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Life, Volume 11, Issue 11 (November 2021) – 171 articles

Cover Story (view full-size image): The receptor tyrosine kinase HER2 is strongly overexpressed on different tumors and is an established target of drugs designed to overcome the HER2 addiction. A biparatopic symmetric antibody, composed of pertuzumab Fab and an anti-HER2 Fc fragment with a novel antigen binding site (Fcab), induced a potent antiproliferative effect on HER2-overexpressing cell line, accompanied with a rapid reduction of HER2 surface levels. This could not be achieved with the mixture of pertuzumab and standalone Fcab, indicating that the incorporation of both HER2-reactive epitopes in one molecule was necessary to trigger cell death. Increased numbers of apoptotic cells certified that the effect of the bispecific molecule is cytotoxic and leads to efficient eradication of HER2-overexpressing cells. View this paper
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Article
COVID-19 and Artificial Intelligence: An Approach to Forecast the Severity of Diagnosis
Life 2021, 11(11), 1281; https://doi.org/10.3390/life11111281 - 22 Nov 2021
Cited by 3 | Viewed by 1518
Abstract
(1) Background: The new SARS-COV-2 pandemic overwhelmed intensive care units, clinicians, and radiologists, so the development of methods to forecast the diagnosis’ severity became a necessity and a helpful tool. (2) Methods: In this paper, we proposed an artificial intelligence-based multimodal approach to [...] Read more.
(1) Background: The new SARS-COV-2 pandemic overwhelmed intensive care units, clinicians, and radiologists, so the development of methods to forecast the diagnosis’ severity became a necessity and a helpful tool. (2) Methods: In this paper, we proposed an artificial intelligence-based multimodal approach to forecast the future diagnosis’ severity of patients with laboratory-confirmed cases of SARS-CoV-2 infection. At hospital admission, we collected 46 clinical and biological variables with chest X-ray scans from 475 COVID-19 positively tested patients. An ensemble of machine learning algorithms (AI-Score) was developed to predict the future severity score as mild, moderate, and severe for COVID-19-infected patients. Additionally, a deep learning module (CXR-Score) was developed to automatically classify the chest X-ray images and integrate them into AI-Score. (3) Results: The AI-Score predicted the COVID-19 diagnosis’ severity on the testing/control dataset (95 patients) with an average accuracy of 98.59%, average specificity of 98.97%, and average sensitivity of 97.93%. The CXR-Score module graded the severity of chest X-ray images with an average accuracy of 99.08% on the testing/control dataset (95 chest X-ray images). (4) Conclusions: Our study demonstrated that the deep learning methods based on the integration of clinical and biological data with chest X-ray images accurately predicted the COVID-19 severity score of positive-tested patients. Full article
(This article belongs to the Special Issue Old and New Pandemics: Challenges for Humans)
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Article
Detection of pks Island mRNAs Using Toehold Sensors in Escherichia coli
Life 2021, 11(11), 1280; https://doi.org/10.3390/life11111280 - 22 Nov 2021
Cited by 2 | Viewed by 1345
Abstract
Synthetic biologists have applied biomolecular engineering approaches toward the goal of novel biological devices and have shown progress in diverse areas of medicine and biotechnology. Especially promising is the application of synthetic biological devices towards a novel class of molecular diagnostics. As an [...] Read more.
Synthetic biologists have applied biomolecular engineering approaches toward the goal of novel biological devices and have shown progress in diverse areas of medicine and biotechnology. Especially promising is the application of synthetic biological devices towards a novel class of molecular diagnostics. As an example, a de-novo-designed riboregulator called toehold switch, with its programmability and compatibility with field-deployable devices showed promising in vitro applications for viral RNA detection such as Zika and Corona viruses. However, the in vivo application of high-performance RNA sensors remains challenging due to the secondary structure of long mRNA species. Here, we introduced ‘Helper RNAs’ that can enhance the functionality of toehold switch sensors by mitigating the effect of secondary structures around a target site. By employing the helper RNAs, previously reported mCherry mRNA sensor showed improved fold-changes in vivo. To further generalize the Helper RNA approaches, we employed automatic design pipeline for toehold sensors that target the essential genes within the pks island, an important target of biomedical research in connection with colorectal cancer. The toehold switch sensors showed fold-changes upon the expression of full-length mRNAs that apparently depended sensitively on the identity of the gene as well as the predicted local structure within the target region of the mRNA. Still, the helper RNAs could improve the performance of toehold switch sensors in many instances, with up to 10-fold improvement over no helper cases. These results suggest that the helper RNA approaches can further assist the design of functional RNA devices in vivo with the aid of the streamlined automatic design software developed here. Further, our solutions for screening and stabilizing single-stranded region of mRNA may find use in other in vivo mRNA-sensing applications such as cas13 crRNA design, transcriptome engineering, and trans-cleaving ribozymes. Full article
(This article belongs to the Special Issue Synthetic Genetic Elements, Devices, and Systems)
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Review
HPV and Recurrent Respiratory Papillomatosis: A Brief Review
Life 2021, 11(11), 1279; https://doi.org/10.3390/life11111279 - 22 Nov 2021
Cited by 5 | Viewed by 1872
Abstract
Recurrent Respiratory Papillomatosis (RRP) is a rare but severe manifestation of human papillomavirus (HPV). As our knowledge about HPV infections has expanded, it has become possible to understand the course of RRP disease and unravel plausible efficient methods to manage the disease. However, [...] Read more.
Recurrent Respiratory Papillomatosis (RRP) is a rare but severe manifestation of human papillomavirus (HPV). As our knowledge about HPV infections has expanded, it has become possible to understand the course of RRP disease and unravel plausible efficient methods to manage the disease. However, the surge in reports on HPV has not been accompanied by a similar increase in research about RRP specifically. In this paper, we review the clinical manifestation and typical presentation of the illness. In addition, the pathogenesis and progression of the disease are described. On the other hand, we discuss the types of treatments currently available and future treatment strategies. The role of vaccination in both the prevention and treatment of RRP will also be reviewed. We believe this review is essential to update the general knowledge on RRP with the latest information available to date to enhance our understanding of RRP and its management. Full article
(This article belongs to the Special Issue Microbiome of the Respiratory Tract)
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Article
The Influence of Depression on Biased Diagnosis of Premenstrual Syndrome and Premenstrual Dysphoric Disorder by the PSST Inventory
Life 2021, 11(11), 1278; https://doi.org/10.3390/life11111278 - 22 Nov 2021
Cited by 3 | Viewed by 1333
Abstract
The diagnosis of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) poses a challenge for clinicians due to the overdiagnosis of retrospective methods and overlapping symptoms with depression. The present study utilized an Item Response Theory analysis to examine the predictive utility of [...] Read more.
The diagnosis of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) poses a challenge for clinicians due to the overdiagnosis of retrospective methods and overlapping symptoms with depression. The present study utilized an Item Response Theory analysis to examine the predictive utility of the Premenstrual Symptom Screening Tool (PSST) in women with and without depression. Two hundred and fifteen women aged 20–35 completed the PSST, a daily symptom calendar, SCID-I, and CES-D for two consecutive menstrual cycles. PSST items: fatigue, depressed mood, feeling overwhelmed, anxiety/tension, and decreased interest in everyday activities were the best predictors of PMS. Unlike the daily symptom ratings, the PSST over-diagnosed PMS/PMDD in the depressed group but not in the group of women without PMS/PMDD. While diagnosing premenstrual disorders, clinicians should be aware that a retrospective diagnosis with PSST can be more sensitive to mood disorders and cycle phases than a prospective diagnosis with a daily symptoms calendar. Full article
(This article belongs to the Special Issue Depressive Disorders-New Challenges)
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Systematic Review
Treatment-Related Adverse Events with PD-1 or PD-L1 Inhibitors: A Systematic Review and Meta-Analysis
Life 2021, 11(11), 1277; https://doi.org/10.3390/life11111277 - 22 Nov 2021
Cited by 3 | Viewed by 1278
Abstract
Objective: to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. Methods: randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science [...] Read more.
Objective: to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. Methods: randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed. Results: a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85–2.96), rash (RR: 1.53, 95% CI: 1.25–1.87), ALT elevation (RR 1.54, 95% CI 1.23–1.92), AST elevation (AST: RR 1.49, 95% CI 1.20–1.85), hepatitis (RR: 3.54, 95% CI: 1.96–6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00–6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21–1.48), dyspnea (RR:1.23, 95% CI: 1.12–1.35) and chest pain (RR: 1.26, 95% CI: 1.07–1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13–2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10–1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45–0.70) compared with that of chemotherapy. Conclusions: our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration. Full article
(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Effect of Drugs in Cancer)
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Article
Short-Term Effect of Induced Alterations in Testosterone Levels on Fasting Plasma Amino Acid Levels in Healthy Young Men
Life 2021, 11(11), 1276; https://doi.org/10.3390/life11111276 - 22 Nov 2021
Cited by 2 | Viewed by 1254
Abstract
Long term effect of testosterone (T) deficiency impairs metabolism and is associated with muscle degradation and metabolic disease. The association seems to have a bidirectional nature and is not well understood. The present study aims to investigate the early and unidirectional metabolic effect [...] Read more.
Long term effect of testosterone (T) deficiency impairs metabolism and is associated with muscle degradation and metabolic disease. The association seems to have a bidirectional nature and is not well understood. The present study aims to investigate the early and unidirectional metabolic effect of induced T changes by measuring fasting amino acid (AA) levels in a human model, in which short-term T alterations were induced. We designed a human model of 30 healthy young males with pharmacologically induced T changes, which resulted in three time points for blood collection: (A) baseline, (B) low T (3 weeks post administration of gonadotropin releasing hormone antagonist) and (C) restored T (2 weeks after injection of T undecanoate). The influence of T on AAs was analyzed by spectrophotometry on plasma samples. Levels of 9 out of 23 AAs, of which 7 were essential AAs, were significantly increased at low T and are restored upon T supplementation. Levels of tyrosine and phenylalanine were most strongly associated to T changes. Short-term effect of T changes suggests an increased protein breakdown that is restored upon T supplementation. Fasting AA levels are able to monitor the early metabolic changes induced by the T fluctuations. Full article
(This article belongs to the Section Medical Research)
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Review
The Interplay of Nutriepigenomics, Personalized Nutrition and Clinical Practice in Managing Food Allergy
Life 2021, 11(11), 1275; https://doi.org/10.3390/life11111275 - 22 Nov 2021
Viewed by 1618
Abstract
Food allergy in children has been a common issue due to the challenges of prescribing personalized nutrition with a lack of nutriepigenomics data. This has indeed further influenced clinical practice for appropriate management. While allergen avoidance is still the main principle in food [...] Read more.
Food allergy in children has been a common issue due to the challenges of prescribing personalized nutrition with a lack of nutriepigenomics data. This has indeed further influenced clinical practice for appropriate management. While allergen avoidance is still the main principle in food allergy management, we require more information to advance the science behind nutrition, genes, and the immune system. Many researchers have highlighted the importance of personalized nutrition but there is a lack of data on how the decision is made. Thus, this review highlights the relationship among these key players in identifying the solution to the clinical management of food allergy with current nutriepigenomics data. The discussion integrates various inputs, including clinical assessments, biomarkers, and epigenetic information pertaining to food allergy, to curate a holistic and personalized approach to food allergy management in particular. Full article
(This article belongs to the Special Issue Pediatric Nutrition for a Healthy Life)
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Review
Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition
Life 2021, 11(11), 1269; https://doi.org/10.3390/life11111269 - 22 Nov 2021
Cited by 12 | Viewed by 2299
Abstract
Cells have the ability to adapt to stressful environments as a part of their evolution. Physical exercise induces an increase of a demand for energy that must be met by mitochondria as the main (ATP) provider. However, this process leads to the increase [...] Read more.
Cells have the ability to adapt to stressful environments as a part of their evolution. Physical exercise induces an increase of a demand for energy that must be met by mitochondria as the main (ATP) provider. However, this process leads to the increase of free radicals and the so-called reactive oxygen species (ROS), which are necessary for the maintenance of cell signaling and homeostasis. In addition, mitochondrial biogenesis is influenced by exercise in continuous crosstalk between the mitochondria and the nuclear genome. Excessive workloads may induce severe mitochondrial stress, resulting in oxidative damage. In this regard, the objective of this work was to provide a general overview of the molecular mechanisms involved in mitochondrial adaptation during exercise and to understand if some nutrients such as antioxidants may be implicated in blunt adaptation and/or an impact on the performance of exercise by different means. Full article
(This article belongs to the Special Issue Mitochondrial Function and Signaling to Regulate Cellular Life)
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Editorial
Special Issue “Reproductive Health Concerns for Women”
Life 2021, 11(11), 1274; https://doi.org/10.3390/life11111274 - 21 Nov 2021
Cited by 3 | Viewed by 803
Abstract
There are specific health issues concerning the reproductive age of women, including inflammatory disease, fertility, and childbearing [...] Full article
(This article belongs to the Special Issue Reproductive Health Concerns for Women)
Article
A Potential Serum Biomarker for Screening Lung Cancer Risk in High Level Environmental Radon Areas: A Pilot Study
Life 2021, 11(11), 1273; https://doi.org/10.3390/life11111273 - 21 Nov 2021
Cited by 3 | Viewed by 1085
Abstract
Radon is a major cause of lung cancer (LC) deaths among non-smokers worldwide. However, no serum biomarker for screening of LC risk in high residential radon (HRR) areas is available. Therefore, the aim of this study was to determine diagnostic values of serum [...] Read more.
Radon is a major cause of lung cancer (LC) deaths among non-smokers worldwide. However, no serum biomarker for screening of LC risk in high residential radon (HRR) areas is available. Therefore, the aim of this study was to determine diagnostic values of serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment (Cyfra21-1), human epididymis protein 4 (HE4), interleukin 8 (IL-8), migration inhibitory factor (MIF), tumor nuclear factor-alpha (TNF-α) and vascular endothelial growth factors (VEGF) occurring in high radon areas. Seventy-five LC non-smoker patients and seventy-five healthy controls (HC) were enrolled in this study. Among the HC groups, twenty-five HC were low residential radon (LRR) and fifty HC were HRR. Significantly higher (p < 0.0004) serum levels of CEA, Cyfra21-1, IL-8 and VEGF were found in the LC compared with the LRR and HRR groups. More importantly, significantly higher levels (p < 0.009) of serum CEA, Cyfra21-1 and IL-8 were observed in HRR compared with the LRR group. Likewise, a ROC curve demonstrated that serum CEA and Cyfra21-1 could better distinguish LC risk from HRR groups than IL-8. These results indicated that serum CEA and Cyfra21-1 were significantly increased in the HRR group and may be considered as potential biomarkers for individuals at high-risk to develop LC. Full article
(This article belongs to the Special Issue Radioactive Pollution and Biological Effects of Radioactivity)
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Article
Ovarian Malignancies Frequency in the Female Population from the Bryansk Region Living in Conditions of Radioactive, Chemical and Combine Contamination (2000–2020)
Life 2021, 11(11), 1272; https://doi.org/10.3390/life11111272 - 21 Nov 2021
Cited by 1 | Viewed by 870
Abstract
Background: Radioactive contamination and chemical pollution of the environment can affect the processes of carcinogenesis, including the formation of malignant neoplasms of the ovaries in women. We used the data of official state statistics for 2000–2020 to test the hypothesis about the effect [...] Read more.
Background: Radioactive contamination and chemical pollution of the environment can affect the processes of carcinogenesis, including the formation of malignant neoplasms of the ovaries in women. We used the data of official state statistics for 2000–2020 to test the hypothesis about the effect of radioactive contamination (following the Chernobyl disaster) and chemical pollutants on the incidence of ovarian malignancies in the female population of the Bryansk region. Methods: A variety of statistical approaches were used to estimate the incidence of ovarian malignancies, including the Shapiro–Wilk test, Mann–Whitney U test, Spearman’s rank correlation test and linear regression. Results: We did not establish statistically significant differences in the frequency of primary morbidity of women with malignant neoplasms of the ovaries, regardless of the environmental conditions of living. Furthermore, no significant correlations were found between the frequency of primary morbidity of ovarian malignancies, both with the level of contamination by Cesium-137 and Strontium-90, and air pollution with volatile organic compounds, carbon monoxide, sulfur dioxide and nitrogen oxides. A statistically significant increase in the long-term trend in the frequency of ovarian malignant neoplasms was revealed in the areas of chemical pollution (p = 0.02), however, in other territories, no statistically significant regularities were established. The forecast of the frequency of newly diagnosed malignant neoplasms of the ovaries on average in the Bryansk region shows an increase of 12.4% in 2020 in comparison with the real data for 2020, while the largest increase in predicted values is recorded in the territories of radioactive contamination (by 79.6%), and the least in the combined territories (by 6.9%). Conclusions: The results obtained indicate the need for further work to understand the trends in the presence/absence of independent and combined effects of pollutants and the growth of oncogynecological pathology from the perspective of assessing the distant and regional metastasis, histological and immunohistochemical profile of a specific malignant ovarian neoplasm with levels of environmental contamination. Full article
(This article belongs to the Special Issue State-of-the-Art in Biomedicine in Russia Federation)
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Article
Modelling Combined Intravenous Thrombolysis and Mechanical Thrombectomy in Acute Ischaemic Stroke: Understanding the Relationship between Stent Retriever Configuration and Clot Lysis Mechanisms
Life 2021, 11(11), 1271; https://doi.org/10.3390/life11111271 - 20 Nov 2021
Cited by 1 | Viewed by 1554
Abstract
Background: Combined intravenous thrombolysis and mechanical thrombectomy (IVT-MT) is a common treatment in acute ischaemic stroke, however the interaction between IVT and MT from a physiological standpoint is poorly understood. In this pilot study, we conduct numerical simulations of combined IVT-MT with [...] Read more.
Background: Combined intravenous thrombolysis and mechanical thrombectomy (IVT-MT) is a common treatment in acute ischaemic stroke, however the interaction between IVT and MT from a physiological standpoint is poorly understood. In this pilot study, we conduct numerical simulations of combined IVT-MT with various idealised stent retriever configurations to evaluate performance in terms of complete recanalisation times and lysis patterns. Methods: A 3D patient-specific geometry of a terminal internal carotid artery with anterior and middle cerebral arteries is reconstructed, and a thrombus is artificially implanted in the MCA branch. Various idealised stent retriever configurations are implemented by varying stent diameter and stent placement, and a configuration without a stent retriever provides a baseline for comparison. A previously validated multi-level model of thrombolysis is used, which incorporates blood flow, drug transport, and fibrinolytic reactions within a fibrin thrombus. Results: Fastest total recanalisation was achieved in the thrombus without a stent retriever, with lysis times increasing with stent retriever diameter. Two mechanisms of clot lysis were established: axial and radial permeation. Axial permeation from the clot front was the primary mechanism of lysis in all configurations, as it facilitated increased protein binding with fibrin fibres. Introducing a stent retriever channel allowed for radial permeation, which occurred at the fluid-thrombus interface, although lysis was much slower in the radial direction because of weaker secondary velocities. Conclusions: Numerical models can be used to better understand the complex physiological relationship between IVT and MT. Two different mechanisms of lysis were established, providing a basis towards improving the efficacy of combined treatments. Full article
(This article belongs to the Special Issue Challenges in Stroke Care)
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Review
Will Remotely Based Pulmonary Rehabilitation Water Down Its Effectiveness?
Life 2021, 11(11), 1270; https://doi.org/10.3390/life11111270 - 20 Nov 2021
Viewed by 1759
Abstract
Despite numerous benefits, traditional Pulmonary Rehabilitation (PR) as a resource remains underutilized in chronic lung disease. Less than 3% of eligible candidates for PR attend one or more sessions after hospitalization due to many barriers, including the ongoing COVID-19 pandemic. Emerging alternative models [...] Read more.
Despite numerous benefits, traditional Pulmonary Rehabilitation (PR) as a resource remains underutilized in chronic lung disease. Less than 3% of eligible candidates for PR attend one or more sessions after hospitalization due to many barriers, including the ongoing COVID-19 pandemic. Emerging alternative models of PR delivery such as home-based PR, tele-rehabilitation, web-based PR, or hybrid models could help address these barriers. Numerous studies have tested the feasibility, safety, and efficacy of these methods, but there is wide variability across studies and methods. We conducted a literature review to help determine if these alternative delivery methods watered down the effectiveness of PR. To evaluate the effectiveness of remotely based PR, the authors performed a literature search for randomized controlled trials (RCTs), cohort studies, and case series using PubMed, CINAHL, and Medline to identify relevant articles through 1 May 2021. Twenty-six applicable studies were found in which 11 compared tele-rehabilitation to conventional clinic-based PR; 11 evaluated tele-rehabilitation using the patient’s baseline status as control; and four compared tele-rehabilitation to no rehabilitation. Despite the different technologies used across studies, tele-rehabilitation was found to be both a feasible and an efficacious option for select patients with lung disease. Outcomes across these studies demonstrated similar benefits to traditional PR programs. Thus the existing data does not show that remotely based PR waters down the effectiveness of conventional PR. Use of remotely based PR is a feasible and effective option to deliver PR, especially for patients with significant barriers to conventional clinic-based PR. Additional, well-conducted RCTs are needed to answer the questions regarding its efficacy, safety, cost-effectiveness and who, among patients with COPD and other lung diseases, will derive the maximum benefit. Full article
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Article
Association of Contemporary Statin Pretreatment Intensity and LDL-C Levels on the Incidence of STEMI Presentation
Life 2021, 11(11), 1268; https://doi.org/10.3390/life11111268 - 19 Nov 2021
Viewed by 952
Abstract
Constituting hypolipidemic and pleiotropic effects, statins stabilize coronary artery plaque and may prevent STEMI events. This study investigated the association between contemporary statin pretreatment intensity, low-density lipoprotein cholesterol (LDL-C) levels, and the type of acute coronary syndrome (ACS) presentation: STEMI vs. NSTE-ACS. Data [...] Read more.
Constituting hypolipidemic and pleiotropic effects, statins stabilize coronary artery plaque and may prevent STEMI events. This study investigated the association between contemporary statin pretreatment intensity, low-density lipoprotein cholesterol (LDL-C) levels, and the type of acute coronary syndrome (ACS) presentation: STEMI vs. NSTE-ACS. Data were drawn from the ACS Israeli Survey (ACSIS), a biennial prospective national survey that took place in 2008–2018. The rate of STEMI vs. NSTE-ACS was calculated by statin use, including statin intensity (high-intensity statin therapy (HIST) and low-intensity statin therapy (LIST) prior to the index ACS event. Among 5103 patients, 2839 (56%) were statin-naive, 1389 (27%) used LIST and 875 (17%) used HIST. Statin pretreated patients were older and had a higher rates of co-morbidities, cardiovascular disease history and pretreatment with evidence-based medications. STEMI vs. NSTE-ACS was lower among HIST vs. LIST vs. statin-naive patients (31.0%, 37.8%, and 54.0%, respectively, p for trend < 0.001). Multivariate analysis revealed that HIST was independently associated with lower STEMI presentation (ORadj 0.70; 95% CI 0.57–0.86), while LIST (ORadj 0.92; 95% CI 0.77–1.10) and LDL-C < 70 mg/dL (ORadj 0.96; 95% CI 0.82–1.14) were not. In conclusion, among patients admitted with ACS, pretreatment with HIST was independently associated with a lower probability of STEMI presentation, while LIST and LDL-C < 70 mg/dL were not. Full article
(This article belongs to the Special Issue Myocardial Infarction 2021)
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Article
Peripheral Neuropathy Presents Similar Symptoms and Pathological Changes in Both High-Fat Diet and Pharmacologically Induced Pre- and Diabetic Mouse Models
Life 2021, 11(11), 1267; https://doi.org/10.3390/life11111267 - 19 Nov 2021
Cited by 4 | Viewed by 1117
Abstract
The objective of the study was to compare the effects of experimentally induced type 1 or type 2 diabetes (T1D or T2D) on the functional, structural and biochemical properties of mouse peripheral nerves. Eight-week-old C57BL/6 mice were randomly assigned into three groups, including [...] Read more.
The objective of the study was to compare the effects of experimentally induced type 1 or type 2 diabetes (T1D or T2D) on the functional, structural and biochemical properties of mouse peripheral nerves. Eight-week-old C57BL/6 mice were randomly assigned into three groups, including the control (CTRL, chow-fed), STZ (streptozotocin (STZ)-injected), and HFD (high-fat diet (HFD)-fed) group. After 18-weeks of experimental treatment, HFD mice had higher body weights and elevated levels of plasma lipids, while STZ mice developed hyperglycemia. STZ-treated mice, after an extended period of untreated diabetes, developed motor and sensory nerve conduction-velocity deficits. Moreover, relative to control fibers, pre- and diabetic axons were lower in number and irregular in shape. Animals from both treatment groups manifested a pronounced overexpression of nNOS and a reduced expression of SOD1 proteins in the sciatic nerve, indicating oxidative–nitrosative stress and ineffective antioxidant protection in the peripheral nervous system of these mice. Collectively, STZ- and HFD-treated mice revealed similar characteristics of peripheral nerve damage, including a number of morphological and electrophysiological pathologies in the sciatic nerve. While hyperglycemia is a large component of diabetic neuropathy pathogenesis, the non-hyperglycemic effects of diabetes, including dyslipidemia, may also be of importance in the development of this condition. Full article
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Article
Leydig Cells in Patients with Non-Obstructive Azoospermia: Do They Really Proliferate?
Life 2021, 11(11), 1266; https://doi.org/10.3390/life11111266 - 19 Nov 2021
Cited by 5 | Viewed by 1304
Abstract
Background: Non-obstructive azoospermia (NOA) is a form of male infertility caused by disorders of the testicular parenchyma and impaired spermatogenesis. This study aimed to investigate the nature of Leydig cell changes in patients with NOA, especially whether their actual proliferation occurred. Methods: 48 [...] Read more.
Background: Non-obstructive azoospermia (NOA) is a form of male infertility caused by disorders of the testicular parenchyma and impaired spermatogenesis. This study aimed to investigate the nature of Leydig cell changes in patients with NOA, especially whether their actual proliferation occurred. Methods: 48 testicular biopsies from infertile patients with NOA and 24 testicular biopsies originating from azoospermic patients suffering from obstructive azoospermia (OA) were included in the study. Leydig cells and their possible proliferative activity were analysed by immunohistochemistry and morphometry (stereology). Results: Unlike in the OA group, Leydig cells in NOA patients were sometimes organised into larger clusters and displayed an abundant cytoplasm/hypertrophy. Moreover, significant fibrosis of the interstitial compartment was demonstrated in some NOA samples, often accompanied by inflammatory cells. Stereological analysis showed no increase/proliferation of Leydig cells; on the contrary, these cells decreased in number in the NOA group. Conclusions: The decrease in the number of Leydig cells can be explained by previous inflammatory changes within the testicular interstitium and consequent interstitial fibrosis. The interstitial fibrosis might have a deteriorating effect on Leydig cells. Full article
(This article belongs to the Collection Male Infertility: Current Knowledge and Future Perspectives)
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Article
Origin of Pathogens of Grapevine Crown Gall Disease in Hokkaido in Japan as Characterized by Molecular Epidemiology of Allorhizobium vitis Strains
Life 2021, 11(11), 1265; https://doi.org/10.3390/life11111265 - 19 Nov 2021
Cited by 2 | Viewed by 1017
Abstract
Crown gall is a globally distributed and economically important disease of grapevine and other important crop plants. The causal agent of grapevine crown gall is tumorigenic Allorhizobium vitis (Ti) strains that harbor a tumor-inducing plasmid (pTi). The epidemic of grapevine crown gall has [...] Read more.
Crown gall is a globally distributed and economically important disease of grapevine and other important crop plants. The causal agent of grapevine crown gall is tumorigenic Allorhizobium vitis (Ti) strains that harbor a tumor-inducing plasmid (pTi). The epidemic of grapevine crown gall has not been widely elucidated. In this study, we investigated the genetic diversity of 89 strains of Ti and nonpathogenic A. vitis to clarify their molecular epidemiology. Multi-locus sequence analysis (MLSA) of the partial nucleotide sequences of pyrG, recA, and rpoD was performed for molecular typing of A. vitis strains isolated from grapevines with crown gall symptoms grown in 30 different vineyards, five different countries, mainly in Japan, and seven genomic groups A to F were obtained. The results of MLSA and logistic regression indicated that the population of genetic group A was significantly related to a range of prefectures and that the epidemic of group A strains originated mainly in Hokkaido in Japan through soil infection. Moreover, group E strains could have been transported by infected nursery stocks. In conclusion, this study indicates that both soil infection and transporting of infected nursery stocks are working as infection source in Hokkaido. Full article
(This article belongs to the Collection State of the Art in Plant Science)
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Review
Urinary Tract Virome as an Urgent Target for Metagenomics
Life 2021, 11(11), 1264; https://doi.org/10.3390/life11111264 - 19 Nov 2021
Cited by 5 | Viewed by 1057
Abstract
Virome—a part of a microbiome—is a term used to describe all viruses found in the specific organism or system. Recently, as new technologies emerged, it has been confirmed that kidneys and the lower urinary tract are colonized not only by the previously described [...] Read more.
Virome—a part of a microbiome—is a term used to describe all viruses found in the specific organism or system. Recently, as new technologies emerged, it has been confirmed that kidneys and the lower urinary tract are colonized not only by the previously described viruses, but also completely novel species. Viruses can be both pathogenic and protective, as they often carry important virulence factors, while at the same time represent anti-inflammatory functions. This paper aims to show and compare the viral species detected in various, specific clinical conditions. Because of the unique characteristics of viruses, new sequencing techniques and databases had to be developed to conduct research on the urinary virome. The dynamic development of research on the human microbiome suggests that the detailed studies on the urinary system virome will provide answers to many questions about the risk factors for civilization, cancer, and autoimmune diseases. Full article
Review
Structure, Activity and Function of the PRMT2 Protein Arginine Methyltransferase
Life 2021, 11(11), 1263; https://doi.org/10.3390/life11111263 - 19 Nov 2021
Cited by 6 | Viewed by 1548
Abstract
PRMT2 belongs to the protein arginine methyltransferase (PRMT) family, which catalyzes the arginine methylation of target proteins. As a type I enzyme, PRMT2 produces asymmetric dimethyl arginine and has been shown to have weak methyltransferase activity on histone substrates in vitro, suggesting that [...] Read more.
PRMT2 belongs to the protein arginine methyltransferase (PRMT) family, which catalyzes the arginine methylation of target proteins. As a type I enzyme, PRMT2 produces asymmetric dimethyl arginine and has been shown to have weak methyltransferase activity on histone substrates in vitro, suggesting that its authentic substrates have not yet been found. PRMT2 contains the canonical PRMT methylation core and a unique Src homology 3 domain. Studies have demonstrated its clear implication in many different cellular processes. PRMT2 acts as a coactivator of several nuclear hormone receptors and is known to interact with a multitude of splicing-related proteins. Furthermore, PRMT2 is aberrantly expressed in several cancer types, including breast cancer and glioblastoma. These reports highlight the crucial role played by PRMT2 and the need for a better characterization of its activity and cellular functions. Full article
(This article belongs to the Special Issue Structure, Activity, and Function of Protein Methyltransferases)
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Article
An Episomal CRISPR/Cas12a System for Mediating Efficient Gene Editing
Life 2021, 11(11), 1262; https://doi.org/10.3390/life11111262 - 18 Nov 2021
Cited by 2 | Viewed by 1449
Abstract
(1) Background: Gene editing technology, as represented by CRISPR is a powerful tool used in biomedical science. However, the editing efficiency of such technologies, especially in induced pluripotent stem cells (iPSCs) and other types of stem cells, is low which hinders its application [...] Read more.
(1) Background: Gene editing technology, as represented by CRISPR is a powerful tool used in biomedical science. However, the editing efficiency of such technologies, especially in induced pluripotent stem cells (iPSCs) and other types of stem cells, is low which hinders its application in regenerative medicine; (2) Methods: A gene-editing system, COE, was designed and constructed based on CRISPR/Cas12a and Orip/EBNA1, and its editing efficiency was evaluated in human embryonic kidney 293T (HEK-293T) cells with flow cytometry and restriction fragment length polymorphism (RFLP) analysis. The COE was nucleofected into iPSCs, then, the editing efficiency was verified by a polymerase chain reaction and Sanger sequencing; (3) Results: With the extension of time, COE enables the generation of up to 90% insertion or deletion rates in HEK-293T cells. Furthermore, the deletion of a 2.5 kb fragment containing Exon 51 of the dystrophin gene (DMD) in iPSCs was achieved with high efficiency; out of 14 clones analyzed, 3 were positive. Additionally, the Exon 51-deleted iPSCs derived from cardiomyocytes had similar expression profiles to those of Duchenne muscular dystrophy (DMD) patient-specific iPSCs. Moreover, there was no residue of each component of the plasmid in the editing cells; (4) Conclusions: In this study, a novel, efficient, and safe gene-editing system, COE, was developed, providing a powerful tool for gene editing. Full article
(This article belongs to the Section Genetics and Genomics)
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Article
Generation and Characterization of the Drosophila melanogaster paralytic Gene Knock-Out as a Model for Dravet Syndrome
Life 2021, 11(11), 1261; https://doi.org/10.3390/life11111261 - 18 Nov 2021
Cited by 2 | Viewed by 1546
Abstract
Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type [...] Read more.
Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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Article
Characterization of Haemophilus influenzae Strains with Non-Enzymatic Resistance to β-Lactam Antibiotics Caused by Mutations in the PBP3 Gene in the Czech Republic in 2010–2018
Life 2021, 11(11), 1260; https://doi.org/10.3390/life11111260 - 18 Nov 2021
Cited by 2 | Viewed by 952
Abstract
The surveillance data on antibiotic resistance of Haemophilus influenzae have shown that strains with non-enzymatic resistance to β-lactam antibiotics have been on the rise in the Czech Republic over the last decade. This type of resistance is more difficult to detect than β-lactamase [...] Read more.
The surveillance data on antibiotic resistance of Haemophilus influenzae have shown that strains with non-enzymatic resistance to β-lactam antibiotics have been on the rise in the Czech Republic over the last decade. This type of resistance is more difficult to detect than β-lactamase production. Analysis of 228 H. influenzae strains revealed that isolates with non-enzymatic resistance to β-lactams due to mutations in the ftsI gene could be reliably demonstrated by single run testing of susceptibility to amoxicillin/clavulanic acid (sensitivity of detection is 84.6%), cefuroxime (92.6%), ampicillin and penicillin (both 95.7%). Thirty-seven different amino acid substitution combinations were detected in the PBP3 protein at 23 positions (V329I, D350N, S357N, A368T, M377I, S385T, A388V, L389F, P393L, A437S, I449V, G490E, I491V, R501L, A502S, A502T, A502V, V511A, R517H, I519L, N526K, A530S, and T532S). The most common combination (35%) of amino acid substitutions was the combination D350N, M377I, A502V, N526K. Epidemiological typing does not indicate a clonal spread of a particular MLST type. Altogether there has been detected 74 STs. The most prevalent ST 1034 was associated mainly with a combination D350N, M377I, A502V, N526K. Clonal analysis revealed six clonal complexes (CCs) with the founder found, eight CCs without founder and 33 singletons. Full article
(This article belongs to the Section Microbiology)
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Article
Emerging Mutations Potentially Related to SARS-CoV-2 Immune Escape: The Case of a Long-Term Patient
Life 2021, 11(11), 1259; https://doi.org/10.3390/life11111259 - 18 Nov 2021
Viewed by 1279
Abstract
SARS-CoV-2 isolates from long-term COVID-19 patients play a significant role in understanding the mechanisms of infection and virus persistence. This study describes a SARS-CoV-2 isolate from a 53-year-old woman from Apulia (Italy), who was COVID-19 positive for approximately four months. In this paper [...] Read more.
SARS-CoV-2 isolates from long-term COVID-19 patients play a significant role in understanding the mechanisms of infection and virus persistence. This study describes a SARS-CoV-2 isolate from a 53-year-old woman from Apulia (Italy), who was COVID-19 positive for approximately four months. In this paper we aimed to investigate any potential correlation between genetic mutations and clinical features of this case of infection. The viral isolate was assigned to lineage B.1.177.51 through whole-genome sequencing (WGS) and harbored a novel set of mutations on the Spike protein (V143D, del144/145 and E484K); furthermore, seroneutralization assays showed impaired response of the surveyed strain to BNT162b2 (Comirnaty) Pfizer/BioNTech vaccine-induced (average reduction of 70%) and convalescent sera (average reduction of 19.04%), when compared to VOC P.1. This study highlights the importance of genomic surveillance for the management of the COVID-19 pandemic, the relevance of monitoring of emerging SARS-CoV-2 mutations in all lineages, and the necessity of testing the response of emerging variants to available therapies and vaccines. Full article
(This article belongs to the Special Issue Virology Applications to COVID-19 Pandemic)
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Article
Genome-Wide Investigation and Analysis of Microsatellites and Compound Microsatellites in Leptolyngbya-like Species, Cyanobacteria
Life 2021, 11(11), 1258; https://doi.org/10.3390/life11111258 - 18 Nov 2021
Cited by 2 | Viewed by 1046
Abstract
Microsatellites (simple sequence repeats, SSRs) are ubiquitously distributed in almost all known genomes. Here, the first investigation was designed to examine the SSRs and compound microsatellites (CSSRs) in genomes of Leptolyngbya-like strains. The results disclosed diversified patterns of distribution, abundance, density, and [...] Read more.
Microsatellites (simple sequence repeats, SSRs) are ubiquitously distributed in almost all known genomes. Here, the first investigation was designed to examine the SSRs and compound microsatellites (CSSRs) in genomes of Leptolyngbya-like strains. The results disclosed diversified patterns of distribution, abundance, density, and diversity of SSRs and CSSRs in genomes, indicating that they may be subject to rapid evolutionary change. The numbers of SSRs and CSSRs were extremely unevenly distributed among genomes, ranging from 11,086 to 24,000 and from 580 to 1865, respectively. Dinucleotide SSRs were the most abundant category in 31 genomes, while the other 15 genomes followed the pattern: mono- > di- > trinucleotide SSRs. The patterns related to SSRs and CSSRs showed differences among phylogenetic groups. Both SSRs and CSSRs were overwhelmingly distributed in coding regions. The numbers of SSRs and CSSRs were significantly positively correlated with genome size (p < 0.01) and negatively correlated with GC content (p < 0.05). Moreover, the motif (A/C)n and (AG)n was predominant in mononucleotide and dinucleotide SSRs, and unique motifs of CSSRs were identified in 39 genomes. This study provides the first insight into SSRs and CSSRs in genomes of Leptolyngbya-like strains and will be useful to understanding their distribution, predicting their function, and tracking their evolution. Additionally, the identified SSRs may provide an evolutionary advantage of fast adaptation to environmental changes and may play an important role in the cosmopolitan distribution of Leptolyngbya strains to globally diverse niches. Full article
(This article belongs to the Special Issue Microbial Adaptations and Acclimation to Extreme Environments)
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Review
Salvia miltiorrhiza Protects Endothelial Dysfunction against Mitochondrial Oxidative Stress
Life 2021, 11(11), 1257; https://doi.org/10.3390/life11111257 - 18 Nov 2021
Cited by 1 | Viewed by 1221
Abstract
Salvia miltiorrhiza (SM) is a common traditional Chinese medicine used in the treatment of cardiovascular and cerebrovascular diseases. Endothelial dysfunction plays an important role in the pathology of cardiovascular diseases. Endothelial dysfunction may induce inflammation and change vascular tone and permeability. The main [...] Read more.
Salvia miltiorrhiza (SM) is a common traditional Chinese medicine used in the treatment of cardiovascular and cerebrovascular diseases. Endothelial dysfunction plays an important role in the pathology of cardiovascular diseases. Endothelial dysfunction may induce inflammation and change vascular tone and permeability. The main pathological mechanism of endothelial dysfunction is the formation of reactive oxygen species (ROS). Mitochondria are the main source of energy and can also produce large amounts of ROS. Recent studies have shown that extracts of SM have antioxidative, anti-inflammatory, and antithrombus properties. In this review, we discuss the mechanism of oxidative stress in the mitochondria, endothelial dysfunction, and the role of SM in these oxidative events. Full article
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Review
The Pleiotropic Potential of BDNF beyond Neurons: Implication for a Healthy Mind in a Healthy Body
Life 2021, 11(11), 1256; https://doi.org/10.3390/life11111256 - 17 Nov 2021
Cited by 8 | Viewed by 1780
Abstract
Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation [...] Read more.
Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation of energy balance. BDNF and its receptor are extensively expressed in the hypothalamus, regions where peripheral signals, associated with feeding control and metabolism activation, and are integrated to elaborate anorexigenic and orexigenic effects. Thus, BDNF coordinates adaptive responses to fluctuations in energy intake and expenditure, connecting the central nervous system with peripheral tissues, including muscle, liver, and the adipose tissue in a complex operational network. This review discusses the latest literature dealing with the involvement of BDNF in the maintenance of energy balance. We have focused on the physiological and molecular mechanisms by which BDNF: (I) controls the mitochondrial function and dynamics; (II) influences thermogenesis and tissue differentiation; (III) mediates the effects of exercise on cognitive functions; and (IV) modulates insulin sensitivity and glucose transport at the cellular level. Deepening the understanding of the mechanisms exploited to maintain energy homeostasis will lay the groundwork for the development of novel therapeutical approaches to help people to maintain a healthy mind in a healthy body. Full article
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Review
CRISPR-Based Genetic Switches and Other Complex Circuits: Research and Application
Life 2021, 11(11), 1255; https://doi.org/10.3390/life11111255 - 17 Nov 2021
Cited by 2 | Viewed by 1866
Abstract
CRISPR-based enzymes have offered a unique capability to the design of genetic switches, with advantages in designability, modularity and orthogonality. CRISPR-based genetic switches operate on multiple levels of life, including transcription and translation. In both prokaryotic and eukaryotic cells, deactivated CRISPR endonuclease and [...] Read more.
CRISPR-based enzymes have offered a unique capability to the design of genetic switches, with advantages in designability, modularity and orthogonality. CRISPR-based genetic switches operate on multiple levels of life, including transcription and translation. In both prokaryotic and eukaryotic cells, deactivated CRISPR endonuclease and endoribonuclease have served in genetic switches for activating or repressing gene expression, at both transcriptional and translational levels. With these genetic switches, more complex circuits have been assembled to achieve sophisticated functions including inducible switches, non-linear response and logical biocomputation. As more CRISPR enzymes continue to be excavated, CRISPR-based genetic switches will be used in a much wider range of applications. Full article
(This article belongs to the Special Issue Synthetic Genetic Elements, Devices, and Systems)
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Article
Minimally Invasive Internal Fixation of Femoral Shaft Fractures—A Biomechanical Study with a Disruptive Technique
Life 2021, 11(11), 1254; https://doi.org/10.3390/life11111254 - 17 Nov 2021
Cited by 1 | Viewed by 1160
Abstract
(1) Background: In polytrauma patients, femur fractures are usually stabilised by external fixation for damage control, later being treated with definitive plate or nail osteosynthesis. Screw/rod systems established in spinal surgery might be inserted for internal fixation, providing sufficient fracture stability that subsequent [...] Read more.
(1) Background: In polytrauma patients, femur fractures are usually stabilised by external fixation for damage control, later being treated with definitive plate or nail osteosynthesis. Screw/rod systems established in spinal surgery might be inserted for internal fixation, providing sufficient fracture stability that subsequent intervention is unnecessary. This was to be investigated biomechanically. (2) Methods: The unilaterally applied spinal internal fixator (IF) was subjected to load and deformation analysis on artificial femurs with 32-A3 fracture according to AO classification. Distance of screws to fracture and rod to cortical bone were analysed as parameters influenced surgically as stiffness and deformation of the treated fracture. In addition, the stability of another construct with a second screw/rod system was determined. The axial load in stance phase during walking was simulated. The results were compared against an established fixed-angle plate osteosynthesis (IP). (3) Results: There were no implant failures in the form of fractures, avulsions or deformations. All unilateral IF combinations were inferior to IP in terms of stability and stiffness. The bilateral construct with two screw/rod systems achieved biomechanical properties comparable to IP. 4) Conclusion: Biomechanically, a biplanar screw/rod system is suitable for definitive fracture stabilisation of the femur, despite a damage control approach. Full article
(This article belongs to the Special Issue Healing after Trauma)
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Review
Master Protocols for Precision Medicine in Oncology: Overcoming Methodology of Randomized Clinical Trials
Life 2021, 11(11), 1253; https://doi.org/10.3390/life11111253 - 17 Nov 2021
Cited by 1 | Viewed by 1303
Abstract
Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of [...] Read more.
Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of many cancer types, with the spread of different biomarker-driven therapies (or targeted therapies). This scenario of “personalized medicine” revolutionized therapeutic strategies and the methodology of the supporting clinical research. New clinical trial designs are emerging to answer to the unmet clinical needs related to the development of these targeted therapies, overcoming the “classical” structure of randomized studies. Innovative trial designs able to evaluate more than one treatment in the same group of patients or many groups of patients with the same treatment (or both) are emerging as a possible future standard in clinical trial methodology. These are identified as “master protocols”, and include umbrella, basket and platform trials. In this review, we described the main characteristics of these new trial designs, focusing on the opportunities and limitations of their use in the era of personalized medicine. Full article
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Article
Selective Inhibition of IL-6 Trans-Signaling Has No Beneficial Effect on the Posttraumatic Cytokine Release after Multiple Trauma in Mice
Life 2021, 11(11), 1252; https://doi.org/10.3390/life11111252 - 17 Nov 2021
Cited by 1 | Viewed by 936
Abstract
While improvements in pre-hospital and in-hospital care allow more multiple trauma patients to advance to intensive care, the incidence of posttraumatic multiple organ dysfunction syndrome (MODS) is on the rise. Herein, the influence of a selective IL-6 trans-signaling inhibition on posttraumatic cytokine levels [...] Read more.
While improvements in pre-hospital and in-hospital care allow more multiple trauma patients to advance to intensive care, the incidence of posttraumatic multiple organ dysfunction syndrome (MODS) is on the rise. Herein, the influence of a selective IL-6 trans-signaling inhibition on posttraumatic cytokine levels was investigated as an approach to prevent MODS caused by a dysbalanced posttraumatic immune reaction. Therefore, the artificial IL-6 trans-signaling inhibitor sgp130Fc was deployed in a murine multiple trauma model (femoral fracture plus bilateral chest trauma). The traumatized mice were treated with sgp130Fc (FP) and compared to untreated mice (WT) and IL-6 receptor knockout mice (RKO), which received the same traumas. The overall trauma mortality was 4.4%. Microscopic pulmonary changes were apparent after multiple trauma and after isolated bilateral chest trauma. Elevated IL-6, MCP-3 and RANTES plasma levels were measured after trauma, indicating a successful induction of a systemic inflammatory reaction. Significantly reduced IL-6 and RANTES plasma levels were visible in RKO compared to WT. Only a little effect was visible in FP compared to WT. Comparable cytokine levels in WT and FP indicate neither a protective nor an adverse effect of sgp130Fc on the cytokine release after femoral fracture and bilateral chest trauma. Full article
(This article belongs to the Special Issue Healing after Trauma)
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