YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression.

Hippo-Yes-associated protein 1 (YAP1) plays an important role in gastric cancer (GC) progression; however, its regulatory network remains unclear. In this study, we identified Copine III (CPNE3) was identified as a novel direct target gene regulated by the YAP1/TEADs transcription factor complex. The downregulation of CPNE3 inhibited proliferation and invasion, and increased the chemosensitivity of GC cells, whereas the overexpression of CPNE3 had the opposite biological effects. Mechanistically, CPNE3 binds to the YAP1 protein in the cytoplasm, inhibiting YAP1 ubiquitination and degradation mediated by the E3 ubiquitination ligase ß-transducin repeat-containing protein (ß-TRCP). Thereby activating the transcription of YAP1 downstream target genes, which creates a positive feedback cycle to facilitate GC progression. Immunohistochemical analysis demonstrated significant upregulation of CPNE3 in GC tissues. Survival and Cox regression analyses indicated that high CPNE3 expression was an independent prognostic marker for GC. This study elucidated the pivotal involvement of an aberrantly activated CPNE3/YAP1 positive feedback loop in the malignant progression of GC, thereby uncovering novel prognostic factors and therapeutic targets in GC.

TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer.

BACKGROUND: The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. METHODS: Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). RESULTS: In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8A expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression. CONCLUSIONS: Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

Plastome Evolution, Phylogenomics, and DNA Barcoding Investigation of Gastrochilus (Aeridinae, Orchidaceae), with a Focus on the Systematic Position of Haraella retrocalla.

Gastrochilus is an orchid genus containing about 70 species in tropical and subtropical Asia with high morphological diversity. The phylogenetic relationships among this genus have not been fully resolved, and the plastome evolution has not been investigated either. In this study, five plastomes of Gastrochilus were newly reported, and sixteen plastomes of Gastrochilus were used to conduct comparative and phylogenetic analyses. Our results showed that the Gastrochilus plastomes ranged from 146,183 to 148,666 bp, with a GC content of 36.7-36.9%. There were 120 genes annotated, consisting of 74 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. No contraction and expansion of IR borders, gene rearrangements, or inversions were detected. Additionally, the repeat sequences and codon usage bias of Gastrochilus plastomes were highly conserved. Twenty hypervariable regions were selected as potential DNA barcodes. The phylogenetic relationships within Gastrochilus were well resolved based on the whole plastome, especially among main clades. Furthermore, both molecular and morphological data strongly supported Haraella retrocalla as a member of Gastrochilus (G. retrocallus).

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment.

BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. CONCLUSION: Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".

Modular access to 1,2-allenyl ketones based on a photoredox-catalysed radical-polar crossover process.

Herein, a new protocol dealing with the preparation of 1,2-allenyl ketones has been successfully developed via the reactions of enynes with radicals enabled by dual photoredox/copper catalysis. Based on the results of a deuteration experiment and the competition reaction between cyclopropanation and allenation, the mechanism based on a photoredox-neutral-catalysed radical-polar crossover process has been proposed. Synthetic applications of allenes have also been demonstrated.

Protective effect of Phaeoporus obliquus polysaccharide against acute liver injury induced by carbon tetrachloride and alcohol in mice.

Studied the optimum extraction process of polysaccharide from Phaeoporus obliquus and the effect of Phaeoporus obliquus polysaccharide on carbon tetrachloride (CCl4)- or alcohol-induced acute liver injury in mice. The main factor in influencing the extraction rate of Phaeoporus obliquus polysaccharide were extraction power and time, which was a kind of pyran glucose by infrared spectroscopy. CCl4 and alcohol were employed respectively to establish CCl4 and alcohol-induced acute liver injury mouse models. Compared with model groups mice, Phaeoporus obliquus polysaccharide treatment at the doses of 100mg/kg and 200mg/kg exhibited an obvious reduction liver index, ALP, ALT, AST levels, MDA content and TNF-α level (p<0.01) and SOD activity was increased, which was in a dose-dependent manner. Compared with the model group, the necrosis degree of hepatocytes was obviously reduced and the small fat droplets were formed in some cytoplasm, especially in high dose group, which the liver cells recovered to the level of normal group. Rt-PCR results showed that the expression of CYP2E1 mRNA in liver tissues of Phaeoporus obliquus polysaccharide groups were significantly reduced, and the difference were statistically significant compared with the model group (p<0.05). These results demonstrated that Phaeoporus obliquus polysaccharide has significantly hepatoprotective effect on CCl4 and alcohol-induced acute liver injury in mice.

Synovial and pulmonary dysfunctions are induced by crosstalk of Smad and Erk pathways in an arthritis model.

In the current experiment, the effects of transforming growth factor (TGF)-ß1/Smad and ERK pathway crosstalk on synovial and pulmonary systems during rheumatoid arthritis have been investigated. For this purpose, rats were divided into normal control (NC) and model control (MC) groups. In the MC group, 0.1 ml Freund's complete adjuvant was injected intradermally into the right hind paw, and the resulting inflammation represented a rheumatoid arthritis model. Joint swelling and changes in lung functions were observed in arthritic rats. Synovial and lung were observed by light and electron microscopies. Enzyme-linked immunosorbent assays were used to detect TGF-ß1, interleukin (IL)-1ß, IL-4, IL-10, interferon-γ (IFN-γ), connective tissue growth factor (CTGF), and fibroblast growth factor (FGF). PCR, immunohistochemistry, and immunoblotting were used to detect changes in Smad and ERK pathways of synovial and lung tissues. Compared with the NC group, toe swelling was elevated in the MC group. Pulmonary functions FEV1, FEF50, FEF75, MMF, and PEF were decreased (P< 0.01). Serum cytokines IL-1ß, IL-4, TGF-ß1, and CTGF were increased, while IFN-γ, IL-10, Th1/Th2 cell ratio, and FGF were decreased (P< 0.01 or P< 0.05). Expression of TGF-ß1 and Smad2/3/4 mRNAs and TGF-ß1, TßRI, TßRII, Smad2/3, p-Smad2/3, and Smad4 proteins in the synovial membrane and lung tissue were increased, and expression of Smad7 mRNA and protein was decreased (P<0.01) or P<0.05). Expression of ERK2 mRNA and p-ERK1/2 protein was increased in the synovial membrane and lung tissue, and expression of ERK1/2 mRNAs and ERK1/2 and p-ERK1/2 proteins was increased in lung tissue (P< 0.01 or P< 0.05). Correlation analysis showed that FEV1 was negatively correlated with TGF-ß1 mRNA and protein in arthritic rats, FEF25 was negatively correlated with Smad4 protein, and FEF50 was negatively correlated with the TßRII protein, and FEF75, TGF-ß1 and Smad3 mRNAs. There was a negative correlation between Smad2/3 protein and a negative correlation between PEF and TGF-ß1 protein (P< 0.05). FEF50 and MMF were positively correlated with Smad7 mRNA (P< 0.05). FEV1 was negatively correlated with ERK2 mRNA, and FEF25 was negatively correlated with p-ERK1/2 protein. FEF75 and MMF were negatively correlated with ERK1/2 and p-ERK1/2, respectively (P< 0.05). ERK1 mRNA was positively correlated with Smad3 mRNA and TßRII protein, ERK2 mRNA was positively correlated with p-Smad2/3, and ERK1/2 protein was positively correlated with Smad2 mRNA, Smad4 protein, p-ERK1/2 protein, Smad4 mRNA, and p-Smad2/3 protein (P< 0.05). p-ERK1/2 protein was negatively correlated with Smad7 protein (P< 0.05). It is concluded that arthritic rats have synovial and systemic pulmonary damage. Smad and ERK pathway crosstalk leads to systemic lesions. Smad and ERK pathways are gradually activated by phosphorylation under the induction of the TGF-ß1 promoter, and then participate in transcriptional activities, leading to the increase in synovial inflammation of arthritis, pulmonary lesions, and decreases in lung functions.

LINC00662 promotes gastric cancer cell growth by modulating the Hippo-YAP1 pathway.

Long non-coding RNAs (lncRNAs) function as vital regulators of the progression of various diseases, particularly cancers. In the present study, utilizing the Cancer Genome Atlas (TCGA) data set and a series of cell experiments and clinical tissue samples assays, we found that LINC00662 expression was significantly up-regulated in gastric cancer (GC) tissues and cell lines. High expression of LINC00662 predicted poor prognosis compared to in patients showing low expression. Knockdown of LINC00662 expression decreased GC cell proliferation and increased the chemo-sensitivity of GC cells. Further, we demonstrated that knockdown of LINC00662 suppressed the Hippo-YAP1 signaling pathway in GC cells. Mechanistically, LINC00662 regulated YAP1-mediated GC cell proliferation by sponging miR-497-5p. Overall, our results revealed a critical role for the LINC00662-miR-497-5p-YAP1 axis in GC cell growth, providing a new target for GC.

Insights into the involvement of noncoding RNAs in 5-fluorouracil drug resistance.

5-Fluorouracil is a classic chemotherapeutic drug that is widely used to treat various cancers. However, patients often exhibit primary or acquired drug resistance during treatment with 5-fluorouracil chemotherapy. 5-Fluorouracil resistance is a multifactorial event that involves abnormal enzyme metabolism, transport deregulation, cell cycle disorders, apoptosis resistance, and mismatch repair deficiency. Despite advancements in bioresearch technologies in the past several decades, the molecular mechanisms of 5-fluorouracil resistance have not been completely clarified. Recently, microarray analyses have shown that noncoding RNAs (i.e. microRNAs and long noncoding RNAs) play a vital role in 5-fluorouracil resistance in multiple cancer cell lines. These noncoding RNAs can function as oncogenes or tumor suppressors, contributing to 5-fluorouracil drug resistance. In this review, we discuss the effects of microRNAs on 5-fluorouracil sensitivity via targeting of metabolic enzymes, the cell cycle, apoptosis, autophagy, the epithelial-mesenchymal transition, and cancer stem cells. In particular, we focus on summarizing current knowledge on the molecular mechanisms through which long noncoding RNAs mediate 5-fluorouracil drug resistance. Moreover, we describe the specific microRNAs that may function as markers for prediction of chemotherapeutic response to 5-fluorouracil. This review will help to improve the current understanding of how to reverse 5-fluorouracil resistance and may facilitate the establishment of new strategies for alleviating drug resistance in the future.

Enhancement of Anti-Inflammatory Activity of Curcumin Using Phosphatidylserine-Containing Nanoparticles in Cultured Macrophages.

Macrophages are one kind of innate immune cells, and produce a variety of inflammatory cytokines in response to various stimuli, such as oxidized low density lipoprotein found in the pathogenesis of atherosclerosis. In this study, the effect of phosphatidylserine on anti-inflammatory activity of curcumin-loaded nanostructured lipid carriers was investigated using macrophage cultures. Different amounts of phosphatidylserine were used in the preparation of curcumin nanoparticles, their physicochemical properties and biocompatibilities were then compared. Cellular uptake of the nanoparticles was investigated using a confocal laser scanning microscope and flow cytometry analysis in order to determine the optimal phosphatidylserine concentration. In vitro anti-inflammatory activities were evaluated in macrophages to test whether curcumin and phosphatidylserine have interactive effects on macrophage lipid uptake behavior and anti-inflammatory responses. Here, we showed that macrophage uptake of phosphatidylserine-containing nanostructured lipid carriers increased with increasing amount of phosphatidylserine in the range of 0%-8%, and decreased when the phosphatidylserine molar ratio reached over 12%. curcumin-loaded nanostructured lipid carriers significantly inhibited lipid accumulation and pro-inflammatory factor production in cultured macrophages, and evidently promoted release of anti-inflammatory cytokines, when compared with curcumin or phosphatidylserine alone. These results suggest that the delivery system using PS-based nanoparticles has great potential for efficient delivery of drugs such as curcumin, specifically targeting macrophages and modulation of their anti-inflammatory functions.

MicroRNA-506 inhibits gastric cancer proliferation and invasion by directly targeting Yap1.

Increasing evidence indicates that microRNA (miR)-506 plays a vital role in tumorigenesis; however, the role of miR-506 in gastric cancer (GC) is unclear and needs further investigation. In the present study, we showed that the decrease in the expression of miR-506 is associated with tumor size, pathological tumor node metastasis (TNM) stage, and lymph node metastasis in 63 GC patient tumors. We found that patients with lower expression of miR-506 had a poor prognosis than that with the patients with high expression of miR-506. Notably, the ectopic expression of miR-506 was sufficient to inhibit cell proliferation, invasion, and epithelial-mesenchymal transition in the GC cells. Moreover, results from luciferase reporter assays identified miR-506 as a direct regulator of Yes-associated protein 1 (Yap1). Reintroduction of Yap1 rescues miR-506-induced effects on SGC-7901 cell proliferation and invasion. This function of miR-506/Yap1 axis is clinically significant, as the level of miR-506 is inversely correlated with Yap1 mRNA expression in matched tissues. Thus, our study demonstrates that miR-506 may act as a tumor suppressor in GC and that the miR-506/Yap1 axis may help us better understand the molecular mechanisms of GC progression.

Microglia activation: one of the checkpoints in the CNS inflammation caused by Angiostrongylus cantonensis infection in rodent model.

Angiostrongylus cantonensis (A. cantonensis) is a rodent nematode. Adult worms of A. cantonensis live in the pulmonary arteries of rats; humans are non-permissive hosts like the mice. The larva cannot develop into an adult worm and only causes serious eosinophilic meningitis or meningo-encephalitis if humans or mice eat food containing larva of A. cantonensis in the third stage. The differing consequences largely depend on differing immune responses of hosts to parasite during A. cantonensis invasion and development. To further understand the reasons why mice and rats attain different outcomes in A. cantonensis infection, we used the HE staining to observe the pathological changes of infected mice and rats. In addition, we measured mRNA levels of some cytokines (IL-5, IL-6, IL-13, Eotaxin, IL-4, IL-10, TGF-ß, IFN-γ, IL-17A, TNF-α, IL-1ß, and iNOS) in brain tissues of mice and rats by real-time PCR. The result showed that brain inflammation in mice was more serious than in rats. Meanwhile, mRNA expression levels of IL-6, IL-1ß, TNF-α, and iNOS increased after mice were infected. In contrast, mRNA levels of these cytokines in rats brain tissues decreased at post- infection 21 days. These cytokines mostly were secreted by activated microglia in central nervous system. Microglia of mice and rats were showed by Iba-1 (microglia marker) staining. In micee brains, microglia got together and had more significant activation than in rats brains. The results demonstrate that mice and rats have different CNS inflammation after infection by A. cantonensis, and it is in line with other researchers' reported findings. In conclusion, it is suggested that microglia activation is probably to be one of the most important factors in angiostrongyliasis from our study.

Ardipusilloside-I Metabolites from Human Intestinal Bacteria and Their Antitumor Activity.

Ardipusilloside-I (ADS-I) is a triterpenoid saponin extracted from Ardisia pusilla DC, and has been demonstrated to have potent antitumor activity. However, ADS-I metabolism in humans has not been investigated. In this study, we studied the biotransformation of ADS-I in human intestinal bacteria, and examined the in vitro antitumor activity of the major metabolites. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to detect ADS-I biotransformation products, and their chemical structures were identified by high performance liquid chromatography-nuclear magnetic resonance (HPLC-NMR). The antitumor activity of the major metabolites was determined by the MTT assay. Here, we show that main reaction seen in the metabolism of ADS-I in human intestinal bacteria was deglycosylation, which produced a total of four metabolites. The structures of the two major metabolites M1 and M2 were confirmed by using NMR. MTT assay showed that ADS-I metabolites M1 and M2 have the same levels of inhibitory activities as ADS-I in cultured SMMC-7721 cells and MCF-7 cells. In conclusion, this study demonstrates deglycosylation as a primary pathway of ADS-I metabolism in human intestinal bacteria, and suggests that the pharmacological activity of ADS-I may be mediated, at least in part, by its metabolites.

Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro.

5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

[Expression of intestinal defensin-5, soluble phospholipase A2 and lysozyme and the relation to bacterial translocation in rat models of acute liver failure].

OBJECTIVE: To study the intestinal expression of defensin-5 (RD-5), soluble phospholipase A2 (sPLA2) and lysozyme in acute liver failure (ALF) using rat models, and to determine the relation of these expressions to intestinal bacterial translocation. METHODS: Forty-eight healthy male Sprague-Dawley rats were divided into a control group (n=8) and a model group (n=40; intraperitoneal injection of 10% D-galactosamine). The model group was further divided into five subgroups according to the time lapse after model establishment (8, 16, 24, 48, and 72 hours). At the end of the experiments, homogenates of mesenteric lymph nodes, liver and spleen were cultured in agar for bacterial outgrowth.Hematoxylin-eosin stained sections of liver and terminal ileum were examined under an optical microscope to assess pathological changes. mRNA expression of RD-5, sPLA2 and lysozyme in the terminal ileum was determined by reverse transcription-polymerase reaction (RT-PCR), and protein expression of sPLA2 and lysozyme from the same anatomic location was determined by western blotting and immunohistochemistry. Means between groups were compared with one-way analysis of variance. RESULTS: ALF was successfully induced in the D-galactosamine injected rats. No bacteria grew in the organ cultures from the control group, while 8.3%, 37.5% and 58.3% of the rats in the 24-, 48-and 72-hour model groups showed positive cultures. Despite this, the structure of the terminal ileum from the rats in the 72-hour model group was nearly intact, without obvious necrosis of mucosal epithelial cells. Expression of RD-5 and sPLA2 mRNA in the model groups gradually increased at early time points and peaked at 16 hours after induction of ALF (1.291+/-0.153 and 1.131+/-0.128), which was significantly higher than that detected in the control group (0.725+/-0.116 and 0.722+/-0.112, t=69.25, 95.71, all P<0.01). After that, the expression of RD-5 and sPLA2 mRNA progressively decreased, and by 72 hours after the induction of ALF, the expression (0.415+/-0.104 and 0.425+/-0.076) was significantly lower than that of the control group (t=31.55 and 44.98, all P<0.01). Lysozyme mRNA expression in the model group peaked at 8 hours after ALF induction (1.211+/-0.107), which was higher than that of the control group at this time point (0.853+/-0.093), and by 72 hours after ALF induction it declined to 0.704+/-0.103, which was significantly lower than that of the control group (t=9.224; all P=0.009). In addition, at 72 hours after ALF induction the protein expression of both lysozyme and sPLA2 was significantly lower in the model group (0.327+/-0.086 and 0.382+/-0.057) than in the control group (0.583+/-0.121 and 0.650+/-0.093, t=12.28 and 15.83, P=0.004 and 0.001). Similar results were obtained with immunohistochemical staining. CONCLUSION: The function of the ileal mucosal immune barrier in the rat model of acute liver failure decreased, along with decreases in expression of RD-5, sPLA2 and lysozyme in the Paneth cells.At the same time, the rate of organ bacterial translocation increased without obvious injury to the intestinal mucosa structure.

Diversified access to di- and trisubstituted allenes via nickel-catalysed reactions of 1,3-enynes with alkyl N-hydroxyphthalimide esters.

Herein, a new nickel-catalysed protocol for the preparation of di- and trisubstituted allenes has been successfully developed via the reactions of 1,3-enynes with alkyl N-hydroxyphthalimide esters. The new method based on a reductive radical-polar crossover (RPC) process features broad substrate scope, wide functional group tolerance, and a simple catalyst system. The late-stage allenylation of drugs has also been illustrated.

Application of postmortem computed tomography angiography to settle a medical dispute after aortic dissection surgery: a forensic case report.

BACKGROUND: In the present case, we applied postmortem computed tomography angiography (PMCTA) in a medical dispute involving sudden death after cardiovascular surgery. CASE PRESENTATION: A 39-year-old man underwent aortic arch replacement combined with stented elephant trunk implantation surgery under extracorporeal circulation. All vital signs were stable and he was arranged for discharge seven days after surgery. Several days later, the patient was sent back to the hospital for chest pain and poor appetite. Unfortunately, his condition worsened and he ultimately died. PMCT scanning detect pericardial effusion. Family members suspected that the surgical sutures were not dense enough, causing the patient's postoperative bleeding and resulting in cardiac tamponade and death. PMCTA was performed before autopsy, which showed pericardial effusion. However, postmortem angiography with simulated blood pressure showed no leakage of contrast agent, which guided the subsequent autopsy and histological examinations. CONCLUSIONS: While many previous postmortem imaging case reports have shown positive results that provided evidence of medical malpractice, the current case excludes the possibility of physician negligence and reasonably settles the medical dispute from another perspective. In short, the PMCTA approach we describe here was an effective tool that can be applied to certain medical-related forensic cases.

Pan-cancer analysis reveals potential of FAM110A as a prognostic and immunological biomarker in human cancer.

Background: Despite great success, immunotherapy still faces many challenges in practical applications. It was previously found that family with sequence similarity 110 member A (FAM110A) participate in the regulation of the cell cycle and plays an oncogenic role in pancreatic cancer. However, the prognostic value of FAM110A in pan-cancer and its involvement in immune response remain unclear. Methods: The Human Protein Atlas (HPA) database was used to detect the expression of FAM110A in human normal tissues, the Tumor Immune Estimation Resource (TIMER) and TIMER 2.0 databases were used to explore the association of FAM110A expression with immune checkpoint genes and immune infiltration, and the Gene Set Cancer Analysis (GSCA) database was used to explore the correlation between FAM110A expression and copy number variations (CNV) and methylation. The LinkedOmics database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Statistical analysis and visualization of data from the The Cancer Genome Atlas (TCGA) or the Genotype-Tissue Expression (GTEx) databases were performed using the R software (version 3.6.3). Clinical samples were validated using immunohistochemistry. Results: FAM110A expression was elevated in most tumor tissues compared with that in normal tissues. CNV and methylation were associated with abnormal FAM110A mRNA expression in tumor tissues. FAM110A affected prognosis and was associated with the expression of multiple immune checkpoint genes and abundance of tumor-infiltrating immune cells across multiple types of cancer, especially in liver hepatocellular carcinoma (LIHC). FAM110A-related genes were involved in multiple immune-related processes in LIHC. Conclusion: FAM110A participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in LIHC. FAM110A may serve as a prognostic and immunological biomarker for human cancer.

Intestinal ischemia/reperfusion enhances microglial activation and induces cerebral injury and memory dysfunction in rats.

OBJECTIVE: The mortality of critically ill patients associated with intestinal ischemia/reperfusion remains very high, which results from multiorgan dysfunction or failure due to intestinal injury induced by intestinal ischemia/reperfusion. This study was carried out to investigate whether intestinal ischemia/reperfusion can cause cerebral injury and concomitant memory dysfunction, and explore the potential mechanisms. DESIGN: Prospective, controlled, and randomized animal study. SETTING: University research laboratory. SUBJECTS: Male, adult Sprague-Dawley rats (weighing 250-300 g). INTERVENTIONS: Intestinal ischemia/reperfusion was established by clamping the superior mesenteric artery for 90 mins followed by different reperfusion durations (2, 6, 12, 24, or 48 hrs). The sham surgical preparation including isolation of the superior mesenteric artery without occlusion was performed as control. MEASUREMENTS AND MAIN RESULTS: In comparison with sham control, intestinal ischemia/reperfusion caused severe intestinal injury, accompanied by notable cerebral damage evidenced by increased wet-to-dry brain weight ratio reflecting brain edema and neuronal cell apoptosis manifested by increased apoptotic cell number and cleaved caspase-3 protein expressions. All these changes were concomitant with reduced survival rates as well as impaired memory function determined by Morris water maze test at 24 and 48 hrs after reperfusion. In addition, intestinal ischemia/reperfusion resulted in significant increases in the levels of tumor necrosis factor-α and interleukin-6 both in the serum and in cortices and hippocampal Cornu Ammonis area 1 regions, concomitant with the activation of microglia, a key cellular mediator involved in neuroinflammation and neurodegeneration, which was evidenced by increased protein expressions of ionized calcium binding adaptor molecule 1. Furthermore, the releases of reactive oxygen species evidenced by increased malondialdehyde levels and decreased superoxide dismutase activities in cortices and hippocampal Cornu Ammonis area 1 regions were found after reperfusion. CONCLUSIONS: These findings indicate that intestinal ischemia/reperfusion-induced intestinal injury can lead to cerebral damage and memory dysfunction partly via microglia activation which further facilitates oxidative injury, inflammatory response, and neuronal cell apoptosis.

Small change in structure leads to large difference in protein photocleavage: two porphyrins bearing rhodanine-based pendants.

Two 5,10,15,20-tetraphenylporphyrins with one phenyl group anchored to a rhodanine-terminated side chain, RhD-TPP and RhDCOOH-TPP, were designed and synthesized, and their protein photocleavage activities were investigated using bovine serum albumin (BSA) as a model protein. Both porphyrins exhibit similar absorption spectra, fluorescence spectra, fluorescence quantum yields, and singlet oxygen ((1)O(2)) quantum yields in organic solvents due to their structure similarity. They also show similar binding affinities and binding sites toward BSA. However, RhD-TPP is nearly inactive in protein photocleavage while RhDCOOH-TPP can lead to distinct photocleavage of BSA under the same experimental conditions. Such a difference may be attributed to the different binding modes of the two porphyrin derivatives toward BSA, though the apparent binding affinities and the binding sites are similar, and consequently a great difference in the (1)O(2) quantum yields of the two porphyrins bound on BSA. The presence of the COOH group in RhDCOOH is proposed to play an important role, leading to less hydrophobic character and additional interactions towards BSA.