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- Turkington, RC, et al.
(författare)
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Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:11, s. 1918-1927
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Tidskriftsartikel (refereegranskat)abstract
- Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.DesignTranscriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).ResultsA total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).ConclusionThe DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.
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- Mourikis, TP, et al.
(författare)
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Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3101-
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Tidskriftsartikel (refereegranskat)abstract
- The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
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- Fan, Jincheng, et al.
(författare)
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P-Type ZnO materials : Theory, growth, properties and devices
- 2013
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Ingår i: Progress in Materials Science. - : Elsevier BV. - 0079-6425 .- 1873-2208. ; 58:6, s. 874-985
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Tidskriftsartikel (refereegranskat)abstract
- In the past 10 years, ZnO as a semiconductor has attracted considerable attention due to its unique properties, such as high electron mobility, wide and direct band gap and large exciton binding energy. ZnO has been considered a promising material for optoelectronic device applications, and the fabrications of high quality p-type ZnO and p-n junction are the key steps to realize these applications. However, the reliable p-type doping of the material remains a major challenge because of the self-compensation from native donor defects (VO and Zni) and/or hydrogen incorporation. Considerable efforts have been made to obtain p-type ZnO by doping different elements with various techniques. Remarkable progresses have been achieved, both theoretically and experimentally. In this paper, we discuss p-type ZnO materials: theory, growth, properties and devices, comprehensively. We first discuss the native defects in ZnO. Among the native defects in ZnO, VZn and O i act as acceptors. We then present the theory of p-type doping in ZnO, and summarize the growth techniques for p-type ZnO and the properties of p-type ZnO materials. Theoretically, the principles of selection of p-type dopant, codoping method and XZn-2VZn acceptor model are introduced. Experimentally, besides the intrinsic p-type ZnO grown at O-rich ambient, p-type ZnO (MgZnO) materials have been prepared by various techniques using Group-I, IV and V elements. We pay a special attention to the band gap of p-type ZnO by band-gap engineering and room temperature ferromagnetism observed in p-type ZnO. Finally, we summarize the devices based on p-type ZnO materials.
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- Mahadeva, R, et al.
(författare)
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Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo
- 2005
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Ingår i: American Journal of Pathology. - 1525-2191. ; 166:2, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- The molecular mechanisms that cause emphysema are complex but most theories suggest that an excess of proteinases is a crucial requirement. This paradigm is exemplified by severe deficiency of the key antielastase within the lung: alpha(1)-antitrypsin. The Z mutant of alpha(1)-antitrypsin has a point mutation Glu342Lys in the hinge region of the molecule that renders it prone to intermolecular linkage and loop-sheet polymerization. Polymers of Z alpha(1)-antitrypsin aggregate within the liver leading to juvenile liver cirrhosis and the resultant plasma deficiency predisposes to premature emphysema. We show here that polymeric alpha(1)-antitrypsin co-localizes with neutrophils in the alveoli of individuals with Z alpha(1)-antitrypsin-related emphysema. The significance of this finding is underscored by the excess of neutrophils in these individuals and the demonstration that polymers cause an influx of neutrophils when instilled into murine lungs. Polymers exert their effect directly on neutrophils rather than via inflammatory cytokines. These data provide an explanation for the accelerated tissue destruction that is characteristic of Z alpha(1)-antitrypsin-related emphysema. The transition of native Z alpha(1)-antitrypsin to polymers inactivates its anti-proteinase function, and also converts it to a proinflammatory stimulus. These findings may also explain the progression of emphysema in some individual despite alpha(1)-antitrypsin replacement therapy.
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- Mahadeva, Sreekanth K., et al.
(författare)
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A comparative study of room temperature ferromagnetism in MgO films deposited by rf/dc sputtering using high purity Mg and MgO targets
- 2013
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Ingår i: Materials Express. - : American Scientific Publishers. - 2158-5849 .- 2158-5857. ; 3:4, s. 328-334
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Tidskriftsartikel (refereegranskat)abstract
- Thin films of nanocrystalline MgO were deposited on glass/Si substrates by rf/dc sputtering from metallic Mg, and ceramic MgO targets. The purpose of this study is to identify the differences in the properties, magnetic in particular, of MgO films obtained on sputter deposition from 99.99% pure metallic Mg target in a controlled [Nitrogen + Oxygen partial pressure (O(2)pp)] atmosphere as against those deposited using an equally pure ceramic MgO target in argon + identical oxygen ambience conditions while maintaining the same total pressure in the chamber in both cases. Characterization of the films was carried out by X-ray diffraction, focussed ion beam cross sectioning, atomic force microscopy and SQUID-magnetometry. The 'as-obtained' films from pure Mg target are found to be predominantly X-ray amorphous, while the ceramic MgO target gives crystalline films, (002) oriented with respect to the film plane. The films consisted of nano-crystalline grains of size in the range of about 0.4 to 4.15 nm with the films from metallic target being more homogeneous and consisting of mostly subnanometer grains. Both the types of films are found to be ferromagnetic to much above room temperature. We observe unusually high maximum saturation magnetization (MS) values of 13.75 emu/g and similar to 4.2 emu/g, respectively for the MgO films prepared from Mg, and MgO targets. The origin of magnetism in MgO films is attributed to Mg vacancy (V-Mg), and 2p holes localized on oxygen sites. The role of nitrogen in enhancing the magnetic moments is also discussed.
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- Mahadeva, Sreekanth K., et al.
(författare)
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Magnetism of amorphous and nanocrystalized dc-sputter-deposited MgO Thin Films
- 2013
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Ingår i: Nanomaterials. - : MDPI AG. - 2079-4991. ; 3:3, s. 486-497
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Tidskriftsartikel (refereegranskat)abstract
- We report a systematic study of room-temperature ferromagnetism (RTFM) in pristine MgO thin films in their amorphous and nano-crystalline states. The as deposited dc-sputtered films of pristine MgO on Si substrates using a metallic Mg target in an O-2 containing working gas atmosphere of (N-2 + O-2) are found to be X-ray amorphous. All these films obtained with oxygen partial pressure (P-O2) similar to 10% to 80% while maintaining the same total pressure of the working gas are found to be ferromagnetic at room temperature. The room temperature saturation magnetization (MS) value of 2.68 emu/cm(3) obtained for the MgO film deposited in P-O2 of 10% increases to 9.62 emu/cm3 for film deposited at P-O2 of 40%. However, the MS values decrease steadily for further increase of oxygen partial pressure during deposition. On thermal annealing at temperatures in the range 600 to 800 degrees C, the films become nanocrystalline and as the crystallite size grows with longer annealing times and higher temperature, MS decreases. Our study clearly points out that it is possible to tailor the magnetic properties of thin films of MgO. The room temperature ferromagnetism in MgO films is attributed to the presence of Mg cation vacancies.
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| 17. |
- Mahadeva, Sreekanth K., et al.
(författare)
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Suppression of Ferromagnetic Ordering in thicker co-sputtered Mn doped MgO Films
- 2013
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Ingår i: Nanostructured metal oxides for advanced applications. - : Materials Research Society. - 9781605115290 ; , s. 83-88
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Konferensbidrag (refereegranskat)abstract
- We report on preliminary studies of low (14 at.%) and high (53at.%) concentration Mn doped MgO films deposited by co-sputtering from metallic Mn and Mg targets. The structural, surface morphologies and magnetic properties of the films of different thickness were studied. All the as grown films are found to be amorphous and film surfaces are found to be flawless and homogeneous. We observe at room temperature robust ferromagnetic loops with a saturation magnetization value that is a function of film thickness reaching a maximum of ~38.5 emu/cm3 in the Mn0.53Mg0.47O film at a thickness of ~92 nm. In thicker films room-temperature ferromagnetic ordering is suppressed and eventually at a thickness around 120nm the expected diamagnetism of the bulk appears. The origin of ferromagnetism may be attributed to cation defects at the Mg-site.
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