Search

Highlight Distinct mechanical cues in the tumor microenvironment drive tumor behaviors and highlight potential therapeutic targets.

Abstract Background The emergence of new molecular targeted drugs marks a breakthrough in asthma treatment, particularly for severe cases. Yet, options for moderate-to-severe asthma treatment remain limited, highlighting the urgent need for novel therapeutic drug targets. In this study, we aimed to identify new treatment targets for asthma using the Mendelian randomization method and large-scale genome-wide association data (GWAS). Methods We utilized GWAS data from the UK Biobank (comprising 56,167 patients and 352,255 control subjects) and the FinnGen cohort (including 23,834 patients and 228,085 control subjects). Genetic instruments for 734 plasma proteins and 154 cerebrospinal fluid proteins were derived from recently published GWAS. Bidirectional Mendelian randomization analysis, Steiger filtering, colocalization, and phenotype scanning were employed for reverse causal inference detection, further substantiating the Mendelian randomization results. A protein-protein interaction network was also constructed to reveal potential associations between proteins and asthma medications. Results Under Bonferroni significance conditions, Mendelian randomization analysis revealed causal relationships between seven proteins and asthma. In plasma, we observed that an increase of one standard deviation in IL1R1[1.30 (95% CI 1.20–1.42)], IL7R[1.07 (95% CI 1.04–1.11)], ECM1[1.03 (95% CI 1.02–1.05)], and CD200R1[1.18 (95% CI 1.09–1.27)] were associated with an increased risk of asthma, while an increase in ADAM19 [0.87 (95% CI 0.82–0.92)] was found to be protective. In the brain, each 10-fold increase in IL-6 sRa [1.29 (95% CI 1.15–1.45)] was associated with an increased risk of asthma, while an increase in Layilin [0.61 (95% CI 0.51–0.73)] was found to be protective. None of the seven proteins exhibited a reverse causal relationship. Colocalization analysis indicated that ECM1 (coloc.abf-PPH4 = 0.953), IL-6 sRa (coloc.abf-PPH4 = 0.966), and layilin (coloc.abf-PPH4 = 0.975) shared the same genetic variation as in asthma. Conclusion A causal relationship exists between genetically determined protein levels of IL1R1, IL7R, ECM1, CD200R1, ADAM19, IL-6 sRa, and Layilin (LAYN) and asthma. Moreover, the identified proteins may serve as attractive drug targets for asthma, especially ECM1 and Layilin (LAYN). However, further research is required to comprehensively understand the roles of these proteins in the occurrence and progression of asthma.

Abstract Background Abdominal fluid collection (AFC) is one of the most common complications after pancreatic surgery, yet there are few recommendations on how to manage it. Most cases of AFC only require observation, while others may require more invasive techniques. Unfortunately, there are no drugs that effectively promote the absorption of AFCs. The aim of this study was to evaluate the potential efficacy of Glauber’s salt solution for promoting the absorption of AFCs after pancreatectomy. Methods This study included 196 patients who underwent pancreatomy and had AFCs on at least 2 cross-sectional follow-up CT images between 2020 and 2022. AFCs were defined as effusion with a diameter ≥ 3 cm and located around the pancreatic resection margin. We retrospectively investigated the relationship between Glauber’s salt concentration and clinical variables. Results The rate of clinically significant pancreatic fistula (grades B + C) was significantly higher in the control group (62.8% vs. 40.7%, P = 0.014). The median maximum diameter of the AFC was smaller, and the median time for the AFC to decrease to 30 mm in diameter was shorter in the Glauber’s salt group than in the control group (41.9 mm vs. 53.5 mm, P = 0.008; 35.5 d vs. 100 d, P

Abstract Background Small cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes. Methods The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. Results In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3β/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. Conclusions Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.

Abstract Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9). Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. Trial registration ClinicalTrials.gov, NCT04228601.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. Methods Differentially expressed genes (DEGs) were screened. A protein‒protein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. Results Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. Conclusions NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

Abstract Research into the potential benefits of artificial intelligence for comprehending the intricate biology of cancer has grown as a result of the widespread use of deep learning and machine learning in the healthcare sector and the availability of highly specialized cancer datasets. Here, we review new artificial intelligence approaches and how they are being used in oncology. We describe how artificial intelligence might be used in the detection, prognosis, and administration of cancer treatments and introduce the use of the latest large language models such as ChatGPT in oncology clinics. We highlight artificial intelligence applications for omics data types, and we offer perspectives on how the various data types might be combined to create decision-support tools. We also evaluate the present constraints and challenges to applying artificial intelligence in precision oncology. Finally, we discuss how current challenges may be surmounted to make artificial intelligence useful in clinical settings in the future.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Radical surgical resection offers the only potential cure. There is increasing agreement that radical antegrade modular pancreatosplenectomy (RAMPS) may benefit patients with tumors in the body and tail of the pancreas. To address this, the Chinese Study Group for Pancreatic Cancer (CSPAC)-3 trial is proposed to compare the effect of RAMPS and standard retrograde pancreatosplenectomy (SRPS) on patient survival and preoperative safety Methods The randomized controlled trial will be multicenter and two-armed with blinded outcomes and intention-to-treat analysis. Three hundred patients with resectable body and tail pancreatic adenocarcinoma will be enrolled and randomly assigned to RAMPS or SRPS. Adjuvant chemotherapy based on an initial regimen will be recommended 4–6 weeks after surgery if no serious complication occurs. The hypothesis that RAMPS improves survival outcomes compared with SRPS will be tested using a superiority trial. The primary outcome will be overall survival (OS). Secondary outcomes will include recurrence-free survival (RFS), R0 resection rate, the number of harvested lymph nodes, postoperative complications, and quality of life scores. Discussion The use of RAMPS has increased over the past decade. It is reported that RAMPS is superior to SRPS in improving both the rate of R0 resection and lymph node yield. Despite these advantages, however, there is little high-level documentation of the superiority of RAMPS in terms of survival and this needs to be investigated. To address this issue, CSPAC has instigated the first prospective, randomized phase III control trials, aiming to explore the optimal surgical strategy for improving the prognosis and OS of patients with left-sided pancreatic cancer Trial registration Chinese Clinical Trial Registry ChiCTR2100053844; pre-results. Registered on December 1, 2021.

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Abstract Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

Abstract Background Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. Methods Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo. Results We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance. Conclusion Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.

Abstract Background Extensive studies have demonstrated the pivotal roles of circular RNAs (circRNAs) in the occurrence and development of different human cancers. However, the expression and regulatory roles of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear. Methods CircEYA3 was explored based on Gene Expression Omnibus (GEO) dataset analysis. qRT-PCR was applied to determine the expression of circRNAs, miRNAs and mRNAs in PDAC cells and tissues. The biological roles of circEYA3 in vitro and in vivo were determined by performing a series of functional experiments. Further, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA pull-down assays, and RNA immunoprecipitation (RIP) assays were used to confirm the interaction of circEYA3 with miR-1294. Results CircEYA3 was elevated in PDAC tissues and cells, and a higher level of circEYA3 was significantly associated with a poorer prognosis in patients with PDAC. Functionally, circEYA3 increased energy production via ATP synthesis to promote PDAC progression in vitro and in vivo. Mechanistically, circEYA3 functions as an endogenous miR-1294 sponge to elevate c-Myc expression, thus exerting its oncogenic functions. Conclusion CircEYA3 promotes the progression of PDAC through the miR-1294/c-Myc signalling axis, and circEYA3 may be an efficient molecular therapeutic target in PDAC.

Abstract Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

Abstract Background Nasopharyngeal carcinoma (NPC) is one of the most common malignancy in head and neck. With the development of treatments, the prognosis has improved these years, but metastasis is still the main cause of treatment failure. The endoplasmic reticulum (ER) resident protein 44 is a UPR-induced ER protein of the protein disulphide isomerase (PDI) family. This study investigated the role of ERp44 in NPC progression. Methods Firstly, immunohistochemistry, western blot and qRT-PCR were used to investigate the expression of ERp44 in NPC samples and cell lines. We analyzed 44 NPC samples for ERp44 expression and investigated the association between its expression level with clinicopathologic parameters. Then we took CCK8, Transwell migration assay and used the zebrafish model to access the role of ERp44 on the malignant phenotype in NPC cells. Secondly, we used co-IP to gain the proteins that interact with ERp44 and took proteomic analysis. Furthermore, we successfully constructed the mutant variants of ERp44 and found the interaction domain with ATP citrate lyase(ACLY). Lastly, we subcutaneously injected NPC cells into nude mice and took immunohistochemistry to exam the expression of ACLY and ERp44. Then we used western blot to detect the expression level of epithelial-mesenchymal transition (EMT) markers. Results In the present study, we found ERp44 was elevated in NPC tissues and correlated with clinical stages and survive state of the patients. In vitro, the downregulation of ERp44 in NPC cells (CNE2, 5-8F) could suppress cells proliferation and migration. After that, we recognized that ACLY might be a potential target that could interact with ERp44. We further constructed the mutant variants of ERp44 and found the interaction domain with ACLY. The promotion of ERp44 on cell migration could be inhibited when ACLY was knocked down. More importantly, we also observed that the interaction of ERp44 with ACLY, especially the thioredoxin region in ERp44 play a vital role in regulating EMT. Lastly, we found ERp44 was positively correlated with the expression of ACLY and could promote NPC cells growth in nude mice. Conclusion Our data indicated that ERp44 participates in promoting NPC progression through the interaction with ACLY and regulation of EMT.

Abstract As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.

Abstract Background Studies on anxiety and depression in unruptured intracranial aneurysm (UIA) patients after treatment via endovascular intervention are rare and controversial. We aimed to explore the prevalence of anxiety and depression among Chinese patients with UIAs treated by endovascular intervention and to identify which factors contribute to the development of these symptoms. Methods We performed a cross-sectional study on anxiety and depression in patients who underwent endovascular treatment for UIAs using the Hospital Anxiety and Depression Scale (HADS). The demographic, clinical and radiological data for all patients were retrospectively collected from the aneurysm database and medical records. Moreover, we utilized data from a large sample of 200 UIA patients and multivariate logistic regression analysis to investigate the risk factors for anxiety and depression in these patients. Candidate variables with P values less than 0.20 in univariate analysis were included in the multivariate logistic regression analysis. Results Two hundred patients returned completed questionnaires in this study. Of these 200 patients, 34 (17.0%) suffered from anxiety and 31 (15.5%) suffered from depression 30.67 ± 8.6 months after being discharged. The multivariate analysis results indicated that shorter sleep times were statistically significantly associated with depression (OR = 1.62, 95% CI: 1.14 ~ 2.29, P = 0.007, Adjusted P = 0.02). . Conclusion The prevalences of anxiety and depression in UIA patients treated by endovascular intervention were 17.0 and 15.5%, respectively. Shorter sleep times were significantly associated with depression. Our findings provide evidence for the clinical and psychological management of these patients.

Abstract In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.

Abstract Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.

Abstract Background The purpose of this study was to use the modified Delphi method to identify the influencing factors of health-related quality of life (HRQoL) in patients with unruptured intracranial aneurysms (UIAs) after endovascular treatment. Methods A modified Delphi method to obtain expert consensus on the content of potential influencing factors of HRQoL in patients with UIAs treated by endovascular intervention was employed. The research team consists of three neuroradiologists and one epidemiologist from Xuanwu Hospital of Capital Medical University. They randomly selected 21 well-known experts in cerebrovascular disease diagnosis and treatment as participating experts. The importance of the indicator is based on the 5-Likert scale. The standard deviation (SD), coefficient of variation (CV), mean ( x ¯ $$ \overline{x} $$ ), and minimum and maximum scores of each indicator were calculated. The consistency was described by Kendall coefficient of concordance with a p value

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.

Abstract Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

Abstract Background Plaque morphology directly correlates with risk of embolism and the recently developed dual-source computed tomography angiography (DSCTA) may help to detect plaques more precisely. The aim of our study was to evaluate the prevalence and morphology of carotid and cerebrovascular atherosclerotic plaques in patients with symptomatic type 2 diabetes mellitus (DM) by DSCTA. Methods From July 2009 to August 2010, DSCTA was prospectively performed in 125 consecutive patients with symptomatic type 2 DM. We retrospectively analyzed plaque type, distribution, and extensive and obstructive natures were determined for each segment for all patients. Results Atherosclerotic plaques were detected in 114 (91.2%) patients. Relatively more noncalcified (45%) and calcified (39%) plaques and less mixed (16%) plaques were observed (p < 0.001). Noncalcified plaques were found mainly in the intracranial arteries (81.8%), mixed plaques in the intracranial arteries (25.2%) and intracranial internal carotid artery (ICA) (56.1%). Calcified plaques were found mainly in the intracranial ICA (65.9%) and extracranial arteries (28.2%) (for all, p < 0.001). Extension of plaques from the 1st to 5th segments was observed in 67 (58.8%) patients and from the 6th to 10th segments in 35 (30.7%) patients. The most common site of all detected plaques was the cavernous segment. Regarding stenosis, there were significantly more nonobstructive than obstructive stenosis (91% vs. 9%, p < 0.001). Conclusion DSCTA detected a high prevalence of plaques in patients with symptomatic type 2 DM. A relatively high proportion of plaques were noncalcified, as well as with nonobstructive stenosis. The distribution of plaques was extensive, with the cavernous portion of ICA being the most common site.

Abstract Background Coronary artery disease (CAD) is a common and severe complication of type 2 diabetes mellitus (DM). The aim of this study is to identify the features of CAD in diabetic patients using coronary CT angiography (CTA). Methods From 1 July 2009 to 20 March 2010, 113 consecutive patients (70 men, 43 women; mean age, 68 ± 10 years) with type 2 DM were found to have coronary plaques on coronary CTA. Their CTA data were reviewed, and extent, distribution and types of plaques and luminal narrowing were evaluated and compared between different sexes. Results In total, 287 coronary vessels (2.5 ± 1.1 per patient) and 470 segments (4.2 ± 2.8 per patient) were found to have plaques, respectively. Multi-vessel disease was more common than single vessel disease (p < 0.001), and the left anterior descending (LAD) artery (35.8%) and its proximal segment (19.1%) were most frequently involved (all p < 0.001). Calcified plaques (48.8%) were the most common type (p < 0.001) followed by mixed plaques (38.1%). Regarding the different degrees of stenosis, mild narrowing (36.9%) was most common (p < 0.001); however, a significant difference was not observed between non-obstructive and obstructive stenosis (50.4% vs. 49.6%, p = 0.855). Extent of CAD, types of plaques and luminal narrowing were not significantly different between male and female diabetic patients. Conclusions Coronary CTA depicted a high plaque burden in patients with type 2 DM. Plaques, which were mainly calcified, were more frequently detected in the proximal segment of the LAD artery, and increased attention should be paid to the significant prevalence of obstructive stenosis. In addition, DM reduced the sex differential in CT findings of CAD.