Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung.

We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides' ester structures is an effective strategy for enhancing prodrug activation in the lung.

Low-Intensity Pulsed Ultrasound Promotes the Repair of Achilles Tendinopathy by Downregulating the JAK/STAT Signaling Pathway in Rabbits.

Tendinopathy is a complex tendon injury or pathology outcome, potentially leading to permanent impairment. Low-intensity pulsed ultrasound (LIPUS) is emerging as a treatment modality for tendon disorders. However, the optimal treatment duration and its effect on tendons remain unclear. This study aims to investigate the efficacy of LIPUS in treating injured tendons, delineate the appropriate treatment duration, and elucidate the underlying treatment mechanisms through animal experiments. Ninety-six three-month-old New Zealand white rabbits were divided into normal control (NC) and model groups. The model group received Prostaglandin E2 (PGE2) injections to induce Achilles tendinopathy. They were then divided into model control (MC) and LIPUS treatment (LT) groups. LT received LIPUS intervention with a 1-MHz frequency, a pulse repetition frequency (PRF) of 1 kHz, and spatial average temporal average sound intensity ( [Formula: see text]) of 100 mW/cm2. MC underwent a sham ultrasound, and NC received no treatment. Assessments on 1, 4, 7, 14, and 28 days after LT included shear wave elastography (SWE), mechanical testing, histologic evaluation, ribonucleic acid sequencing (RNA-seq), polymerase chain reaction (PCR), and western blot (WB) analysis. SWE results showed that the shear modulus in the LT group was significantly higher than that in the MC group after LT for seven days. Histological results demonstrated improved tendon tissue alignment and fibroblast distribution after LT. Molecular analyses suggested that LIPUS may downregulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and regulate inflammatory and matrix-related factors. We concluded that LT enhanced injured tendon elasticity and accelerated Achilles tendon healing. The study highlighted the JAK/STAT signaling pathway as a potential therapeutic target for LT of Achilles tendinopathy, guiding future research.

Two-pronged microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention for synergistic tumor immunotherapy.

Immunotherapy is an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Despite the potential for eliminating primary tumor cells and depressing cancer metastasis, immunotherapy has huge challenges including low tumor immunogenicity and undesirable immunosuppressive tumor microenvironment (TME). Herein, the two-pronged microenvironmental modulation nanoplatform is developed to overcome these limitations. Specifically, hollow mesoporous MnO2 (HM) nanoparticles with pH responsive property are prepared and modified with glucose oxidase (GOX) by amide bond, which are further loaded with a potent glutaminase inhibitor CB839 to obtain HM-GOX/CB839. Under the low pH values in TME, HM was disintegrated, thereby releasing Mn2+, GOX and CB839. On the one hand, Mn2+ can convert H2O2 that increased by GOX catalysis in tumors into highly toxic hydroxyl radicals (•OH) and further induce immunogenic cell death (ICD) through the metal-oxidase cascade catalytic reaction, enhancing immunogenicity. On the other hand, GOX and CB839 can block glycolytic and glutamine metabolism pathways, respectively, which effectively reduce the number of immunosuppressive cells and reshape TME, improving anti-tumor immune efficacy. It is demonstrated that HM-GOX/CB839 can effectively activate the body's immunity and inhibit tumor growth and metastasis, providing a potential strategy for comprehensive tumor therapy. STATEMENT OF SIGNIFICANCE: Integrated microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention offers a potential avenue for tumor immunotherapy. Under this premise, we constructed a two-pronged microenvironmental modulation nanoplatform (HM-GOX/CB839). On the one hand, the metal oxidase cascade could catalyze the generation of hydroxyl radicals (•OH) and induce immunogenic cell death (ICD), enhancing immunogenicity; on the other hand, metabolic intervention reprogrammed tumor microenvironment to relieve immunosuppression and thereby enhancing anti-tumor immune response. The resulting data demonstrated that HM-GOX/CB839 effectively inhibited tumor growth and metastasis, providing therapeutic potential for cancer immunotherapy.

Extracellular vesicle-packaged circBIRC6 from cancer-associated fibroblasts induce platinum resistance via SUMOylation modulation in pancreatic cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic. METHODS: High-throughput sequence was used to screened the key circRNAs transmitted by extracellular vesicles (EVs) from CAFs to pancreatic cancer cells. The associations between EV-packaged circBIRC6 and chemotherapy responsiveness were validated in a cohort of 82 cases of advanced PDAC patients. Then, the effects of EV-packaged circBIRC6 on CAF-induced oxaliplatin resistance were investigated by flow cytometry, colony formation, viability of pancreatic cancer organoids in vitro and by xenograft models in vivo. RNA pulldown, RNA immunoprecipitation, and sites mutation assays were used to reveal the underlying mechanism. RESULTS: We identified a circRNA, circBIRC6, is significantly upregulated in CAF-derived EVs and is positively associated with oxaliplatin-based chemoresistance. In vitro and in vivo functional assays showed that CAF-derived EV-packaged circBIRC6 enhance oxaliplatin resistance of pancreatic cancer cells and organoids via regulating the non-homologous end joining (NHEJ) dependent DNA repair. Mechanistically, circBIRC6 directly binds with XRCC4 and enhanced the interaction of XRCC4 with SUMO1 at the lysine 115 residue, which facilitated XRCC4 chromatin localization. XRCC4K115R mutation dramatically abrogated the EV-packaged circBIRC6 induced effect. Moreover, combination of antisense oligonucleotide inhibitors against circBIRC6 with Olaparib dramatically suppressed chemoresistance in patient-derived xenograft models. CONCLUSIONS: Our study revealed that EV-packaged circBIRC6 confer oxaliplatin resistance in PDAC by mediating SUMOylation of XRCC4, introducing a promising predictive and therapeutic target for PDAC on oxaliplatin resistance.

Cell-Dependent Activation of ProTide Prodrugs and Its Implications in Antiviral Studies.

The ProTide prodrug design is a powerful tool to improve cell permeability and enhance the intracellular activation of nucleotide antiviral analogues. Previous in vitro studies showed that the activation of ProTide prodrugs varied in different cell lines. In the present study, we investigated the activation profiles of two antiviral prodrugs tenofovir alafenamide (TAF) and sofosbuvir (SOF) in five cell lines commonly used in antiviral research, namely, Vero E6, Huh-7, Calu-3, A549, and Caco-2. We found that TAF and SOF were activated in a cell-dependent manner with Vero E6 being the least efficient and Huh-7 being the most efficient cell line for activating the prodrugs. We also demonstrated that TAF was activated at a significantly higher rate than SOF. We further analyzed the protein expressions of the activating enzymes carboxylesterase 1, cathepsin A, histidine triad nucleotide-binding protein 1, and the relevant drug transporters P-glycoprotein and organic anion-transporting polypeptides 1B1 and 1B3 in the cell lines using the proteomics data extracted from the literature and proteome database. The results revealed significant differences in the expression patterns of the enzymes and transporters among the cell lines, which might partially contribute to the observed cell-dependent activation of TAF and SOF. These findings highlight the variability of the abundance of activating enzymes and transporters between cell lines and emphasize the importance of selecting appropriate cell lines for assessing the antiviral efficacy of nucleoside/nucleotide prodrugs.

Effects of electronic personal health information technology on American women's cancer screening behaviors mediated through cancer worry: Differences and similarities between 2017 and 2020.

Backgrounds: Thanks to their accessibility and low cost, electronic personal health information (ePHI) technologies have been widely used to facilitate patient-physician communication and promote health prevention behaviors (e.g. cancer screening). Despite that empirical evidence has supported the association between ePHI technology use and cancer screening behaviors, the underlying mechanism through which ePHI technology use influences cancer screening behaviors remains a topic of discussion. Objective: This study investigates the relationship between ePHI technology uses and cancer screening behaviors of American women and examines the mediating role of cancer worry. Methods: Data for this study were from the Health Information National Trends Survey (HINTS) collected in 2017 (HINTS 5 Cycle 1) and 2020 (HINTS 5 Cycle 4). The final sample included 1914 female respondents in HINTS 5 Cycle 1 and 2204 in HINTS 5 Cycle 4. Mann-Whitney U test, two-sample t-test, and mediation analysis were performed. We also referred to the regression coefficients generated by min-max normalization as percentage coefficients (bp) for the comparison. Results: This study reports increased usage of ePHI technologies (from 1.41 in 2017 to 2.19 to 2020), increased cancer worry (from 2.60 in 2017 to 2.84 in 2020), and a stable level of cancer screening behaviors (from 1.44 in 2017 to 1.34 in 2020) among American women. Cancer worry was found to mediate the ePHI effect on cancer screening behaviors (bp = 0.005, 95% confidence interval [0.001, 0.010]) in a positive complementary mediation in 2020. Conclusions: The research findings support a positive association between ePHI technology use and cancer screening behaviors, and cancer worry has been identified as a salient mediator. An understanding of the mechanism that prompts US women's cancer screening practices provides practical implications for health campaign practitioners.

Low-intensity pulsed ultrasound and parathyroid hormone improve muscle atrophy in estrogen deficiency mice.

Due to aging and long-term estrogen deficiency, postmenopausal women suffer muscle atrophy (MA), which is characterized by decreased muscle mass and muscle quality. Low-intensity pulsed ultrasound (LIPUS) is an acoustic wave inducing biological effects mainly by the mechanical stimulation and used as a non-invasive physical therapy for muscle repair. Parathyroid hormone (PTH) is an 84-amino-acid polypeptide, and its bioactive fragment [PTH (1-34)] has potential application in the treatment of MA. We speculate that the combination of physical therapy (i.e., the LIPUS) and regulatory hormone (i.e., the PTH) would be more effective in the treatment of MA. The objective of this study was to evaluate the individual and combined effects of LIPUS and PTH therapy on MA in estrogen deficiency mice. Seventy 8-week-old female C57BL/6J mice were used in this study and the MA model was induced by an intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days. The VCD-induced MA mice were randomly divided into MA, LIPUS, PTH and LIPUS + PTH (Combined) groups (n = 10/group). In the LIPUS group, the mice were treated by LIPUS in bilateral quadriceps muscles for 20 min, five times a week for 6 weeks. In the PTH group, the mice received subcutaneous injection of PTH (1-34) (80 ug/kg/d) five times a week, for 6 weeks. In the Combined group, the PTH was administrated 30 min before each LIPUS session. Hematoxylin-eosin (H&E) staining, serum biochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to evaluate the therapeutic effects of related treatments. The results showed that the MA mice had a disordered estrus cycle, significantly decreased muscle mass and myofibers cross-sectional area (CSA). After treatments, LIPUS, PTH and Combined groups had a significantly increased CSA, compared with the MA mice without treatment. In addition, Combined group had a significantly increased mRNA expression of Pax7, MyoD and MyoG, compared with LIPUS and PTH monotherapy groups. Our findings indicated that the combination of LIPUS and PTH treatment improves muscle regeneration ability, which might have potential for treating MA in postmenopausal women.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Disruption of ß-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells.

Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating ß-catenin pathway. Suppression of ß-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized ß-catenin through direct phosphorylation of the molecule and inhibition of GSK-3ß. The activated ß-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.

Irreversible Electroporation Plus Anti-PD-1 Antibody versus Irreversible Electroporation Alone for Patients with Locally Advanced Pancreatic Cancer.

BACKGROUND: Irreversible electroporation (IRE) is shown to not only improve the prognosis of patients with locally advanced pancreatic cancer (LAPC) but also activate the immune system. Considering the immune-activating function of IRE, IRE may enhance the effect of immune checkpoint inhibitors in the treatment of LAPC. We aimed to compare the effect and safety of IRE combined with toripalimab versus IRE alone for LAPC. METHODS: We retrospectively collected data from LAPC patients treated with IRE plus toripalimab (240mg, 7 days after IRE) or IRE alone at Sun Yat­sen University Cancer Center. Overall and progression-free survival and treatment-related adverse events were evaluated and compared. RESULTS: From August 2015 to June 2020, a total of 85 patients were collected and analyzed in this study: 70 in the IRE group and 15 in the IRE plus toripalimab group. The IRE plus toripalimab group showed longer OS [44.33 months (95% CI 17.39-71.27) versus 23.37 months (95% CI 21.20-25.54), P=0.010] and PFS [27.5 months (95% CI not reached) versus 10.6 months (95% CI 7.79-13.42), P=0.036], compared with IRE group. There were no treatment-related deaths in all patients of this study. Although pancreatic fistula, biliary fistula, abscess, vomiting and gastroparesis were a little more common in IRE plus toripalimab group, no significant differences in the rates of all adverse events between these two groups were observed. CONCLUSION: IRE plus toripalimab had acceptable toxic effects and might improve survival in LAPC compared with IRE alone.

Identification of Circulating Biomarkers and Construction of a Prognostic Signature for Survival Prediction in Locally Advanced Pancreatic Cancer After Irreversible Electroporation.

BACKGROUND: Irreversible electroporation (IRE) is a novel treatment for locally advanced pancreatic cancer (LAPC), but the predictive factors, based on cytokines and immunocytes of survival, are still lacking. This study aimed to establish a risk model based on cytokines and immunocytes for LAPC patients undergoing IRE treatment. PATIENTS AND METHODS: Peripheral blood samples were obtained from 31 LAPC patients and 8 healthy control subjects before IRE. The phenotypes of lymphocytes were analyzed by flow cytometry, and the cytokines were evaluated with Luminex microarray assay. Least absolute shrinkage and selection operator (LASSO) and Cox regression were applied to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). A receiver operating characteristic (ROC) curve and a concordance index (C-index) were used to compare the abilities to predict survival rates. RESULTS: The relationship between multiple cytokines and clinical factors was evaluated and their prognostic value was compared. The five best predictors for OS and PFS, including CA19-9, CD3+CD4+ T cells, CD3+CD8+ T cells, IL-17A, and TNF-α were selected and incorporated into a new immune panel. A risk model based on this immune panel was established and exhibited significantly higher values of C-indexes and AUC for OS and PFS prediction as compared with tumor marker score and TNM stage system. CONCLUSION: We presented a risk model based on a microarray assay of cytokines and lymphocytes for LAPC patients after receiving IRE treatment for the first time. The established risk model showed relatively good performance in survival prediction and was able to facilitate tailed patient management in clinical practice.

Integrated Bioinformatic Analysis of SARS-CoV-2 Infection Related Genes ACE2, BSG and TMPRSS2 in Aerodigestive Cancers.

BACKGROUND: Cancer patients are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the general population, with lung epithelial cells or enterocytes being the main targets. However, the expressions of SARS-CoV-2 entry-related genes in aerodigestive cancers have not been fully elucidated. METHODS: In this study, the expressions of SARS-CoV-2 receptors and cofactors, including angiotensin I-converting enzyme 2 (ACE2), basigin (BSG) and transmembrane serine protease 2 (TMPRSS2), were comprehensively assessed. We compared BSG and TMPRSS2 expressions between aerodigestive cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Furthermore, expressions in healthy colon tissues at different anatomical locations were explored using the Genotype-Tissue Expression (GTEx) dataset. In addition, expressions among different tumor stages and the prognostic values were detected through GEPIA2. Moreover, the correlation between gene expression and immune infiltration was explored via Tumor Immune Estimation Resource (TIMER). Finally, expressions in primary colorectal cancer (CRC), lung metastasis and liver metastasis were investigated using the Gene Expression Omnibus (GEO) dataset GSE41258. RESULTS: Similar to ACE2, TMPRSS2 and BSG were also highly expressed in the digestive tracts. Intriguingly, BSG/TMPRSS2 expression in adjacent normal colon tissue or lung tissue was higher than that in corresponding healthy tissue, whereas they varied not among different tumor stages and correlated not with prognosis in aerodigestive cancers. Moreover, ACE2 was expressed at higher levels in lung metastases from CRC than in normal lung tissues. CONCLUSION: SARS-CoV-2 entry genes were highly expressed in CRC, and we reported for the first time higher expression of ACE2 in lung metastases from CRC than in normal lung, indicating that these patients may be more susceptible to extrapulmonary or pulmonary SARS-CoV-2 infection. Since our study is a bioinformatic analysis, further experimental evidences and clinical data are urgently needed.

LINC00460 promotes pancreatic cancer progression by sponging miR-491-5p.

BACKGROUND: A growing body of studies have suggested that LINC00460 is instrumental in tumorigenesis and tumour progression. Nonetheless, the biological function and mechanisms of LINC00460 in pancreatic ductal adenocarcinoma (PDAC) remain vague. METHODS: Analysis based on public databases and a quantitative reverse transcription-polymerase chain reaction were performed to screen for differentially expressed lncRNAs in PDAC and to detect LINC00460 expression in PDAC cell lines and clinical samples. The survival of patients in the up-regulated and down-regulated LINC00460 expression groups was compared by using the Kaplan-Meier method. In addition, the potential biological functions of LINC00460 in PDAC were explored by cell counting kit-8, colony formation, flow cytometry and transwell assays. Furthermore, bioinformatics analysis, luciferase reporter assays and rescue experiments were applied to demonstrate the mechanism by which LINC00460 could directly bind to and inhibit miR-491-5p. RESULTS: LINC00460 is up-regulated in PDAC and correlates with adverse survival outcomes. The results of functional tests verified that LINC00460 knockdown inhibited both cell proliferation and cell migration. Additionally, knockdown led to G0/G1 cell cycle blockage and enhanced cell apoptosis. Mechanistic investigations revealed that LINC00460 directly binds to and attenuates the tumour suppressor miR-491-5p, thus accelerating PDAC progression. CONCLUSIONS: This research showed that LINC00460 is overexpressed in PDAC and correlates with adverse clinical outcomes. Additionally, LINC00460 promotes the aggressiveness of PDAC by targeting miR-491-5p. Thus, LINC00460 may serve as diagnostic biomarker of PDAC and a new target for PDAC therapy.

The role of irreversible electroporation in promoting M1 macrophage polarization via regulating the HMGB1-RAGE-MAPK axis in pancreatic cancer.

Irreversible electroporation (IRE) is an effective method for treating pancreatic ductal adenocarcinoma (PDAC). It remains unclear whether IRE can induce a specific immune response by stimulating macrophages. Here, the associated markers of macrophages were analyzed after exposure to tumor culture supernatant (TSN) of tumor cells treated with electroporation. Subcutaneous and orthotopic PDAC models were also used to evaluate the effect of macrophage polarization induced by IRE. Aside from its direct killing effect, IRE could induce the immunogenic cell death of tumor cells by increasing the synthesis and secretion of damage associated molecular patterns. Moreover, IRE could increase the release of HMGB1, which activates the MAPK-p38 pathway and leads to the increased expression of M1 markers in macrophages, through binding to the receptor of the advanced glycation end-product (RAGE) receptor. M1 polarization was inhibited by the inhibitors of HMGB1 release, the RAGE receptor, and the MAPK-p38 signaling pathway, but it was activated by rHMGB1 or the stimulator of MAPK-p38. In addition, the promotion of M1 macrophage polarization was enhanced by the positive-feedback release or expression of HMGB1 and RAGE through the MAPK-ERK pathway in macrophages. The promotion of M1 macrophage polarization induced by IRE provided a specific rationale for the combination of IRE and immune therapy in treating PDAC.

Combining NanoKnife with M1 oncolytic virus enhances anticancer activity in pancreatic cancer.

NanoKnife, a nonthermal ablation technique also termed irreversible electroporation (IRE), has been adopted in locally advanced pancreatic cancer (LAPC) treatment. However, reversible electroporation (RE) caused by heterogeneous electric field magnitude leads to inadequate ablation and tumor recurrence. Alphavirus M1 has been identified as a novel natural oncolytic virus which is nonpathogenic and with high tumor selectivity. This study evaluated improvements to therapeutic efficacy through combination therapy incorporating NanoKnife and M1 virus. We showed that IRE triggered reactive oxygen species (ROS)-dependent apoptosis in pancreatic cancer cells (PCCs) mediated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. When NanoKnife was combined with M1 virus, the therapeutic efficacy was synergistically enhanced. The combinatorial treatment further inhibited tumor proliferation and prolonged the survival of orthotopic pancreatic cancer (PC)-bearing immunocompetent mice. In depth, NanoKnife enhanced the oncolytic effect of M1 by promoting its infection. The combination turned immune-silent tumors into immune-inflamed tumors characterized by T cell activation. Clinicopathologic analysis of specific M1 oncolytic biomarkers indicated the potential of the combination regimen. The combinatorial therapy represents a promising therapeutic efficacy and may ultimately improve the prognosis of patients with LAPC.

A Novel Nomogram to Predict Survival in Patients With Recurrence of Pancreatic Ductal Adenocarcinoma After Radical Resection.

The post-progression survival (PPS) of patients with pancreatic ductal adenocarcinoma (PDAC) after radical resection is varied and influenced by the characteristics of tumor progression. We aimed to establish and validate a nomogram to predict PPS for PDAC patients after surgery. A total of 302 PDAC patients who had undergone curative resection from 2008 to 2018 were enrolled in this study and randomly divided into training and validation cohorts at a ratio of 3:1. The nomogram was established based on independent prognostic factors selected by LASSO and Cox regression and measured by the area under the receiver operating characteristic curve (AUC) and the concordance index (C-index). Significant prognostic factors included carbohydrate antigen 19-9 (CA19-9), lymph node (LN)9 metastasis, LN14 metastasis, LN16 metastasis, tumor differentiation, imaging-detected tumor size, local progression, liver-only metastasis, lung-only metastasis, and multiple metastases. The nomogram built on these factors showed powerful efficacy in PPS prediction, with C-index values of 0.751 (95% CI 0.692-0.0.810) and 0.710 (95% CI 0.645-0.755) for the training and validation cohorts, respectively. The AUC values for the 1-year and 2-year PSS rates were 0.745, 0.747, and 0.783, 0.748, respectively; these values were higher than those of the 8th tumor-node-metastasis (TNM) stage system. The exploration of risk factors and the establishment of a nomogram can provide new versions of personalized recurrence management for PDAC patients after surgery.

SYPL1 Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma via Suppression of ROS-Induced ERK Activation.

Synaptophysin-like 1 (SYPL1) is a neuroendocrine-related protein. The role of SYPL1 in pancreatic ductal adenocarcinoma (PDAC) and the underlying molecular mechanism remain unclarified. Here, after analyzing five datasets (GSE15471, GSE16515, GSE28735, TCGA, and PACA-AU) and 78 PDAC patients from Sun Yat-sen University Cancer Center, we demonstrated that SYPL1 was upregulated in PDAC and that a high level of SYPL1 indicated poor prognosis. Bioinformatics analysis implied that SYPL1 was related to cell proliferation and cell death. To validate these findings, gain-of-function and loss-of-function experiments were carried out, and we found that SYPL1 promoted cell proliferation in vitro and in vivo and that it protected cells from apoptosis. Mechanistic studies revealed that sustained extracellular-regulated protein kinase (ERK) activation was responsible for the cell death resulting from knockdown of SYPL1. In addition, bioinformatics analysis showed that the expression of SYPL1 positively correlated with antioxidant activity. Reactive oxygen species (ROS) were upregulated in cells with SYPL1 knockdown and vice versa. Upregulated ROS led to ERK activation and cell death. These results suggest that SYPL1 plays a vital role in PDAC and promotes cancer cell survival by suppressing ROS-induced ERK activation.

The prognostic significance of inflammation-based scores in patients with ampullary carcinoma after pancreaticoduodenectomy.

BACKGROUND: Growing evidence indicates that the systemic inflammatory response plays an important role in cancer development and progression. Several inflammatory markers have been reported to be associated with clinical outcomes in patients with various types of cancer. This study was designed to evaluate the prognostic value of inflammatory indexes in patients with ampullary cancer (AC) who underwent pancreaticoduodenectomy (PD). METHODS: We retrospectively reviewed the data of 358 patients with AC who underwent PD between 2009 and 2018. R software was used to compare the area under the time-dependent receiver operating characteristic (ROC) curves (AUROCs) of the inflammation-based indexes, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI) and prognostic index (PI), in terms of their predictive value for survival. The survival differences of these indexes were compared by the Kaplan-Meier method and univariate and multivariate analyses were performed to determine the prognostic factors of disease-free survival (DFS) and overall survival (OS). RESULTS: The estimated 1-, 2-, and 3-year OS and DFS rates were 83.9, 65.8, and 55.2% and 58.0, 42.8, and 37.8%, respectively, for the entire cohort. The survival differences were significant in terms of OS and DFS when patients were stratified by these inflammation-based indexes. The comparisons of the AUROCs of these inflammation-based indexes illustrated that NLR and PI displayed the highest prognostic value, compared to the other indexes. When NLR and PI were combined, NLR-PI showed even higher AUROC values and was identified as a significant prognostic factor for OS and DFS. CONCLUSION: Specific inflammatory indexes, such as NLR, PLR and dNLR, were found to be able to predict the OS or DFS of patients. As a novel inflammatory index, the level of NLR-PI, which can be regarded as a more useful prognostic index, exhibited strong predictive power for predicting the prognosis of patients with AC after the PD procedure.

Bioinformatic Analysis of Correlation between Immune Infiltration and COVID-19 in Cancer Patients.

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused infections worldwide. However, the correlation between the immune infiltration and coronavirus disease 2019 (COVID-19) susceptibility or severity in cancer patients remains to be fully elucidated. ACE2 expressions in normal tissues, cancers and cell lines were comprehensively assessed. Furthermore, we compared ACE2 expression between cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we performed gene set enrichment analysis (GSEA) to investigate the related signaling pathways. Finally, the correlations between ACE2 expression and immune infiltration were investigated via Tumor Immune Estimation Resource (TIMER) and GEPIA. We found that ACE2 was predominantly expressed in both adult and fetal tissues from the digestive, urinary and male reproductive tracts; moreover, ACE2 expressions in corresponding cancers were generally higher than that in matched healthy tissues. GSEA showed that various metabolic and immune-related pathways were significantly associated with ACE2 expression across multiple cancer types. Intriguingly, we found that ACE2 expression correlated significantly with immune cell infiltration in both normal and cancer tissues, especially in the stomach and colon. These findings proposed a possible fecal-oral and maternal-fetal transmission of SARS-CoV-2 and suggested that cancers of the respiratory, digestive or urinary tracts would be more vulnerable to SARS-CoV-2 infection.