| 1. |
- Jayne, David R W, et al.
(författare)
-
Glomerulonephritides.
- 2014
-
Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3, s. 27-29
-
Konferensbidrag (refereegranskat)
|
|
| 2. |
- Kumar, Manish, et al.
(författare)
-
MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway.
- 2015
-
Ingår i: Cell host & microbe. - : elsevier. - 1934-6069 .- 1931-3128. ; 17:3, s. 345-56
-
Tidskriftsartikel (refereegranskat)abstract
- The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-κB pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1β, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1β. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.
|
|
| 3. |
- Sahu, Sanjaya Kumar, et al.
(författare)
-
MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBP beta regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection
- 2017
-
Ingår i: PLoS Pathogens. - : Public Library Science. - 1553-7366 .- 1553-7374. ; 13:5
-
Tidskriftsartikel (refereegranskat)abstract
- For efficient clearance of Mycobacterium tuberculosis (Mtb), macrophages tilt towards M1 polarization leading to the activation of transcription factors associated with the production of antibacterial effector molecules such as nitric oxide (NO) and proinflammatory cytokines such as interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha). At the same time, resolution of inflammation is associated with M2 polarization with increased production of arginase and cytokines such as IL-10. The transcriptional and post-transcriptional mechanisms that govern the balance between M1 and M2 polarization, and bacteria-containing processes such as autophagy and trafficking of Mtb to lysosomes, are incompletely understood. Here we report for the first time, that the transcription factor KLF4 is targeted by microRNA-26a (miR-26a). During Mtb infection, downregulation of miR-26a (observed both ex vivo and in vivo) facilitates upregulation of KLF4 which in turn favors increased arginase and decreased iNOS activity. We further demonstrate that KLF4 prevents trafficking of Mtb to lysosomes. The CREB-C/EBP beta signaling axis also favors M2 polarization. Downregulation of miR-26a and upregulation of C/ebpbeta were observed both in infected macrophages as well as in infected mice. Knockdown of C/ebpbeta repressed the expression of selected M2 markers such as Il10 and Irf4 in infected macrophages. The importance of these pathways is substantiated by observations that expression of miR-26a mimic or knockdown of Klf4 or Creb or C/ebpbeta, attenuated the survival of Mtb in macrophages. Taken together, our results attribute crucial roles for the miR-26a/KLF4 and CREB-C/EBP beta signaling pathways in regulating the survival of Mtb in macrophages. These studies expand our understanding of how Mtb hijacks host signaling pathways to survive in macrophages, and open up new exploratory avenues for host-targeted interventions.
|
|
| 4. |
- Bender, Brendan C., 1967-, et al.
(författare)
-
A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
- 2012
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 70:4, s. 591-601
-
Tidskriftsartikel (refereegranskat)abstract
- Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEMA (R) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. The model described the platelet data well and predicted the incidence of grade a parts per thousand yen3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the similar to 8 % incidence of grade a parts per thousand yen3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.
|
|
| 5. |
- Blanco, Ana Maria, et al.
(författare)
-
Impact of flat-top voltage waveform distortion on harmonic current emission and summation of electronic household appliances
- 2018
-
Ingår i: The Renewable Energies and Power Quality Journal. - : EA4EPQ-European Association for the Development of Renewable Energy, Environment and Power Quality. - 2172-038X. ; 1:16, s. 698-703
-
Tidskriftsartikel (refereegranskat)abstract
- Electronic household appliances are non-linear loads and emit harmonics into the low voltage networks. Usually, these loads are simply modelled by constant current source models, which only represent the harmonic emission of the appliances for a single supply voltage distortion, mostly sinusoidal conditions. Measurements have shown that the harmonic currents emitted by electronic devices can significantly depend on the circuit topology and the existing supply voltage distortion. This paper studies the impact of supply voltage distortion, which can be typically found in public low voltage networks (so-called flat-top voltage waveform), on the harmonic current emission of individual devices with different circuit topologies as well as the impact of supply voltage distortion on the harmonic summation of these devices.
|
|
| 6. |
- Bransford, Philip, et al.
(författare)
-
ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers : An Industrial Perspective from the IQ Consortium
- 2020
-
Ingår i: Molecular Pharmaceutics. - : AMER CHEMICAL SOC. - 1543-8384 .- 1543-8392. ; 17:2, s. 361-372
-
Tidskriftsartikel (refereegranskat)abstract
- In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.
|
|
| 7. |
- Deswal, Renu, et al.
(författare)
-
Plant proteomics in India and Nepal : Current status and challenges ahead
- 2013
-
Ingår i: Physiology and Molecular Biology of Plants. - : Springer-Verlag New York. - 0971-5894 .- 0974-0430. ; 19:4, s. 461-477
-
Forskningsöversikt (refereegranskat)abstract
- Plant proteomics has made tremendous contributions in understanding the complex processes of plant biology. Here, its current status in India and Nepal is discussed. Gel-based proteomics is predominantly utilized on crops and non-crops to analyze majorly abiotic (49 %) and biotic (18 %) stress, development (11 %) and post-translational modifications (7 %). Rice is the most explored system (36 %) with major focus on abiotic mainly dehydration (36 %) stress. In spite of expensive proteomics setup and scarcity of trained workforce, output in form of publications is encouraging. To boost plant proteomics in India and Nepal, researchers have discussed ground level issues among themselves and with the International Plant Proteomics Organization (INPPO) to act in priority on concerns like food security. Active collaboration may help in translating this knowledge to fruitful applications.
|
|
| 8. |
|
|
| 9. |
- Jung, Christian, et al.
(författare)
-
A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
-
Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
|
|
| 10. |
- Kim, Min Seo, et al.
(författare)
-
Global burden of peripheral artery disease and its risk factors, 1990-2019 : a systematic analysis for the Global Burden of Disease Study 2019
- 2023
-
Ingår i: The Lancet Global Health. - : Elsevier. - 2214-109X. ; 11:10, s. E1553-E1565
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures.Methods: Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed.Findings: In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99 center dot 2-128 center dot 4), with a global prevalence of 1 center dot 52% (95% UI 1 center dot 33-1 center dot 72), of which 42 center dot 6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14 center dot 91% [12 center dot 41-17 center dot 87] in those aged 80-84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69 center dot 4% (64 center dot 2-74 center dot 3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles.Interpretation: The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors.
|
|
