Longitudinal plasma proteomic profiling of EML4-ALK positive lung cancer receiving ALK-TKIs therapy.

BACKGROUND: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) has demonstrated remarkable therapeutic effects in ALK-positive non-small cell lung cancer (NSCLC) patients. Identifying prognostic biomarkers can enhance the clinical efficacy of relapsed or refractory patients. METHODS: We profiled 737 plasma proteins from 159 pre-treatment and on-treatment plasma samples of 63 ALK-positive NSCLC patients using data-independent acquisition-mass spectrometry (DIA-MS). The consensus clustering algorithm was used to identify subtypes with distinct biological features. A plasma-based prognostic model was constructed using the LASSO-Cox method. We performed the Mfuzz analysis to classify the patterns of longitudinal changes in plasma proteins during treatment. 52 baseline plasma samples from another independent ALK-TKI treatment cohort were collected to validate the potential prognostic markers using ELISA. RESULTS: We identified three subtypes of ALK-positive NSCLC with distinct biological features and clinical efficacy. Patients in subgroup 1 exhibited activated humoral immunity and inflammatory responses, increased expression of positive acute-phase response proteins, and the worst prognosis. Then we constructed and verified a prognostic model that predicts the efficacy of ALK-TKI therapy using the expression levels of five plasma proteins (SERPINA4, ATRN, APOA4, TF, and MYOC) at baseline. Next, we explored the longitudinal changes in plasma protein expression during treatment and identified four distinct change patterns (Clusters 1-4). The longitudinal changes of acute-phase proteins during treatment can reflect the treatment status and tumor progression of patients. Finally, we validated the prognostic efficacy of baseline plasma CRP, SAA1, AHSG, SERPINA4, and TF in another independent NSCLC cohort undergoing ALK-TKI treatment. CONCLUSIONS: This study contributes to the search for prognostic and drug-resistance biomarkers in plasma samples for ALK-TKI therapy and provides new insights into the mechanism of drug resistance and the selection of follow-up treatment.

Immunogenicity assessment of elder hepatocellular carcinoma patients after inactivated whole-virion SARS-CoV-2 vaccination.

BACKGROUND: Research on immunogenicity after 3rd SARS-CoV-2 vaccine in elder hepatocellular carcinoma (HCC) was limited. This study aimed to investigate the efficacy and influencing factors of inactivated SARS-CoV-2 vaccine in elder HCC. RESEARCH DESIGN AND METHODS: We assessed total antibodies, anti-RBD IgG, and neutralizing antibodies (NAb) toward SARS-CoV-2 wild type (WT) as well as BA.4/5 in 304 uninfected HCC, 147 matched healthy control (HC), and 53 SARS-CoV-2 infected HCC, all aged over 60 years. The levels of antibodies were compared in the period 7-90, 91-180, and >180 days after 2nd or 3rd vaccination, respectively. RESULTS: HCC had lower seropositivity than HC after 2nd dose (total antibodies, 64% vs. 92%, P < 0.0001; anti-RBD IgG, 50% vs. 77%, P < 0.0001). But 3rd dose can efficaciously close the gap (total antibodies, 96% vs. 100%, P = 0.1212; anti-RBD IgG: 87% vs. 87%, P > 0.9999). Booster effect of 3rd dose can persist >180 days in HCC (2nd vs. 3rd: total antibodies, 0.60 vs. 3.20, P < 0.0001; anti-RBD IgG, 13.86 vs. 68.85, P < 0.0001; WT NAb, 11.70 vs. 22.47, P < 0.0001). Vaccinated HCC had more evident humoral responses than unvaccinated ones after infection (total antibodies: 3.85 vs. 3.20, P < 0.0001; anti-RBD IgG: 910.92 vs. 68.85, P < 0.0001; WT NAb: 96.09 vs. 22.47, P < 0.0001; BA.4/5 NAb: 86.53 vs. 5.59, P < 0.0001). CONCLUSIONS: Our findings highlight the booster effect and protective role of 3rd dose. Our results could provide a theoretical foundation for informing decisions regarding SARS-CoV-2 vaccination in elder HCC.

Regio- and enantioselective CuH-catalyzed 1,2- and 1,4-hydrosilylation of 1,3-enynes.

We report a copper-catalyzed ligand-controlled selective 1,2- and 1,4-hydrosilylation of 1,3-enynes, which furnishes enantiomerically enriched propargyl- and 1,2-allenylsilane products in high yields with excellent enantioselectivities (up to 99% ee). This reaction proceeds under mild conditions, shows broad substrate scope for both 1,3-enynes and trihydrosilanes, and displays excellent regioselectivities. Mechanistic studies based on deuterium-labeling reactions and density functional theory (DFT) calculations suggest that allenylcopper is the dominant reactive intermediate under both 1,2- and 1,4-hydrosilylation conditions, and it undergoes metathesis with silanes via selective four-membered or six-membered transition state, depending on the nature of the ligand. The weak interactions between the ligands and the reacting partners are found to be the key controlling factor for the observed regioselectivity switch. The origin of high enantiocontrol in the 1,4-hydrosilylation is also revealed by high level DLPNO-CCSD(T) calculations.

Copper-Catalyzed Enantioselective Desymmetric Protosilylation of Prochiral Diynes: Access to Optically Functionalized Tertiary Alcohols.

In this protocol, a copper-catalyzed desymmetric protosilylation of prochiral diynes was developed. The corresponding products were obtained in moderate to high yields and enantiomeric ratios. This approach provides a simple method for synthesizing functionalized chiral tertiary alcohols in the presence of a chiral pyridine-bisimidazoline (Pybim) ligand.

Antibody response to SARS-CoV-2 WT and Omicron BA.4/5 of inactivated COVID-19 vaccine in patients with lung cancer after second and booster immunization.

COVID-19 inactivated vaccine-induced humoral responses in patients with lung cancer (LCs) to SARS-CoV-2 wild-type (WT) strain and variants BA.4/5 after the primary 2-dose and booster vaccination remained unknown. We conducted a cross-sectional study in 260 LCs, 140 healthy controls (HC) and additional 40 LCs with serial samples by detecting total antibodies, IgG anti-RBD and neutralizing antibodies (NAb) toward WT and BA.4/5. SARS-CoV-2-specific antibody responses were augmented by the booster dose of inactivated vaccines in LCs, whereas they were lower than that in HCs. Enhanced humoral responses waned over time after triple injection, notably in NAb against WT and BA.4/5. The NAb against BA.4/5 was much lower than WT. Age ≥ 65 was risk factor for immunization of NAb to WT. Undergoing treatment resulted in a lower antibody response than those without and radiotherapy was a also risk factor for seroconversion of NAb to WT. Lower lymphocyte counts contributed to a lower titer of IgG anti-RBD and NAb against BA.4/5 in LCs than HCs. Specifically, total B cells, CD4+T cells and CD8+T counts were correlated with the humoral response. These results should be taken into consideration for the elderly patients under treatment.

Integrative analyses of bulk and single-cell RNA-seq identified cancer-associated fibroblasts-related signature as a prognostic factor for immunotherapy in NSCLC.

An emerging view regarding cancer-associated fibroblast (CAF) is that it plays a critical role in tumorigenesis and immunosuppression in the tumor microenvironment (TME), but the clinical significance and biological functions of CAFs in non-small cell lung cancer (NSCLC) are still poorly explored. Here, we aimed to identify the CAF-related signature for NSCLC through integrative analyses of bulk and single-cell genomics, transcriptomics, and proteomics profiling. Using CAF marker genes identified in weighted gene co-expression network analysis (WGCNA), we constructed and validated a CAF-based risk model that stratifies patients into two prognostic groups from four independent NSCLC cohorts. The high-score group exhibits a higher abundance of CAFs, decreased immune cell infiltration, increased epithelial-mesenchymal transition (EMT), activated transforming growth factor beta (TGFß) signaling, and a limited survival rate compared with the low-score group. Considering the immunosuppressive feature in the high-score group, we speculated an inferior clinical response for immunotherapy in these patients, and this association was successfully verified in two NSCLC cohorts treated with immune checkpoint blockades (ICBs). Furthermore, single-cell RNA sequence datasets were used to clarify the molecular mechanisms underlying the aggressive and immunosuppressive phenotype in the high-score group. We found that one of the genes in the risk model, filamin binding LIM protein 1 (FBLIM1), is mainly expressed in fibroblasts and upregulated in CAFs compared to fibroblasts from normal tissue. FBLIM1-positive CAF subtype was correlated with increased TGFß expression, higher mesenchymal marker level, and immunosuppressive tumor microenvironment. Finally, we demonstrated that FBLIM1 might serve as a poor prognostic marker for immunotherapy in clinical samples. In conclusion, we identified a novel CAF-based classifier with prognostic value in NSCLC patients and those treated with ICBs. Single-cell transcriptome profiling uncovered FBLIM1-positive CAFs as an aggressive subtype with a high abundance of TGFß, EMT, and an immunosuppressive phenotype in NSCLC.

Privacy by Projection: Federated Population Density Estimation by Projecting on Random Features.

We consider the problem of population density estimation based on location data crowdsourced from mobile devices, using kernel density estimation (KDE). In a conventional, centralized setting, KDE requires mobile users to upload their location data to a server, thus raising privacy concerns. Here, we propose a Federated KDE framework for estimating the user population density, which not only keeps location data on the devices but also provides probabilistic privacy guarantees against a malicious server that tries to infer users' location. Our approach Federated random Fourier feature (RFF) KDE leverages a random feature representation of the KDE solution, in which each user's information is irreversibly projected onto a small number of spatially delocalized basis functions, making precise localization impossible while still allowing population density estimation. We evaluate our method on both synthetic and real-world datasets, and we show that it achieves a better utility (estimation performance)-vs-privacy (distance between inferred and true locations) tradeoff, compared to state-of-the-art baselines (e.g., GeoInd). We also vary the number of basis functions per user, to further improve the privacy-utility trade-off, and we provide analytical bounds on localization as a function of areal unit size and kernel bandwidth.

Chelation-Controlled Stereospecific Cross-Coupling Reaction between Alkenes for Atroposelective Synthesis of Axially Chiral Conjugated Dienes.

In this protocol, an efficient palladium-catalyzed asymmetric synthesis of axially chiral conjugated dienes via alkenyl C-H olefination is reported. The corresponding atropisomeric styrenes containing a conjugated diene scaffold were obtained in good yields with good enantioselectivities. This synthetic strategy features an easy operation, mild reaction conditions, a wide functionality tolerance, and high efficiency.

One-pot synthesis of spherical nanoscale zero-valent iron/biochar composites for efficient removal of Pb(ii).

In this study, a spherical Fe/C composite (AIBC) was successfully prepared via carbonization of Fe3+-crosslinked sodium alginate. The removal capacity and mechanism of AIBC were evaluated for the adsorption of Pb(ii) from aqueous solution and compared with that of commercial nanoscale zero-valent iron (nZVI). The effects of the initial concentration, pH of Pb(ii) solution, the contact time, coexisting anions, and aging under air were investigated. The results showed that the pH had a strong impact on the adsorption of Pb(ii) by AIBC. The adsorption data for AIBC followed the Langmuir model, while the maximum adsorption capacity at pH 5 was 1881.73 mg g-1. The AIBC had a higher adsorption capability than nZVI, especially under the condition of relatively high Pb(ii) concentrations. The oxidation-reduction reaction between Fe and Pb(ii) was the main mechanism for the adsorption of Pb(ii) onto nZVI. AIBC converted the largest amount of Pb(ii) into PbO·XH2O/Pb(OH)2 mainly by generating Fe2+.

Method of shoulder delivery and neonatal outcomes: A meta-analysis of prospective controlled studies.

Background: We compared the neonatal outcomes between 2 methods of shoulder delivery: 2-step and 1-step. Methods: We did a comprehensive search of 7 electronic databases up to 31 October 2016. Two of the authors independently identified relevant studies for inclusion in the review, assessed their quality and extracted data. The primary outcome was the rate of neonatal asphyxia; secondary outcomes were neonatal brachial plexus injury and clavicular fracture of newborns. Review Manager 5.3 was used for the metaanalysis. The pooled relative risk (RR) was estimated by the fixed or random effect model, based on heterogeneity. Seven cohort studies were included in the meta-analysis. Results: A total of 14 627 women had successful vaginal delivery; 7212 women had 2-step and 7415 women had 1-step delivery. The rate of neonatal asphyxia (RR 0.55; 95% confidence interval [CI] 0.35-0.86; p = 0.008) and occurrence of neonatal clavicular fracture (RR 0.19; 95% CI 0.07-0.51; p = 0.001 ) were lower in the 2-step group than in the 1-step group. The neonatal brachial plexus injury rate was not statistically significant between the 2 groups (RR 0.2; 95% CI 0.04-1.10; p = 0.06). Conclusions: Current evidence supports the use of 2-step method of shoulder delivery with no major adverse neonatal outcomes, lower incidence of neonatal asphyxia rate, and neonatal clavicular fracture rate than delivery by the 1-step method. The clinical value is high for the adoption of 2-step method for better neonatal outcomes.

Modulation of Staphylococcus aureus spreading by water.

Staphylococcus aureus is known to spread rapidly and form giant colonies on the surface of soft agar and animal tissues by a process called colony spreading. So far, the mechanisms underlying spreading remain poorly understood. This study investigated the spreading phenomenon by culturing S. aureus and its mutant derivatives on Tryptic Soy Agarose (TSA) medium. We found that S. aureus extracts water from the medium and floats on water at 2.5 h after inoculation, which could be observed using phase contrast microscopy. The floating of the bacteria on water could be verified by confocal microscopy using an S. aureus strain that constitutively expresses green fluorescence protein. This study also found that as the density of bacterial colony increases, a quorum sensing response is triggered, resulting in the synthesis of the biosurfactants, phenolic-soluble modulins (PSMs), which weakens water surface tension, causing water to flood the medium surface to allow the bacteria to spread rapidly. This study reveals a mechanism that explains how an organism lacking a flagellar motor is capable of spreading rapidly on a medium surface, which is important to the understanding of how S. aureus spreads in human tissues to cause infections.