LI-RADS Morphological Type Predicts Prognosis of Patients with Hepatocellular Carcinoma After Radical Resection.

PURPOSE: This study aimed to explore the association of preoperative magnetic resonance imaging (MRI) tumor morphological classification with early recurrence (ER) and overall survival (OS) after radical surgery of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A retrospective analysis of 296 patients with HCC who underwent radical resection was performed. On the basis of LI-RADS, tumor imaging morphology was classified into three types. The clinical imaging features, ER, and survival rates of three types were compared. Univariate and multivariate Cox regression analyses were conducted to identify prognostic factors associated with OS and ER after hepatectomy for HCC. RESULTS: There were 167 tumors of type 1, 95 of type 2, and 34 of type 3. In patients with type 3 HCC, postoperative mortality and ER were significantly higher than in patients with type 1 and type 2 (55.9% versus 32.6% versus 27.5% and 52.9% versus 33.7% versus 28.7%). In multivariate analysis, the LI-RADS morphological type was a stronger risk factor for predicting poor OS [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.59-4.85, P < 0.001] and ER (HR 2.14, 95% CI 1.24-3.70, P = 0.007). A subgroup analysis revealed that type 3 was associated with poor OS and ER in > 5 cm cases but not in < 5 cm cases. CONCLUSIONS: ER and OS of patients with HCC undergoing radical surgery can be predicted using the preoperative tumor LI-RADS morphological type, which could help to select personalized treatment plans for patients with HCC in the future.

Picomole-Scale Transition Metal Electrocatalysis Screening Platform for Discovery of Mild C-C Coupling and C-H Arylation through in Situ Anodically Generated Cationic Pd.

Development of new transition-metal-catalyzed electrochemistry promises to improve overall synthetic efficiency. Here, we describe the first integrated platform for online screening of electrochemical transition-metal catalysis. It utilizes the intrinsic electrochemical capabilities of nanoelectrospray ionization mass spectrometry (nano-ESI-MS) and picomole-scale anodic corrosion of a Pd electrode to generate and evaluate highly efficient cationic catalysts for mild electrocatalysis. We demonstrate the power of the novel electrocatalysis platform by (1) identifying electrolytic Pd-catalyzed Suzuki coupling at room temperature, (2) discovering Pd-catalyzed electrochemical C-H arylation in the absence of external oxidant or additive, (3) developing electrolyzed Suzuki coupling/C-H arylation cascades, and (4) achieving late-stage functionalization of two drug molecules by the newly developed mild electrocatalytic C-H arylation. More importantly, the scale-up reactions confirm that new electrochemical pathways discovered by nano-ESI can be implemented under the conventional electrolytic reaction conditions. This approach enables in situ mechanistic studies by capturing various intermediates including transient transition metal species by MS, and thus uncovering the critical role of anodically generated cationic Pd catalyst in promoting otherwise sluggish transmetalation in C-H arylation. The anodically generated cationic Pd with superior catalytic efficiency and novel online electrochemical screening platform hold great potential for discovering mild transition-metal-catalyzed reactions.

Cupric Ions Selectively Modulate TRAAK-Phosphatidylserine Interactions.

TRAAK and TREK2 are two-pore domain K+ (K2P) channels and are modulated by diverse factors including temperature, membrane stretching, and lipids, such as phosphatidic acid. In addition, copper and zinc, both of which are essential for life, are known to regulate TREK2 and a number of other ion channels. However, the role of ions in the association of lipids with integral membrane proteins is poorly understood. Here, we discover cupric ions selectively modulate the binding of phosphatidylserine (PS) to TRAAK but not TREK2. Other divalent cations (Ca2+, Mg2+, and Zn2+) bind both channels but have no impact on binding PS and other lipids. Additionally, TRAAK binds more avidly to Cu2+ and Zn2+ than TREK2. In the presence of Cu2+, TRAAK binds similarly to PS with different acyl chains, indicating a crucial role of the serine headgroup in coordinating Cu2+. High-resolution native mass spectrometry (MS) enables the determination of equilibrium binding constants for distinct Cu2+-bound stoichiometries and uncovered the highest coupling factor corresponds to a 1:1 PS-to-Cu2+ ratio. Interestingly, the next three highest coupling factors had a ∼1.5:1 PS-to-Cu2+ ratio. Our findings bring forth the role of cupric ions as an essential cofactor in selective TRAAK-PS interactions.

Voltage-Controlled Divergent Cascade of Electrochemical Reactions for Characterization of Lipids at Multiple Isomer Levels Using Mass Spectrometry.

Cascading divergent reactions in a single system is highly desirable for their intrinsic efficiency and potential to achieve multilevel structural characterization of complex biomolecules. In this work, two electrochemical reactions, interfacial electro-epoxidation and cobalt anodic corrosion, are divergently cascaded in nanoelectrospray (nESI) and can be switched at different voltages. We applied these reactions to lipid identification at multiple isomer levels using mass spectrometry (MS), which remains a great challenge in structural lipidomics. The divergent cascade reactions in situ derivatize lipids to produce epoxidized lipids and cobalt-adducted lipids at different voltages. These lipids are then fragmented upon low-energy collision-induced dissociation (CID), generating diagnostic fragments to indicate C═C locations and sn-positions that cannot be achieved by the low-energy CID of native lipids. We have demonstrated that lipid structural isomers show significantly different profiles in the analysis of healthy and cancerous mouse prostate samples using this strategy. The application of divergent cascade reactions in lipid identification allows the four-in-one analysis of lipid headgroups, fatty acyl chains, C═C locations, and sn-positions simply by tuning the nESI voltages within a single experiment. This feature as well as its low sample consumption, no need for an extra apparatus, and quantitative analysis capability show its great potential in lipidomics.

Characterization of glycerophospholipids at multiple isomer levels via Mn(II)-catalyzed epoxidation.

Characterization of glycerophospholipid isomers is of significant importance as they play different roles in physiological and pathological processes. In this work, we present a novel and bifunctional derivatization method utilizing Mn(II)-catalyzed epoxidation to simultaneously identify carbon-carbon double bond (CC bond)- and stereonumbering (sn)-positional isomers of phosphatidylcholine. Mn(II) coordinates with picolinic acid and catalyzes epoxidation of unsaturated lipids by peracetic acid. Collision-induced dissociation (CID) of the epoxides generates diagnostic ions that can be used to locate CC bond positions. Meanwhile, CID of Mn(II) ion-lipid complexes produces characteristic ions for determination of sn positions. This bifunctional derivatization takes place in seconds, and the diagnostic ions produced in CID are clear and easy to interpret. Moreover, relative quantification of CC bond-and sn-positional isomers was achieved. The capability of this method in identifying lipids at multiple isomer levels was shown using lipid standards and lipid extracts from complex biological samples.

Characterization of lipid carbon-carbon double-bond isomerism via ion mobility-mass spectrometry (IMS-MS) combined with cuprous ion-induced fragmentation.

Characterization of phospholipid isomers is challenging due to their identical masses and similarities in structures. Here, we report that copper (I) ion complexed with phospholipids can be used to characterize both carbon-carbon double-bond (C=C bond) positional and geometric isomers. We investigate the distinct fragmentation patterns induced by the π-Cu+ interaction and developed strategies to rapidly characterize the isomerism of phospholipids. The multi-stage fragmentation of Cu+-adducted lipids by collision-induced dissociation can generate diagnostic ions to locate C=C bonds in unsaturated lipids. Furthermore, the collision cross sections of Cu+-adducted parent lipids and product ions can be used as molecular descriptors in distinguishing C=C bond geometric isomers. A bovine heart lipid extract containing Z-configuration lipids spiked with an E-configuration lipid was analyzed to demonstrate rapidness and effectiveness of the method in distinguishing lipid geometric isomers from a real sample.

Lipid Mass Tags via Aziridination for Probing Unsaturated Lipid Isomers and Accurate Relative Quantification.

Knowing concentrations of lipids is essential for understanding their physiological functions and discovering new disease biomarkers. However, it is highly challenging to accurately quantify lipids due to structural diversity and multiple isomeric forms of lipids. To address these critical gaps, we have developed a novel aziridine-based isobaric tag labelling strategy that allows (i) determination of lipid double-bond positional isomers, (ii) accurate relative quantification of unsaturated lipids, and (iii) improvement of ionization efficiencies of nonpolar lipids. The power of this method is demonstrated in characterization and quantification of various categories of lipids such as fatty acids, phosphoglycerol lipids, cholesteryl esters (CE), and glycerides. 17 CE lipid isomers were identified and quantified simultaneously from Alzheimer's disease (AD) mouse serum without using lipid standards. Among them, 6 CE isomers showed significant changes in concentrations in AD serum.

LINC01559 accelerates pancreatic cancer cell proliferation and migration through YAP-mediated pathway.

Pancreatic cancer (PC) is one of the top two most fatal cancers, with the poorest survival rate among all human malignancies. Increasing evidence suggests the involvement of long noncoding RNAs (lncRNAs) in the initiation and progression of various cancers. Herein, we investigated the role of lncRNA LINC01559 in PC. Several online databases indicated that LINC01559 was at a low expression in normal pancreatic tissues but was obviously upregulated in PAAD tissues. Further, our results showed that LINC01559 was stimulated in PC cell lines relative to normal controls. Furthermore, we validated that LINC01559 facilitated PC cell proliferation and migration in vitro. Also, silencing LINC01559 obstructed PC cell growth in vivo. Besides, LINC01559 was revealed to be mainly in the cytoplasm of PC cells and therefore served as a ceRNA of Yes-associated protein (YAP) in PC cells via sponging miR-607. Surprisingly, we also proved that LINC01559 could interact with YAP protein, which might hinder YAP phosphorylation and enhance YAP transcriptional activity in PC cells. Furthermore, we demonstrated that YAP was the downstream effector in LINC01559-regulated PC development. Collectively, our findings unmasked that LINC01559 accelerates PC progression through relying on YAP, providing a new potential target for clinical treatment of patients with PC.

The prognostic value of preoperative fibrinogen-to-prealbumin ratio and a novel FFC score in patients with resectable gastric cancer.

BACKGROUND: Chronic inflammation is considered as a hallmark of gastric cancer (GC) and plays a critical role in GC progression and metastasis. This study aimed to explore the prognostic values of preoperative fibrinogen-to-prealbumin ratio (FPR), fibrinogen-to-albumin ratio (FAR), and novel FPR-FAR-CEA (FFC) score in patients with GC undergoing gastrectomy. METHODS: A total of 273 patients with resectable GC were included in this retrospective study. We performed Kaplan-Meier and Cox regression analyses to assess the prognostic role of preoperative FPR, FAR, and FFC score in patients with GC and analyze their relationships with clinicopathological features. RESULTS: Receiver operating characteristic curve (ROC) analysis revealed that the optimal cutoff values for FPR and FAR were 0.0145 and 0.0784, respectively. The FFC score had a higher area under the ROC curve than FAR and CEA. Elevated FPR (≥ 0.0145) and FAR (≥ 0.0784) were significantly associated with old age, large tumor size, tumor invasion depth, lymph nodes metastasis, advanced TNM stage, large Borrmann type, and anemia status. Kaplan-Meier analysis showed that high FPR, FAR, and FFC score were related to poor survival. Multivariate analyses indicated that FPR, FFC score, TNM stage, and tumor size were significant independent factors for survival. CONCLUSIONS: Preoperative FPR and FFC score could be used as prospective noninvasive prognostic biomarkers for resectable GC.

On-Demand Electrochemical Epoxidation in Nano-Electrospray Ionization Mass Spectrometry to Locate Carbon-Carbon Double Bonds.

Reported here is the first on-demand electrochemical epoxidation incorporated into the standard nano-electrospray ionization mass spectrometry (nanoESI-MS) workflow for double-bond identification. The capability lies in a novel tunable electro-epoxidation of double bonds, where onset of the reaction can be controlled by simply tuning the spray voltage. On-demand formation of mono-/multiple epoxides is achieved at different voltages. The electro-epoxidized products are then fragmented by tandem MS to generate diagnostic ions, indicating the double bond position(s). The process is completed within seconds, holding great potential for high-throughput analysis. The rapid switch-on/off electro-epoxidation of a single sample, the low sample consumption, the demonstrated applicability to complex lipids containing multiple double bonds, and the advantage of not requiring extra apparatus make this method attractive for use in lipid-related biological studies.

Accelerating Electrochemical Reactions in a Voltage-Controlled Interfacial Microreactor.

Microdroplet chemistry is attracting increasing attention for accelerated reactions at the solution-air interface. We report herein a voltage-controlled interfacial microreactor that enables acceleration of electrochemical reactions which are not observed in bulk or conventional electrochemical cells. The microreactor is formed at the interface of the Taylor cone in an electrospray emitter with a large orifice, thus allowing continuous contact of the electrode and the reactants at/near the interface. As a proof-of-concept, electrooxidative C-H/N-H coupling and electrooxidation of benzyl alcohol were shown to be accelerated by more than an order of magnitude as compared to the corresponding bulk reactions. The new electrochemical microreactor has unique features that allow i) voltage-controlled acceleration of electrochemical reactions by voltage-dependent formation of the interfacial microreactor; ii) "reversible" electrochemical derivatization; and iii) in situ mechanistic study and capture of key radical intermediates when coupled with mass spectrometry.

Lipid Isobaric Mass Tagging for Enhanced Relative Quantification of Unsaturated sn-Positional Isomers.

Changes in the levels of lipid sn-positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing the concentrations of these lipids holds significant importance for unraveling their involvement in disease diagnosis and pathological mechanisms. However, existing methods for lipid quantification often fall short in accuracy due to the structural diversity and isomeric forms of lipids. To address this challenge, we have developed an aziridine-based isobaric tag labeling strategy that allows (i) differentiation and (ii) enhanced relative quantification of lipid sn-positional isomers from distinct samples in a single run. The methodology enabled by aziridination, isobaric tag labeling, and lithiation has been applied to various phospholipids, enabling the determination of the sn-positions of fatty acyl chains and enhanced relative quantification. The analysis of Escherichia coli lipid extracts demonstrated the enhanced determination of the concentration ratios of lipid isomers by measuring the intensity ratios of mass reporters released from sn-positional diagnostic ions. Moreover, we applied the method to the analysis of human colon cancer plasma. Intriguingly, 17 PC lipid sn-positional isomers were identified and quantified simultaneously, and among them, 7 showed significant abundance changes in the colon cancer plasma, which can be used as potential plasma markers for diagnosis of human colon cancer.

Cancer Immunotherapy and Medical Imaging Research Trends from 2003 to 2023: A Bibliometric Analysis.

Purpose: With the rapid development of immunotherapy, cancer treatment has entered a new phase. Medical imaging, as a primary diagnostic method, is closely related to cancer immunotherapy. However, until now, there has been no systematic bibliometric analysis of the state of this field. Therefore, the main purpose of this article is to clarify the past research trajectory, summarize current research hotspots, reveal dynamic scientific developments, and explore future research directions. Patients and Methods: A comprehensive search was conducted on the Web of Science Core Collection (WoSCC) database to identify publications related to immunotherapy specifically for the medical imaging of carcinoma. The search spanned the period from the year 2003 to 2023. Several analytical tools were employed. These included CiteSpace (6.2.4), and the Microsoft Office Excel (2016). Results: By searching the database, a total of 704 English articles published between 2003 and 2023 were obtained. We have observed a rapid increase in the number of publications since 2018. The two most active countries are the United States (n=265) and China (n=170). Pittock, Sean J and Abu-sbeih, Hamzah are very concerned about the relationship between cancer immunotherapy and medical images and have published more academic papers (n = 5; n = 4). Among the top 10 co-cited authors, Topalian Sl (n=43) cited ranked first, followed by Graus F (n=40) cited. According to clustering, timeline, and burst word analysis, the results show that the current research focus is on "MRI", "deep learning", "tumor microenvironment" and so on. Conclusion: Medical imaging and cancer immunotherapy are hot topics. The United States is the country with the most publications and the greatest influence in this field, followed by China. "MRI", "PET/PET-CT", "deep learning", "immune-related adverse events" and "tumor microenvironment" are currently hot research topics and potential targets.

Three-dimensional morphology scoring of hepatocellular carcinoma stratifies prognosis and immune infiltration.

BACKGROUND: The morphological attributes could serve as pivotal indicators precipitating early recurrence and dismal overall survival in hepatocellular carcinoma (HCC), and quantifying morphological features may better stratify the prognosis of HCC. OBJECTIVE: To develop a radiomics approach based on 3D tumor morphology features for predicting the prognosis of HCC and identifying differentially expressed genes related to morphology to guide HCC treatment. MATERIALS AND METHODS: Retrospective study of 357 HCC patients. Radiomic features were extracted from MRI tumor regions; 14 morphology-related features predicted early HCC recurrence and patient stratification via LASSO-Cox modeling. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. RNA sequencing from the Cancer Imaging Archive (TCIA) examined drug sensitivity and stratified HCC using morphological immunity genes, validating recurrence and prognosis. RESULTS: Patients were split into training (n = 225), test (n = 132), and 50 TCIA dataset cohorts. Two features (Maximum2DdiameterColumn, Sphericity) in Cox regression stratified patients into high/low-risk Morphological Radiological Score (Morph-RS) groups. Significant OS and RFS were seen across all sets. Differentially expressed genes focused on T cell receptor signaling; low-risk group had higher T cells (P = 0.039), B cells (P = 0.041), NK cells (P = 0.018). SN-38, GSK2126458 might treat high-risk morphology. Morphology-immune genes stratified HCC, showing significant RFS/OS differences. CONCLUSION: Tumor Morph-RS effectively stratifies HCC patients' recurrence and prognosis. Limited immune infiltration seen in Morph-RS high-risk groups signifies the potential of employing tumor morphology as a potent visual biomarker for diagnosing and managing HCC.

Irinotecan plus raltitrexed as second­line chemotherapy for metastatic colorectal cancer: A retrospective study.

The present study evaluated the efficiency, prognostic factors for and the safety of irinotecan combined with raltitrexed (TOMIRI) in patients with metastatic colorectal cancer (CRC). Outcome data of patients who received TOMIRI as first-, second- and third- or later-line treatment regimens were assessed to compare the efficacy of this regimen. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Kaplan-Meier curves and univariate and multivariate analyses were performed to evaluate efficacy. From January 2017 to December 2019, TOMIRI was administered as a first-line treatment in 23 patients, second-line treatment in 164 patients and third- or later-line treatment in 18 patients. Irinotecan and 5-fluorouracil (FOLFIRI) was administered to another 50 patients, who served as the control group. The median PFS was 9, 7 and 6 months and the median OS was 37, 21 and 17 months for first-, second- and third- or later-line treatments, respectively. The ORRs of the included patients were 21.7, 13.4 and 11.1%, respectively, and the DCRs were 91.3, 81.7 and 66.7%, respectively. Compared with FOLFIRI, TOMIRI as a second-line chemotherapy treatment was associated with longer survival of the patients with CRC. Further analysis demonstrated that pathologic tumor-node-metastasis category, carcinoembryonic antigen, carbohydrate antigen 19-9, treatment cycles, targeted therapy, treatment of local metastases and first-line PFS were prognostic factors for second-line treatment. Among these, the number of treatment cycles was of vital importance. Hepatic dysfunction was the most commonly reported grade 1-2 (55.1%) and grade 3-4 (7.3%) adverse event. Neutropenia (12.2%), thrombocytopenia (10.2%), anemia (27.3%), proteinuria (38.1%) and hematuria (21.0%) were also common grade 1-2 adverse events. In conclusion, TOMIRI may be recommended as an effective and safe second-line treatment for metastatic CRC in the clinic.

Distinct chemical degradation pathways of AAV1 and AAV8 under thermal stress conditions revealed by analytical anion exchange chromatography and LC-MS-based peptide mapping.

Adeno-associated virus (AAV)-based gene therapy is experiencing a rapid growth in the field of medicine and holds great promise in combating a wide range of human diseases. For successful development of AAV-based products, comprehensive thermal stability studies are often required to establish storage conditions and shelf life. However, as a relatively new modality, limited studies have been reported to elucidate the chemical degradation pathways of AAV products under thermal stress conditions. In this study, we first presented an intriguing difference in charge profile shift between thermally stressed AAV8 and AAV1 capsids when analyzed by anion exchange chromatography. Subsequently, a novel and robust peptide mapping protocol was developed and applied to elucidate the underlying chemical degradation pathways of thermally stressed AAV8 and AAV1. Compared to the conventional therapeutic proteins, the unique structure of AAV capsids also led to some key differences in how modifications at specific sites may impact the overall charge properties. Finally, despite the high sequency identity, the analysis revealed that the opposite charge profile shifts between thermally stressed AAV8 and AAV1 could be mainly attributed to a single modification unique to each serotype.

Self-supported system of MoO2@Ni2P heterostructures as an efficient electrocatalyst for hydrogen evolution reactions in alkaline media.

Efficient, stable and low-cost catalysts are essential for improving the efficiency of hydrogen evolution reactions. Herein, the MoO2@Ni2P heterostructure electrocatalyst was synthesized in a self-supported system on a carbon paper (CP) by two-step deposition and phosphorization at low temperature. The self-supported nanoarray structure makes the catalyst to effectively and efficiently transfer electrons and exposes more of its active sites. Moreover, the strong interaction between Ni2P and MoO2 helps to effectively optimize the electronic structure. The density of states calculations demonstrate that there is an increase in the density of electronic states near the MoO2/Ni2P Fermi level. This shows that MoO2/Ni2P has fast charge transfer kinetics. MoO2 modulates the d-band center of nickel, resulting in moderate adsorption/desorption of hydrogen. The above results show that MoO2@Ni2P has good hydrogen evolution activity. The experimental results show that the overpotential (η10) of MoO2@Ni2P/CP in the alkaline environment is only 57 mV with a Tafel slope of 61 mV dec-1. It is similar to the commercial noble-metal catalysts and outperforms most reported catalysts.

Intrinsic resistance and efficacy of immunotherapy in microsatellite instability-high colorectal cancer: A systematic review and meta-analysis.

Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the intrinsic resistance to and efficacy of immunotherapy in patients with MSI-H CRC. The PubMed and Web of Science databases were searched using keywords such as "colorectal cancer," "immunotherapy," and "clinical experiment." Random-effects models were used to generate the combined complete response, partial response, stable disease, progressive disease, objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. We then performed a subgroup analysis based on the ORR and incidence of intrinsic resistance. The meta-analysis included seven clinical trials. The incidences of complete response, partial response, stable disease, and progressive disease summarized by the random-effects model were 8%, 37%, 26%, and 25%, respectively. The ORR and DCR were 45% and 71%, respectively. The ORRs of programmed cell death protein 1 inhibitor (anti-PD-1), programmed death ligand 1 inhibitor (anti-PD-L1), and anti-PD-1 combined with cytotoxic T lymphocyte-associated antigen 4 inhibitor (anti-CTLA-4) immunotherapy were 38%, 54%, and 57%, respectively. The ORR of immune checkpoint inhibitors for first- and third-line therapy was 56% and 32%, respectively. Dual-drug immunotherapy significantly reduced the incidence of intrinsic resistance to immunotherapy (12% vs 31%). The incidences of intrinsic resistance to first-line therapy and second-line and later therapy were 29% and 26%, respectively. Approximately 25% of patients with MSI-H CRC had intrinsic resistance to immunotherapy. Anti-PD-1 combined with anti-CTLA-4 significantly increased the ORR, thereby reducing the incidence of intrinsic resistance. Moving immunotherapy into earlier lines of therapy, although not reducing the incidence of intrinsic resistance, can improve the ORR in patients with MSI-H CRC.