Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.Extensive het-erogeneity exists in the clinical course and prognosis of GISTs due to multiple genetic mutations.Since the advent of tyrosine kinase inhibit-ors(TKIs),such as imatinib,the survival of patients with GISTs has substsntially improved.However,progression or metastasis often occurs in these patients.For advanced and metastatic GISTs,drug selection and surgical indications have been studied and debated in recent years.With further research in etiology and TKI resistance,novel target agents such as ripretinib,avapritinib,and other pathway inhibitors have been introduced into clinical practice,enabling a more individualized and accurate treatment modality for advanced and metastatic GISTs.This review provides an update on the current therapeutic development landscape in advanced and metastatic GISTs.

Objective:To evaluate the prognostic value of tumor burden score(TBS)combined with serum tumor markers in patients with resectable colorectal liver metastasis(CRLM)after curative hepatectomy.Methods:We retrospectively retrieved and analyzed clinicalpatho-logical data of patients with CRLM who underwent curative hepatectomy between Jan 2012 to Dec 2023 in The First Affiliated Hospital of Chongqing Medical University.Serological tumor markers and TBS were utilized to generate prediction model,where the serological index was derived from the sum of carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9)levels,and TBS was calculated from preoperative radiological images.The cutoff values were determined as the sum of CEA and CA19-9 levels and preoperative TBS.The pa-tients were then categorized based on prediction parameters into low-risk(lacking any high-level index),medium-risk(with one high-level in-dex)and high-risk(with two high-level indices)groups.Overall survival(OS)and disease-free survival(DFS)were compared using Kaplan-Meier curves,and multivariate Cox regression analysis was performed to determine possible prognostic risk factors.The receiver operating characteristic curve(ROC)and C-index were employed to assess the discriminatory power of the prediction model.Results:Median follow-up time was 43(4-112)months.Kaplan-Meier survival analysis suggested that the median OS time and 5-year OS of low-,median-,and high-risk groups were 64,54,and 30 months and 55%,38%,and 23%respectively(P=0.001 9).The median DFS time and 3-year DFS were 36,22,and 11 months,and 47%,35%,and 16%respectively(P<0.001).Multivariate Cox regression analysis revealed that in-dependent prognostic risk factors for postoperative OS were the sum of CEA and CA19-9 level(hazard rstio[HR]=1.81,95%confidence inter-val[CI]:1.09-3.01,P=0.021),TBS(HR=1.42,95%CI:1.02-2.84,P=0.032),bilobar metastasis(HR=1.99,95%CI:1.25-3.16,P=0.004),and primary tumor nodal invasion(HR=1.51,95%CI:1.37-3.34,P=0.028).Multivariate Logistic regression analysis showed that the sum of CEA and CA19-9 levels(odds ratio[OR]=2.44,95%CI 1.26-4.71,P=0.008)and TBS(OR=2.95,95%CI:1.50-5.78,P=0.002)associated significantly with postoper-ative recurrence.The ROC curve and C-index revealed that serum tumor markers combined with TBS(area under the curve=0.630,95%CI:0.552-0.707,P<0.05;C-index=0.627)were more effective in predicting the prognosis of patients with CRLM than either CEA or TBS alone.Conclusions:The prediction model based on serum tumor markers combined with TBS demonstrated better efficacy than any single serolo-gical or radiological index and may provide new insights aiding individualized and accurate clinical decision-making for patients with CRLM.

OBJECTIVETo investigate the antioxidant and anti-endotoxin effects of propofol on endothelial cells and the possible mechanisms.

METHODSCultured endothelial cells were treated with hydrogen peroxide (H(2)O(2)), propofol + H(2)O(2), lipopolysaccharide (LPS) and propofol + LPS, respectively. Endothelial cell damage was monitored for possible lactic dehydrogenase (LDH) release. The transcription and the protein expression levels of endothelial nitric oxide synthase (eNOS) were measured.

RESULTSLDH release was higher in groups treated with H(2)O(2) or LPS than in the control group. After pretreatment with propofol, the effects induced by H(2)O(2) were attenuated, but propofol did not decrease the LDH release induced by LPS. Both H(2)O(2) and LPS significantly increased the eNOS transcript levels and the increases were significantly attenuated after pretreatment with propofol. Both H(2)O(2) and LPS significantly increased the eNOS protein expression and the increase was attenuated after pretreatment with propofol.

CONCLUSIONPropofol could protect endothelial cells against oxidative stress by inhibiting eNOS transcription and protein expression, but could not antagonise endotoxin induced cell injuries.

Antioxidants ; pharmacology ; Endothelium, Vascular ; cytology ; drug effects ; metabolism ; Endotoxins ; antagonists & inhibitors ; Free Radical Scavengers ; pharmacology ; Humans ; In Vitro Techniques ; Lipopolysaccharides ; pharmacology ; Nitric Oxide ; pharmacology ; Nitric Oxide Synthase ; biosynthesis ; Nitric Oxide Synthase Type III ; Propofol ; pharmacology

Background: Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway. Methods: We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole. Results: 1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3–cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group. Conclusion We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

This article reported a patient with familial dysalbuminemic hyperthyroxinemia (FDH). A 38-year-old male occasionally found to have increased FT 4 level with normal FT 3 and TSH on routine physical examination was admitted to our hospital. Thyroid function was rechecked and found that the levels of TT 4, FT 4, rT 3 were increased, while TT 3, FT 3, TSH, TRAb, TPOAb and TGAb were normal. The patient had no other symptoms of thyrotoxicosis except occasional diarrhea. Gene sequencing revealed a heterozygous mutation of c. 653G>A (p.R218H) in exon 7 of albumin (ALB) gene, therefore the patient was confirmed as a case of FDH.

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice ; Animals ; Butyric Acid/metabolism* ; Ketone Bodies/metabolism* ; Liver/metabolism* ; Hydroxybutyrates/metabolism* ; Down-Regulation ; Sirtuins/metabolism* ; Hydroxymethylglutaryl-CoA Synthase/metabolism*

The transcription factor nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-κB) is expressed in brown adipocytes, but its role remains largely unknown in the cells. This issue was addressed in current study by examining NF-κB in brown adipocytes in vitro and in vivo. NF-κB activity was increased by differentiation of brown adipocytes through elevation of p65 (RelA) expression. The transcriptional activity of NF-κB was induced by the cold stimulation with an elevation in S276 phosphorylation of p65 protein. Inactivation of NF-κB in brown adipocytes made the knockout mice [uncoupling protein 1 (Ucp1)-CreER-p65^f/f, U-p65-KO] intolerant to the cold environment. The brown adipocytes exhibited an increase in apoptosis, a decrease in cristae density and uncoupling activity in the interscapular brown adipose tissue (iBAT) of p65-KO mice. The alterations became severer after cold exposure of the KO mice. The brown adipocytes of mice with NF-κB activation (p65 overexpression, p65-OE) exhibited a set of opposite alterations with a reduction in apoptosis, an increase in cristae density and uncoupling activity. In mechanism, NF-κB inhibited expression of the adenine nucleotide translocase 2 (ANT2) in the control of apoptosis. Data suggest that NF-κB activity is increased in brown adipocytes by differentiation and cold stimulation to protect the cells from apoptosis through down-regulation of ANT2 expression.