The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. ...Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.
Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.
A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on (18)Ffluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.
The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Tumor-initiating cells (TICs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be relatively rare in most human cancers. Recent data in ...melanoma indicate that the frequency of TICs increases dramatically via more permissive xenotransplantation conditions, raising the possibility that the true frequency of TICs has been greatly underestimated in most human tumors. We compared the growth of human pancreatic, non-small cell lung, and head and neck carcinomas in NOD/SCID and NSG mice. Although TIC frequency was detected up to 10-fold higher in NSG mice, it remained low (<1 in 2500 cells) in all cases. Moreover, aldehyde dehydrogenase-positive (ALDH
+) and CD44
+CD24
+ cells, phenotypically distinct cells enriched in TICs, were equally tumorigenic in NOD/SCID and NSG mice. Our findings demonstrate that TICs are rare in these cancers and that the identification of TICs and their frequency in other human malignancies should be validated via primary tumors and highly permissive xenotransplantation conditions.
Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the ...impact of CAFs on PDAC cancer stem cells (CSCs).
Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor.
Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth.
Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.
Natural fiber‐reinforced polymer composites (NFPCs) have gained limelight in many applications during the recent years, owing to their availability, as well as superior mechanical characteristics, ...cost‐effectiveness, biodegradability, and lightweight. A comprehensive understanding of the manufacturing methods, proeprties and characteristics of natural fibers pave way for begetting a wide spectrum of applications for the NFPCs in automobile, aerospace, electronics, and other engineering fields. The current review article is about natural fiber‐reinforced composites, the commonly used fabrication methods, including fiber pre‐treatments, and numerous intermediate steps added to achieve improved bonding, processability of these composites, their properties and application prospects. Various state‐of‐the‐art methods like additive manufacturing, vaccum bag molding, and autoclave has also been discussed. The mechanical properties obtained through various fiber reinforcements in accordance with process parameters has a substantial impact in the industrial applications of NFPCs. The tribological applications of NFPCs are becoming increasingly important in order to deal with the mechanical and chemical wear and tear during their service life in contact applications. Flammability behavior and biodegradability assessment of NFPCs are important for high‐temperature and outdoor environmental applications of these materials. The review also includes a comprehensive discussion about the trending applications and future prospects for NFPCs.
The equimolar High Entropy Alloy (HEA) is incorporated on the surface of SS410 steel to enhance the mechanical properties for the current industrial scenario. The objective of the present work is to ...make a first attempt at surface modification of SS410 steel with gas atomization synthesized AlCrCoFeNi HEA powder through Friction Stir Processing (FSP). The microhardness and ultimate tensile strength of the FSP-HEA sample are increased by 41.3 % and 39.1 % respectively due to the high degree of refined grains with 2.84 μm and evenly distributed HEA particles. The wear rate of FSP-HEA samples is optimized by response surface methodology with process parameters including applied load, sliding distance, and sliding velocity. The most influential factor and regression model are derived from experimental results that predict the wear rate by the analysis of variance technique. The worn surface of FSP-HEA samples is evaluated by morphological analysis with corresponding induced wear mechanisms. The minimum wear rate is achieved by optimum process parameters along with higher hardness through particle-stimulated nucleation mechanism, Hall-Petch relation, and dynamic recrystallization. The grain refinement, barrier effect, and grain growth hindrance of HEA particles lead to enhancement in the strength of processed HEA samples.
Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) (henceforth referred to as Ref-1) is a multifunctional protein that in addition to its base excision DNA repair activity exerts redox ...control of multiple transcription factors, including nuclear factor κ-light chain enhancer of activated B cells (NF-κB), STAT3, activator protein-1 (AP-1), hypoxia-inducible factor-1 (HIF-1), and tumor protein 53 (p53). In recent years, Ref-1 has emerged as a promising therapeutic target in cancer, particularly in pancreatic ductal carcinoma. Although a significant amount of research has centered on Ref-1, no wide-ranging approach had been performed on the effects of Ref-1 inhibition and transcription factor activity perturbation. Starting with a broader approach, we identified a previously unsuspected effect on the nuclear factor erythroid-related factor 2 (NRF2), a critical regulator of cellular defenses against oxidative stress. Based on genetic and small molecule inhibitor-based methodologies, we demonstrated that repression of Ref-1 potently activates NRF2 and its downstream targets in a dose-dependent fashion, and that the redox, rather than the DNA repair function of Ref-1 is critical for this effect. Intriguingly, our results also indicate that this pathway does not involve reactive oxygen species. The link between Ref-1 and NRF2 appears to be present in all cells tested in vitro, noncancerous and cancerous, including patient-derived tumor samples. In particular, we focused on understanding the implications of the novel interaction between these two pathways in primary pancreatic ductal adenocarcinoma tumor cells and provide the first evidence that this mechanism has implications for overcoming the resistance against experimental drugs targeting Ref-1 activity, with clear translational implications.
Background: The redox activity of Ref-1 activates the binding of several transcription factors important in cancer.
Results: Repression of Ref-1 potently activates NRF2 resulting in up-regulation of target gene expression.
Conclusion: Activation of NRF2 is a potential mechanism of resistance to therapies based on Ref-1 inhibition.
Significance: Dual blockade of Ref-1 and NRF2 or the specific downstream target, HMOX-1, represents a strategy for overcoming resistance.
Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown ...that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data revealed distinct patterns of both overall proteome expression and tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver- and lung-metastasis-derived cell lines as compared with tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve the administration of a combination of agents, with each agent targeted to the features of different subclones.
Magnesium alloys are well known for their light weight and low density, which facilitates their utilization in a wide range of engineering applications. When softer magnesium alloys are reinforced ...with hard ceramic particles, the machinability of magnesium alloys is expected to improve. In the current work, limestone powder (LSP) was used as a bioceramic reinforcement in AZ31 magnesium alloy, and the composites were fabricated through gravity stir casting technique. LSP particles were characterized by x-ray diffraction (XRD). Magnesium composite specimens were initially subjected to tensile tests to identify the best composite configuration. Composites with 6% LSP possessed high tensile strength and only these composites were subjected to drilling analysis. Generalized regression neural network (GRNN) has been used to forecast the surface roughness of AZ31 magnesium alloy composites during drilling. Outputs of drilling operations were utilized to train the neural network model and the values predicted by the GRNN technique were ascertained using confirmation experiments. It was concluded that bioceramics improved the machinability of the magnesium alloy composites and the GRNN application towards prediction of surface roughness showed satisfactory results exhibiting less deviation from the experimental results even for any value considered within the limits of the parametric levels.
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