Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance.

H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. HP1 proteins are required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how HP1 protein binding to heterochromatin establishes and maintains transcriptional silencing. Here, we demonstrate that the S.pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1 and an H3K14 acetyltransferase, Mst2 are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identifies a genetically separable function in maintaining epigenetic memory.

Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance.

H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. HP1 proteins are required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how these different HP1 properties are involved in establishing and maintaining transcriptional silencing. Here, we demonstrate that the S. pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1, and an H3K14 acetyltransferase, Mst2, are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identify a genetically separable function in maintaining epigenetic memory.

Assessment of prognostic role of a novel 7-lncRNA signature in HCC patients.

Background: Hepatocellular carcinoma (HCC) is characterized by extensive risk factors, high morbidity and mortality. Clinical prognostic evaluation assay assumes a nonspecific quality. Better HCC prognostics are urgently needed. Long noncoding RNAs (lncRNAs) exerts a crucial role in tumorigenesis and development. Excavating specific lncRNAs signature to ameliorate the high-risk survival prediction in HCC patients is worthwhile. Methods: Differentially expressed lncRNAs (DElncRNAs) profile was acquired from The Cancer Genome Atlas database (TCGA). Then, the lncRNAs high-risk survival prognostic model was established using the least absolute shrinkage and selection operator (LASSO)-Cox regression algorithm. The lncRNAs were evaluated in clinical specimen by PCR. The receiver operating characteristic curve (ROC) analysis was further conducted to assess the potential prognostic value of the model. Moreover, a visible nomogram containing clinicopathological features and prognostic model was developed for prediction of survival property. Potential molecular mechanism was assessed by GO, KEGG, GSEA enrichment analysis and CIBERSORT immune infiltration analysis. Results: A novel 7-lncRNA risk model (AL161937.2, LINC01063, AC145207.5, POLH-AS1, LNCSRLR, MKLN1-AS, AC105345.1) was constructed and validated for HCC prognosis prediction. Kaplan-Meier analysis revealed that patients in the high-risk group suffered a poor prognosis (p = 1.813 × 10-8). These genes were detected by PCR, and the expression trend was in accordance with TCGA database. Interestingly, the risk score served as an independent risk factor for HCC patients (HR: 1.166, 95% CI:1.119-1.214, p < 0.001). The nomogram was established, and the predictive accuracy in the nomogram was prior to the TNM stage according to the ROC curve analysis. Cell proliferation related pathway, decreased CD4+ T cell, CD8+ T cell, NK cell and elevated Neutrophil, Macrophage M0 were observed in high-risk group. Besides, suppression of MKLN1-AS expression inhibited cell proliferation of HCC cells by CCK8 assay in vitro. Conclusion: The 7-lncRNA signature may exert a particular prognostic prediction role in HCC and provide new insight in HCC carcinogenesis.

Comprehensive Analysis of PPMs in Pancreatic Adenocarcinoma Indicates the Value of PPM1K in the Tumor Microenvironment.

Early metastasis and resistance to traditional therapy are responsible for the poor prognosis of pancreatic adenocarcinoma patients. Metal-dependent protein phosphatases (PPMs) have been proven to play a crucial role in the initiation and progression of various tumors. Nevertheless, the expression and function of distinct PPMs in pancreatic adenocarcinoma have not been fully elucidated. In this study, we investigated the mRNA expression level, prognostic value, and the relationship between the expression of PPMs and the tumor microenvironment in pancreatic adenocarcinoma using Oncomine, TCGA and GTEx, GEO, Kaplan-Meier plotter, STRING, GeneMANIA, and HPA databases and R packages. GO and KEGG analysis revealed that PPMs and their differential co-expression genes are attributed to cell-cell adhesion and immune cell infiltration. Among these, PPM1K was downregulated in the tissue and peripheral blood of PAAD patients, whose expression level was negatively related to poor prognosis. Further to this, PPM1K was found to play a role in the epithelial-mesenchymal transition and immune infiltration. ROC curves showed that PPM1K had a good predictive value for pancreatic adenocarcinoma. The knockdown of PPM1K markedly promoted the proliferation and migration of pancreatic cancer cells, confirming its role in tumor suppressor activity in PAAD. This study demonstrates the potential clinical utility of PPM1K in tumor immunotherapy and brings about novel insights into the prognostic value of PPM1K in pancreatic adenocarcinoma.

Characterization of the complete chloroplast genome of Zanthoxylum esquirolii Levl. (Rutaceae).

Zanthoxylum esquirolii Léveillé 1914 is mainly distributed in southwest China, and its wild germplasm resources are scarce and in urgent need of conservation. In this study, we report the first complete chloroplast genome sequence of Z. esquirolii using next-generation sequencing. The circular genome is 158,390 bp in length, containing two inverted repeat (IR) regions of 27,622 bp separated by a large single copy (LSC) region of 85,580 bp and a small single copy (SSC) region of 17,566 bp. The chloroplast genome contains a total of 132 genes, including 87 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The overall GC content of the chloroplast genome was 38.46%, with corresponding values in the LSC, SSC, and IR regions of 36.84%, 33.55%, and 42.51%, respectively. The phylogenetic tree revealed that Z. esquirolii Levl. formed a clade with Z. piperitum DC., Z. bungeanum Maxim., Z. simulans Hance and Z. sp. NH-2018, and had a strongly supported sister relationship with Z. bungeanum.

METTL16 predicts a favorable outcome and primes antitumor immunity in pancreatic ductal adenocarcinoma.

Pancreatic carcinogenesis is a complicated and multi-step process. It is substantially assisted by N6-methyladenosine (m6A) RNA modification, especially when mutations of driver genes (KRAS, TP53, CDKN2A, and SMAD4) occur. However, the underlying mechanism remains obscure. In this research, we identified m6A regulators as potential biomarkers when mutations of driver genes occur, and investigated the role of these m6A candidates in pancreatic ductal adenocarcinoma (PDA). We first estimated the abnormal expression patterns of potential m6A regulators when all the driver genes are mutated, using The Cancer Genome Atlas and Gene Expression Omnibus databases. METTL16, an m6A"writer," was chosen as a unique candidate of PDA, owing to its markedly differential expression under mutations of all driver genes (KRAS, TP53, CDKN2A, and SMAD4) and its favorable prognostic value. Moreover, METTL16 was under-expressed in PDA tissues and cell lines. Consistently, gain- and loss-of-function experiments indicated that it had a tumor suppressor role in vitro and in vivo. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that METTL16 may have an effect on the tumor microenvironment. Notably, a markedly positive association between METTL16 expression and infiltration of B cells and CD8+ T cells was observed according to the CIBERSORT and TIMER databases. Enhanced expression of immune checkpoints and cytokines was elicited in patients with over-expression of METTL16. Notably, decreased expression of PD-L1 was observed when upregulation of METTL16 expression occurred in MIA PaCa-2 cells, while increased expression of PD-L1 existed when downregulation of METTL16 happened in HPAF-II cells. Collectively, these findings highlight the prognostic value of METTL16, and indicate that it is a potential immunotherapy target that could be used to regulate the tumor microenvironment and promote antitumor immunity in PDA.

The complete chloroplast genome of Zanthoxylum stenophyllum Hemsl. (Rutaceae), a traditional Chinese medicinal plant.

Zanthoxylum stenophyllum Hemsl., a type species for the genus Zanthoxylum (Rutaceae), is a traditional medicinal plant. We studied the complete chloroplast genome of this species using BGISEQ-500 platform. The chloroplast genome was 158,314 bp in size with a GC content of 38.45%. The genome contained two short inverted repeat (IRa and IRb) regions of 27,052 bp, a large single-copy region (LSC, 86,029 bp) and a small single-copy region (SSC, 18,181 bp). The annotated complete chloroplast genome contains 133 distinct genes, including 88 protein-coding genes, 37 transfer RNAs (tRNAs), and 8 ribosomal RNAs (rRNAs). Phylogenetic analysis indicated that Z. stenophyllum is clustered with Z. schiniflium and Z. pinnatum in the same branch with 100% bootstrap support. This complete chloroplast genome provides valuable genomic information for the molecular phylogeny and sustainable utilization of Zanthoxylum.

CircMYOF triggers progression and facilitates glycolysis via the VEGFA/PI3K/AKT axis by absorbing miR-4739 in pancreatic ductal adenocarcinoma.

Emerging evidence has demonstrated that circular RNAs (circRNAs) take part in the initiation and development of pancreatic ductal adenocarcinoma (PDA), a deadly neoplasm with an extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumour development, including PDA. In this research, we evaluated the role of circRNAs in reprogrammed glucose metabolism in PDA. RNA sequencing under various glucose incubation circumstances was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real-time PCR indicated that it was highly expressed in PDA clinical specimens and cell lines. Gain-of- and loss-of-function assays showed that circMYOF induced progression in PDA. Mechanistically, RNA pull-down and luciferase reporter experiments elucidated that circMYOF, as a competing endogenous RNA for miR-4739, facilitated glycolysis via the VEGFA/PI3K/AKT pathway. Taken together, our findings indicate that circMYOF may work as a desirable biomarker and therapeutic target for PDA patients.

Primary Esophageal Lymphoma: Clinical Experience in Diagnosis and Treatment.

Primary esophageal lymphoma is a rare malignant tumor, which is often misdiagnosed. To improve the diagnosis and treatment of this disease, we presented one case admitted at our institution and a literature review of primary esophageal lymphoma cases, including the clinical data, features of imaging, endoscopy and pathology, treatment, and prognosis. The symptoms were non-specific. Under endoscopy, most of the lesions were located in the middle and lower segment of the esophagus, behaving as ulcers, polyps, or submucosal masses, always accompanying with esophageal stricture. The diagnosis of primary esophageal lymphoma was highly dependent on pathological and immunohistochemical examination, hence stacked sampling was suggested to improve the positive rate of mucosal biopsy. Combination of chemotherapy and radiotherapy may be the first choice of treatment, surgical and endoscopic resections may be an alternative solution as well. The therapeutic effect and prognosis were slightly better than those of other esophageal malignant tumors.

Rational Design, Pharmacomodulation, and Synthesis of [68Ga]Ga-Alb-FAPtp-01, a Selective Tumor-Associated Fibroblast Activation Protein Tracer for PET Imaging of Glioma.

Dynamic changes in the tumor-associated fibroblast activation protein (FAP) expression in tumors of different stages may be helpful for prognostic evaluation and treatment response monitoring, making this protein a promising surveillance biomarker for timely diagnosis of malignant tumors and effective planning of patient care. To prospectively verify the diagnostic efficacy value of the developed FAP tracers, [68Ga]Ga-FAPtp and [68Ga]Ga-Alb-FAPtp-01, dynamic/static positron emission tomography (PET)/computed tomography scans were acquired for tumor-targeting studies in vivo and in comparison with the well-established clinically used tracer [68Ga]Ga-FAPI-04. The optimized rationally designed FAP-targeting PET tracer, [68Ga]Ga-Alb-FAPtp-01, with albumin-binding capability demonstrated prominent tumor uptake over time. The mean standard uptake value (SUV) and the tumor/muscle (T/M) ratio were as high as 1.775 ± 0.179 SUV and T/M = 5.9, 1.533 ± 0.222 SUV and T/M = 6.7, and 1.425 ± 0.204 SUV and T/M = 9.5, respectively, at 1, 2, and 3 h. Its improved tumor uptake and pharmacokinetics suggest that the [68Ga]Ga-Alb-FAPtp-01 tracer can noninvasively detect FAP activation in vivo, permitting a precise definition of its roles in tumors of different stages and yielding insights regarding FAP-targeted radiotherapeutic strategies at the molecular level.

Wetting-Enhanced Structural Color for Convenient and Reversible Encryption of Optical Information.

Encrypted storage of optical information has attracted increasing interest for anticounterfeiting, information transmission, and military applications. In this study, an inverse opal-structured titanium dioxide/heptadecafluorodecyltrimethoxysilane (IOS-T/F) panel is developed. Based on a unique wetting-enhanced mechanism of structural color vision derived from a reduced light scattering and strengthened effective refractive index, this panel is capable of reversible writing/erasing and encryption/decryption of optical information. Multiple levels of information can be compiled, concealed, and erased simply using controlled ultraviolet irradiation to form patterned hydrophilic/hydrophobic differences, and the process of revealing or concealing the information only requires a few drops of water or evaporation, respectively. Importantly, the functions of the IOS-T/F panel can be well maintained under harsh conditions, including strongly acidic/alkaline environments or extreme temperatures (from -40 to 80 °C), as well as can be recovered after staining by various pollutants. This system provides simple encryption, rapid decryption, and the ability to store multiple sets of information under diverse application scenarios, which represents a novel material design strategy for security-related applications and smart optical systems.

Integrin α2ß1-targeting ferritin nanocarrier traverses the blood-brain barrier for effective glioma chemotherapy.

BACKGROUND: Ferritin, the natural iron storage protein complex, self-assembles into a uniform cage-like structure. Human H-ferritin (HFn) has been shown to transverse the blood-brain barrier (BBB) by binding to transferrin receptor 1 (TfR1), which is abundant in endothelial cells and overexpressed in tumors, and enters cells via endocytosis. Ferritin is easily genetically modified with various functional molecules, justifying that it possesses great potential for development into a nanocarrier drug delivery system. RESULTS: In this study, a unique integrin α2ß1-targeting H-ferritin (2D-HFn)-based drug delivery system was developed that highlights the feasibility of receptor-mediated transcytosis (RMT) for glioma tumor treatment. The integrin targeting α2ß1 specificity was validated by biolayer interferometry in real time monitoring and followed by cell binding, chemo-drug encapsulation stability studies. Compared with naïve HFn, 2D-HFn dramatically elevated not only doxorubicin (DOX) drug loading capacity (up to 458 drug molecules/protein cage) but also tumor targeting capability after crossing BBB in an in vitro transcytosis assay (twofold) and an in vivo orthotopic glioma model. Most importantly, DOX-loaded 2D-HFn significantly suppressed subcutaneous and orthotopic U-87MG tumor progression; in particular, orthotopic glioma mice survived for more than 80 days. CONCLUSIONS: We believe that this versatile nanoparticle has established a proof-of-concept platform to enable more accurate brain tumor targeting and precision treatment arrangements. Additionally, this unique RMT based ferritin drug delivery technique would accelerate the clinical development of an innovative drug delivery strategy for central nervous system diseases with limited side effects in translational medicine.

SLC45A4 promotes glycolysis and prevents AMPK/ULK1-induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma.

BACKGROUND: Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). Solute carrier family 45 member A4 (SLC45A4) is a H+ -dependent sugar cotransporter. The role of SLC45A4 in PDA, especially in TP53 mutant PDA, remains poorly understood. METHODS: We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium], colony formation and 5-ethynyl-2'-deoxyuridine (Edu) assays were performed to investigate the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization. Extracellular acidification rate and oxygen consumption rate assays were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNA-sequencing and gene set enrichment analysis were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blotting was performed to evaluate the activation of glycolysis, as well as the AMPK pathway and autophagy. RESULTS: SLC45A4 was overexpressed in PDA for which the expression was significantly higher in TP53 mutant PDA than that in wild-type PDA tissues. Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production, which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice. CONCLUSIONS: The present study found that SLC45A4 prevents autophagy via AMPK/ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA.

Irisin, an exercise myokine, potently suppresses tumor proliferation, invasion, and growth in glioma.

Glioblastoma multiforme is the most common and aggressive glial tumor with poor prognosis. Importantly, effective treatment options for glioblastoma are unmet needs. Obesity and low physical activity have been linked with a high risk of cancer, and exercise is related to delayed cancer development and progression. Epidemiological studies have revealed a correlation between exercise and the survival rate of patients with glioblastoma. Nevertheless, the mechanisms by which exercise exerts its anticancer effects in glioblastoma remain unclear. Here, we found that irisin, an exercise-induced myokine, induced G2 /M cell cycle arrest and increased p21 levels in glioblastoma cells, leading to the inhibition of cell proliferation. In addition, irisin inhibited glioblastoma cell invasion by upregulating TFPI-2 and even reversed the aggressive tumor phenotype promoted by co-cultivation with cancer-associated adipocytes. Furthermore, irisin retarded xenograft glioblastoma tumor growth, and radiolabeled irisin demonstrated specific tumor-targeting capability in vivo. Therefore, this study identified one potential molecular mechanism by which exercise prevents cancer progression via irisin. Intriguingly, irisin has the potential to be developed as a molecular imaging and therapeutic anticancer agent.

MSCs exosomal miR-1470 promotes the differentiation of CD4+CD25+FOXP3+ Tregs in asthmatic patients by inducing the expression of P27KIP1.

Exosomes derived from Mesenchymal Stem Cells (MSCs) possesses similar immunomodulatory effect as MSCs. It had been suggested that MSCs exosomes contain higher level of miR-1470 compared to exosomes derived from fibroblast. Here, we show that MSCs exosomal miR-1470 can elevate the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in asthmatic patients. Moreover, mechanistic studies revealed that miR-1470 can promote the upregulation of P27KIP1 by directly targeting the 3' region of c-Jun mRNA. Furthermore, miR-1470 mimic transfection could significantly upregulate the proportion of CD4+CD25+FOXP3+ Tregs in CD4+ T cells. P27KIP1 knockdown via siRNA silencing significantly inhibited the proportion of CD4+CD25+FOXP3+ Tregs with over-expression of miR-1470, which indicates that miR-1470 induces the differentiation of CD4+CD25+FOXP3+ Tregs through P27KIP1.

A novel long noncoding RNA OECC promotes colorectal cancer development and is negatively regulated by miR-143-3p.

Emerging evidence indicates that aberrant long non-coding RNA (lncRNA) expression contributes to CRC pathogenesis. To explore the biological functions of lncRNAs in CRC and to identify the underlying mechanisms, we first conducted a lncRNA microarray assay to investigate lncRNA expression patterns in CRC. We identified a novel lncRNA OECC, originating from chromosome 8q24 that is highly expressed in CRC tissues and cell lines and has a positive correlation with liver metastasis. Attenuation of lncRNA OECC expression prohibited CRC cell proliferation, induced apoptosis, and inhibited migration. Furthermore, an inverse correlation between lncRNA OECC and miR-143-3p was observed. Bioinformatic analyses predicted, and a luciferase reporter assay demonstrated, that lncRNA OECC is a direct target of miR-143-3p, leading to down-regulation in the expression of its target genes, the NF-κB and p38 MAPK pathways. Taken together, our results suggest that lncRNA OECC is overexpressed in CRC and may play an oncogenic role through NF-κB and p38 MAPK pathway activation via miR-143-3p.

LncRNA PVT1 triggers Cyto-protective autophagy and promotes pancreatic ductal adenocarcinoma development via the miR-20a-5p/ULK1 Axis.

BACKGROUND: Defective autophagy is thought to contribute to the pathogenesis of many diseases, including cancer. Human plasmacytoma variant translocation 1 (PVT1) is an oncogenic long non-coding RNA that has been identified as a prognostic biomarker in pancreatic ductal adenocarcinoma, but how PVT1 operates in the regulation of autophagy in pancreatic ductal adenocarcinoma (PDA) is unclear. METHODS: PVT1 expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and hybridization in situ (ISH). Western blot or qRT-PCR was performed to assess the ULK1 protein or mRNA level. Autophagy was explored via autophagic flux detection under a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). The biological role of PVT1 in autophagy and PDA development was determined by gain-of-function and loss-of-function assays. RESULTS: We found that PVT1 levels paralleled those of ULK1 protein in PDA cancer tissues. PVT1 promoted cyto-protective autophagy and cell growth by targeting ULK1 both in vitro and in vivo. Moreover, high PVT1 expression was associated with poor prognosis. Furthermore, we found that PVT1 acted as sponge to regulate miR-20a-5p and thus affected ULK1 expression and the development of pancreatic ductal adenocarcinoma. CONCLUSIONS: The present study demonstrates that the "PVT1/miR-20a-5p/ULK1/autophagy" pathway modulates the development of pancreatic ductal adenocarcinoma and may be a novel target for developing therapeutic strategies for pancreatic ductal adenocarcinoma.

The Use of PET Imaging for Prognostic Integrin α2ß1 Phenotyping to Detect Non-Small Cell Lung Cancer and Monitor Drug Resistance Responses.

PURPOSE: Growing evidence has demonstrated that aberrant expression of integrin α2ß1 might contribute to the invasion, metastasis and drug resistance of non-small cell lung cancer (NSCLC). Thus, the integrin α2ß1 targeting 68Ga-DOTA-A2B1 tracer was validated in NSCLC in contrast to accumulation of the clinically used 18F-FDG PET tracer to see if 68Ga-DOTA-A2B1-PET imaging can offer a valuable and critical diagnostic imaging criterion for the identification of phenotypes of aggressive lung cancer. METHODS: To verify the prognostic value of integrin α2ß1, several quantitative and functional in vitro assays were validated in different NSCLC cell lines (CL1-0, CL1-5, A549 and selected A549++ cells). Positron emission tomography (PET) imaging studies using both standard 18F-FDG and a newly developed 68Ga-labeled integrin α2ß1 (68Ga-DOTA-A2B1) tracer were sequentially performed on mice with lung tumor xenografts in different anatomic locations (subcutaneous, orthotopic and osseous) to validate the targeting capability of the 68Ga-DOTA-A2B1 tracers. Treatment responses were monitored by injecting animals with metastatic bone tumors with 5 mg/kg doxorubicin. All in vivo treatment responses in each treatment subgroup were monitored with a PET imaging system to evaluate the up-regulation of integrin expression at the earliest stage of treatment (6 h). RESULTS: The PET and computed tomography (CT) images from NSCLC xenograft animals unambiguously demonstrated accumulation of the integrin tracer 68Ga-DOTA-A2B1 in the tumor lesions at all locations. The average tumor uptake and tumor-to-normal (T/N) ratio were 2.51 ± 0.56 %ID/g and T/N = 2.82, 3.40 ± 0.42 %ID/g and T/N = 1.52, and 1.58 ± 0.108 %ID/g and T/N = 2.31 in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). The xenograft tumors were all clearly visible. In contrast, the accumulation of 18F-FDG reached 3.6 ± 0.76 %ID/g, 1.39 ± 0.075 %ID/g and 3.78 ± 0.73 %ID/g in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). However, due to the high background uptake by normal tissue, the T/N values were less than or close to 1, making the tumors almost indistinguishable in the PET imaging analysis. Furthermore, 68Ga-DOTA-A2B1-PET imaging of the treated osseous tumor model demonstrated more than 19% tracer uptake in A549 lesions (1.72 ± 0.95 %ID/g vs. pretreatment 1.44 ± 0.12 %ID/g,p = 0. 015) 6 h post-treatment with doxorubicin. The elevated intensity of tracer uptake was in accordance with the results of in vitroWestern blot and ex vivo integrin staining, demonstrating elevated integrin α2ß1 expression. CONCLUSION: In this study, integrin α2ß1 was identified as a biomarker of aggressive malignant NSCLC. Thus, efforts should be devoted to validating integrin α2ß1 as a potential target for non-invasive diagnosis and as a predictive marker for monitoring treatment responses using a preclinical PET imaging system.

Prognostic value of PD-L1 overexpression for pancreatic cancer: evidence from a meta-analysis.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is often activated in cancer and plays a pivotal role in the initiation and progression of cancer. However, the clinicopathologic significance and prognostic value of PD-L1 in pancreatic cancer (PC) remains controversial. In this study, we conducted a meta-analysis to retrospectively evaluate the relationship between PD-L1 and PC. PubMed and other databases were searched for the clinical studies published up to March 21, 2017, to be included in the meta-analysis. Hazard ratios and their 95% CIs were calculated. Risk ratios (RRs) were extracted to assess the correlations between the clinicopathologic parameters and PD-L1 expression. Ten studies including 1,058 patients were included in the meta-analysis. The pooled results indicated that positive PD-L1 expression was correlated with a poor overall survival outcome in PC patients (hazard ratio =1.76, 95% CI: 1.43-2.17, P<0.00001). Interestingly, high PD-L1 expression was correlated with poor pathologic differentiation (RR =1.57, 95% CI: 1.25-1.98, P=0.0001) and neural invasion (RR =1.30, 95% CI: 1.03-1.64, P=0.03). However, there were no significant correlations between PD-L1 expression and other clinicopathologic characteristics. In summary, our meta-analysis implied that PD-L1 could serve as a negative predictor for the overall survival of PC patients, and high expression of PD-L1 was correlated with poor differentiation and neural invasion, indicating that anti-PD-L1 treatments should be evaluated in PC patients, especially in those who exhibit these two characteristics.