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Robust Photodynamic Therapy Using 5-ALA-Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4 <sup>+</sup> CD8 <sup>+</sup> Double Positive T Cells
摘要： Advanced melanoma can rarely be cured. Photodynamic therapy (PDT) readily eradicates the primary melanoma but has limited ability to destroy the spreading tumor cells unless supported by other combinative interventions to augment systemic antitumor immunity. Based on the previously synthesized penetration-enhancing biomaterials, a topically administered nanoformulation is developed, which profoundly assists 5-aminolevulinic acid (5-ALA) in circumventing skin barrier to be selectively delivered to tumor cells. After endocytosis, accumulated 5-ALA is efficiently metabolized to a photosensitizer protoporphyrin IX (PpIX) which stimulates a large production of cytotoxic reactive oxygen species (ROS) under illumination. Accompanied by the robust inflammatory responses followed by primary tumor destruction, CD4+CD8+ double positive T cells are highly boosted to harness host immunity to purge metastases in lymphoid organs. Compared with dacarbazine and programmed death 1 (PD-1) antibody, this treatment in advanced melanoma murine models, achieves a striking curable rate of 90% without melanoma prognostic markers LDH and S-100B detection, followed by a relapse-free survival rate of 83.33% in 300 days. Moreover, the cured mice’s immune system function recovers to an extent similar to healthy mice without prolonged or exaggerated inflammation. This study using the synergistic biomaterials approach may thus render 5-ALA-mediated PDT a potentially curative therapy for advanced melanoma in clinic.
关键词： advanced melanoma,CD4+CD8+ double positive cells,relapse-free survival,5-aminolevulinic acid,cure
更新于2025-11-25 10:30:42
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Quantum decay law: critical times and the equivalence of approaches
摘要： Methods based on the use of Green's functions or Jost functions and the Fock–Krylov method are apparently very different approaches to understand the time evolution of unstable states. We show that the two former methods are equivalent up to some constants and as an outcome find an analytic expression for the energy density of states in the Fock–Krylov amplitude in terms of the coefficients introduced in the Green's functions and the Jost functions methods. This model-independent density is further used to obtain an analytical expression for the survival amplitude and study its behaviour at large times. Using these expressions, we investigate the origin of the oscillatory behaviour of the decay law in the region of the transition from the exponential to the non-exponential at large times. With the objective of understanding the failure of nuclear and particle physics experiments in observing the non-exponential decay law predicted by quantum mechanics for large times, we derive analytical formulae for the critical transition time, tc, from the exponential to the inverse power law behaviour at large times. Evaluating τc = Γtc for some particle resonances and narrow nuclear states which have been tested experimentally to verify the exponential decay law, we conclude that the large time power law in particle and nuclear decay is hard to find experimentally.
关键词： analytical survival amplitude,non-exponential decay law,critical transition time
更新于2025-09-23 15:23:52
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IPSI vs CONTRA TRAMa??Old Doubts New Answers: Evaluation TRAM Flap Survival with Static and Active Dynamic Thermography in Pedicled Flap Breast Reconstruction
摘要： Breast reconstruction is increasingly being considered as the next step in breast cancer treatment. There are many ways to recreate a new breast mound. In current times, the trend for breast reconstruction is reconstruction microsurgery which is the method of choice, but newcomers should know the alternative traditional methods. Since 1982 the pedicled TRAM (trans rectus abdominal myocutaneous) flap has become one of the most popular autologous tissue breast reconstruction procedures. It has also been debated for many years which method of transferring the tissue island is more reliable and has fewer complications—IPSI vs CONTRA [1]. The reasons for complications are the manner of twisting the nourishing blood supply and the tension due to the distance of the pedicle in both procedures [2]. Static thermography and dynamic thermography seem to provide the solution. In our experiment, we measured the medial surface temperature of flaps using static thermography and active dynamic thermography. The results were compared against the number of flap failures in each type of reconstruction. The study was conducted on a group of 20 female patients who underwent breast reconstruction.
关键词： Breast reconstruction,Active dynamic thermography,Thermography,Flap survival,TRAM flap,Flap necrosis,Skin necrosis
更新于2025-09-23 15:21:01
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Intraoperative radiotherapy with low energy photons in recurrent colorectal cancer: a single centre retrospective study
摘要： Aim of the study: Intraoperative radiotherapy (IORT) may improve outcome of surgical treatment of recurrent colorectal cancer (CRC). The aim of this study is to determine the feasibility, safety and long-term results of surgical treatment of recurrent CRC with orthovolt IORT. Material and methods: Fifty-nine consecutive CRC patients with local recurrence (LR), undergoing surgery, were included in the retrospective analysis of prospectively collected data. The modified Wanebo classification was used to stage LR (Tr). Twenty-five (43%) patients received IORT using INTRABEAM? PRS 500. The complications were classified according to the Clavien-Dindo classification. Results: There were 32 males and 27 females, with a median age of 63 years. Multi-visceral resections were performed in 37 (63%) patients. Median hospitalization time after surgery with IORT was 7 days. One (1.7%) in-hospital postoperative death was reported. Grade 3/4 postoperative complications were found in 11 (19%) patients. Intraoperative radiotherapy had no effect on the postoperative hospitalization time, morbidity and mortality. Median survival after R0 resection was 32 months. Complete resection (R0), no synchronous liver metastases (M0), and no lateral and posterior pelvic wall involvement, were significant predictors of improved survival. Stage of LR was found to be an independent prognostic factor in the multivariate analysis (p = 0.03; Cox regression model). In patients with LR stage < Tr5, a 3-year overall survival (OS) rate was 52%. Conclusions: Combination of surgical resection and orthovolt IORT is a safe and feasible procedure that does not increase the risk of postoperative complications or prolongs the hospital stay. Despite aggressive surgery supported by IORT, the advanced stage of LR is a limiting factor of long-term survival.
关键词： colorectal cancer,recurrence,intraoperative radiotherapy,survival,surgery
更新于2025-09-23 15:21:01
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Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN): 12-Month Outcomes and Quality of Life After Brain Tumor Ablation
摘要： Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN) is an ongoing multicenter prospective NeuroBlate (Monteris Medical) LITT (laser interstitial thermal therapy) registry collecting real-world outcomes and quality-of-life (QoL) data. To compare 12-mo outcomes from all subjects undergoing LITT for intracranial tumors/neoplasms. Demographics, intraprocedural data, adverse events, QoL, hospitalizations, health economics, and survival data are collected; standard data management and monitoring occur. A total of 14 centers enrolled 223 subjects; the median follow-up was 223 d. There were 119 (53.4%) females and 104 (46.6%) males. The median age was 54.3 yr (range 3-86) and 72.6% had at least 1 baseline comorbidity. The median baseline Karnofsky Performance Score (KPS) was 90. Of the ablated tumors, 131 were primary and 92 were metastatic. Most patients with primary tumors had high-grade gliomas (80.9%). Patients with metastatic cancer had recurrence (50.6%) or radiation necrosis (40%). The median postprocedure hospital stay was 33.4 h (12.7-733.4). The 1-yr estimated survival rate was 73%, and this was not impacted by disease etiology. Patient-reported QoL as assessed by the Functional Assessment of Cancer Therapy-Brain was stabilized postprocedure. KPS declined by an average of 5.7 to 10.5 points postprocedure; however, 50.5% had stabilized/improved KPS at 6 mo. There were no significant differences in KPS or QoL between patients with metastatic vs primary tumors. Results from the ongoing LAANTERN registry demonstrate that LITT stabilizes and improves QoL from baseline levels in a malignant brain tumor patient population with high rates of comorbidities. Overall survival was better than anticipated for a real-world registry and comparative to published literature.
关键词： Brain tumor,Laser ablation,Quality of life,LITT,Survival
更新于2025-09-23 15:19:57
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Monitoring Neuronal Survival via Longitudinal Fluorescence Microscopy
摘要： Standard cytotoxicity assays, which require the collection of lysates or fixed cells at multiple time points, have limited sensitivity and capacity to assess factors that influence neuronal fate. These assays require the observation of separate populations of cells at discrete time points. As a result, individual cells cannot be followed prospectively over time, severely limiting the ability to discriminate whether subcellular events, such as puncta formation or protein mislocalization, are pathogenic drivers of disease, homeostatic responses, or merely coincidental phenomena. Single-cell longitudinal microscopy overcomes these limitations, allowing the researcher to determine differences in survival between populations and draw causal relationships with enhanced sensitivity. This video guide will outline a representative workflow for experiments measuring single-cell survival of rat primary cortical neurons expressing a fluorescent protein marker. The viewer will learn how to achieve high-efficiency transfections, collect and process images enabling the prospective tracking of individual cells, and compare the relative survival of neuronal populations using Cox proportional hazards analysis.
关键词： fluorescence microscopy,automation,Cell death,transfection,neurodegeneration,survival analysis
更新于2025-09-19 17:15:36
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Radical Laser Interstitial Thermal Therapy Ablation Volumes Increase Progression-Free Survival in Biopsy-Proven Radiation Necrosis
摘要： Radical Laser Interstitial Thermal Therapy Ablation Volumes Increase Progression-Free Survival in Biopsy-Proven Radiation Necrosis
关键词： oncology,brain tumor,radiation necrosis,brain metastasis,progression free survival,Laser interstitial thermal therapy,post-radiation treatment effects
更新于2025-09-16 10:30:52
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Dynamic Contrast-Enhanced MRI in Patients with Brain Metastases Undergoing Laser Interstitial Thermal Therapy: A Pilot Study
摘要： BACKGROUND AND PURPOSE: Tumor recurrence is difficult to predict in patients receiving laser ablation for intracranial malignancy. We assessed the efficacy of the initial area under the time-to-signal intensity curve at 60 seconds (iAUC60) from dynamic contrast-enhanced MR imaging in predicting progression-free survival in patients with brain metastases following laser interstitial thermal therapy. MATERIALS AND METHODS: The study population was a consecutive series of patients undergoing laser interstitial thermal therapy for brain metastases. Patient demographics including age, sex, tumor histology, and Karnofsky Performance Scale were collected prospectively. Preoperative, postoperative, and 1-month follow-up dynamic contrast-enhanced MRIs were analyzed. Values of iAUC60 were computed using a trapezoidal rule applied to the time history of contrast uptake over the first 60 seconds postenhancement. The change in iAUC60 (ΔiAUC60) was calculated by taking the difference between the values of iAUC60 from 2 time points. Pearson correlation coefficients were calculated between progression-free survival, defined as the time from laser interstitial thermal therapy to tumor recurrence, and iAUC60 or ΔiAUC60 values. RESULTS: Thirty-three cases of laser interstitial thermal therapy for 32 brain metastases in a cohort of 27 patients were prospectively analyzed. A significant relationship was observed between the values of iAUC60 from postoperative dynamic contrast-enhanced MR imaging and progression-free survival with Pearson correlation (P = .03) and Cox univariate analysis (P = .01). The relationship between preoperative and 1-month follow-up dynamic contrast-enhanced MR imaging was not significantly correlated with progression-free survival. Similarly, no statistically significant relationship was observed with ΔiAUC60 and progression-free survival between any time points. CONCLUSIONS: Progression-free survival is difficult to predict in patients undergoing laser interstitial thermal therapy for brain metastases due to confounding with posttreatment change. iAUC60 extracted from postoperative dynamic contrast-enhanced MR imaging shows promise for accurately prognosticating patients following this operative therapy.
关键词： Dynamic contrast-enhanced MRI,Progression-free survival,Laser interstitial thermal therapy,Brain metastases,iAUC60
更新于2025-09-12 10:27:22
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Internal Energy Deposition in Infrared Matrix-Assisted Laser Desorption Electrospray Ionization With and Without the Use of Ice as a Matrix
摘要： The internal energy deposited into analytes during the ionization process largely influences the extent of fragmentation, thus the appearance of the resulting mass spectrum. The internal energy distributions of a series of para-substituted benzyl pyridinium cations in liquid and solid-state generated by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) were measured using the survival yield method, of which results were subsequently compared with conventional electrospray ionization (ESI). The comparable mean internal energy values (e.g., 1.8–1.9 eV at a collision energy of 15 eV) and peak widths obtained with IR-MALDESI and ESI support that IR-MALDESI are essentially a soft ionization technique where analytes do not gain considerable internal energy during the laser-induced desorption process and/or lose energy during uptake into charged electrospray droplets. An unusual fragment ion, protonated pyridine, was only found for solid IR-MALDESI at relatively high collision energies, which is presumably resulted from direct ionization of the pre-charged analytes in form of salts. Analysis of tissue with an ice layer consistently yielded ion populations with higher internal energy than its counterpart without an ice layer, likely due to a substantially enhanced number of IR absorbers with ice. Further measurements with holo-myoglobin show that IR-MALDESI-MS retains the noncovalently bound heme-protein complexes under both native-like and denaturing conditions, while complete loss of the heme group occurred in denaturing ESI-MS, showing that the softness of IR-MALDESI is equivalent or superior to ESI for biomolecules.
关键词： Ambient ionization,Survival yield method,Internal energy deposition,Mass spectrometry imaging,Thermometer ions,IR-MALDESI
更新于2025-09-11 14:15:04
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Effects of Pulsed 810?nm Al‐Ga‐As Diode Laser on Wound Healing Under Immunosuppression: A Molecular Insight
摘要： Background and Objectives: Dysregulated inflammation is one of the major contributing factors for the prevalence of non‐healing chronic wound in immunosuppressed subjects. Photobiomodulation (PBM) has emerged as a potential non‐thermal, light‐based therapeutic healing intervention for the treatment of impaired wounds. Study Design/Materials and Methods: The present study delineates the underlying molecular mechanisms of PBM 810 nm laser‐induced full‐thickness cutaneous wound repair in immunosuppressed rats at continuous and pulsed wave‐mode with power‐density of 40 mW/cm2, fluence 22.6 J/cm2 for 10 minutes daily for 7 post‐wounding days. Molecular markers were assessed using biochemical, assay quantification, enzyme kinetics and immunoblots analyses pertaining to inflammation, oxidative stress, cell survival, calcium signaling, and proliferation cascades. Results: Results distinctly revealed that pulsed 810 nm (10 Hz) PBM potentially influenced the cell survival and proliferation signaling pathway by significantly upregulated phospho‐protein kinase B(phospho‐Akt), phospho‐extracellular‐signal‐regulated kinase 1 (ERK1), transient receptor potential vanilloid‐3 (TRPV3), Ca2+, calmodulin, transforming growth factor‐β1 (TGF‐β1), TGF‐βR3, and Na+/K+‐ATPase pump levels. PBM treatment resulted in reduction of exaggerated inflammatory responses evident by significantly repressed levels of interleukin‐1β (IL‐1β), IL‐6, cyclooxygenase 2 (COX‐2), and substance‐P receptor (SPR), as well as inhibited apoptotic cell death by decreasing p53, cytochrome C, and caspase 3 levels (P < 0.05), which, in turn, effectively augment the wound repair in immunosuppressed rats. PBM treatment also lowered 4‐hydroxynoneal (HNE) adduct level and NADP/NADPH ratio and upregulated the GRP78 expression, which might culminate into reduced oxidative stress and maintained the redox homeostasis. Conclusions: Taken together, these findings would be helpful in better understanding of the molecular aspects involved in pulsed 810 nm laser‐mediated dermal wound healing in immunosuppressed rats through regulation of cell survival and proliferation via Ca2+‐calmodulin, Akt, ERK, and redox signaling.
关键词： immunosuppressed,dermal wound healing,inflammation,TRPV3,cell survival,TGF‐β,proliferation signaling cascade,photobiomodulation
更新于2025-09-11 14:15:04