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Abstract Pancreatic cancer is among the most immune-resistant tumor types due to its unique tumor microenvironment and low cancer immunogenicity. Single-agent immune modulators have thus far proven clinically ineffective. However, a growing body of evidence suggests that combination of these modulators with other strategies could unlock the potential of immunotherapy in pancreatic cancer. Herein, we describe the case of a 59-year-old male with metastatic pancreatic ductal adenocarcinoma, referred to our center to receive immunotherapy (serplulimab, a novel anti-PD-1 antibody) combined with chemotherapy (gemcitabine/nab-paclitaxel). During the initial three treatment cycles, the patient was assessed as having stable disease (SD) according to RECIST 1.1 criteria. However, following two additional cycles of combination therapy, the primary tumor mass increased from 4.9 cm to 13.2 cm, accompanied by the development of new lung lesions, ascites, and pelvic metastases. He succumbed to respiratory failure one month later. Retrospective analysis revealed that the patient had MDM4 amplification, identified as a high-risk factor for hyperprogressive disease (HPD). To our knowledge, this is the first reported case of HPD in pancreatic cancer with multiple metastases treated using combination therapy. We investigated the potential mechanisms and reviewed the latest literature on predictive factors for HPD. These findings suggest that while chemotherapy combined with immunotherapy may hold promise for treating pancreatic cancer, it is imperative to identify and closely monitor patients with high-risk factors for HPD when using immunotherapy.

Pancreatic cancer is one of the most malignant digestive system tumors. The effectiveness of pancreatic cancer treatment is still dismal, and the 5-year survival rate is only about 10%. Further improving the diagnosis and treatment of pancreatic cancer is the top priority of oncology research and clinical practice. Based on the existing clinical and scientific research experience, the review provides insight into the hotspots and future directions for pancreatic cancer, which focuses on early detection, early diagnosis, molecular typing and precise treatment, new drug development and regimen combination, immunotherapy, database development, model establishment, surgical technology and strategy change, as well as innovation of traditional Chinese medicine and breakthrough of treatment concept.

We report a feasible method to realize tunable surface plasmon-polariton (SPP) resonance in organic light-emitting devices (OLEDs) by employing corrugated Ag-Al alloy electrodes. The excited SPP resonance induced by the periodic corrugations can be precisely tuned based on the composition ratios of the Ag-Al alloy electrodes. With an appropriate composition ratio of the corrugated alloy electrode, the photons trapped in SPP modes are recovered and extracted effectively. The 25% increasement in luminance and 21% enhancement in current efficiency have been achieved by using the corrugated Ag-Al alloy electrodes in OLEDs.

Abstract Pancreatic cancer is one of the most common causes of cancer-related deaths worldwide. The two major histological subtypes of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all cases, and pancreatic neuroendocrine neoplasm (PanNEN), which makes up 3–5% of all cases. PanNEN is classified into well-differentiated pancreatic neuroendocrine tumor and poorly-differentiated pancreatic neuroendocrine carcinoma (PanNEC). Although PDAC and PanNEN are commonly thought to be different diseases with distinct biology, cell of origin, and genomic abnormalities, the idea that PDAC and PanNEC share common cells of origin has been gaining support. This is substantiated by evidence that the molecular profiling of PanNEC is genetically and phenotypically related to PDAC. In the current review, we summarize published studies pointing to common potential cells of origin and speculate about how the distinct paths of differentiation are determined by the genomic patterns of each disease. We also discuss the overlap between PDAC and PanNEC, which has been noted in clinical observations.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial “network” to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.

BackgroundExtracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs.MethodsA total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS.ResultsPatients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p

Objectives: Numerous studies have suggested that an increase in neutrophil-to-lymphocyte ratio (NLR) before treatment is associated with worse survival in pancreatic adenocarcinoma (PAC). The aim of this study was to investigate the prognostic value of treatment-induced NLR change among PAC patients so as to better identify the characteristics of those who can benefit more from treatment. Methods: This meta-analysis was undertaken using the PRISMA statement. Previously published studies between the correlation of NLR change and patients’ survival were searched in Pubmed, Embase, and Web of Science databases. RevMan 5.3 was used to conduct statistical analysis. Results: A total of 1213 patients with PAC from 6 retrospective studies were included in this meta-analysis. Four studies investigated the HR of pre-treatment NLR, demonstrating its prognostic impact on overall survival (OS) (HR = 2.21, 95%CI: 1.45-3.36). One study reported that an elevated post-treatment NLR was associated with poorer OS (HR = 1.28, 95%CI = 1.08-1.52). Pooled analysis indicated that NLR reduction might predict favorable survival in both the overall population (HR = 1.52, 95% CI: 1.34–1.73) and the subgroup treated with chemotherapy (HR = 1.50, 95% CI: 1.32-1.70). Conclusion: Treatment-induced NLR change can act as an early predictor for PAC. Patients with reduced NLR after chemotherapy are expected to have better survival.

Background Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs.Methods Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry.Results TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p

Sorafenib, a multi-tyrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC). The present study was undertaken to determine whether the growth and metastasis of HCC were influenced in mice receiving sorafenib prior to implantation with tumors, and to investigate the in-vivo and in-vitro effect of sorafenib on natural killer (NK) cells. In sorafenib-pretreated BALB/c nu/nu mice and C57BL/6 mice, tumor growth was accelerated, mouse survival was decreased, and lung metastasis was increased. However, the depletion of NK1.1(+) cells in C57BL/6 mice eliminated sorafenib-mediated pro-metastatic effects. Sorafenib significantly reduced the number of NK cells and inhibited reactivity of NK cells against tumor cells, in both tumor-bearing and tumor-free C57BL/6 mice. Sorafenib down-regulated the stimulatory receptor CD69 in NK cells of tumor-bearing mice, but not in tumor-free mice, and inhibited proliferation of NK92-MI cells, which is associated with the blocking of the PI3K/AKT pathway, and inhibited cytotoxicity of NK cells in response to tumor targets, which was due to impaired ERK phosphorylation. These results suggest immunotherapeutic approaches activating NK cells may enhance the therapeutic efficacy of sorafenib in HCC patients.

BACKGROUND AIMS: We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma (HCC), which is mediated by down-regulation of tumor suppressor HTATIP2. The aim of the present study was to determine whether aspirin minimizes this effect and improves survival. METHODS: The effects of sorafenib, aspirin, and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice. Tumor growth, intrahepatic metastasis (IHM), lung metastasis, and survival were assessed. Polymerase chain reaction (PCR) array, real-time (RT)-PCR, and Western blotting were used to examine gene expression. The anti-invasion and anti-metastasis effects of aspirin were studied in HTATIP2-knockdown and HTATIP2-overexpressing HCC cell lines. The molecular mechanism of HTATIP2 regulation by aspirin was explored. RESULTS: Aspirin suppressed the pro-invasion and pro-metastasis effects of sorafenib in HCC and up-regulated HTATIP2 expression. Aspirin did not inhibit the proliferation of HCC cells, but it decreased the invasiveness of HCC with lower expression of HTATIP2 and increased expression of a set of markers, indicating a mesenchymal-to-epithelial transition in tumor cells. The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase (COX) 2 expression. CONCLUSIONS: Aspirin minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor HTATIP2; this mechanism is mediated through inhibition of COX2.

Our previous study has found that the abundance of peritumoral CD68(+) macrophages was associated with poor prognosis in hepatocellular carcinoma (HCC) after resection. However, CD68 staining could not discriminate the protumoral or tumoricidal subpopulations from pan-macrophages. CD163 is a marker of alternatively activated macrophages. In this study, the clinical significance of CD163(+) cells in tumors and peritumoral liver tissues was evaluated in a cohort of 295 patients with HCC after curative resection. We found that the density of CD163(+) cells was well correlated with that of CD68(+) cells in both tumors and peritumoral liver tissues but was much more. Immunostaining on consecutive sections and flow cytometry assay on surgical resected specimens further supported the findings that the CD163(+) cells was more abundant than CD68(+) cells. The density of peritumoral CD68(+) cells was associated with poor recurrence-free survival (RFS) and poor overall survival (OS) (P = 0.004 and P = 0.001, respectively), whereas the CD163(+) cells have no prognostic values either in tumors or in peritumoral liver tissues. In another cohort of 107 HCC patients, preoperative plasma concentration of soluble form of CD163 (sCD163) was associated with active hepatitis-related factors but not associated with the markers of tumor invasion. In conclusion, both the CD163(+) cells local infiltration and plasma sCD163 were of limited significance in HCC, and they were more likely markers related to active hepatitis rather than tumor progression.

Microvessel density (MVD) as an angiogenesis predictor is inefficient per se in cancer prognosis. We evaluated prognostic values of combining intratumoral alpha-smooth muscle actin (α-SMA)-positive stromal cell density and MVD after curative resection in hypervascular hepatocellular carcinoma (HCC) and hypovascular pancreatic cancer (PC). Tissue microarrays were constructed from tumors of 305 HCC and 57 PC patients who underwent curative resection and analyzed for α-SMA and CD34 expression by immunostaining. Prognostic values of these two proteins and other clinicopathological features were examined. Both low α-SMA density and high MVD-CD34 were associated in HCC with the presence of intrahepatic metastasis and microvascular invasion, and they were related to lymph node involvement and microvascular invasion in PC (p

Pancreatic adenocarcinoma characterized by a mere 10% 5-year survival rate, poses a formidable challenge due to its specific anatomical location, making tumor tissue acquisition difficult. This limitation underscores the critical need for novel biomarkers to stratify this patient population. Accordingly, this study aimed to construct a prognosis prediction model centered on S100 family members. Leveraging six S100 genes and their corresponding coefficients, an S100 score was calculated to predict survival outcomes. The present study provided comprehensive internal and external validation along with power evaluation results, substantiating the efficacy of the proposed model. Additionally, the study explored the S100-driven potential mechanisms underlying malignant progression. By comparing immune cell infiltration proportions in distinct patient groups with varying prognoses, the research identified differences driven by S100 expression. Furthermore, the analysis explored significant ligand-receptor pairs between malignant cells and immune cells influenced by S100 genes, uncovering crucial insights. Notably, the study identified a novel biomarker capable of predicting the sensitivity of neoadjuvant chemotherapy, offering promising avenues for further research and clinical application. [ABSTRACT FROM AUTHOR]

Background: microRNAs (miRNAs) have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages. The aim of this study was to find whether miR-26a can suppress M-CSF expression and the recruitment of macrophages. Methods: Hepatocellular carcinoma (HCC) cell lines with decreased or increased expression of miR-26a were established in a previous study. M-CSF expression by tumor cells was measured by enzyme-linked immunosorbent assay, and cell migration assays were used to explore the effect of HCC cell lines on macrophage recruitment in vitro. Real-time PCR measured a panel of mRNAs expressed by macrophages. Xenograft models were used to observe tumor growth. Immunohistochemistry was conducted to study the relation between miR-26a expression and M-CSF expression and macrophage recruitment in patients with HCC. Results: Ectopic expression of miR-26a reduced expression of M-CSF. The conditioned medium (CM) from HepG2 cells that overexpressed miR-26a reduced the migration ability of THP-1 cells stimulated by phorbol myristate acetate (PMA) increased expression of interleukin (IL)-12b or IL-23 mRNA and decreased expression of chemokine (C-C motif) ligand (CCL)22, CCL17, and IL-10 mRNA, in comparison to the medium from the parental HepG2 cells. These effects could be interrupted by the PI3K/Akt pathway inhibitor LY294002. Ectopic expression of miR-26a in HCC cells suppressed tumor growth, M-CSF expression, and infiltration of macrophages in tumors. Similar results were also found when using HCCLM3 cells. Furthermore, the expression of miR-26a was inversely correlated with M-CSF expression and macrophage infiltration in tumor tissues from patients with HCC. Conclusions: miR-26a expression reduced M-CSF expression and recruitment of macrophages in HCC. [ABSTRACT FROM AUTHOR]

Background: Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC). Methods: A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA. Results: PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization. Conclusions: Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence. [ABSTRACT FROM AUTHOR]

The article reports on a study investigating placental growth factor (PlGF) expression in tumor and peritumoral liver tissues from 105 patients with hepatocellular carcinoma (HCC). It was found in the study that peritumoral PlGF expression was significantly higher than intratumoral PlGF expression which was not associated with patients time to recurrence (TTR). Also, peritumoral PlGF expression was an independent risk factor for patients' overall survival and TTR.

Background: The opposite effects of chemotherapy, which enhance the malignancy of treated cancers such as hepatocellular carcinoma (HCC), are not well understood. We investigated this phenomenon and corresponding mechanisms to develop a novel approach for improving chemotherapy efficacy in HCC. Methods: Human hepatocellular carcinoma cell lines HepG2 (with low metastatic potential) and MHCC97L (with moderate metastatic potential) were used for the in vitro study. An orthotopic nude mouse model of human HCC was developed using MHCC97L cells. We then assessed the metastatic potential of surviving tumor cells after in vitro and in vivo oxaliplatin treatment. The molecular changes in surviving tumor cells were evaluated by western blot, immunofluorescence, and immunohistochemistry. The Chinese herbal extract Songyou Yin (composed of five herbs) was investigated in vivo to explore its effect on the metastatic potential of oxaliplatin-treated cancer cells. Results: MHCC97L and HepG2 cells surviving oxaliplatin treatment showed enhanced migration and invasion in vitro. Residual HCC after in vivo oxaliplatin treatment demonstrated significantly increased metastasis to the lung (10/12 vs. 3/12) when re-inoculated into the livers of new recipient nude mice. Molecular changes consistent with epithelialmesenchymal transition (EMT) were observed in oxaliplatin-treated tumor tissues and verified by in vitro experiments. The Chinese herbal extract Songyou Yin (4.2 and 8.4 g/kg) attenuated EMT and inhibited the enhanced metastatic potential of residual HCC in nude mice (6/15 vs. 13/15 and 3/15 vs. 13/15, respectively). Conclusions: The surviving HCC after oxaliplatin treatment underwent EMT and demonstrated increased metastatic potential. Attenuation of EMT by Songyou Yin may improve the efficacy of chemotherapy in HCC. [ABSTRACT FROM AUTHOR]

AbstractAim:To test the effect of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) on doxorubicin (DOX)-induced cardiotoxicity.Methods:We used neonate rat cardiomyocytes and an acute mouse model of DOX-induced cardiotoxicity to examine the protective effect of THSG.Results:In the mouse model, administration of THSG significantly reduced DOX-induced cardiotoxicity, including animal mortality, histopathological changes, and levels of serum creatine kinase (CK) and lactate dehydrogenase (LDH). Moreover, THSG was able to attenuate the increased malondialdehyde (MDA) and decreased reduced glutathione (GSH) caused by DOX. In in vitro studies, THSG 10−300 μmol/L ameliorated DOX-induced cardiomyocyte apoptosis in a concentration-dependent manner. Further studies showed that THSG inhibited reactive oxygen species (ROS) generation and prevented DOX-induced loss of mitochondrial membrane potential, caspase-3 activation and upregulation of Bax protein expression. We observed a protective response against damage after DOX treatment. The level of Bcl-2 protein was increased. Additionally, THSG inhibited a DOX-induced [Ca2+] increase.Conclusion:These results showed that THSG protected against DOX-induced cardiotoxicity by decreasing ROS generation and intracellular [Ca2+] and by inhibiting apoptotic signaling pathways. [ABSTRACT FROM AUTHOR]

The phases and magnetic properties of Co-Zr-C melt-spun ribbon were studied. The Co80Zr20 melt-spun ribbon consisted of a metastable Co5Zr phase together with fcc-Co and Co23Zr6 phases and showed a high coercivity. The small substitution of C for Zr in the Co-Zr melt-spun ribbon resulted in the increase in the saturation magnetization. However, the substitution resulted in the decrease in the coercivity. Unlike the Co-Zr melt-spun ribbon, annealing of the Co-Zr-C melt-spun ribbon resulted in the further decrease in the coercivity. Thermomagnetic studies showed that the Co-Zr-C melt-spun ribbon consisted of the new magnetic phase with a high Curie temperature and a high-saturation magnetization. X-ray diffraaction studies of the Co-Zr-C melt-spun ribbon revealed that the new magnetic phase with a high Curie temperature and a high-saturation magnetization is believed to be the Co11Zr2 phase. [ABSTRACT FROM AUTHOR]

The tensile strength and ductility of a high nitrogen nickel-free austenitic stainless steel with solution and cold rolling treatment were investigated by performing tensile tests at different strain rates and at room temperature. The tensile tests demonstrated that this steel exhibits a significant strain rate and cold rolling dependence of the tensile strength and ductility. With the increase of the strain rate from 10−4 s−1 to 1 s−1, the yield strength and ultimate tensile strength increase and the uniform elongation and total elongation decrease. The analysis of the double logarithmic stress—strain curves showed that this steel exhibits a two-stage strain hardening behavior, which can be well examined and analyzed by using the Ludwigson equation. The strain hardening exponents at low and high strain regions (n2 and n1) and the transition strain (εL) decrease with increasing strain rate and the increase of cold rolling RA. Based on the analysis results of the stress–strain curves, the transmission electron microscopy characterization of the microstructure and the scanning electron microscopy observation of the deformation surfaces, the significant strain rate and cold rolling dependence of the strength and ductility of this steel were discussed and connected with the variation in the work hardening and dislocation activity with strain rate and cold rolling. [ABSTRACT FROM AUTHOR]

A three-dimensional transient computational fluid dynamics model is developed to analyze the influence of rotational/non-rotational shoulder and pin characteristics on the thermal and material flow behavior in friction stir welded (FSW) aluminum alloy joints. Four tool designs with rotational/non-rotational shoulder and the pin with/without triple facets are considered. The heat cycle of the rotational and non-rotational shoulder friction stir welded joint (RS-FSW and NRS-FSW) is simulated and experimentally verified, and the welding temperature fields are analyzed. The welding peak temperature of the RS-FSWed joint is the highest, and the non-rotational shoulder significantly reduces the welding peak temperature and the range of the heat-affected zone (HAZ). The rotational shoulder promotes material flow and enhances flow velocity, whereas the non-rotational shoulder reduces both. An increase in the triple facets on the pin facilitates the material flow during NRS-FSW. Viscosity is a physical quantity associated with the welding temperature and strain rate, which is affected by the tool characteristics. The deformation zone caused by the tool is related to the viscosity of the material, the closer the tool, the lower the viscosity of the material. The viscosity of the material gradually increases with an increase in the distance from the tool surface.