"MS/MS spectrum to structure"plays a critical role in the confirmative identification of complicated matrices and is currently regarded as an extremely challenging endeavor.MS/MS information provides vital clues to structural identification.In this study,a strategy was proposed to facilitate unambiguous identification through matching MS3 with MS2 spectra.Initially,MS3 spectra of the featured ions(c-and y-type ions)generated by the decomposition of ester functional group in esters and the MS2 spectrum of the structural unit([M-H]-)were all captured on the Qtrap-MS platform equipped with two tandem-in-space collision cells,including the second quadrupole cell(q2)and linear ion trap(LIT)chambers(actually the third quadrupole unit).Subsequently,the MS/MS spectrum matching between MS3 spectra of the ester compound and MS2 spectra of the structural unit(s)were achieved.As a result,the findings corresponding to MS3 and MS2 spectra matching were summarized.Finally,based on HR-MS/MS information of total salvianolic acid derivatives(TSA),36 kinds of compounds were preliminarily identified through matching with literature information and database retrieval.The applicability of MS3 and MS2 spectra matching strategy was further justified by the confirmative identification of phenolic acid compounds(Rosmarinic acid and salvianolic acid B)in TSA.Above all,MS3 and MS2 spectra matching strategy was quite meaningful towards advancing"MS/MS spectrum to structure"analysis through recognizing and identifying featured fragment ions,and also provided inspiration and new insights for the structural characterization.

Objective To comprehensively analyze the clinical outcomes of total cavopulmonary connection (TCPC) in the treatment of functional single ventricle combined with heterotaxy syndrome (HS). Methods A retrospective analysis was conducted on the patients with functional single ventricle and HS who underwent TCPC (a HS group) in Guangdong Provincial People's Hospital between 2004 and 2021. The analysis focused on postoperative complications, long-term survival rates, and identifying factors associated with patient survival. Early and late postoperative outcomes were compared with matched non-HS patients (a non-HS group). Results Before propensity score matching, 55 patients were collected in the HS group, including 42 males and 13 females, with a median age of 6.0 (4.2, 11.8) years and a median weight of 17.0 (14.2, 28.8) kg. Among the patients, there were 53 patients of right atrial isomerism and 2 patients of left atrial isomerism. Eight patients underwent TCPC in one stage. TCPC procedures included extracardiac conduit (n=39), intracardiac-extracardiac conduit (n=14), and direct cavopulmonary connection (n=2). Postoperative complications included infections in 27 patients, liver function damage in 19 patients, and acute kidney injury in 11 patients. There were 5 early deaths. The median follow-up time was 94.7 (64.3, 129.8) months. The 1-year, 5-year, and 10-year survival rates were 87.2%, 85.3%, and 74.3%, respectively. After propensity score matching, there were 45 patients in the HS group and 81 patients in the non-HS group. Compared to the non-HS group, those with HS had longer surgical and mechanical ventilation time, higher infection rates (P<0.05), and a 12.9% lower 10-year survival rate. Multivariate Cox regression analysis identified asplenia was a risk factor for mortality (HR=8.98, 95%CI 1.86-43.34, P=0.006). Conclusion Compared to non-HS patients, patients with HS have lower survival rates after TCPC, and asplenia is an independent risk factor for the survival of these patients.

ObjectiveTo explore the impact of Gegen Qinliantang（GQT） on the fecal short-chain fatty acids（SCFAs） metabolism in antibiotic-associated diarrhea（AAD） through targeted metabolomics. MethodA total of 240 SD rats were randomly divided into six groups（n=40， half male and half female）， including blank group， model group， bifidobiogen group（0.15 g·kg^-1）， and GQT high-， medium-， and low-dose groups（10.08， 5.04， 2.52 g·kg^-1）， except for the blank group， clindamycin（250 mg·kg^-1） was given to all groups by gavage for modeling every day for 7 d. After successful modeling， each administered group was gavaged with the corresponding dose of the drug， and the blank and model groups were gavaged with an equal volume of normal saline solution， 1 time/d， for 14 d. At 0， 3， 7， 14 d after the drug intervention， eight rats were randomly selected from each group， respectively. Gas chromatography-time-of-flight mass spectrometry（GC-TOF-MS） was used to perform targeted metabolomic analysis of SCFAs in the feces of rats， and partial least squares-discriminant analysis（PLS-DA） was applied to compare the differences in metabolic profiles between groups at different treatment times， and to compare the changes in the contents of SCFAs in rat feces between groups. ResultPLS-DA results showed that the blank group could be clearly distinguishable from the model group， with GQT exhibiting a closer proximity to the blank group after 7 d of treatment. After further analyzing the composition of SCFAs， it was found that the proportion of acetic acid increased and the proportions of butyric acid， valeric acid， hexanoic acid and isovaleric acid decreased in the model group compared with the blank group. After the treatment with GQT， the proportions of butyric acid， isobutyric acid， valeric acid， and isovaleric acid increased， and the proportions of acetic acid， propionic acid and caproic acid decreased. Subsequent differential analysis revealed that GQT could significantly improve the content of butyric acid， and had a certain retrogressive effect on the contents of valeric acid and hexanoic acid. ConclusionThe medium dose group of GQT can improve the contents of SCFAs in AAD feces after 7 days of treatment， which may be related to the improvement of the composition ratio of SCFAs and the contents of butyric acid， valeric acid and caproic acid.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective:To investigate the biological effects of acute high-dose radon exposure on mice.Methods:BALB/c male mice aged 6 to 8 weeks were exposed once in an HD-3 ecological radon chamber with an average radon concentration of 7 × 10 5 Bq/m 3 for 10 h. Mice were weighed, their lung tissues and blood samples were collected at 1, 2 and 3 months after exposure. Control groups were set up at the three time points with four mice in each group. For these mice, the lung tissue pathology was observed using hematoxylin-eosin (HE) staining method, routine blood tests were conducted using a hematology analyzer and the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in the serum and lung tissues were measured using corresponding assay kits. Results:The HE staining result revealed that compared to the control groups, the experimental groups exhibited thickening of alveolar walls and increased infiltration of granulocyte, whose degrees, however, reduced over time and displayed no significant difference at 3 months after exposure. There was no significant difference in body weight or blood routine between the experimental and control groups. The detection result revealed decreased SOD levels in the lung tissues at 2 months after exposure, which were (11.34 ± 1.03) U/mgprot and (9.75 ± 0.71) U/mgprot, respectively for the control and experimental groups ( t = 2.54, P < 0.05). The MDA levels in lung tissue increased at 1 month after exposure, which were(2.30 ± 0.24) and (2.77 ± 0.29) nmol/mgprot, respectively for the control and experimental groups ( t = 2.49, P < 0.05). At 3 months after exposure, the SOD and MDA levels differed insignificantly between the control and experimental groups ( P > 0.05). Conclusions:After acute high-dose radon exposure, the mice suffered damage to the lung tissue, with changes in their oxidative stress indicators being detected. However, these effects gradually diminished at 3 months after exposure. Additionally, acute high-dose radon exposure did not give rise to significant changes in the body weight or routine blood result of the mice.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective To investigate the impact of cardiomyocyte ferroptosis on acute myocardial infarction(AMI)and its relationship with the expression of long non-coding RNA(lncRNA)GAS5.Methods An AMI model was established in eighteen male SD rats(6-8 weeks old),and then the subjected rats were randomly divided into blank control group,sham operation group,and model group,6 animals in each group.In 2 weeks after surgery,echocardiography was used to evaluate heart function,and TTC staining,HE staining and TUNEL staining were employed re-spectively to observe myocardial infarct area,histopathological changes of myocardial tissues and apoptosis in cardiomyocytes.Serum Fe2+concentration was measured with an iron ion detection kit.The expression levels of lncRNA GAS5,nuclear factor erythroid-derived 2-like 2(Nrf2),and glutathione peroxidase 4(GPX4)in myocardial tissues were detected with QT-PCR.Linear corre-lation analysis was performed to investigate the relationship between the expression of lncRNA GAS5,Nrf2 and GPX4 with Fe2+concentration.Western blotting was conducted for the protein levels of ferroptosis-related proteins,glutathione peroxidase 4(GPX4),nuclear factor erythroid-derived 2-like 2(Nrf2),glucose-regulated protein 78(GRP78),and cysteinyl aspartate specific proteinase 12(Caspase-12)in myocardial tissues.Results Western blotting revealed obvious in-creases in the protein levels of ferroptosis related proteins GRP78(1.11±0.13 vs 0.51±0.08,P＜0.01)and Caspase-12(1.23±0.05 vs 0.92±0.07,P＜0.05)and a decrease in those of ferroptosis inhibitor GPX4(0.27±0.11 vs 0.68±0.10,P＜0.01)and Nrf2(0.30±0.12 vs 0.58±0.04,P＜0.05)in the model group than the sham operation group.Additionally,QT-PCR showed that the mRNA levels of GPX4 and Nrf2 were notably lower,indicating cardiomyocyte ferroptosis,while that of lncRNA GAS5 was remarkably higher in the myocardial tissues of the model group than the sham operation group(P＜0.01).What's more,the expression of lncRNA GAS5 had a positive correlation with serum Fe2+concentration(P＜0.05).Conclusion AMI is closely associated with cardiomyocyte ferroptosis.lncRNA GAS5 is involved in the regulation of ferroptosis by Nrf2/GPX4 signaling pathway,which thus mediating the occurrence of heart failure after AMI.

AIM To investigate the clinical effects of Lingxian Tongluo Capsules combined with Wentong Acupuncture Method on patients with lumbar disc herniation.METHODS One hundred and four patients were randomly assigned into control group(52 cases)for 30-day intervention of both Wentong Acupuncture Method and conventional treatment,and observation group(52 cases)for 30-day intervention of Lingxian Tongluo Capsules,Wentong Acupuncture Method and conventional treatment.The changes in clinical effects,TCM syndrome scores,lumbar function indices(ODI index score,JOA score),VAS score,inflammatory factors(TNF-α,IL-1β,IL-6),hemorheological indices(plasma viscosity,whole blood high-shear viscosity,whole blood low-shear viscosity)and incidence of adverse reactions were detected.RESULTS The observation group demonstrated higher total effective rate than the control group(P＜0.05).After the treatment,the two groups displayed decreased TCM syndrome scores,ODI index score,VAS score,inflammatory factors and hemorheological indices(P＜0.05),and increased JOA score(P＜0.05),especially for the observation group(P＜0.05).No significant difference in incidence of adverse reactions was found between the two groups(P＞0.05).CONCLUSION For the patients with lumbar disc herniation,Lingxian Tongluo Capsules combined with Wentong Acupuncture Method can safely and effectively relieve clinical symptoms,promote lumbar function recovery,reduce pain degree,alleviate inflammatory responses,and improve hemorheology.

During the development of therapeutic microRNAs (miRNAs or miRs), it is essential to define their pharmacological actions. Rather, miRNA research and therapy mainly use miRNA mimics synthesized in vitro. After experimental screening of unique recombinant miRNAs produced in vivo, three lead antiproliferative miRNAs against human NSCLC cells, miR-22-3p, miR-9-5p, and miR-218-5p, were revealed to target folate metabolism by bioinformatic analyses. Recombinant miR-22-3p, miR-9-5p, and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells. Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs, inhibition of glucose uptake by miR-22-3p, and reduction of serine biosynthesis from glucose by miR-9-5p and -218-5p in NSCLC cells. With greater activities to interrupt NSCLC cell respiration, glycolysis, and colony formation than miR-9-5p and -218-5p, recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity. These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine, which shall provide insight into developing antimetabolite RNA therapies.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*