OBJECTIVE To analyze the specific risks and long-term toxicities of four BCR-ABL1 tyrosine kinase inhibitors （TKIs）（imatinib， dasatinib， nilotinib， and bosutinib） in pediatric patients with hematological malignancies. METHODS Adverse drug event （ADE） reports submitted to the the United States FDA Adverse Event Reporting System （FAERS） from January 2012 to December 2024， with imatinib， dasatinib， nilotinib， and bosutinib as the primary suspect drugs， were collected. Data mining was performed using the reporting odds ratio method and proportional reporting ratio method. ADE terms were classified and summarized by system organ class （SOC） and preferred term （PT） according to the Medical Dictionary for Drug Regulatory Activities （MedDRA， version 26.0）. Meanwhile， the ADE reports were divided by age into the adult group （≥18 years） and the pediatric group （＜18 years） to compare the differences in ADE between the two groups. RESULTS A total of 1 512 pediatric ADE reports were included： 993 for imatinib， 391 for dasatinib， 112 for nilotinib， and 16 for bosutinib. Among the reported ADEs， the patients were mainly aged 12-＜18 years； the reports mainly originated from the United States， France， and Japan； and the primary indications were chronic myeloid leukemia and acute lymphoblastic leukemia. A total of 5 256 ADE signals were mined， among which 235 were positive signals， involving 1 103 PT across 27 SOC. The top five PT ranked by the number of positive signals were nausea， febrile neutropenia， abdominal pain， neutropenia， and anemia. The top two SOC were general disorders and administration site conditions， and gastrointestinal disorders. Compared with the adult group， the pediatric group had relatively higher proportions of events related to infections and infestations as well as blood and lymphatic system disorders. Pediatric long-term toxicity signals primarily included growth retardation， accompanied by signals related to endocrine system abnormalities and bone metabolism abnormalities. Specific signals included imatinib-associated septic shock， dasatinib-associated chylothorax， and nilotinib-associated electrocardiographic QT interval prolongation. CONCLUSIONS When pediatric patients use BCR-ABL1 TKIs， priority monitoring of infection risk and hematologic parameters is required， along with long-term follow-up of height， endocrine， and bone metabolism parameters. Targeted screening and management of drug-specific signals should be performed to ensure the long-term safety of pediatric medication.

ObjectiveTo investigate the impact of preoperative frailty on the prognosis of patients with pancreatic cancer who underwent pancreaticoduodenectomy. MethodsA retrospective analysis was conducted on the clinical data of 435 pancreatic cancer patients who underwent pancreaticoduodenectomy at Sun Yat-sen Memorial Hospital of Sun Yat-sen University. Preoperative frailty was assessed using the FRAIL questionnaire. Binary logistics regression analysis was employed to identify factors influencing frailty， and Cox regression analysis was used to evaluate the effect of frailty on survival. According to the demographic characteristics， subgroup analyses were performed on the effect of frailty on prognosis of patients with pancreatic cancer with pancreaticoduodenectomy. ResultsAmong the 435 patients enrolled， 119 （27.4%） exhibited frailty， while 316 （72.6%） did not. Significant differences were observed between the two groups in various clinical parameters， including age， body mass index， American Society of Anesthesiologists （ASA） score， postoperative red blood cell transfusion， postoperative abdominal abscess， serum levels of glycoantigens 199， glycoantigens 125， and alpha fetoprotein， leukocyte count， neutrophil， high density lipoprotein （HDL） level， and pain intensity （P＜0.05）. Advanced age and an ASA score of Ⅲ were identified as risk factors for frailty， whereas HDL level was a protective factor. Non-frail patients had better postoperative survival times than frail patients. HDL was determined to be an independent protective factor for prognosis， while LDL was an independent risk factor. ConclusionsThis study demonstrates that preoperative frailty is a significant predictor of poor prognosis in pancreatic cancer patients who underwent pancreaticoduodenectomy.These findings suggest that preoperative frailty assessment and targeted interventions to improve nutritional and metabolic status could potentially enhance postoperative survival and quality of life in pancreatic cancer patients.

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Liver size is regulated by circadian clock and exhibits a diurnal rhythm. Pregnane X receptor (PXR) and peroxisome proliferator-activated receptor α (PPARα), members of nuclear receptor superfamily, are important regulators of liver size. We previously demonstrated that mPXR agonist pregnenolone 16α-carbonitrile (PCN) and mPPARα agonist pirinixic acid (WY-14643) promoted liver enlargement and liver regeneration after partial hepatectomy. However, whether PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations remains unclear. The aim of this study was to investigate the diurnal rhythm of PXR or PPARα activation-induced liver enlargement. Male C57BL/6 mice were intraperitoneally injected with corn oil, PCN or WY-14643 for three days, and liver samples were weighed and collected at various time points for analysis. The animal experiment protocol was reviewed and approved by Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2023-001613, SYSU-IACUC-2023-001783). The results showed that PXR or PPARα activation at various time points significantly induced liver enlargement, and liver size maintained normal diurnal oscillations during PXR or PPARα activation-induced hepatomegaly, without significant effects on the expression of core clock genes. This study reveals PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations, and provides novel data for nuclear receptor-induced liver enlargement and liver diurnal rhythm.

Objective:To explore the value of pre-ablation stimulated thyroglobulin (psTg) before 131I treatment combined with lymph node ratio (LNR) in predicting 131I treatment response in patients with papillary thyroid cancer (PTC). Methods:From January 2016 to December 2018, 178 PTC patients (47 males, 131 females; age (43.2±12.6) years) treated with 131I in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. According to 131I treatment response, patients were divided into excellent response (ER) group and non-ER group. The clinical data of the two groups were compared by χ2 test, independent-sample t test and Mann-Whitney U test. The cut-off values and AUCs of psTg and LNR to predict treatment response were calculated according to the ROC curve. Factors affecting 131I treatment response were analyzed by logistic multivariate regression analysis. Results:There were 118 patients (66.3%, 118/178) in ER group and 60 patients (33.7%, 60/178) in non-ER group, and there were significant differences in N stage ( χ2=11.15, P=0.004), 131I treatment dose ( χ2=12.65, P<0.001), American Thyroid Association (ATA) initial risk stratification ( χ2=15.25, P<0.001), number of metastatic lymph nodes ( χ2=22.63, P<0.001), LNR ( U=1 506.00, P<0.001) and psTg ( U=919.00, P<0.001) between the two groups. The cut-off values of psTg and LNR predicting ER were 3.97 μg/L and 0.29, with the AUC of 0.870 and 0.787 respectively. PsTg (odds ratio ( OR)=10.88, 95% CI: 4.67-25.36, P<0.001) and LNR ( OR=5.30, 95% CI: 1.85-15.23, P=0.002) were independent factors to predict 131I treatment response in PTC patients. When psTg≥3.97 μg/L, LNR ( OR=9.40, 95% CI: 2.06-42.92, P=0.004) was an independent factor affecting 131I treatment response in PTC patients. Conclusions:PsTg and LNR are independent factors affecting 131I treatment response in PTC patients. When psTg≥3.97 μg/L, LNR can be used as a supplementary factor to predict 131I treatment response. The combination of psTg and LNR can better predict 131I treatment response in PTC patients.

ObjectiveTo investigate whether there exists gender differences in mechanical pain hypersensitivity induced by the subcutaneous injection of macrophage colony-stimulating factor （M-CSF） in normal mice and to explore the preliminary mechanism. MethodsThirty 10-week-old C57BL/6J mice were randomly divided into three groups， (n = 10 mice/group, half male and half female). The albumin control group （BSA， 0.3 μg）， low dose M-CSF group （L M-CSF， 0.075 μg） and high dose M-CSF group （H M-CSF， 0.3 μg） received 50 μL BSA or M-CSF injected subcutaneously into the left medial thigh once daily for 3 consecutive days. Before and after drug administration， von-Frey mechanical sensitivity test was used to detect the mechanical paw withdrawal threshold （PWT） in each group. Immunofluorescence was performed to examine the expression changes of Ionized calcium-binding adaptor molecule 1 (Iba1) in skin， calcitonin gene-related peptide （CGRP） and phosphorylated ERK1/2 （p-ERK） in L5-L6 DRG and lumbar spinal dorsal horn. ResultsIn female mice， only high dose of M-CSF caused mechanical allodynia， whereas in male mice both doses produced marked allodynia. Mechanically， high-dose M-CSF induced massive aggregation of subcutaneous macrophages （marked by Iba1） in male and female mice， but more dramatic dependence in female mice. Similar gender differences were also found in the increase of p-ERK and CGRP expression in dorsal root ganglion （DRGs）. Notably， CGRP expression was especially elevated in the fibers of DRG in male mice. Correspondingly， the expressions of p-ERK and CGRP⁺ terminals in the superficial spinal dorsal horn of male mice were significantly higher than those of female mice after M-CSF treatment. ConclusionSubcutaneous injection of M-CSF triggers sexual dimorphism in mechanical pain hypersensitivity, which is related with differential changes in peripheral macrophage expansion and sensitization of the nociceptive pathway.

The complexity of oral ulcerations poses considerable diagnostic and therapeutic challenges to oral specialists. The expert consensus was conducted to summarize the diagnostic work-up for difficult and complicated oral ulcers, based on factors such as detailed clinical medical history inquiry, histopathological examination, and ulceration-related systemic diseases screening. Not only it can provide a standardized procedure of oral ulceration, but also it can improve the diagnostic efficiency, in order to avoid misdiagnosis and missed diagnosis.
Consensus ; Humans ; Oral Ulcer/therapy*

AIM: To explore the therapeutic effect and mechanism of Shugan Jianpi Formula on liver fibrosis mice based on TLR4/MyD88/NLRP3 signaling axis. METHODS: The chemical liver fibrosis mouse model was established by carbon tetrachloride (CCl

objectiveTo investigate the mechanism of histone deacetylase inhibitors （HDACIs） in suppressing glioma cell proliferation. MethodsGlioma cell lines U251 and H4 were cultured in vitro and treated with HDACIs， including LBH589， M344 and SAHA， MTT assay， flow cytometry， RT-qPCR assay and western blotting were perfomed to determine the cell viability， cell cycle progression， mRNA and protein expression of minichromosome maintenance protein family （MCM2-7）， respectively. BrdU assay was performed to detect the DNA replication in the U251 cells after they were treated with 0.5 µmol/L LBH589 and 0.5 µmol/L TSA. MTT assay and flow cytometry were performed to determine the viability and cell cycle progression of U251 and H4 cells respectively after they were treated with ciprofloxacin （CPX）. ResultsCompared with those in control group， in HDACIs group， the cell viability was significantly decreased； the viability of cells treated with 0.5 µmol/L LBH589 for 12， 16， 24 h was significantly lower and the longer the LBH589 treatment， the lower the viability （P<0.05）. The percentage of U251 and H4 cells in S-phase was significantly lower （P<0.05）. The mRNA and protein expression of MCM2-7 was significantly decreased （P<0.05）. BrdU incorporation rate was lower. The cell viability and S-phase cell percentage of U251 and H4 cells treated with 0.5 mmol/L LBH589 in CPX group were significantly decreased （both P<0.05）. ConclusionHDACIs suppress glioma cell proliferation via downregulating MCM2-7 expression.

ObjectiveTo investigate the consistency of the brain structure volume estimation based on Synthetic MRI （SyMRI） and T1-FSPGR images in healthy children and youths. MethodsWe prospectively collected the brain SyMRI and T1-FSPGR images of 38 healthy children with age range of 6~13 years old and 30 healthy youths with age range of 22~26 years old. The Sythetic MR software and FreeSurfer software were used to measure the total gray matter volume （GMV）， total white matter volume （WMV）， brain parenchyma volume （BPV） and intracranial volume （ICV） based on SyMRI and T1-FSPGR images respectively. Paired t test， Pearson’s correlation analysis and interclass correlation coefficient （ICC） were used to evaluate the association between SyMRI and T1 derived measurements. ResultsThe volumes estimated by two methods in two groups showed differences in paired t test （P＜0.05）. Nevertheless， both in children and youths， the measurements of GMV， WMV， BPV and ICV all showed noticeable correlation and consistency between the two brain volume estimation methods ［r values are 0.691， 10.577， 0.938， 0.796 in children group and 0.657， 0.623， 0.933， 0.881 in adult group， P＜0.001； ICC95%CIs are 0.816 （0.647， 0.905）， 0.732 （0.484， 0.861）， 0.968 （0.938， 0.983） and 0.880 （0.770， 0.938］ in children group and 0.751 （0.476， 0.881）， 0.760 （0.496， 0.886）， 0.962 （0.920， 0.982）， and 0.936 （0.866， 0.970）in youth group］. ConclusionsThe brain segmentation and volume estimation based on SyMRI can acquire the measurements which have statistical difference but powerful association with that acquired from T1-FSPGR images， which suggests this new method have a good prospect for clinical use and scientific research.