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Recombinant monoclonal antibodies (mAbs) intended for therapeutic usage are required to be thoroughly characterized, which has promoted an extensive effort towards the understanding of the structures and heterogeneity of this major class of molecules. Batch consistency and comparability are highly relevant to the successful pharmaceutical development of mAbs and related products. Small structural modifications that contribute to molecule variants (or proteoforms) differing in size, charge or hydrophobicity have been identified. These modifications may impact (or not) the stability, pharmacokinetics, and efficacy of mAbs. The presence of the same type of modifications as found in endogenous immunoglobulin G (IgG) can substantially lower the safety risks of mAbs. The knowledge of modifications is also critical to the ranking of critical quality attributes (CQAs) of the drug and define the Quality Target Product Profile (QTPP). This review provides a summary of the current understanding of post-translational and physico-chemical modifications identified in recombinant mAbs and endogenous IgGs at physiological conditions.

In this paper we consider the minimization of a continuous function that is potentially not differentiable or not twice differentiable on the boundary of the feasible region. By exploiting an interior point technique, we present first- and second-order optimality conditions for this problem that reduces to classical ones when the derivative on the boundary is available. For this type of problems, existing necessary conditions often rely on the notion of subdifferential or become non-trivially weaker than the KKT condition in the (twice-)differentiable counterpart problems. In contrast, this paper presents a new set of first- and second-order necessary conditions that are derived without the use of subdifferential and reduce to exactly the KKT condition when (twice-)differentiability holds. As a result, these conditions are stronger than some existing ones considered for the discussed minimization problem when only non-negativity constraints are present. To solve for these optimality conditions in the special but important case of linearly constrained problems, we present two novel interior point trust-region algorithms and show that their worst-case computational efficiency in achieving the potentially stronger optimality conditions match the best known complexity bounds. Since this work considers a more general problem than those in the literature, our results also indicate that best known existing complexity bounds are actually held for a wider class of nonlinear programming problems. This new development is significant since optimality conditions play a fundamental role in computational optimization and more and more nonlinear and nonconvex problems need to be solved in practice.

Immunocyte infiltration and cytotoxicity play critical roles in both inflammation and immunotherapy. However, current cancer immunotherapy screening methods overlook the capacity of the T cells to penetrate the tumor stroma, thereby significantly limiting the development of effective treatments for solid tumors. Here, we present an automated high-throughput microfluidic platform for simultaneous tracking of the dynamics of T cell infiltration and cytotoxicity within the 3D tumor cultures with a tunable stromal makeup. By recourse to a clinical tumor-infiltrating lymphocyte (TIL) score analyzer, which is based on a clinical data-driven deep learning method, our platform can evaluate the efficacy of each treatment based on the scoring of T cell infiltration patterns. By screening a drug library using this technology, we identified an epigenetic drug (lysine-specific histone demethylase 1 inhibitor, LSD1i) that effectively promoted T cell tumor infiltration and enhanced treatment efficacy in combination with an immune checkpoint inhibitor (anti-PD1) in vivo. We demonstrated an automated system and strategy for screening immunocyte-solid tumor interactions, enabling the discovery of immuno- and combination therapies.

As a momentous post-transcriptional regulator, microRNAs (miRNAs) are attracting more and more attention. The classical miRNAs regulated mechanism shows it binds to the targets’ 3′UTR thus play the role in post-transcription. Meanwhile, single miRNA can target multiple genes, so those should compete to bind that miRNA. Vice versa, single gene can sponge mass of miRNAs as well. Thus the competitive endogenous RNAs (ceRNAs) hypothesis was put forward in 2011. The ceRNA hypothesis has made huge achievements, in particular in non-coding genes, which including long non-coding RNAs (lncRNAs), circle RNAs (circRNAs) and pseudogenes, even viral transcripts. It also contributed greatly to epigenetics development. However, an increasing number of controversies have occurred with applause. Based on this situation, this review introduces something in detail about the ceRNAs hypothesis achieved in lncRNAs, circRNAs, pseudogenes and viral transcripts, respectively. Meanwhile, it also covers controversy of the ceRNAs hypothesis.

Background Bloodstream infection of Klebsiella pneumoniae (BSI-KP) were associated with increased mortality. Klebsiella pneumoniae was tested to susceptible to colistin by E-test and broth microdilution method in clinical laboratory. This study aimed to assess the efficacy of colistin versus tigecycline, carbapenem monotherapy and combination in the treatment of BSI-KP. Methods Electronic databases such as PubMed, Web of Science and Embase were searched. The last search was in November 24th, 2022, addressing the colistin, carbapenems and tigecycline monotherapy and combination treatments in patients with BSI-KP. The primary outcomes were 30-day or 28-day mortality. OR where available with 95% CI were pooled in random-effects meta-analysis. Results Following the outlined search strategy, a total of 658 articles were identified from the initial database searching. Six studies, 17 comparisons were included. However, they all were observational design, lacking high-quality randomized controlled trials (RCTs). Moderate or low-quality evidences suggested that colistin monotherapy was associated with an OR = 1.35 (95% CI = 0.62–2.97, P  = 0.45, Tau 2  = 0.00, I 2  = 0%) compared with tigecycline monotherapy, OR = 0.81 (95% CI = 0.27–2.45, P  = 0.71, Tau 2  = 0.00, I 2  = 0%) compared with carbapenem monotherapy. Compared with combination with tigecycline or carbapenem, Colistin monotherapy resulted in OR of 3.07 (95% CI = 1.34–7.04, P  = 0.008, Tau 2  = 0.00, I 2  = 0%) and 0.98 (95%CI = 0.29–3.31, P  = 0.98, Tau 2  = 0.00, I 2  = 0% ), respectively. Conclusions Colistin, carbapenem and tigecycline monotherapy showed similar treatment effects in patients who suffered from BSI-KP. Compared with colistin monotherapy, colistin combined tigecycline therapy might play the synergism effects. Trial registration retrospectively registered.

Background Pulmonary arterial hypertension (PH) secondary to pulmonary fibrosis (PF) is one of the most common complications in PF patients, it causes severe disease and usually have a poor prognosis. Whether the combination of PH and PF is a unique disease phenotype is unclear. We aimed to screen the key modules associated with PH–PF immune infiltration based on WGCNA and identify the hub genes for molecular typing. Method Using the gene expression profile GSE24988 of PF patients with or without PH from the Gene Expression Omnibus (GEO) database, we evaluated immune cell infiltration using Cibersortx and immune cell gene signature files. Different immune cell types were screened using the Wilcoxon test; differentially expressed genes were screened using samr . The molecular pathways implicated in these differential responses were identified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses. A weighted co-expression network of the differential genes was constructed, relevant co-expression modules were identified, and relationships between modules and differential immune cell infiltration were calculated. The modules most relevant to this disease were identified using weighted correlation network analysis. From these, we constructed a co-expression network; using the STRING database, we integrated the values into the human protein–protein interaction network before constructing a co-expression interaction subnet, screening genes associated with immunity and unsupervised molecular typing, and analyzing the immune cell infiltration and expression of key genes in each disease type. Results Of the 22 immune cell types from the PF GEO data, 20 different immune cell types were identified. There were 1622 differentially expressed genes (295 upregulated and 1327 downregulated). The resulting weighted co-expression network identified six co-expression modules. These were screened to identify the modules most relevant to the disease phenotype (the green module). By calculating the correlations between modules and the differentially infiltrated immune cells, extracting the green module co-expression network (46 genes), extracting 25 key genes using gene significance and module-membership thresholds, and combining these with the 10 key genes in the human protein–protein interaction network, we identified five immune cell-related marker genes that might be applied as biomarkers. Using these marker genes, we evaluated these disease samples using unsupervised clustering molecular typing. Conclusion Our results demonstrated that all PF combined with PH samples belonged to four categories. Studies on the five key genes are required to validate their diagnostic and prognostic value.

A method was developed to identify and trace the geographic sources of Erigeron breviscapus using high-resolution mass spectrometry and chemometrics. The representative samples were collected from the geographic area of Honghe Dengzhanhua and other areas in Yunnan province and Guizhou province. The data points could be determined well using the PCA and PLS-DA diagram. A total of 46 characteristic compounds were identified from Honghe Dengzhanhua and within Guizhou province, but 37 compounds were different from Honghe Dengzhanhua and other counties in Yunnan province. Two biomarkers were found from three regions. Their structures were inferred as 8-amino-7-oxononanoic acid and 8-hydroxyquinoline, and they had the same molecular composition. This may suggest that a possible synthesis pathway can be proven in the future.

With the wide application of hydrogen-doped natural gas (HBNG) in end users, laying pipelines in urban, comprehensive pipe corridors has become increasingly common. However, the leakage and diffusion of hydrogen-doped natural gas in confined or semi-confined spaces (e.g., utility corridors) can pose a severe safety hazard, as methane and hydrogen gas mixtures have a higher risk of explosion. Therefore, studying hydrogen-doped natural gas’s leakage and diffusion behavior in the comprehensive pipe gallery is essential to ensure its safe operation. This paper establishes a numerical model to study the diffusion law of hydrogen-doped natural gas leakage, and the concentration distribution under different conditions is analyzed. The evolution of the leakage and diffusion of hydrogen-doped natural gas under different hydrogen doping ratios, wind speeds, inlet and outlet spacing, and leakage port sizes were simulated, and the effects of these factors on gas diffusion and explosion hazard volume were discussed. In addition, the backpropagation neural network (BPNN) combined with the global optimization capability of genetic algorithm and the nonlinear mapping capability of neural network is used in this paper to provide a reliable technical means for the accurate prediction of explosion risk volume, which has important application value in the safety design of pipeline corridor and accident prevention and control. The results show that the diffusion range of gas in the pipe corridor increases significantly with the increase of hydrogen mixing ratio. When the hydrogen mixing ratio decreases from 20% to 0, the explosion volume of CH 4 decreases by 12.25%. The explosion volume of H 2 is close to 0. At the same time, the greater the distance between inlet and outlet, the wider the spread of the dangerous area, when the distance between inlet and outlet is reduced from 200 m to 100 m, the explosion volume of CH 4 is reduced by 99.92%, and the explosion volume of H 2 is reduced by 100%. In the case of emergency, the reasonable design of Distance between inlet and outlet and air flow configuration can help to quickly discharge harmful gases, ensure the safe evacuation and equipment maintenance in the pipe corridor, and have guiding significance for the ventilation design of the pipe corridor.

The detection of partial discharge and analysis of the composition and content of sulfur hexafluoride SF6 gas components are important to evaluate the operating state and insulation level of gas-insulated switchgear (GIS) equipment. This paper reported a novel sensing material made of pure ZnO and NiO-decorated ZnO nanoflowers which were synthesized by a facile and environment friendly hydrothermal process for the detection of SF6 decomposition byproducts. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) were used to characterize the structural and morphological properties of the prepared gas-sensitive materials. Planar-type chemical gas sensors were fabricated and their gas sensing performances toward the SF6 decomposition byproducts SO2, SO2F2, and SOF2 were systemically investigated. Interestingly, the sensing behaviors of the fabricated ZnO nanoflowers-based sensor to SO2, SO2F2, and SOF2 gases can be obviously enhanced in terms of lower optimal operating temperature, higher gas response and shorter response-recovery time by introducing NiO. Finally, a possible gas sensing mechanism for the formation of the p–n junctions between NiO and ZnO is proposed to explain the enhanced gas response. All results demonstrate a promising approach to fabricate high-performance gas sensors to detect SF6 decomposition byproducts.

Background This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II–III non-small-cell lung cancer (NSCLC). Methods Patient eligibility mainly involved treatment-naive, clinical stage II–III and wild-type EGFR/ALK NSCLC. The patients received 2–4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. Results In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS ( P =0.017) and PFS ( P =0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). Conclusions Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II–III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. Trial registration ChiCTR1900024014, June 22, 2019.