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International Journal of Molecular... Aug 2019A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, since...
A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of anti-inflammatory mediators, cell membrane fluidity, intracellular signaling, and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represents a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.
Topics: Clinical Trials as Topic; Fatty Acids, Omega-3; Humans; Neurodegenerative Diseases; Observational Studies as Topic
PubMed: 31480294
DOI: 10.3390/ijms20174256 -
Pharmacological Reviews Apr 2021The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the...
The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.
Topics: COVID-19; Collectins; Complement Activating Enzymes; Complement C3; Complement Inactivating Agents; Complement System Proteins; Genetic Therapy; Humans; Inflammation Mediators; Lectins; Mannose-Binding Protein-Associated Serine Proteases; Pandemics; Rare Diseases; SARS-CoV-2; Synapses; Ficolins
PubMed: 33687995
DOI: 10.1124/pharmrev.120.000072 -
Journal of Applied Physiology... Jul 2021Muscle atrophy and decline in muscle strength appear very rapidly with prolonged disuse or mechanical unloading after acute hospitalization or experimental bed rest. The...
Muscle atrophy and decline in muscle strength appear very rapidly with prolonged disuse or mechanical unloading after acute hospitalization or experimental bed rest. The current study analyzed data from short-, medium-, and long-term bed rest (5-120 days) in a pooled sample of 318 healthy adults and modeled the mathematical relationship between muscle strength decline and atrophy. The results show a logarithmic disuse-induced loss of strength and muscle atrophy of the weight-bearing knee extensor muscles. The greatest rate of muscle strength decline and atrophy occurred in the earliest stages of bed rest, plateauing later, and likely contributed to the rapid neuromuscular loss of function in the early period. In addition, during the first 2 wk of bed rest, muscle strength decline is much faster than muscle atrophy: on , the ratio of muscle atrophy to strength decline as a function of bed rest duration is 4.2, falls to 2.4 on , and stabilizes to a value of 1.9 after ∼35 days of bed rest. Positive regression revealed that ∼79% of the muscle strength loss may be explained by muscle atrophy, while the remaining is most likely due to alterations in single fiber mechanical properties, excitation-contraction coupling, fiber architecture, tendon stiffness, muscle denervation, neuromuscular junction damage, and supraspinal changes. Future studies should focus on neural factors as well as muscular factors independent of atrophy (single fiber excitability and mechanical properties, architectural factors) and on the role of extracellular matrix changes. Bed rest results in nonuniform loss of isometric muscle strength and atrophy over time, where the magnitude of change was greater for muscle strength than for atrophy. Future research should focus on the loss of muscle function and the underlying mechanisms, which will aid in the development of countermeasures to mitigate or prevent the decline in neuromuscular efficiency. Our study contributes to the characterization of muscle loss and weakness processes reflected by a logarithmic decline in muscle strength induced by chronic bed rest. Acute short-term hospitalization (≤5 days) associated with periods of disuse/immobilization/prolonged time in the supine position in the hospital bed is sufficient to significantly decrease muscle mass and size and induce functional changes related to weakness in maximal muscle strength. By bringing together integrated evaluation of muscle structure and function, this work identifies that 79% of the loss in muscle strength can be explained by muscle atrophy, leaving 21% of the functional loss unexplained. The outcomes of this study should be considered in the development of daily countermeasures for preserving neuromuscular integrity as well as preconditioning interventions to be implemented before clinical bed rest or chronic gravitational unloading (e.g., spaceflights).
Topics: Adult; Bed Rest; Humans; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Neuromuscular Junction
PubMed: 33703945
DOI: 10.1152/japplphysiol.00363.2020 -
The Cochrane Database of Systematic... Apr 2021Alveolar bone changes following tooth extraction can compromise prosthodontic rehabilitation. Alveolar ridge preservation (ARP) has been proposed to limit these changes... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alveolar bone changes following tooth extraction can compromise prosthodontic rehabilitation. Alveolar ridge preservation (ARP) has been proposed to limit these changes and improve prosthodontic and aesthetic outcomes when implants are used. This is an update of the Cochrane Review first published in 2015.
OBJECTIVES
To assess the clinical effects of various materials and techniques for ARP after tooth extraction compared with extraction alone or other methods of ARP, or both, in patients requiring dental implant placement following healing of extraction sockets.
SEARCH METHODS
Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 19 March 2021), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2021, Issue 2), MEDLINE Ovid (1946 to 19 March 2021), Embase Ovid (1980 to 19 March 2021), Latin American and Caribbean Health Science Information database (1982 to 19 March 2021), Web of Science Conference Proceedings (1990 to 19 March 2021), Scopus (1966 to 19 March 2021), ProQuest Dissertations and Theses (1861 to 19 March 2021), and OpenGrey (to 19 March 2021). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. A number of journals were also handsearched.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) on the use of ARP techniques with at least six months of follow-up. Outcome measures were: changes in the bucco-lingual/palatal width of alveolar ridge, changes in the vertical height of the alveolar ridge, complications, the need for additional augmentation prior to implant placement, aesthetic outcomes, implant failure rates, peri-implant marginal bone level changes, changes in probing depths and clinical attachment levels at teeth adjacent to the extraction site, and complications of future prosthodontic rehabilitation.
DATA COLLECTION AND ANALYSIS
We selected trials, extracted data, and assessed risk of bias in duplicate. Corresponding authors were contacted to obtain missing information. We estimated mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (95% CI). We constructed 'Summary of findings' tables to present the main findings and assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 16 RCTs conducted worldwide involving a total of 524 extraction sites in 426 adult participants. We assessed four trials as at overall high risk of bias and the remaining trials at unclear risk of bias. Nine new trials were included in this update with six new trials in the category of comparing ARP to extraction alone and three new trials in the category of comparing different grafting materials. ARP versus extraction: from the seven trials comparing xenografts with extraction alone, there is very low-certainty evidence of a reduction in loss of alveolar ridge width (MD -1.18 mm, 95% CI -1.82 to -0.54; P = 0.0003; 6 studies, 184 participants, 201 extraction sites), and height (MD -1.35 mm, 95% CI -2.00 to -0.70; P < 0.0001; 6 studies, 184 participants, 201 extraction sites) in favour of xenografts, but we found no evidence of a significant difference for the need for additional augmentation (RR 0.68, 95% CI 0.29 to 1.62; P = 0.39; 4 studies, 154 participants, 156 extraction sites; very low-certainty evidence) or in implant failure rate (RR 1.00, 95% CI 0.07 to 14.90; 2 studies, 70 participants/extraction sites; very low-certainty evidence). From the one trial comparing alloplasts versus extraction, there is very low-certainty evidence of a reduction in loss of alveolar ridge height (MD -3.73 mm; 95% CI -4.05 to -3.41; 1 study, 15 participants, 60 extraction sites) in favour of alloplasts. This single trial did not report any other outcomes. Different grafting materials for ARP: three trials (87 participants/extraction sites) compared allograft versus xenograft, two trials (37 participants, 55 extraction sites) compared alloplast versus xenograft, one trial (20 participants/extraction sites) compared alloplast with and without membrane, one trial (18 participants, 36 extraction sites) compared allograft with and without synthetic cell-binding peptide P-15, and one trial (30 participants/extraction sites) compared alloplast with different particle sizes. The evidence was of very low certainty for most comparisons and insufficient to determine whether there are clinically significant differences between different ARP techniques based on changes in alveolar ridge width and height, the need for additional augmentation prior to implant placement, or implant failure. We found no trials which evaluated parameters relating to clinical attachment levels, specific aesthetic or prosthodontic outcomes for any of the comparisons. No serious adverse events were reported with most trials indicating that the procedure was uneventful. Among the complications reported were delayed healing with partial exposure of the buccal plate at suture removal, postoperative pain and swelling, moderate glazing, redness and oedema, membrane exposure and partial loss of grafting material, and fibrous adhesions at the cervical part of previously preserved sockets, for the comparisons xenografts versus extraction, allografts versus xenografts, alloplasts versus xenografts, and alloplasts with and without membrane.
AUTHORS' CONCLUSIONS
ARP techniques may minimise the overall changes in residual ridge height and width six months after extraction but the evidence is very uncertain. There is lack of evidence of any differences in the need for additional augmentation at the time of implant placement, implant failure, aesthetic outcomes, or any other clinical parameters due to lack of information or long-term data. There is no evidence of any clinically significant difference between different grafting materials and barriers used for ARP. Further long-term RCTs that follow CONSORT guidelines (www.consort-statement.org) are necessary.
Topics: Adult; Alveolar Process; Alveolar Ridge Augmentation; Bias; Biocompatible Materials; Bone Regeneration; Bone Remodeling; Confidence Intervals; Dental Implantation, Endosseous; Heterografts; Humans; Middle Aged; Organ Sparing Treatments; Randomized Controlled Trials as Topic; Time Factors; Tooth Extraction; Tooth Socket; Treatment Outcome
PubMed: 33899930
DOI: 10.1002/14651858.CD010176.pub3 -
Frontiers in Immunology 2022Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT),... (Review)
Review
Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case-control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.
Topics: Adult; Child; Humans; Adolescent; Prognosis; Prospective Studies; Biomarkers; Graft vs Host Disease; Thrombotic Microangiopathies
PubMed: 36818475
DOI: 10.3389/fimmu.2022.1064203 -
Frontiers in Surgery 2020Bone augmentation techniques have increasingly been indicated for re-creating adequate bone height and volume suitable for dental implant sites. This is particularly...
Bone augmentation techniques have increasingly been indicated for re-creating adequate bone height and volume suitable for dental implant sites. This is particularly applicable in the severely atrophic posterior maxilla where sinus perforation (ruptured Schneiderian membrane) is a very common complication and sinus floor elevation or lift is frequently considered a standard procedure. The augmentation of the maxillary sinus can be performed with or without grafting biomaterials. Herein, numerous biomaterials and bone substitutes have been proposed, primarily to sustain the lifted space. In addition, cytokines and growth factors have been used to stimulate angiogenesis, enhance bone formation as well as improve healing and recovery period, either as the sole filling material or in combination with bone substitute materials. Within such, is the family of autologous blood extracts, so-called platelet concentrates, which are simply the "product" resulting from the simple centrifugation of collected whole blood samples of the patient, immediately pre-surgery. Platelet-Rich Fibrin (PRF), a sub-family of platelet concentrates, is a three-dimensional (3-D) autogenous biomaterial obtained, without including anti-coagulants, bovine thrombin, additives, or any gelifying agents during the centrifugation process. Today, it is safe to say that, in implant dentistry and oral and maxillofacial surgery, PRFs (particularly, the pure platelet-rich fibrin or P-PRF and leukocyte and platelet-rich fibrin or L-PRF sub-classes) are receiving the most attention, essentially due to their simplicity, rapidness, user-friendliness/malleability, and cost-effectiveness. Whether used as the sole "bioactive" filling/additive material or combined with bone substitutes, the revolutionary second-generation PRFs have been very often associated with clinical results. Hence, this review aims to provide a 10-years update on the clinical effectiveness of L-PRF when applied/used as the "sole" biomaterial in maxillary sinus augmentation procedures. An electronic search using specific keywords for L-PRF and maxillary sinus augmentation was conducted in three main databases (PubMed-MEDLINE database, Google Scholar and Cochrane library) for the period between January 2009-February 2020. The quest yielded a total of 468 articles. Based on the pre-established inclusion/exclusion criteria, only seven articles were deemed eligible and included in the analysis. Surprisingly, of the 5 studies which used de-proteinized bovine bone mineral (DBBM) in combination with L-PRF, 60% acclaimed no significant effects and only 40% declared positive effects. Of the two articles which had used allogenous bone graft, 50% declared no significant effects and 50% acclaimed positive effects. Only one study had used L-PRF as the sole grafting material and reported a positive effect. Likewise, positive effects were reported in one other study using L-PRF in combination with a collagen membrane. Due to the heterogeneity of the included studies, this review is limited by the inability to perform a proper systematic meta-analysis. Overall, most of the published studies reported results of L-PRF application as a grafting material (sole or adjuvant) in maxillary sinus augmentation and dental implant restorative procedures. Yet, distinct technical processing for L-PRF preparation was noted. Hence, studies should be approached with caution. Here in, in sinus lift and treatment of Schneider membrane, the formation of mature bone remains inconclusive. More studies are eagerly awaited in order to prove the beneficial or detrimental effects of PRFs, in general and L-PRFs, in specific; especially in their tissue regenerative potential pertaining to the promotion of angiogenesis, enhancing of cell proliferation, stimulation of cell migration and autocrine/paracrine secretion of growth factors, as well as to reach a consensus or a conclusive and distinct determination of the effect of leukocytes (and their inclusion) on inflammation or edema and pain; a call for standardization in PRFs and L-PRFs composition reporting and regimenting the preparation protocols.
PubMed: 33330603
DOI: 10.3389/fsurg.2020.537138 -
The Cochrane Database of Systematic... Dec 2020Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.
OBJECTIVES
To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.
SELECTION CRITERIA
Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.
MAIN RESULTS
We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence).
AUTHORS' CONCLUSIONS
There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.
Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Bias; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Phenylbutyrates; Pyrazoles; Pyridines; Quality of Life; Quinolines; Quinolones; Randomized Controlled Trials as Topic
PubMed: 33331662
DOI: 10.1002/14651858.CD010966.pub3 -
Cell Proliferation Oct 2023The liver is a common secondary metastasis site of many malignant tumours, such as the colorectum, pancreas, stomach, breast, prostate, and lung cancer. The clinical... (Review)
Review
The liver is a common secondary metastasis site of many malignant tumours, such as the colorectum, pancreas, stomach, breast, prostate, and lung cancer. The clinical management of liver metastases is challenging because of their strong heterogeneity, rapid progression, and poor prognosis. Now, exosomes, small membrane vesicles that are 40-160 nm in size, are released by tumour cells, namely, tumour-derived exosomes (TDEs), and are being increasingly studied because they can retain the original characteristics of tumour cells. Cell-cell communication via TDEs is pivotal for liver pre-metastatic niche (PMN) formation and liver metastasis; thus, TDEs can provide a theoretical basis to intensively study the potential mechanisms of liver metastasis and new insights into the diagnosis and treatment of liver metastasis. Here, we systematically review current research progress about the roles and possible regulatory mechanisms of TDE cargos in liver metastasis, focusing on the functions of TDEs in liver PMN formation. In addition, we discuss the clinical utility of TDEs in liver metastasis, including TDEs as potential biomarkers, and therapeutic approaches for future research reference in this field.
Topics: Humans; Exosomes; Liver Neoplasms; Cell Communication; Pancreas; Biomarkers, Tumor; Tumor Microenvironment; Neoplasm Metastasis
PubMed: 36941028
DOI: 10.1111/cpr.13452 -
International Journal of Molecular... Oct 2023Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine... (Review)
Review
Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.
Topics: Animals; Humans; Pituitary Neoplasms; Pituitary Gland; Neuroendocrine Tumors; Aggression; Tumor Microenvironment
PubMed: 37958702
DOI: 10.3390/ijms242115719 -
Intensive Care Medicine Jun 2020Despite increasing improvement in extracorporeal membrane oxygenation (ECMO) technology and knowledge, thrombocytopenia and impaired platelet function are usual findings... (Meta-Analysis)
Meta-Analysis Review
Despite increasing improvement in extracorporeal membrane oxygenation (ECMO) technology and knowledge, thrombocytopenia and impaired platelet function are usual findings in ECMO patients and the underlying mechanisms are only partially elucidated. The purpose of this meta-analysis and systematic review was to thoroughly summarize and discuss the existing knowledge of platelet profile in adult ECMO population. All studies meeting the inclusion criteria (detailed data about platelet count and function) were selected, after screening literature from July 1975 to August 2019. Twenty-one studies from 1.742 abstracts were selected. The pooled prevalence of thrombocytopenia in ECMO patients was 21% (95% CI 12.9-29.0; 14 studies). Thrombocytopenia prevalence was 25.4% (95% CI 10.6-61.4; 4 studies) in veno-venous ECMO, whereas it was 23.2% (95% CI 11.8-34.5; 6 studies) in veno-arterial ECMO. Heparin-induced thrombocytopenia prevalence was 3.7% (95% CI 1.8-5.5; 12 studies). Meta-regression revealed no significant association between ECMO duration and thrombocytopenia. Platelet function impairment was described in 7 studies. Impaired aggregation was shown in 5 studies, whereas loss of platelet receptors was found in one trial, and platelet activation was described in 2 studies. Platelet transfusions were needed in up to 50% of the patients. Red blood cell transfusions were administered from 46 to 100% of the ECMO patients. Bleeding events varied from 16.6 to 50.7%, although the cause and type of haemorrhage was not consistently reported. Thrombocytopenia and platelet dysfunction are common in ECMO patients, regardless the type of ECMO mode. The underlying mechanisms are multifactorial, and understanding and management are still limited. Further research to design appropriate strategies and protocols for its monitoring, management, or prevention should be matter of thorough investigations.
Topics: Adult; Blood Platelets; Extracorporeal Membrane Oxygenation; Hemorrhage; Humans; Platelet Count; Thrombocytopenia
PubMed: 32328725
DOI: 10.1007/s00134-020-06031-4