A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients ...with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
In severe low-visibility environments full of smoke, because of the performance degeneration of the near-infrared (NIR) collimation system of quantum drones communication networks, the improved ...dual-threshold method based on trend line analysis for long-wave infrared (LWIR) quantum cascade lasers (QCLs) is proposed, to achieve target acquisition. The simulation results show that smoke-scattering noise is a steeply varying medium–high-frequency modulation. At particle sizes less than 4 μm, the traditional dual-threshold method can effectively distinguish the target information from the smoke noise, which is the advantage of the LWIR laser compared to the NIR laser. For detecting lasers with high signal-to-noise ratios (SNRs), the method can achieve good target acquisition, by setting reasonable conventional thresholds, such as 0.7 times the peak intensity and 0.8 times the peak rising velocity. At low SNRs and steep intensity variation, the method can also achieve good target acquisition, by adaptively resetting new thresholds after filtering the detecting laser, such as 0.6 times the peak intensity and 0.6 times the peak rising velocity. The results of this paper will provide a reference for the performance improvement and refinement of the collimation system for wireless quantum communication networks in low visibility.
In biological evolution, organisms that are more adapted to the environment tend to survive better, which can be explained in part by evolutionary game theory. In this paper, we propose an improved ...spatial prisoner’s dilemma game model, which allows the focal player to access the strategy of other agents beyond their nearest neighbors with a specified probability. During the strategy update, a focal player usually picks up a randomly chosen neighbor according to a Fermi-like rule. However, in our model, unlike the traditional strategy imitation, a focal agent will decide to update their strategy through the modified rule with a specific probability q. In this case, the focal agent accesses n other individuals who have the same strategy as the imitated neighbor, where the information accessing cost needs to be paid, and then compares their discounted payoff with the average payoff of those n+1 agents to make the decision of strategy adoption; otherwise, they only refer to their own payoff and their neighbor’s payoff to decide whether the strategy spread happens. Numerical simulations indicate that a moderate value of n can foster the evolution of cooperation very well, and increase in q will also improve the dilemma of cooperators. In addition, there exists an optimal product of n×c to cause the emergence of cooperation under the specific simulation setup. Taken together, the current results are conducive to understanding the evolution of cooperation within a structured population.
Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer ...cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear.
In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo.
Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo.
Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.
Insects produce a variety of highly acrobatic maneuvers in flight owing to their ability to achieve various wing-stroke trajectories. Among them, beetles can quickly change their flight velocities ...and make agile turns. In this work, we report a newly discovered phasic wing-tip-folding phenomenon and its aerodynamic basis in beetles. The wings' flapping trajectories and aerodynamic forces of the tethered flying beetles were recorded simultaneously via motion capture cameras and a force sensor, respectively. The results verified that phasic active spanwise-folding and deployment (PASFD) can exist during flapping flight. The folding of the wing-tips of beetles significantly decreased aerodynamic forces without any changes in flapping frequency. Specifically, compared with no-folding-and-deployment wings, the lift and forward thrust generated by bilateral-folding-and-deployment wings reduced by 52.2% and 63.0%, respectively. Moreover, unilateral-folding-and-deployment flapping flight was found, which produced a lateral force (8.65 mN). Therefore, a micro-flapping-wing mechanism with PASFD was then designed, fabricated, and tested in a motion capture and force measurement system to validate its phasic folding functions and aerodynamic performance under different operating frequencies. The results successfully demonstrated a significant decrease in flight forces. This work provides valuable insights for the development of flapping-wing micro-air-vehicles with high maneuverability.
Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the ...tumor microenvironment, which is poorly understood.
For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data.
This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B
CD8
effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1
EOMES
CD8
effector T cells are associated with long-term survival. However, only the density of PD-1
EOMES
CD8
T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1
tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1
M1 or M2, PD-L1
M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1
M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1
tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion.
This study suggests that the densities of Granzyme-B
CD8
effector T cells and non-exhausted PD-1
EOMES
CD8
T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1
tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.
Hypersonic vehicles are susceptible to considerable aerodynamic heating and noticeable aerothermoelastic effects during flight due to their high speeds. Functionally graded materials (FGMs), which ...enable continuous changes in material properties by varying the ratio of different materials, provide both thermal protection and load-bearing capabilities. Therefore, they are widely used in thermal protection structures for hypersonic vehicles. In this work, the aerothermoelastic behaviors of functionally graded (FG) plates under arbitrary temperature fields are analyzed via a semianalytical method. This research develops a method considering the influence of thermal loading, specifically the decrease in stiffness due to thermal stresses, as well as the correlation between material properties and temperatures under arbitrary temperature fields, based on Ritz’s method. The classical plate theory, von–Karman’s large defection plate theory and piston theory are employed to formulate the strain energy, kinetic energy and external work functions of the system. This paper presents a novel analysis of static aerothermoelasticity of FG plates, in addition to the linear/nonlinear flutter under arbitrary temperature fields, such as uniform, linear and nonlinear temperature fields. In addition, the effects of the volume fraction index, dynamic pressure, and temperature increase on the aerothermoelastic characteristics of FG plates are analyzed.
Neoadjuvant therapy for pancreatic neuroendocrine tumors may potentially aid downstaging, increase the possibility of radical surgery. We herein report a case of a 63-year-old man who had been ...diagnosed with locally advanced small-cell neuroendocrine carcinomas of the pancreas according to the diagnostic biopsy. The patient received 6 courses of etoposide and cisplatin as neoadjuvant therapy in an attempt to stop tumor progression, which promoted obvious tumor shrinkage without adverse effects and allowed subsequent Appleby procedure, the distal pancreatectomy with celiac artery resection. The patient showed no recurrence in the follow-up of a contrast-enhanced computed tomographic scan, which is 8 months after surgery. To the best of our knowledge, this is a rare case to report etoposide and cisplatin administration before surgery for unresectable pancreatic neuroendocrine carcinoma promoted a pathological partial response and finally achieved a radical surgery, providing a novel therapeutic option for patients with locally advanced pancreatic neuroendocrine carcinoma.
Increasing evidence supports a role for N‐myc downstream‐regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) ...progression. In the present study, expression of NDRG2, microRNA (miR)‐181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR‐181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR‐181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR‐181c, and the down‐regulation of NDRG2 was attributed to miR‐181c overexpression in CCA. Furthermore, miR‐181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down‐regulation of NDRG2 and overexpression of miR‐181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR‐181c, and LIF expression is a strong predictor of prognosis in CCA patients. Conclusion: These results establish the counteraction between NDRG2 and LIF/miR‐181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2‐mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR‐181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606‐1622)
Chimeric antigen receptor–engineered T cells therapy has become the hottest topic of immunotherapy, as its great successes achieved in treating refractory hematological malignancies. These successes ...also paved the road to novel strategies of treating various solid tumors including liver cancer. Many specific proteins can be expressed aberrantly in liver cancers; therefore, a series of experimental and clinical researches exploring chimeric antigen receptor–engineered T cells and liver cancer are in progress, acquiring obvious antitumor effect and revealing its feasibility in treating liver cancer. However, lots of challenges and obstacles are emerging simultaneously, such as low infiltration, side effects, safety of chimeric antigen receptor–engineered T cells, and limited data of studies or clinical trials. Researchers have been working out many innovative ways to directly stroke these obstacles, theoretically or practically. This review focuses more on the progress and obstacles from chimeric antigen receptor–engineered T cells therapy to treat liver cancer, summarizing new breakthroughs in shooting those obstacles, meanwhile, hoping to provide enlightenment to this promising immunotherapeutic method.
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