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Viruses Apr 2021The ubiquitin-proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary... (Review)
Review
The ubiquitin-proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary proteins from the (HIV-1) divert this system to its own advantage, notably to induce the degradation of cellular restriction factors. For instance, the HIV-1 viral infectivity factor (Vif) has been shown to specifically counteract several cellular deaminases belonging to the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 or A3) family (A3A to A3H) by recruiting an E3-ubiquitin ligase complex and inducing their polyubiquitination and degradation through the proteasome. Although this pathway has been extensively characterized so far, Vif has also been shown to impede A3s through degradation-independent processes, but research on this matter remains limited. In this review, we describe our current knowledge regarding the degradation-independent inhibition of A3s, and A3G in particular, by the HIV-1 Vif protein, the molecular mechanisms involved, and highlight important properties of this small viral protein.
Topics: APOBEC-3G Deaminase; HIV Infections; HIV-1; Host Microbial Interactions; Humans; Proteasome Endopeptidase Complex; Protein Binding; Ubiquitin; vif Gene Products, Human Immunodeficiency Virus
PubMed: 33916704
DOI: 10.3390/v13040617 -
Musculoskeletal Surgery Dec 2021Loosening is considered as a main cause of implant failure in total knee replacement (TKR). Among the predictive signs of loosening, migration is the most investigated... (Review)
Review
Loosening is considered as a main cause of implant failure in total knee replacement (TKR). Among the predictive signs of loosening, migration is the most investigated quantitative parameter. Several studies focused on the migration of the tibial component in TKR, while no reviews have been focused on the migration of the femoral component and its influence on patients' clinical outcomes. The aim of this narrative review was (1) to provide information about of the influence of migration in femoral component of TKR prostheses, (2) to assess how migration may affect patient clinical outcomes and (3) to present alternative solution to the standard cobalt-chrome prostheses. A database search was performed on PubMed Central® according to the PRISMA guidelines for studies about Cobalt-Chrome femoral component migration in people that underwent primary TKR published until May 2020. Overall, 18 articles matched the selection criteria and were included in the study. Few studies investigated the femoral component through the migration, and no clear migration causes emerged. The Roentgen Stereophotogrammetric Analysis has been mostly used to assess the migration for prognostic predictions. An annual migration of 0.10 mm seems compatible with good long-term performance and good clinical and functional outcomes. An alternative solution to cobalt-chrome prostheses is represented by femoral component in PEEK material, although no clinical evaluations have been carried out on humans yet. Further studies are needed to investigate the migration of the femoral component in relation to clinical outcomes and material used.
Topics: Arthroplasty, Replacement, Knee; Chromium Alloys; Humans; Knee Prosthesis; Prosthesis Design; Prosthesis Failure; Tibia
PubMed: 33315156
DOI: 10.1007/s12306-020-00690-8 -
Translational Lung Cancer Research Oct 2014The clinical expectations how pathologists should submit lung cancer diagnosis have changed dramatically. Until mid 90-ties a clear separation between small cell lung... (Review)
Review
The clinical expectations how pathologists should submit lung cancer diagnosis have changed dramatically. Until mid 90-ties a clear separation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) was mostly sufficient. With the invention of antiangiogenic treatment a differentiation between squamous and non-squamous NSCLC was requested. When epidermal growth factor receptor (EGFR) mutation was detected in patients with pulmonary adenocarcinomas and subsequent specific treatment with tyrosine kinase inhibitors (TKIs) was invented, sub-classification of NSCLC and molecular analysis of the tumor tissue for mutations was asked for. Pathologists no longer submit just a diagnosis, but instead are involved in a multidisciplinary team for lung cancer patient management. After EGFR several other driver genes such as echinoderm microtubule associated protein like 4-AL-Kinase 1 (EML4-ALK1), c-ros oncogene 1, receptor tyrosine kinase (ROS1), discoidin domain receptor tyrosine kinase 2 (DDR2), fibroblast growth factor receptor 1 (FGFR1) were discovered, and more to come. Due to new developments in bronchology (EUS, EBUS) the amount of tissue submitted for diagnosis and molecular analysis is decreasing, however, the genes to be analyzed are increasing. Many of these driver gene aberrations are inversions or translocations and thus require FISH analysis. Each of these analyses requires a certain amount of tumor cells or one to two tissue sections from an already limited amount of tissues or cells. In this respect new genetic test systems have been introduced such as next generation sequencing, which enables not only to detect multiple mutations in different genes, but also amplifications and fusion genes. As soon as these methods have been validated for routine molecular analysis this will enable the analysis of multiple genetic changes simultaneously. In this review we will focus on genetic aberrations in NSCLC, resistance to new target therapies, and also to methodological requirements for a meaningful evaluation of lung cancer tissue and cells.
PubMed: 25806314
DOI: 10.3978/j.issn.2218-6751.2014.10.01 -
Radiology. Cardiothoracic Imaging Feb 2022To assess the technical success and complication rates of CT-guided fiducial marker placement for the localization of pulmonary nodules and to assess the surgical...
PURPOSE
To assess the technical success and complication rates of CT-guided fiducial marker placement for the localization of pulmonary nodules and to assess the surgical localization failure rate.
MATERIALS AND METHODS
This was a single-center, retrospective analysis of consecutive patients who underwent CT-guided fiducial marker placement procedures between 2014 and 2020. End points included the technical success of the fiducial marker placement, procedural complications, and the surgical localization failure rate. A two-sample test and a Fisher exact test were used to compare continuous and categorical variables, respectively. Multivariate logistic regression was used to identify independent risk factors for complications.
RESULTS
A total of 198 preoperative CT-guided fiducial marker placement procedures were performed in 190 patients (mean age, 64 years ± 12 [standard deviation]; 121 women) to localize 205 nodules (mean size, 10 mm ± 4; mean distance to the pleura, 10 mm ± 9). The technical success rate was 98.5% (195 of 198). There were no major complications. A total of 202 nodules were resected during 193 procedures performed 5 days ± 13 after the fiducial marker placement (range, 0-123 days). Surgical localization failure occurred in one patient (0.5%). Of the resected nodules, 146 were lung cancers, 26 nodules were metastases, two were carcinoid tumors, and 28 were benign.
CONCLUSION
The CT-guided fiducial marker placement of pulmonary nodules was safe, effective, and resulted in a low surgical localization failure rate. CT, Percutaneous, Thorax, Lung.
PubMed: 35782764
DOI: 10.1148/ryct.210194 -
Physica Medica : PM : An International... Jun 2023Dosimetric characteristics of 3D-printed plates using different infill percentage and materials was the purpose of our study.
PURPOSE
Dosimetric characteristics of 3D-printed plates using different infill percentage and materials was the purpose of our study.
METHODS
Test plates with 5%, 10%, 15% and 20% honeycomb structure infill were fabricated using TPU and PLA polymers. The Hounsfield unit distribution was determined using a Python script. Percentage Depth Dose (PDD) distribution in the build-up region was measured with the Markus plane-parallel ionization chamber for an open 10x10 cm field of 6 MV. PDD was measured at a depth of 1 mm, 5 mm, 10 mm and 15 mm. Measurements were compared with Eclipse treatment planning system calculations using AAA and Acuros XB algorithms.
RESULTS
The mean HU for CT scans of 3D-printed TPU plates increased with percentage infill increase from -739 HU for 5% to -399 HU for 20%. Differences between the average HU for TPU and PLA did not exceed 2% for all percentage infills. Even using a plate with the lowest infill PDD at 1 mm depth increase from 44.7% (without a plate) to 76.9% for TPU and 76.6% for PLA. Infill percentage did not affect the dose at depths greater than 5 mm. Differences between measurements and TPS calculations were less than 4.1% for both materials, regardless of the infill percentage and depth.
CONCLUSIONS
The use of 3D-printed light boluses increases the dose in the build-up region, which was shown based on the dosimetric measurements and TPS calculations.
Topics: Radiometry; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Printing, Three-Dimensional; Polyesters; Phantoms, Imaging
PubMed: 37167778
DOI: 10.1016/j.ejmp.2023.102600 -
Current Oncology (Toronto, Ont.) Feb 2024Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific... (Review)
Review
Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.
Topics: Humans; Nanomedicine; Melanoma; Immunotherapy; Molecular Biology; Uveal Neoplasms
PubMed: 38392052
DOI: 10.3390/curroncol31020058 -
BioRxiv : the Preprint Server For... Nov 2022Eukaryotic cell-free protein synthesis (CFPS) systems have the potential to simplify and speed up the expression and high-throughput analysis of complex proteins with...
Eukaryotic cell-free protein synthesis (CFPS) systems have the potential to simplify and speed up the expression and high-throughput analysis of complex proteins with functionally relevant post-translational modifications (PTMs). However, low yields and the inability to scale such systems have so far prevented their widespread adoption in protein research and manufacturing. Here, we present a detailed demonstration for the capabilities of a CFPS system derived from BY-2 cell culture (BY-2 lysate; BYL). BYL is able to express diverse, functional proteins at high yields in under 48 hours, complete with native disulfide bonds and N-glycosylation. An optimised version of the technology is commercialised as 'ALiCE ', engineered for high yields of up to 3 mg/mL. Recent advances in the scaling of BYL production methodologies have allowed scaling of the CFPS reaction. We show simple, linear scale-up of batch mode reporter proten expression from a 100 μL microtiter plate format to 10 mL and 100 mL volumes in standard Erlenmeyer flasks, culminating in preliminary data from 1 L reactions in a CELL-tainer® CT20 rocking motion bioreactor. As such, these works represent the first published example of a eukaryotic CFPS reaction scaled past the 10 mL level by several orders of magnitude. We show the ability of BYL to produce the simple reporter protein eYFP and large, multimeric virus-like particles directly in the cytosolic fraction. Complex proteins are processed using the native microsomes of BYL and functional expression of multiple classes of complex, difficult-to-express proteins is demonstrated, specifically: a dimeric, glycoprotein enzyme, glucose oxidase; the monoclonal antibody adalimumab; the SARS-Cov-2 receptor-binding domain; human epidermal growth factor; and a G protein-coupled receptor membrane protein, cannabinoid receptor type 2. Functional binding and activity are shown using a combination of surface plasmon resonance techniques, a serology-based ELISA method and a G protein activation assay. Finally, in-depth post-translational modification (PTM) characterisation of purified proteins through disulfide bond and N-glycan analysis is also revealed - previously difficult in the eukaryotic CFPS space due to limitations in reaction volumes and yields. Taken together, BYL provides a real opportunity for screening of complex proteins at the microscale with subsequent amplification to manufacturing-ready levels using off-the-shelf protocols. This end-to-end platform suggests the potential to significantly reduce cost and the time-to-market for high value proteins and biologics.
PubMed: 36380753
DOI: 10.1101/2022.11.10.515920 -
RoFo : Fortschritte Auf Dem Gebiete Der... Mar 2017This joint consensus paper of the German Roentgen Society and the German Cardiac Society provides physical and electrophysiological background information and specific...
This joint consensus paper of the German Roentgen Society and the German Cardiac Society provides physical and electrophysiological background information and specific recommendations for the procedural management of patients with cardiac pacemakers (PM) and implantable cardioverter defibrillators (ICD) undergoing magnetic resonance (MR) imaging. The paper outlines the responsibilities of radiologists and cardiologists regarding patient education, indications, and monitoring with modification of MR sequences and PM/ICD reprogramming strategies being discussed in particular. The aim is to optimize patient safety and to improve legal clarity in order to facilitate the access of SM/ICD patients to MR imaging. · Conventional PM and ICD systems are no longer an absolute but rather a relative contraindication for performing an MR examination. Procedural management includes the assessment of the individual risk/benefit ratio, comprehensive patient informed consent about specific risks and "off label" use, extensive PM/ICD-related and MR-related safety precautions to reduce these risks to the greatest extent possible, as well as adequate monitoring techniques.. · MR conditional pacemaker and ICD systems have been tested and approved for MR examination under specific conditions ("in-label" use). Precise understanding of and compliance with the terms of use for the specific pacemaker system are essential for patient safety.. · The risk for an ICD patient during MR examinations is to be considered significantly higher compared to PM patients due to the higher vulnerability of the structurally damaged myocardium and the higher risk of irreversible damage to conventional ICD systems. The indication for a MR examination of an ICD patient should therefore be determined on a stricter basis and the expected risk/benefit ratio should be critically reviewed.. · This complex subject requires close collaboration between radiology and cardiology.. · Sommer T, Bauer W, Fischbach K et al. MR Imaging in Patients with Cardiac Pacemakers and Implantable Cardioverter Defibrillators. Fortschr Röntgenstr 2017; 189: 204 - 217.
Topics: Cardiology; Contraindications; Defibrillators, Implantable; Germany; Humans; Informed Consent; Magnetic Resonance Imaging; Pacemaker, Artificial; Patient Education as Topic; Practice Guidelines as Topic
PubMed: 28201839
DOI: 10.1055/s-0043-102029 -
Scientific Reports Jun 2022Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85-95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R,...
Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85-95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18-59) years, and 60% were female. With a median (range) follow up of 9 (1-17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography-computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Positron Emission Tomography Computed Tomography; Rituximab; Vincristine
PubMed: 35732790
DOI: 10.1038/s41598-022-14067-3 -
International Journal of Legal Medicine Nov 2023The AGFAD (Arbeitsgemeinschaft für Forensische Alterdiagnostik, Study Group on Forensic Age Diagnostics) has published several recommendations regarding both technical... (Review)
Review
The AGFAD (Arbeitsgemeinschaft für Forensische Alterdiagnostik, Study Group on Forensic Age Diagnostics) has published several recommendations regarding both technical aspects of computed tomography (CT) of the medial clavicular epiphysis (MCE) and the process of reading and interpreting the CT images for forensic age estimations (FAE). There are, however, no published recommendations regarding CT scan protocols and no dose reference values for CT of the MCE. The objective of this analysis was to assess adherence to AGFAD recommendations among practitioners of FAE and analyse reported dose-relevant CT scan parameters with the objective of helping to establish evidence-based dose reference values for FAE. A systematic literature search was conducted in PubMed and in Google Scholar with specific MeSH terms to identify original research articles on FAE with CT of the MCE from 1997 to 2022. A total of 48 studies were included. Adherence to AGFAD recommendations among practitioners of FAE is high regarding the use of Schmeling main stages (93%), bone window (79%), ≤ 1 mm CT slices (67%), axial/coronal CT images (65%), and Kellinghaus sub-stages (59%). The reporting of CT technique and CT dose-relevant scan parameters is heterogeneous and often incomplete in the current literature. Considering the success achieved by the AGFAD in creating standards of practice of FAE in living subjects, there is potential for the AGFAD to establish standards for radiation protection in FAE as well.
Topics: Humans; Age Determination by Skeleton; Clavicle; Epiphyses; Tomography, X-Ray Computed; Radiation Dosage; Guideline Adherence; Forensic Anthropology
PubMed: 37691040
DOI: 10.1007/s00414-023-03061-7