Plasma proteomic characterization of colorectal cancer patients with FOLFOX chemotherapy by integrated proteomics technology.

BACKGROUND: Colorectal Cancer (CRC) is a prevalent form of cancer, and the effectiveness of the main postoperative chemotherapy treatment, FOLFOX, varies among patients. In this study, we aimed to identify potential biomarkers for predicting the prognosis of CRC patients treated with FOLFOX through plasma proteomic characterization. METHODS: Using a fully integrated sample preparation technology SISPROT-based proteomics workflow, we achieved deep proteome coverage and trained a machine learning model from a discovery cohort of 90 CRC patients to differentiate FOLFOX-sensitive and FOLFOX-resistant patients. The model was then validated by targeted proteomics on an independent test cohort of 26 patients. RESULTS: We achieved deep proteome coverage of 831 protein groups in total and 536 protein groups in average for non-depleted plasma from CRC patients by using a Orbitrap Exploris 240 with moderate sensitivity. Our results revealed distinct molecular changes in FOLFOX-sensitive and FOLFOX-resistant patients. We confidently identified known prognostic biomarkers for colorectal cancer, such as S100A4, LGALS1, and FABP5. The classifier based on the biomarker panel demonstrated a promised AUC value of 0.908 with 93% accuracy. Additionally, we established a protein panel to predict FOLFOX effectiveness, and several proteins within the panel were validated using targeted proteomic methods. CONCLUSIONS: Our study sheds light on the pathways affected in CRC patients treated with FOLFOX chemotherapy and identifies potential biomarkers that could be valuable for prognosis prediction. Our findings showed the potential of mass spectrometry-based proteomics and machine learning as an unbiased and systematic approach for discovering biomarkers in CRC.

A Study of Electroplated Nanoporous Copper Using Aberration-Corrected Transmission Electron Microscopy.

Nanoporous Cu foam is widely applied in many fields such as the packaging of electronic power devices. In this study, a sandwich-structured Cu-Zn eutectic alloy precursor composed of Cu0.53Zn0.47/Cu5Zn8/Cu0.53Zn0.47 is prepared through electroplating. The surface layer of the precursor, Cu0.53Zn0.47, has a flat surface with numerous grain boundaries, which effectively promotes its dealloying behavior. By contrast, Cu5Zn8 has a porous structure, which promotes the dealloying behavior at the center of the precursor. The dealloying of Cu0.53Zn0.47 is dominated by the coherent surface diffusion of Cu atoms, and the crystal lattice and orientation show no changes before and after dealloying. By contrast, the dealloying behavior of Cu5Zn8 requires the renucleation of Cu crystals; in this process, Cu atoms are transported to the surface of the layer by capillary forces to form clusters, which nucleate and grow.

Effect of CoSn3 nanocrystals on Sn3Ag plating for electronic packaging.

Plating Sn3Ag on copper substrates represents a crucial electronic packaging technique. In this study, we propose a novel composite plating approach, wherein CoSn3 nanocrystals are deposited within the Sn3Ag coating. The resulting reflowed Sn3Ag joints exhibit a range of distinctive properties. Notably, CoSn3 nanocrystals dissolve in Sn during the reflow process, thereby lowering the supercooling required for Sn nucleation. Consequently, Sn crystals grow in six-fold cyclic twins. Additionally, the dissolution of Co atoms in Sn leads to a reduced solubility of Cu atoms in Sn, consequently lowering the supercooling required for the nucleation of Cu6Sn5. Simultaneously, this phenomenon promotes the nucleation of Cu6Sn5, resulting in a considerable precipitation of Cu6Sn5 nanoparticles within the joints. Therefore, the mechanical properties of the joints are significantly enhanced, leading to a notable 20% increase in shear strength. Furthermore, the presence and distribution of Co elements within Sn induce changes in the growth pattern of interfacial Cu6Sn5. The growth process of Cu6Sn5 is dominated by the interfacial reaction, leading to its growth in a faceted shape. During the aging process, the dissolution of Co elements in Sn impedes the continuous growth of Cu6Sn5 at the interface, causing Cu6Sn5 to be distributed in the form of islands inside the joint. Remarkably, elemental Co acts as an inhibitor for the development of Cu3Sn and reduces the occurrence of Kirkendall voids.

Chemical Proteomic Approach for In-Depth Glycosylation Profiling of Plasma Carcinoembryonic Antigen in Cancer Patients.

Carcinoembryonic antigen (CEA) of human plasma is a biomarker of many cancer diseases, and its N-glycosylation accounts for 60% of molecular mass. It is highly desirable to characterize its glycoforms for providing additional dimension of features to increase its performance in prognosis and diagnosis of cancers. However, to systematically characterize its site-specific glycosylation is challenging because of its low abundance. Here, we developed a highly sensitive strategy for in-depth glycosylation profiling of plasma CEA through chemical proteomics combined with multienzymatic digestion. A trifunctional probe was utilized to generate covalent bond of plasma CEA and its antibody upon UV irradiation. As low as 1 ng/ml CEA in plasma could be captured and digested with trypsin and chymotrypsin for intact glycopeptide characterization. Twenty six of 28 potential N-glycosylation sites were well identified, which were the most comprehensive N-glycosylation site characterization of CEA on intact glycopeptide level as far as we known. Importantly, this strategy was applied to the glycosylation analysis of plasma CEA in cancer patients. Differential site-specific glycoforms of plasma CEA were observed in patients with colorectal cancers (CRCs) and lung cancer. The distributions of site-specific glycoforms were different as the progression of CRC, and most site-specific glycoforms were overexpressed in stage II of CRC. Overall, we established a highly sensitive chemical proteomic method to profile site-specific glycosylation of plasma CEA, which should generally applicable to other well-established cancer glycoprotein biomarkers for improving their cancer diagnosis and monitoring performance.

Synthesis and Atomic Transport of CoSn3 NanoIMC by In Situ TEM.

In order to optimize the interfacial properties by adding Co to the bumps of copper pillars and to overcome the strong tendency of Co to oxidize, an intermetallic compound (IMC) "capsule" was developed for the purpose of transporting elements through the intermetallic compound. In this study, we present a comprehensive analysis of the transformation process of CoSn2 nanoparticles into CoSn3 at the nanoscale using in situ heating transmission electron microscopy (TEM). The experimental results reveal that CoSn2 nanoparticle growth occurs through polymerization, whereas CoSn3 nanoparticle formation relies on the reaction between CoSn2 and Sn. During the initial stages of the reaction, Co dissolves and diffuses into Sn, leading to the nucleation and growth of CoSn2 in Sn via Ostwald ripening. As the input energy increases, vacancies in CoSn2 drive a reaction at the Sn/CoSn2 interface, resulting in the generation of CoSn3. In this process, Sn nanoparticles enter the CoSn2 structure through the "Anti Structure Bridge (ASB) mechanism" to fill vacancies. Following the codeposition process, CoSn3 nanoparticles were successfully plated within the Sn layer of the Cu-pillar bumps. Upon reflow heating, the CoSn3 nanoparticles exhibited a preference for precipitating the vacant sites within the Sn layer. This process facilitated the release of Co atoms from CoSn2, enabling their diffusion throughout the entire Sn layer.

Malignant mediastinal mesothelioma treated with anlotinib: a case report and review of the literature.

Malignant mesothelioma that originates from mediastinal (MMM) is a rare form of malignant pleural mesothelioma (MPM). The prognosis of advanced stage MPM was poor, and the traditional treatment was chemotherapy. Here, we present a patient with MMM that was treated with anlotinib, a multitargeted tyrosine kinase inhibitor (TKI) who had a 24-month progression-free survival (PFS). Further review of the literature showed that, despite some explorations of applying small-molecule multitargeted TKIs in the treatment of MPM, until today, no large series had a positive result. Anlotinib had been approved by the China Food and Drug Administration on treating non-small cell lung cancer, soft tissue sarcoma, renal cell carcinoma, and medullary thyroid cancer. We assumed that the ability of anlotinib to target more tyrosine kinase receptors than most of other TKIs could contribute to the long duration of PFS in this case, but further study is needed to further validate the efficacy of anlotinib in treatment of MPM.

Combination of automated sample preparation and micro-flow LC-MS for high-throughput plasma proteomics.

BACKGROUND: Non-invasive detection of blood-based markers is a critical clinical need. Plasma has become the main sample type for clinical proteomics research because it is easy to obtain and contains measurable protein biomarkers that can reveal disease-related physiological and pathological changes. Many efforts have been made to improve the depth of its identification, while there is an increasing need to improve the throughput and reproducibility of plasma proteomics analysis in order to adapt to the clinical large-scale sample analysis. METHODS: We have developed and optimized a robust plasma analysis workflow that combines an automated sample preparation platform with a micro-flow LC-MS-based detection method. The stability and reproducibility of the workflow were systematically evaluated and the workflow was applied to a proof-of-concept plasma proteome study of 30 colon cancer patients from three age groups. RESULTS: This workflow can analyze dozens of samples simultaneously with high reproducibility. Without protein depletion and prefractionation, more than 300 protein groups can be identified in a single analysis with micro-flow LC-MS system on a Orbitrap Exploris 240 mass spectrometer, including quantification of 35 FDA approved disease markers. The quantitative precision of the entire workflow was acceptable with median CV of 9%. The preliminary proteomic analysis of colon cancer plasma from different age groups could be well separated with identification of potential colon cancer-related biomarkers. CONCLUSIONS: This workflow is suitable for the analysis of large-scale clinical plasma samples with its simple and time-saving operation, and the results demonstrate the feasibility of discovering significantly changed plasma proteins and distinguishing different patient groups.

CoSn3 Intermetallic Nanoparticles for Electronic Packaging.

At present, composite solder pastes are getting a lot of attention, especially composite Sn based solders reinforced by nanoparticles. Indeed, CoSn3 is a strong nucleating agent of Sn crystal, which has potential application value in the field of electronic packaging. However, there is no reliable synthetic path for CoSn3 nanoparticles at present. In this article, a chemical synthesis method for CoSn3 nanoparticles is developed. Here, CoCl2 and SnCl2 are reduced by NaHB4 in triethylene glycol (TEG), dispersed by ultrasonics, and heated to 350 °C in a tube furnace for growth. The CoSn3 nanoparticles with a diameter of about 150 nm are obtained by heating at 350 °C for 10 min. The CoSn3 nanoparticles undergo a step reaction in the process of synthesis and go through different stages of merging and annexation during their growth. The crystal growth behavior and the process of orientation change during the nucleation and growth of CoSn3 nanoparticles are studied, especially the two growth mechanisms, namely OU (orientation unified) and OA (orientation attached). By mixing CoSn3 nanoparticles with SAC305, we obtain a kind of strengthened composite soldering paste. There are obvious six-fold cyclic twins in the joints made by this soldering paste.

Robust Capillary- and Micro-Flow Liquid Chromatography-Tandem Mass Spectrometry Methods for High-Throughput Proteome Profiling.

Capillary- and micro-flow liquid chromatography-tandem mass spectrometry (capLC-MS/MS and µLC-MS/MS) is becoming a valuable alternative to nano-flow LC-MS/MS due to its high robustness and throughput. The systematic comparison of capLC-MS/MS and µLC-MS/MS systems for global proteome profiling has not been reported yet. Here, the capLC-MS/MS (150 µm i.d. column, 1 µL/min) and µLC-MS/MS (1 mm i.d. column, 50 µL/min) systems were both established based on UltiMate 3000 RSLCnano coupled to an Orbitrap Exploris 240 by integrating with different flowmeters. We evaluated both systems in terms of sensitivity, analysis throughput, separation efficiency, and robustness. capLC-MS/MS was about 10 times more sensitive than µLC-MS/MS at different gradient lengths. Compared with capLC-MS/MS, µLC-MS/MS was able to achieve higher analysis throughput and separation efficiency. During the 7 days' long-term performance test, both systems showed good reproducibility of chromatographic full width (RSD < 3%), retention time (RSD < 0.4%), and protein identification (RSD < 3%). These results demonstrate that capLC-MS/MS is more suitable for high-throughput analysis of clinical samples with a limited starting material. When enough samples are available, µLC-MS/MS is preferred. Together, capLC and µLC coupled to Orbitrap Exploris 240 with moderate sensitivity should well meet the needs of large-cohort clinical proteomic analysis.

A Multilayer Paste Based on Ag Nanoparticles with Cu@Sn for Die Attachment in Power Device Packaging.

A 3-5 µm Cu@Sn core-shell powder was prepared by chemical plating. Based on the mixture of this Cu@Sn and Ag NPs (nanoparticles), a soldering material for third-generation semiconductors was prepared. The joints prepared with this soldering material had a shear strength of over 40 MPa at 25 °C. This joint did not fail after more than 600 thermal cycles from -40 °C to 140 °C. The special feature of this joint is that the energy potential difference between nanoparticles and micron particles generated in the surface force field during reflow promoted the surface pre-melting of the particles by releasing the excess energy. By this mechanism, it was possible to reduce the porosity of the sintered layer. At the same time, due to the high surface activity energy of nano-silver, the diffusion of the Sn atoms was promoted, further enhancing the bond strength.

Long term leaching behavior of arsenic from cemented paste backfill made of construction and demolition waste: Experimental and numerical simulation studies.

The arsenic long-term leaching behavior of the cemented paste backfill obtained from the construction and demolition waste (CPB-CDW) is captured, which can be utilized in the potential engineering application. Laboratory studies were conducted on samples obtained from a mining site and the test results were imported into a numerical simulation model. It was found that the Elovich equation can describe well the As leaching behavior. Initially, the As concentrations decreased in the roadway in the mine and then increased along the roadway and attained a maximum concentration (8.149 × 10-3 mg/L) at the lower segment. When the groundwater was in the static mode, the As concentration increased dramatically followed by a gradual increase. Eventually, the concentration decreased gradually. For the dynamic condition, the As tended to move in a cluster form and the associated leaching and mass transfer process of As in the CPB-CDW were similar to those observed when the groundwater was in a static condition. However, the difference in the distribution of the amount of As in the leachate fluctuated continuously and the overall trend was to approach a steady state. As such, the time frame of such a mass transfer in the mobilized water is reduced significantly.