| 1. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 2. |
- Amin, Risul, et al.
(författare)
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The kidney injury caused by the onset of acute graft-versus-host disease is associated with down-regulation of alpha Klotho
- 2020
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 78
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Tidskriftsartikel (refereegranskat)abstract
- Acute graft-versus-host disease (aGVHD) and kidney injury are the major complications after allogeneic hematopoietic stem cell transplantation (HSCT). Although the underlying mechanisms for the development of these complications are not yet fully understood, it has been proposed that emergence of aGVHD contributes to the development of kidney injury after HSCT. We have shown previously that aGVHD targets the kidney in a biphasic manner: at the onset, inflammatory genes are up-regulated, while when aGVHD becomes established, donor lymphocytes infiltrate the kidney. Here, we characterize renal manifestations at the onset of aGVHD. Mice receiving allogeneic bone marrow and spleen cells displayed symptoms of aGVHD and elevated serum levels of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) within 4 days. There was concurrent kidney injury with the following characteristics: (1) elevated expression of the kidney injury biomarker, neutrophil gelatinase-associated lipocalin (NGAL), (2) accumulation of hetero-lysosomes in proximal tubule epithelial cells, and (3) reductions in alpha Klotho mRNA and protein and increased serum levels of fibroblast growth factor 23 (Fgf23), phosphate and urea. This situation resembled acute renal injury caused by bacterial lipopolysaccharide. We conclude that the onset of aGVHD is associated with kidney injury involving down-regulation of alpha Klotho, a sight that may inspire novel therapeutic approaches.
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| 3. |
- Asem, Heba, 1987-, et al.
(författare)
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Functional nano-carriers for drug delivery by surface engineering of polymeric nanoparticles post-PISA
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Engineered polymeric nanoparticles (NPs) have been comprehensively explored as potential platforms for diagnosis and targeted therapy for several diseases including cancer. Herein, we designed functional poly(acrylic acid)-b-poly(butyl acrylate) (PAA-b-PBA) NPs using reversible addition-fragmentation chain-transfer (RAFT)-mediated emulsion polymerization via polymerization-induced self-assembly (PISA). The hydrophilic PAA-macroRAFT, forming a stabilizing shell (i.e. corona), was chain-extended using the hydrophobic monomer n-butyl acrylate (n-BA), resulting in stable, monodisperse and reproducible PAA-b-PBA NPs, typically having a diameter of 130 nm. Two approaches of surface engineering of the PAA-b-PBA NPs post-PISA were explored; a two-step and a one-step approach. In the two-step approach, the hydrophilic NP-shell corona was modified with allyl-groups under mild conditions using allylamine in water which resulted in stable allyl-functional NPs (allyl-NPs) suitable for further bio-conjugation. Their versatility was investigated by the subsequent conjugation of a thiol-functional fluorescent dye (BODIPY-SH) to the allyl-groups using click chemistry, in order to mimic the attachment of a thiol-functional target ligand. The average size and size distribution of the corresponding NPs did not change after BODIPY-conjugation. Neither the NPs nor allyl-NPs showed significant cytotoxicity towards RAW264.7 or MCF-7 cell lines, which indicates their desirable safety profile. A one-step approach to concurrently conjugate allyl-groups and a fluorescent dye (FITC) to the preformed PAA-b-PBA NPs was investigated. The cellular uptake of the FITC-NPs using J774A cells in vitro was found to be time- and concentration-dependent. The anti-cancer drug, doxorubicin, was efficiently (90%) encapsulated into the PAA-b-PBA NPs during NP formation. After a small burst release during the first two hours, a controlled release pattern over 7 days was observed. The present investigation demonstrates a potential method to functionalize polymeric NPs post-PISA to produce targeted drug delivery carriers.
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| 4. |
- El-Serafi, Ahmed, 1977-, et al.
(författare)
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Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study
- 2021
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Ingår i: Bone Marrow Transplantation. - : SPRINGERNATURE. - 0268-3369 .- 1476-5365. ; 56, s. 807-817
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.
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| 5. |
- El-Serafi, Ibrahim, et al.
(författare)
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The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P amp;lt; 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure). In conclusion: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.
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| 6. |
- Li, Chen, et al.
(författare)
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Cutaneous squamous cell carcinoma-derived extracellular vesicles exert an oncogenic role by activating cancer-associated fibroblasts
- 2023
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Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous squamous cell carcinoma (cSCC) is a fast-increasing cancer with metastatic potential. Extracellular vesicles (EVs) are small membrane-bound vesicles that play important roles in intercellular communication, particularly in the tumor microenvironment (TME). Here we report that cSCC cells secrete an increased number of EVs relative to normal human epidermal keratinocytes (NHEKs) and that interfering with the capacity of cSCC to secrete EVs inhibits tumor growth in vivo in a xenograft model of human cSCC. Transcriptome analysis of tumor xenografts by RNA-sequencing enabling the simultaneous quantification of both the human and the mouse transcripts revealed that impaired EV-production of cSCC cells prominently altered the phenotype of stromal cells, in particular genes related to extracellular matrix (ECM)-formation and epithelial-mesenchymal transition (EMT). In line with these results, co-culturing of human dermal fibroblasts (HDFs) with cSCC cells, but not with normal keratinocytes in vitro resulted in acquisition of cancer-associated fibroblast (CAF) phenotype. Interestingly, EVs derived from metastatic cSCC cells, but not primary cSCCs or NHEKs, were efficient in converting HDFs to CAFs. Multiplex bead-based flow cytometry assay and mass-spectrometry (MS)-based proteomic analyses revealed the heterogenous cargo of cSCC-derived EVs and that especially EVs derived from metastatic cSCCs carry proteins associated with EV-biogenesis, EMT, and cell migration. Mechanistically, EVs from metastatic cSCC cells result in the activation of TGFβ signaling in HDFs. Altogether, our study suggests that cSCC-derived EVs mediate cancer-stroma communication, in particular the conversion of fibroblasts to CAFs, which eventually contribute to cSCC progression.
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| 7. |
- Zhao, Ying, et al.
(författare)
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Multimodal Imaging of Pancreatic Ductal Adenocarcinoma Using Multifunctional Nanoparticles as Contrast Agents
- 2020
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 12:48, s. 53665-53681
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Tidskriftsartikel (refereegranskat)abstract
- Late diagnosis and refractory behavior toward current treatment protocols make pancreatic ductal adenocarcinoma (PDAC) one of the most difficult cancer forms to treat. The imaging-based approach plays an important role to identify potentially curable PDAC patients in high-risk groups at the early stage. In the present study, we developed a core-shell structured gold nanorod (AuNR) as a contrast agent for multimodal imaging and investigated its application for PDAC diagnosis. The composite nanopartides composed of a AuNR core inside a layer of mesoporous silica that was then coated with a gadolinium oxide carbonate shell (AuNR-SiO2 -Gd) are designed to be used in magnetic resonance imaging (MRI), X-ray computed tomography (CT), and photoacoustic imaging (PM). A phantom study with the AuNR-SiO2-Gd NPs demonstrated higher MRI contrast compared to Gadovist and higher X-ray attenuation than Visipaque. A strong, stable, and broad wavelength range signal with a peak at 800 nm was observed in PAI. The AuNR-SiO2-Gd NPs showed significant contrast enhancement under PAI/MRI/CT in both the liver and spleen of control mice after intravenous administration. The utility in PDAC was studied in a genetically engineered mouse model carrying Kras and p53 mutations, which develops spontaneous tumors and keeps the desmoplasia and hypovascularity feature of PDAC in patients. The AuNR-SiO2-Gd NPs were highly accumulated in the surrounding soft tissues but were sparsely distributed throughout the tumor due to dense stroma infiltration and poor tumor vascularization. Hence, a negative contrast within the tumor area in CT/PAI and a positive contrast in MRI were observed. In conclusion, AuNR-SiO2-Gd NPs have good potential to be developed as a multimodal contrast agent for PDAC, which might improve early diagnosis and benefit the clinical outcome for PDAC patients.
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| 8. |
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| 9. |
- Zheng, Wenyi
(författare)
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Selenocompounds in leukemia treatment : advantages and pitfalls
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In 2018, cancer was reported to be the second top cause of morbidity and mortality globally with over 9 million deaths. Hematological malignancies including leukemia constitute about 7% of the total cancer cases. Substantial developments in treatment modalities and strategies have increased the 5-year survival rate in leukemia to around 60% in developed countries. However, complete remission and long-term disease control are not yet achieved. Oxidative stress is imprinted in many types of cancer including leukemia and represents a valuable trait for achieving leukemiaselective cytotoxicity. The present thesis represents a systematic study of the role of redox-active selenocompounds (SeCs) in leukemia treatment. Six diverse selenocompounds representing different compound classes were studied. Among them, p-xyelenselenocyanate (p-XSC) was shown to have the most potent cytotoxic activity against several leukemia cell lines carrying distinct oncogenes. p-XSC exerted its cytotoxicity in a concentration- and time-dependent manner. Mechanistic studies revealed that the cytotoxicity of p-XSC was mediated by upregulation of oxidative stress and accompanied with massive mitochondria damages. Importantly, the cytotoxicity of SeCs was antagonized by albumin which is ubiquitously present in biological conditions. By the combination of two distinct, but complementary selenium speciation methods including liquid chromatographymass spectrometry and X-ray absorption spectroscopy, we showed that cytotoxic SeCs were capable of transforming into selenol intermediates that subsequently bound to albumin via selenium-sulfur bond. Furthermore, we found that the macromolecular selenocompound-albumin conjugate was also internalized and able to kill leukemia cells. In addition to interfering with cytotoxicity, binding of SeCs to albumin also hindered the quantification of these compounds in biological matrix e.g. plasma. To elucidate the pharmacokinetics properties of SeCs for in vivo applications, we developed a novel REductive Cleavage and Instant Derivatization (RECID) method, by which we were able to measure both free and albumin-bound SeCs. In the leukemia mouse model, intravenous administration of p-XSC was shown to reduce the disease burden in whole body as well as in bone marrow. In conclusion, the results obtained in the present thesis provide substantial experimental evidences that redox-active SeCs, in particular p-XSC, possess high therapeutic potential as treatment for leukemia. Further investigations to optimize treatment regimen and to design an appropriate drug carrier are needed to achieve successful clinical trials.
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