CircBIRC6 facilitates the malignant progression via miR-488/GRIN2D-mediated CAV1-autophagy signal axis in gastric cancer.

Circular RNAs (circRNAs) represent a novel class of non-coding RNAs that play significant roles in tumorigenesis and tumor progression. High-throughput sequencing of gastric cancer (GC) tissues has identified circRNA BIRC6 (circBIRC6) as a potential circRNA derived from the BIRC6 gene, exhibiting significant upregulation in GC tissues. The expression of circBIRC6 is notably elevated in GC patients. Functionally, it acts as a molecular sponge for miR-488, consequently upregulating GRIN2D expression and promoting GC proliferation, migration, and invasion. Moreover, overexpression of circBIRC6 leads to increased GRIN2D expression, which in turn enhances caveolin-1 (CAV1) expression, resulting in autophagy deficiency due to miR-488 sequestration. This cascade of events significantly influences tumorigenesis in vivo. Our findings collectively illustrate that the CircBIRC6-miR-488-GRIN2D axis fosters CAV1 expression in GC cells, thereby reducing autophagy levels. Both circBIRC6 and GRIN2D emerge as potential targets for treatment and independent prognostic factors for GC patients.

Overexpression of Copines-1 is associated with clinicopathological parameters and poor outcome in gastric cancer.

BACKGROUND: Copines-1 (CPNE1) is a soluble membrane-binding protein that includes two tandem C2 domains at the N-terminus and a C terminal A domain. Importantly, it is associated with the prognosis of various tumors, but there are only a few studies regarding the role of CPNE1 in gastric cancer (GC). This study aimed to explore the clinicopathological significance and prognostic potential of CPNE1 expression in GC. METHODS: Data from the TIMER2.0 and UALCAN were analyzed to assess CPNE1 mRNA levels in GC. The prognostic role of CPNE1 mRNA was examined via the Kaplan-Meier plotter. CPNE1 protein expression in tumor tissues was analyzed via immunohistochemistry of clinical samples from 99 GC patients. The relationship of CPNE1 expression with clinicopathological parameters and overall survival (OS) was evaluated using Cox proportional hazards regression models and Kaplan-Meier survival curves. RESULTS: Copines-1 mRNA levels were higher in GC tissues than in adjacent normal tissue (ANT) (p < 0.05). Further, high CPNE1 mRNA expression indicated poor OS (p = 9.4 e-10) and was significantly associated with first progression (FP) (p = 1.6 e-06) and post-progression survival (PPS) (p = 1.5 e-12). In addition, CPNE1 protein expression was higher in GC tissues than in ANT (p < 0.0001). Moreover, CPNE1 high expression was significantly related to advanced tumor-node-metastasis (TNM) stage (p = 0.004), lymph node metastasis (p = 0.003), and vascular invasion (p = 0.001). Kaplan-Meier analysis showed that GC patients with high expression CPNE1 group had worse OS than low expression group (p = 0.003). Univariate analysis showed that age (hazard ratio [HR] = 1.992; 95% confidence interval [CI], 1.009-3.934; p = 0.047), advanced TNM stage (HR = 4.941; 95% CI, 2.052-11.897; p = 0.000), tumor invasion (HR = 3.472; 95% CI, 1.349-8.937; p = 0.010), lymph node metastasis (HR = 8.846; 95% CI, 2.708-28.897; p = 0.000), vascular invasion (HR = 3.237; 95% CI, 1.521-6.891; p = 0.002), nervous invasion (HR = 2.324; 95% CI, 1.205-4.479; p = 0.012), and CPNE1 expression (HR = 3.464; 95% CI, 1.440-8.334; p = 0.006) were correlated with OS. In the multivariate analysis, age (HR = 2.514; 95% CI, 1.264-4.999; p = 0.009), lymph node metastasis (HR = 8.441; 95% CI, 2.553-27.906; p < 0.05), and CPNE1 expression (HR = 2.549; 95% CI, 1.051-6.186; p = 0.039) were significant prognostic predictors for GC. CONCLUSIONS: Copines-1 overexpression in GC is significantly associated with poor prognosis. Thus, CPNE1 levels may serve as a prognostic biomarker in GC patients.

Molecular networking as a dereplication strategy for monitoring metabolites of natural product treated cancer cells.

RATIONALE: Natural products have been great sources for drug discovery. However, the structures of natural products are diverse and difficult to elucidate. Cordyceps militaris is a parasitic fungus which usually grows on host insects. The metabolites of C. militaris have been reported to act as chemotherapeutic agents. In this study, we aimed for the structural elucidation of specialized metabolites derived from C. militaris, and the metabolic impact in leukemia cells. METHODS: We describe a liquid chromatography data-dependent mass spectrometric platform combining tandem mass analysis and molecular networking. Leukemia cells treated with C. militaris extract and control groups were visualized in terms of their metabolic profiles using Global Natural Product Social (GNPS) molecular networking. By this method, we were able to elucidate the structures of metabolites from medicinal fungus extracts and cancer cells and then to recognize their changes in a semi-quantitative manner. RESULTS: Using C. militaris and leukemia cells as examples, we found that approximately 100 new ion species were present in the treated leukemia cells, suggesting a highly altered metabolic profile. Specifically, based on the tandem mass spectral similarity, we proposed that cordycepin, a key fungus-derived therapeutic agent known for its antitumor activity, was transformed into its methylthio form in leukemia cells. CONCLUSIONS: The platform described provides an ability to investigate complex molecular interactions of natural products in mammalian cells. By incorporating tandem mass spectrometry and molecular networking, we were able to reveal the chemical modification of crude bioactive compounds, for example potential bioactive compounds which might be modified from cordycepin. We envision that such a mass spectrometry (MS)-based workflow, combined with other metabolomics platforms, would enable much wider applicability to cell biology and be of great potential to pharmacological study as well as drug discovery.

EphA8 acts as an oncogene and contributes to poor prognosis in gastric cancer via regulation of ADAM10.

EphA8 is a member of the erythropoietin-producing hepatocellular receptor (Eph) family of receptor tyrosine kinases. Ephs and their ephrins ligands play crucial roles in many cellular processed by mediating intracellular signaling resulting from cell-cell interactions. But the underlying mechanisms of EphA8 in gastric cancer (GC) remains unclearly. 298 clinical specimens in tissues microarray, and was found to be significantly higher in GC tissues compared with nontumor tissues (p < 0.001). EphA8 expression was also strongly associated with differentiation level (p = 0.025), tumor-node-metastasis stage (p = 0.019), and poor 5 years survival (p < 0.001). A panel of GC cell lines showed reduced proliferation, invasion, and migration capacities after RNA-mediated knockdown of EphA8, concomitant with downregulation of the proliferation-related proteins (cyclin A, cyclin D1, and cyclin-dependent kinase 4) and the metastasis-related (matrix metalloproteinases MMP2, and MMP9). EphA8 knockdown also decreased expression of the protease ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM10-related protein AKT, suggesting an interaction between EphA8 and ADAM10. In conclusion, we found that EphA8, which is highly expressed in GC tissues, stimulates proliferation, invasion, and migration of cancer cells, and is an independent risk factor for poor prognosis of GC. These dates suggest that EphA8 could be new diagnostic and/or therapeutic targets for GC.

Ophiocordyceps formosana improves hyperglycemia and depression-like behavior in an STZ-induced diabetic mouse model.

BACKGROUND: A newly defined Cordyceps species, Ophiocordyceps formosana (O. formosana) has been implicated in multitudinous bioactivities, including lowering glucose and cholesterol levels and modulating the immune system. However, few literatures demonstrate sufficient evidence to support these proposed functions. Although the use of Cordyceps spp. has been previously addressed to improve insulin insensitivity and improve the detrimental symptoms of depression; its mechanistic nature remains unsettled. Herein, we reveal the effects of O. formosana in ameliorating hyperglycemia accompanied with depression. METHODS: Diabetes was induced in mice by employing streptozotocin(STZ), a chemical that is toxic to insulin-producing ß cells of the pancreas. These streptozotocin (STZ)-induced diabetic mice showed combined symptoms of hyperglycemia and depressive behaviors. Twenty-four STZ-induced mice were randomly divided into 3 groups subjected to oral gavage with 100 µL solution of either PBS or 25 mg/mL Ophiocordyceps formosana extract (OFE) or 2 mg/mL rosiglitazone (Rosi, positive control group). Treatments were administered once per day for 28 days. An additional 6 mice without STZ induction were treated with PBS to serve as the control group. Insulin sensitivity was measured by a glucose tolerance test and levels of adiponectin in plasma and adipose tissue were also quantified. Behavioral tests were conducted and levels of monoamines in various brain regions relating to depression were evaluated. RESULTS: HPLC analysis uncovered three major constituents, adenosine, D-mannitol and cordycepin, within O. formosana similar to other prestigious medicinal Cordyceps spp.. STZ-induced diabetic mice demonstrated decreased body weight and subcutaneous adipose tissue, while these symptoms were recovered in mice receiving OFE treatment. Moreover, the OFE group displayed improved insulin sensitivity and elevated adiponectin within the plasma and adipose tissue. The anti-depressive effect of OFE was observed in various depression-related behavior tests. Concurrently, neurotransmitters, like 5-HT and dopamine in the frontal cortex, striatum and hippocampus were found to be up-regulated in OFE-treated mice. CONCLUSIONS: Our findings illustrated, for the first time, the medicinal merits of O. formosana on Type I diabetes and hyperglycemia-induced depression. OFE were found to promote the expression of adiponectin, which is an adipokine involved in insulin sensitivity and hold anti-depressive effects. In addition, OFE administration also displayed altered levels of neurotransmitters in certain brain regions that may have contributed to its anti-depressive effect. Collectively, this current study provided insights to the potential therapeutic effects of O. formosana extracts in regards to hyperglycemia and its depressive complications.

Synthesis, characterization, and application of amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) copolymer for paclitaxel.

In this paper, we successfully synthesized amino-terminated poly(ethylene glycol)-block-poly (epsilon-caprolactone) (NH2-PEG-PCL) block copolymer from polyethylene glycol 2000, epsilon-caprolactone (epsilon-CL) and hydrazine hydrate. The obtained copolymer was characterized by nuclear magnetic resonance (1H-NMR), the molecular weight and distribution of NH2-PEG-PCL were characterized by Gel permeation chromatography (GPC). The NH2-PEG-PCL copolymer could self-assemble into micelles in water. Paclitaxel (PTX) loaded NH2-PEG-PCL (PNPP) micelles were prepared by solid dispersion technique without organic solvent. The micelles were characterized by XRD, TEM and Malvern laser particle size. The results of this work indicated that PNPP micelles were uniform and spherical shapes in solution. The average size and zeta potential of PNPP (DL = 8%) in water was about 97.1 +/- 1.2 nm, +13.9 +/- 0.6 mV, respectively. The in vitrodrug release profile of PNPP micelles showed a clear slow-release effect. The results suggested that NH2-PEG-PCL copolymer might be an excellent carrier for hydrophobic drugs such as PTX. In particular, the NH2-PEG-PCL polymer has potential value for modifying with ligands to work as active targeting drug delivery carriers, which has great significance for cancer therapeutics.

Diagnostic, clustering, and immune cell infiltration analysis of m6A regulators in patients with sepsis.

RNA N6-methladenosine (m6A) regulators are required for a variety of biological processes, including immune responses, and increasing evidence indicates that their dysregulation is closely associated with many diseases. However, the potential roles of m6A regulators in sepsis remain unknown. We comprehensively analyzed the transcriptional variations in and interactions of 26 m6A regulators in sepsis based on the Gene Expression Omnibus (GEO) database. A random forest (RF) model and nomogram were established to predict the occurrence and risk of sepsis in patients. Then, two different m6A subtypes were defined by consensus clustering analysis, and we explored the correlation between the subtypes and immune cells. We found that 17 of the 26 m6A regulators were significantly differentially expressed between patients with and without sepsis, and strong correlations among these 17 m6A regulators were revealed. Compared with the support vector machine (SVM) model, the RF model had better predictive ability, and therefore was used to construct a reliable nomogram containing 10 candidate m6A regulators to predict the risk of sepsis in patients. In addition, a consensus clustering algorithm was used to identify two different subtypes of m6A, which helped us distinguish different levels of immune cell infiltration and inflammation in patients with sepsis. Comprehensive analysis of m6A regulators in sepsis revealed their potential roles in sepsis occurrence, immune cell infiltration and inflammation in patients with sepsis. This study may contribute to the development of follow-up treatment strategies for sepsis.

Delayed Chronic Acidic Postconditioning Improves Poststroke Motor Functional Recovery and Brain Tissue Repair by Activating Proton-Sensing TDAG8.

Acidic postconditioning by transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects in the acute phase of stroke. However, the effects of delayed chronic acidic postconditioning (DCAPC) initiated during the subacute phase of stroke or other acute brain injuries are unknown. Mice received daily DCAPC by inhaling 5%/10%/20% CO2 for various durations (three cycles of 10- or 20-min CO2 inhalation/10-min break) at days 3-7, 7-21, or 3-21 after photothrombotic stroke. Grid-walk, cylinder, and gait tests were used to assess motor function. DCAPC with all CO2 concentrations significantly promoted motor functional recovery, even when DCAPC was delayed for 3-7 days. DCAPC enhanced the puncta density of GAP-43 (a marker of axon growth and regeneration) and synaptophysin (a marker of synaptogenesis) and reduced the amoeboid microglia number, glial scar thickness and mRNA expression of CD16 and CD32 (markers of proinflammatory M1 microglia) compared with those of the stroke group. Cerebral blood flow (CBF) increased in response to DCAPC. Furthermore, the mRNA expression of TDAG8 (a proton-activated G-protein-coupled receptor) was increased during the subacute phase of stroke, while DCAPC effects were blocked by systemic knockout of TDAG8, except for those on CBF. DCAPC reproduced the benefits by re-expressing TDAG8 in the peri-infarct cortex of TDAG8-/- mice infected with HBAAV2/9-CMV-TDAG8-3flag-ZsGreen. Taken together, we first showed that DCAPC promoted functional recovery and brain tissue repair after stroke with a wide therapeutic time window of at least 7 days after stroke. Brain-derived TDAG8 is a direct target of DCAPC that induces neuroreparative effects.

Upregulation of XIAP promotes lung adenocarcinoma brain metastasis by modulating ceRNA network.

Dysregulation of XIAP has been shown to affect the progression of a variety of cancers, including lung adenocarcinoma (LUAD). However, the function and mechanisms of XIAP in lung adenocarcinoma with brain metastasis (LUAD-BM) remains poorly understood. In this study, we analyzed the differential mRNA of 58 lung adenocarcinomas samples and 28 lung adenocarcinomas with brain metastases in GEO database. 191 differentially expressed mRNAs were significantly associated with immune response, the proliferation of the immune cell, cell-cell adhesion. Subsequent analyzed by lasso and SVM found that XIAP was significantly elevated in LUAD-BM and significantly associated with LUAD grade and metastasis. Then we constructed a molecular regulatory network of ncRNA-miRNA-mRNA ceRNA by Cystoscope based on the correlation obtained from Starbase. It was found that SBF2-AS1 or RUNDC3A-AS1, has-miR-338-3p and XIAP may have a regulatory relationship. Furthermore, we also initially found that XIAP was closely correlation with T cells, B cells, Mast cells, macrophages, and dendritic cells. In conclusion, we found that XIAP was significantly higher expressed in LUAD-BM compared with LUAD without brain metastasis, suggesting that XIAP may play an important role in the future prediction and clinical treatment of LUAD-BM.

Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report.

It remains a huge challenge for clinicians to diagnose Pneumocystis jirovecii pneumonia (PJP) by a conventional method, which leads to delay in diagnosing PJP, accounting for higher mortality in patients with rheumatoid arthritis (RA). A 69-year-old woman, who suffered from RA for years, developed acute respiratory failure. The computed tomography scan showed diffused effusion and ground glass opacity in both lungs, which could not be differentiated from interstitial pneumonia. Metagenomic next-generation sequencing (mNGS) revealed P. jirovecii in both serum and bronchoalveolar lavage fluid with reads per million (RPM) of 17 and 437, while other diagnostic tests did not detect any pathogenic microorganism. The results were verified by quantitative polymerase chain reaction (mtSSU region) against the same samples. The DNA RPM of P. jirovecii declined notably after treatment with trimethoprim/sulfamethoxazole. The patient was discharged without treatment and finally passed away. This case fully highlights the sensitivity of mNGS in early diagnosis of PJP, which is of great significance for prognosis and treatment. Nonetheless, the clinical application of mNGS is worth further standardization and normalization.

Correction: A highly active Z-scheme SnS/Zn2SnO4 photocatalyst fabricated for methylene blue degradation.

[This corrects the article DOI: 10.1039/D2RA05519H.].

A highly active Z-scheme SnS/Zn2SnO4 photocatalyst fabricated for methylene blue degradation.

Herein, a highly active Z-scheme SnS/Zn2SnO4 photocatalyst is fabricated by a one-step hydrothermal route. The structure, composition, photoelectric and photocatalytic properties of the as-prepared photocatalysts are systematically researched. The results demonstrate that SZS-6 displays a good photocatalytic performance with an efficiency of 94.5% to degrade methylene blue (MB) under visible light irradiation (λ > 420 nm). And its degradation rate constant is up to 0.0331 min-1, which is 3.9 and 4.4 times faster than SnS and Zn2SnO4, respectively. The formation of a Z-scheme heterojunction facilitates the separation and transfer of charges, which improves the degradation of MB. The Z-scheme charge transfer pathway of the SnS/Zn2SnO4 photocatalyst is verified by the shifted peaks of the X-ray photoelectron spectroscopy (XPS) spectrum, the relative position of the bandgap, work function as well as free radical trapping experiments. The photocatalytic mechanism for the degradation of MB by SnS/Zn2SnO4 is proposed.

The low expression of NUP62CL indicates good prognosis and high level of immune infiltration in lung adenocarcinoma.

A primary factor in tumor morbidity and mortality, lung adenocarcinoma (LUAD) is known to be a major subtype of lung cancer, having the lowest survival rate among all other cancers. Using The Cancer Genome Atlas (TCGA) database the relationship between the immune infiltrate and the NUP62CL was explored and the value of the NUP62CL expression in the prognosis and diagnosis LUAD was examined. Using the logistic regression and the Wilcoxon signed-rank test the relationship between the NUP62CL and the clinico-pathological features was analyzed. There was a significant correlation between the clinical stage (p = 0.005), the N (p = 0.004), and the decreased expression of NUP62CL. The prognosis of LUAD with high NUP62CL expression was revealed to be worse than that with low NUP62CL expression (p < 0.001) by the Kaplan-Meier survival analysis. The potentiality of NUP62CL to be a significant factor of prognosis for LUAD was indicated by the analyses of the multivariate and the univariate Cox regression models. In LUAD, the crucial role of recombination and maintenance of telomere as a significant pathway for NUP62CL was suggested by the Gene Set Enrichment Analysis (GSEA). To analyze the correlation between the genes and the tumor infiltrating immune cells the CIBERSORT was used. Moreover the positive correlation with the NUP62CL expression in LUAD of the infiltration level of the tumor infiltrating B lymphocytes and memory CD4+ T cells was exhibited by CIBERSORT. Therefore, NUP62CL may be a new valuable prognostic indicator for LUAD.

GPR115 Contributes to Lung Adenocarcinoma Metastasis Associated With LAMC2 and Predicts a Poor Prognosis.

GPR115, a member of the adhesion G protein-coupled receptor family, is dysregulated in many cancers. However, the expression and function of GRP115 in non-small cell lung cancer (NSCLC) is not clear. Here, we examined the expression pattern, clinical significance, and function of GPR115 in NSCLC by analysis of clinical specimens and human cell lines and bioinformatics analysis. Immunohistochemical analysis of clinical samples showed that GPR115 was significantly upregulated in NSCLC tissues compares with normal lung epithelial tissue (P < 0.05). And GPR115 overexpression is an independent prognostic factor for 5-year overall survival of NSCLC patients [hazard ratio (HR)=1.625, P = 0.008]. Interestingly, higher expression of GPR115 was strongly correlation with differentiation level (P = 0.027), tumor size (P = 0.010), lymph node metastasis (P = 0.022), tumor-node-metastasis stage (P = 0.008), and poor prognosis of lung adenocarcinoma (LUAD, all P = 0.039), but not lung squamous cell carcinoma (LUSC, P > 0.05). Moreover, downregulation of GPR115 by RNA interference in human lung cancer lines inhibited cell proliferation, migration, and invasion. Preliminary bioinformatic analysis confirmed that GPR115 was closely associated with LAMC2 (Spearman correlation coefficient=0.67, P < 0.05), which was accumulated in ECM-receptor interaction and focal adhesion. Consistent with these findings, deceased of GPR115 was associated with E-cadherin, N-cadherin and Vimentin confirmed by western blot. In conclusion, these data suggest that GPR115 may play a role in the tumor growth and metastasis and may have utility as a diagnostic and prognostic marker for LUAD, but not LUSC.

Development and Validation of a Clinical Prognostic Model Based on Immune-Related Genes Expressed in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most frequent and terminal subtype of RCC. Reliable markers associated with the immune response are not available to predict the prognosis of patients with ccRCC. We exploited the extensive number of ccRCC samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository to perform a comprehensive analysis of immune-related genes (IRGs). Methods: Based on TCGA data, we incorporated IRGs and their expression profiles of 72 normal and 539 ccRCC samples. Univariate Cox analysis was used to evaluate the relationship between overall survival (OS) and IRGs expression. The Lasso Cox regression model identified prognostic genes used to establish a clinical immune prognostic model. The TF-IRG network was used to study the potential molecular mechanisms of action and properties of ccRCC-specific IRGs. Multivariate Cox analysis established a clinical prognostic model of IRGs. Results: We found a significant correlation among 15 differentially expressed IRGs with the OS of patients with ccRCC. Gene function enrichment analysis showed that these IRGs are significantly associated with response to receptor ligand activity. Lasso Cox regression analysis identified 10 genes with the greatest prognostic value. A clinical prognostic model based on six IRGs, which performed well for predicting prognosis, revealed significant associations of patients' survival with age, sex, stage, tumor, node, and metastasis. Moreover, these findings reflect the infiltration of tumors by various immune cells. Conclusion: We identified six clinically significant IRGs and incorporated them into a clinical prognostic model with great significance for monitoring and predicting prognosis of ccRCC.

Delayed metformin treatment improves functional recovery following traumatic brain injury via central AMPK-dependent brain tissue repair.

Accumulating evidence suggests that chronic metformin posttreatment offers potent neuroreparative effects against acute brain injury. However, in previous studies, metformin was not initially administered beyond 24 h postinjury, and the effects of delayed metformin treatment in traumatic brain injury (TBI) and other types of acute brain injury and the related mechanisms are unclear. To test this, male C57BL/6 mice received once daily metformin treatment (20, 50 or 100 mg/kg/d, i.p.) at day 1-14, day 1-2, day 1-10, day 3-10, day 5-12 or day 5-28 after cryogenic TBI (cTBI). The results showed that 100 mg/kg/d metformin administered at day 1-14 postinjury significantly promoted motor functional recovery in the beam walking and gait tests and reduced the infarct volume. Metformin (100 mg/kg/d) administered at day 1-10 or day 3-10 but not day 1-2 or day 5-12 after cTBI significantly improved motor functional outcomes at day 7 and 14, and reduced the infarct volume at day 14. Interestingly, the therapeutic time window was further expanded when the duration of metformin treatment starting at day 5 postinjury was extended to 2 weeks. Furthermore, compared with cTBI, the administration of metformin at day 3-10 or day 5-28 after cTBI significantly elevated the expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and growth associated protein 43 (an axonal regeneration marker) and the number of vascular branch points and decreased the area of glial scar and the number of amoeboid microglia in the peri-infarct area at day 14 or 28 postinjury. The above beneficial effects of metformin were blocked by the intracerebroventricular injection of the AMPK inhibitor compound C (40 µg/mouse/d). Our data provide the first evidence that metformin has a wide therapeutic time window for at least 5 days after cTBI, during which it can improve functional recovery by promoting tissue repair and inhibiting glial scar formation and microglial activation in a central AMPK-dependent manner.

High expression of ALPPL2 is associated with poor prognosis in gastric cancer.

Alkaline phosphatase placental-like 2 (ALPPL2) is a member of the ALPP alkaline phosphatase family and is reported to be associated with the growth of some tumors. Gastric cancer is one of the most common cancers worldwide. We previously identified a distinct expression pattern of ALPPL2 between gastric cancer and adjacent normal tissues. In this study, we examined the expression of ALPPL2 in gastric adenocarcinoma and its ability to predict prognosis. We used bioinformatics analysis and immunohistochemistry to examine the expression pattern of ALPPL2 and analyzed the associations between ALPPL2 level and perioperative characteristics and the prognosis of gastric adenocarcinoma patients by Kaplan-Meier plotter analysis. Our results indicated that the expression of ALPPL2 was significantly increased in gastric adenocarcinoma (P < .01) and was an independent factor (P < .05) that could provide reliable prognostic information on gastric adenocarcinoma patients. High expression of ALPPL2 was associated with advanced TNM stage (P < .05) and high HER-2 expression (P < .01). Our study suggests that ALPPL2 has the potential to reveal prognostic information on gastric cancer.

Effect of region on the Outcome of Patients Receiving PD-1/PD-L1 Inhibitors for Advanced Cancer.

BACKGROUND: Regional differences were associated with cancer incidence and mortality. However, the correlation between regional differences and cancer immunotherapy efficacy was still not evaluated. In this study, we performed a meta-analysis to investigate whether regional differences play a role in efficacy of PD-1/L1 inhibitors in cancer patients. METHODS: A meticulous review of relevant randomized controlled trials that were sourced from the PubMed, Embase and MEDLINE databases. Overall survival (OS) and progression-free survival (PFS) were the primary outcome and secondary outcome in our study, respectively. We also assessed difference on the hazard ratio (HR) between European and North American groups. RESULTS: A total of 14 randomized clinical trials including 9387 patients were finally eligible for meta-analysis in our study. With respect to the pooled HR in treatment with PD-1/L1 inhibitors, North American patients presented OS as 0.60 (95% CI 0.53 to 0.67), and PFS as 0.49 (95% CI 0.40 to 0.59), whereas European patients presented OS as 0.76 (95% CI 0.62 to 0.90), and PFS as 0.58 (95% CI 0.44 to 0.72), relative to their corresponding control groups. OS efficacy thus varied significantly (Pheterogeneity = 0.028) between North American and European patients when treated with PD-1/L1 inhibitors. CONCLUSIONS: Our findings were very surprising especially considering the higher prevalence of cancer in Europe. Although PD-1/L1 inhibitors improved OS and PFS in both North American and European patients compared with controls, the magnitude of benefit was region-dependent. North American patients can benefit more from PD-1/L1 inhibitors than European patients. More researches were urgently demanded to explore its potential molecular mechanisms.

Cardiac ICAM-1 mediates leukocyte-dependent decreased ventricular contractility in endotoxemic mice.

OBJECTIVE: Binding of ICAM-1 expressed on cardiomyocytes decreases cardiomyocyte contractility in vitro by altering the intracellular Ca2+ transient. We tested the hypothesis that signaling via ICAM-1 contributes to decreased left ventricular contractility in an in vivo model of systemic inflammation. METHODS: C57B6 wild-type mice and ICAM-1 knock-out mice were treated with intraperitoneal lipopolysaccharide (LPS) then left ventricular contractility was measured 6 h later using a volume-conductance micromanometer catheter. We repeated this experiment in chimeric mice lacking ICAM-1 expression in bone marrow-derived cells (M-) and/or lacking ICAM-1 expression in the heart and other tissues (H-). RESULTS: In C57B6 wild-type mice LPS injection significantly increased cardiac ICAM-1 expression and decreased in vivo measures of left ventricular contractility (end-systolic elastance, Ees decreased 58 +/- 4%, p < 0.05, [dP/dtmax]/EDV decreased 60 +/- 6%, p < 0.05). Cyclophosphamide pretreatment to decrease leukocyte count prevented the LPS-induced decrease in contractility. In ICAM-1 knock-out mice LPS did not decrease any measure of contractility. LPS did not decrease left ventricular contractility in M+/H- mice but decreased contractility in M+/H+ and M-/H+ mice to the same extent as in C57B6 wild-type mice implicating the importance of cardiac ICAM-1. CONCLUSIONS: We conclude that signaling via cardiac ICAM-1 is necessary to mediate leukocyte-dependent decreases of left ventricular contractility in endotoxemic mice.

Evaluation of an Epitypified Ophiocordyceps formosana (Cordyceps s.l.) for Its Pharmacological Potential.

The substantial merit of Cordyceps s.l. spp. in terms of medicinal benefits is largely appreciated. Nevertheless, only few studies have characterized and examined the clinical complications of the use of health tonics containing these species. Here, we epitypified C. formosana isolates that were collected and characterized as Ophiocordyceps formosana based on morphological characteristics, molecular phylogenetic analyses, and metabolite profiling. Thus, we renamed and transferred C. formosana to the new protologue Ophiocordyceps formosana (Kobayasi & Shimizu) Wang, Tsai, Tzean & Shen comb. nov. Additionally, the pharmacological potential of O. formosana was evaluated based on the hot-water extract from its mycelium. The relative amounts of the known bioactive ingredients that are unique to Cordyceps s.l. species in O. formosana were found to be similar to the amounts in O. sinensis and C. militaris, indicating the potential applicability of O. formosana for pharmacological uses. Additionally, we found that O. formosana exhibited antioxidation activities in vitro and in vivo that were similar to those of O. sinensis and C. militaris. Furthermore, O. formosana also displayed conspicuously effective antitumor activity compared with the tested Cordyceps s.l. species. Intrinsically, O. formosana exhibited less toxicity than the other Cordyceps species. Together, our data suggest that the metabolites of O. formosana may play active roles in complementary medicine.