Comprehensive genomic profiling of small bowel adenocarcinoma by tissue and plasma biopsy.

Small bowel adenocarcinoma (SBA) is a rare and aggressive malignancy with limited treatment options and poor prognosis. The molecular landscape and immunological characteristics of SBA are poorly understood. Here, we performed comprehensive mutation profiling of tissue and plasma biopsies from 143 and 42 patients with SBA. Analysis showed that SBA had a distinct mutation spectrum from left- and right-sided colorectal carcinoma. Plasma biopsy had high concordance with tissue biopsy for single nucleotide variants and structural variants, but low concordance for copy number variations, which showed that plasma biopsy can be an alternative to tissue biopsy. Moreover, we analyzed the association of TMB with clinical and molecular features, and found that TMB was significantly higher in tumors with DNA damage response alterations. Our findings provide valuable insights into the molecular and immunological features of SBA and demonstrate the potential of plasma biopsy as a non-invasive method for SBA diagnosis and treatment.

Genomic landscape defines peritoneal metastatic pattern and related target of peritoneal metastasis in colorectal cancer.

The primary objective of this study is to develop a prediction model for peritoneal metastasis (PM) in colorectal cancer by integrating the genomic features of primary colorectal cancer, along with clinicopathological features. Concurrently, we aim to identify potential target implicated in the peritoneal dissemination of colorectal cancer through bioinformatics exploration and experimental validation. By analyzing the genomic landscape of primary colorectal cancer and clinicopathological features from 363 metastatic colorectal cancer patients, we identified 22 differently distributed variables, which were used for subsequent LASSO regression to construct a PM prediction model. The integrated model established by LASSO regression, which incorporated two clinicopathological variables and seven genomic variables, precisely discriminated PM cases (AUC 0.899; 95% CI 0.860-0.937) with good calibration (Hosmer-Lemeshow test p = .147). Model validation yielded AUCs of 0.898 (95% CI 0.896-0.899) and 0.704 (95% CI 0.622-0.787) internally and externally, respectively. Additionally, the peritoneal metastasis-related genomic signature (PGS), which was composed of the seven genes in the integrated model, has prognostic stratification capability for colorectal cancer. The divergent genomic landscape drives the driver genes of PM. Bioinformatic analysis concerning these driver genes indicated SERINC1 may be associated with PM. Subsequent experiments indicate that knocking down of SERINC1 functionally suppresses peritoneal dissemination, emphasizing its importance in CRCPM. In summary, the genomic landscape of primary cancer in colorectal cancer defines peritoneal metastatic pattern and reveals the potential target of SERINC1 for PM in colorectal cancer.

Involvement of Bile Acid Metabolism and Gut Microbiota in the Amelioration of Experimental Metabolism-Associated Fatty Liver Disease by Nobiletin.

Metabolism-associated fatty liver disease (MAFLD), a growing health problem worldwide, is one of the major risks for the development of cirrhosis and liver cancer. Oral administration of nobiletin (NOB), a natural citrus flavonoid, modulates the gut microbes and their metabolites in mice. In the present study, we established a mouse model of MAFLD by subjecting mice to a high-fat diet (HFD) for 12 weeks. Throughout this timeframe, NOB was administered to investigate its potential benefits on gut microbial balance and bile acid (BA) metabolism using various techniques, including 16S rRNA sequencing, targeted metabolomics of BA, and biological assays. NOB effectively slowed the progression of MAFLD by reducing serum lipid levels, blood glucose levels, LPS levels, and hepatic IL-1ß and TNF-α levels. Furthermore, NOB reinstated diversity within the gut microbial community, increasing the population of bacteria that produce bile salt hydrolase (BSH) to enhance BA excretion. By exploring further, we found NOB downregulated hepatic expression of the farnesoid X receptor (FXR) and its associated small heterodimer partner (SHP), and it increased the expression of downstream enzymes, including cholesterol 7α-hydroxylase (CYP7A1) and cytochrome P450 27A1 (CYP27A1). This acceleration in cholesterol conversion within the liver contributes to mitigating MAFLD. The present findings underscore the significant role of NOB in regulating gut microbial balance and BA metabolism, revealing that long-term intake of NOB plays beneficial roles in the prevention or intervention of MAFLD.

[Research progress on chemical constituents and pharmacological effects of Ajania plants].

Ajania belonging to the subtribe Artemisiinae of Anthemideae(Asteraceae) is a genus of semi-shrubs closely related to Chrysanthemum. There are 24 species of Ajania in northwestern China, most of which are folk herbal medicines with strong stress tolerance. Modern medical studies have demonstrated that the chemical constituents of Ajania mainly include terpenoids, flavonoids, phenylpropanoids, alkynes, and essential oils. These compounds endow the plants with antimicrobial, anti-inflammatory, antitumor, antimalarial, antioxidant, and insecticide effects. In this study, we reviewed the research progress in the chemical constituents and pharmacological activities of Ajania, aiming to provide reference for the further research and development of Ajania.

One-stop molecular classification of endometrial carcinoma using comprehensive next-generation sequencing.

This study aims to investigate the feasibility of molecular classification using only comprehensive next-generation sequencing-based techniques and its relationship with survival outcomes in patients with endometrial cancer. Paired tumor-normal sequencing data of 1021 cancer-related genes using tumor tissues or peripheral blood samples and clinical data were retrospectively collected from a cohort of endometrial cancers. The microsatellite instability status was inferred using the MSIsensor (v0.5) with a cut-off of 8%. Sixty patients were classified into four groups: POLEMUT group (13.3%), MSI-H group (20%), TP53WT group (45%) and TP53MUT group (21.7%). Patients within TP53MUT group were more common in serous carcinoma compared to endometrioid carcinoma (P = .0098). TP53WT was significantly correlated with early stage and low grade. TP53MUT group was associated with significantly worse DFS compared to MSI-H group and TP53WT group (P = .014 and .004, respectively). Comprehensive next-generation sequencing is a reliable and simple method to stratify the prognosis of endometrial carcinoma. It can be potentially used to guide treatment of patients with endometrial cancer in routine practice.

[Protective effect of Forsythiae Fructus extract on mice with herpes simplex encephalitis].

This study aims to explore the protective effect of Forsythiae Fructus extract(FFE) against herpes simplex virus encephalitis(HSE) in mice. To be specific, life extension rate of mice, viral load in mouse brain, levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interferon-α(IFN-α), and nitric oxide(NO) content in mouse brain were determined. Mice were classified into normal group, model group, acyclovir(ACV) group, and high-dose, medium-dose, and low-dose(100, 50, 25 mg·kg~(-1), respectively) FFE groups. HSE was induced in mice in corresponding groups. Then, the life extension rate was compared among groups. Viral load in brain was detected by real-time fluorescent quantitative PCR, the changes of TNF-α, IL-1ß, and IFN-α in brain by enzyme-linked immunosorbent assay(ELISA), NO content in brain with nitrate reduction method, and pathological changes by hematoxylin-eosin(HE) staining. The result showed that the life extension rate in the high-dose, medium-dose, and low-dose FFE groups was 27.93%, 19.94%, and 10.66%, respectively, and the difference between the high-dose group and the model group was statistically significant(P<0.05). FFE decreased the viral load in brains of HSE mice. The levels of TNF-α, IL-1ß, and IFN-α in ACV group and high-dose and medium-dose FFE groups were lower than those in the model group(P<0.01,P<0.05), and NO content in the three FFE groups was lower than that in the model group(P<0.01). In conclusion, FFE can improve the survival rate of HSE mice, reduce the load of herpes simplex virus type Ⅰ(HSV-1) in the brains of HSE mice, decrease the levels of inflammatory factors and NO content, and alleviate inflammation and pathological damage, thereby protecting the central nervous system.

[Anti-herpes simplex virus type â of tectorigenin derivative and effect on Toll-like receptors in vitro].

The study investigated the inhibitory effect and mechanism of tectorigenin derivative(SGY) against herpes simplex virus type Ⅰ(HSV-1) by in vitro experiments. The cytotoxicity of SGY and positive drug acyclovir(ACV) on African green monkey kidney(Vero) cells and mouse microglia(BV-2) cells was detected by cell counting kit-8(CCK-8) method, and the maximum non-toxic concentration and median toxic concentration(TC_(50)) of the drugs were calculated. After Vero cells were infected with HSV-1, the virulence was determined by cytopathologic effects(CPE) to calculate viral titers. The inhibitory effect of the tested drugs on HSV-1-induced cytopathy in Vero cells was measured, and their modes of action were initially explored by virus adsorption, replication and inactivation. The effects of the drugs on viral load of BV-2 cells 24 h after HSV-1 infection and the Toll-like receptor(TLR) mRNA expression were detected by real-time fluorescence quantitative PCR(RT-qPCR). The maximum non-toxic concentrations of SGY against Vero and BV-2 cells were 382.804 µg·mL~(-1) and 251.78 µg·mL~(-1), respectively, and TC_(50) was 1 749.98 µg·mL~(-1) and 2 977.50 µg·mL~(-1), respectively. In Vero cell model, the half maximal inhibitory concentration(IC_(50)) of SGY against HSV-1 was 54.49 µg·mL~(-1), and the selection index(SI) was 32.12, with the mode of action of significantly inhibiting replication and directly inactivating HSV-1. RT-qPCR results showed that SGY markedly reduced the viral load in cells. The virus model group had significantly increased relative expression of TLR2, TLR3 and tumor necrosis factor receptor-associated factor 3(TRAF3) and reduced relative expression of TLR9 as compared with normal group, and after SGY intervention, the expression of TLR2, TLR3 and TRAF3 was decreased to different degrees and that of TLR9 was enhanced. The expression of inflammatory factors inducible nitric oxide synthase(iNOS), tumor necrosis factor-α(TNF-α), and interleukin-1ß(IL-1ß) was remarkably increased in virus model group as compared with that in normal group, and the levels of these inflammatory factors dropped after SGY intervention. In conclusion, SGY significantly inhibited and directly inactivated HSV-1 in vitro. In addition, it modulated the expression of TLR2, TLR3 and TLR9 related pathways, and suppressed the increase of inflammatory factor levels.

Successful Treatment of Patients with Refractory High-Grade Serous Ovarian Cancer with GOPC-ROS1 Fusion Using Crizotinib: A Case Report.

BACKGROUND: Recently, multiple poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors. CASE PRESENTATION: A patient with high-grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor-normal next-generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC-ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow-up interrogation. CONCLUSION: This study suggested that crizotinib was an off-the-shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS-based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment. IMPLICATIONS FOR PRACTICE: Despite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC-ROS1 fusion identified by next-generation sequencing in a patient with chemotherapy-resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1-rearranged ovarian carcinomas.

Validated UHPLC-MS/MS method for simultaneous determination of four triterpene saponins from Akebia trifoliata extract in rat plasma and its application to a pharmacokinetic study.

Saponin PH, akemisaponins E, saponin PJ1 and scheffoleoside A, the main bioactive triterpene saponins of Chinese traditional medicine Akebia trifoliata, contribute to its diuretic pharmacological activity. Because of interactions of the multiple ingredients in vivo, pharmacokinetic studies of multiple triterpenes after administration of A. trifoliata extract are essential to clarify their pharmacological effects. The purpose of this study was to develop an efficient and sensitive UHPLC-MS/MS method for simultaneous determination of these four triterpene saponins in rat plasma. The biosamples were prepared by liquid-liquid extraction with n-butanol. The chromatographic separation was performed on a Phenomenex Luna® C18 (150 × 2 mm, 3 µm) with a mobile phase consisting of acetonitrile and water at a flow rate of 0.5 mL/min. The MS/MS system was operated in a negative multiple reaction monitoring mode, and the precursor-product ion transitions were optimized as m/z 941.6 → 471.1 for saponin PH, 941.7 → 471.2 for akemisaponins E, 1089.7 → 601.1 for saponin PJ1 , 957.6 → 487.4 for scheffoleoside A and 799.5 → 637.3 for ginsenoside Rg1 (Rg1 , internal standard). Method validation parameters (calibration curve linearity, lower limit of detection, recovery, matrix effect, intra- and inter-day precision) were within the acceptable ranges. This is the first reported on the UHPLC-MS/MS detection of saponin PH, akemisaponins E, saponin PJ1 and scheffoleoside A, and applied to a preclinical pharmacokinetic study after oral administration of A. trifoliata extract in rats. This study provides a basis for clinical application and further development of A. trifoliata extract.

Peroxotantalate-Based Ionic Liquid Catalyzed Epoxidation of Allylic Alcohols with Hydrogen Peroxide.

The efficient and environmentally benign epoxidation of allylic alcohols has been attained by using new kinds of monomeric peroxotantalate anion-functionalized ionic liquids (ILs=[P4,4,4,n ]3 [Ta(O)3 (η-O2 )], P4,4,4,n =quaternary phosphonium cation, n=4, 8, and 14), which have been developed and their structures determined accordingly. This work revealed the parent anions of the ILs underwent structural transformation in the presence of H2 O2 . The formed active species exhibited excellent catalytic activity, with a turnover frequency for [P4,4,4,4 ]3 [Ta(O)3 (η-O2 )] of up to 285 h-1 , and satisfactory recyclability in the epoxidation of various allylic alcohols under very mild conditions by using only one equivalent of hydrogen peroxide as an oxidant. NMR studies showed the reaction was facilitated through a hydrogen-bonding mechanism, in which the peroxo group (O-O) of the peroxotantalate anion served as the hydrogen-bond acceptor and hydroxyl group in the allylic alcohols served as the hydrogen-bond donor. This work demonstrates that simple monomeric peroxotantalates can catalyze epoxidation of allylic alcohols efficiently.

A simple and selective UHPLC-MS/MS method for quantification of plantagoguanidinic acid in rat plasma and its application to a pharmacokinetic study.

A simple, sensitive and specific UHPLC-MS/MS method for quantification of plantagoguanidinic acid (PGA) in rat plasma was applied to investigate the pharmacokinetic behavior in vivo, using protopine as internal standard. The chromatography was separated on a Phenomenex® Luna-C18 column (2.1 × 150 mm, 3.0 µm) within 7.0 min using a mobile phase consisting of acetonitrile-0.1% formic acid solution under gradient elution at a flow rate of 0.4 mL/min. Prepared samples were monitored by multiple reaction monitoring mode, with the target fragmentions m/z 226.2 → 84.2 for PGA and m/z 354.2 → 188.9 for IS in positive electrospray ionization. The calibration curve of PGA was linear throughout the range 1-1000 ng/mL (r = 0.9962). The lower limit of quantitation in plasma for PGA was 0.1 ng/mL, and the recovery was >88.6%. Intra- and interday accuracy ranged from -8.6 to 4.9%. Furthermore, this validated method was successfully used for a pre-clinical pharmacokinetic study of PGA at a single dose of 20 and 5 mg/kg in rats via oral and intravenous administration. The study showed that PGA was absorpted rapidly and eliminated gradually with a greater absolute oral bioavailability of 70.1% in rats.

TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular carcinoma and predicts prognosis.

BACKGROUND: Toll-like receptor 3 (TLR3) plays a key role in innate immunity. In the present study, we analyzed tissues of patients with human hepatocellular carcinoma (HCC) to determine the significance of the relationship between TLR3 expression and cell proliferation, apoptosis, hepatitis B virus infections, angiogenesis and prognosis. METHODS: We collected paraffin-embedded tissues from 85 patients with HCC who had complete histories and were followed for >5 years. The expression and intracellular localization of TLR3 and downstream proteins (TRIF, NF-κB, and IRF3) were detected using immunohistochemistry. Further, we determined the expression of proteins that mediate cell proliferation (Ki67, cyclin D1), apoptosis (survivin, bcl-2, caspases 3, 8, and 9), and angiogenesis (CD34, MMP-2) as well as the HBV proteins HBsAg and HBcAg. Apoptosis in HCC tissues was detected using TUNEL. We conducted dual-labeling immunohistochemical analyses of TLR3 expression and TUNEL activity. RESULTS: TLR3 expression was significantly lower in HCC tissues compared with adjacent tissues. TRIF, NF-κB, and IRF3 correlated positively with TLR3 expression. Survivin and Bcl-2 expression correlated negatively with TLR3. The frequencies of caspases 3, 8, and 9 expression correlated positively with TLR3 signaling proteins. Cytoplasmic TLR3 and serum levels of HBsAg correlated positively. The apoptotic index determined using the TUNEL method and correlated positively with TLR3 expression. TLR3 expression in the cytoplasm correlated positively with TUNEL-positive cells and HBsAg. Ki67 and cyclin D1 correlated negatively with TLR3 expression. MMP-2 expression, microvessel density (CD34(+)) and endothelial progenitor cells (EPCs) correlated negatively with TLR3 expression. Kaplan-Meier survival analysis shows that TLR3 expression correlated with longer survival. CONCLUSIONS: The expression of TLR3 in HCC tissues may exert a synergistic effect on apoptosis and inhibit the proliferation of HCC cells, MMP-2 expression, generation of EPCs, and angiogenesis. Moreover, TLR3 expression may serve as a prognostic marker of HCC.

Two new triterpenoids from Callicarpa kwangtungensis.

Two new triterpenoids, 2α,3ß,16α,19α,23-pentahydroxyolean-12-en-28-oic acid (1) and 2α,3α,11α,21α,23-pentahydroxyurs-12-en-28-oic acid (2), were isolated from the aerial parts of Callicarpa kwangtungensis. Their structures were elucidated by 1D and 2D analyses, as well as MS and IR spectra.

Four New Triterpenoids from Callicarpa kwangtungensis.

Four new triterpenoids which were identifed as 2α,3ß,6ß,19α-tetrahydroxy- oleanolic acid 28-O-ß-D-glucopyranoside (1), 2-O-ß-D-glucopyranosyloxy-3α,19α-di-hydroxyoleanolic acid (2), 2-O-ß-D-glucopyranosyloxy-3α,19α-dihydroxyursolic acid (3), 2α,3α,6ß,19α-tetrahydroxyursolic acid 28-O-ß-D-glucopyranoside (4), were isolated from the aerial parts of Callicarpa kwangtungensis together with three known triterpenoids identified as 2α,3ß,21ß-trihydroxyursolic acid 28-O-ß-D-glucopyranoside (5), 2α,3α,19α,23-tetrahydroxyoleanolic acid 28-O-ß-D-glucopyranoside (6), 2α,3α,19α,23-tetrahydroxyursolic acid 28-O-ß-D-glucopyranoside (7). Their structures were elucidated by the combination of mass spectrometry (MS), one and two-dimensional NMR experiments.

[Ethyl Acetate-Soluble Chemical Constituents from Callicarpa kwangtungensis (II)].

OBJECTIVE: To study the ethyl acetate-soluble chemical constituents of Callicarpa kwangtungensis. METHODS: The chemical constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and MPLC. Their chemical structures were elucidated on the basis of special analysis. RESULTS: Eleven compounds were isolated from the ethyl acetate-soluble part of Callicarpa kwangtungensis, whose structures were elucidated as 4-methoxybenzoic acid (1), 3,4-dihydroxybenzoic acid (2), 4-hydroxy cinnamic acid(3), phenyl-ß-D-glucopyranoside (4), 3,4,5-trimethoxyphenyl-ß-D-glucopyranoside (5), 2α,3ß,22ß,23-tetrahydroxyursolic-12-en-28-oic acid (6), 2α,3ß,6ß,19α-tetrahydroxy-urs-12-en-28-O-ß-D-glucopyranoside (7), 2ß,3ß,6ß,16α-tetrahydroxy-olean-12-en-28-O-ß-D-glucopyranoside (8), (3S, 6E, 10R)-10-ß-D-glucopyranosyloxy-3,11-dihydroxy-3,7,11-trimethyldodeca-1,6-diene (9), icariside C5(10), and (2E, 6E)-10-ß-D-glucopyranosyl-1, 11-dihydroxy-3, 7, 11-trimethyldodeca-2,6-diene (11). CONCLUSION: Compounds 4 - 11are isolated from Callicarpa genus for the first time, compounds 1 - 3 are isolated from this plant for the first time.

[Ethyl acetate-soluble chemical constituents from Callicarpa kwangtungensis].

OBJECTIVE: To study the ethyl acetate-soluble chemical constituents of Callicarpa kwangtungensis. METHODS: The chemical constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and MPLC. Their chemical structures were elucidated on the basis of special analysis. RESULTS: Seven compounds were isolated from ethyl acetate part, whose structures were elucidated as caffeic acid(1),2α,3α, 19α-trihyhydroxy-urs-12-en-28-O-ß-D-glucopyranoside (2),2α,3, 19α-trihyhydroxy-olean-12-en-28-O-ß-D-glucopyranoside (3), 2α, 3α, 19α-trihyhydroxy-olean-12-en-28-O-ß-D-glucopyranoside (4), ferulic acid (5), 2α, 3ß, 19α-trihyhydroxy-urs-12-en-28-O-ß-D-glucopyranoside(6), and ( + )-isolariciresinol-9-O-ß-D-glucopyranoside(7). CONCLUSION: All these compounds are isolated from this plant for the first time.

The value of the combined MR imaging features and clinical factors Nomogram model in predicting intractable postpartum hemorrhage due to placenta accreta.

To explore the value of the combined MR imaging features and clinical factors Nomogram model in predicting intractable postpartum hemorrhage (IPH) due to placenta accreta (PA). We conducted a retrospective study with 270 cases of PA patients admitted to our hospital from January 2015 to December 2022. The clinical data of these patients were analyzed, and they were divided into 2 groups: the IPH group and the non-IPH group based on the presence of IPH. The differences in data between the 2 groups were compared, and the risk factors for IPH were analyzed. A Nomogram model was constructed using independent high-risk factors, and the predictive value of this model for IPH was analyzed. The results of multivariable binary Logistic regression analysis showed higher number of cesareans, placenta previa, placenta accreta type (implantation, penetration), low signal strip on T2 weighted image (T2WI) were independent high-risk factor for IPH (P < .05). ROC analysis and Hosmer-Lemeshow goodness-of-fit test showed the Nomogram predictive model constructed with the high-risk factor has good discrimination and calibration. Decision curve analysis (DCA) showed that when the probability threshold for the Nomogram model's prediction was in the range from 0.125 to 0.99, IPH patients could obtain more net benefits, making it suitable for clinical application. The higher number of cesareans, placenta previa, placental accreta type (implantation, penetration), and low signal strip on T2WI are independent high-risk factor for IPH. The Nomogram predictive model constructed with the high-risk factor demonstrates good clinical efficacy in predicting the occurrence of IPH due to PA.

Diverse terpenoid glycosides with in vitro cytotoxicity from Glechoma longituba.

Terpenoids are the largest class of all known natural products, possessing structural diversity and numerous biological activities. Ten previously undescribed terpenoid glycosides, glechlongsides A-J (1-10), were isolated from the ethanol extract of the whole plant of Glechoma longituba, including diterpenoid glycoside and pentacyclic triterpenoid saponin. The structures of these compounds were characterized by extensive analysis of 1D and 2D NMR as well as HRESIMS spectra. In addition, glechlongsides F-I (6-9) exhibited weak cytotoxicity against human cancer cell lines BGC-823, Be1, HCT-8, A2780, and A549 with IC50 values ranging from 3.77 to 30.95 µM, respectively.

Genomic and T cell repertoire biomarkers associated with malignant mesothelioma survival.

BACKGROUND: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. METHODS: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. RESULTS: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vß-Jß rearrangements associated with MM immunotherapy efficacy. CONCLUSIONS: The present study reported the largest-scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR-specific clones.

Comprehensive identification strategy for rapid profiling of chemical constituents using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry with Rhubarb as an example.

In this study, the collision induced dissociation tandem mass spectrometry (CID-MS/MS) fragmentation pathway of chemical components in rhubarb was wholly explored using 34 standards by UHPLC-QTOF-MS/MS in negative ion mode. In consequently, the diagnostic product ions for speedy screening and categorization of chemical components in rhubarb were ascertained based on their MS/MS splitting decomposition patterns and intensity analysis. According to these findings, a fresh two-step data mining strategy had set up. The initial key step involves the use of characteristic product ions and neutral loss to screen for different types of substituents and basic skeletons of compounds. The subsequent key step is to screen and classify different types of compounds based on their characteristic product ions. This method can be utilized for rapid research, classification, and identification of compounds in rhubarb. A total of 356 compounds were rapidly identified or tentatively characterized in three rhubarb species extracts, including 150 acylglucoside, 125 anthraquinone, 65 flavanols and 15 other compounds. This study manifests that the analytical strategy is feasible for the analysis of complex natural products in rhubarb.