A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and ...significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.
Objectives
This study was conducted in order to assess the performance of the Liver Imaging Reporting and Data System (LI-RADS) treatment response (TR) (LR-TR) categorization on gadoxetic ...acid-enhanced MRI (Gd-EOB-MRI) for detecting viable tumors in hepatocellular carcinoma (HCC) treated with locoregional treatment (LRT) and to investigate the added value of ancillary features (AFs) to conventional enhancement-based criteria.
Methods
This retrospective study included 183 patients with Gd-EOB-MRI after LRT for HCC and appropriate reference standards for tumor viability (84 viable and 99 nonviable). Two independent radiologists assigned per-lesion mRECIST and TR categories (TR-nonviable, TR-equivocal, or TR-viable) according to the LR-TR algorithm and modified LR-TR algorithms including mLR-TR(TP) allowing transitional phase (TP) washout and mLR-TR(AF) allowing category adjustment by applying AFs. Diagnostic performances of imaging criteria were compared using the Cochran’s
Q
test with post hoc analysis.
Results
For detecting viable tumors, LR-TR-viable resulted in sensitivities of 64.5%/39.3% and specificities of 98.0%/98.0% in reviewers 1/2. In comparison to LR-TR-viable, mRECIST-viable, mLR-TR(TP)-viable, and mLR-TR(AF)-viable showed significantly higher sensitivities (92.9%/94.0%, 77.4%/56.6%, and 86.9%/83.3% in reviewers 1/2) (
p
s < 0.001). The specificity of mRECIST-viable (73.7%/62.6%) was significantly lower than that of LR-TR-viable (
p
s < 0.001), while those of mLR-TR(TP)-viable and mLR-TR(AF)-viable were greater than 95% (98.0%/96.0% and 97.0%/96.0%), statistically equivalent to LR-TR-viable (
p
s > 0.05). TR-equivocal was least assigned on mLR-TR(AF) (1.1%/7.7%) than LR-TR (15.8%/32.2%) or mLR-TR(TP) (6.6%/23.5%) in both reviewers.
Conclusion
The LR-TR algorithm on Gd-EOB-MRI provides a specific diagnosis of viable tumor but with limited sensitivity. By applying AFs in the category adjustment, more sensitive and confident diagnosis can be achieved without significant loss of specificity.
Key Points
• The LI-RADS treatment response (LR-TR) algorithm on Gd-EOB-MRI provides a highly specific diagnosis of viable HCC but with limited sensitivity.
• The inferior sensitivity of LR-TR-viable category to that of mRECIST can be improved by applying ancillary features in the category adjustment.
Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated “oncogene-addicted” cancer cells ...engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.
•Many oncogene-addicted cancer cells initially respond well to pathway-targeted drugs•Multiple resistance mechanisms limit the overall efficacy of most cancer drugs•A Stat3-mediated feedback loop engaged by drug treatment contributes to resistance•Disrupting Stat3 feedback enhances drug efficacy in many oncogene-addicted cells
Lee et al. identify a specific autocrine feedback activation loop of Stat3 signaling following receptor tyrosine kinase or MEK inhibition in oncogene-addicted cells that promotes drug resistance, suggesting that disrupting this loop could enhance the efficacy of drugs targeting these oncogenic pathways.
Over the past number of years, the power conversion efficiency of perovskite solar cells has remained at 25.5%, reflecting a respectable result for the general incorporation of organometallic ...trihalide perovskite solar cells. However, perovskite solar cells still suffer from long-term stability issues. Perovskite decomposes upon exposure to moisture, thermal, and UV-A light. Studies related to this context have remained ongoing. Recently, research was mainly conducted on the stability of perovskite against non-radiative recombination. This study improved a critical instability in perovskite solar cells arising from non-radiative recombination and UV-A light using a passivation layer. The passivation layer comprised a polyaniline (PANI) polymer as an interfacial modifier inserted between the active layer and the electron transport layer. Accordingly, the UV-A light did not reach the active layer and confined the Pb
ions at PANI passivation layer. This study optimized the perovskite solar cells by controlling the concentration, thickness and drying conditions of the PANI passivation layer. As a result, the efficiency of the perovskite solar cell was achieved 15.1% and showed over 84% maintain in efficiency in the ambient air for one month using the 65 nm PANI passivation layer.
Vehicle-IT convergence technology is a rapidly rising paradigm of modern vehicles, in which an electronic control unit (ECU) is used to control the vehicle electrical systems, and the controller area ...network (CAN), an in-vehicle network, is commonly used to construct an efficient network of ECUs. Unfortunately, security issues have not been treated properly in CAN, although CAN control messages could be life-critical. With the appearance of the connected car environment, in-vehicle networks (e.g., CAN) are now connected to external networks (e.g., 3G/4G mobile networks), enabling an adversary to perform a long-range wireless attack using CAN vulnerabilities. In this paper we show that a long-range wireless attack is physically possible using a real vehicle and malicious smartphone application in a connected car environment. We also propose a security protocol for CAN as a countermeasure designed in accordance with current CAN specifications. We evaluate the feasibility of the proposed security protocol using CANoe software and a DSP-F28335 microcontroller. Our results show that the proposed security protocol is more efficient than existing security protocols with respect to authentication delay and communication load.
Objectives
To investigate the performance of the Liver Imaging Reporting and Data System (LI-RADS) v2017 for combined hepatocellular cholangiocarcinoma (cHCC-CCA) in the differential diagnosis from ...hepatocellular carcinoma (HCC) and prediction of prognosis on gadoxetic acid-enhanced MRI (Gd-EOB-MRI).
Methods
Patients at high risk of HCC with pathologically confirmed cHCC-CCAs (
n
= 70) and a matched control of HCCs (
n
= 70) who had undergone Gd-EOB-MRI were included. LI-RADS category was assigned for each lesion by two radiologists. Imaging features and surgical outcomes were compared between cHCC-CCAs of LR-M and LR-5/4 using the χ
2
test or Fisher’s exact test. Recurrence-free survival (RFS) was estimated using Kaplan–Meier survival curves and compared using the log-rank test.
Results
cHCC-CCAs and HCCs were categorised as LR-M, LR-5/4 and LR-TIV in 61.4% (43/70), 37.1% (26/70) and 1.4% (1/70) and 10.0% (7/70), 88.6% (62/70) and 1.4% (1/70), respectively. cHCC-CCAs of LR-5/4, in comparison to LR-M, showed significantly higher frequencies of major HCC features: arterial hyperenhancement (96.2% (25/26) vs. 58.1% (25/43),
p
= 0.001), washout appearance (80.8% (21/26) vs. 48.8% (21/43),
p
= 0.011) and enhancing capsule (34.6% (9/26) vs. 11.6% (5/43),
p
= 0.031). After curative surgery, patients with cHCC-CCAs of LR-M showed a higher early recurrence rate (≤ 6 months) than did those with LR-5/4 (27.8% (10/36) vs. 4.8% (1/21),
p
= 0.041), whereas no significant difference was observed in RFS (log-rank
p
= 0.084).
Conclusions
By using LI-RADS on Gd-EOB-MRI, a substantial proportion of cHCC-CCAs can be categorised as non-LR-M. In addition, cHCC-CCAs mimicking HCCs on imaging (LR-5/4) may indicate better surgical outcomes with regard to early recurrence than those of LR-M.
Key Points
• cHCC-CCAs can be categorised as either LR-M or non-LR-M on Gd-EOB-MRI.
• cHCC-CCAs of LR-5/4 frequently demonstrate major HCC imaging features.
• LI-RADS categorisation may provide prognostic information after surgery in cHCC-CCAs.
Background and purpose - We aimed to evaluate the ability of artificial intelligence (a deep learning algorithm) to detect and classify proximal humerus fractures using plain anteroposterior shoulder ...radiographs.
Patients and methods - 1,891 images (1 image per person) of normal shoulders (n = 515) and 4 proximal humerus fracture types (greater tuberosity, 346; surgical neck, 514; 3-part, 269; 4-part, 247) classified by 3 specialists were evaluated. We trained a deep convolutional neural network (CNN) after augmentation of a training dataset. The ability of the CNN, as measured by top-1 accuracy, area under receiver operating characteristics curve (AUC), sensitivity/specificity, and Youden index, in comparison with humans (28 general physicians, 11 general orthopedists, and 19 orthopedists specialized in the shoulder) to detect and classify proximal humerus fractures was evaluated.
Results - The CNN showed a high performance of 96% top-1 accuracy, 1.00 AUC, 0.99/0.97 sensitivity/specificity, and 0.97 Youden index for distinguishing normal shoulders from proximal humerus fractures. In addition, the CNN showed promising results with 65-86% top-1 accuracy, 0.90-0.98 AUC, 0.88/0.83-0.97/0.94 sensitivity/specificity, and 0.71-0.90 Youden index for classifying fracture type. When compared with the human groups, the CNN showed superior performance to that of general physicians and orthopedists, similar performance to orthopedists specialized in the shoulder, and the superior performance of the CNN was more marked in complex 3- and 4-part fractures.
Interpretation - The use of artificial intelligence can accurately detect and classify proximal humerus fractures on plain shoulder AP radiographs. Further studies are necessary to determine the feasibility of applying artificial intelligence in the clinic and whether its use could improve care and outcomes compared with current orthopedic assessments.
Over‐activation of microglia cells in the brain contributes to neurodegenerative processes promoted by the production of various neurotoxic factors including pro‐inflammatory cytokines and nitric ...oxide. Recently, accumulating evidence has suggested that mitochondrial dynamics are an important constituent of cellular quality control and function. However, the role of mitochondrial dynamics in microglial activation is still largely unknown. In this study, we determined whether mitochondrial dynamics are associated with the production of pro‐inflammatory mediators in lipopolysaccharide (LPS)‐stimulated immortalization of murine microglial cells (BV‐2) by a v‐raf/v‐myc carrying retrovirus (J2). Excessive mitochondrial fission was observed in lentivirus‐transfected BV‐2 cells stably expressing DsRed2‐mito following LPS stimulation. Furthermore, mitochondrial localization of dynamin‐related protein 1 (Drp1) (a key regulator of mitochondrial fission) was increased and accompanied by de‐phosphorylation of Ser637 in Drp1. Interestingly, inhibition of LPS‐induced mitochondrial fission and reactive oxygen species (ROS) generation by Mdivi‐1 and Drp1 knock‐down attenuated the production of pro‐inflammatory mediators via reduced nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling. Our results demonstrated for the first time that mitochondrial fission regulates mitochondrial ROS production in activated microglial cells and influences the expression of pro‐inflammatory mediators through the activation of NF‐κB and MAPK. We therefore suggest that mitochondrial dynamics may be essential for understanding pro‐inflammatory mediator expression in activated microglial cells. This could represent a new therapeutic approach for preventing neurodegenerative diseases.
LPS induced excessive mitochondrial fission through mitochondrial localization of de‐phosphorylation of Ser637 Drp1. Interestingly, inhibition of LPS‐induced mitochondrial fission and mitochondrial ROS generation by Mdivi‐1 and Drp1 shRNA attenuate the production of pro‐inflammatory mediators via reduced NF‐κB and MAPK signaling. Our results suggest that mitochondrial dynamics may be essential for understanding pro‐inflammatory mediator expression in activated microglial cells.
LPS induced excessive mitochondrial fission through mitochondrial localization of de‐phosphorylation of Ser637 Drp1. Interestingly, inhibition of LPS‐induced mitochondrial fission and mitochondrial ROS generation by Mdivi‐1 and Drp1 shRNA attenuate the production of pro‐inflammatory mediators via reduced NF‐κB and MAPK signaling. Our results suggest that mitochondrial dynamics may be essential for understanding pro‐inflammatory mediator expression in activated microglial cells.
Rheumatoid arthritis is an autoimmune disease that causes serious functional loss in patients. Early and accurate diagnosis of rheumatoid arthritis may attenuate its severity. Despite a diagnosis ...guideline in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis, the practical difficulties in its diagnosis highlight the need of developing new methods for diagnosing rheumatoid arthritis. The current study aimed to identify rheumatoid arthritis diagnostic biomarkers by using a proteomics approach. Serum protein profiling was conducted using mass spectrometry, and five distinguishable biomarkers were identified therefrom. In the validation study, the five biomarkers were quantitatively verified by multiple reaction monitoring (MRM) analysis. Two proteins, namely serum amyloid A4 and vitamin D binding protein, showed high performance in distinguishing patients with rheumatoid arthritis from healthy controls. Logistic analysis was conducted to evaluate how accurately the two biomarkers distinguish patients with rheumatoid arthritis from healthy controls. The classification accuracy was 86.0% and 81.4% in patients with rheumatoid arthritis and in healthy controls, respectively. Serum amyloid A4 and vitamin D binding protein could be potential biomarkers related to the inflammatory response and joint destruction that accompany rheumatoid arthritis.
Abstract
TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane’s surface but also interacts with ...intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.
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