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Amoasii, L., Long, C., Li, H., Mireault, A. A., Shelton, J. M., Sanchez-Ortiz, E., et al. (2017). Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci Transl Med, 9(418).
Abstract: Duchenne muscular dystrophy (DMD) is a severe, progressive muscle disease caused by mutations in the dystrophin gene. The majority of DMD mutations are deletions that prematurely terminate the dystrophin protein. Deletions of exon 50 of the dystrophin gene are among the most common single exon deletions causing DMD. Such mutations can be corrected by skipping exon 51, thereby restoring the dystrophin reading frame. Using clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9), we generated a DMD mouse model by deleting exon 50. These ΔEx50 mice displayed severe muscle dysfunction, which was corrected by systemic delivery of adeno-associated virus encoding CRISPR/Cas9 genome editing components. We optimized the method for dystrophin reading frame correction using a single guide RNA that created reframing mutations and allowed skipping of exon 51. In conjunction with muscle-specific expression of Cas9, this approach restored up to 90% of dystrophin protein expression throughout skeletal muscles and the heart of ΔEx50 mice. This method of permanently bypassing DMD mutations using a single cut in genomic DNA represents a step toward clinical correction of DMD mutations and potentially those of other neuromuscular disorders.
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Amr, S. S., Al Turki, S. H., Lebo, M., Sarmady, M., Rehm, H. L., & Abou Tayoun, A. N. (2017). Using large sequencing data sets to refine intragenic disease regions and prioritize clinical variant interpretation. Genet Med, 19(5), 496–504.
Abstract: PURPOSE: Classification of novel variants is a major challenge facing the widespread adoption of comprehensive clinical genomic sequencing and the field of personalized medicine in general. This is largely because most novel variants do not have functional, genetic, or population data to support their clinical classification. METHODS: To improve variant interpretation, we leveraged the Exome Aggregation Consortium (ExAC) data set (N = ~60,000) as well as 7,000 clinically curated variants in 132 genes identified in more than 11,000 probands clinically tested for cardiomyopathies, rasopathies, hearing loss, or connective tissue disorders to perform a systematic evaluation of domain level disease associations. RESULTS: We statistically identify regions that are most sensitive to functional variation in the general population and also most commonly impacted in symptomatic individuals. Our data show that a significant number of exons and domains in genes strongly associated with disease can be defined as disease-sensitive or disease-tolerant, leading to potential reclassification of at least 26% (450 out of 1,742) of variants of uncertain clinical significance in the 132 genes. CONCLUSION: This approach leverages domain functional annotation and associated disease in each gene to prioritize candidate disease variants, increasing the sensitivity and specificity of novel variant assessment within these genes.Genet Med advance online publication 22 September 2016.
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Amrani, N., Gao, X. D., Liu, P., Gupta, A., Edraki, A., Ibraheim, R., et al. (2017). NmeCas9 is an intrinsically high-fidelity genome editing platform. bioRxiv, , 172650.
Abstract: The development of CRISPR-Cas9 RNA-guided genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it
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Amsen, D. (2017). T cells take directions from supporting cast in graft-versus-host disease. J Clin Invest, 127(4), 1215–1217.
Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only treatment option for several severe hematological malignancies. The development of graft-versus-host disease (GVHD) is a common complication of the procedure and results when donor T cells become activated against recipient-specific antigens. The factors that drive the alloreactive T cell response are not completely understood. In this issue of the JCI, Chung and colleagues present evidence that stromal cells within lymphoid tissue express the Notch ligands Delta-like 1/4 (DLL1 and DLL4), which in turn directly activate T cells. Importantly, inhibition of DLL1/DLL4-mediated Notch signaling in murine HSCT models dramatically reduced GVHD and improved graft survival.
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Andrews, L. M., Li, Y., De Winter, B. C. M., Shi, Y. Y., Baan, C. C., Van Gelder, T., et al. (2017). Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients. Expert Opin Drug Metab Toxicol, 13(12), 1225–1236.
Abstract: INTRODUCTION: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren’t sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don’t necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure – research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.
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Aravanis, A. M., Lee, M., & Klausner, R. D. (2017). Next-Generation Sequencing of Circulating Tumor DNA for Early Cancer Detection. Cell, 168(4), 571–574.
Abstract: Curative therapies are most successful when cancer is diagnosed and treated at an early stage. We advocate that technological advances in next-generation sequencing of circulating, tumor-derived nucleic acids hold promise for addressing the challenge of developing safe and effective cancer screening tests.
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Ardissino, G., Perrone, M., Tel, F., Testa, S., Morrone, A., Possenti, I., et al. (2017). Late Onset Cobalamin Disorder and Hemolytic Uremic Syndrome: A Rare Cause of Nephrotic Syndrome. Case Rep Pediatr, 2017, 2794060.
Abstract: Hemolytic uremic syndrome (HUS) is an unrare and severe thrombotic microangiopathy (TMA) caused by several pathogenetic mechanisms among which Shiga toxin-producing Escherichia coli infections and complement dysregulation are the most common. However, very rarely and particularly in neonates and infants, disorders of cobalamin metabolism (CblC) can present with or be complicated by TMA. Herein we describe a case of atypical HUS (aHUS) related to CblC disease which first presented in a previously healthy boy at age of 13.6 years. The clinical picture was initially dominated by nephrotic range proteinuria and severe hypertension followed by renal failure. The specific treatment with high dose of hydroxycobalamin rapidly obtained the remission of TMA and the complete recovery of renal function. We conclude that plasma homocysteine and methionine determinations together with urine organic acid analysis should be included in the diagnostic work-up of any patient with TMA and/or nephrotic syndrome regardless of age.
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Arepally, G. M. (2017). Heparin-induced thrombocytopenia. Blood, 129(21), 2864–2872.
Abstract: Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management.
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Ariadne Esmene Afaganis, M. K. T., Alice Branton, Dahryn Trivedi, Gopal Nayak. (2017). An Impact of Energy of Consciousness (The Trivedi Effect®) on the Physicochemical, Thermal, Structural, and Behavioral Properties of Magnesium Gluconate. Biomedical Sciences, 3(2). Retrieved February 23, 2019, from http://dx.doi.org/10.11648/j.bs.20170302.11
Abstract: Magnesium gluconate is a potent antioxidant used for the prevention and treatment of hypomagnesia. The current research was aimed to investigate the impact of The Trivedi Effect® – Energy of Consciousness Healing Treatment (Biofield Energy Healing Treatment) on magnesium gluconate for the change in the physicochemical, structural, thermal and behavioral properties using PXRD, PSD, FT-IR, UV-vis spectroscopy, TGA, and DSC analysis. Magnesium gluconate was divided into two parts – one part was control, while another part was treated with The Trivedi Effect® – Energy of Consciousness Healing Treatment (Biofield Energy Healing Treatment) remotely by twenty renowned Biofield Energy Healers and defined as The Trivedi Effect® treated sample. The PXRD analysis exhibited that the crystallite size of the treated sample was remarkably changed from range -37.52% to 180.14% compared with the control sample. The average crystallite size was reduced in the treated sample by 0.11% compared with the control sample. PSD analysis revealed that the particle sizes in the treated sample at d10 and d50 values were significantly decreased by 11.36% and 8.25%, respectively, while the particle size at d90 was increased in the treated sample by 2.43% compared with the control sample. The treated sample’s surface area was significantly increased by 9.54% compared with the control sample. The FT-IR and UV-vis analysis showed that the structure of the magnesium gluconate remained the same in both the treated and control samples. The TGA analysis revealed the four steps thermal degradation of the both samples and the total weight loss of the treated sample was reduced by 2.32% compared with the control sample. This result indicated that the thermal stability of the treated sample was improved compared with the control sample. The DSC analysis revealed that the melting temperature of the treated sample (171.05°C) was decreased by 0.17% compared with the control sample (171.34°C). The latent heat of fusion was decreased by 1.16% in the treated sample compared with the control sample. The current study infers that The Trivedi Effect® – Energy of Consciousness Healing Treatment (Biofield Energy Healing Treatment) might lead to a new polymorphic form of magnesium gluconate, which would be more soluble, bioavailable, and thermally stable compared with the untreated compound. Hence, The Trivedi Effect® Treated magnesium gluconate would be very useful to design better nutraceutical and/or pharmaceutical formulations that might offer better therapeutic responses against inflammatory diseases, immunological disorders, stress, aging and other chronic infections.
Keywords: Melting Temperature of Magnesium Gluconate; Bioavailability of Magnesium; Magnesium Gluconate Solubility; Magnesium Gluconate Absorption; MgC12H22O14
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Ariadne Esmene Afaganis, M. K. T., Alice Branton, Dahryn Trivedi, Gopal Nayak. (2017). Evaluation of the Physico-chemical, Thermal and Behavioral Properties of Ashwagandha Root Extract: Effects of Consciousness Energy Healing Treatment. International Journal of Pharmacy and Chemistry, 3(3). Retrieved February 23, 2019, from http://dx.doi.org/10.11648/j.ijpc.20170303.13
Abstract: Withania somnifera (Ashwagandha) root extract has a broad range of pharmacological activities due to the presence of many biologically active metabolites. The current study was designed to evaluate the influence of The Trivedi Effect® – Consciousness Energy Healing Treatment (Biofield Energy Healing) on the physical, spectroscopic, thermal and behavioral properties of ashwagandha root extract using PXRD, PSD, FT-IR, UV-vis spectroscopy, TGA, and DSC analysis. Ashwagandha root extract was divided into two parts – one part was control without any Biofield Energy Treatment and another part was treated with the Consciousness Energy Healing Treatment remotely by twenty renowned Biofield Energy Healers and defined as Biofield Energy Treated sample. The PXRD analysis exhibited that both the control and treated samples were amorphous in nature. The particle size values at d10, d50, and d90 of the treated sample were increased significantly by 8.69%, 7.32%, and 6.50%, respectively compared with the control sample. Similarly, the surface area of the treated sample was significantly decreased by 12.69% compared to the control sample. The FT-IR analysis indicated no significant alteration of the force constant for the functional groups in the treated sample compared to the control sample. The UV-vis analysis revealed that the wavelength for the maximum absorbance of the control and treated samples were at 207.5 and 205.2 nm, respectively. The TGA revealed the two major thermal degradation steps and the total weight loss was decreased by 0.86% in the treated sample compared with the control sample. Consequently, the maximum thermal degradation temperature at 273.53°C and 389.39°C for two broad peaks in treated sample was increased by 0.78% and 0.31%, respectively compared to the control the sample (271.40°C and 388.48°C). The DSC analysis indicated that the evaporation temperature was significantly increased by 10.95% in the Biofield Energy Treated sample with a 5.34% reduced the latent heat of vaporization compared with the control sample. The overall thermal analysis indicated that the treated sample was thermally more stable as compared to the control sample. The Trivedi Effect® – Energy of Consciousness Healing Treatment might lead to have better powder flowability and long-term storage stability compared with the control sample. Thus, the treated ashwagandha root extract might provide better therapeutic response against inflammatory diseases, immunological disorders, stress, arthritis, cancer, diabetes, sexual disorders, ageing, and other chronic infections.
Keywords: Withania somnifera; The Trivedi Effect®; Biofield Energy Healing Treatment; Consciousness Energy Healing; PXRD; Particle Size; TGA; DSC
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