| 1. |
- Ferreira, Mjv, et al.
(författare)
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Poster Session 3 : Tuesday 5 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 5. |
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| 6. |
- Durno, C., et al.
(författare)
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Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
- 2021
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet Oncology. - 1470-2045. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 11. |
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| 12. |
- Mushtaq, Afshan, et al.
(författare)
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Catalytic oxidative desulfurization of thio-compounds by employing χ-Anderson-type polyoxometalates-porphyrin covalent organic framework (COF)
- 2023
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Ingår i: Tetrahedron. - : Elsevier. - 0040-4020 .- 1464-5416. ; 144
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Tidskriftsartikel (refereegranskat)abstract
- Severe environmental sulfur contents due to the consumption of fuels in automobiles and industries resulted in serious health hazards and pollution because of it, desulfurization of diesel become inevitable. Targeting the profound desulfurization of diesel, we performed experiments to deeply desulphurized the thio-compounds by catalytic-oxidative desulfurization technique. We synthesized new metalloporphyrin (C52H36N4O8Sn)4MeO-SnPor which after conversion into (C64H64N8O16Sn)4Tris-SnTP leading towards the synthesis of covalent organic framework [(N(C4H9)4]12[HNC(CH2O)3]4[(CO)4C44H24N4Sn] [NiMo6O18]4(SnTP@NiAdCOF). SnTP@NiAd COF showed the outstanding catalytic property for deep desulfurization of thio-compounds above than 96% of thiobenzoic acid (TB) and 99% of 2-aminothiophenol (2-ATP) sulfur contents were oxides after 100 min of reaction using H2O2 as an oxidant at room temperature with constant stirring. During desulfurization percentage desulfurization efficiency was checked for different time intervals by TLC and further confirmed by reverse phase high-performance liquid chromatography (RP-HPLC). Reverse-phase high-performance liquid chromatograms indicated that the peak area and peak height of thio-compounds decrease gradually with the passage of reaction time which confirmed the removal of thio-compounds from the reaction mixture. Sulfur contents removed up to 5 ppmw showed excellent catalytic characteristics of synthesized SnTP@NiAdCOF. The exceptional catalytic efficiency of prepared catalyst SnTP@NiAdCOF was because of the existence of active oxidizing centers of χ-NiAd and metalloporphyrin that are MoO and [(Por)SnII], respectively. The potential mechanism appeared to be the formation of Mo(O2) and [(Por)SnII–OOH] from MoO and [(Por)SnII], respectively that act as active oxidizing centers and efficiently converted the thio-group into oxides and sulfones. Effective removal of sulfur grants the desulfurization of fuels by using SnTP@NiAdCOF catalyst to lessen the energy expenditure and also to enhance the production of environmentally-safe fuels.
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| 13. |
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| 14. |
- Yousaf, M., et al.
(författare)
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Evaluation of rare earth (Yb, La) doped (Sm3Fe5O12) garnet ferrite membrane for LT-SOFC
- 2020
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Ingår i: International journal of hydrogen energy. - : Elsevier Ltd. - 0360-3199 .- 1879-3487.
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Tidskriftsartikel (refereegranskat)abstract
- Rare earth element doping is a popular methodology for improving the electrical and electrochemical properties of materials. Inspired by this ideology, garnet ferrite material Sm3Fe5O12 (SFO) doped by rare earth (Yb, La) metal ions to form Sm3-0.5Yb0.5Fe5O12 (SYFO) and Sm3-0.5La0·5Fe5O12 (SLFO). The samples are synthesized by sol gel auto combustion and have been applied as electrolyte membrane for the first time in low temperature solid oxide fuel cell (LT-SOFC). The results indicate that the as-prepared materials have triple charge transport (H+/O−2/e−) carrier which promotes the hydrogen oxidation reaction (HOR) and oxygen reduction reactions (ORR) in SOFC at triple phase boundary region (TPB). Electrochemical impedance spectroscopy (EIS) reveals that the polarization resistance of SLFO membrane significantly reduces from 0.92 Ω-cm2 to 0.45 Ω-cm2 and the power output improve from 310 mW/cm2 to 650 mW/cm2 at 550 °C temperature in comparison with that of SYFO and SFO electrolyte supported cells. UV-vis diffused spectroscopy explains the semiconducting nature of the prepared materials due to the existence of optical bandgap in the semiconductor region. The further investigation also verifies the protonic conduction of SLFO membrane by constructing oxygen ion blocking fuel cell with configuration of Ni-NCAL/BZCY/SLFO/BZCY/Ni-NCAL having 427.94 mW/Cm2 fuel cell performance with 1.03 OCV at 550 °C temperature.
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| 15. |
- Zahra, M., et al.
(författare)
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Tailoring the ions and bandgaps in a novel semi-ionic energy conversion device for electrochemical performance
- 2020
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Ingår i: Materials Today Energy. - : Elsevier BV. - 2468-6069. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- The new semi-ionic energy conversion (SIEC) device has attracted remarkable attention owing to its clean and environmentally friendly applications. In this device, novel materials and mechanisms have been explored using electronic and ionic conductor materials. The tuning effect of the ions and bandgap has been studied to investigate the structural, optical, and electrochemical performance of the material. Composite materials, gadolinium-doped ceria-cadmium-doped ZnO (GDC-ZnCdO), based on ionic gadolinium-doped ceria (GDC) and semiconductor (ZnCdO) in molar ratios of 1:4, 2:3, 3:2, and 4:1 have been prepared by a wet chemical route. The crystalline structure of the GDC-ZnCdO was studied and found to have cubic and hexagonal wurtzite phases with an average crystallite size of 30–40 nm. The morphology of the prepared composite materials is a homogenous and porous structure. It was found that the addition of GDC increases the transmittance and shows a red shift in the bandgap from 2.70 eV to 2.46 eV. The maximum conductivity of 2.0 S/cm1 was achieved for the sample 4GDC-1ZnCdO at 700°C. Electrochemical impedance spectra and X-ray photoelectron spectroscopy analysis were performed to investigate the electrochemical properties of the prepared semi-ionic composite materials. The SIEC device showed a much better performance than a conventional solid oxide fuel cell. The maximum open-circuit voltage (OCV) of about 1.013 Vand power density of 0.65 W/cm2 were obtained using hydrogen fuel at 600°C, as compared with a conventional fuel cell with 0.72 V and 0.27 W/cm2, respectively. Hence, the results reveal that the ions and bandgap tuning play a crucial role in fuel cell functions. Therefore, it has been determined that the bandgap can be tuned to obtain a better and more stable performance of the SIEC device. This study presents a novel approach to enhance the electrochemical performance with the tailoring of the new semi-ionic materials.
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| 16. |
- Almas, A, et al.
(författare)
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Acuity level of care as a predictor of case fatality and prolonged hospital stay in patients with COVID-19: a hospital-based observational follow-up study from Pakistan
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:5, s. e045414-
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Tidskriftsartikel (refereegranskat)abstract
- To determine if there is an association between acuity level of care (ALC), case fatality and length of stay in patients admitted to hospital due to COVID-19.DesignA hospital-based observational follow-up study.SettingInternal Medicine Service of the Aga Khan University Hospital, Pakistan, from 26 February 2020 to 30 June 2020.ParticipantsAdult patients with confirmed COVID-19, aged ≥18 years.MethodsALC was categorised into low, intermediate and high level and patients were triaged using the standard emergency severity illness score. All patients were followed until the end of hospital admission for the outcome of case fatality and length of stay.ResultsA total of 822 patients with COVID-19 were admitted during the study period and 699 met inclusion criteria. The mean age was 54.5 years and 67% were males; 50.4% were triaged to low, 42.5% to intermediate and 7.2% to high acuity care. The overall case-fatality rate was 11.6%, with the highest (52%) in high acuity level followed by 16.2% in intermediate and 2% in low acuity care. Acuity level was associated with case fatality, with an HR (95% CI) of 5.0 (2.0 to 12.1) for high versus low acuity care and an HR of 2.7 (1.2, 6.4) for intermediate versus low acuity care, after adjusting for age, sex and common comorbidities including diabetes, hypertension, ischaemic heart disease and chronic lung disease. Similarly, acuity level was also associated with length of hospital stay.ConclusionHigh and intermediate acuity level is associated with higher case fatality rate and prolonged length of hospital stay in patients admitted with COVID-19. In resource-limited settings where the provision of high acuity care is limited, the intermediate care acuity could serve as a useful strategy to treat relatively less critical patients with COVID-19.
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| 17. |
- Clifton, Luke A., et al.
(författare)
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Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis
- 2023
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:22
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Tidskriftsartikel (refereegranskat)abstract
- Apotosis is an essential process tightly regulated by the Bcl-2 protein family where proapoptotic Bax triggers cell death by perforating the mitochondrial outer membrane. Although intensively studied, the molecular mechanism by which these proteins create apoptotic pores remains elusive. Here, we show that Bax creates pores by extracting lipids from outer mitochondrial membrane mimics by formation of Bax/lipid clusters that are deposited on the membrane surface. Time-resolved neutron reflectometry and Fourier transform infrared spectroscopy revealed two kinetically distinct phases in the pore formation process, both of whichwere critically dependent on cardiolipin levels. The initially fast adsorption of Bax on the mitochondrial membrane surface is followed by a slower formation of pores and Bax-lipid clusters on the membrane surface. Our findings provide a robust molecular understanding of mitochondrial membrane perforation by cell-killing Bax protein and illuminate the initial phases of programmed cellular death.
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| 18. |
- Clifton, Luke A., et al.
(författare)
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Insight into Bcl-2 proteins' functioning at mitochondrial membrane level
- 2023
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Ingår i: Biophysical Journal. - : Elsevier. - 0006-3495 .- 1542-0086. ; 122:3S1, s. 232a-232a
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Tidskriftsartikel (refereegranskat)abstract
- Programmed cell death (apoptosis) is essential in life. In its intrinsic apoptotic pathway opposing members of the B-cell lymphoma 2 (Bcl-2) protein family control the permeability of the mitochondrial outer membrane (MOM) and the release of apoptotic factors such as cytochrome c. Any misregulation of this process can cause disorders most prominently cancer, where often upregulation of cell protecting (anti-apoptotic) Bcl-2 members such as the Bcl-2 membrane protein itself plays a notorious role by blocking MOM perforation by - often drug induced - apoptotic proteins such as Bax which would cause cancer cell death normally. Here, we apply neutron reflectometry (NR) on supported lipid bilayers which mimic MOM environment and solid state/liquid state NMR spectroscopy to unravel the molecular basis driving opposing proteins to interact with each other at the MOM; a mechanism which is not really understood yet due to lack of high-resolution structural insight. Based on our central hypothesis that Bcl-2 drives its cell-protecting function at a membrane-embedded location as revealed by NR (1), we focus i) to determine the structure of human Bcl-2 protein in its membrane setting by combining solution and solid-state NMR; ii) use NR to study the kinetics and lipid/protein pore assemblied upon binding of Bax to mitochondrial membranes and its membrane destroying activities there; and iii) unravel the nature of direct interaction between Bcl-2 and Bax to neutralize each other. Knowledge generated here, will be indispensable in understanding the regulative function of the Bcl-2 family at mitochondrial membranes.
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| 19. |
- Czeszumski, Artur, et al.
(författare)
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#EEGManyLabs: Investigating the Replicability of Influential EEG Experiments
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There is growing awareness across the neuroscience community that the replicability of findings on the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardized analysis pipelines. Inspired by efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.
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| 20. |
- Hussain, Showket, et al.
(författare)
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Association of cyclin D1 gene polymorphisms with risk of esophageal squamous cell carcinoma in Kashmir Valley : a high risk area
- 2011
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Ingår i: Molecular Carcinogenesis. - : Wiley-Blackwell. - 0899-1987 .- 1098-2744. ; 50:7, s. 487-98
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Tidskriftsartikel (refereegranskat)abstract
- Investigation of potential association of SNPs (G870A, rs9344; G1722C, rs678653) of cyclin D1 gene (CCND1) with susceptibility to esophageal squamous cell carcinoma (ESCC) in Kashmir valley (India). The study included 302 subjects comprising 151 ESCC cases and 151 controls. PCR-RFLP and direct sequencing were employed for genotyping. The G870A polymorphism, the individuals carrying GA + AA genotype was having 2.80-fold increased risk for development of ESCC (OR 2.8, 95% CI = 1.77-4.4; P = 0.0001) compared to GG genotype. Further a significantly higher risk was observed in individuals who consume >3 cups per day of salted tea (OR = 5.1; 95% CI = 1.6-16.7; P = 0.0016) and had smoking habits (OR = 6.3; 95% CI = 2.9-13.9; P = 0.0005). We also demonstrate for the first time in CCND1 1722 locus, the CC genotype was strongly associated with increased risk of developing ESCC (OR = 2.58; 95% CI = 1.61-4.15; P = 0.0001). In addition, the frequency of polymorphic C allele was also found to be higher in cases (OR = 1.92; 95% CI = 1.37-2.69; P = 0.0002). There appears to be an influence of CCND1 G870A/G1772C genotypes on genetic susceptibility to ESCC.
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| 21. |
- Hussain, Showket, et al.
(författare)
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Methylation-mediated gene silencing of suppressor of cytokine signaling-1 (SOCS-1) gene in esophageal squamous cell carcinoma patients of Kashmir valley
- 2011
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Ingår i: Journal of Receptor and Signal Transduction Research. - : Informa Healthcare. - 1079-9893 .- 1532-4281. ; 31:2, s. 147-56
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir. The negative regulation of tumor suppressor gene leading to change in signaling pathway is one of the major mechanisms responsible for tumorigenic transformation.OBJECTIVE: In the present study, the role of silencing of suppressor of cytokine signaling-1 (SOCS-1) gene, a negative regulator of JAK/STAT pathway, was analyzed in ESCC.METHODS: The expression pattern of SOCS-1 gene was analyzed in esophageal tumor biopsies although normal adjacent tissues that served as controls. Reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry, methylation-specific PCR (MSP), and human papillomavirus (HPV) detection were performed to assess the expression pattern and promoter methylation of SOCS-1 gene including HPV status in a total of 75 surgically resected tissue specimens.RESULTS: Compared with the level of SOCS-1 expression in normal tissues, 53% (40/75) of the tumor tissues expressed either undetectable or reduced SOCS-1 expression (>50% loss of expression), which was significantly associated with advanced clinical stage or severe histopathological grade of the disease (P < 0.01). Aberrant promoter methylation of the SOCS-1 gene was found in 45% (34/75) of the esophageal tumor tissues, which was also found to be significantly associated with advanced stage of esophageal carcinoma (P < 0.01). The prevalence of HPV infection was found in 19% of tumor cases, whereas no HPV could be detected in any of the normal adjacent tissues.CONCLUSION: Transcriptional inactivation of SOCS-1 gene, primarily due to its promoter hypermethylation although HPV infection, may play an important role in esophageal carcinogenesis in Kashmir.
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| 22. |
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| 23. |
- Mushtaq, N., et al.
(författare)
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Perovskite SrFe1-xTixO3-δ (x < = 0.1) cathode for low temperature solid oxide fuel cell
- 2018
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Ingår i: Ceramics International. - : Elsevier. - 0272-8842 .- 1873-3956. ; 44:9, s. 10266-10272
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Tidskriftsartikel (refereegranskat)abstract
- Stable and compatible cathode materials are a key factor for realizing the low-temperature (LT, ≤600 °C) operation and practical implementations of solid oxide fuel cells (SOFCs). In this study, perovskite oxides SrFe1-xTixO3-δ (x < = 0.1), with various ratios of Ti doping, are prepared by a sol-gel method for cathode material for LT-SOFCs. The structure, morphology and thermo-gravimetric characteristics of the resultant SFT powders are investigated. It is found that the Ti is successfully doped into SrFeO3-δ to form a single phase cubic perovskite structure and crystal structure of SFT shows better stability than SrFeO3-δ. The dc electrical conductivity and electrochemical properties of SFT are measured and analysed by four-probe and electrochemical impedance spectra (EIS) measurements, respectively. The obtained SFT exhibits a very low polarization resistance (Rp),.01 Ωcm2 at 600◦C. The SFT powders using as cathode in fuel cell devices, exhibit maximum power density of 551 mW cm−2 with open circuit voltage (OCV) of 1.15 V at 600◦C. The good performance of the SFT cathode indicates a high rate of oxygen diffusion through the material at cathode. By enabling operation at low temperatures, SFT cathodes may result in a practical implementation of SOFCs.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Snyder, Joel S., et al.
(författare)
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#EEGManyLabs: Investigating the replicability of influential EEG experiments
- 2021
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Ingår i: Cortex. - : Elsevier. - 1973-8102 .- 0010-9452. ; 144, s. 213-229
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Tidskriftsartikel (refereegranskat)abstract
- There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalog-raphy (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound in-fluence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and se-lection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 28. |
- Ul Mushtaq, Ameeq, et al.
(författare)
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Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation
- 2021
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region. Through neutron reflectometry and NMR spectroscopy studies, Mushtaq et al study the full-length Bcl-2 protein reconstituted in lipid bilayers. They find that, in contrast to previously studied truncated, soluble protein versions, intact Bcl-2 is mainly embedded in the membrane with its regulatory loop highly flexible.
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| 29. |
- Verma, Apoorv, et al.
(författare)
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Insights into the evolution of enzymatic specificity and catalysis : from Asgard archaea to human adenylate kinases
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:44
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Tidskriftsartikel (refereegranskat)abstract
- Enzymatic catalysis is critically dependent on selectivity, active site architecture, and dynamics. To contribute insights into the interplay of these properties, we established an approach with NMR, crystallography, and MD simulations focused on the ubiquitous phosphotransferase adenylate kinase (AK) isolated from Odinarchaeota (OdinAK). Odinarchaeota belongs to the Asgard archaeal phylum that is believed to be the closest known ancestor to eukaryotes. We show that OdinAK is a hyperthermophilic trimer that, contrary to other AK family members, can use all NTPs for its phosphorylation reaction. Crystallographic structures of OdinAK-NTP complexes revealed a universal NTP-binding motif, while 19F NMR experiments uncovered a conserved and rate-limiting dynamic signature. As a consequence of trimerization, the active site of OdinAK was found to be lacking a critical catalytic residue and is therefore considered to be "atypical." On the basis of discovered relationships with human monomeric homologs, our findings are discussed in terms of evolution of enzymatic substrate specificity and cold adaptation.
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| 30. |
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