To report diagnosis and treatment of a patient with rectal cancer and synchronous liver metastases, accompanied by severe coronary artery stenosis and cardiac insufficiency, and to provide a reference for clinical decision-making in such cases through introducing the treatment contradiction, the choice of systemic treatment plan and the timing of operation, and the final outcome. After definitive diagnosis, the patient received systemic therapy with cetuximab＋irinotecan＋oxaliplatin＋raltitrexed, and along with oral medication to improve cardiac function, followed by elective coronary revascularization. After revascularization, the cardiac function of patient was fully improved. And the tumor lesion was effectively controlled after antitumor therapy. Once the cardiac condition of patient stabilized, two-stage surgical resection of the primary rectal cancer and liver metastases was performed, ultimately achieving tumor-free status, and discharged.

BACKGROUND:Previous studies have found that neuronal damage caused by continuous excessive fluoride exposure is related to Ca2+overload,but the mechanism of Ca2+flow conversion between intracellular calcium stores and cell apoptosis damage is still unclear.OBJECTIVE:To investigate the effect of fluoride exposure on Ca2+transport channel proteins and apoptosis levels in the mitochondria-associated endoplasmic reticulum membrane of primary cultured neural cells.METHODS:Primary nerve cells of neonatal SD rats were cultured in vitro and identified by immunofluorescence staining with neuronal nucleus-specific antibody up to day 7.The nerve cells were divided into control group(containing 0 mmol/L sodium fluoride),low fluoride group(containing 0.5 mmol/L sodium fluoride),and high fluoride group(containing 1 mmol/L sodium fluoride).The cell morphological changes were observed by light microscope 24 hours after fluorine exposure.The expression levels of apoptosis-related protein BAX/BCL-2 and calcium transfer-related pathways VDAC1,GRP 75,and IP3R were detected using western blot assay.The expression levels of VDAC1,GRP 75,and IP3R mRNA were detected by RT-PCR.Ca2+levels were detected by Rhood-2AM Ca2+probe.Mitochondrial membrane potential detection kit was used to detect the change in mitochondrial membrane potential.The level of apoptosis was determined by flow cytometry and TUNEL staining.RESULTS AND CONCLUSION:(1)The purity of neurons cultured on day 7 had been determined to be over 90％,with few impurities,good growth status,and tight cell network connections,meeting the requirements of subsequent experiments.(2)Compared with the control group,growth of neural cell clusters in the low-fluoride group and the high-fluoride group increased;the processes were broken;the cell body was rounded,and the connection network between cells was destroyed.Compared with the low-fluoride group,the cell damage changes in the high-fluoride group were more obvious.(3)Compared with the control group,the protein expressions of VDAC1,GRP75,and IP3R were increased in the low-fluoride group and the high-fluoride group(P＜0.05),and the ratio of apoptosis-related protein BAX/BCL-2 was increased(P＜0.05).Compared with the control group,the expression of VDAC1 and GRP75 mRNA in the low-fluoride group was significantly increased(P＜0.05);the expression levels of VDAC1,GRP75,and IP3R mRNA in the high-fluoride group were significantly increased(P＜0.01).(4)The level of cell apoptosis increased significantly after fluoride exposure,and the high-fluoride group was significantly higher than the control and low-fluoride groups(P＜0.01).(5)After fluoride exposure,the concentration of mitochondrial Ca2+in nerve cells increased significantly(P＜0.05),the mitochondrial membrane potential decreased(P＜0.01),and the degree of damage in the high-fluoride group was more obvious(P＜0.05).The results show that fluoride exposure impairs the morphological structure of primary neural cells,resulting in upregulation of Ca2+transfer pathway protein expression between the endoplasmic reticulum and mitochondria,mitochondrial Ca2+overload,mitochondrial damage,and increased levels of apoptosis.

BACKGROUND:Previous studies have found that neuronal damage caused by continuous excessive fluoride exposure is related to Ca2+overload,but the mechanism of Ca2+flow conversion between intracellular calcium stores and cell apoptosis damage is still unclear.OBJECTIVE:To investigate the effect of fluoride exposure on Ca2+transport channel proteins and apoptosis levels in the mitochondria-associated endoplasmic reticulum membrane of primary cultured neural cells.METHODS:Primary nerve cells of neonatal SD rats were cultured in vitro and identified by immunofluorescence staining with neuronal nucleus-specific antibody up to day 7.The nerve cells were divided into control group(containing 0 mmol/L sodium fluoride),low fluoride group(containing 0.5 mmol/L sodium fluoride),and high fluoride group(containing 1 mmol/L sodium fluoride).The cell morphological changes were observed by light microscope 24 hours after fluorine exposure.The expression levels of apoptosis-related protein BAX/BCL-2 and calcium transfer-related pathways VDAC1,GRP 75,and IP3R were detected using western blot assay.The expression levels of VDAC1,GRP 75,and IP3R mRNA were detected by RT-PCR.Ca2+levels were detected by Rhood-2AM Ca2+probe.Mitochondrial membrane potential detection kit was used to detect the change in mitochondrial membrane potential.The level of apoptosis was determined by flow cytometry and TUNEL staining.RESULTS AND CONCLUSION:(1)The purity of neurons cultured on day 7 had been determined to be over 90％,with few impurities,good growth status,and tight cell network connections,meeting the requirements of subsequent experiments.(2)Compared with the control group,growth of neural cell clusters in the low-fluoride group and the high-fluoride group increased;the processes were broken;the cell body was rounded,and the connection network between cells was destroyed.Compared with the low-fluoride group,the cell damage changes in the high-fluoride group were more obvious.(3)Compared with the control group,the protein expressions of VDAC1,GRP75,and IP3R were increased in the low-fluoride group and the high-fluoride group(P＜0.05),and the ratio of apoptosis-related protein BAX/BCL-2 was increased(P＜0.05).Compared with the control group,the expression of VDAC1 and GRP75 mRNA in the low-fluoride group was significantly increased(P＜0.05);the expression levels of VDAC1,GRP75,and IP3R mRNA in the high-fluoride group were significantly increased(P＜0.01).(4)The level of cell apoptosis increased significantly after fluoride exposure,and the high-fluoride group was significantly higher than the control and low-fluoride groups(P＜0.01).(5)After fluoride exposure,the concentration of mitochondrial Ca2+in nerve cells increased significantly(P＜0.05),the mitochondrial membrane potential decreased(P＜0.01),and the degree of damage in the high-fluoride group was more obvious(P＜0.05).The results show that fluoride exposure impairs the morphological structure of primary neural cells,resulting in upregulation of Ca2+transfer pathway protein expression between the endoplasmic reticulum and mitochondria,mitochondrial Ca2+overload,mitochondrial damage,and increased levels of apoptosis.

Bronchiolar adenoma (BA) is a rare type of lung tumor characterized by bilayered epithelial cells having a continuous basal layer and a luminal layer. It resembles mucinous adenocarcinoma (MA) on frozen section, with difficulty in distinguishing the basal layer. Immunohistochemistry is the best choice for verifying the diagnosis. This study aimed to comprehensively characterize three cases of BA-combined carcinoma using clinical, histopathological, and genetic features. BA and carcinoma sections were subjected to next-generation sequencing, respectively. It was hypothesized that while different mutation forms matched different regions, BA and lung adenocarcinoma shared the same gene mutation when they co-occurred in the same location. BA with extensive carcinoma is extremely rare and presents diagnostic challenges due to its overlap with conditions such as MA. Because of its distinctive morphological characteristics, BA may be regarded as a low-grade malignancy, particularly during a confusing evaluation. A multifaceted examination of clinical, radiological, immunohistochemical, and genetic data is necessary for an accurate diagnosis.

OBJECTIVE: To evaluate the effect of palliative care on drug use, medical service utilization and medical expenditure of patients with advanced cancer. METHODS: A cohort of patients including pal-liative care and standard care was constructed using the medical records of the patients in Peking University Cancer Hospital from 2018 to 2020, and coarsened exact matching was used to match the two groups of patients. The average monthly opioid consumption, hospitalization rate, intensive care unit (ICU) rate and operation rate, and the average monthly total cost were selected to evaluate drug use, medical service utilization and medical expenditure. Chi-square test and Wilcoxon signed rank test were used to compare the differences between the two groups before and after exposure and the change in the palliative care group. The net impact of palliative care on the patients was calculated using the difference-in-differences analysis. RESULTS: In this study, 180 patients in the palliative care group and 3 101 patients in the stan-dard care group were finally included in the matching, and the matching effect of the two groups was good (L₁ < 0.1). Before and after exposure, the average monthly opioid consumption in the palliative care group was significantly higher than that in the standard care group (Before exposure: 0.3 DDD/person-month vs. 0.1 DDD/person-month, P < 0.01; After exposure: 0.7 DDD/person-month vs. 0.1 DDD/person-month, P < 0.01; DDD refers to defined daily dose), palliative care significantly increased the average monthly opioid consumption in the patients (0.3 DDD/person-month, P < 0.01). The hospitalization rate (48.9% vs. 74.3%, P < 0.01) and operation rate (3.9% vs. 8.8%, P < 0.01) of the patients in palliative care group were significantly lower than those in standard care group, and the ICU rate became similar between the two groups (1.1% vs. 1.6%, P=0.634). Palliative care significantly reduced the patients ' hospitalization rate (-25.6%, P < 0.01), ICU rate (-4.9%, P < 0.01) and operation rate (-14.5%, P < 0.01). Before and after exposure, the average monthly total costs of pal-liative care group were slightly higher than those of standard care group (Before exposure: 20 092.3 yuan vs. 19 132.8 yuan, P=0.725; After exposure: 9 719.8 yuan vs. 8 818.8 yuan, P=0.165). Palliative care increased the average monthly total cost by 2 208.8 yuan, but it was not statistically significant (P=0.316). CONCLUSION Palliative care can increase the opioid consumption in advanced cancer patients, reduce the rates of hospitalization, ICU and surgery, but has no significant effect on medical expenditure.
Humans ; Palliative Care/economics* ; Neoplasms/drug therapy* ; Analgesics, Opioid/economics* ; Male ; Female ; Middle Aged ; Aged ; Hospitalization/economics* ; Intensive Care Units/statistics & numerical data* ; Health Expenditures/statistics & numerical data* ; Adult ; Drug Utilization/statistics & numerical data* ; Patient Acceptance of Health Care/statistics & numerical data*

Objective:To compare the clinical outcomes of reconstruction of oral and maxillofacial soft tissue defects using superficial circumflex iliac artery perforator flap （SCIA PF） and radial forearm free flap （RFF）. Methods:A retrospective analysis was conducted on 90 patients with head, neck, and maxillofacial tumors who were treated in our department from June 2019 to January 2024. Patients were divided into two groups based on the surgical method used: the SCIA group（n=45）, who underwent reconstruction with SCIA PF, and the RFF group（n=45）, who received RFF reconstruction. Six months postoperatively, clinical efficacy was evaluated by comparing flap swelling, flap survival rate, and patient satisfaction. Oral function was assessed using standardized scoring systems before surgery, at 1 week, 3 months, and 6 months post-surgery. Hemorheological parameters, including high-shear viscosity（shear rate 200/s）, low-shear viscosity（shear rate 30/s）, plasma viscosity, erythrocyte aggregation index, and erythrocyte sedimentation rate（ESR）, were also measured at each time point. Results:Compared with the RFF group, the SCIA group showed significantly larger flap size, longer flap harvesting and reconstruction times, earlier nasogastric tube removal and oral intake initiation, higher scores in all aspects of oral function, reduced flap edema and faster resolution, higher flap survival rates, and greater overall satisfaction （all P<0.05）. During the follow-up period （preoperative, 1 week, 3 months, and 6 months post-surgery）, hemorheological indices including high-and low-shear viscosity, plasma viscosity, erythrocyte aggregation index, and ESR progressively decreased in the SCIA group （P<0.05）. In the RFF group, these parameters improved significantly by 6 months postoperatively compared with preoperatively and 1-week postoperatively, with a notable decrease in erythrocyte aggregation index at 6 months （P<0.05）. Conclusion:Compared with RFF, SCIA PF provides larger flaps, better functional recovery, higher patient satisfaction, improved flap survival, fewer complications, and more favorable hemorheological profiles following reconstructive surgery for oral and maxillofacial defects.
Humans ; Perforator Flap/blood supply* ; Plastic Surgery Procedures/methods* ; Retrospective Studies ; Free Tissue Flaps ; Iliac Artery/transplantation* ; Forearm/surgery* ; Male ; Female ; Soft Tissue Injuries/surgery* ; Head and Neck Neoplasms/surgery* ; Middle Aged ; Treatment Outcome ; Adult

Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

Coronary atherosclerotic heart disease is a major cardiovascular condition driven by atherosclerosis, distinguished by chronic inflammation and dysregulated lipid metabolism. The gut microbiota plays an essential role in human health and disease, with research indicating a strong association between gut microbial metabolism and the development and progression of coronary heart disease. This article provides a review of the relationship between gut microbiota and coronary heart disease, as well as the mechanisms by which traditional Chinese medicine regulates digestive tract microbiota to treat coronary heart disease, which systematically explains how the gut microbiota, through metabolic products and immune regulation, contributes to the occurrence and progression of coronary heart disease, and summarizes recent advances in research on traditional Chinese medicine's regulation of gut microbiota for treating coronary heart disease. It aims to provide further reference and insights for exploring the relationship between gut microbiota and coronary heart disease, as well as traditional Chinese medicine approaches for treating coronary heart disease.