Role of prognostic gene DKK1 in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common squamous cell carcinomas of the head and neck. The morbidity and mortality rates of OSCC have increased in recent years. However, the pathogenesis of this disease remains unknown. The present study aimed to identify predictive biomarkers and therapeutic targets for OSCC. Bioinformatics screening of differentially expressed genes in OSCC was performed based on data from The Cancer Genome Atlas and Gene Expression Omnibus databases. Dickkopf Wnt signaling pathway inhibitor 1 (DKK1) was identified to be associated with survival, tumor immunity and DNA repair in OSCC. Furthermore, the effects of DKK1 were evaluated by the knockdown of DKK1 in two OSCC cell lines. The proliferation, clonogenicity, migration and invasion of the cells were assessed in vitro using Cell Counting Kit-8, colony formation, wound healing and Transwell assays, respectively, and were found to be inhibited by DKK1 knockdown. The present study suggests that DKK1 may be used in the prognosis of patients with OSCC and that targeting DKK1 is a potential strategy for OSCC therapy.

NMNATs expression inhibition mediated NAD+ deficiency plays a critical role in doxorubicin-induced hepatotoxicity in mice.

Doxorubicin (DOX) is one of the most widely used antineoplastic drugs with known cardiotoxicity while other organ toxicity, such as hepatotoxicity is not well defined. This study was to explore the role of nicotinamide adenine dinucleotide (NAD+) in DOX-induced hepatotoxicity. DOX (20 mg/kg) induced acute liver injury and oxidative stress in C57BL/6 J mice at 48 h. Notably, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H dehydrogenase quinone 1 (NQO1) were downregulated. NAD+ deficiency was confirmed due to DOX exposure. Mechanistically, the downregulation of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), NMNAT2 and NMNAT3, while no alteration of nicotinamide phosphoribosyl transferase was proved. As a consequence of NAD+ deficiency, the expression of poly-ADP-ribose polymerase1 (PARP1), CD38 and Sirtuin1 (SIRT1) were reduced. Furthermore, supplementation of NAD+ (200 mg/kg/day) or its precursor nicotinamide mononucleotide (NMN) (500 mg/kg/day) alleviated liver injury, attenuated oxidative stress, and elevated the downregulation of Nrf2 and NQO1. More importantly, compromised expression of NMNAT1-3, PARP1, CD38 and SIRT1 were improved by NAD+ and NMN. In conclusion, NAD+ deficiency due to NMNATs expression inhibition may attribute to the pathogenesis of DOX-induced hepatotoxicity, thus providing new insights for mitigating DOX side effects.

Typing and modeling of hepatocellular carcinoma based on disulfidptosis-related amino acid metabolism genes for predicting prognosis and guiding individualized treatment.

Introduction: Hepatocellular carcinoma (HCC) is the most common type of cancer worldwide and is a major public health problem in the 21st century. Disulfidopathy, a novel cystine-associated programmed cell death, plays complex roles in various tumors. However, the relationship between disulfidoptosis and prognosis in patients with HCC remains unclear. This study aimed to explore the relationship between disulfideptosis and the prognosis of liver cancer and to develop a prognostic model based on amino acid metabolism and disulfideptosis genes. Methods: We downloaded the clinicopathological information and gene expression data of patients with HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and classified them into different molecular subtypes based on the expression patterns of disulfidoptosis-associated amino acid metabolism genes (DRAGs). Patients were then classified into different gene subtypes using the differential genes between the molecular subtypes, and the predictive value of staging was assessed using survival and clinicopathological analyses. Subsequently, risk prognosis models were constructed based on Cox regression analysis to assess patient prognosis, receiver operating characteristic (ROC) curves, somatic mutations, microsatellite instability, tumor microenvironment, and sensitivity to antitumor therapeutic agents. Results: Patients were classified into two subtypes based on differential DRAGs gene expression, with cluster B having a better survival outcome than cluster A. Three gene subtypes were identified based on the differential genes between the two DRAGs molecular subtypes. The patients in cluster B had the best prognosis, whereas those in cluster C had the worst prognosis. The heat map showed better consistency in the patient subtypes obtained using both typing methods. We screened six valuable genes and constructed a prognostic signature. By scoring, we found that patients in the low-risk group had a better prognosis, higher immune scores, and more abundant immune-related pathways compared to the high-risk group, which was consistent with the tumor subtype results. Discussion: In conclusion, we developed a prognostic signature of disulfidptosis-related amino acid metabolism genes to assist clinicians in predicting the survival of patients with HCC and provide a reference value for targeted therapy and immunotherapy for HCC.

Case report: sudden death following the administration of CAR-NK cells for lung cancer immunotherapy.

Lung cancer is a high degree of malignancy. Although surgery, radiotherapy, and chemotherapy have made significant progress and become general methods of clinical treatment, the overall survival rate is still low. In recent years, targeted therapy and immunotherapy have a rapid development in the clinical treatment of tumors. Among them, natural killer (NK) cells have the advantages of rapid killing of diseased cells and low risk of graft-versus-host reaction. It is considered a great vector for chimeric antigen receptors (CARs), making them have good application prospects in tumor immunotherapy. However, its clinical application in lung cancer needs further research. Herein, we reported a case of a lung cancer patient undergoing CAR-NK cell immunotherapy after resection, which caused a cytokine storm and sudden death after the fourth treatment. This case report provides a reference for the forensic examination of cadavers that died after immunotherapy and challenges the clinical application of cell immunotherapy.

A case of cardiac tamponade caused by T4N2M1 lung squamous cell carcinoma invading the aorta.

In patients with known lung squamous cell carcinoma, it is necessary to be alert to the presence of cancer cell infiltration in the large blood vessels and the heart. In this report, we report a case of a 49-year-old man who was previously diagnosed with squamous cell carcinoma of the lung, underwent autoimmune cell therapy, and was diagnosed posthumously with lung cancer invading the aorta and heart, resulting in severe cardiac tamponade. This case illustrates the value and key points of autopsy in evaluating sudden deaths.

Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat.

OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing. METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference. RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below. CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.

Antiplatelet effect, safety, and pharmacokinetics of vicagrel in patients with coronary artery disease undergoing percutaneous coronary intervention.

AIMS: Vicagrel, a novel antiplatelet prodrug to overcome the residual high platelet reactivity of clopidogrel induced by inactive metabolism and cytochrome P450 (CYP) 2C19 polymorphisms, provides favourable antiplatelet inhibition in healthy volunteers. However, its antiplatelet effect and safety in patients with coronary artery disease (CAD) are unclear. METHODS AND RESULTS: This was a multicentre, randomized, double-blind, triple-dummy, dose-exploring phase II trial comparing the antiplatelet activity and safety of vicagrel at different doses vs. those of clopidogrel in patients with CAD undergoing percutaneous coronary intervention (PCI). The primary endpoint was inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (%IPA) after loading and maintenance doses (LD/MD) at 28 days. Safety endpoints included adverse events (AEs) and Bleeding Academic Research Consortium-defined any bleeding. Pharmacokinetic (PK) profiles and the influence of CYP2C19 polymorphisms were explored in subgroup analysis. Two hundred and seventy-nine patients diagnosed with stable CAD (51.97%), unstable angina (40.86%), and myocardial infarction (7.17%) were randomized to receive vicagrel 20/5 mg (LD/MD), 24/6 mg, or 30/7.5 mg or clopidogrel 300/75 mg in combination with aspirin. %IPAs on Day 28 were 30.19%, 35.02%, 45.61%, and 32.55% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, and were comparable across all groups (P = 0.0694). The plasma concentration of the vicagrel active metabolite M15-2 had a similar area under curve and Tmax to those of clopidogrel. There were no significant differences in AEs (4.35%, 0%, 1.45%, and 5.56% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, P = 0.6667) or any bleeding (13.04%, 14.06%, 11.59%, and 11.11% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, P = 0.95) across four groups. %IPAs and PK profiles of vicagrel did not vary significantly among different CYP2C19 metabolizers. CONCLUSION: Vicagrel had comparable antiplatelet effect and safety to clopidogrel in patients with CAD undergoing PCI.

The Molecular Brakes of Adipose Tissue Lipolysis.

Adaptation to changes in energy availability is pivotal for the survival of animals. Adipose tissue, the body's largest reservoir of energy and a major source of metabolic fuel, exerts a buffering function for fluctuations in nutrient availability. This functional plasticity ranges from energy storage in the form of triglycerides during periods of excess energy intake to energy mobilization via lipolysis in the form of free fatty acids for other organs during states of energy demands. The subtle balance between energy storage and mobilization is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance, type 2 diabetes and cancer cachexia. As a result, adipocyte lipolysis is tightly regulated by complex regulatory mechanisms involving lipases and hormonal and biochemical signals that have opposing effects. In thermogenic brown and brite adipocytes, lipolysis stimulation is the canonical way for the activation of non-shivering thermogenesis. Lipolysis proceeds in an orderly and delicately regulated manner, with stimulation through cell-surface receptors via neurotransmitters, hormones, and autocrine/paracrine factors that activate various intracellular signal transduction pathways and increase kinase activity. The subsequent phosphorylation of perilipins, lipases, and cofactors initiates the translocation of key lipases from the cytoplasm to lipid droplets and enables protein-protein interactions to assemble the lipolytic machinery on the scaffolding perilipins at the surface of lipid droplets. Although activation of lipolysis has been well studied, the feedback fine-tuning is less well appreciated. This review focuses on the molecular brakes of lipolysis and discusses some of the divergent fine-tuning strategies in the negative feedback regulation of lipolysis, including delicate negative feedback loops, intermediary lipid metabolites-mediated allosteric regulation and dynamic protein-protein interactions. As aberrant adipocyte lipolysis is involved in various metabolic diseases and releasing the brakes on lipolysis in thermogenic adipocytes may activate thermogenesis, targeting adipocyte lipolysis is thus of therapeutic interest.

Bariatric Surgery is Effective and Safe for Obese Patients with Compensated Cirrhosis: A Systematic Review and Meta-Analysis.

BACKGROUND: With the global pandemic of obesity and nonalcoholic fatty liver disease (NAFLD), the incidence of cirrhosis associated with nonalcoholic steatohepatitis (NASH) has greatly increased. This study aimed to evaluate the efficacy and safety of bariatric surgery in obese cirrhotic patients. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for relevant studies. Effectiveness outcomes were weight loss, remission of comorbidities, and improvement in liver function. Safety outcomes were procedural complications and mortality. RESULTS: A total of 15 studies were included in this meta-analysis. Patients with compensated cirrhosis lost weight significantly after surgery, and the percentage of excess weight loss was 60.44 (95% CI, 44.34 to 76.55). Bariatric surgery resulted in remission of NAFLD in 57.9% (95% CI, 27.5% to 88.3%), T2DM in 58.4% (95% CI, 48.4% to 68.4%), hypertension in 53.1% (95% CI, 43% to 63.3%), dyslipidemia in 59.8% (95% CI, 41.1% to 78.5%) of patients with cirrhosis. Bariatric surgery reduced the levels of alanine aminotransferase and aspartate aminotransferase. The incidence of surgical complications in patients with cirrhosis was about 19.2% (95% CI, 11.7% to 26.6%), which was higher than that in patients without cirrhosis (OR 2.67 [95% CI, 1.26 to 5.67]). Patients with cirrhosis had an overall mortality rate of 1.3%, and the mortality rates for compensated cirrhosis and decompensated cirrhosis were 0.9% and 18.2%, respectively. CONCLUSIONS: Bariatric surgery is effective for weight loss, remission of comorbidities, and reversal of liver damage. Although cirrhotic patients have a higher risk of complications and death, bariatric surgery is relatively safe for well-compensated cirrhosis.

Two cases of fatal iatrogenic air embolism confirmed by autopsies.

The occurrence of air embolism is highly related to medical operations, and air embolism can cause sudden death. Such situations require attention in forensic work. This article reports two cases of iatrogenic air embolism confirmed by autopsy. In case 1, air embolism occurred after hydrogen peroxide was used to irrigate and disinfect a wound on the patient's left forearm. Approximately 90 ml of 3% hydrogen peroxide solution was used in case 1, and this volume can produce approximately 890 ml of oxygen by complete decomposition, which is far more than the average lethal air embolism volume. Attention should be given to the risk of air embolism when using hydrogen peroxide for irrigation and disinfection. In case 2, air embolism occurred during left ureteroscopy and stent placement. Due to inappropriate processing, the normal saline pump infused air into the patient at a high pressure of 120 mmHg. Based on our autopsy findings, we discuss the pathways of arterial air embolism and cerebral air embolism. In addition to the air entrainment volume and accumulation rate, the location of air accumulation also significantly impacts the risk of air embolism. After an arterial air embolus develops into a coronary and/or cerebral air embolus, the lethal air volume drops to only a few milliliters.

Investigating the forensic pathological characteristics of systemic vasculitis: A retrospective study of 20 deaths caused by systemic vasculitis.

Systemic vasculitis (SV) is a condition characterized by vascular inflammatory disease that often involves the medium and small arteries of various organs throughout the body. SV is difficult to diagnose due to the diversity of clinical symptoms and manifestations, and only tissue biopsy is of great significance. Even so, complications or secondary lesions of SV can also lead to death. In forensic medicine, we can often observe multiple vasculitis in histological observations, which is easily overlooked as a primary cause of death in the final diagnosis. Twenty SV cases were registered in our institution from a total of 1088 completed autopsies, which represents 1.83% of the total autopsies. The ages of these 20 SV patients ranged from 16 to 73 years, and the mean age was 41.1 ± 15.9 years. SV usually involves multiple organs, such as the heart, lung, liver, kidney, gastrointestinal system and brain, simultaneously. The intensity of the lesions in the heart and kidney seemed to be more severe than the lesion intensity in other organs in most cases. The causes of death were identified as acute myocarditis (8 cases), acute heart failure (3 cases), cerebral artery rupture (3 cases), cardiovascular artery rupture (2 cases), acute interstitial pneumonia (2 cases), aortic aneurysm rupture (1 case) and acute renal failure (1 case). The typical histopathological changes (smooth muscle degeneration, fibrinoid necrosis, inflammatory cell infiltration and microthrombosis) of arteries observed in this study were of great significance for diagnosing SV. In this article, we try to analyse and summarize the lesion characteristics in cases of death caused by SV in order to provide some help for forensic workers in identifying such cases.

Secretin as a Satiation Whisperer With the Potential to Turn into an Obesity-curbing Knight.

The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight, and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, only recently has it been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our as yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these 2 entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery and chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin's metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

TNF-α/NF-κB signaling epigenetically represses PSD4 transcription to promote alcohol-related hepatocellular carcinoma progression.

BACKGROUND: Chronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N-glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate-ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression. METHODS: R-based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real-time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation-specific PCR. Phospho-p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN-induced and DEN only-induced transgenic murine models of HCC. RESULTS: We identified PSD4 as a hypermethylated, suppressed gene in alcohol-related HCC tumors; however, PSD4 was not dysregulated in all-cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF-α-induced phospho-p65(S276)'s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro-EMT CDC42 activity, resulting in downregulation of E-cadherin and upregulation of N-cadherin and vimentin. Hepatocyte-specific PSD4 overexpression reduced ethanol/DEN-induced HCC tumor progression and EMT marker expression in vivo. CONCLUSIONS: PSD4 is a hypermethylated, suppressed gene in alcohol-related HCC tumors that negatively modulated pro-EMT CDC42 activity. Furthermore, we present a novel phospho-NF-κB p65(S276)/DNMT1-mediated promoter methylation mechanism by which TNF-α/NF-κB signaling represses PSD4 transcription in HCC cells.

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans.

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

E. coli diversity: low in colorectal cancer.

BACKGROUND: Escherichia coli are mostly commensals but also contain pathogenic lineages. It is largely unclear whether the commensal E. coli as the potential origins of pathogenic lineages may consist of monophyletic or polyphyletic populations, elucidation of which is expected to lead to novel insights into the associations of E. coli diversity with human health and diseases. METHODS: Using genomic sequencing and pulsed field gel electrophoresis (PFGE) techniques, we analyzed E. coli from the intestinal microbiota of three groups of healthy individuals, including preschool children, university students, and seniors of a longevity village, as well as colorectal cancer (CRC) patients, to probe the commensal E. coli populations for their diversity. RESULTS: We delineated the 2280 fresh E. coli isolates from 185 subjects into distinct genome types (genotypes) by PFGE. The genomic diversity of the sampled E. coli populations was so high that a given subject may have multiple genotypes of E. coli, with the general diversity within a host going up from preschool children through university students to seniors. Compared to the healthy subjects, the CRC patients had the lowest diversity level among their E. coli isolates. Notably, E. coli isolates from CRC patients could suppress the growth of E. coli bacteria isolated from healthy controls under nutrient-limited culture conditions. CONCLUSIONS: The coexistence of multiple E. coli lineages in a host may help create and maintain a microbial environment that is beneficial to the host. As such, the low diversity of E. coli bacteria may be associated with unhealthy microenvironment in the intestine and hence facilitate the pathogenesis of diseases such as CRC.

Identification of a novel fusion gene, TRIM52-RACK1, in oral squamous cell carcinoma.

Gene fusion is caused by the linkage of previously separate genes or sequences. Recently, an increasing number of novel fusion genes have been identified and associated with tumor progression, and several of them have been suggested as promising targets for tumor therapy. However, there are hardly any studies reporting the association of fusion genes with the progression of oral squamous cell carcinoma (OSCC). In this study, we identified a total of 11 fused genes in OSCC cells. We further analyzed the structure of one fused gene, TRIM52-RACK1, and detected its function in tumor progression in vitro. We found that TRIM52-RACK1 was caused by a deletion of 181,257,187-181,247,386 at 5q35.3 and it promoted OSCC cell proliferation, migration, and invasion. Therefore, TRIM52-RACK1 can be a promising target for tumor therapy in OSCC.

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas.

BACKGROUND: Gliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas. METHODS: Tumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdcscid ll2rgnull mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient's original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing. RESULTS: A total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations. CONCLUSIONS: The panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.

Cancer Stem Cells of Diffuse Large B Cell Lymphoma Are Not Enriched in the CD45+CD19- cells but in the ALDHhigh Cells.

Although the existence of cancer stem cells (CSCs) has been suggested in diffuse large B cell lymphoma (DLBCL), there is still no definitive marker. CD45+CD19- has been regarded as a potential marker of CSCs in mantle cell lymphoma (MCL). So, we explored the role of CD45+CD19- in DLBCL. However, both CD45+CD19- cells and CD45+CD19+ cells did not generate tumors until more than 100,000 cells were inoculated in NOD/SCID mice, even CD45+CD19+ cells generated more and larger tumors, as well as the soft agar colony formation in vitro; The aldehyde dehydrogenase (ALDH) activity was also identified in this study. Only 1,500 ALDHhigh cells were enough to generate tumors in mice while the same number of ALDH- cells were not. Moreover, both groups formed tumors when more cells were inoculated, but ALDHhigh cells formed more and larger tumors. The similar result was obtained in vitro clonogenicity experiments. OCT4, SOX2, Nanog, and ABCG2 genes did not show any difference in CD45+CD19+, CD45+CD19-, ALDHhigh and ALDH- cells. Taken together, CSCs are not enriched in the CD45+CD19- cells but in the ALDHhigh cells in DLBCL cell lines.

Long noncoding RNA LINC00052 inhibits colorectal cancer metastasis by sponging microRNA-574-5p to modulate CALCOCO1 expression.

The dysregulation of long-chain noncoding ribonucleic acid (lncRNA) is a common phenomenon in many human cancers. Some studies on the biological function of long intergenic non-protein-coding RNA 52 (LINC00052) in cancer indicate that this gene can act as either oncogene or tumor suppressor in some kinds of cancers, such as breast cancer, gastric cancer, liver cancer, and lung cancer. However, the biological function of LINC00052 in colorectal cancer (CRC) has not been studied. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) techniques were applied to detect the expression levels of LINC00052, miR-574-5p, and calcium-binding and coiled-coil domain 1 (CALCOCO1) in CRC cells and tissues. We authenticated the biological function of LINC00052 and miR-574-5p in CRC, and find some target genes for LINC00052 and miR-574-5p via bioinformatics methods. Dual-luciferase reporter gene assay was performed to identify the interaction between LINC00052 and miR-574-5p or CALCOCO1 and miR-574-5p. The results demonstrated that LINC00052 was downregulated in CRC tissues compared with their adjacent tissues. And LINC00052 could suppress CRC cells metastasis both in vivo and in vitro. Beyond that, miR-574-5p was upregulated in CRC tissues, and as an oncogene, it accelerated CRC cell migration and invasion. More importantly, the results of our research demonstrated that LINC00052 could regulate the expression of CALCOCO1 via sponging miR-574-5p in CRC. Overall, our study illuminated the lncRNA-miRNA functional networks in CRC, and these results might provide a new research direction for the diagnosis and treatment of CRC.

Dysbiosis of the Gut Microbiome in Lung Cancer.

Lung cancer (LC) is one of the most serious malignant tumors, which has the fastest growing morbidity and mortality worldwide. A role of the lung microbiota in LC pathogenesis has been analyzed, but a comparable role of the gut microbiota has not yet been investigated. In this study, the gut microbiota of 30 LC patients and 30 healthy controls were examined via next-generation sequencing of 16S rRNA and analyzed for diversity and biomarkers. We found that there was no decrease in significant microbial diversity (alpha diversity) in LC patients compared to controls (P observed = 0.1422), while the composition (beta diversity) differed significantly between patients and controls (phylum [stress = 0.153], class [stress = 0.16], order [stress = 0.146], family [stress = 0.153]). Controls had a higher abundance of the bacterial phylum Actinobacteria and genus Bifidobacterium, while patients with LC showed elevated levels of Enterococcus. These bacteria were found as possible biomarkers for LC. A decline of normal function of the gut microbiome in LC patients was also observed. These results provide the basic guidance for a systematic, multilayered assessment of the role of the gut microbiome in LC, which has a promising potential for early prevention and targeted intervention.