP1 was localized to the CDRs, the sizes of which were reduced by deletion of this protein. High-resolution scanning electron micrographs revealed that CDRs comprise small vertical lamellipodia, the expression pattern of which was disrupted in ARAP1 KO cells. Extracellular solute uptake, rate of cell growth, and malignant potential were attenuated in the KO cells. ARAP1 is also localized in Hep3B cell mitochondria, although not in those of the Huh7 hepatocellular carcinoma cell line. On the basis of these findings, we propose that the aberrant expression of ARAP1 in Hep3B cells modulates CDRs, thereby resulting in an excess uptake of nutrients as an initial event in cancer development. SUMMARY STATEMENT: ARAP1 regulates circular dorsal ruffles (CDRs) in the Hep3B HCC cell line and deletion of this protein attenuates malignant potential, thereby indicating the involvement of CDRs in cancer development.

Novel superhard semiconducting structures of C8B2N2 predicted using the first-principles approach.

Using first-principles calculations, we predicted three novel superhard semiconducting structures of C8B2N2 with a space group of P3m1. We investigated their mechanical properties and electronic structures up to 100 GPa. These three structures were successfully derived by substituting carbon (C) atoms with isoelectronic boron (B) and nitrogen (N) atoms in the P3m1 phase, which is the most stable structure of BCN and exhibits exceptional mechanical properties. Our results indicated that these structures had superior energy over previously reported t-C8B2N2, achieved by replacing C atoms in the diamond supercell with B and N atoms. To ensure their stable existence, we thoroughly examined their mechanical and dynamical stabilities, and we found that their hardness values reached 82.4, 83.1, and 82.0 GPa, which were considerably higher than that of t-C8B2N2 and even surpassing the hardness of c-BN. Calculations of the electron localization function revealed that the stronger carbon-carbon covalent bonds made them much harder than t-C8B2N2. Additionally, our further calculations of band structures revealed that these materials had indirect bandgaps of 4.164, 4.692, and 3.582 eV. These findings suggest that these materials have the potential to be used as superhard semiconductors, potentially surpassing conventional superhard materials.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Novel Selective Quantification of Zinpentraxin Alfa Biotherapeutic in the Presence of Endogenous Isomer in Plasma Samples of Idiopathic Pulmonary Fibrosis Patients Using Immunoaffinity LC-MS.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease that affects three million patients worldwide and currently without an effective cure. Zinpentraxin alfa, a recombinant human pentraxin-2 (rhPTX-2) protein, has been evaluated as a potential drug candidate for the treatment of IPF. Clinical pharmacokinetic analysis of zinpentraxin alfa has been challenging historically due to interference from serum amyloid P component (SAP), an endogenous human pentraxin-2 protein. These molecules share an identical primary amino acid sequence and glycan composition; however, zinpentraxin alfa possesses α2,3-linked terminal sialic acid residues while SAP is an α2,6-linked isomer. By taking advantage of this only structural difference, we developed a novel assay strategy where α2,3-sialidase was used to selectively hydrolyze α2,3-linked sialic acid residues, resulting in desialylated zinpentraxin alfa versus unchanged sialylated SAP, following an immunoaffinity capture step. Subsequent tryptic digestion produced a unique surrogate asialo-glycopeptide from zinpentraxin alfa and allowed specific quantification of the biotherapeutic in human plasma. In addition, a common peptide shared by both molecules was selected as a surrogate to determine total hPTX-2 concentrations, i.e., sum of zinpentraxin alfa and SAP. The quantification methods for both zinpentraxin alfa and total hPTX-2 were validated and used in pharmacokinetic assessment in IPF patients. The preliminary results suggest that endogenous SAP levels remained largely constant in IPF patients throughout the treatment with zinpentraxin alfa. Our novel approach provides a general bioanalytical strategy to selectively quantify α2,3-sialylated glycoproteins in the presence of their corresponding α2,6-linked isomers.

Development and validation of a nomogram for predicting pulmonary infections after Intracerebral hemorrhage in elderly people.

OBJECTIVES: The purpose of this study was to develop and validate a nomogram for the prediction of pulmonary infections in elderly patients with intracerebral hemorrhage (ICH) during hospitalization in the intensive care unit (ICU). METHODS: A total of 1183 elderly patients diagnosed with ICH were included from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and randomly grouped into training (n=831) and validation (n=352) cohorts. Candidate predictors were identified using the least absolute shrinkage and selection operator (LASSO) regression. Meanwhile, the variables derived from the LASSO regression were included in the multivariate logistic regression analysis, the variables with P < 0.05 were included in the final model and the nomogram was constructed. The discriminatory ability was assessed by plotting the receiver operating curve (ROC) and calculating the area under the curve (AUC). The Performance of the model was assessed by calibration plots and the Hosmer-Lemeshow goodness-of-fit test (HL test). In addition, clinical decision curves assess the net clinical benefit. RESULTS: The nomogram included chronic lung disease, dysphagia, mechanical ventilation, use of antibiotics, Glasgow Coma Scale (GCS), Logical Organ Dysfunction System (LODS), blood oxygen saturation (SpO2), white blood cell count (WBC) and prothrombin time (PT). The AUC of the predictive model was 0.905 (95 % CI: 0.877, 0.764) in the training cohort and 0.888 (95 % CI: 0.754, 0.838) in the validation cohort, which showed satisfactory discriminative ability. Second, the nomogram showed good calibration. Decision curve analysis showed that the predictive nomogram was clinically useful. CONCLUSION: A prediction model for predicting pulmonary infections in elderly ICH patients was constructed. The model can help clinicians to identify high-risk patients as soon as possible and prevent the occurrence of pulmonary infections.

Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. METHODS: From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. RESULTS: Compared with ctDNA-negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37-5.48; P = 0.003], while patients with positive post-ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08-72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival (RFS). Moreover, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index (0.78; 95% CI = 0.71-0.84) than the model without ctDNA (0.71; 95% CI = 0.64-0.79; P = 0.009). CONCLUSIONS: Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue-based and circulating tumor features could achieve better risk prediction.