Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: These include those injuries that cause large bone defects to occur and develop, such as necrosis, tumors (e. g. , osteosarcoma), high-energy traumas, and compound-, multiple-, gunshot-, open-, comminuted-, and osteoporosis-related fractures [Frohlich et al. , 2008; Amini et al. , 2012; Oryan et al. , 2015]. This failed healing process can eventually lead to the formation of malunions, delayed unions, nonunions, and osteomyelitis. Today, the correction of bone regeneration impairment has been achieved by advances in healing process management. Using the latest equipment and surgical techniques, better protocols and more effective rehabilitation procedures have contributed to a better prognosis for bone healing [Houlden et al. , 2007; Moshiri et al. , 2015b]. Despite these advancements, malunions, delayed unions, or nonunions occur and persist in clinical cases where the osteogenesis and subsequent bone remodeling are impaired, particularly in those involving large bone defects [Oryan et al. , 2014b]. In order to improve and accelerate the healing process, several options are currently available in clinical practice [Amini et al. , 2012]. First of all, after the diseased bony tissue has been removed and the remaining bones fixed, the resulting defect should be reconstructed and filled with various grafts and materials [Amini et al. , 2012; Oryan et al. , 2014b; Moshiri et al. , 2015b]. An ideal bone graft substitute should have certain properties, including osteoconduction, osteoinduction, osteoincorporation, osteointegration, and osteogenesis [Oryan et al. , 2014a]. Despite several efforts that have been made to invent and characterize various bone graft substitutes and engineered tissue scaffolds, none could be globally accepted as an ideal alternative option to autografts due to the low ability of the bone substitutes to enhance osteoinduction and osteogenesis [Zomorodian and Eslaminejad, 2012; Mallick and Cox, 2013; Bigham-Sadegh and Oryan, 2015]. Stem cell therapy, as one of the methods used in the bone repair process, has been developed over the last 2 decades [Giuliani et al. , 2013].

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: Overall, the adjusted hazard ratios for glitazones and gliptins were similar to those in table 5⇑, except confidence intervals were wider, and there was no longer a significant decrease in risk of heart failure and cardiovascular disease among people prescribed dual treatment with sulphonylureas and glitazones. DiscussionWe have conducted a large cohort study of risks for cardiovascular disease, heart failure, and all cause mortality associated with different diabetes drugs in people with type 2 diabetes attending for routine clinical care in the UK. Our companion paper27 presented the corresponding analysis for other complications of diabetes, including blindness, amputation, severe kidney failure, hyperglycaemia, and hypoglycaemia. The approach we have taken allows assessment of the relative benefits and hazards of diabetes drugs in a real world clinical setting for a range of clinically important outcomes. It enables analysis of treatment periods that are substantially longer than those reported in clinical trials,9 including more events than in previous similar observational studies. 5 12We have found clinically relevant differences between different diabetes drugs (alone and in combination) in the risk of three key outcomes—heart failure, cardiovascular disease, and death—in people with type 2 diabetes. Compared with non-use, use of glitazones was significantly associated with a decreased risk of all three outcomes (all cause mortality; heart failure, and cardiovascular disease), whereas use of gliptins was significantly associated with a decreased risk of two outcomes (all cause mortality and heart failure) but no significant change in risk of cardiovascular disease. Compared with periods of no treatment, dual treatment (ie, metformin and gliptins or metformin and glitazones) was associated with a decreased risk of all three outcomes, as was triple treatment with metformin, sulphonylureas, and either gliptins or glitazones. However, since the use of gliptins and glitazones is usually recommended as a second line treatment in combination with other agents such as metformin, the clinical question is whether the addition of gliptins or glitazones to metformin monotherapy is associated with net benefit or net harm. Compared with metformin monotherapy, dual treatment (metformin and glitazones) and triple treatment (metformin, sulphonylureas, and glitazones) were associated with decreased risk of all three outcomes (see table 6⇑).

Output: contrast


Input: Claim: Genetic markers can be used to trace inheritance patterns in populations. [SEP] Text: Conservation programs that are a compromise between what is feasible and what is desirable should focus not only on the highly diverse mainland breeds but also promote and explore the conservation possibilities for island breeds. περισσότερα Διαβάστε τη διατριβή (Online) Κατεβάστε τη διατριβή σε μορφή PDF (15. 82 MB) (Η υπηρεσία είναι διαθέσιμη μετά από δωρεάν εγγραφή) Δηλώνω ότι έλαβα γνώση και ανεπιφύλακτα συμφωνώ και αποδέχομαι τους Όρους Χρήσης του Εθνικού Αρχείου Διδακτορικών Διατριβών, καθώς και της Κατέβασμα αρχείου PDF Όλα τα τεκμήρια στο ΕΑΔΔ προστατεύονται από πνευματικά δικαιώματα. DOI10.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: The involvement of mesenchymal stem cells (MSCs) in the bone healing process is critical, in particular for difficult nonunion fractures resulting from trauma, blood insufficiency, and other conditions [Grayson et al. , 2015; Melek, 2015]. The reparative process of bone regeneration is initiated by MSCs with the formation of soft and hard calluses. Bone remodeling can eventually start after the gap has been filled by this process. Modern strategies of tissue engineering and regenerative medicine (TERM) utilize tissue scaffolds, healing promotive factors (e. g. , growth factors such as BMP-2), and MSCs to improve bone repair and regeneration. Most in vitro and many in vivo studies have suggested that the MSCs have the potential to increase osteoinduction and osteogenesis [Li et al. , 2007; Otsuru et al. , 2007; Hayashi et al. , 2008; Pitchford et al. , 2009; de Girolamo et al. , 2013]. However, little proof is available from the standard clinical trials. In addition, some controversies are apparent between the results and conclusions of the studies, making them difficult to interpret. In order to achieve successful results, an understanding of several mechanisms related to MSCs, such as homing, differentiation, apoptosis, and inflammation, together with various current and future options for which MSCs may be used, is necessary to determine the outcome of cell therapy [Qin et al. , 2014b]. In this review we summarize recent advances in understanding of the mechanisms of MSCs in bone repair. Moreover, we update the most important delivery approaches of MSCs in bone TERM. We also review the reported effects of MSC therapy on bone healing in various clinical trials according to the site of damage. The side effects of this therapy are also illustrated to help readers to draw better conclusions regarding its use. Finally, we discuss the role of TERM approaches in bone healing and illustrate the prospects and directions for the future of MSC-related research. Mechanisms of MSC Action in Characteristics of are multipotent stromal cells present in most adult connective tissues. They have been extensively studied because of their ability to differentiate into multiple cell types [Eslaminejad and Nadri, 2009; Eslaminejad et al. , 2009]. Friedenstein et al.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: Dual treatment (metformin and gliptins) was associated with a decreased risk of cardiovascular disease and all cause mortality compared with metformin monotherapy. Triple treatment (metformin, sulphonylureas, and gliptins) was associated with a 24% reduced risk of all cause mortality (see table 6⇑). GliptinsOur study included over 70 000 person years of exposure to gliptins from over 32 500 patients, which represents one of the largest studies to date, with over four times more gliptin users than in the observational study by Eurich et al. 20 Our results differ from those reported by Eurich et al, since we found that use of gliptins compared with non-use was associated with a reduction in all cause mortality. We also found that dual treatment (metformin and gliptins) and triple treatment (metformin, sulphonylureas, and gliptins) seems to be associated with a lower risk of all cause mortality compared with monotherapy with metformin. The median duration of use of gliptins in our study was 5. 7 years, compared with 2. 5 years in the study by Eurich et al,20 and the mean age of our cohort was 63 years compared with 52 years. 20 We also had more events and more statistical power—there were 996 deaths during 71 524 person years of exposure to gliptins in our study compared with 32 deaths during 11 307 person years in the study by Eurich et al. 20 Our findings of a reduction in risk of all cause mortality are relatively novel and deserve further investigation, especially as there was no overall reduction in cardiovascular events. Our results are consistent with another recent real world observational study, which found gliptins associated with reduced all cause mortality. 48 Park et al hypothesised that their findings might reflect reduced hypoglycaemic events, although their study, like ours, was observational and susceptible to unmeasured confounding. 48 In our companion paper, we reported reduced risks of hypoglycaemia among gliptin users compared with non-users, which is broadly consistent with this hypothesis.

Output: contrast


Input: Claim: Genetic markers can be used to trace inheritance patterns in populations. [SEP] Text: 12681/eadd/56176 Διεύθυνση Handle ND56176 Εναλλακτικός τίτλοςGenetic identification of Greek bovine breeds/populations using molecular markers ΣυγγραφέαςΠαπαχρήστου, Δημήτριος (Πατρώνυμο: Αναστάσιος) Ημερομηνία2023 ΊδρυμαΓεωπονικό Πανεπιστήμιο Αθηνών. Σχολή Επιστημών των Ζώων. Τμήμα Επιστήμης Ζωικής Παραγωγής.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: [1970] demonstrated a rare population of plastic-adherent cells in bone marrow (approx. 1 in 10,000 nucleated cells) that were able to form a spindle-shaped cell morphology and round-shaped colonies. These cell clones expanded into round-shaped fibroblastoid colonies, which are termed colony-forming unit-fibroblasts, or CFU-Fs. Some of the colonies could differentiate into bone, cartilage, or adipose tissue [Bianco et al. , 2008]. Other research groups extended these initial observations through the study of the proliferative abilities and phenotypic characteristics of CFU-Fs [Caplan and Bruder, 2001; Eslaminejad and Taghiyar, 2010; Eslaminejad et al. , 2011; Lotfy et al. , 2014; Baker et al. , 2015]. MSCs have been widely used in stem cell transplantation, tissue engineering, gene therapy, and immunotherapy [Reiser et al. , 2005; Marion and Mao, 2006; Zhao et al. , 2016]. These cells express CD105, CD73, and CD90, and are not able to express CD45, CD34, CD14, or CD11b, CD79α or CD19 antigens. In addition, they are able to differentiate into at least 3 cell lineages in vitro, including chondroblasts, osteoblasts, and adipocytes [Eslaminejad et al. , 2007; Wyse et al. , 2014]. MSCs can migrate to defect sites and facilitate bone regeneration, but the fundamental mechanisms in this process remain unclear. In regenerative medicine, among all types of stem cells, MSCs are the most commonly used stem cells because of their beneficial properties [Murphy et al. , 2013]. The advantages and disadvantages of different types of MSCs are listed in Table 1. MSC populations and maintenance of their homeostasis are established in MSC niches [Ehninger and Trumpp, 2011]. Niches are specific anatomic locations that regulate tissue generation, maintenance, and repair by MSCs [Glenn and Whartenby, 2014]. The niche has a dual role by which it saves MSCs from depletion and also protects the host from overexuberant MSC proliferation.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: 27Our results are also broadly consistent with recent non-inferiority trials18 and meta-analyses of randomised controlled trials, reporting that various gliptins (alogliptin, dutogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) are associated with statistically significant 30-60% reductions in major adverse cardiac events and non-significant 33% and 48% reductions in all cause and cardiovascular death compared with other active drugs or placebo treatment. 49 50 However, Monami et al urge caution in interpreting the results because the events were not the principle endpoints, the trial duration was short, and the characteristics of patients could be different from those of patients in routine clinical practice. 50 We found an inverse association for gliptins, with a 15% lower risk of heart failure, whereas trials did not find such a strong benefit. This may reflect residual confounding owing to the observational study design or differences in study duration. However, our findings are consistent with the recently published multicentre nested case-control study,51 which also reported a 14-18% lower risk of hospital admission for heart failure with gliptins compared with other diabetes drugs. It is also consistent with a new user cohort study, which did not find a higher risk of heart failure among patients prescribed gliptins compared with other diabetes drugs. 52Some of the differences in results between our observational study and earlier clinical trials may reflect the type of gliptin studied—80% of patients prescribed gliptins were prescribed sitagliptin in our study compared with saxagliptin in some of the trials. Currently there are too few patients prescribed linagliptin, saxagliptin, and vildagliptin to support separate analyses by individual drug, which is a limitation of the study as there may be differences between individual gliptins and their effect on haemoglobin A1c. 53 However, the numbers of people taking different types of gliptin is likely to increase over time, and further analyses can be undertaken once more data have accrued. GlitazonesOur study included over 55 000 person years of exposure to glitazones arising from 21 308 patients.

Output: contrast


Input: Claim: Genetic markers can be used to trace inheritance patterns in populations. [SEP] Text: Εργαστήριο Γενικής & Ειδικής Ζωοτεχνίας Εξεταστική επιτροπήΜπιζέλης ΙωσήφΚουτσούλη ΠαναγιώταMedugorac IvicaΚομινάκης ΑντώνιοςΜπεμπέλη ΠηνελόπηΠαφίλης ΠαναγιώτηςΜπουγιούκος Κωνσταντίνος Επιστημονικό πεδίοΓεωπονικές Επιστήμες και Κτηνιατρική ➨ Επιστήμη Ζωικής Παραγωγής ➨ Επιστήμη ζωικής παραγωγής Λέξεις-κλειδιάΕλληνικές φυλές βοοειδών; Γενετική ποικιλομορφία; Γενετική δομή ΧώραΕλλάδα ΓλώσσαΑγγλικά Άλλα στοιχείαεικ. , πιν.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: In fact, it controls the balanced response of MSCs to the necessary requirements of the body [Glenn and Whartenby, 2014]. It may also preclude aberrant function on MSCs or other targets that cause malfunctions. MSC niches are located adjacent to vessel walls, on the endosteal surfaces of trabecular bone, umbilical cord blood (vein, arteries, Wharton jelly, and lining membrane) [Lee et al. , 2004], dental tissues (dental pulp, exfoliated deciduous teeth, periodontal ligament, apical papilla, dental follicle, and periapical cyst-MSCs [Kim et al. , 2011; Marrelli et al. , 2015b], adipose tissue [Zuk et al. , 2002], and synovium (synovial membrane and fluid) [Jones et al. , 2004]. The sources of MSCs are shown in Figure 1. Table 1Advantages and disadvantages of different types of MSlargeFig. 1View largeDownload slideSources of MSCs. Fig. 1View largeDownload slideSources of MSCs. Close modal MSCs and Blood clotting and inflammatory reactions are 2 immediate responses when bone fractures occur. In fact, inflammation can initiate the cascades and pathways for bone regeneration by producing chemotactic factors [Jacobs et al. , 2013]. In the second phase of inflammation (chronic phase), chronic inflammatory cells, particularly the macrophages and lymphocytes, enter the injured site. The role of macrophages and T helper lymphocytes should be highlighted. Macrophages have many important roles during bone healing. They not only phagocytize the necrotic tissues, micro-organisms, and hematoma, but also release several beneficial cytokines and growth factors that facilitate the transition from the inflammatory stage to the reparative phase of bone healing. There are at least 2 important inflammatory behaviors in response to exogenous cell/graft/scaffold/matrix implantation. In the type I response, the lymphocyte T helper type I cells trigger macrophage type I cells, which causes an inflammatory reaction to occur. This type results in graft/cell rejection.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: The predominant glitazone was pioglitazone, which was prescribed to 90% of glitazone users, and hence our results most closely reflect associations for pioglitazone rather than rosiglitazone (withdrawn in the UK in 2010). Our study is substantially larger than a previous UK study of 92 000 people with diabetes, which finished in 20054 and includes newer drugs available over the past decade. It supplements information from the Canadian study,12 of people aged 66 and over which compared three outcomes (heart failure, myocardial infarction, and death) among 16 951 users of pioglitazone compared with 22 785 users of rosiglitazone between 2002 and 2008. Our study is more recent and includes more patients prescribed pioglitazone over a longer duration (mean exposure of 4. 5 years in our study compared with 294 days). It also includes more events—the Canadian study12 included 461 cases of heart failure, 273 of myocardial infarction, and 377 deaths. We have found significant reductions in two outcomes—cardiovascular disease and all cause mortality—among users of glitazones compared with non-users (table 3⇑). This reduction is similar in magnitude to that reported in clinical trials and meta-analyses of pioglitazone. 9 11 In 2007, Lincoff et al reported a meta-analysis of 19 trials of pioglitazone with a treatment duration ranging from four months to 3. 5 years. 11 The results showed an 18% decreased risk of their composite primary outcome (risk of death, myocardial infarction, or stroke). However, we have reported a decreased risk of heart failure among users of glitazones compared with non-users. This contrasts with the increase in heart failure that occurred in other studies, without an associated increase in mortality. 9 11 The authors of the PROactive study partially attributed this finding to a diagnostic bias due to the increase of oedema in the pioglitazone group. 9 Our observational study differs from the clinical trial not only in design, size, and setting but also in the calendar time during which it was conducted and in the selection of patients. For example, the PROactive study9 selectively recruited high risk patients with pre-existing macrovascular disease, whereas our study included a more representative population from primary care.

Output: contrast


Input: Claim: Genetic markers can be used to trace inheritance patterns in populations. [SEP] Text: , χαρτ. , σχημ. , γραφ. Στατιστικά χρήσης ΠΡΟΒΟΛΕΣ Αφορά στις μοναδικές επισκέψεις της διδακτορικής διατριβής για την χρονική περίοδο 07/2018 - 07/2023. Πηγή: Google Analytics. ΞΕΦΥΛΛΙΣΜΑΤΑ Αφορά στο άνοιγμα του online αναγνώστη για την χρονική περίοδο 07/2018 - 07/2023. Πηγή: Google Analytics. ΜΕΤΑΦΟΡΤΩΣΕΙΣ Αφορά στο σύνολο των μεταφορτώσων του αρχείου της διδακτορικής διατριβής. Πηγή: Εθνικό Αρχείο Διδακτορικών Διατριβών.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: , 2013]. The antiapoptotic effect of MSCs could also accelerate the process of bone healing. It has been suggested that faster bone healing with MSC transplantation may be especially correlated with lower levels of TNF-α expression in the callus [Kovach et al. , 2015]. This may favor bone formation since it has been reported that TNF-α can have proapoptotic effects on osteoblasts. MSCs and we know, angiogenesis is a very important factor for bone formation and it is logical to speculate that angiogenesis also contributes to bone regeneration and repair. In this regard, many studies have attempted to incorporate angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, insulin-like growth factor, platelet-derived growth factor, and bone morphogenetic proteins (BMPs) into scaffolds to improve the bone healing process [Chen et al. , 2004; Simmons et al. , 2004; Formiga et al. , 2010]. The process of angiogenesis involves a complex interaction between endothelial cells and the corresponding microenvironment, including endothelial cell survival, proliferation, migration, tube formation, and maturation. In previous in vivo studies, the angiogenic activity of MSCs has been suggested to contribute to their regenerative capability [Smadja et al. , 2012; Manieri et al. , 2015]. The angiogenesis could be increased with the help of their paracrine signal. The microenvironment of the damaged tissue changes due to the angiogenesis, which then benefits osteogenesis [et al. , 2011]. Some biomatrices, such as platelet-rich fibrin (PRF), play critical roles as a biological niche in stimulating the resident MSCs in the angiogenesis process. PRF (fibrin sealant or fibrin glue) is the second-generation plasma-rich plasma (PRP), which is an improved version of the traditionally prepared PRP. PRF significantly enhances the healing of soft and hard tissues and is widely used in regenerative dentistry. The PRF not only enhances the healing process through reducing bone resorption, but it also promotes neoangiogenesis in the defect site of oral bone [Marrelli and Tatullo, 2013].

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: Two thirds of patients in the PROactive study9 had evidence of myocardial infarction or stroke compared with 14% in our study. It is also possible that, given the growing concerns about rosiglitazone and its subsequent withdrawal, patients with symptoms or signs suggestive of early heart failure (such as breathlessness or oedema) in our study might not have been prescribed pioglitazone or might have switched to another diabetes drug. Other diabetes drugsAlthough our research question focuses on associations between gliptins and glitazones and adverse clinical outcomes, for comparison we have results for other diabetes drugs. Overall, metformin monotherapy was associated with reduced risks of all cause mortality, heart failure, and cardiovascular disease compared with non-use. This is important because metformin is generally recommended as the first line diabetes drug and is commonly used in combinations with other drugs. Sulphonylureas were associated with an increased risk of all cause mortality both in the main analysis and in the sensitivity analyses restricted to new users of sulphonylureas. Monotherapy with sulphonylureas was also associated with an increased risk of cardiovascular disease and as triple treatment with metformin and insulin was associated with an increased risk of heart failure compared with metformin alone. These unfavourable results are consistent with some studies linking sulphonylureas with increased adverse cardiovascular events,5 but not all studies. 26 Further research into the safety of sulphonylureas compared with other types of diabetes drugs is warranted. However, this research needs to distinguish between individual types of sulphonylureas, as different individual drugs have different mortality risks. 54As in our companion paper,27 we excluded prevalent users of insulin at baseline but included in the analysis those patients subsequently prescribed insulin because insulin is part of the treatment ladder and some of these people will also have had other drugs of interest during follow-up. Although insulin was not the primary drug of interest, patients prescribed insulin had higher risks of all three outcomes, despite adjustment for higher levels of comorbidity. It is unlikely that this increased risk was a direct result of treatment with insulin. Instead, residual confounding and reverse causality could have occurred—that is, the insulin treated group was at much higher risk of complications than the groups treated with diet or oral drugs, and these result in their apparently worse outcomes and not their treatment with insulin.

Output: contrast


Input: Claim: Genetic markers can be used to trace inheritance patterns in populations. [SEP] Text: ΧΡΗΣΤΕΣ Αφορά στους συνδεδεμένους στο σύστημα χρήστες οι οποίοι έχουν αλληλεπιδράσει με τη διδακτορική διατριβή. Ως επί το πλείστον, αφορά τις μεταφορτώσεις. Πηγή: Εθνικό Αρχείο Διδακτορικών Διατριβών. "Γενετική ταυτοποίηση των αυτόχθονων πληθυσμών βοοειδών με τη χρήση μοριακών δεικτών" Πληκτρολογήστε το κείμενο της εικόνας!

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: It has been shown that the angiogenic activity of PRF is due to the slow and steady release of growth factors such as VEGF, which is primarily responsible for endothelial cell proliferation via the extracellular signal-regulated kinase activation pathway [Roy et al. , 2011]. MSC Homing and Recruitment to Many challenges are involved in the healing of critical-sized bone defects (CSDs). In bone, CSD is the term used for any orthopedic defect that will not heal without intervention and where nonunion would subsequently occur [Poser et al. , 2014]. Basically, there are 3 main reasons for the occurrence of nonunions, including a lack of MSC migration into the defect site, insufficient numbers of osteoblast progenitor cells (MSCs) in the CSD, and failure to differentiate into osteoblasts or the wrong differentiation of MSCs [Wang et al. , 2009]. As the first step of the chain in the treatment of nonunions, many researchers attempt to recruit MSCs to the defect site. The exact mechanism of MSC homing to the injury site is still not clear; however, chemotactic factors released at the site of the bone defect must play an essential role in MSC homing and recruitment. It is known that MSCs express at least 19 chemokine receptors [Li et al. , 2012]. Specific chemokine receptors (e. g. , CCR1, CCR7, CCR9, CXCR4, CXCR5, and CXCR6) are important mediators in this matter, and among them CXCR4 and its ligand (CXCL12 or stromal-derived factor 1; SDF1) are the most widely investigated mediators in the MSC recruitment process [Kitaori et al. , 2009]. A localized hypoxic condition occurs in the initial stage of fracture due to vascular damage that acts as a useful recruitment factor and regulatory stimulus for MSCs and other progenitor cells [Mehta et al. , 2012; Toupadakis et al. , 2012]. It has also been suggested that new bone formation occurs under hypoxic conditions [Olmsted-Davis et al. , 2007].

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: For example, in table 2⇑, the insulin treated group had the highest haemoglobin A1c and creatinine values before treatment, although both factors were adjusted for in the analyses. An alternative explanation could be that patients with symptoms that indicated cardiovascular disease or heart failure were prescribed insulin rather than glitazones or gliptins before subsequently having a diagnosis of these conditions. Strengths and limitations of this studyGeneralisabilityThis is a large study based on an ethnically diverse contemporaneous, representative population of people with type 2 diabetes during an eight year study period. We included all eligible patients to minimise selection bias. Hence we think the results are likely to be generalisable to similar populations of people with type 2 diabetes. Although our observational study has limitations inherent in its design, it also has advantages over meta-analyses of clinical trials as these tend to be limited by ascertainment and reporting of events, short follow-up, lack of time to event data, and insufficient power to report on rare cardiovascular events. 23Clinical outcomesStrengths of our analysis are the inclusion of hard clinical endpoints of cardiovascular disease, heart failure, and death based on clinical diagnoses recorded on at least one of three linked electronic data sources. Use of all three linked data sources was designed to minimise under-ascertainment of outcomes, which would otherwise lead to under-estimation of absolute risks. The cardiovascular disease and heart failure outcomes are based on clinical diagnoses made by the treating clinician rather than formally adjudicated events as would occur in a clinical trial. Although it is possible that some patients were recorded as having heart failure or cardiovascular disease who did not have this condition, such misclassification will not have affected the mortality outcome. UK general practices have good levels of accuracy and completeness in recording clinical diagnoses and prescribed drugs. 55 Also, the diagnostic validity of such diagnoses in general practice has been shown to be high. 56 Possible ascertainment bias of outcomes is unlikely to vary according to the type of diabetes drug prescribed so would not explain the associations we found. Exposure to diabetes drugsWe had detailed information on use of diabetes drugs prescribed throughout the follow-up period, enabling us to develop a detailed categorisation of drug exposure time into 21 different treatment groups, including combinations of treatments. Recording of prescriptions issued in UK general practices has high levels of completeness.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: Skip to Content eLife home page your research Search by keyword or author Reset form my search to and Genomics Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial for Regulomes, United States; School of Medicine, United States; Apr 8, 2019 Open access Copyright information Version of RecordApril 17, 2019 Accepted ManuscriptApril 9, 2019 Accepted ManuscriptApril 8, 2019 Open annotations (there are currently 0 annotations on this page). 12,455 views 1,543 downloads 102 5105. Copy to clipboard Download BibTeX Download. RIS Full text Figures and data Peer review Side by side files 2 figures and 4 additional files 1 with 5 supplements Download asset Open asset reveals cell lineage from mtDNA mutations. (A) workflow. Usings standard ATAC-seq data as input (left), an SNV calling step was added to enumerate all single nucleotide variants in mtDNA (middle). identifies heteroplasmic mtDNA mutations in single cells, groups mutations into diagnostic sets, and infers cell lineage based on mtDNA variants, and overlays clonotype information on epigenomic profile of the same cells (right). (B) ATAC-seq enriches for mtDNA reads compared to whole exome sequencing (WES), low coverage whole genome sequence (WGS_L), or PCR-free, high-coverage whole genome sequence (WGS_H). (C) Bimodal distribution of variant allele frequency (VAF) of mtDNA mutations discovered using ATAC-seq. Yellow bar presents the homoplastic variants that can distinguish different individuals. Heteroplasmic variants can distinguish clonal cell populations within one individual. (D) Two possible models for 25% mtin bulk: Homoplastic variants in a small proportion of cells (top) or heteroplasmic variants in nearly every single cell (bottom). Blue cells: cells with mutated mtDNA, blue dots: mtDNA with mutated allele. (E) VAF of mtDNA mutations in single cell ATAC-seq data of human B cells. Each dot presents the VAF (y-axis) in single cells, and rotated kernel density on each side presents their distribution. The x-axis indicates the mutation site (the nucleotide position in mitochondrial genome). (F) mtDNA mutations in human AML.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: Hypoxia can express special genes that increase cell survival under low oxygen tension and induce the reestablishment of blood vessels for oxygen delivery [Papandreou et al. , 2006]. In addition, hypoxia by the expression of the hypoxia-inducible factor 1-α (HIF-1α) subunit transcription factor may induce the upregulation of SDF1 and ultimately regulate the homing of progenitor cells. The SDF1/CXCR4 (CXC chemokine receptor R4) axis is thought to be a master mediator of MSC recruitment and migration [Yellowley, 2013]. Because of the hypoxic condition at the injured (fracture) site, it is possible that the expression of chemokines such as SDF1 is regulated by hypoxia and HIF-1α. The homing of leukocytes and their role in transporting hematopoietic precursors in tissues are very similar to mechanisms that govern the migration of MSCs [Trautmann et al. , 2014] (Fig. 2). It has been discovered that mobilization of MSCs to the site of fracture, where they are thought to contribute to the regeneration of bone, is mainly facilitated through paracrine support of angiogenic factors (e. g. ). Furthermore, secretion of angiogenic factors in injured tissue could be due to the activation of HIFs [Mallela et al. , 2013]. MSCs can also recruit the other MSCs or progenitor cells towards the injury/defect site via paracrine effects [Shao et al. , 2015]. Fig. 2View largeDownload slideMSC homing to the fracture site. HIF-1α may increase the transcription of CXCL12 (SDF1) production in the cells of damaged bone. In normoxia conditions, HIF-1α is hydroxylated by the activity of prolyl hydroxylase domain protein 2 (PHD2), leading to HIF-1α binding to the von Hippel-Lindau protein (VHL) and subsequent ubiquitination (Ub) and proteasomal degradation. Otherwise, in hypoxia (low O2), due to a reduction of PHD2 activity, HIF-1α levels are stabilized and migrate into the nucleus to form a complex with HIF-1β.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: 57 We ascertained patient characteristics, concurrent drugs, clinical values, and diagnoses at the beginning of each treatment period. This enabled us to account for switching between different treatments or treatment combinations, making adjustments for a large number of potential confounders. We undertook a time varying analysis, which analysed different types of monotherapy, dual treatment, and triple treatment over the study period. This reflects real world prescribing patterns over a long duration, allowing multiple comparisons not only between drugs but also between different combinations of drugs compared with untreated periods of time (diet only treatment). Our study analysed prescribed drugs rather than the drug actually taken by the patients, although renewal of prescriptions is likely to indicate drug use, as patients need to initiate repeat prescriptions. This could result in misclassification of exposure if patients were prescribed drugs that they did not actually take and could underestimate associations between use of diabetes drugs and clinical outcomes. Unlike previous studies, we have included comparisons of risk against periods of no treatment,5 which is important as about 40% of people with type 2 diabetes are managed without diabetes drugs throughout follow-up. Limitations include lack of analyses for different subtypes of each type of drug and for different dose levels. Assessment of other types of biasOther types of bias that can affect observational studies include recall bias, indication bias, and channelling bias. Recall bias will not have occurred as data on prescriptions for diabetes drugs and confounding variables were recorded before the clinical outcomes. We restricted the study population to people with type 2 diabetes to limit indication bias (ie, bias that occurs when people are prescribed drugs for a condition that is itself associated with the risk of the adverse event under consideration). We used an incident user design to reduce, but not eliminate, confounding and biases that can otherwise arise from adjustment for intermediate characteristics in the causal path. 36 There were some differences at baseline between patients prescribed different treatment groups (tables 1 and 2⇓), although these were predominantly increased levels of comorbidities for insulin and lower levels of concurrent use of drugs (such as statins and aspirin) for metformin. To reduce channelling bias (where the choice of a particular drug is influenced by patient characteristics), we adjusted for a wide range of potential confounding variables.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: Each row in the heap map is a single cell (LSC or AML blast); each column is a heteroplasmic mtDNA mutation. Blue color indicates the mtDNA variant is detected (>1 reads); white color indicates no mutation. The nucleotide position in mitochondrial genome for each mutation is indicated. (G) Combined set of heteroplasmic mtDNA mutations improve cell lineage assignment in single cells. Cells were first separated into bins according to their mtDNA coverage (x-axis). The detection rate (y-axis) for each site (indicated by different color and shape) is calculated with the number of cells with that mutations divided by total number of cells in that bin. The detection rate of combining four sites (black line, ) is substantially increased. (H) Quantitation of mtDNA mutation detection rate as a function of sequencing depth and number of single cells. Cells were sorted in descending order by their sequencing depth and grouped into bins (10% of cells in each row). Distribution of sequencing depth is shown on the left panel. The black line and dark blue shade indicate mean ± standard deviation, respectively. The light blue shade indicates remaining value of the bin. Cells with or without mtDNA variants are shown in blue and orange on the right panel, respectively. Figure 1—figure supplement 1 Download asset Open asset workflow for SNP calling and lineage inference. (A) Workflow for mitochondrial DNA variant calling from ATAC-seq data. This workflow was applied to both bulk and single cell ATAC-seq. The steps indicated with dotted lines were not applied to single-cell data. (B) Workflow for inferring lineage relationships from single-cell ATAC-seq data. BAM files from single cells were first merged and confident mtDNA variants were called. Mutated alleles from these variant sites were then counted for each single cell. The cell lineage was then inferred from mtDNA variants and analyzed alongside the chromatin profile for each cell. Figure 1—figure supplement 2 Download asset Open asset mtDNA coverage and variants from different sequencing libraries from GM12878 human B cells. (A) Mitochondrial genome coverage from each of four different sequencing libraries including WGS_H (high coverage PCR-free whole genome sequencing), WGS_L (low coverage whole genome sequencing), WES(whole exome sequencing), ATAC-seq. axis shows coverage scaled in log10.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: HIF-1α then binds to the hypoxia-responsive element (HRE) on the promoter of the CXCL12 gene with the cooperation of the transcriptional coactivating CREB-binding protein (CBP). This cascade can drive the upregulation of CXCL12 levels at the site of injury and promotes the migration of MSCs from the blood circulation to the defect site. The CXCL12 ligand binds to its receptor CXCR4 on circulating cells and converts cell surface integrins to a high-affinity state. This process is necessary for the binding of MSCs to vascular endothelial cells. MSCs then migrate through the endothelium towards the CXCL12 gradient. This process of chemokine-mediated cell extravasation is very similar to leukocyte transmigration. Fig. 2View largeDownload slideMSC homing to the fracture site. HIF-1α may increase the transcription of CXCL12 (SDF1) production in the cells of damaged bone. In normoxia conditions, HIF-1α is hydroxylated by the activity of prolyl hydroxylase domain protein 2 (PHD2), leading to HIF-1α binding to the von Hippel-Lindau protein (VHL) and subsequent ubiquitination (Ub) and proteasomal degradation. Otherwise, in hypoxia (low O2), due to a reduction of PHD2 activity, HIF-1α levels are stabilized and migrate into the nucleus to form a complex with HIF-1β. HIF-1α then binds to the hypoxia-responsive element (HRE) on the promoter of the CXCL12 gene with the cooperation of the transcriptional coactivating CREB-binding protein (CBP). This cascade can drive the upregulation of CXCL12 levels at the site of injury and promotes the migration of MSCs from the blood circulation to the defect site. The CXCL12 ligand binds to its receptor CXCR4 on circulating cells and converts cell surface integrins to a high-affinity state. This process is necessary for the binding of MSCs to vascular endothelial cells. MSCs then migrate through the endothelium towards the CXCL12 gradient.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: This included demographic characteristics (age, sex, ethnicity, and deprivation), different comorbidities, clinical values (including haemoglobin A1c, body mass index, blood pressure, creatinine level, and cholesterol to high density lipoprotein cholesterol ratio), and concurrent drugs. However, we are unable to exclude the possibility of residual confounding because other unmeasured patient characteristics might have affected the selection of diabetes drug treatment. Although randomised controlled trials of diabetes drugs are not influenced by residual confounding, they tend to be small, of short duration, and might not report on relevant clinical outcomes. An alternative design would be an observational study of a cohort of patients specifically assembled for the purpose rather than using routinely collected data as in our study. Studies using routinely collected data are susceptible to missing data, although in our study over 99% of patients had smoking status recorded, 87% had ethnic group recorded, and over 82% had complete data for all five clinical values (table 2⇑). We also used multiple imputation to deal with missing data. Other problems with routine data include coding errors and variable timing between measurements of risk factors because of differences in when patients present to their general practitioner. Advantages of using routinely collected data rather than a purposeful cohort include size, efficiency, better generalisability, and less susceptibility to selection bias or attrition bias. We fitted several different models and carried out sensitivity analyses that showed some heterogeneity of results with variations in point estimates. The results are therefore sensitive to the assumptions made in the study design and modelling and have uncertainty; however, our findings were generally consistent across the different analyses for glitazones and gliptins. ConclusionsWe have found clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination compared with no drug treatment. Overall, use of gliptins or glitazones was associated with a decreased risk of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs. These results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, may have implications for prescribing of diabetes drugs.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: 43M paired-end ATAC-seq reads (2 × 50 bp) yielded the same coverage of mtDNA as 747M paired-end reads (2 × 250 bp) from WGS-H data. (B) Comparison of variants detected in sequencing data from four different library preparations. The number of variants detected in each library is shown on the bottom left. The intersection of different libraries (bottom-right) and the number of variants are shown on the top. Homoplasmic variants are in yellow and heteroplasmic variants are in blue. (C) Heteroplasmic mtDNA mutations detected by WGS_H (in blue) and ATAC-seq (in red). axis is the position of the mutation on mitochondrial genome and Y axis is the variant allele frequency in percentage. Figure 1—figure supplement 3 Download asset Open asset Heteroplasmic mtDNA mutation in K562 cells. (A) Percentage of mtDNA reads in ATAC-seq and whole genome sequence(WGS) libraries from human K562 cells. Four millions mtDNA reads from 32 millions total mapped reads in ATAC, seven millions mtDNA reads from 1775 millions total reads in WGS. (B) The average coverage of the mitochondrial genome in ATAC and WGS from K562 cells. (C) Number of heterplasmic mtDNA mutations detected in ATAC and WGS. The intersection size represents mutations detected by single or both methods. (D) Variant allele frequency of mtDNA mutations and their correlation between ATAC and WGS. The red dots indicate the mutations detected by both ATAC and WGS, with the same criteria. The black dots indicate the mutations detected by ATAC or WGS only. Figure 1—figure supplement 4 Download asset Open asset Heteroplasmic variants in single cells from AML blasts and LSCs (SU353). (A) Heatmap showing variant mitochrondrial sites (columns) in each AML blast from patient SU353(rows). The color represents the number of reads supporting the variant allele (log2(depth)). The first two sites are negative controls, which are detected in pHSCs only. (B) Bar plot showing the number of cells in which we detect each mitochondrial variant. The last bar shows the number of cells with any one of the four variants detected.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: This process of chemokine-mediated cell extravasation is very similar to leukocyte transmigration. Close modal Some studies have focused on the recruitment of MSCs to the bone defect site for treating the nonunions. Das et al. [2014] showed that FTY720 (a small molecule) enhances MSC recruitment to the calvarial defect of rats, thus promoting skeletal repair. They suggested that sustained release of FTY720 from injected microspheres used alone or in combination with rhBMP-2 improves the recruitment of MSCs and subsequently increases bone repair. Zwingenberger et al. [2014] showed that SDF-1α mediates stem cell mobilization and enhances BMP-2-induced bone regeneration in CSDs. They implanted adenovirally activated fat tissue grafts expressing SDF-1α and/or BMP-2 at the defect site in the treatment group. CT-scans and histological analysis confirmed a higher degree of bone healing in the BMP-2 and SDF-1α combined group compared with the negative control group. In this area, another investigation showed that cobalt can activate HIF-α, through which it contributes to the recruitment of MSCs for the initiation of the bone healing process [Wu et al. , 2012]. With these promising results, endogenous MSC recruitment into the bone injury/defect site via small molecules or protein mobilizing factors could be another interesting field for researchers working on stem cell-based therapy in bone regeneration. MSCs and Differentiation of have great potential to differentiate into various cell types, such as osteoblasts, and it has also been hypothesized that MSC transplantation would induce tissue regeneration by replacing cells in the injured site, the incidence of MSC engraftment has remained surprisingly low. Accumulating evidence indicates that the general therapeutic effects of MSCs are due to their ability to support a regenerative microenvironment rather than their capacity to differentiate and incorporate into the host tissue [Horwitz et al. , 2002; Amin et al. , 2014]. As previously mentioned, MSCs reduce the TNF-α level at the injured site. Another important effect of TNF-α is the blockage of osteoblast differentiation, which occurs by inhibiting the expression of 2 essential transcription factors for bone formation: Runx2 and its downstream target, osterix [Nanes, 2003].

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: What is already known on this topicCardiovascular disease and heart failure are major causes of morbidity and mortality in people with type 2 diabetesSeveral diabetes drugs have been associated with an unexpected increased risk of heart failure during clinical trials and post-marketing surveillance raising concerns about overall risks and benefitsThere is a need to quantify risks of clinical outcomes in large representative populations of people with type 2 diabetes prescribed these drugs over longer periodsWhat this study addsClinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality were found between different diabetes drugs alone and in combinationCompared with non-use of gliptins, gliptin use was significantly associated with an 18% decreased risk of all cause mortality, a 14% decreased risk of heart failure, and no significant change in risk of cardiovascular diseaseCompared with non-use of glitazones, glitazones were significantly associated with a 23% decreased risk of all cause mortality, a 26% decreased risk of heart failure, and a 25% decreased risk of cardiovascular diseaseFootnotesWe acknowledge the contribution of the practices that contribute to QResearch and (EMIS), and the University of Nottingham for expertise in establishing, developing, and supporting the database. The data from hospital episode statistics used in this analysis are re-used by permission from the Health and who retain the copyright. We thank the Office for for providing the mortality data. ONS bear no responsibility for the analysis or interpretation of the data. Contributors: JH-C initiated the study, undertook the literature review, data extraction, data manipulation, and primary data analysis, and wrote the first draft of the paper. CC contributed to the design, analysis, data manipulation, interpretation, and drafting of the paper. JH-C had access to all the data for this project. JH-C is the guarantorFunding: This study received no external funding. Competing interests: All authors have completed the ICMJE uniform disclosure form at www. icmje. org/coi_disclosure. pdf (available on request from the corresponding author) and declare: JH-C is professor of clinical epidemiology at the University of Nottingham and codirector of QResearch, a not-for-profit organisation, which is a joint partnership between the University of Nottingham and (leading commercial supplier of IT for 60% of general practices in the UK).

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: (C) The top right shows the number of cells with each different combination of variants detected. The number of cells is shown on top of the bar. The combination of variants detected is annotated below the bar. The total number of cells with each variant site detected is shown to the left. The average coverage of the mitochondrial genome for each intersection group is shown below. (D) VAF of mtDNA variants. The x-axis indicates the variant site notated by the nucleotide position in the mitochondrial genome. Each dot represents the VAF (y-axis) in single cells and the rotated kernel density on each side shows their distribution. (E–H) Same as (A–D), for leukemia stem cells (LSCs) from patient SU353. Figure 1—figure supplement 5 Download asset Open asset Heteroplasmic variants in single cells from AML blasts and LSCs (SU070). (A–D) Same as Figure 1—figure supplement 3A–D for AML blasts from SU070. (E–H) Same as Figure 1—figure supplement 3A–D for LSCs from SU070. (I) Quantification of the detection rate for each heteroplasmic variant from mtDNA. Cells (both LSCs and AML blasts) were first separated into bins according to their coverage of mtDNA (x-axis). The detection rate (y-axis) for each site (notated by different color and shape) is calculated as the number of cells with that variant detected divided by the total number of cells in that bin. (J) Quantitation of mtDNA mutation detection rate as a function of sequencing depth and the number of single cells. Cells were sorted in descending order by their sequencing depth and grouped into bins (10% cells in each row). Distribution of sequencing depth is shown on the left panel. Cells with or without mtDNA mutations are shown in blue or orange, respectively. Figure 2 with 4 supplements Download asset Open asset Clonal evolution of pre-leukemic HSCs inferred from joint lineage tracing and single cell chromatin accessibility. (A) Lineage hierarchy in acute myeloid leukemia based on and prior genetic information. mtDNA mutations reveals pHSC clonal heterogeneity.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: Therefore, MSCs make an indirect contribution to osteoblast cell differentiation and bone regeneration. An interesting experimental study showed that transplanted MSCs contribute to fracture healing by expressing BMP-2, which induces bone and cartilage formation [Granero-Moltó et al. , 2009]. Some of the mechanisms of MSC action on bone regeneration and repair are illustrated in Figure 3. Fig. 3View largeDownload slideSome mechanisms of MSC action on bone reconstruction and repair. The beneficial effects of MSCs include immunomodulatory effects, stimulation of angiogenesis, antiapoptotic effects in osteoblastic lineage cells, recruitment of host MSCs/progenitor cells, and stimulation of their differentiation into osteoblasts. Fig. 3View largeDownload slideSome mechanisms of MSC action on bone reconstruction and repair. The beneficial effects of MSCs include immunomodulatory effects, stimulation of angiogenesis, antiapoptotic effects in osteoblastic lineage cells, recruitment of host MSCs/progenitor cells, and stimulation of their differentiation into osteoblasts. Close modal of MSCs for So far, several different approaches have been utilized to deliver MSCs into the injured area of the bone (i. e. , bone defects) [Bernardo et al. , 2007; Sorrell et al. , 2009; Lee et al. , 2010; Achille et al. , 2011]. The most common method for using MSCs is direct injection [Chabner et al. , 2004]. Some studies have also shown that seeding MSCs on biocompatible scaffolds could be an attractive candidate for treating nonunion fractures [Oryan et al. , 2014b]. In general, MSCs can be applied through systemic and local injections or by tissue engineering approaches. injection of MSCs has been used in the treatment of osteoporosis and fracture healing for many years [Huang et al. , 2015]. Several factors are involved in order to achieve more successful results from cell therapy in bone healing. These include the vehicle and type of cells, cell concentration, differentiating status of the cells, treatment period, and route of administration [Granero-Moltó et al. , 2009].

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: Guidance on rosiglitazone for type 2 diabetes mellitus. for Clinical Excellence, 2000. ↵Cohen D. Insiders criticise FDA’s decision not to withdraw rosiglitazone. BMJ2010;341:c5333. ↵. The record on rosiglitazone and the risk of myocardial infarction. N Med2007;357:67-9. doi:10. 1056/NEJMe078116 pmid:17551162. of Science↵ PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PR(PROspective pioglitmacroVascular Events): a randomised controlled trial. Lancet2005;366:1279-89. doi:10. 1016/S0140-6736(05)67528-9 pmid:16214598. of Science↵Scheen AJ. Outcomes and lessons from the PROactive study. Clin Pract2012;98:175-86. doi:10. 1016/j. diabres. 2012. 09. 001 pmid:23020930. ↵. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA2007;298:1180-8. doi:10. 1001/jama. 298. 10. 1180 pmid:17848652. of Science↵. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ2009;339:b2942. OpenUrlAbstract/↵Graham DJ, Ouellet- Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA2010;304:411-8. doi:10. 1001/jama. 2010. 920 pmid:20584880. of Science↵ Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care2011;34:916-22. doi:10. 2337/dc10-1068 pmid:21447663.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: The clonal precursor of the leukemic stem cell is not the clone with most representation in the pHSC pool, but rather the clone with epigenomic bias towards the leukemic regulatory program, as depicted by related color schemes. (B) deconvolutes AML clonal heterogeneity. Heteroplasmic mtDNA mutations in three cell populations from patients SU070 are shown. Mutations sites (in rows) in each FACS-sorted cell population (in columns) are shown, with size of each circle representing its VAF. Several mtDNA mutations (sites shown in purple) are detected in pHSCs and transmitted to LSCs and blasts, confirming those pHSC clones at the apex of leukemia lineage. LSCs accumulated additional mtDNA mutations (sites shown in green) and are transmitted to leukemic blasts in patient SU070. Allele frequency, sequencing depth and annotation of the variant allele are shown in Figure 2—figure supplement 1 and Supplementary file 2. (C) Same plot as (B) shown for patient SU353. In addition to the shared mtDNA mutations in pand blasts (purple), two pHSCs-specific mtDNA mutations are also detected (yellow). Allele frequency, sequencing depth and annotation of the variant allele are shown in Figure 2—figure supplement 1 and Supplementary file 2. (D) Heteroplasmic mutations in single pHSCs from one patient reveal clonal heterogeneity. Each column is a mtDNA nucleotide position; each row is one cell. Blue color indicates the presence of the mtDNA variant. Shown are cells with any mtDNA mutation detected, or cells with more than 40X coverage of the mitochondrial genome without any detected mutation(pHSC with WT mtDNA). The number of cells in each clonotype are indicated on the right. (E) Landscape of single-cell chromatin accessibility of blood progenitor and leukemic cells in patient SU353. tSNE map using bias-corrected deviations from chromatin accessibility showing cluster of AML blasts, LSCs, pHSCs and normal HSC, colored by cell types. (F) Chromatin accessibility of the FOS:JUN binding motif across the same single cells. tSNE map colored by deviation z-score for motif associated to FOS:JUN, the most variable TF motif. (G) pHSC clones possess distinct epigenomic signatures.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: Bone marrow-derived MSCs and adipose tissue-derived MSCs (ADMSCs) are the most applicable type of MSCs that have been used in bone regenerative medicine. Among these, the stromal vascular fraction (SVF) is a component of adipose tissue that has attracted much attention recently, specifically for the use of this fabulous extraction in bone and cartilage defects [Jurgens et al. , 2013]. SVF of adipose tissue is a rich source of preadipocytes, MSCs, different types of progenitor and inflammatory cells, and cytokines, which are extracted by the processing of body fat [Gentile et al. , 2012]. Evidence from experimental and clinical studies has shown that SVF is more effective in bone and cartilage healing than ADMSCs alone. It is believed that the more advantageous effects of SVF may be a reflection of different growth promotion factors and cytokines, which not only support the proliferation, differentiation, and viability of ADMSCs, but also play a critical role in the tissue repair process [Pak et al. , 2014]. SVF can be easily collected and enriched with platelet-rich plasma [Moshiri and Oryan, 2013]. In addition, ADMSCs in SVF can be activated by photostimulation with low-level lasers and light-emitting diodes [Peng et al. , 2012]. Similar to drug studies, there is an effective cell dose (ECD) for stem cell therapy, which is defined as the minimum cell number required to discern a remarkable therapeutic effect [Horwitz et al. , 2002]. In clinical trials that have focused on bone regenerative medicine, the MSC dose per person is determined as a mean of 1. 86 × 108 cells, or is based on body weight, calculated as a mean of 6. 64 × 106 cells/kg. However, there is no precise available ECD for the treatment of bone defects and disorders, meaning further studies are needed to illustrate a guideline in this regard. It is important to select an appropriate route of administration for MSC therapy in order to improve bone healing. Intravascular injection of MSCs (including intravenous, IV, and intra-arterial, IA, cell delivery) has been used by many clinicians in bone defects and some promising results have been reported [Horwitz et al. , 1999, 2001; et al.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: OpenUrlAbstract/↵ Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the Association (ADA) and the for the Study of Diabetes (EASD). Diabetologia2012;55:1577-96. doi:10. 1007/s00125-012-2534-0 pmid:22526604. of Science↵. Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Drug Saf2014;5:138-46. doi:10. 1177/2042098614523031 pmid:25083269. OpenUrlAbstract/↵. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Med2013;369:1327-35. doi:10. 1056/NEJMoa1305889 pmid:23992602. of Science↵Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. J Med2015;373:232-42. ↵ Sitagliptin and the risk of hospitalization for heart failure: a population-based study. Cardiol2014;177:86-90. doi:10. 1016/j. ijcard. 2014. 09. 038 pmid:25499347. ↵-. Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study. BMJ2013;346:f2267. doi:10. 1136/bmj. f2267 pmid:23618722. OpenUrlAbstract/↵. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol2013;12:3. doi:10. 1186/1475-2840-12-3 pmid:23286208. ↵. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Med2007;147:578-81. doi:10. 7326/0003-4819-147-8-200710160-00182 pmid:17679700. of Science↵. Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: the case of rosiglitazone. J2008;156:23-30.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: Clone 1 that gives rise to the AML has a chromatin accessibility profile that more resembles LSCs and leukemic blasts. ‘WT’ pHSC refers to the pHSC with WT mtDNA. Clonotype information from is overlaid on the tSNE map defined by TF motif deviations, and colored by different lineal sub-populations defined by mtDNA mutations. (H) Quantitation of distinct single-cell chromatin accessibility at FOS:JUN motifs among different pHSC clones defined by EMBLE. Clone 1 pHSCs tend to down regulate FOS:JUN accessibility, while clone 2 pHSC shows substantially greater cell-to-cell variability. pHSCs with no detectable mtDNA variants and normal HSCs are shown for comparison. TF deviation of single cells (black dots) is shown on the distribution box-plot. The statistical significant were indicated by ‘*” when p<0. 05, ‘**” when p<0. 01(Wilcoxon rank-sum test). Figure 2—figure supplement 1 Download asset Open asset Heteroplasmic mtDNA mutations detected in bulk ATAC-seq from AML patients. (A) The number of heteroplasmic variants detected using ATAC-seq data from normal primary blood cells and cancer cells from AML patients. (B) The number of mtDNA variants identified from normal and cancer samples in different substitution classes are shown as a bar plot. Mutations from normal (gray) and cancer (yellow) samples are separated. > T and T > C signature in mtDNA mutations has been observed in previous studies and it's equivalent to the one that has been operating during the evolution of human germline mtDNAs. (C) Annotation of mtDNA mutations and the proportion of mutations in coding and non-coding regions. Coding mutations are divided into synonymous, nonsynonymous, and gain of stop codon. Heteroplasmic mutations detected from cancer samples show a similar distribution as those from normal samples, with a slightly higher proportion falling within coding regions. (D) Heteroplasmic mutations in three cell stages for each AML patient. Variant alleles (in rows) in each cell population (in columns) are shown with a circle, with size indicating their variant allele frequency.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: , 2005]. Intravascular delivery of MSCs is the most common systemic method that is minimally invasive and has the potential for a broad distribution of cells throughout the body. Despite the suggested beneficial effectiveness of an IV injection method on bone repair, some drawbacks have been reported previously, such as significant entrapment of cells after passing through the lungs and formation of vascular microemboli [Castelo-Branco et al. , 2012]. This effect in IV delivery of MSCs is called the pulmonary first pass effect [Fischer et al. , 2009]. However, some investigations have suggested that MSCs trapped inside the lungs can potentially have therapeutic effects [Lee et al. , 2009; Choi et al. , 2011; Roddy et al. , 2011]. Alternatively, MSCs can be systemically delivered by IA injection that overcomes the drawbacks of an IV delivery method. The pulmonary first pass effect of IV injection is bypassed by an IA route of administration. In addition, the ECD can be decreased by simply switching from IV to IA delivery due to the bypassing of the lungs and lower risk of cellular embolism. However, cellular embolism has also been reported with the IA delivery route of bone marrow stromal cells (BMSCs) in rats, which is related to the cell dose and infusion velocity [Cui et al. , 2015]. Overall, use of a local delivery route for MSC transplantation has been suggested because many researchers believe that after systemic infusion virtually all MSCs are trapped in the lungs and rapidly disappear. The occurrence of some cells in extravascular spaces is most likely due to the vascular leakage created by the injury. A comparison of IV and IA delivery of MSCs is provided in Figure 4. Fig. 4View largeDownload slideBioluminescence imaging of the IV and IA route of cell delivery in rats. Rats were irradiated unilaterally (white arrow) before IV (a) or IA (b) injection with 1 × 106 BMC9 MSCs expressing a luciferase reporter [Kean et al. , 2013]. Copyright© 2013 Thomas J. Kean et al. This is an open access 0. 4 mL (12 × 106 cells) and fibrin was prepared and injected locally into the fracture site. Eventually, a significant fracture healing acceleration was observed.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: doi:10. 1016/j. ahj. 2008. 03. 002 pmid:18585493. of Science↵Department of Health and for and Research. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. ↵. Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus. 2010. ↵Bell DS. Do sulfonylurea drugs increase the risk of cardiac events? CMAJ2006;174:185-6. doi:10. 1503/cmaj. 051237 pmid:16415463. ↵Hippisley-Cox J, Coupland C. Diabetes treatments and risk of amputation, blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia: open cohort study in primary care. BMJ2016;352:i1450. doi:10. 1136/bmj. i1450 pmid:27029547. OpenUrlAbstract/↵Wikipedia. Readcodes 2015 J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ2005;330:1366-74. doi:10. 1136/bmj. 330. 7504. 1366 pmid:15947398. OpenUrlAbstract/↵Hippisley-. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ2005;331:1310-6. doi:10. 1136/bmj. 331. 7528. 1310 pmid:16322018. OpenUrlAbstract/↵Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ2010;340:c2197. doi:10. 1136/bmj. c2197 pmid:20488911. OpenUrlAbstract/↵Parker C, Coupland C, Hippisley-Cox J.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: Sequencing depth of the variant allele is indicated by the color of the circle (in log2 scale). pHSC-specific mutation sites are in red. Allele frequency and annotation of mtDNA mutations were shown in Supplementary file 2 (E) Heteroplasmic mutations in two cell stages for each AML patient. Variant alleles (in rows) in each cell population (in columns) are shown with a circle, with size indicating their variant allele frequency. Sequencing depth of the variant allele is indicated by the color of the circle (in log2 scale). pHSC-specific mutation sites are in red. Allele frequency and annotation of mtDNA mutations were shown in Supplementary file 2. Figure 2—figure supplement 2 Download asset Open asset Single cell chromatin accessibility. (A) Phylogenetic relationship of cells from SU353 was inferred using the Neighbor-Joining method. The phylogenetic tree is drawn to scale, with branch lengths in the units of the number of base difference per site. The clade in purple matched to clone 1 and the clade in yellow matched to clone 2 in Figure 2D. The cell type and mtDNA variants in each single cell are shown on the right. 229 single cells with at least one of the six heteroplasmic mtDNA mutations were included. (B) Heat map showing clusters of pHSCs from SU353 and normal HSCs from a healthy donor, based on the z-score of TF deviation. The Z-score deviation is shown for individual cells (columns) for each TF (rows). Clone information is shown on the top of the heat map. Top 50 most variable motifs were used in this heat map. (C) Volcano plot showing the difference in chromatin accessibility for transcription factor binding motifs between Clone 1 and Clone 2. The x-axis shows the mean difference of bias-corrected deviations and the y-axis shows the p-value (in log10 scale). The most significant differential motifs are annotated with TF names. (D) Same as in (C) for Clone 1 vs. WT cells. (E) Same as in (C) for Clone 2 vs. WT cells. No significantly differential motifs were detected. Figure 2—figure supplement 3 Download asset Open asset for pHSCs. Scheme of FACS sorting of the pHSC population from AML patient SU353.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: This is the only published clinical trial that has used differentiated MSCs in long bone fracture healing [Kim et al. , 2009]. In the field of stem cell therapy, considerable clinical information about the myriad possibilities are available for consideration. Many registered international or national clinical trials have been conducted to investigate the role of MSCs in long bone defect healing. However, so far almost none of them have reported their results, with only a few providing initial information about their research. This review used available information in clinical trial databases such as the ( the ClinicalTrials. gov database ( the ( and the Australian and clinical trials registry (www. anzctr. org. au/). In order to show the current status of clinical MSC therapy for bone repair, the available clinical trials are listed in Table 3. All the clinical trials related with MSCs and long bone defects cited in clinical trial registries were included, and those labeled as “unknown status,” “withdraw,” or “not yet recruiting” were excluded. Finally, 16 clinical trials related to long bone fracture, delayed union or nonunion, and MSC therapy were identified that were cited in clinical trial registries as completed (10 of them) or recruiting patients. These trials used MSCs for treating long bone fracture/nonunion via different procedures, including direct injection/implantation of the MSCs with or without scaffolds/matrices. They can be classified into 3 groups to allow for a comparative analysis. The first group, with 4 clinical trials (3 completed), used local injection of MSCs without in vitro culture and expansion, and none of these trials have been published so far. The second group (5 clinical trials, 2 completed, none published) used expanded MSCs by local injection in the defect site. The third group consisted of 8 trials intending to test MSCs with bone substitutes. Just 1 among the completed trails has published the results [Liebergall et al. , 2013]. Table 3Randomized clinical trials using MSCs to treat long bone defects View largeNeedless to say, the main criticism of these completed clinical trials is their failure to report results. This may reflect: (1) lack of expected results (e. g. , beneficial effects of MSCs on bone regeneration), (2) inconsistency in results, (3) the need to conduct further phases of study, or (4) other unknown reasons.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: Antipsychotic drugs and risk of venous thromboembolism: nested case-control study. BMJ2010;341:c4245. doi:10. 1136/bmj. c4245 pmid:20858909. OpenUrlAbstract/↵Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data. BMJ2013;346:f114. doi:10. 1136/bmj. f114 pmid:23325866. OpenUrlAbstract/↵-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ2015;350:h517. doi:10. 1136/bmj. h517 pmid:25693810. OpenUrlAbstract/↵Hippisley-Cox J, Pringle M. Prevalence, care, and outcomes for patients with diet-controlled diabetes in general practice: cross sectional survey. Lancet2004;364:423-8. doi:10. 1016/S0140-6736(04)16765-2 pmid:15288740. of Science↵ The incident user design in comparative effectiveness research. Saf2013;22:1-6. doi:10. 1002/pds. 3334 pmid:23023988. ↵Hippisley- Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ2008;336:1475-82. doi:10. 1136/bmj. 39609. 449676. 25 pmid:18573856. OpenUrlAbstract/↵ UK Study (UKDPS) Group. A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the Study (UKPDS) (UKPDS no. 68). Diabetologia2004;47:1747-59. doi:10. 1007/s00125-004-1527-z pmid:15517152. of Science↵. .

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: community resource of transposable element families, sequence models, and genome annotations access Published: 12 January 2021 community resource of transposable element families, sequence models, and genome annotations Jessica Storer1, : orcid. org/0000-0001-9261-38211, Jeb Rosen1, Travis J. Wheeler2 & …Arian F. Smit1 Show authors Mobile DNA 3. 0–3. 3 releases of Dfam ( represent an evolution from a proof-of-principle collection of transposable element families in model organisms into a community resource for a broad range of species, and for both curated and uncurated datasets. In addition, releases since Dfam 3. 0 provide auxiliary consensus sequence models, transposable element protein alignments, and a formalized classification system to support the growing diversity of organisms represented in the resource. The latest release includes 266,740 new de novo generated transposable element families from 336 species contributed by the EBI. This expansion demonstrates the utility of many of Dfam’s new features and provides insight into the long term challenges ahead for improving de novo generated transposable element datasets. IntroductionSignificant portions of many genomes are composed of transposable element (TE) copies. TE-derived sequence decays in the genome over time, making its discovery and characterization challenging. However, accurate annotation and description of these elements is crucial in understanding their impact on the genome in which they reside and the evolution of a species as a whole. The influence of TEs on the genome and/or species can be direct, such as insertions into coding regions, exaptation to new functions, or chromosomal rearrangements as a consequence of non-homologous recombination, or indirect, as with an “arms race” between the host and resident parasite. TE instances have long been identified in genomes through a combination of two complementary strategies: de novo detection, and database-driven annotation. In de novo detection, a variety of methods are used to recognize and categorize remnants of TE activity. The families identified in this fashion are typically further curated and cataloged in databases such as Dfam. In database-driven annotation each sequence in that database is aligned to the genome being annotated, with the best-scoring alignment determining the label of the genomic sequence. Such databases have long used consensus sequences to represent each family.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: Analysis showed that only gene-transduced MSCs could induce osteogenesis in vivo, whereas adenoviral vector or nontransduced MSCs alone did not induce osteogenesis. The osteogenic genes can also be transduced to MSCs using a gene-activated matrix (GAM). GAM is one of the tissue engineering approaches that consists of collagenous scaffold impregnated with plasmid DNA encoding osteogenic genes. When GAM is inserted into a bone defect, host MSCs entering the scaffold are transfected by plasmid and consequently secrete the osteogenic gene product. The usefulness of GAM in bone tissue regeneration was investigated by Umebayashi et al. [2015]. GAM with atelocollagen containing cDNA of BMP4 (pBMP4) or Runx2 (pRunx2) was transplanted into the cranial bone surface under the periosteum of F344 rats. At 2, 4, and 8 weeks after surgery, the results showed that the bone induction effect of GAM is dose-dependent and bone formation was detectable in specimens containing 1 mg of pBMP4 or pRunx2 at 8 weeks. Epigenetic regulation and RNA interference are major strategies routinely used to modify genes. Gordon et al. [2011] showed that loss of the PBX1 (pre-B-cell leukemia homeobox 1) gene from the osterix promoter is associated with an increase in the recruitment of histone acetylases (p300). Based on this result, it was proposed that PBX1 plays a central role in weakening the activity of the HOXA10 (homeobox A10) gene as an activator of osteoblast-related genes and functions to establish the appropriate timing of gene expression during osteogenesis. Furthermore, Zeng et al. [2012] found that knockdown of BMPR-2 by RNA interference inhibits osteogenic differentiation of ADMSCs. Although promising results have been generated in the experimental studies, gene-manipulated MSC transplantation for treating bone injuries in humans has limited application and its safety and efficacy need to be elucidated in the near future. In addition, developing clinical grade vectors is a very complex process and does not seem to be cost effective. Genetic modification strategies of MSCs for bone healing are shown in Figures 5 and 6. Fig.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: 2. 147 pmid:12090408. of Science↵ Effect of dipeptidyl peptidase-4 inhibitor on all-cause mortality and coronary revascularization in diabetic patients. J Cardiovasc Ultrasound2015;23:233-43. doi:10. 4250/jcu. 2015. 23. 4. 233 pmid:26755932. ↵ Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Cardiol2012;110:826-33. doi:10. 1016/j. amjcard. 2012. 04. 061 pmid:22703861. ↵. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Res Opin2011;27(Suppl 3):57-64. doi:10. 1185/03007995. 2011. 602964 pmid:22106978. ↵. A multicenter observational study of incretin-based drugs and heart failure. N Med2016;374:1145-54. doi:10. 1056/NEJMoa1506115 pmid:27007958. ↵ Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: a retrospective cohort study. Med2016;164:705-14. doi:10. 7326/M15-2568 pmid:27110660. ↵ A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ Open2015;5:e005892. doi:10. 1136/bmjopen-2014-005892 pmid:25687897. OpenUrlAbstract/↵. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Endocrinol2015;3:43-51. doi:10. 1016/S2213-8587(14)70213-X pmid:25466239. ↵Majeed A. Sources, uses, strengths and limitations of data collected in primary care in England. Q2004;(21):5-14.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: However, such searches tend to miss highly-diverged sequences, prompting us to explore the utility of profile methods [1, 2] to increase sensitivity. In 2012, we released Dfam [3], a database of TE families from the human genome in which each family was represented by a multiple sequence alignment (MSA) and a profile hidden Markov model (HMM). Profile HMMs [4, 5] yield sensitivity gains in part by modeling the position-specific residue and indel (insertion and deletion) variability found in family MSAs. The first release of Dfam was based on the design of similar databases of protein (Pfam) and RNA (Rfam) families [6, 7]. In addition to improving annotation sensitivity through the use of profile HMMs, Dfam demonstrated decreased false discovery rates through rigorously defined thresholds [8]. An additional advantage of these databases is the preservation of a multiple sequence alignment of representative family members, the seed alignment. The seed alignment is model-agnostic, provides details on coverage and fragmentation, and supplies essential provenance for the family. Subsequent releases of Dfam refined the prototype database and modestly expanded the curated libraries to five model organisms (4150 families). In 2018, Dfam received funding to move from a proof-of-principle to a production community resource by (1) scaling the system architecture, (2) supporting multiple model types (HMMs and consensus sequences) derived from the seed alignment, (3) improving annotation speed and quality, and most importantly (4) engaging the community in its further development. In this paper we will describe accomplishments represented in the latest release series (Dfam 3. 0 through 3. 3) and the challenges that lay ahead. These accomplishments include support for consensus models, a hierarchical TE classification system with an interactive explorer, a TE termini library encompassing various DNA transposon classes, and a framework for “uncurated” or “raw” data sets in Dfam alongside the existing curated data sets. Dfam 3.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: 5View largeDownload slideDifferent approaches in gene-modified MSCs. Fig. 5View largeDownload slideDifferent approaches in gene-modified MSCs. Close modal Fig. 6View largeDownload slideThe gene delivery process for MSCs: (1) the carrier or nanop4. Table 4A useful guide for MSC therapy research View largeThe healing rate increases in close relation with the implanted MSC concentration [Wu et al. , 2007]. Concentrated MSCs can be mixed with a synthetic or natural osteoconductive matrix [Bornes et al. , 2014]. As a novel strategy for MSC therapy in fracture healing, combination therapy might be used in the future. In this approach, MSCs can be implanted with a biodegradable scaffold in the fracture site and 1-2 weeks later osteoinductive genes can be injected locally at the site of implantation. Another way to achieve this goal is a reversed procedure. The various MSC delivery approaches are shown in Figure 7. Fig. 7View largeDownload slideMSC delivery approaches. Systemic delivery of MSCs (a), osteoinductive genes (b), and gene-modified MSCs (c) by injection into the circulatory system. Local delivery of MSCs with or without culture media (d), osteoinductive genes (e), and gene-modified MSCs with or without growth factors (f) by direct injection at the fracture site. Local delivery of MSCs (g), osteoinductive genes (h), and MSCs with osteoinductive genes (i) by incorporation in scaffolds, which are implanted at the fracture site. Combination therapy: MSCs are implanted with scaffolds in the fracture site and osteoinductive genes are injected locally at the site of implantation 1-2 weeks later (j). By an alternative method, osteoinductive genes with scaffolds can be implanted in the fracture site and MSCs injected locally at the site of implantation 1-2 weeks later (k). Fig. 7View largeDownload slideMSC delivery approaches. Systemic delivery of MSCs (a), osteoinductive genes (b), and gene-modified MSCs (c) by injection into the circulatory system.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: English 简体中文 6Publishing-Submit a Manuscript F6Publishing-世界华人消化杂志在线投稿 is committed to discovery and dissemination of knowledge About the a All 10. 4254/wjh. v7. i22. 2363] of This 2. it of This 4. 0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: Counts in Google of This 2015. Published by Group Inc. All rights reserved. Hepatol. Oct 8, 2015; 7(22): 2363-2368 Published online Oct 8, 2015. doi: 10. 4254/wjh. v7. i22. 2363 All-oral interferon-free treatments: The end of hepatitis C virus story, the dream and the reality of Medical, Surgical, Neurological, Geriatric and Metabolic Sciences, of Naples, 80100 number: $[] Author contributions: Adinolfi LE and conceive and wrote the paper. Conflict-of-interest statement: The authors do not have conflict of interest. Open-Access: This 4. 0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: to: of Medical, Surgical, Neurological, Geriatric and Metabolic Sciences, of 80100 Naples, Italy. luigielio. adinolfi@unina2. it Telephone: +39-823-690642 Fax: +39-823-690642 Received: May 27, 2015Peer-review started: May 28, 2015First decision: July 27, 2015Revised: August 14, 2015Accepted: September 16, 20154. 1 The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus (HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: 3 currently houses 273,655 families: 112,455 retrotransposons, 101,711 DNA transposons, and 59,489 other repeats that include interspersed repeats of unknown origin, satellite regions and/or other non-TE entries to avoid annotating non-coding RNA genes as TEs. At present, Dfam’s coverage of organismal diversity is smaller than that of Repbase, owing to Repbase being a closed database and having two decades longer to accumulate data; with the development of an open framework for community contribution, the pace of data acquisition in Dfam is expected to close that gap quickly. Consensus modelsWhile the use of HMMs allows for improved detection of TE copies in genomes, most sequence analysis algorithms (Smith-Waterman, Needleman-Wunsch etc. ) and popular sequence analysis tools (etc. ) act directly on string representations of sequences (e. g. consensus sequences). Likewise, programs used to define new TEs (de-novo repeat finders), to extend fragmented models, to unravel the relationship of related TEs, to classify elements or to describe biological features like exons are not typically able to generate or take advantage of HMMs directly. Each TE model in Dfam therefore should be accompanied by a simple sequence model; a consensus sequence derived from the seed alignment is the logical candidate. The use of a consensus sequence as a first-order model for sequence families has a rich history of demonstrated utility [2, 9,10,11]. A consensus is typically made by considering the occupancy and composition of columns in a multiple sequence alignment of TE copies. A basic consensus caller might assign for any given column the majority nucleotide found in the column regardless of occupancy (the number of homologous nucleotides in the column vs the number of gaps). A more sophisticated caller would account for gaps and make base calls reflecting the observed rates of substitutions in the given genome. Most TE-derived sequences are under no functional constraint and accumulate mutations in a random and neutral fashion. Given this random noise, an informed consensus for a sufficient number of properly aligned copies may be expected to reproduce the original active TE sequence.

Output: pass


Input: Claim: Stem cells are used in regenerative medicine to repair damaged tissues. [SEP] Text: Local delivery of MSCs with or without culture media (d), osteoinductive genes (e), and gene-modified MSCs with or without growth factors (f) by direct injection at the fracture site. Local delivery of MSCs (g), osteoinductive genes (h), and MSCs with osteoinductive genes (i) by incorporation in scaffolds, which are implanted at the fracture site. Combination therapy: MSCs are implanted with scaffolds in the fracture site and osteoinductive genes are injected locally at the site of implantation 1-2 weeks later (j). By an alternative method, osteoinductive genes with scaffolds can be implanted in the fracture site and MSCs injected locally at the site of implantation 1-2 weeks later (k). Close modal Another challenge for bone regenerative medicine at this early stage is the isolation of a specific category of cells from donors with different individual genetic profiles due to patient variability [Nsair and MacLellan, 2011]. Moreover, different biomaterials that have been used for the scaffolding of MSCs raise technical challenges (i. e. , the type of material, the special effect on bone, the effect on MSCs) [Gomez-Barrena et al. , 2011]. It is important to prepare biodegradable scaffolds with osteoinductive properties; their application can provide a 3D environment for MSCs at the site of the defect in which they promote angiogenesis and can contribute to the healing process [Cao et al. , 2014]. Finally, differentiation of the MSCs into preosteogenic cells is not fully supported by the in vivo release of osteogenic factors. Thus, by using the appropriate scaffold in an alternative approach, such problems may be solved. Furthermore, MSCs can be used together with PRP and different growth/healing promotive factors in order to improve their beneficial effects on bone healing. However, it is very difficult to conclude which elements are particularly critical and effective in stem cell therapy for bone healing because of the lack of comparative and randomized clinical studies [Evans et al. , 2006]. The implementation of accurate clinical trials may help to further define and spread these therapies as a standardized cost-beneficial procedure for bone regeneration cell therapy, if their safety and efficacy is proven.

Output: corroborate


Input: Claim: All treatments using nanotechnology are completely risk-free. [SEP] Text: The scientific hepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However, the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition, many other conditions such as modality of access and delivery of care, inadequate knowledge of HCV epidemiology and political commitments to be undertaken, hamper the fulfillment of the dream to eliminate the virus. Since, such conditions are not impossible to overcome, a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths. Key Words: Sofosbuvir; Simeprevir; New-oral hepatitis C virus treatments; Paritaprevir; Dasabuvir; Daclatasvir; Ledipasvir; tip: It is begun the era of all-oral direct-acting antiviral drugs for hepatitis C virus (HCV) treatment allowing interferon-free therapeutic regimens. These regimens are safe and yield cure rate greater than 90%. The therapeutic success has posed the basis for HCV elimination, although, confirmation are waiting from real world. However, many conditions hinder the fulfillment of the dream. These conditions are the excessive cost of drugs, the access and delivery of care, the epidemiology of HCV and the political commitments. Thus, an urgent effort must be done to make accessible on large-scale all-oral anti-HCV therapies allowing saving millions of lives. Citation: Adinolfi LE, Guerrera B. All-oral interferon-free treatments: The end of hepatitis C virus story, the dream and the reality. Hepatol 2015; 7(22): 2363-2368 URL: DOI: the years 2014-2015 the scientific hepatology community virtually laid the milestone that could mark the beginning of the end of the hepatitis C virus (HCV) story. The milestone marked the advent of the first new oral drugs approved for HCV treatment, namely sofosbuvir and simeprevir, which were quickly followed by several others allowing interferon (IFN)-free therapeutic regimens. These innovative therapies, which yield a cure rate of over 90%, have been approved in many regions of the world, including Europe and the United States.

Output: contrast


Input: Claim: The Human Genome Project mapped the entire sequence of human DNA. [SEP] Text: This bears out particularly well for most “class II elements” or “DNA transposons” in eukaryotes; due to the trans-activity of the transposase on the genomic copies, these do not tend to evolve during their short life in a genome, and thus create copies that have a star-like phylogenetic relationship to the original sequence (Fig. 1) [12]. The situation is more complicated for most class I elements, which duplicate via a reverse transcription step; thanks to the cis-activity of the reverse transcriptase on its own mRNA, they may evolve, e. g. to escape the host’s defense mechanisms, and propagate in a genome for hundreds of millions of years. For these elements, careful clustering of copies into so-called subfamilies will result in a series of interrelated consensus sequences that can be interpreted as snapshots of the TE sequence during its evolution, though each may still be a composition of divergent active elements. Fig. 1Typical phylogenetic structure of retroposon and DNA transposon families. After multiple mutations have occurred in the evolving class I TE, the relative ordering of copies may be distinguished by these changes as they cosegregate. The presence of such clusters or “subfamilies” of TE copies is a good indication that they arose via retrotranspositionFull size imageThe concept that consensus sequences approach the original TE sequence has been demonstrated by the resurrection of recently extinct TEs through modification of a dead copy to the consensus [13, 14] and by the recovery of expected sequence features for ancient elements. For example, the consensus sequences of many coding TEs that were active > 100 MYA in our genome contain full-length ORFs [15], despite the fact that their individual copies have accumulated so many mutations that they on average share less than half the original nucleotides with each other and often cannot be pairwise aligned. was initiated as a reference database containing (single copy) prototypes of genomic interspersed repetitive DNA [16], we began developing consensus sequence representations by 1994 [11]. Not only did this endeavor explain the biological origin of most repetitive DNA, the use of consensus sequences rather than genomic copies improved the detection of older and therefore more diverged copies as well. A collection of genomic copies has redundancy and contains low complexity sequences like simple repeats expanded in individual copies, both of which result in lower specificity.

Output: pass