Small Leucine-Rich Proteoglycan PODNL1 Identified as a Potential Tumor Matrix-Mediated Biomarker for Prognosis and Immunotherapy in a Pan-Cancer Setting.

The podocan-like protein 1 (PODNL1), an important member of the small leucine-rich proteoglycans (SLRP) family, is a crucial component of the tumor microenvironment (TME). But its prognostic values and the role in the TME have not been systematically estimated in a pan-cancer setting. Targeting PODNL1, a systematic exploration into the TCGA datasets, reconciling with the analyses of single-cell transcriptomes and immunotherapeutic cohorts in cancers, and validation by tissue microarray-based multiplex immunofluorescence staining was performed. PODNL1 was significantly correlated with the poor prognosis and immunotherapeutic responses in various cancers. In-depth demonstration of molecular mechanisms indicated that PODNL1 expressions were notably positively correlated with cancer-associated fibroblast (CAF) infiltration levels in 33 types of cancers. It also positively correlated with the pan-fibroblast TGF-ß response signature score, and the hallmarks including TGF-ß, TNF-α, inflammatory response, apical junction, epithelial-mesenchymal transition and hedgehog in pan-cancer. Furthermore, high PODNL1 expressions were positively related with the regulation of tumor-promoting TGF-ß signaling through downregulating SMAD2/3:4 heterotrimer regulations transcription and up-regulating the pathway restricted SMAD protein phosphorylation. Single-cell transcriptome analyses and immunofluorescence validations indicated that PODNL1 was predominantly expressed in the cancer cells and CAFs in various cancers. Additionally, the heterogeneity of cancer genotype-phenotype cross-talking was also observed associated with PODNL1. Our systematic study indicates that PODNL1 plays an important role in the complex regulation network of tumor progression, and lays a foundation for further exploration to develop PODNL1 as a valuable matrix-mediated biomarker for cancer immunotherapy and prognosis in a pan-cancer setting.

A TMVP1-modified near-infrared nanoprobe: molecular imaging for tumor metastasis in sentinel lymph node and targeted enhanced photothermal therapy.

BACKGROUND: TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging. RESULTS: In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine. CONCLUSION: TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.

Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response.

Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that affect cell cycle arrest, apoptosis, and autophagy. Here, we found that GA decreased the viability of the CRC cell lines, HCT116 and CT26, in a dose- and time-dependent manner, and multiple pores and large bubbles in the membranes, which are morphological characteristics of pyroptosis, were observed by light microscopy and transmission electron microscopy (TEM). Furthermore, the cleavage of gasdermin E (GSDME) was observed after exposure to GA, along with concomitant activation of caspase-3. Additionally, GSDME-dependent pyroptosis triggered by GA could be attenuated by siRNA-mediated knockdown of GSDME and treatment with the caspase-3 inhibitor. Moreover, we found that GA induced pyroptosis and significantly inhibited tumor growth in CT26 tumor-bearing mice. Strikingly, significantly increased proportions of CD3+ T cells, cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) were observed in the tumor microenvironment in the GA-treated groups. Moreover, significantly increased proportions of CTLs and effector memory T cells (TEM) (CD8+ CD44+ CD62L-) were also detected in the spleens of the GA-treated groups, suggesting that the pyroptosis-induced immune response generated a robust memory response that mediated protective immunity. In this study, we revealed a previously unrecognized mechanism by which GA induces GSDME-dependent pyroptosis and enhances the anticancer immune response. Based on this mechanism, GA is a promising antitumor drug for CRC treatment that induces caspase-3-GSDME-dependent pyroptosis. This study provides novel insight into cancer chemoimmunotherapy.

Human Chrysomya bezziana myiasis: A systematic review.

BACKGROUND: Myiasis due to Old World screw-worm fly, Chrysomya bezziana, is an important obligate zoonotic disease in the OIE-list of diseases and is found throughout much of Africa, the Indian subcontinent, southeast and east Asia. C. bezziana myiasis causes not only morbidity and death to animals and humans, but also economic losses in the livestock industries. Because of the aggressive and destructive nature of this disease in hosts, we initiated this study to provide a comprehensive understanding of human myiasis caused by C. bezziana. METHODS: We searched the databases in English (PubMed, Embase and African Index Medicus) and Chinese (CNKI, Wanfang, and Duxiu), and international government online reports to 6th February, 2019, to identify studies concerning C. bezziana. Another ten human cases in China and Papua New Guinea that our team had recorded were also included. RESULTS: We retrieved 1,048 reports from which 202 studies were ultimately eligible for inclusion in the present descriptive analyses. Since the first human case due to C. bezziana was reported in 1909, we have summarized 291 cases and found that these cases often occurred in patients with poor hygiene, low socio-economic conditions, old age, and underlying diseases including infections, age-related diseases, and noninfectious chronic diseases. But C. bezziana myiasis appears largely neglected as a serious medical or veterinary condition, with human and animal cases only reported in 16 and 24 countries respectively, despite this fly species being recorded in 44 countries worldwide. CONCLUSION: Our findings indicate that cryptic myiasis cases due to the obligate parasite, C. bezziana, are under-recognized. Through this study on C. bezziana etiology, clinical features, diagnosis, treatment, epidemiology, prevention and control, we call for more vigilance and awareness of the disease from governments, health authorities, clinicians, veterinary workers, nursing homes, and also the general public.

Codon usage variation of Zika virus: The potential roles of NS2B and NS4A in its global pandemic.

A comprehensive demonstration of Zika virus (ZIKV) molecular evolution is essential for understanding its adaptation and expansion in its recent pandemics. Despite several studies on mutations and codon usage in ZIKVs, the variations in codon usage patterns across individual genes and their biological implication remains unclear. Here, we performed a gene-by-gene comparison of the codon usage variation in ZIKVs of the African and Asian lineages. We found that besides the evidence of positive selection (Ka/Ks >1) in the Asian lineage of the ZIKV genome, codon usage patterns were gene-specific and codon usage variation of ZIKV genes, was possibly constrained by their individual functional features, such as transmembrane domains, or antigenicity. In particular, the NS2B and NS4A genes showed distinct codon usage patterns, clearly separating them from the clusters of other genes in the correspondence analysis (CA). In the Asian lineage, the NS2B and NS4A genes showed the highest codon usage bias (ENC values: 51.01 ±â€¯0.72 and 48.89 ±â€¯0.99 respectively), and were subjected to the highest translation selection (ENCobs/ENCexp ratio: 0.847 ±â€¯0.0297 and 0.828 ±â€¯0.0233 respectively) in comparison to the African lineages of ZIKV. The CpG frequency of the NS2B showed a gradual ascending trend in the Asian ZIKV lineages, while in NS4A it was constrained along with the expansion of the Asian lineage. Furthermore, between the African and Asian lineages, differentiated and specific over-represented codons were more prominent in the NS2B and NS4A. Together, our study implies that ZIKVs are in the process of evolutionary fine tuning their codon as seen in the recent pandemics, and NS2B and NS4A could have played a potential role in the molecular evolution of the Asian lineage and their establishment.

[Splenic thickness combined with routine clinical markers predicts esophageal varices in patients with liver cirrhosis].

OBJECTIVE: To explore the noninvasive indicators for predicting the occurrence of esophageal varices (EV) in patients with liver cirrhosis. METHODS: A total of 202 patients with liver cirrhosis caused by hepatitis B or C or alcoholic hepatic disease were enrolled in this study. EV and high risk esophageal varices (HREV) were confirmed in these patients by gastroscopy. The hematological, serum biochemical and ultrasonic parameters of the patients were analyzed, and a model for predicting EV was established by stepwise logistic regression analysis. RESULTS: The areas under receiver operating characteristics curve (AUROC) of splenic thickness (SPT) for detecting EV and HREV were 0.827 and 0.766, respectively. The combined index USWA (SPT, US, WBC and albumin [ALB]) showed an AUROC of 0.873 for detecting EV, and the index SPA (combining SPT and ALB) showed an AUROC of 0.777 for detecting HREV. The direct combination of SPT with USWA or with platelet/splenic thickness ratio (PSA) was capable of completely excluding a definite diagnosis of EV, while the sequential combination of SPT with USWA or with platelet was capable of a diagnosis of EV and clarifying the condition of EV in approximately half of the cirrhotic patients in the absence of gastroscopic findings. The combination of SPT and SPA allowed for a definite diagnosis of the condition of HREV in 10% of the cirrhotic patients. CONCLUSION: SPT combined with SPT derived indexes or platelet status allows for a definite diagnosis of EV in patients with liver cirrhosis to offer a noninvasive option for diagnosis.