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The single-pass second-harmonic generation (SHG) of a vortex beam under low fundamental wave depletion is systematically studied. Vortex modes at 1064 nm with integer topological charges from ±1 to ±9 and fractional ones at ±0.75 are generated by modulating the fundamental Gaussian beam with different spiral phase plates. The frequency doubling of these fundamental vortex modes is realized via single-pass SHG through the KTP. A detailed theoretical model is set up in the single-pass SHG of the vortex beams. Theoretical analysis indicates that the higher the order of the vortex beams, the lower the SHG efficiency, when the beam waists and fundamental power are given. The experimentally measured SHG output characteristics verify those obtained via theoretical analysis. Conservation of the orbital angular momentum during the SHG process is also verified, regardless of the fractional or integer vortex beams. SH LG0,2l vortex beams with high mode purity are obtained. The beam waists of fundamental/SH in KTP measured using a 4f system demonstrate that the Rayleigh ranges of the fundamental wave and SH wave are the same. The paper comprehensively presents some basic laws in the single-pass SHG of a vortex beam. In addition, it also indicates that SHG is an effective method to improve the mode purity of vortex beam.

Genetic therapies, including transfected immune cells and viral vectors, continue to show clinical responses as systemically deliverable and targeted therapeutics, with the first such approaches having been approved for cancer treatment. The majority of these employ cytokine transgenes. However, expression of cytokines early after systemic delivery can result in increased toxicity and nonspecific induction of the immune response. In addition, premature immune-mediated clearance of the therapy may result, especially for viral-based approaches. Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity. However, all these limitations could be overcome through incorporation of exogenous regulation of cytokine or chemokine transgene function through fusion of a small and externally controllable destabilizing domain to the protein of interest. Regulation allowed an initial phase without cytokine function, permitting enhanced delivery and oncolytic activity before activation of cytokine function and a subsequent phase of enhanced and tumor-targeted immunotherapeutic activity. As a result of this exogenous regulation of cytokine function, both oncolytic and immune-mediated mechanisms of action were optimized, greatly enhancing therapeutic activity, while toxicity was significantly reduced.

BackgroundNatural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells.MethodsThe CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells.ResultsIn NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus.ConclusionEnhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

Intratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor. Cal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in clinical PET scans. IR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous (18)F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors. Hypoxia is associated with increased intratumoral metabolic heterogeneity. (18)F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis.

The combination of an oncolytic virus, that directly destroys tumor cells and mediates an acute immune response, with an immune cell therapy, capable of further enlisting and enhancing the host immune response, has the potential to create a potent therapeutic effect. We have previously developed several strategies for optimizing the delivery of oncolytic vaccinia virus vectors to their tumor targets, including the use of immune cell-based carrier vehicles and the incorporation of mutations that increase production of the enveloped form of vaccinia (extracellular enveloped viral (EEV)) that is better adapted to spread within a host. Here, we initially combine these approaches to create a novel therapeutic, consisting of an immune cell (cytokine-induced killer, CIK) preloaded with an oncolytic virus that is EEV enhanced. This resulted in direct interaction between the viral and immune cell components with each assisting the other in directing the therapy to the tumor and so enhancing the antitumor effects. This effect could be further improved through CCL5 expression from the virus. The resulting multicomponent therapy displays the ability for synergistic crosstalk between components, so significantly enhancing tumor trafficking and antitumor effects.

Optical imaging of whole, living animals has proven to be a powerful tool in multiple areas of preclinical research and has allowed noninvasive monitoring of immune responses, tumor and pathogen growth, and treatment responses in longitudinal studies. However, fluorescence-based studies in animals are challenging because tissue absorbs and autofluoresces strongly in the visible light spectrum. These optical properties drive development and use of fluorescent labels that absorb and emit at longer wavelengths. Here, we present a far-red absorbing fluoromodule-based reporter/probe system and show that this system can be used for imaging in living mice. The probe we developed is a fluorogenic dye called SC1 that is dark in solution but highly fluorescent when bound to its cognate reporter, Mars1. The reporter/probe complex, or fluoromodule, produced peak emission near 730 nm. Mars1 was able to bind a variety of structurally similar probes that differ in color and membrane permeability. We demonstrated that a tool kit of multiple probes can be used to label extracellular and intracellular reporter-tagged receptor pools with 2 colors. Imaging studies may benefit from this far-red excited reporter/probe system, which features tight coupling between probe fluorescence and reporter binding and offers the option of using an expandable family of fluorogenic probes with a single reporter gene.

Purpose To evaluate clinical effectiveness and radiologic results of anterior cervical diskectomy with fusion (ACDF) comparing with laminoplasty (LP) in treating multilevel cervical spondylotic myelopathy (MCSM) with developmental canal stenosis (DCS). Methods This was a retrospective analysis of 41 patients who had MCSM with DCS treated with ACDF or LP from December 2018 to April 2023. Patients were split into ACDF and LP groups for comparison, and patients were further separated into subgroups based on whether or not a reserving canal space was present. The operation time, hemoglobin, hospital stay, modified Japanese Orthopaedic Association (mJOA) score, and visual analog scale (VAS) score were used to assess clinical efficacy. The C2–C7 Cobb angle, C2–C7 sagittal vertical axis, T1 slope, and cervical range of motion were applied to evaluate imaging changes. Results Of the 41 patients, 19 received ACDF, and 22 received LP. At the final follow-up, both groups’ mJOA scores significantly improved, and the intercomparison showed no differences; the VAS score was much lower in the ACDF group but remained unchanged in the LP group. At the final follow-up, the C2–C7 Cobb angle and T1 slope had significantly increased in the ACDF group, while the LP group showed no change; the cervical range of motion had significantly decreased in both groups, with the ACDF group exhibiting a more marked reduction. Within the ACDF subgroup, there was no postoperative symptom improvement for those with reserving space, whereas there was postoperative symptom resolution for those with non-reserving space; however, postoperative symptom in the LP subgroup was resolved. Conclusions Both ACDF and LP were efficacious for MCSM patients with DCS. While ACDF could improve cervical lordosis and alleviate neck pain more effectively, it can also result in cervical sagittal imbalance and decreased mobility. Furthermore, the recovery from LP was superior to that from ACDF for patients with reserving space. In contrast, the recovery from both decompression techniques was comparable for individuals in non-reserving space.

Having designed and achieved a sort of wireless video network system based on 3G TDCDMA, this system is applied to provide users witht function which is online browsing service of real-time natural landscape on the Mt. Everest. By means of erecting the video cameras on the Mt. Everest and 3G network service based on H.264 video coding technique to preview post-coding data via WEB server on the internet. Through the use of 3G network technology and H.264 video coding technology, users are able to get access to the video with higher quality, implementing the function of browsing scenery in scenic.

This paper presents a new method, Diffusing Winding Gradients (DWG), for reconstructing watertight 3D surfaces from unoriented point clouds. Our method exploits the alignment between the gradients of the generalized winding number (GWN) field and globally consistent normals to orient points effectively. Starting with an unoriented point cloud, DWG initially assigns a random normal to each point. It computes the corresponding GWN field and extract a level set whose iso-value is the average GWN values across all input points. The gradients of this level set are then utilized to update the point normals. This cycle of recomputing the GWN field and updating point normals is repeated until the GWN level sets stabilize and their gradients cease to change. Unlike conventional methods, our method does not rely on solving linear systems or optimizing objective functions, which simplifies its implementation and enhances its suitability for efficient parallel execution. Experimental results demonstrate that our method significantly outperforms existing methods in terms of runtime performance. For large-scale models with 10 to 20 million points, our CUDA implementation on an NVIDIA GTX 4090 GPU achieves speeds 30-120 times faster than iPSR, the leading sequential method, tested on a high-end PC with an Intel i9 CPU. Additionally, by employing a screened variant of GWN, DWG demonstrates enhanced robustness against noise and outliers, and proves effective for models with thin structures and real-world inputs with overlapping and misaligned scans. For source code and more details, visit our project webpage: https://dwgtech.github.io/.