It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. We report that radiation-induced endothelial-to-mesenchymal transition (EndMT) leads to tumour ...vasculature with abnormal SMA
NG2
pericyte recruitment during tumour regrowth after radiotherapy. Trp53 (but not Tgfbr2) deletion in endothelial cells (ECs) inhibited radiation-induced EndMT, reducing tumour regrowth and metastases with a high CD44v6
cancer-stem-cell (CSC) content after radiotherapy. Osteopontin, an EndMT-related angiocrine factor suppressed by EC-Trp53 deletion, stimulated proliferation in dormant CD44v6
cells in severely hypoxic regions after radiation. Radiation-induced EndMT significantly regulated tumour-associated macrophage (TAM) polarization. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1
TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp53 deletion. These EndMT-related phenomena were also observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the re-activation of dormant hypoxic CSCs and promoting anti-tumour immune responses.
Mutations in the
(
) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of
-related intellectual disability remain poorly ...understood. We investigated the role of
in synaptic function and animal behavior using male mouse and
models.
knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and
G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in
KO mice. In addition, paxilline treatment also restored normal cognitive behavior in
KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in
mutations.
(
), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of
knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that
KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene
and will contribute to the development of therapeutic strategies for
-related intellectual disability.
Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer ...treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.
The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo 3’,4’:6,7 naphtho 2,3-d 1,3dioxol-6-one (JNC-1043), which is a novel chemical ...derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.
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Hepatocellular carcinoma (HCC), one of the most common malignant cancers worldwide, is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic ...agents, novel therapeutic strategies are needed to improve survival in patients with HCC. The multicellular tumor spheroid (MCTS) model is a powerful method for anticancer research because of its ability to mimic the complexity and heterogeneity of tumor tissue, the three-dimensional cellular context of tumor tissue, and the pathophysiological gradients of in vivo tumors. However, it is difficult to obtain meaningful results from the MCTS model without considering the conditions of clinical tumors. We, therefore, provided a proof of concept to determine whether spheroid models simulate in vivo tumor microenvironments. Through a high-throughput screening for HCC therapy using the MCTS model, we selected inhibitors of Na
/K
-ATPase (ouabain and digoxin) that could suppress cell growth and migration via inhibition of the epithelial-mesenchymal transition of HCC in vivo and in vitro. The results showed that this model provides a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for HCC treatment. Through utilization of MCTS models, here we found that inhibitors of Na
/K
-ATPase may be feasible as a novel target to sensitize HCC cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Haptics applications such as surgery simulations require collision detections that are more precise than others. An efficient collision detection method based on the clustering of bounding spheres ...was proposed in our prior study. This paper analyzes and compares the applied effects of the five most common subdivision surface methods on some 3D models for haptic collision detection. The five methods are Butterfly, Catmull-Clark, Mid-point, Loop, and LS3 (Least Squares Subdivision Surface). After performing a number of experiments, we have concluded that LS3 method is the most appropriate for haptic simulations. The more we applied surface subdivision, the more the collision detection results became precise. However, it is observed that the performance becomes better until a certain threshold and degrades afterward. In order to reduce the performance degradation, we adopted our prior work, which was the fast and precise collision detection method based on adaptive clustering. As a result, we obtained a notable improvement of the speed of collision detection.
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Background
Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment‐related toxicity varies and has not ...been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus‐endemic area.
Methods
This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment‐related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2‐year local control, progression‐free survival, and overall survival rates.
Results
In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation‐induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment‐related severe toxicity at 1 year was 3%. The pre‐SBRT and post‐SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2‐year and 3‐year local control rates were 97% and 95%, respectively. The progression‐free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively.
Conclusions
With a median follow‐up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.
This multicenter phase 2 trial is focused on hepatic toxicity and esophagogastroendoscopy‐based gastroduodenal toxicity after stereotactic body radiotherapy in patients with hepatocellular carcinoma. On the basis of a low severe toxicity rate of 3% at 1 year, stereotactic body radiotherapy can be safely applied for the treatment of unresectable hepatocellular carcinoma in a hepatitis B virus‐endemic area.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Spondyloarthritis (SpA) is a systemic inflammatory arthritis mediated mainly by interleukin (IL)-17. The vitronectin-derived bioactive peptide, VnP-16, exerts an anti-osteoporotic effect via β1 and ...αvβ3 integrin signaling. SpA is associated with an increased risk of osteoporosis, and we investigated the effect of VnP-16 in mice with SpA.
SpA was induced by curdlan in SKG ZAP-70W163C mice, which were treated with vehicle, celecoxib, VnP-16, or VnP-16+celecoxib. The clinical score, arthritis score, spondylitis score, and proinflammatory cytokine expression of the spine were evaluated by immunohistochemical staining. Type 17 helper T cell (Th17) and regulatory T cell (Treg) differentiation in the spleen was evaluated by flow cytometry and in the spine by confocal staining. Splenocyte expression of signal transducer and activator of transcription (STAT) 3 and pSTAT3 was evaluated by in vitro Western blotting.
The clinical score was significantly reduced in the VnP16+celecoxib group. The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group. In the spine, the levels of IL-1β, IL-6, tumor necrosis factor-α, and IL-17 expression were reduced and Th17/Treg imbalance was regulated in the VnP-16 alone and VnP-16+celecoxib groups. Flow cytometry of splenocytes showed increased polarization of Tregs in the VnP-16+celecoxib group. In vitro, VnP-16 suppressed pSTAT3.
VnP-16 plus celecoxib prevented SpA progression in a mouse model by regulating the Th17/Treg imbalance and suppressing the expression of proinflammatory cytokines.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Assessing ecosystem services with land cover change scenarios can support Indonesian peatland restoration.•Resotration of can add $2.38 billion from Current $75.41 billion economic value of the ...peatlands of Jambi and Sumatra Selatan.•Developing forest and wetland restoration scenario has higher benefits comparing the current status and business as usual.•More international restoration efforts are required for sustainable land use management in Indonesian peatlands.
Conserving tropical forests and peatlands is considered a key strategy for international forest project cooperation and the promotion of carbon neutrality. Focusing on peatlands in the Sumatra Selatan and Jambi provinces in Indonesia, this study aimed to assess land-cover changes from 1992 to 2020 and associated ecosystem services to assist in the development of effective forest and peatland-related projects. This study first analyzed the historical land-cover changes as a baseline for establishing potential project scenarios. Carbon storage, habitat suitability, water yield, and crop production were selected as the key ecosystem services in the peatlands, and these were assessed for the current land cover and two possible project scenarios in 2050 – business-as-usual (BAU) and forest and wetland restoration (FOR) – using the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) tool. In terms of land-cover changes, the area of forests and wetlands decreased, but that of agriculture, grassland, and built-up areas increased in the peatlands. Based on the land-cover scenarios, the carbon storage, habitat suitability, water yield, and crop production varied on 2.32–2,74 billion tC, 92.02–93.46 %, 16.45–16,91 billion m3, and 2.34–2.73 million ton, respectively. The total economic value of the ecosystem services for the current land cover was $75.41 billion, while that predicted for BAU and FOR was estimated to be $70.59 billion and $77.79 billion, respectively. Restoration plans have the environmental and economic benefit of provincial-level assessment, so the development of appropriate projects for tropical forest and peatland conservation and restoration is necessary for international cooperation projects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors ...are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C–C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2–CCR2 is being studied as part of various topics including the treatment of OA.
Methods
In this study, we evaluated the potential therapeutic effects the sCCR2 E3 gene may exert on OA. The effects of sCCR2 E3 were investigated in animal experiments consisting of intra-articular injection of sCCR2 E3 in a monosodium iodoacetate (MIA)-induced OA rat model. The effects after intra-articular injection of sCCR2 E3 (fusion protein encoding 20 amino acids of the E3 domain of the CCL2 receptor) in a monosodium iodoacetate-induced OA rat model were compared to those in rats treated with empty vector (mock treatment) and full-length sCCR2.
Results
Pain improved with expression of the sCCR2 gene. Improved bone resorption upon sCCR2 E3 gene activation was confirmed via bone analyses using micro-computed tomography. Histologic analyses showed that the sCCR2 E3 gene exerted protective effects against cartilage damage and anti-inflammatory effects on joints and the intestine.
Conclusions
These results show that sCCR2 E3 therapy is effective in reducing pain severity, inhibiting cartilage destruction, and suppressing intestinal damage and inflammation. Thus, sCCR2 E3 may be a potential therapy for OA.
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