Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown. METHODS: mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts. RESULTS: We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway. CONCLUSION: Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.

Serum Lipid Level in Evaluating Chinese Pancreatic Neuroendocrine Neoplasms: A Retrospective Study.

BACKGROUND: Pancreatic neuroendocrine neoplasms (p-NENs) are relatively rare and highly heterogeneous. Dyslipidemia may be related to the risk of developing p-NENs, although dyslipidemia in patients with p-NENs is rarely reported. In this study, the clinical characteristics of p-NENs patients with different lipid levels and their prognostic value in p-NENs patients were evaluated. METHODS: Patients (n=211) with p-NENs hospitalized at Jiangsu Neuroendocrine Tumor Centre of Jiangsu Province Hospital from December 2018 to December 2022 were enrolled. Clinical data related to p-NENs were collected. Based on the EGA database, the related lipoprotein, low-density lipoprotein receptor (LDLR) and high-density lipoprotein binding protein (HDLBP) mRNA in p-NENs and paratumoral tissues and the follow-up information of p-NENs were evaluated. RESULTS: A total of 175 p-NENs patients ultimately met the inclusion criteria. The ki67 index was higher in p-NENs patients with elevated lipid with the proportion of≥5, and in those with AJCC stage III and stage IV than p-NENs patients with low-level lipid. In p-NENs patients, the expression of HDLBP mRNA was downregulated in p-NENs tissues compared to the paratumoral tissues. Survival analysis showed that serum lipids had no effect on the prognosis of p-NENs; however, high LDLR level p-NENs were at the risk of poor survival. CONCLUSION: Serum lipid level in p-NENs can affect the grading and staging, but the correlation with the prognosis of p-NENs is not significant. However, dyslipidemia may be a potential predictor of p-NENs.

Anti-VEGF Drugs in Age-Related Macular Degeneration: A Focus on Dosing Regimen-Related Safety and Efficacy.

Age-related macular degeneration (AMD) is one of the main causes of visual impairment and severe visual loss, and can progress to two advanced forms-neovascularization and atrophic. The field of anti-AMD drugs has undergone huge developments in recent years, from single-target intravitreal administration to current clinical studies with multi-target and non-invasive agents, offering interesting new pharmacological opportunities for the treatment of this disease. Hence, we summarize some of the approved anti-vascular endothelial growth factor (VEGF) drugs for neovascular AMD, especially their structural characteristics, clinical manifestations, dosing regimens, and safety issues of the anti-VEGF drugs highlighted. In addition, advances in atrophic AMD drug research are also briefly described.

Efficacy and safety of modified endoscopic submucosal tunnel dissection for superficial esophageal circumferential lesions.

To evaluate the efficacy and safety of intra-tunnel dissection using hemostatic forceps and needle-type device for patients with esophageal circumferential lesions (ECLs). Patients with ECLs were enrolled in the study and underwent endoscopic submucosal tunnel dissection (ESTD) or hemostatic forceps-based ESTD (ESFTD). All patients were divided into three subgroups according to longitudinal length of the lesions (LLLs): >8 cm, 4-8 cm and < 4 cm. The clinical data such as gender, age, length of lesions and operating time were collected. A total of 152 patients were included in this study and comprised 80 cases of ESFTD and 72 cases of ESTD. The procedure time was markedly shorter in the ESFTD group than in the ESTD group (P < 0.001). Moreover, ESFTD significantly increased the rate of complete resection and reduced specimen injury in LLLs >8 cm and 4-8 cm subgroup compared with ESTD (P < 0.001), but not in <4 cm subgroup (P > 0.05). The perforation and infection rate were similar in ESFTD and ESTD group (P > 0.05). However, ESFTD effectively decreased the muscular injury rate' the duration of chest pain and the time from endoscopic surgery to first occurrence of esophageal stenosis compared with ESTD group (P < 0.01). ESFTD has better efficacy and safety than ESTD in the treatment of ECLs, especially for large lesions. ESFTD could be recommended for patients with ECLs.

Diagnosis and treatment of a small intestinal neuroendocrine neoplasm by double balloon enteroscopy combined with laparoscopy: a case report

We report the case of a jejunum neuroendocrine neoplasm with liver metastases, the lesion showed somatostatin receptor expression in the junction of duodenum and jejunum without enlarged lymph nodes in 68Ga-DOTA-NOC PET/CT scan, definitive diagnosis and treatment depend on double-balloon enteroscopy and laparoscopy. This is a meaningful and thought-provoking process. (AU)

Investigation of the pharmacological effect and mechanism of mountain-cultivated ginseng and garden ginseng in cardiovascular diseases based on network pharmacology and zebrafish experiments.

Ginseng (Panax ginseng C.A. Mey) is a kind of perennial herb of the Panax genus in the Araliaceae family. The secondary metabolites of mountain-cultivated ginseng (MCG) and garden ginseng (GG) vary greatly due to their different growth environments. To date, the differences in their pharmacological effects on cardiovascular diseases (CVDs) and their clinical applications remain unclear. To distinguish between the components of MCG and GG, ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. Next, the relationship between the expression of metabolites and the categories of the sample were analyzed using supervised partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis. A network-based pharmacology approach was developed and applied to determine the underlying mechanism of different metabolites in CVD. In the present study, the role of MCG and GG in angiogenesis and their protective effects on damaged blood vessels in a vascular injury model of zebrafish were investigated. Using UPLC-Q-TOF/MS, 11 different metabolites between MCG and GG were identified. In addition, 149 common target genes associated with the metabolites and CVD were obtained; these targets were related to tumor protein P53, proto-oncogene tyrosine-protein kinase Src, human ubiquitin-52 amino acid fusion protein, ubiquitin-40S ribosomal protein S27a, polyubiquitin B, signal transducer and activator of transcription 3, isocitrate dehydrogenase 1, vascular endothelial growth factor A, glycose synthase kinase-3B, and coagulation factor II and were associated with the regulation of the phosphoinositide 3-kinase-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the hypoxia-inducible factor-1 (HIF-1) signaling pathway, which play important roles in the curative effect in CVD treatment. Both types of ginseng can promote the growth of the subintestinal vessel plexus and protect injured intersegmental vessels through the HIF-1α/vascular endothelial growth factor signaling pathway in a dose-dependent manner. In addition, MCG has a stronger impact than GG. This is the first time metabolomics and network pharmacology methods were combined to study the difference between MCG and GG on CVDs, which provides a significant theoretical basis for the clinical treatment of CVD with two kinds of ginseng.

[Textual research on classical famous prescription Dajianzhong Decoction].

The classical famous prescription Dajianzhong Decoction is recorded in Synopsis of the Golden Chamber written by Zhang Zhongjing in the Eastern Han Dynasty. It has a long history and definite clinical effects, while this prescription has not been manufactured into Chinese patent medicine preparation. We collected many ancient books of traditional Chinese medicine(TCM) by using the method of bibliometrics and got 211 valid data terms which involved 67 ancient books. The history, main treated syndromes, formulation principle, origins and processiong of medicinal materials, and decoction method of Dajianzhong Decoction were analyzed. Despite the different views of various generations of medical experts toward the composition of this prescription, the compatibility ratio of Ginseng Radix et Rhizoma to Zingiberis Rhizoma Recens is constant. Furthermore, we explored the origins of synonyms of Dajianzhong Decoction. On the basis of this study, we hope to gain an insight into the research and development of the compound preparations of Dajianzhong Decoction and provide reference for the heritage and innovation of other classical prescriptions.

Diagnosis and treatment of a small intestinal neuroendocrine neoplasm by double balloon enteroscopy combined with laparoscopy: a case report.

We report the case of a jejunum neuroendocrine neoplasm with liver metastases, the lesion showed somatostatin receptor expression in the junction of duodenum and jejunum without enlarged lymph nodes in 68Ga-DOTA-NOC PET/CT scan, definitive diagnosis and treatment depend on double-balloon enteroscopy and laparoscopy. This is a meaningful and thought-provoking process.

Distinct Serum and Fecal Metabolite Profiles Linking With Gut Microbiome in Older Adults With Frailty.

Frailty is a critical aging-related syndrome but the underlying metabolic mechanism remains poorly understood. The aim of this study was to identify novel biomarkers and reveal potential mechanisms of frailty based on the integrated analysis of metabolome and gut microbiome. In this study, twenty subjects consisted of five middle-aged adults and fifteen older adults, of which fifteen older subjects were divided into three groups: non-frail, pre-frail, and frail, with five subjects in each group. The presence of frailty, pre-frailty, or non-frailty was established according to the physical frailty phenotype (PFP). We applied non-targeted metabolomics to serum and feces samples and used 16S rDNA gene sequencing to detect the fecal microbiome. The associations between metabolites and gut microbiota were analyzed by the Spearman's correlation analysis. Serum metabolic shifts in frailty mainly included fatty acids and derivatives, carbohydrates, and monosaccharides. Most of the metabolites belonging to these classes increased in the serum of frail older adults. Propylparaben was found to gradually decrease in non-frail, pre-frail, and frail older adults. Distinct changes in fecal metabolite profiles and gut microbiota were also found among middle-aged adults, non-frail and frail older subjects. The relative abundance of Faecalibacteriu, Roseburia, and Fusicatenibacter decreased while the abundance of Parabacteroides and Bacteroides increased in frailty. The above altered microbes were associated with the changed serum metabolites in frailty, which included dodecanedioic acid, D-ribose, D-(-)-mannitol, creatine and indole, and their related fecal metabolites. The changed microbiome and related metabolites may be used as the biomarkers of frailty and is worthy of further mechanistic studies.

ADAM17 Mediates Hypoxia-Induced Keratinocyte Migration via the p38/MAPK Pathway.

Although hypoxia has been shown to promote keratinocyte migration and reepithelialization, the underlying molecular mechanisms remain largely unknown. ADAM17, a member of the metalloproteinase superfamily, has been implicated in a variety of cellular behaviors such as proliferation, adhesion, and migration. ADAM17 is known to promote cancer cell migration under hypoxia, and whether or how ADAM17 plays a role in hypoxia-induced keratinocyte migration has not been identified. Here, we found that ADAM17 expression and activity were significantly promoted in keratinocytes under hypoxic condition, inhibition of ADAM17 by TAPI-2, or silencing of ADAM17 using small interfering RNA which suppressed the hypoxia-induced migration of keratinocytes significantly, indicating a pivotal role for ADAM17 in keratinocyte migration. Further, we showed that p38/MAPK was activated by hypoxia. SB203580, an inhibitor of p38/MAPK, significantly attenuated the upregulation of ADAM17 as well as the migration of keratinocytes induced by hypoxia. Activation of p38/MAPK by MKK6 (Glu) overexpression, however, had adverse effects. Taken together, our study demonstrated that hypoxia-induced keratinocyte migration requires the p38/MAPK-ADAM17 signal axis, which sheds new light on the regulatory mechanisms of keratinocyte migration. Our study might also help in developing therapeutic strategies to facilitate wound healing in vivo, where cells are migrated in a hypoxic microenvironment.

Cardioprotective Properties of Ginkgo Biloba Extract 80 via the Activation of AKT/GSK3ß/ß-Catenin Signaling Pathway.

Elderly people are more likely to experience myocardial infarction (MI) than young people, with worse post-MI mortality and prognosis. Ginkgo biloba extract 50 (GBE50) is an oral GBE product that matches the German product, EGb761, which has been used to treat acute myocardial infarction (AMI). The extraction purity of GBE50 was improved to form a new formulation, Ginkgo biloba extract 80 (GBE80). This study investigates the effect of GBE80 on aged acute myocardial infarction rats. GBE80 injection is a novel formulation that was prepared by mixing Ginkgo flavonoids and lactones in a 4:1 weight ratio, with a Ginkgo content of more than 80%. Cell Counting Kit-8 was used to determine the biological safety and protective effect of GBE80 on cardiomyocytes against oxidative damage. An aged AMI rat model was developed and used to determine the myocardial infarction weight ratio using triphenyltetrazolium chloride staining. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was applied to detect cell apoptosis in myocardial tissue. Western blotting and immunohistochemistry were used to measure the protein levels of members of the AKT/GSK3ß/ß-catenin pathway in vitro and in vivo, respectively. We found that GBE80 in vitro suppressed H2O2-induced cytotoxicity by promoting AKT/GSK3ß/ß-catenin signaling, while it did not show cytotoxicity to normal cardiomyocytes in the 0-500 µg/ml dose range. After 7 days of administration to aged AMI rats, GBE80 markedly reduced the weight ratio of the infarction and inhibited cell apoptosis in myocardial tissue. Furthermore, the AKT/GSK3ß/ß-catenin signaling pathway was activated by GBE80. These results suggest that GBE80 injection effectively inhibited AMI-induced myocardial damage and in vitro H2O2-induced cardiomyocyte cytotoxicity by activating the AKT/GSK3ß/ß-catenin signaling pathway.

Polarization of ADAM17-driven EGFR signalling in electric field-guided collective migration of epidermal sheets.

Endogenous electric field is considered to play an important role in promoting collective migration of epidermis to the wound centre. However, most studies are focused on the effect of bioelectric field on the movement and migration of single epithelial cell; the molecular mechanisms about collective migration of epidermal monolayers remain unclear. Here, we found that EFs dramatically promoted the collective migration of HaCaT cells towards the anode, activated the sheddase activity of ADAM17 and increased the phosphorylation level of EGFR. Moreover, EGFR phosphorylation and HB-EGF shedding level were significantly decreased by the ADAM17 inhibitor TAPI-2 or siADAM17 under EFs, which subsequently attenuated the directed migration of HaCaT sheets. Notably, the inhibition of EF-regulated collective migration by siADAM17 was rescued by addition of recombinant HB-EGF. Furthermore, we observed that F-actin was dynamically polarized along the leading edge of the migrated sheets under EFs and that this polarization was regulated by ADAM17/HB-EGF/EGFR signalling. In conclusion, our study indicated that ADAM17 contributed to the collective directional movement of the epidermal monolayer by driving HB-EGF release and activating EGFR under EFs, and this pathway also mediated the polarization of F-actin in migrating sheets, which is essential in directional migration.

Changes of Extravascular Lung Water as an Independent Prognostic Factor for Early Developed ARDS in Severely Burned Patients.

An important feature of acute respiratory distress syndrome (ARDS) is fluid lost into the interstitium of lung combined with its compromised reabsorption, resulting in the elevation of extravascular lung water (EVLW). Although ARDS is known as an early, common, and life-threatening complication in major burns, the issue of whether or how the EVLW index (EVLWI) correlates with its prognosis has not been identified yet. In this retrospectively study, 121 severely burned adults with ARDS occurred in 2 weeks postburn were analyzed and divided into two groups: survivors (73 patients) and nonsurvivors (48 patients) according to the 28-day outcome after injury. Compared with nonsurvivors, survivors exhibited bigger EVLWI reduction in day 2 after ARDS onset (ΔEVLWI2), with no differences in ARDS timing and other EVLWI variables. ΔEVLWI2, rather than EVLWI on 2 days after ARDS onset, was identified as an independent prognostic factor even after adjusting other significant factors by Cox proportional hazard analysis. ROC curve analysis showed that ΔEVLWI2 [AUC = 0.723, 95% CI = (0.631-0.816), P < .001] was a relative predictor for survival on 28-day postburn, with a threshold of 1.9 ml/kg (63.0% sensitivity, 77.1% specificity). Kaplan-Meier survival curve analysis confirmed a significantly higher survival rate on 28-day postburn in patients with ΔEVLWI2 > 1.9 ml/kg (log-rank test: χ 2 =14.780, P < .001). Taken together, our study demonstrated that ΔEVLWI2 is an independent prognostic factor for early ARDS in severe burns. ΔEVLWI2 higher than 1.9 ml/kg might predict a higher survival rate in those patients.

[Review of classical prescription Ganjiang Lingzhu Decoction].

Ganjiang Lingzhu Decoction is one of the first 100 classical prescriptions published by China in 2018. According to the published literature, it was found that there is no review on the history, evolution and research progress of this prescription. In order to reflect the history, modifications, quality control and clinical applications, this paper focuses on the origination, evolution, current development and modern studies of Ganjiang Lingzhu Decoction, in the hope of providing a reference for the heritage and innovation of other classical prescriptions.

Disseminated histoplasmosis in an immunocompetent individual diagnosed with gastrointestinal endoscopy: a case report.

BACKGROUND: Histoplasmosis is one of the invasive fungal infections and presents with symptoms mainly in the lungs. Disseminated histoplasmosis (DH) is rare and its lesions in the gastrointestinal tract are even uncommon. The concomitant involvement of the upper and lower gastrointestinal tract has never been described in the immunocompetent individuals. CASE PRESENTATION: A 44-year-old immunocompetent Chinese man presented with fever, hepatosplenomegaly, fungal esophagitis and protuberant lesions with central depression and erosion along the mucous membrane of the colon. The patient was diagnosed as disseminated histoplasmosis by gastrointestinal endoscopy. CONCLUSIONS: Histoplasmosis should be taken caution in patients with fever and hepatosplenomegaly. Actions should be taken to avoid its disseminated infection associated high mortality.

Octreotide-Conjugated Core-Cross-Linked Micelles with pH/Redox Responsivity Loaded with Etoposide for Neuroendocrine Neoplasms Therapy and Bioimaging with Photoquenching Resistance.

The study of multifunctional polymer micelles combined with chemotherapy due to reduced systemic toxicity and enhanced efficacy has attracted intensive attention. Herein, a multifunctional core-cross-linked hybrid micelle system based on mPEG- b-PGu(BA-TPE) and OCT-PEG- b-PGu(DA-TPE) with pH- and redox-triggered drug release and aggregation-induced emission (AIE) active imaging has been developed for active targeting of neuroendocrine neoplasms (NENs), especially neuroendocrine carcinomas (NECs) with poor prognosis. These micelles showed excellent biocompatibility and stability. After the formation of borate ester bonds, core-cross-linked micelles (CCLMs) showed enhanced emission properties. In addition, etoposide (ETO), one of the most important anticancer drugs of NECs, was loaded into the hydrophobic core of micelles by self-assembly with an average diameter of 274.6 nm and spherical morphology. Octreotide (OCT) conjugated onto the micelles enhanced cellular uptake by receptor-mediated endocytosis. ETO-loaded micelles demonstrated the dual-responsive triggered intracellular drug release and great tumor suppression ability in vitro. Compared with free ETO, ETO-loaded CCLMs exhibited a considerable antitumor effect and significantly reduced side effects. Considering the active tumor targeting, dual-responsive drug release and the AIE effect, the polymer micelle system will be a potential candidate for diagnosis and oncotherapy of NENs.

CD9 regulates keratinocyte migration by negatively modulating the sheddase activity of ADAM17.

CD9 is a trans-membrane protein, and has recently been implicated in different physiological and cellular processes, such as cell migration and adhesion. According to previous study, down-regulation of CD9 contributes to keratinocyte migration, critical for wound re-epithelialization. Nevertheless, it is widely believed that tetraspanin CD9 does not have ligands or function as the cell surface receptor, rather it is thought to associate with other transmembrane molecules, thereby mediate keratinocyte migration. Little is known about how CD9 associates with transmembrane molecules in migratory keratinocytes. Here, using confocal microscopy, we observed that tetraspanin CD9 and ADAM17 co-localized on the surface of keratinocytes in the course of wound repair in vivo and in vitro. Co-immunoprecipitation experiments demonstrated a direct association between CD9 and ADAM17 in HaCaT cells and C57-MKs. Functional studies revealed that down-regulation or over-expression of CD9 exerted negative regulatory effects on ADAM17 sheddase activity. This activity is involved in CD9-regulated cell motility and migration. Further studies found that ADAM17 inhibitor-TAPI-2 or siADAM17 significantly abolished the enhanced effect of keratinocyte migration induced by CD9 down-regulation. Meanwhile, the sheddase activity of ADAM17 was inhibited by TAPI-2, which decreased this release of AREG and HB-EGF in CD9-silenced HaCat cells and C57-MKs. Importantly, neutralizing antibody against HB-EGF significant weakened keratinocyte migration and motility in CD9-silenced keratinocytes, and the inhibition of CD9-regulated keratinocyte migration by siADAM17 was rescued by addition of recombinant HB-EGF, activating EGFR/ERK pathway. Collectively, our results suggest that ADAM17 sheddase activity is activated by down-regulation of CD9, thereby mediating shedding of HB-EGF and activation of EGFR/ERK signaling, which crucially affects the keratinocyte migration and wound healing.

Risk factors and the associated limit values for abnormal elevation of extravascular lung water in severely burned adults.

BACKGROUND: Increased extravascular lung water (EVLW) correlates with pulmonary morbidity and mortality in critical illness. The extravascular lung water index (EVLWI), which reflects the degree of EVLW in an individual, increases in the fluid reabsorption stage rather than the initial resuscitation stage in severe burn cases. While many factors contribute to EVLWI variation, the risk factors contributing to its abnormal elevation in severe burns remain unclear. The aim of this study was to identify the risk factors and associated limit values for abnormal elevation of EVLWI during the fluid reabsorption stage in a cohort of severely burned adults. METHOD: This prospective, single-center study included only adults with burn sizes≥50% of the total body surface area (TBSA) who were admitted within 24h after burn. Demographic data were collected, and transpulmonary thermodilution (TPTD) measurements and blood biochemistry tests were performed upon admission and up to day (PBD) 9. Risk factors for abnormal EVLWI were analyzed by logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-offs for each risk factor. RESULTS: Seventy-two patients were ultimately enrolled, with a mean age of 40.3 years and mean burn size of 69.4% TBSA. EVLWI began to abnormally increase (>7ml/kg) on day 3 and up to PBD 9, indicating that a supranormal EVLWI developed in the fluid reabsorption stage. Several relevant factors were considered, including patient age, burn size, intrathoracic blood volume index (ITBVI), pulmonary vascular permeability index (PVPI), cardiac index (CI), systemic vascular resistance index (SVRI), serum albumin, time of first excision and grafting, and number of operations and daily fluid administration. Among these factors, we found that only burn size and ITBVI were significantly correlated with EVLWI variation and were further identified as the independent risk factors for EVLWI abnormality. ROC analysis showed that the limits for predicting a supranormal EVLWI during the fluid reabsorption stage were 65.5% TBSA for burn size and 845ml/m2 for ITBVI. Patients with burn sizes or ITBVIs higher than the limit showed significantly longer mechanical ventilation time and substantially higher occurrences of acute respiratory distress syndrome (ARDS) and pneumonia within two weeks after burn. CONCLUSIONS: Burn size and ITBVI are the independent risk factors for EVLWI abnormality during the fluid reabsorption stage in severely burned adults. The limit values for predicting a supranormal EVLWI in those patients are 65.5% TBSA for burn size and 845ml/m2 for ITBVI.

The Superior Anticancer Effect of Self-Assembled Paclitaxel Nanofibers is Mediated Through Co-Operation Between Enhanced Apoptosis and Autophagic Cell Death.

Paclitaxel (Ptx) has been recommended as one of the main components of first-line chemotherapy for gastric cancer. However, the side effects of Ptx have greatly limited its clinical application because of its poor solubility and emerging resistance. In the current study, we designed novel self-assembled Ptx nanofibers with extremely high drug loading efficiency through conjugation of Ptx with succinic acid (sa), resulting in self-assembled nanofibers without the need for additional polymeric carriers. Cytotoxicity tests showed the superior effect of Ptx-sa against the gastric cancer cell lines SCG7901 and BGC823, but there was an obvious discrepancy between the number of apoptotic cells and dead cells, which indicates that other mechanisms may be involved in Ptx-sa-induced cell death. Mechanism studies, including apoptosis and autophagy detection, showed that Ptx-sa induced apoptosis and autophagy-induced cell death more efficiently than an equivalent dose of free Ptx. Most importantly, based on TEM and transfection with dual fluorescencelabeled LC3, more autophagosomes and increased autophagic flux were elicited by Ptx-sa in gastric cancer cells than an equivalent dose of free Ptx. Western blotting demonstrated that Ptx-sa induced the expression of LC3 II, a marker of autophagy, much more effectively than free Ptx. Moreover, an in vivo study demonstrated that Ptx-sa nanofibers significantly enhanced the anti-cancer effect of Ptx. Therefore, the self-assembled Ptx-sa nanofibers may exert cytotoxicity by inducing both apoptosis and autophagic cell death and thus might be a promising strategy to strengthen the therapeutic efficacy of Ptx in gastric cancer.

Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma.

Ursolic acid (UA) induces apoptosis in gastric cancer cells by inhibiting cyclooxygenase-2 (COX-2). Paclitaxel (PTX) is an important chemotherapy agent used to treat solid tumors. We evaluated the in vitro antitumor activity of UA in combination with PTX against gastric cancer cells and investigated the mechanisms underlying the combined effects. A cytotoxicity test and flow cytometry were utilized to study the effects of UA and PTX on proliferation and apoptosis, respectively. To further elucidate the mechanism, Western blot analysis was used to assess changes in the expression of a series of related proteins, including COX-2, proliferating cell nuclear antigen (PCNA), Bcl-2, and Bax. UA and PTX dose- and time-dependently inhibited BGC-823 and SGC-7901 gastric cancer cell proliferation. Combined delivery of UA and PTX synergistically reduced cell proliferation and induced apoptosis in these cells by lowering COX-2, PCNA, and Bcl-2 expression and by increasing Bax expression. These results indicate that the synergistic inhibition of proliferation and induction of apoptosis by UA and PTX may be induced by reducing COX-2 expression in gastric cancer cells.