scholarly journals Pharmacogenetics of Antidepressants: from Genetic Findings to Predictive Strategies

2019 ◽  
Vol 4 (2) ◽  
pp. 33-43
Author(s):  
L. K. Khokhlov ◽  
N. E. Lukyanov
Keyword(s):  
Large Scale ◽  
Depressive Disorders ◽  
Genome Wide Association Study ◽  
Treatment Effectiveness ◽  
Predictive Biomarkers ◽  
Genomic Research ◽  
Control Group ◽  
Variable Activity ◽  
Cytochrome P450 Family ◽  
Almost All

The constantly growing contribution of depressive disorders to the global disease statistics calls for a growth of treatment effectiveness and optimization. Antidepressants are the most frequently prescribed medicines for depressive disorders. However, development of a standardized pharmacotherapeutic approach is burdened by the genomic heterogeneity, lack of reliable predictive biomarkers and variability of the medicines metabolism aggravated by multiple side effects of antidepressants. According to modern assessments up to 20 % of the genes expressed in our brain are involved in the pathogenesis of depression. Large-scale genetic and genomic research has found a number of potentially prognostic genes. It has also been proven that the effectiveness and tolerability of antidepressants directly depend on the variable activity of the enzymes that metabolize medicines. Almost all modern antidepressants are metabolized by the cytochrome P450 family enzymes. The most promising direction of research today is the GWAS (Genome-Wide Association Study) method that is aimed to link genomic variations with phenotypical manifestations. In this type of research genomes of depressive patients with different phenotypes are compared to the genomes of the control group containing same age, sex and other parameters healthy people. Notably, regardless of the large cohorts of patients analyzed, none of the GWA studies conducted so far can reliably reproduce the results of other analogous studies. The explicit heterogeneity of the genes associated with the depression pathogenesis and their pleiotropic effects are strongly influenced by environmental factors. This may explain the difficulty of obtaining clear and reproducible results. However, despite any negative circumstances, the active multidirectional research conducted today, raises the hope of clinicians and their patients to get a whole number of schedules how to achieve remission faster and with guaranteed results

Attitudes to the return of incidental and targeted genomic findings obtained in a high-risk pediatric cancer versus an inherited genetic condition research setting.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10066-10066
Author(s):  
Conrad Vincent Fernandez ◽  
Nada Jabado ◽  
Kym Boycott ◽  
David Malkin ◽  
Eric Bouffet ◽  
...  
Keyword(s):  
Pediatric Cancer ◽  
Large Scale ◽  
Health Impact ◽  
Genomic Research ◽  
Childhood Onset ◽  
Genetic Condition ◽  
Chi Square ◽  
Research Results ◽  
Pediatric Cancer Patients ◽  
Almost All

10066 Background: The disclosure of clinically significant, validated incidental and target findings to participants in genomic research is often recommended. There have been no reports on whether attitudes of parents differ if these findings emerge from an acquired pediatric cancer versus an inherited genetic condition setting. Methods: Parents in 3 large-scale projects [Canadian Pediatric Cancer Genome Consortium (CPCGC), the Finding of Rare Genes Canada Consortium (FORGE) and the Orphan Diseases: identifying Genes and Novel Therapeutics to Enhance Treatment Project (IGNITE)] were surveyed using a mailed, validated 29-item questionnaire. Two reminders were sent. Analysis was by descriptive and Chi-square statistics. Results: Response rate: 64% (n=307/480). 40% were > 50 yrs age; more than half had a grade 12 education. 86 were parents of poor risk pediatric cancer patients and 221 were parents or individuals with rare inherited conditions. Most stated a very strong or strong right to genomic research results, irrespective if from the target condition (97%) or incidental (86%). 70% wish genetic counselling pre- and post-research testing; an additional 20% were uncertain what this entails. Almost all indicated that genomic research for childhood onset conditions should occur, regardless of whether therapy existed (99%) or not (91%). A few indicated that they would not want incidental results showing an untreatable fatal condition (17%). Most want results, even if these suggest susceptibility to multiple conditions (87%) or are of uncertain health impact (84%). Most felt a right to genomic research that showed a serious condition in siblings, whether treatable (94%) or not (89%). 74% strongly support that results discovered after death of the proband be shared with family. Conclusions: Parents of children in both cancer and inherited rare conditions genomic research do not differ in indicating a strong right and desire to receive research results, even if they are of uncertain impact, of childhood onset, or after death of the proband. Clear delineation of what will or will not be offered from genomic research should be established at the time of consent.

scholarly journals The Secretome Deregulations in a Rat Model of Endotoxemic Shock

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
A. Blangy-Letheule ◽  
A. Persello ◽  
S. Michelland ◽  
V. Cunin ◽  
F. Souab ◽  
...  
Keyword(s):  
Septic Shock ◽  
Large Scale ◽  
Biological Fluids ◽  
Predictive Biomarkers ◽  
Control Group ◽  
Label Free ◽  
Good Opportunity ◽  
Time Points ◽  
Arterial Blood ◽  
Endotoxemic Shock

Introduction. Septic shock is a systemic inflammatory response syndrome associated with organ failures. Earlier clinical diagnosis would be of benefit to a decrease in the mortality rate. However, there is currently a lack of predictive biomarkers. The secretome is the set of proteins secreted by a cell, tissue, or organism at a given time and under certain conditions. The plasma secretome is easily accessible from biological fluids and represents a good opportunity to discover new biomarkers that can be studied with nontargeted “omic” strategies. Aims. To identify relevant deregulated proteins (DEP) in the secretome of a rat endotoxemic shock model. Methods. Endotoxemic shock was induced in rats by intravenous injection of lipopolysaccharides (LPS, S. enterica typhi, 0.5 mg/kg) and compared to controls (Ringer Lactate, iv). Under isoflurane anesthesia, carotid cannulation allowed mean arterial blood pressure (MAP) and heart rate (HR) monitoring and blood sampling at different time points (T0 and T50 or T0 and T90, with EDTA and protease inhibitor). Samples were prepared for large-scale tandem mass spectrometry (MS-MS) based on a label-free quantification to allow identification of the proteins deregulated upon endotoxemic conditions. A Gene Ontology (GO) analysis defined several clusters of biological processes (BP) in which the DEP are involved. Results. Ninety minutes after shock induction, the LPS group presents a reduction in MAP (-45%, p < 0.05 ) and increased lactate levels (+27.5%, p < 0.05 ) compared to the control group. Proteomic analyses revealed 10 and 33 DEP in the LPS group, respectively, at 50 and 90 minutes after LPS injection. At these time points, GO-BP showed alterations in pathways involved in oxidative stress response and coagulation. Conclusion. This study proposes an approach to identify relevant DEP in septic shock and brings new insights into the understanding of the secretome adaptations upon sepsis.

Next-Generation Sequencing: An Emerging Tool for Drug Designing

2019 ◽  
Vol 25 (31) ◽  
pp. 3350-3357 ◽  
Author(s):  
Pooja Tripathi ◽  
Jyotsna Singh ◽  
Jonathan A. Lal ◽  
Vijay Tripathi
Keyword(s):  
Next Generation Sequencing ◽  
High Throughput ◽  
Large Scale ◽  
Massively Parallel Sequencing ◽  
Genomic Research ◽  
Biological Research ◽  
Next Generation ◽  
Human Welfare ◽  
Drug Designing ◽  
Generation Sequencing

Background: With the outbreak of high throughput next-generation sequencing (NGS), the biological research of drug discovery has been directed towards the oncology and infectious disease therapeutic areas, with extensive use in biopharmaceutical development and vaccine production. Method: In this review, an effort was made to address the basic background of NGS technologies, potential applications of NGS in drug designing. Our purpose is also to provide a brief introduction of various Nextgeneration sequencing techniques. Discussions: The high-throughput methods execute Large-scale Unbiased Sequencing (LUS) which comprises of Massively Parallel Sequencing (MPS) or NGS technologies. The Next geneinvolved necessarily executes Largescale Unbiased Sequencing (LUS) which comprises of MPS or NGS technologies. These are related terms that describe a DNA sequencing technology which has revolutionized genomic research. Using NGS, an entire human genome can be sequenced within a single day. Conclusion: Analysis of NGS data unravels important clues in the quest for the treatment of various lifethreatening diseases and other related scientific problems related to human welfare.

Evaluation of Ovaries in Patients with Polycystic Ovary Syndrome using Shear Wave Elastography

2020 ◽  
Vol 16 (5) ◽  
pp. 578-583
Author(s):  
Aysegul Altunkeser ◽  
Zeynep Ozturk Inal ◽  
Nahide Baran
Keyword(s):  
Shear Wave ◽  
Large Scale ◽  
Polycystic Ovary ◽  
Shear Wave Elastography ◽  
Left Ovary ◽  
Control Group ◽  
Tissue Elasticity ◽  
Group I ◽  
Pcos Group ◽  
The Right

Background: Shear wave electrography (SWE) is a novel non-invasive imaging technique which demonstrate tissue elasticity. Recent research evaluating the elasticity properties of normal and pathological tissues emphasize the diagnostic importance of this technique. Aims: Polycystic ovarian syndrome (PCOS), which is characterized by menstrual irregularity, hyperandrogenism, and polycystic overgrowth, may cause infertility. The aim of this study was to evaluate the elasticity of ovaries in patients with PCOS using SWE. Methods: 66 patients diagnosed with PCOS according to the Rotterdam criteria (PCOS = group I) and 72 patients with non-PCOS (Control = group II), were included in the study. Demographic and clinical characteristics of the participants were recorded. Ovarian elasticity was assessed in all patients with SWE, and speed values were obtained from the ovaries. The elasticity of the ovaries was compared between the two groups. Results: While there were statistically significant differences between the groups in body mass index (BMI), right and left ovarian volumes, luteinizing hormone and testosterone levels (p<0.05), no significant differences were found between groups I and II in the velocity (for the right ovary 3.89±1.81 vs. 2.93±0.72, p=0.301; for the left ovary 2.88±0.65 vs. 2.95±0.80, p=0.577) and elastography (for the right ovary 36.62±17.78 vs. 36.79±14.32, p=0.3952; for the left ovary 36.56±14.15 vs. 36.26±15.10, p=0.903) values, respectively. Conclusion: We could not obtain different velocity and elastography values from the ovaries of the patients with PCOS using SWE. Therefore, further large-scale studies are needed to elucidate this issue.

scholarly journals Optimizing Manufacturing and Osseointegration of Ti6Al4V Implants through Precision Casting and Calcium and Phosphorus Ion Implantation? In Vivo Results of a Large-Scale Animal Trial

Materials ◽  
2020 ◽  
Vol 13 (7) ◽  
pp. 1670 ◽  
Author(s):  
Wölfle-Roos JV ◽  
Katmer Amet B ◽  
Fiedler J ◽  
Michels H ◽  
Kappelt G ◽  
...  
Keyword(s):  
Ion Implantation ◽  
Large Scale ◽  
In Vivo Studies ◽  
Control Group ◽  
Implant Surface ◽  
Precision Casting ◽  
Pull Out ◽  
Significant Difference ◽  
Calcium And Phosphorus

Background: Uncemented implants are still associated with several major challenges, especially with regard to their manufacturing and their osseointegration. In this study, a novel manufacturing technique—an optimized form of precision casting—and a novel surface modification to promote osseointegration—calcium and phosphorus ion implantation into the implant surface—were tested in vivo. Methods: Cylindrical Ti6Al4V implants were inserted bilaterally into the tibia of 110 rats. We compared two generations of cast Ti6Al4V implants (CAST 1st GEN, n = 22, and CAST 2nd GEN, n = 22) as well as cast 2nd GEN Ti6Al4V implants with calcium (CAST + CA, n = 22) and phosphorus (CAST + P, n = 22) ion implantation to standard machined Ti6Al4V implants (control, n = 22). After 4 and 12 weeks, maximal pull-out force and bone-to-implant contact rate (BIC) were measured and compared between all five groups. Results: There was no significant difference between all five groups after 4 weeks or 12 weeks with regard to pull-out force (p > 0.05, Kruskal Wallis test). Histomorphometric analysis showed no significant difference of BIC after 4 weeks (p > 0.05, Kruskal–Wallis test), whereas there was a trend towards a higher BIC in the CAST + P group (54.8% ± 15.2%), especially compared to the control group (38.6% ± 12.8%) after 12 weeks (p = 0.053, Kruskal–Wallis test). Conclusion: In this study, we found no indication of inferiority of Ti6Al4V implants cast with the optimized centrifugal precision casting technique of the second generation compared to standard Ti6Al4V implants. As the employed manufacturing process holds considerable economic potential, mainly due to a significantly decreased material demand per implant by casting near net-shape instead of milling away most of the starting ingot, its application in manufacturing uncemented implants seems promising. However, no significant advantages of calcium or phosphorus ion implantation could be observed in this study. Due to the promising results of ion implantation in previous in vitro and in vivo studies, further in vivo studies with different ion implantation conditions should be considered.

An Internet-based health gateway device for interactive communication and automatic data uploading: Clinical efficacy for type 2 diabetes in a multi-centre trial

2016 ◽  
Vol 23 (6) ◽  
pp. 595-604 ◽  
Author(s):  
Jae Hyoung Cho ◽  
Hun-Sung Kim ◽  
Seung Hyun Yoo ◽  
Chang Hee Jung ◽  
Woo Je Lee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthcare System ◽  
Glucose Control ◽  
Large Scale ◽  
Diabetes Management ◽  
Intervention Group ◽  
Diabetes Control ◽  
Control Group ◽  
Anthropometric Parameters ◽  
Automatic Data

Introduction The aim of this study was to improve the quality of diabetes control and evaluate the efficacy of an Internet-based integrated healthcare system for diabetes management and safety. Methods We conducted a large-scale, multi-centre, randomized clinical trial involving 484 patients. Patients in the intervention group ( n = 244) were treated with the Internet-based system for six months, while the control group ( n = 240) received the usual outpatient management over the same period. HbA1c, blood chemistries, anthropometric parameters, and adverse events were assessed at the beginning of the study, after three months, and the end of the study. Results There were no initial significant differences between the groups with respect to demographics and clinical parameters. Upon six-month follow-up, HbA1c levels were significantly decreased from 7.86 ± 0.69% to 7.55 ± 0.86% within the intervention group ( p < 0.001) compared to 7.81 ± 0.66% to 7.70 ± 0.88% within the control group. Postprandial glucose reduction was predominant. A subgroup with baseline HbA1c higher than 8% and good compliance achieved a reduction of HbA1c by 0.8 ± 1.05%. Glucose control and waist circumference reduction were more effective in females and subjects older than 40 years of age. There were no adverse events associated with the intervention. Discussion This e-healthcare system was effective for glucose control and body composition improvement without associated adverse events in a multi-centre trial. This system may be effective in improving diabetes control in the general population.

scholarly journals ‘CTRL’: an online, Dynamic Consent and participant engagement platform working towards solving the complexities of consent in genomic research

2021 ◽  
Author(s):  
Matilda A. Haas ◽  
Harriet Teare ◽  
Megan Prictor ◽  
Gabi Ceregra ◽  
Miranda E. Vidgen ◽  
...  
Keyword(s):  
Large Scale ◽  
Genomic Medicine ◽  
International Standards ◽  
Security And Privacy ◽  
Genomic Research ◽  
Return Of Results ◽  
Future Research ◽  
Design And Development ◽  
Participant Engagement ◽  
Dynamic Consent

AbstractThe complexities of the informed consent process for participating in research in genomic medicine are well-documented. Inspired by the potential for Dynamic Consent to increase participant choice and autonomy in decision-making, as well as the opportunities for ongoing participant engagement it affords, we wanted to trial Dynamic Consent and to do so developed our own web-based application (web app) called CTRL (control). This paper documents the design and development of CTRL, for use in the Australian Genomics study: a health services research project building evidence to inform the integration of genomic medicine into mainstream healthcare. Australian Genomics brought together a multi-disciplinary team to develop CTRL. The design and development process considered user experience; security and privacy; the application of international standards in data sharing; IT, operational and ethical issues. The CTRL tool is now being offered to participants in the study, who can use CTRL to keep personal and contact details up to date; make consent choices (including indicate preferences for return of results and future research use of biological samples, genomic and health data); follow their progress through the study; complete surveys, contact the researchers and access study news and information. While there are remaining challenges to implementing Dynamic Consent in genomic research, this study demonstrates the feasibility of building such a tool, and its ongoing use will provide evidence about the value of Dynamic Consent in large-scale genomic research programs.

scholarly journals The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma

2021 ◽  
Author(s):  
Ekaterina Bourova-Flin ◽  
Samira Derakhshan ◽  
Afsaneh Goudarzi ◽  
Tao Wang ◽  
Anne-Laure Vitte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Specific Gene ◽  
Specific Expression ◽  
Intrinsic Nature ◽  
Independent Cohort

Abstract Background Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. Methods A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. Results A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. Discussion The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.

The effect of preloading statins prior to primary reperfusion on in-hospital mortality risk in a contemporary large-scale cohort of patients with ST-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Fu ◽  
C.X Song ◽  
X.D Li ◽  
Y.J Yang
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Hospital Mortality ◽  
Mortality Risk ◽  
Large Scale ◽  
Reperfusion Therapy ◽  
St Elevation Myocardial Infarction ◽  
Control Group ◽  
Funding Source ◽  
St Elevation

Abstract Background The benefit of statins in secondary prevention of patients stabilized after acute coronary syndrome (ACS) has been well established. However, the benefit of preloading statins, i.e. high-intensity statins prior to reperfusion therapy remains unclear. Most previous studies included all types of ACS patients, and subgroup analysis indicated the benefit of preloading statins was only seen in ST-elevation myocardial infarction (STEMI) patients who underwent percutaneous coronary intervention (PCI). However, the sample size of subgroup population was relatively small and such benefit requires further validation. Objective To investigate the effect of loading dose of statins before primary reperfusion on 30-mortality in patients with STEMI. Methods We enrolled patients in China Acute Myocardial Infarction (CAMI) registry from January 2013 to September 2014. CAMI registry was a prospective multicenter registry of patients with acute acute myocardial infarction in China. Patients were divided into two groups according to statins usage: preloading group and control group. Patients in preloading group received loading does of statins before primary reperfusion and during hospitalization. Patients in control group did not receive statins during hospitalization or at discharge. Primary outcome was in-hospital mortality. Baseline characteristics, angiographic characteristics and outcome were compared between groups. Propensity score (PS) matching was used to mitigate baseline differences between groups and examine the association between preloading statins on in-hospital mortality risk. The following variables were used to establish PS matching score: age, sex, classification of hospitals, clinical presentation (heart failure at presentation, cardiac shock, cardiac arrest, Killip classification), hypertension, diabetes, prior angina, prior myocardial infarction history, prior stroke, initial treatment. Results A total of 1169 patients were enrolled in control group and 6795 in preloading group. A total of 833 patients (334 in control group and 499 in preloading group) died during hospitalization. Compared with control group, preloading group were younger, more likely to be male and present with Killip I classification. The proportion of hypertension and diabetes were higher in preloading group. After PS matching, all the variables used to generate PS score were well balanced. In the PS-matched cohort, 30-day mortality risk was 26.3% (292/1112) in the control group and 11.9% (132/1112) in the preloading group (p&lt;0.0001). Conclusions The current study found preloading statins treatment prior to reperfusion therapy reduced in-hospital mortality risk in a large-scale contemporary cohort of patients with STEMI. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Chinese Academy of Medical Sciences

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