Category Archives: Genetic medicine

In recent years, the idea of the microbiome has gone from being an esoteric term used in scientific circles, to a mainstream concept employed in adverts to sell microbiome-boosting health drinks and supplements. The increase in public interest has been fed by a series of headline-grabbing research breakthroughs, and the fact that the microbiome has a key role to play in the development of precision medicine.The trillions of microbes contained in the human body are a key element of a personalized approach to treatment; the microbiome influences endocrinology, physiology, and even neurology, and has a crucial role in disease progression. The growing awareness of the various ways in which microbiota affects each of us individually in sickness and in health is also leading to an increase in research. An area in which this interest is growing particularly quickly is oncology.

Multiple publications implicate microbiota in the onset and progression of cancers, as well as toxicity and the response rate of cancer treatments. An analysis of 12 million full-text publications, 29 million abstracts and 521 thousand grant applications for semantic relations between cancers and microbiota is shown in figure 1. The data show a considerable increase in the number of articles linking cancers to microbiota for five cancer types with the highest number of reports overall.

Figure 1.Trend of reports linking cancers to microbiota 20082019. Credit: Graph generated using Elsevier Text Mining and Scopus.

With overall cancer rates set to increase worldwide, the current interest in the microbiome and its role in precision medicine is likely to continue because it offers new hope of treatments. Evidence suggests the importance of looking for predictors of therapeutic response beyond the tumor by focusing on host factors, such as microbiota and host genomics.1 Importantly, the microbiota is a modifiable factor, and potentially can become not just a predictive marker but also a potential target in order to improve outcomes for patients.

Progress is also being made in clinical trials looking at the microbiome and melanoma. Since 2018, four clinical trials that aim to study and modulate the gut microbiomes impact on response to immunotherapy of melanoma have been registered at clinicaltrials.gov. Dr Marc Hurlbert, Chief Science Officer for the Melanoma Research Alliance, commented on the findings: As noted in the report, there has been an explosion of knowledge about melanoma with an ever-increasing list of protein targets. Also noted, the role of the microbiome in melanoma and in response to immunotherapy is of increasing interest in the field.

To further develop targeted precision therapies, further research is now required. Firstly, to map genetic variants; secondly, to determine which variant is clinically significant; thirdly, to understand the impact of variant on gene function, and whether variation activates or inhibits the gene. This is particularly important for increased understanding of specific, precision medicine and to enhance therapeutic efficacy.

For non-hereditary (sporadic) melanoma, the analysis showed that there are 752 genes genetically linked to sporadic melanomas and its subtypes, and 449 genetic variants genetically linked to sporadic melanoma and its subtypes. Out of the 449 genetic variants, 395 are from 78 genes that are genetically linked to melanoma. The remaining missing 54 variants are not currently genetically linked in the platform to any known melanoma gene; this could therefore be a potential area for further research.

Understanding whether specific genetic variants exist and/or contribute to melanomas severity and prevalence in populations will help the research and development (R&D) industry to develop more effective and profitable therapeutics. These types of data will provide the R&D community with a greater depth of understanding and of the increased likelihood of hitting the target. Through our analysis we found an increased incidence of drugs targeting genetic mutations over the last decade, particularly targeting protein kinases and growth factor receptors.

It is an attractive future research avenue to recognize how a patients microorganisms genome, both symbiotic and pathogenic, can dramatically effect treatment plans and outcomes. Positively influencing the microbiome in patients needs further study that could lead to exciting opportunities for patients and for drug discovery. For the therapeutic pipeline it would be beneficial to understand these host-microbiota interactions and ways to positively tip the balance towards improving treatment outcomes.

One other interesting future consideration during drug development for all cancers is the influence of the microbiome on treatment-induced adverse events, and whether clinical and post-clinical adverse events are related to a patients microbial composition. It adds a level of complexity as to the efficacy of therapeutics that may not readily be considered, and potentially may be something to consider during future clinical trials.

Moreover, in the current COVID-19 era, in-person and patient interactions are reduced and many research labs are still unable to operate at full capacity. The ability to conduct research, take samples and study real patients is limited at present, so looking at detailed existing literature and data is a vital avenue to support R&D. It will keep R&D functions going and help them to direct efforts to the areas of greatest potential. 2021 will be a year of reduced R&D budgets globally this type of data insight will be vital to empowering future R&D.

Tom is the Life Sciences Group Manager of Project Management, Knowledge Manager, and Research Scientist. He has extensive experience as an academic researcher in neurodegeneration and Alzheimers disease. He is also skilled in biophysical chemistry, dementia disorders, and biochemistry. He is the author of many publications in the field of protein-membrane interactions, protein misfolding, and Alzheimers disease. At Elsevier he delivers and implements information solutions for customers.

Tom discusses the study and unmet needs in melanoma R&D in detail, here, alongside Marc Hurlbert, Ph.D. Chief Science Officer, Melanoma Research Alliance.

Follow this link:
Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer - Technology Networks

Yuan-Yuan Li,* Sheng Zhang,* Hua Wang, Shun-Xiao Zhang, Ting Xu, Shu-Wen Chen, Yan Zhang, Yue Chen

Department of Endocrinology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, Peoples Republic of China

Correspondence: Yan Zhang; Yue ChenDepartment of Endocrinology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 181 You-Yi Road, Shanghai, 201999, Peoples Republic of ChinaTel +86 13818856902; +86 13701994461Email yan_2999@hotmail.com; 13701994461@163.com

Background: Patients with diabetes have more calcification in atherosclerotic plaque and a higher occurrence of secondary cardiovascular events than patients without diabetes. The objective of this study was to identify crucial genes involved in the development of diabetic atherosclerotic plaque using a bioinformatics approach.Methods: Microarray dataset GSE118481 was downloaded from the Gene Expression Omnibus (GEO) database; the dataset included 6 patients with diabetic atherosclerotic plaque (DBT) and 6 nondiabetic patients with atherosclerotic plaque (Ctrl). Differentially expressed genes (DEG) between the DBT and Ctrl groups were identified and then subjected to functional enrichment analysis. Based on the enriched pathways of DEGs, diabetic atherosclerotic plaque-related pathways were screened using the comparative toxicogenomics database (CTD). We then constructed a proteinprotein interaction (PPI) network and transcription factor (TF)miRNAmRNA network.Results: A total of 243 DEGs were obtained in the DBT group compared with the Ctrl group, including 85 up-regulated and 158 down-regulated DEGs. Functional enrichment analysis showed that up-regulated DEGs were mainly enriched in isoprenoid metabolic process, DNA-binding TF activity, and response to virus. Additionally, DEGs participating in the toll-like receptor signaling pathway were closely related to diabetes, carotid stenosis, and insulin resistance. The TFmiRNAmRNA network showed that toll-like receptor 4 (TLR4), BCL2-like 11 (BCL2L11), and glutamate-cysteine ligase catalytic subunit (GCLC) were hub genes. Furthermore, TLR4 was regulated by TF signal transducer and activator of transcription 6 (STAT6); BCL2L11 was targeted by hsa-miR-24-3p; and GCLC was regulated by nuclear factor, erythroid 2 like 2 (NFE2L2).Conclusion: Identification of hub genes and pathways increased our understanding of the molecular mechanisms underlying the atherosclerotic plaque in patients with or without diabetes. These crucial genes (TLR4, BC2L11, and GCLC) might function as molecular biomarkers for diabetic atherosclerotic plaque.

Keywords: diabetes, atherosclerotic plaque, differentially expressed genes, bioinformatics analysis

Atherosclerosis is a chronic inflammation disease and the leading cause of morbidity and mortality globally.1 Atherosclerosis is a slowly progressive process, characterized by an accumulation of lipid in the arterial wall accompanied by multifocal structural alterations, leading to atheromatous plaque formation.2,3 Over time, the large necrotic lipid core is covered by a fibrous cap until, in advanced stages, the stability of the cap is destroyed, inducing plaque rupture and thrombosis, which can manifest as stroke or myocardial infarction. Cardiovascular disease is the leading cause of death in patients with diabetes.4 There is increasing evidence that diabetes induces hypercoagulability, which has a role in plaque rupture and increases the incidence and severity of clinical events.4

Previous researchers have reported the relationship between plaque characteristics and patients with and without diabetes. Burke et al indicated that total plaque in diabetic patients was significantly greater than that of nondiabetic individuals; in addition, the inflammatory response of diabetic plaques was stronger than that of nondiabetic plaque.5 An optical coherence tomography imaging study by Kato et al revealed that plaques in diabetic patients had a higher incidence of calcification and thrombus.6 Furthermore, van Haelst et al found that patients with diabetes had more calcification in atherosclerotic plaque and a higher occurrence of secondary cardiovascular events than patients without diabetes.7 Even though we can distinguish atherosclerotic plaque in diabetic and nondiabetic patients from morphologic fields, the effect of diabetes on gene expression in atherosclerotic plaque is not fully understood.

Macrophage accumulation plays a vital role in both plaque progression and stability, which can promote inflammation and aggravate disease.8,9 Thus, we selected a gene expression dataset (GSE118481) containing diabetic plaque macrophage (DBT) and nondiabetic plaque macrophage (Ctrl) for analysis. Differentially expressed genes (DEGs) between the DBT and Ctrl groups were identified, functional enrichment analysis of the DEGs was performed, and disease-related pathways were screened. We then constructed a proteinprotein interaction (PPI) network and sub-network. Subsequently, microRNA (miRNA) and transcription factors (TFs) of DEGs were predicted and an integrated TFmiRNAmRNA network was constructed. The analysis process of this study is shown in Supplementary Figure 1. We aimed to further understand the molecular mechanism by which diabetes promotes the formation of atherosclerotic plaque and to determine potential gene targets for personalized diagnosis and treatment strategies of diabetic atherosclerotic plaque.

The gene expression profile GSE118481 based on the GPL10558 Illumina HumanHT-12 V4.0 expression BeadChip platform was downloaded from the Gene Expression Omnibus (GEO) database (website: http://www.ncbi.nlm.nih.gov/geo/).10 This microarray data set included 16 nondiabetic samples (6 asymptomatic and 10 symptomatic) and 8 diabetic plaque samples (6 asymptomatic and 2 symptomatic). In order to study the effect of diabetes on atherosclerotic plaque, we selected asymptomatic samples for subsequent analysis. Therefore, 12 samples (6 DBT and 6 Ctrl) were included, and the clinical characteristics of these patients are listed in Supplementary Table 1. There were no significant differences in age (P = 0.24) and sex (P > 0.05) between the two groups.

The series matrix file for GSE118481 dataset was obtained from the GEO database,10 and the expression data of 6 DBT and 6 Ctrl macrophage samples were extracted for further analysis. Microarray expression profiling was standardized by Bioconductor bead array package,11 and the distribution of expression in each sample was visualized by boxplots. The probe ID was converted to a gene symbol using the annotation file, and probes that did not mapped to gene symbols were removed. If multiple probes matched the same gene, the mean value of probes was calculated. Empirical Bayes moderated t-test in the limma package (version 3.40.6)12 was used to identify DEGs between DBT and Ctrl samples. DEGs with P < 0.05 and |log fold change (FC)| >0.585 were considered statistically significant. The ggplot2 and heatmap of R (http://www.R-project.org/) were utilized to visualize the DEGs.

Using Pearson correlation coefficients (r) in the stats of R package (version 3.6.1; http://www.R-project.org/), the co-expression of DEGs in DBT and Ctrl samples was, respectively, analyzed. Pairs with r > 0.95 and P < 0.05 were selected for further study. Cytoscape was applied to construct a co-expression network of Ctrl and DBT groups, and then the topological properties of the two networks were analyzed by using CytoNCA in Cytoscape.13 Furthermore, t-tests were used to calculate the difference between Ctrl and DBT networks. The sub-networks of DBT group were structured using the Cytoscape MCODE plugin,14 and networks with a score >3 were selected.

To understand the major biological functions of DEGs, we analyzed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of up- and down-regulated DEGs using the clusterProfiler package. Significant enrichment was defined by P < 0.05 and count >2.

Diabetes, carotid stenosis, and insulin resistance have effects on the development of diabetic atherosclerotic plaque. Therefore, to further identify diabetic plaque-related pathways, we screened pathways relevant to these diseases from the comparative toxicogenomics database (CTD), and these pathways were integrated with the KEGG pathways in the previous step.

To determine the relationships among DEGs, we mapped the DEGs to the Search Tool for the Retrieval of Interacting Genes (STRING, version 11.0, http://www.string-db.org/) database, and only interactions with a combined score >0.7 were selected. Then, Cytoscape software was used to establish the PPI network, and hub nodes in the network were identified by CytoNCA. The PPI network was further analyzed by MCODE to explore functional modules, and score >5 was selected as the threshold.

To further understand the regulatory mechanism of DEGs, miRNAs of target genes were predicted using four available databases: miRWalk3.0,15 TargetScan,16 MiRDB,17 and MirTarBase.18 Putative miRNAs with score >0.95 and supported by at least two databases were selected; additionally, TFtarget interactions were predicted by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) (https://www.grnpedia.org/trrust/).19 Subsequently, miRNAtarget pairs and TFtarget pairs were integrated to construct the TFmiRNAmRNA regulatory network.

The raw data were processed and the boxplots showed good normalized properties (Figure 1A). A total of 33,984 probes were obtained after annotation. A total of 243 DEGs were identified between the DBT and Ctrl groups, including 85 up-regulated and 158 down-regulated DEGs. The heat map and volcano plot of DEGs are shown in Figure 1B and C.

Figure 1 Gene expression profile data analysis. (A) Boxplot of gene expression data after normalization. (B) Heat map of DEGs between Ctrl and DBT groups; green indicates Ctrl group and red indicates DBT group. (C) Volcano plot of DEGs between Ctrl and DBT groups.

Co-expression network analysis showed that 144 pairs and 162 DEGs were identified in the Ctrl group (Figure 2A), and 191 relationships and 170 DEGs were screened in the DBT group (Figure 2B). The topological properties of the Ctrl and DBT networks indicated that betweenness, closeness, and degree values were significantly higher in the DBT group than in the Ctrl group (Figure 2C), suggesting that co-expression of DEGs was more abundant in the DBT group than in the Ctrl group. The sub-network (score = 3.333) of the DBT group was constructed and included serine/threonine kinase 32B (STK32B), tripartite motif containing 22 (TRIM22), ninjurin 2 (NINJ2), and transmembrane protein 114 (TME114) (Figure 2D).

Figure 2 Disease-related co-expression network. (A) Co-expression network of Ctrl group. (B) Co-expression network of DBT group. (C) Topology properties of Ctrl and DBT group co-expression network. (D) Sub-network of DBT group. Red nodes indicate up-regulated DEGs, blue nodes indicate down-regulated DEGs, red lines represent positive correlation, and blue lines represent negative correlation. *Indicates the average of the data in each group.

Functional enrichment analysis of up-regulated and down-regulated DEGs was performed using the clusterProfiler tool. The top 10 significantly enriched GO terms and KEGG pathways are shown in Figure 3A and B. The up-regulated DEGs were significantly enriched in GO terms related to isoprenoid metabolic process, response to estradiol, and retinal metabolic process, and the down-regulated DEGs were markedly associated with regulation of DNA-binding TF activity, alpha-amino metabolic process, and response to virus (Figure 3A). For the KEGG pathway analysis, up-regulated DEGs were primarily involved in adipocytokine signaling pathway, cosphingolipid biosynthesis-lacto and neolacto series, and non-alcoholic fatty liver disease; in addition, down-regulated DEGs were mainly involved in folate biosynthesis, cysteine and methionine metabolism, and Chagas disease (American trypanosomiasis) pathways (Figure 3B).

Figure 3 Functional enrichment analysis of DEGs. (A) GO analysis of the DEGs. (B) KEGG pathway analysis of the DEGs. The y-axis represents the GO terms or KEGG pathways, and the x-axis represents up-regulated and down-regulated DEGs. The size of bubbles represents the number of assigned genes, and the color of bubbles represents the adjusted P-value. The greater the number of DEGs associated with the term or pathway, the larger the bubble.

A total of 13 pathways were closely related to diabetes mellitus, one pathway was associated with carotid stenosis, and 10 pathways were associated with insulin resistance (Table 1). All three of these diseases were relevant to the toll-like receptor signaling pathway. Genes such as toll-like receptor 8 (TLR8), toll-like receptor 4 (TLR4), mitogen-activated protein kinase 4 (MAP2K4), and interferon regulatory factor 5 (IRF5) were involved in this pathway. In addition, 10 pathways were related to diabetes mellitus and insulin resistance, including acute myeloid leukemia, influenza A, non-alcoholic fatty liver disease (NAFLD), and adipocytokine signaling.

Table 1 Disease-Related Pathways Analysis

The 225 proteins encoded by DEGs were searched in the STRING database and then used to construct the PPI network, which included 76 nodes and 114 pairs of edges (Figure 4A). Among these, several nodes with a higher degree [2-5-oligoadenylate synthetase 2 (OAS2, degree = 15), IRF5 (degree = 11), guanylate binding protein 1 (GBP1, degree = 11), and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3, degree = 11)] could be considered hub proteins. Additionally, a module with score >5 was identified using the MCODE plugin. This sub-network was composed of 12 nodes and 43 pairs (Figure 4B). OAS2 (degree = 5), radical s-adenosyl methionine domain containing 2 (RSAD2, degree = 6), and eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2, degree = 5) were involved in diabetes and insulin resistance-related pathways.

Figure 4 PPI network. (A) PPI network composed of 76 nodes and 114 edges. (B) Sub-network consisted of 12 nodes and 43 pairs. Triangle indicates up-regulated DEG, V-shape indicates down-regulated DEGs. Blue represent genes not involved in diseases-related pathways, yellow represent genes involved in diabetes-related pathways, green indicate genes enriched in diabetes and insulin resistance pathways, and red indicates genes participated in diabetes, insulin resistance, and plaque pathways.

After screening, 102 miRNAmRNA pairs and 114 TF-mRNA pairs were predicted, and then these pairs were integrated to structure a TFmiRNAmRNA regulatory network. A total of 154 interactions were identified, involving 57 genes, 30 miRNA, and 75 TFs (Figure 5). In this regulatory network, we noted glutamate-cysteine ligase catalytic subunit (GCLC), BCL2 like 11 (BCL2L11), and TLR4 had higher degrees. GCLC was targeted by the TF nuclear factor, erythroid 2 like 2 (NFE2L2); BCL2L11 was targeted by hsa-miR-24-3p, and regulated by TF forkhead box O3 (FOXO3), and TLR4 was related to the process of three diseases and regulated by TF signal transducer and activator of transcription 6 (STAT6).

Figure 5 The TFmiRNAmRNA regulatory network. Red nodes represent up-regulated DEGs, blue nodes represent down-regulated DEGs, green triangles represent miRNAs, green diamonds represent TF, and blue and red diamonds represent both TF and DEGs. Red lines indicate activation relationships and blue lines indicate inhibitory relationships.

Abbreviations: TF, transcription factor; miRNA, microRNA; mRNA, messenger RNA; DEG, differentially expressed gene.

Diabetes is known to be associated with atherosclerotic plaque; however, the underlying molecular mechanism of the effect of diabetes on atherosclerotic plaque has not been fully elucidated. We analyzed gene expression patterns involved in diabetic atherosclerotic plaque using the dataset GSE118481. The results revealed that the toll-like receptor signaling pathway was associated with the pathogenesis of diabetic atherosclerotic plaque. Additionally, TLR4, BCL2L11, and GCLC were potential biomarkers for atherosclerotic plaque in patients with diabetes.

The formation and progression of atherosclerotic plaque is related to the accumulation of monocyte-derived macrophage in the arterial wall. Compared with patients without diabetes, the plaques in the coronary arteries of patients with diabetes gene generally exhibit larger necrotic cores and significantly greater inflammation, mainly composed of macrophages and T lymphocytes.20 Based on analysis of disease-related pathways, we observed that the toll-like receptor signaling pathway was significantly associated with diabetes mellitus, carotid stenosis, and insulin resistance; additionally, hub gene TLR4 was involved in this pathway. Madhur et al21 indicated that inflammation response could reduce the stability of atherosclerotic plaques in animal models. It is reported that the TLR signaling pathway is associated with systemic inflammation and immune response, and participates in angiogenesis, survival, and repair.22,23 Meanwhile, TLR4, as a member of the TLR family, is believed to activate nuclear factor-B in response to short-chain fatty acids, triggering further activation of the immune system.24 Thus, TLR4 induced inflammation plays an important role in atherosclerotic plaque stability. Xu et al demonstrated that TLR4 was preferentially expressed by macrophages in human lipid-rich atherosclerotic lesions, where it might play a role to enhance and maintain the innate immunity and inflammation. In addition, the up-regulation of TLR4 in macrophages by oxidized low-density lipoprotein (LDL) suggested that TLR4 might provide a potential pathophysiological link between lipids as well as inflammation and atherosclerosis.25 In this analysis, we also found the relationship between TLR4 and diabetes. Devaraj et al demonstrated that expression of TLR4 was significantly increased in patients with type 1 diabetes, suggesting that TLR4 contributes to the pro-inflammatory state in diabetes.26 Moreover, knockout of TLR4 might alleviate inflammation in diabetic rats27 and TLR4 antagonist could attenuate atherogenesis in mice with diabetes.28 The antidiabetic drug class thiazolidinediones (TZDs) have been reported to reduce the risk of atherosclerosis in patients with type 2 diabetes, which might have an anti-atherosclerotic effect by inhibiting the TLR4 signaling pathway.29 These findings emphasized the importance of TLR4 in plaque formation of patients with diabetes. In the present study, we found that TLR4 was regulated by the TF STAT6. STAT6 has a major role in the immune system30 and is associated with macrophage polarization, which is critically involved in atherosclerosis progression and regression.31 Based on our results, we speculated that TLR4 and STAT6 might participate in the pathogenesis of diabetic atherosclerotic plaque via the TLR signaling pathway.

In the regulatory network, BCL2L11 had higher degree and was considered a hub gene. BCL2L11 encodes BCL-2 protein family, and its members participate in various cellular activities as anti- or proapoptotic regulators.32 A previous study revealed that BCL2L11 was connected to apoptosis of podocytes in diabetes.33 However, there are few reports about the association between BCL2L11 and carotid plaque. Our analysis showed that BCL2L11 was targeted by hsa-miR-24-3p. Erener et al observed that miR-24-3p was an effective biomarker to predict and diagnose diabetes.34 Moreover, miR-24-3p was found to limit macrophage vascular inflammation and slow the progression of atherosclerotic plaque.35 Taken together, hsa-miR-24-3p might affect the progression of diabetic atherosclerotic plaque by directly targeting BCL2L11. However, the specific regulatory mechanism of BCL2L11 in diabetic atherosclerotic plaque needs further elaboration.

We also found that GCLC was closely related to diabetic atherosclerotic plaque. GCLC is a rate-limiting enzyme of glutathione synthesis, and it is involved in susceptibility to myocardial infarction.36 Callegari et al found that the gain and loss of the ability to synthesize glutathione especially in macrophages had reciprocal effects on the initiation and progression of atherosclerosis at multiple sites in apoE-/- mice.37 Jain et al reported that the plasma level of GCLC was lower in diabetic patients than in healthy controls.38 Moreover, the GCLC polymorphism was associated with cellular redox imbalances and modulate the risk for diabetic nephropathy.39 In the TFmiRNAmRNA network, GCLC was regulated by NFE2L2 (also known as NRF2), which is considered to be a master regulator of the antioxidant response.40 It regulates the expression of several genes including Phase II metabolic and antioxidant enzymes, and therefore plays an important role in preventing oxidative stress-mediated diabetes and related complications.41 In addition, overexpression of Nrf2 could protect pancreatic cells from oxidative damage in diabetes.42 Furthermore, a study by Harada et al revealed that activation of Nrf2 was observed in advanced atherosclerotic plaques, suggesting that Nrf2 might influence the inflammatory reactions in the plaques.43 Thus, we speculated that GCLC targeted by NFE2L2 might participate in the pathogenesis of diabetic atherosclerotic plaque.

Some limitations should be noted in the current study. First, the sample size of this study was small; further investigations based on a larger sample should be performed. Second, hub genes were identified using bioinformatics analysis; thus, experimental studies are needed to validate our results. Despite these limitations, this study provided some new insights into the pathogenesis and treatment of diabetic atherosclerotic plaques. Further large-scale studies are needed to corroborate these findings and investigate the potential underlying mechanisms involved. Meanwhile, clinical trials with more detailed investigation are also warranted before genes such as TLR4, BCL2L11, GCLC can be used in clinical setting.

In summary, we have conducted a comprehensive bioinformatics analysis of DEGs between diabetic and nondiabetic atherosclerotic plaque. Several genes have been identified with different expression patterns in diabetic and non-diabetic atherosclerotic plaque, such as TLR4, BCL2L11, GCLC, STAT6, and NFE2L2, as well as hsa-miR-24-3p. Meanwhile, pathway analysis showed that these genes were involved in the toll-like receptor signaling pathway. These findings provided better understanding of the underlying molecular mechanisms of diabetic atherosclerotic plaque. However, further research of these candidate genes was needed to confirm their effects in diabetic atherosclerotic plaque.

We thank Louise Adam, ELS(D), from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac) for editing the English text of a draft of this manuscript.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work; Yan Zhang and Yue Chen are the co-corresponding authors of this study.

This study was supported by the National Natural Science Foundation of China (82004117), Baoshan medical speciality project (BSZK-2018-A02), and the Cultivation Fund of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine for NSFC (Grant Number: GZRPYJJ-201803).

The authors declare that they have no conflicts of interest for this work.

1. Geovanini GR, Libby P. Atherosclerosis and inflammation: overview and updates. Clin Sci. 2018;132(12):12431252. doi:10.1042/CS20180306

2. Wierer M, Prestel M, Schiller HB, et al. Compartment-resolved proteomic analysis of mouse aorta during atherosclerotic plaque formation reveals osteoclast-specific protein expression. Mol Cell Proteomics. 2018;17(2):321334. doi:10.1074/mcp.RA117.000315

3. Camar C, Pucelle M, Ngre-Salvayre A, Salvayre R. Angiogenesis in the atherosclerotic plaque. Redox Biol. 2017;12:1834. doi:10.1016/j.redox.2017.01.007

4. de Gaetano M, McEvoy C, Andrews D, et al. Specialized pro-resolving lipid mediators: modulation of diabetes-associated cardio-, reno-, and retino-vascular complications. Front Pharmacol. 2018;9:1488.

5. Burke AP, Kolodgie FD, Zieske A, et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb Vasc Biol. 2004;24(7):12661271. doi:10.1161/01.ATV.0000131783.74034.97

6. Kato K, Yonetsu T, Kim S-J, et al. Comparison of nonculprit coronary plaque characteristics between patients with and without diabetes: a 3-vessel optical coherence tomography study. JACC Cardiovasc Interv. 2012;5(11):11501158. doi:10.1016/j.jcin.2012.06.019

7. van Haelst ST, Haitjema S, de Vries J-P-P, et al. Patients with diabetes differ in atherosclerotic plaque characteristics and have worse clinical outcome after iliofemoral endarterectomy compared with patients without diabetes. J Vasc Surg. 2017;65(2):41421. e5. doi:10.1016/j.jvs.2016.06.110

8. Tang J, Lobatto ME, Hassing L, et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci Adv. 2015;1(3):e1400223. doi:10.1126/sciadv.1400223

9. Chinetti-Gbaguidi G, Colin S, Staels B. Macrophage subsets in atherosclerosis. Nat Rev Cardiol. 2015;12(1):10. doi:10.1038/nrcardio.2014.173

10. Barrett T, Suzek TO, Troup DB, et al. NCBI GEO: mining millions of expression profilesdatabase and tools. Nucleic Acids Res. 2005;33(suppl_1):D562D6. doi:10.1093/nar/gki022

11. Dunning MJ, Smith ML, Ritchie ME, Tavar S. beadarray: R classes and methods for Illumina bead-based data. Bioinformatics. 2007;23(16):21832184. doi:10.1093/bioinformatics/btm311

12. Smyth GK, Ritchie M, Thorne N, Wettenhall J. LIMMA: linear models for microarray data. in bioinformatics and computational biology solutions using R and bioconductor. Stat Biol Health. 2005.

13. Tang Y, Li M, Wang J, Pan Y, Wu F-X. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems. 2015;127:6772. doi:10.1016/j.biosystems.2014.11.005

14. Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4(1):2.

15. Dweep H, Sticht C, Pandey P, Gretz N. miRWalkdatabase: prediction of possible miRNA binding sites by walking the genes of three genomes. J Biomed Inform. 2011;44(5):839847. doi:10.1016/j.jbi.2011.05.002

16. Agarwal V, Bell GW, Nam J-W, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. elife. 2015;4:e05005. doi:10.7554/eLife.05005

17. Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2014;43(D1):D146D52. doi:10.1093/nar/gku1104

18. Chou C-H, Shrestha S, Yang C-D, et al. miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions. Nucleic Acids Res. 2017;46(D1):D296D302. doi:10.1093/nar/gkx1067

19. Han H, Cho J-W, Lee S, et al. TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2017;46(D1):D380D6. doi:10.1093/nar/gkx1013

20. Yahagi K, Kolodgie FD, Lutter C, et al. Pathology of human coronary and carotid artery atherosclerosis and vascular calcification in diabetes mellitus. Arterioscler Thromb Vasc Biol. 2017;37(2):191204. doi:10.1161/ATVBAHA.116.306256

21. Madhur MS, Funt SA, Li L, et al. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 2011;31(7):15651572. doi:10.1161/ATVBAHA.111.227629

22. Kutikhin AG. Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum Immunol. 2011;72(11):10951116. doi:10.1016/j.humimm.2011.07.307

23. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461. doi:10.3389/fimmu.2014.00461

24. Kim YM, Romero R, Oh SY, et al. Toll-like receptor 4: a potential link between danger signals, the innate immune system, and preeclampsia? Am J Obstet Gynecol. 2005;193(3 Pt 2):921927. doi:10.1016/j.ajog.2005.07.076

25. Xu XH, Shah PK, Faure E, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001;104(25):31033108. doi:10.1161/hc5001.100631

26. Devaraj S, Dasu MR, Rockwood J, Winter W, Griffen SC, Jialal I. Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. J Clin Endocrinol Metab. 2008;93(2):578583. doi:10.1210/jc.2007-2185

27. Devaraj S, Tobias P, Jialal I. Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine. 2011;55(3):441445. doi:10.1016/j.cyto.2011.03.023

28. Lu Z, Zhang X, Li Y, Lopes-Virella MF, Huang Y. TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes. Immunobiology. 2015;220(11):12461254. doi:10.1016/j.imbio.2015.06.016

29. Jia S-J, Niu -P-P, Cong J-Z, Zhang B-K, Zhao M. TLR4 signaling: a potential therapeutic target in ischemic coronary artery disease. Int Immunopharmacol. 2014;23(1):5459. doi:10.1016/j.intimp.2014.08.011

30. Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011;50(1):87. doi:10.1007/s12026-011-8205-2

31. Peled M, Fisher EA. Dynamic aspects of macrophage polarization during atherosclerosis progression and regression. Front Immunol. 2014;5:579. doi:10.3389/fimmu.2014.00579

32. Luo S, Rubinsztein DC. BCL2L11/BIM: a novel molecular link between autophagy and apoptosis. Autophagy. 2013;9(1):104105. doi:10.4161/auto.22399

33. Chuang PY, Dai Y, Liu R, et al. Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One. 2011;6(8):e23566. doi:10.1371/journal.pone.0023566

34. Erener S, Marwaha A, Tan R, Panagiotopoulos C, Kieffer TJ. Profiling of circulating microRNAs in children with recent onset of type 1 diabetes. JCI Insight. 2017;2(4). doi:10.1172/jci.insight.89656

35. Boon RA, Dimmeler S. MicroRNAs in myocardial infarction. Nat Rev Cardiol. 2015;12(3):135. doi:10.1038/nrcardio.2014.207

36. Erdmann J, Stark K, Esslinger UB, et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature. 2013;504(7480):432. doi:10.1038/nature12722

37. Callegari A, Liu Y, White CC, et al. Gain and loss of function for glutathione synthesis: impact on advanced atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2011;31(11):24732482. doi:10.1161/ATVBAHA.111.229765

38. Jain SK, Micinski D, Huning L, Kahlon G, Bass P, Levine SN. Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. Eur J Clin Nutr. 2014;68(10):1148. doi:10.1038/ejcn.2014.114

39. Vieira SM, Monteiro MB, Marques T, et al. Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus. BMC Med Genet. 2011;12(1):129. doi:10.1186/1471-2350-12-129

40. Xu X, Luo P, Wang Y, Cui Y, Miao L. Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is a novel therapeutic target for diabetic complications. J Int Med Res. 2013;41(1):1319. doi:10.1177/0300060513477004

41. Bhakkiyalakshmi E, Shalini D, Sekar TV, Rajaguru P, Paulmurugan R, Ramkumar KM. Therapeutic potential of pterostilbene against pancreatic beta-cell apoptosis mediated through Nrf2. Br J Pharmacol. 2014;171(7):17471757. doi:10.1111/bph.12577

42. Yagishita Y, Fukutomi T, Sugawara A, et al. Nrf2 protects pancreatic -cells from oxidative and nitrosative stress in diabetic model mice. Diabetes. 2014;63(2):605618. doi:10.2337/db13-0909

43. Harada N, Ito K, Hosoya T, et al. Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation. Free Radic Biol Med. 2012;53(12):22562262. doi:10.1016/j.freeradbiomed.2012.10.001

Visit link:
[Full text] Identification of Crucial Genes and Pathways Associated with Atheroscl | PGPM - Dove Medical Press

Gene therapy veteran Ronald Crystal, M.D., has seen it all.

Ive been in the gene therapy field since the beginning, 1987 or so, so Ive seen the wild period, the dark days, and now were back to the wild period, he said.

And one thing he'srealized after being in the field for so long? "Inthe academic world, we are very, very good at coming up with ideas, developing preclinical evidence and moving to the IND stages. But clinical studies much better belong in a company.

Virtual Clinical Trials Summit: The Premier Educational Event Focused on Decentralized Clinical Trials

In this virtual environment, we will look at current and future trends for ongoing virtual trials, diving into the many ways companies can improve patient engagement and trial behavior to enhance retention with a focus on emerging technology and harmonized data access across the clinical trial system.

So,he started one: Lexeo Therapeutics. Founded with National Institutes of Health small business grants in early 2018, the company is coming out of stealth with $85 million in series A cash;18 preclinical and clinical programs primarily developed at Weill Cornell Medicine, where Crystal is a professor and chairman of the department of genetic medicine;and a star-studded team to move it all forward.

RELATED: Taysha Gene Therapies hits the ground running with $30M, 15 programs

Our view is the gene therapy field today is very much focused on rare, monogenic diseases, said Lexeo CEO Nolan Townsend, who previously led rare disease work at Pfizer. The vision we have for gene therapy is it will eventually move to larger diseases, and we have the pipeline to support that vision.

Two of Lexeos lead programs are in rare diseases: Friedreichs ataxia and Batten disease. And its18 programs span rare and more prevalent monogenic diseasesi.e., those caused by a defect in a single geneas well as acquired diseases, which just means diseases that strike during a persons lifetime rather than those that affectthem from birth.

The funding, drawn from the likes of Longitude Capital, Omega Funds, the Alzheimers Drug Discovery Foundation and Alexandria Venture Investments, will push Lexeos three lead programs through the clinic. Its Friedreichs ataxia program is slated to enter phase 1 this year, and its Batten disease treatment has finished a phase 1/2 study and is set for a pivotal trial in 2022. Lexeo is developing its third program for the treatment of Alzheimers disease in people with the APOE4 gene, a variant known to increase the risk of developing the disease. It is in phase 1.

Besides bankrolling its clinical trials, Lexeo is using a meaningful portion of the funding to invest in manufacturing, a major bottleneck in gene therapy. And thats not allthe company is headquartered in New York City and hopes to play a role in building the citys life sciences network.

RELATED: Avrobio tracks improvements in first patient treated with Gaucher gene therapy

Joining Crystal and Townsend is chairmanSteven Altschuler, M.D., the managing director at Ziff Capital Investments who used to chair the board of gene therapy biotech Spark Therapeutics. The company has also recruited Jay Barth, M.D., as chief medical officer. Barth previously held the same role at Amicus Therapeutics, where he oversaw clinical development in rare disease and gene therapy, including the approval of Fabry disease med Galafold.

Lexeo isnt the only new gene therapy player on the block. A group of former AveXis executives and investors unveiled their second act in April last year: Taysha Gene Therapies, which launched with $30 million and 15 programs licensed from UT Southwestern Medical Center. The next month, Kriya Therapeutics debuted with $80.5 million and a mission to develop gene therapies for more complex and more common diseases.

Continued here:
Lexeo Therapeutics emerges with $85M, 18 gene therapy programs and a star-studded team - FierceBiotech

DBMR has added a new report titled Global Precision Medicine Market with analysis provides the insights which bring marketplace clearly into the focus and thus help organizations make better decisions. This Global Precision Medicine Market research report understands the current and future of the market in both developed and emerging markets. The report assists in realigning the business strategies by highlighting the business priorities. It throws light on the segment expected to dominate the industry and market. It forecast the regions expected to witness the fastest growth. This report is a collection of pragmatic information, quantitative and qualitative estimation by industry experts, the contribution from industry across the value chain. Furthermore, the report also provides the qualitative results of diverse market factors on its geographies and Segments.

Global Precision Medicine Market to grow with a substantial CAGR in the forecast period of 2019-2026. Growing prevalence of cancer worldwide and accelerating demand of novel therapies to prevent of cancer related disorders are the key factors for lucrative growth of market

Global Precision Medicine Market By Application (Diagnostics, Therapeutics and Others), Technologies (Pharmacogenomics, Point-of-Care Testing, Stem Cell Therapy, Pharmacoproteomics and Others), Indication (Oncology, Central Nervous System (CNS) Disorders, Immunology Disorders, Respiratory Disorders, Others), Drugs (Alectinib, Osimertinib, Mepolizumab,Aripiprazole lauroxil and Others), Route of Administration (Oral,Injectable), End- Users (Hospitals, Homecare, Specialty Clinics, Others), Geography (North America, South America, Europe, Asia-Pacific, Middle East and Africa) Industry Trends and Forecast to 2026

Download Free PDF Sample Copy of Report@ http://databridgemarketresearch.com/request-a-sample/?dbmr=global-precision-medicine-market

Competitive Analysis:

The precision medicine market is highly fragmented and is based on new product launches and clinical results of products. Hence the major players have used various strategies such as new product launches, clinical trials, market initiatives, high expense on research and development, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of mass spectrometry market for global, Europe, North America, Asia Pacific and South America.

Market Definition:

Precision medicines is also known as personalized medicines is an innovative approach to the patient care for disease treatment, diagnosis and prevention base on the persons individual genes. It allows doctors or physicians to select treatment option based on the patients genetic understanding of their disease.

According to the data published in PerMedCoalition, it was estimated that the USFDA has approved 25 novels personalized medicines in the year of 2018. These growing approvals annually by the regulatory authorities and rise in oncology and CNS disorders worldwide are the key factors for market growth.

Talk to The Author of Report @ http://databridgemarketresearch.com/speak-to-analyst/?dbmr=global-precision-medicine-market

Market Drivers

Market Restraints

Key Developments in the Market:

Competitive Analysis:

Global precision medicine market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of global precision medicine market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Key Market Players:

Few of the major competitors currently working in the global precision medicine market are Neon Therapeutics, Moderna, Inc, Merck & Co., Inc, Bayer AG, PERSONALIS INC, GENOCEA BIOSCIENCES, INC., F. Hoffmann-La Roche Ltd, CureVac AG, CELLDEX THERAPEUTICS, BIONTECH SE, Advaxis, Inc, GlaxoSmithKline plc, Bioven International Sdn Bhd, Agenus Inc., Immatics Biotechnologies GmbH, Immunovative Therapies, Bristol-Myers Squibb Company, Gritstone Oncology, NantKwest, Inc among others.

Get a Detail TOC @ http://databridgemarketresearch.com/toc/?dbmr=global-precision-medicine-market

Market Segmentation:

By technology:- big data analytics, bioinformatics, gene sequencing, drug discovery, companion diagnostics, and others.

By application:- oncology, hematology, infectious diseases, cardiology, neurology, endocrinology, pulmonary diseases, ophthalmology, metabolic diseases, pharmagenomics, and others.

On the basis of end-users:- pharmaceuticals, biotechnology, diagnostic companies, laboratories, and healthcare it specialist.

On the basis of geography:- North America & South America, Europe, Asia-Pacific, and Middle East & Africa. U.S., Canada, Germany, France, U.K., Netherlands, Switzerland, Turkey, Russia, China, India, South Korea, Japan, Australia, Singapore, Saudi Arabia, South Africa, and Brazil among others.

In 2017, North America is expected to dominate the market.

About Data Bridge Market Research:

Data Bridge Market Researchset forth itself as an unconventional and neoteric Market research and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best market opportunities and foster efficient information for your business to thrive in the market. Data Bridge endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process.

Contact:

Data Bridge Market Research

US: +1 888 387 2818

UK: +44 208 089 1725

Hong Kong: +852 8192 7475

Email:Corporatesales@databridgemarketresearch.com

Go here to read the rest:
Global Precision Medicine Market 2020 Overview By Size, Share, Trends, Growth Factors and Leading Players With Detailed Analysis of Industry Structure...

Assaf Halevy, Founder and CEO of 2bPrecise

Electronic medical records (EMRs) are widely expected to serve as a cornerstone technology that drives the delivery of modern patient care.

But can the EMR alone support all the informatics capabilities required by an ever-evolving healthcare industry? The rapid growth of precision medicine, particularly the use of genetic and genomic information during clinical decision making, is a compelling example that functionality beyond the EMR is required. Not only does genomic data represent a category of information used differently than traditional clinical knowledge, but the volume of data generated through molecular testing alone also requires informatics and management of a higher magnitude than previously required.

The EMR is designed to reflect a snapshot (or collection of snapshots) in time: clinical summaries, annotated lab and test results, operation notes, etc. These are mostly stored as isolated documents, loosely coupled with the rest of the patient chart. They need to remain available for reference over time, in some instances, so providers can chart and contextualize ongoing trends and chronic conditions. However, these views are anchored in time and represent limited actionable value during clinical decision-making months, years, and decades later.

Genomic information, on the other hand, represents a patients life signature. DNA rarely changes over the course of an individuals lifetime. This means the results from germline testing a patients molecular profile conducted early in life are relevant, meaningful, and actionable during clinical decision making far into the future. They can also deliver insights exposing heritable proclivities that may be life-changing or life-saving for family members as well.

This recognition in and of itself alerts healthcare leaders that they need to adopt an advanced, more sophisticated strategy for data governance, management, and sharing than the approach traditionally applied to other clinical information systems, such as EMRs.

To be successful, healthcare organizations need an accelerator external to the EMR that is built on a data model unique to the management of molecular knowledge so test results and genomic insights can be used and shared across clinical specialties and care settings, as well as overtime. In addition, the rise of precision medicine requires an agile informatics platform that enables the cross-pollination of genomic data with clinical insights and ever-advancing discoveries in genomic science.

Consider these examples of how EMRs fall short of expectations for optimal use of genomic intelligence:

1. Studies have found that, despite ubiquitous availability of molecular tests, providers consistently fail to identify patients most at risk for heritable diseases. The Journal of the American Medical Informatics Association (JAMIA) recently released research showing that half the women meeting national guidelines for genetic screening are not getting the tests they need to determine their breast and ovarian cancer risk.

The reason? The full story of a patients risk for heritable cancer within their record often does not exist in a single location, says the JAMIA article. It is fragmented across entries created by many authors, over many years, in many locations and formats, and commonly from many different institutions in which women have received care over their lifetimes. In other words, no matter which EMRs they use, health systems routinely miss opportunities to improve care for patients they see. To achieve greater success, providers need tools that exceed EMR functionality and span multiple clinical systems.

2. Shortly after birth, Alexander develops a seizure disorder. The neonatologist orders a germline test to help her arrive at a precise diagnosis and begin targeted treatment. This approach is successful and Alexander thrives. In addition to genomic variants identifying the cause of his seizure disorder, the test results also contain information about other heritable risk factors, including cardiovascular disease.

Decades later, in the 70s, Alexander sees his primary care provider (PCP) with a rapid heartbeat and shortness of breath. After doing routine lab work, the PCP diagnoses congestive heart failure (CHF). If, however, the PCP had access to Alexanders genomic test results which remain as relevant and accurate as when he was an infant the PCP would have noted a variation that indicated the CHF was due to dilated cardiomyopathy, requiring a different treatment regime.

It is vital that health leaders immediately begin to plan an informatics strategy that accommodates genetic and genomic data while empowering providers to leverage these insights at the point of care as they make routine, yet critical, clinical decisions. As they evaluate their approach, they would do well to ask the following questions:

Which providers in my organization are already ordering genomic tests on their patients? How are test results being stored and managed and can they be easily shared with and accessed by others in the health system?

As the volume of genetic and genomic testing accelerates and it will how will we manage the volume of data generated? How will we apply consistent governance to the ordering process? How can we ensure results will be consumed as discrete data so our organization can optimize its value now and in the future?

What steps do we need to take so our precision medicine strategy remains current with changing science? Which informatics tools deliver access to up-to-date knowledge bases and clinical guidelines to ensure optimal medical decisions are made?

The advent of precision medicine represents a new standard of care for healthcare providers from coast to coast. Genetic and genomic information supplies a new data set that can be used to arrive at more accurate diagnoses sooner and more effective treatment faster. This, in turn, supports better outcomes, higher patient (and provider) satisfaction, and competitive differentiation for the health system adopting precision medicine first in its market.

But to capture this value, healthcare leaders must look beyond their legacy EMRs, recognizing that they were not developed nor do they have the capacity to properly handle the upcoming data revolution. Instead, industry innovators are looking for platforms agnostic to individual EMRs and integrated with molecular labs to address the next-generation demands of precision medicine.

About Assaf Halevy

Assaf Halevy is the founder and CEO of 2bPrecise, LLC, leading an international team dedicated to bridging the final mile between the science of genomics and making that data useful at the point of care. He joined Allscripts as senior vice president of products and business development in 2013 when the company acquired Israel-based dbMotion. An initial inventor and co-founder of dbMotion, Halevy helped develop the leading clinical integration and population health management platforms in the industry today.

With 13 patents pending in the areas of actionable clinical integration, interoperability, and precision medicine, Halevy leverages his industry expertise by evaluating strategic alliances and partnerships for U.S. and international markets. Halevy was invited to participate in several U.S. government activities and contribute to an HHS privacy committee task force. In 2016, he was part of a small selective group of executives invited to the White House by Vice President Joe Biden to discuss the future of interoperability.

Originally posted here:
Meaningful Use of Genomics Requires Informatics Beyond EMRs - HIT Consultant

DURBAN, South Africa Doctors and nurses at a South African hospital group noticed an odd spike in the number of Covid-19 patients in their wards in late October. The government had slackened its lockdown grip, and springtime had brought more parties. But the numbers were growing too quickly to easily explain, prompting a distressing question.

Is this a different strain? one hospital official asked in a group email in early November, raising the possibility that the virus had developed a dangerous mutation.

That question touched off a high-stakes genetic investigation that began here in Durban on the Indian Ocean, tipped off researchers in Britain and is now taking place around the world. Scientists have discovered worrisome new variants of the virus, leading to border closures, quarantines and lockdowns, and dousing some of the enthusiasm that arrived with the vaccines.

Britain has been particularly overwhelmed. Infections and hospitalizations have skyrocketed in recent weeks since that country discovered its own variant of the virus, which is more contagious than previous forms. By one estimate, the mutated virus is already responsible for more than 60 percent of new infections in London and surrounding areas.

The coronavirus has evolved as it made its way across the world, as any virus is expected to do. But experts have been startled by the pace at which significant new variants have emerged, adding new urgency to the race between the worlds best defenses vaccinations, lockdowns and social distancing and an aggressive, ever-changing foe.

The new variant pummeling Britain has already been found in about 45 countries, from Singapore to Oman to Jamaica, but many countries are effectively flying blind, with little sense of how bad the problem may be.

Long before the pandemic emerged, public health officials were calling for routine genetic surveillance of outbreaks. But despite years of warnings, many countries including the United States are conducting only a fraction of the genomic studies needed to determine how prevalent mutations of the virus are.

Denmark, which has invested in genetic surveillance, discovered the variant afflicting Britain in multiple Danish regions and recently tightened restrictions. The health minister compared it to a storm surge, predicting that it would dominate other variants by mid-February.

And as countries go looking, they are discovering other variants, too.

With the world stumbling in its vaccination rollout and the number of cases steeply rising to peaks that exceed those seen last spring, scientists see a pressing need to immunize as many people as possible before the virus evolves enough to render the vaccines impotent.

Its a race against time, said Marion Koopmans, a Dutch virologist and a member of a World Health Organization working group on coronavirus adaptations.

The vaccine alone will not be enough to get ahead of the virus: It will take years to inoculate enough people to limit its evolution. In the meantime, social distancing, mask-wearing and hand-washing coupled with aggressive testing, tracking and tracing might buy some time and avert devastating spikes in hospitalizations and deaths along the way. These strategies could still turn the tide against the virus, experts said.

We do know how to dial down the transmission of the virus by a lot with our behavior, said Carl T. Bergstrom, an evolutionary biologist at the University of Washington in Seattle. Weve got a lot of agency there.

Yet in the course of the pandemic, governments have often proven reluctant or unable to galvanize support for those basic defenses. Many countries have all but given up on tracking and tracing. Mask-wearing remains politically charged in the United States, despite clear evidence of its efficacy. Cities like Los Angeles have been gripped by a spike in cases linked to Christmas festivities, and national public health officials are bracing for surges elsewhere, driven by people who ignored advice and traveled during the holidays.

Much remains unknown about the new variants, or even how many are sprouting worldwide. Scientists are racing to sequence enough of the virus to know, but only a handful of countries have the wherewithal or commitment to do so with any regularity.

The rapid spread of the new variants is a reminder of the failings and missteps of major countries to contain the virus earlier. Just as China failed to stop travelers from spreading the virus before the Lunar New Year last year, Britain has failed to move fast enough ahead of the new variants spread. Britain lowered its guard during the holidays, despite a rise in cases now known to be linked to a variant. And just as China became a pariah early on in the pandemic, Britain now has the unfortunate distinction of being called Plague Island.

The spread of the variant lashing Britain has left some countries vulnerable at a time when they seemed on the brink of scientific salvation.

A case in point: Israel. The country, which had launched a remarkably successful vaccine rollout, tightened its lockdown on Friday after having discovered cases of the variant. About 8,000 new infections have been detected daily in recent days, and the rate of spread in ultra-Orthodox communities has increased drastically.

The variant discovered in Britain, known as B.1.1.7, has 23 mutations that differ from the earliest known version of the virus in Wuhan, China, including one or more that make it more contagious, and at least one that slightly weakens the vaccines potency. Some experiments suggest that the variant spreads more easily because mutations enable it to latch more successfully onto a persons airway.

Dr. Bergstrom and other scientists were surprised to see this more transmissible variant emerge, given that the coronavirus was already quite adept at infecting people.

While the exact order of vaccine recipients may vary by state, most will likely put medical workers and residents of long-term care facilities first. If you want to understand how this decision is getting made, this article will help.

Life will return to normal only when society as a wholegains enough protection against the coronavirus. Once countries authorize a vaccine, theyll only be able to vaccinate a few percent of their citizens at most in the first couple months. The unvaccinated majority will still remain vulnerable to getting infected. A growing number of coronavirus vaccines are showing robust protection against becoming sick. But its also possible for people to spread the virus without even knowing theyre infected because they experience only mild symptoms or none at all. Scientists dont yet know if the vaccines also block the transmission of the coronavirus. So for the time being, even vaccinated people will need to wear masks, avoid indoor crowds, and so on. Once enough people get vaccinated, it will become very difficult for the coronavirus to find vulnerable people to infect. Depending on how quickly we as a society achieve that goal, life might start approaching something like normal by the fall 2021.

Yes, but not forever. The two vaccines that will potentially get authorized this month clearly protect people from getting sick with Covid-19. But the clinical trials that delivered these results were not designed to determine whether vaccinated people could still spread the coronavirus without developing symptoms. That remains a possibility. We know that people who are naturally infected by the coronavirus can spread it while theyre not experiencing any cough or other symptoms. Researcherswill be intensely studying this question as the vaccines roll out. In the meantime, even vaccinated people will need to think of themselves as possible spreaders.

The Pfizer and BioNTech vaccine is delivered as a shot in the arm, like other typical vaccines. The injection wont be any different from ones youve gotten before. Tens of thousands of people have already received the vaccines, and none of them have reported any serious health problems. But some of them have felt short-lived discomfort, including aches and flu-like symptoms that typically last a day. Its possible that people may need to plan to take a day off work or school after the second shot. While these experiences arent pleasant, they are a good sign: they are the result of your own immune system encountering the vaccine and mounting a potent response that will provide long-lasting immunity.

No. The vaccines from Moderna and Pfizer use a genetic molecule to prime the immune system. That molecule, known as mRNA, is eventually destroyed by the body. The mRNA is packaged in an oily bubble that can fuse to a cell, allowing the molecule to slip in. The cell uses the mRNA to make proteins from the coronavirus, which can stimulate the immune system. At any moment, each of our cells may contain hundreds of thousands of mRNA molecules, which they produce in order to make proteins of their own. Once those proteins are made, our cells then shred the mRNA with special enzymes. The mRNA molecules our cells make can only survive a matter of minutes. The mRNA in vaccines is engineered to withstand the cell's enzymes a bit longer, so that the cells can make extra virus proteins and prompt a stronger immune response. But the mRNA can only last for a few days at most before they are destroyed.

But other experts had warned from the start that it would only be a matter of time before the virus became an even more formidable adversary.

Every situation we have studied in depth, where a virus has jumped into a new species, it has become more contagious over time, said Andrew Read, an evolutionary microbiologist at Penn State University. It evolves because of natural selection to get better, and thats whats happening here.

Much of the global response has focused on shutting out Britain, with a hodgepodge of national restrictions that harken back to the early reactions to the epidemic.

China has banned flights and travelers from Britain. Japan took an even harsher measure, banning entry to nonresident foreigners from more than 150 countries.

Others like India and New Zealand are allowing some flights from Britain but require passengers to have two negative tests one before departure and another after arrival. Australia is sticking with its policy of requiring hotel quarantines and testing for international travelers.

Experts say that countries should focus instead on ramping up vaccinations, particularly among essential workers who face a high risk with few resources to protect themselves. The longer the virus spreads among the unvaccinated, the more mutations it might collect that can undercut the vaccines effectiveness.

That is why, when the World Health Organization working group saw the first data on the variant circulating in South Africa on Dec. 4, everyone took notice.

Your next question immediately is: Can the vaccines still protect us if we get viruses with these mutations? said Dr. Koopmans, who was in the meeting.

For now, the answer seems to be yes, said Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Koopmans agrees.

The variants that have emerged in South Africa and Brazil are a particular threat to immunization efforts, because both contain a mutation associated with a drop in the efficacy of vaccines. In one experiment, designed to identify the worst-case scenario, Dr. Blooms team analyzed 4,000 mutations, looking for those that would render vaccines useless. The mutation present in the variants from both Brazil and South Africa proved to have the biggest impact.

Still, every sample of serum in the study neutralized the virus, regardless of its mutations, Dr. Bloom said, adding that it would take a few more years before the vaccines need to be tweaked.

There should be plenty of time where we can be prospective, identify these mutations, and probably update the vaccines in time.

That sort of surveillance is precisely what led to the discovery of the new variants.

Liza Sitharam, a nurse and infectious disease specialist in coastal South Africa, was among those who first noticed a small cluster that was quickly bulging.

Wed have five cases and then itd double really quickly, she recalled. The raw numbers werent alarming, she said, but there was something just not looking right.

Her boss at the Netcare hospital group, Dr. Caroline Maslo, figured that with the countrys borders open, business travelers from German auto companies had perhaps brought in a European variant of the virus. She sought help from Tulio de Oliveira, a professor and geneticist at the Nelson Mandela School of Medicine in Durban who had studied viral variants during the first Covid-19 wave.

Soon, his lab was analyzing swabs, shipped on ice by courier overnight. On Dec. 1, he emailed a British scientist, Andrew Rambaut, and asked him to review some of his early findings: a series of strange mutations on the viruss outer surface.

Dr. de Oliveira, a Brazilian-South African scientist who sports long hair and a surfer vibe, shared his findings at a Dec. 4 meeting of the World Health Organization working group. All took notice because of the variants potential to disrupt the vaccines effectiveness.

Days later, Dr. de Oliveira recalled, Dr. Rambaut emailed him with a discovery of his own: British scientists had scoured their databases and found a similar but unrelated mutation that appeared linked to a cluster of infections in the county of Kent.

Coming two weeks before Christmas, Dr. de Oliveira immediately thought of the Lunar New Year early in the pandemic, when millions of people in China traveled far and wide for the holiday, some carrying the virus.

It was crystal clear, Dr. de Oliveira said in an interview. These variants will spread nationally, regionally and globally.

Dr. Rambaut and colleagues released a paper on the variant discovered in Britain on Dec. 19 the same day that British officials announced new measures. The variant had apparently been circulating undetected as early as September. Dr. Rambaut has since credited the South Africa team with the tip that led to the discovery of the variant surging in Britain.

Public health officials have formally recommended that type of swift genetic surveillance and information-sharing as one of the keys to staying on top of the ever-changing virus. But they have been calling for such routine surveillance for years, with mixed results.

The message was very clear, that this is the way surveillance has to go, said Dr. Josep M. Jansa, a senior epidemiologist at the European Centre for Disease Prevention and Control. Just as Covid-19 exposed flaws in the worlds pandemic plans a year ago, the hunt for new variants is exposing gaps in surveillance. Were learning, he said. Slowly.

Britain has one of the most aggressive surveillance regimens, analyzing up to 10 percent of samples that test positive for the virus. But few countries have such robust systems in place. The United States sequences less than 1 percent of its positive samples. And others cannot hope to afford the equipment or build such networks in time for this pandemic.

In Brazil, labs that had redirected their attention from Zika to the coronavirus had discovered a worrisome mutation there as early as this spring. But little is known about the variants circulating in the country, or how quickly they are spreading.

We just dont know because no one is either sequencing or sharing the data, said Dr. Nuno Faria at Imperial College and Oxford University who coordinates genomic sequencing projects with colleagues in Brazil. Genomic surveillance is expensive.

As the virus continues to mutate, other significant variants will almost certainly emerge. And those that make the virus hardier, or more contagious, will be more likely to spread, Dr. Read said.

The faster we can get the vaccines out, the faster we can get on top of these variants, he said. Theres no room for complacency here.

Matt Apuzzo reported from Durban, South Africa, and Brussels, Selam Gebrekidan from London, and Apoorva Mandavilli from New York. Reporting was contributed by Thomas Erdbrink; Melissa Eddy from Berlin; Isabel Kershner from Jerusalem; Manuela Andreoni from Rio de Janeiro; Christina Anderson from Stockholm; Amy Chang Chien and Amy Qin from Taipei, Taiwan; and Jennifer Jett and Tiffany May from Hong Kong.

More:
As Coronavirus Mutates, the World Stumbles Again to Respond - The New York Times

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Verve Therapeutics, a biotech company pioneering gene editing medicines to treat cardiovascular disease, today announced that Sekar Kathiresan, M.D., co-founder and chief executive officer, will present a company overview during the 39th Annual J.P. Morgan Healthcare Conference on Tuesday, January 12, 2021 at 9:15 a.m. ET. Dr. Kathiresans presentation will include an overview of Verves strategy to create once-and-done gene editing medicines for coronary heart disease and an update on the companys preclinical progress.

Gene editing is a promising new treatment approach for coronary heart disease, the leading cause of death worldwide. Genetic studies have revealed gene variants that naturally turn off a disease-causing gene in the liver and dramatically lower some individuals lifetime risk of coronary heart disease. These individuals have low levels of LDL cholesterol or triglycerides lifelong, are protected against heart attack, and are otherwise healthy. Verve is developing gene editing medicines to safely turn off a target gene in the liver and mimic naturally-protective variants to permanently lower LDL cholesterol and triglyceride levels and thereby treat coronary heart disease.

About Verve Therapeutics

Verve Therapeutics is a biotechnology company created with a singular focus: to protect the world from heart disease. The company brings together human genetics analysis and gene editing two of the biggest breakthroughs in 21st century biomedicine to develop transformative therapies for coronary heart disease. Verve is developing medicines, administered once in life, to safely edit the genome of adults and mimic naturally occurring gene variants to permanently lower LDL cholesterol and triglyceride levels and thereby treat coronary heart disease. Founded by world-leading experts in cardiovascular medicine, human genetics and gene editing, Verve is backed by a top-tier syndicate of investors, including GV (formerly Google Ventures), ARCH Venture Partners, F-Prime Capital, Biomatics Capital, Wellington Management, Casdin Capital, and Partners Innovation Fund. Verve is headquartered in Cambridge, Massachusetts. For more information, visit http://www.VerveTx.com.

View original post here:
Verve Therapeutics to Present at the 39th Annual J.P. Morgan Healthcare Conference - Business Wire

BOSTON--(BUSINESS WIRE)--Jnana Therapeutics, a biotechnology company targeting the solute carrier (SLC) family of metabolite transporters to treat underserved diseases, today announced the appointment of two experienced scientific and clinical leaders to the companys boards. Annie C. Chen, MD, MPH, Chief Medical Officer of Nimbus Therapeutics, joins the companys Board of Directors. Katalin Susztak, MD, PhD, Professor of Medicine at the University of Pennsylvania Perelman School of Medicine, joins the companys Scientific Advisory Board.

We are delighted to welcome Annie to our Board. Her experience leading the clinical development of drug candidates at biotech and pharmaceutical companies will be tremendously valuable as we move our pipeline of novel SLC therapeutics toward the clinic, said Joanne Kotz, PhD, Co-founder, Chief Executive Officer and President of Jnana.

Jnanas small molecule approach to targeting SLC transporters represents a promising avenue for discovering new medicines for patients across a range of diseases, said Dr. Annie Chen. I look forward to serving on the Board as the company evolves to its next stage of growth and builds an early clinical pipeline.

Dr. Annie Chen is an expert in clinical development strategy with an extensive background in immunology, where she has brought multiple therapies forward to regulatory approval. In addition to her role as CMO at Nimbus, she is President of the companys Tyk2 subsidiary, Nimbus Lakshmi, Inc. Prior to joining Nimbus, she was Executive Director of Clinical Research, Section Head of Vaccines for Merck, where she oversaw clinical research activities for a broad portfolio of vaccines from discovery through registration and life cycle management. Dr. Chen also held the role of Section Head of Immunology, where she oversaw clinical research for small molecule and protein therapeutics. Prior to Merck, she held roles of increasing responsibility at Genentech and began her industry career at Celera Genomics. She was formerly Assistant Clinical Professor of Medicine at the University of California San Francisco, where she completed her fellowship training in rheumatology. She received her MD from Cornell University, her MPH in epidemiology from the University of California Berkeley and her AB in biological sciences from Harvard University.

It is a pleasure to have Katalin serve on Jnanas scientific advisory board. Her deep expertise in renal diseases will be instrumental as we pursue therapeutic opportunities targeting SLC transporters in the kidney, said Joel Barrish, PhD, Co-founder and Chief Scientific Officer of Jnana.

There is substantial untapped potential to target SLC transporters in important disease areas, including renal diseases, where I am keenly aware of the need for new therapeutic approaches, said Dr. Katalin Susztak. I welcome the opportunity to work with Jnanas scientific leaders and SAB to bring new treatments to patients.

Dr. Katalin Susztak is an accomplished physician-scientist, and her laboratory is focused on understanding the pathological mechanisms of chronic kidney disease. Dr. Susztak is a Professor of Nephrology / Medicine and Genetics at the University of Pennsylvania and Director of the Complications Unit at the Institute of Diabetes, Obesity and Metabolism. Dr. Susztak has made fundamental discoveries towards defining critical genes, cell types and mechanisms of chronic kidney disease. She was instrumental in defining genetic, epigenetic and transcriptional changes in diseased human kidneys, has identified novel kidney disease genes, and has demonstrated the contribution of Notch signaling and metabolic dysregulation to kidney disease development. She is Principal Investigator of the Transformative Research in Diabetic Nephropathy (TRIDENT), a public-private observational clinical study to identify novel therapeutic targets and biomarkers for kidney disease development. Dr. Susztak was the recipient of the 2011 Young Investigator Award of the American Society of Nephrology and American Heart Association. She is an elected member of the American Society for Clinical Investigation and the American Association of Physicians.

About Jnana Therapeutics

Jnana Therapeutics is a biotechnology company focused on opening the solute carrier (SLC) family of metabolite transporters as a target class to develop transformational therapeutics. Jnana uses its RAPID platform, a proprietary, cell-based drug discovery approach, to systematically target SLC transporters and develop best-in-class therapies to treat a wide range of diseases, including immune-mediated, neurological and metabolite-dependent diseases. Headquartered in Boston, Jnana is founded by world-renowned scientists and backed by leading life science investors. For more information, please visit http://www.jnanatx.com and follow us on Twitter and on LinkedIn.

See more here:
Jnana Therapeutics Appoints Dr. Annie Chen to Board of Directors and Dr. Katalin Susztak to Scientific Advisory Board - Business Wire

(CNN) The US reported moreCOVID-19 cases and deathsin the last week than any previous seven days during the pandemic, data showed Friday morning.

And more than 4,080 US coronavirus deaths were reported on Thursday alone the most ever reported in a single day during the pandemic and the first time the daily tally rose above 4,000, Johns Hopkins University (JHU) data showed.

In other words, even though the US is working to distribute vital COVID-19 vaccines a processcriticized as being too slow the pandemic generally isnt showing signs of slowing down, and the virus is advancing with alarming speed in some areas, the White House coronavirus task force said in its report to states this week.

In Los Angeles County, where some ambulance crews have beenreported to wait for hours with their patientsoutside hospitals because the facilities are overwhelmed, one person is dying of COVID-19 on an average of everyeight minutes, officials said.

Were seeing heroes in our hospitals, were seeing angels in our ambulances, stretched thin to just deal with the onslaught right now, Los Angeles Mayor Eric Garcetti said Thursday.

Hospitals in the county are now preparing to ration care with triage officers who will decided which patients will receive care, with a focus of doing the most good for the most people, according to new guidelines issued by the LA County Department of Public Health.

Texas reported record-high COVID-19 hospitalizations statewide for the fifth day in a row Thursday. Hospitals in Dallas County the states second largest county had just 13 adult ICU beds available on Wednesday, County Judge Clay Jenkins said ina tweet.

The US has averaged about 228,400 COVID-19 cases a day over the last week as of Thursday an all-time high, and more than 3.4 times a summertime peak set in late July, JHU data shows.

And the country has averaged 2,764 deaths a day over the last week the highest figure of the pandemic, according to JHU data.

Hospitalizations also are soaring. Some 131,889 COVID-19 patients were in US hospitals on Friday the third-highest figure recorded, the COVID Tracking Project data show.

In a report this week, the White Housecoronavirus task force speculatedthere may be a USA variant that has evolved here that spreads more easily than the known variant.

This fall/winter surge has been at nearly twice the rate of rise of cases as the spring and summer surges. This acceleration suggests there may be a USA variant that has evolved here, in addition to the UK variant that is already spreading in our communities and may be 50% more transmissible, the report said.

So far, theres no evidence of a US variant, the Centers for Disease Control and Prevention and academic researchers said Friday.

Significant continued deterioration, from California across the Sunbelt and up into the Southeast, Mid-Atlantic and Northeast, despite low testing rates during the holidays, suggests aggressive community spread, the task force report said.

But a CDC spokesman said that researchers have been monitoring US strains since the pandemic began, including 5,700 samples collected in November and December. To date, neither researchers nor analysts at CDC have seen the emergence of a particular variant in the United States like those identified in the UK and in South Africa.

Trevor Bedford of the University of Washington and the Fred Hutchinson Cancer Research Center, who helps maintain a database of genetic mutations in the coronavirus, said he saw no evidence of a homegrown US strain that is spreading more aggressively.

The CDC did say at least 63 cases of a variant first identified in the UK have been recorded in eight US states. This includes at least 32 cases in California, 22 cases in Florida, three cases in Colorado, two cases in Connecticut, and one case each in Georgia, New York, Texas and Pennsylvania.

The agency says this does not represent the total number of cases circulating in the US, but rather just those that have been found by analyzing positive samples.

While vaccinations have been happening for several weeks, experts have said it will be months before theyre widespread enough to make a meaningful impact in the pandemics course.

Meanwhile, President-elect Joe Biden aims to release nearly every available dose of the coronavirus vaccine when he takes office, a break with the Trump administrations strategy of holding back half of US vaccine production to ensure second doses are available,CNNs Sara Murray reported Friday.

Releasing nearly all vaccine doses on hand could allow more people access to a first dose during a given time.

It could also be a risky strategy, as the vaccines from both Pfizer/BioNTech and Moderna require two doses, administered 21 days or 28 days apart, respectively, and vaccine manufacturing has not ramped up as rapidly as many experts had hoped.

Thesecond dose is absolutely critical, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases said Friday.

The President-elect believes we must accelerate distribution of the vaccine while continuing to ensure the Americans who need it most get it as soon as possible. He supports releasing available doses immediately, and believes the government should stop holding back vaccine supply so we can get more shots in Americans arms now, said TJ Ducklo, a spokesman for Bidens transition.

A transition official said the Biden team believes that vaccine manufacturers will be able to produce enough second doses in a timely fashion while administering first doses to more Americans.

The Trump administration has said its necessary to hold back doses, to ensure Americans who receive the first course of the two-dose vaccine will be sure to have access to a second dose.

But that had sparked a debate about whether a better strategy would be releasing all available doses as quickly as possible, particularly amid rising death and hospitalization rates.

A study published Monday in the Annals of Internal Medicine found that administering first doses of a COVID-19 vaccine to more people quickly, instead of withholding available supply for use as a second dose, may reduce the number of new cases.

And World Health Organization advisers said Friday that a second dose of Pfizer and BioNTechs vaccine can be delayed as long as six weeks if need be. Thats based on currently available clinical trial data, the WHO guidance document said.

Moderna also believes a second dose of its vaccine can be given effectively 21 to 42 days after the first, a spokesperson for the company told CNN.

Kentucky Gov. Andy Beshear said Friday he agreed with Bidens plan, but wants assurances the second dose will be there.

Nearly 6.7 million people have received their first doses of a vaccine and more than 22 million doses have been distributed,the CDC said Friday.

Federal officials had said 20 million people would have received first dosesby the end of December.

Some health leaders said states need more money and more staff in order to be able to administer the vaccines fast enough.

Pennsylvania Secretary of Health Dr. Rachel Levine said states, cities and territories had been given just $340 million to build the infrastructure for vaccine rollouts up until the end of the year.

That is clearly insufficient to accomplishing what were trying to accomplish, Levine said.

President Donald Trump signed a$900 billion COVID-19 relief packagein December that includes funds for vaccine rollout, something health leaders were absolutely thrilled about, Levine said.

The money will be critical for several aspects of our response, Levine added, including contracting with companies to do community vaccine clinics.

The US Food and Drug Administration has alerted health care providers and labs that genetic variants of the novel coronavirus including an emergingvariant first detected in the United Kingdom could lead to false negative COVID-19 test results.

False negative results can occur with any molecular test for the detection of the virus if a mutation has occurred in the part of the viruss genome that the test examines, the FDA said Friday.

But the risk that these mutations will impact overall testing accuracy is low, the FDA said. If COVID-19 is suspected after a negative test, repeat testing should be done with a different test, the agency recommends.

The agency noted three COVID-19 tests authorized in the United States may be impacted by genetic variants MesaBiotech Accula, TaqPath COVID-19 Combo Kit and Linea COVID-19 Assay Kit but the impact does not appear to be significant.

Since the TaqPath and Linea COVID-19 tests detect multiple genetic targets, the overall test sensitivity should not be impacted, the FDA noted. However, if certain patterns emerge in individual results from those tests, labs might consider further genetic sequencing of specimens.

That may help with early identification of new variants in patients to reduce further spread of infection, the FDA said in its letter to labs and health care providers, noting that the UK variant has been associated with an increased risk of transmission.

The FDA will continue to monitor SARS-CoV-2 genetic viral variants to ensure authorized tests continue to provide accurate results for patients, FDA Commissioner Dr. Stephen Hahn said, referring to the name of the coronavirus that causes COVID-19.

With information from the Indiana Department of Health through Jan. 7, 2021, this timeline reflects updated tallies of deaths and positive tests prior to that date.

Go here to see the original:
1-week US COVID-19 case and death totals are higher than ever - WISHTV.com

After decades of work and mass vaccination campaigns that have spared millions of children from paralysis, the world is close to wiping out polio.

But a small number of outbreaks that have simmered in areas of low vaccination remain. And some happened after weakened virus in the oral polio vaccine, over time, moved around a community and regained the ability to cause disease. No other vaccines made with weakened live viruses have caused outbreaks of disease.

To stamp out vaccine-derived polio outbreaks, the World Health Organization has granted emergency use for a new polio vaccine. The oral vaccine got the go-ahead on November 13.

We are very, very enthusiastically looking forward to using this new vaccine, says medical epidemiologist Chima Ohuabunwo of Morehouse School of Medicine in Atlanta, who has worked on polio eradication in Africa for more than two decades. Along with continuing the crucial work of improving vaccination coverage in places where it is low, the new vaccine will hopefully take us to the finishing line of polio eradication.

Eight years after the WHOs 1980 declaration that the world was free of smallpox, the Global Polio Eradication Initiative launched to tackle polio. The disease was a promising candidate for eradication. An effective, easily administered and cheap vaccine was available. And poliovirus, which naturally infects only humans, doesnt hang around in other animals in between outbreaks.

Headlines and summaries of the latest Science News articles, delivered to your inbox

Most people who become infected with poliovirus dont feel sick, while some have flu-like symptoms. But about one in 200 become paralyzed for life. Although not a routine threat in the United States since the early 1950s (SN: 9/12/19), polio has continued to harm people, especially children, around the world.

In the late 1980s, wild poliovirus paralyzed more than 1,000 children each day, according to the Global Polio Eradication Initiative. Since then, thanks to widespread vaccination campaigns, cases have plummeted by more than 99 percent, and two of the three types of wild poliovirus have been eradicated. The last cases from type 2 and type 3 were reported in 1999 and 2012, respectively. Only wild poliovirus type 1 remains, and only in two countries: As of December 30, 56 cases were reported in Afghanistan and 83 in Pakistan caused by type 1, in 2020.

Much of this progress has been possible because of the oral polio vaccine. Its been the workhorse of the eradication campaign, says virologist and infectious disease physician Adam Lauring of the University of Michigan School of Medicine in Ann Arbor. Immunization with the oral vaccine has prevented more than 13 million cases of polio since 2000, according to WHO.

A big advantage of the oral vaccine, which is made of live but weakened poliovirus, is that it not only protects against paralysis it also can stop wild poliovirus from spreading in a community. Poliovirus moves from person to person when someone ingests water or food contaminated with virus-containing stool. The oral vaccine prevents wild poliovirus from multiplying in the gut and being passed on. (There is another, more expensive, injected polio vaccine with killed virus that prevents paralysis but not viral spread.)

While the oral vaccine has nearly wiped out wild poliovirus, it has a vulnerability. Weakened poliovirus in the vaccine has genetic changes that keep it from causing disease. As vaccine virus multiplies in the gut, it can lose key genetic changes, bringing it closer to behaving like wild poliovirus. And altered vaccine virus can be spread to others and establish community transmission, says biologist Raul Andino of the University of California, San Francisco School of Medicine. That can be a problem if not enough people have been immunized against polio.

More than 80 percent of children need to be vaccinated to keep poliovirus from spreading in a community. The first vaccine-derived polio outbreak to be detected occurred in the Dominican Republic and Haiti two decades ago, in areas with low vaccination. That allowed altered vaccine virus, shed in the stool of the immunized, to spread largely unchecked and, over time, return to a form that causes paralysis (SN: 8/10/04). The full process of vaccine virus reverting to disease-causing virus is rare and takes many months of moving around a community.

Today, vaccine-derived outbreaks are primarily found in Afghanistan, Pakistan and countries in Africa. Most of these outbreaks which have been responsible for more polio cases in the last few years than the remaining type of wild poliovirus are linked to vaccine virus type 2. Vaccination campaigns, which had used an oral vaccine containing weakened versions of all three types of poliovirus, switched to using a formulation with just types 1 and 3 in 2016.

However, the way to stop a type 2 vaccine-derived outbreak is with an oral vaccine containing only the weakened type 2 virus. And that has sparked new outbreaks, researchers reported in Science in April. It is this vicious circle, Lauring says. As of December 22, in 2020 there were 854 polio cases linked to the type 2 vaccine virus.

Hence the quest for a new and improved poliovirus type 2 oral vaccine, one that kept the good parts of the original but with tweaks to try to prevent problematic genetic changes. Its a wonderful vaccine, so we didnt want to change the characteristics that induce the bodys immune response, Andino says. The only thing we wanted to do is prevent the reversion to a disease-causing virus.

Andino and colleagues modified the type 2 vaccine virus in several places. The researchers altered a part of the viruss genetic instruction book, or genome, to make the virus less likely to develop a gatekeeper change: a first, critical step along the road to regaining the ability to cause disease.

Poliovirus can swap pieces of its genome with related viruses called enteroviruses. So the researchers moved a string of genetic letters the virus needs to make more copies of itself close to the gatekeeper modification. That way, if the vaccine virus was able to ditch that modification by way of a swap, it would lose this necessary string of genetic letters too, and die out.

Finally, the team tinkered with an enzyme that RNA viruses, including poliovirus, use to help replicate themselves. The enzyme is sloppy and can introduce a lot of genetic changes, Andino says. Thats advantageous for the viruses, which are continuously trying to adapt to a new environment, he says. Andino and colleagues modified this enzyme in the vaccine virus to introduce fewer mistakes, so the virus cannot evolve so quickly. The researchers described their improved oral polio vaccine in a study in Cell Host & Microbe in May.

The new oral polio vaccine was shown to be safe and to produce an immune response similar to that seen with the original vaccine in infants and children, researchers reported online December 9 in the Lancet. The hope is that the modifications will slow the evolution of the new vaccine virus such that it can end the existing outbreaks without creating new ones.

The vaccine-derived outbreaks are a significant, yet surmountable hurdle to polio eradication, says Ohuabunwo, and science is helping. But the key to ending polio is very high vaccination coverage. Obstacles including war, migrating populations, difficult terrain and lack of vaccine acceptance have created pockets of inaccessible children, he says.

Reaching all children requires engaging community leaders, providing culturally sensitive information and finding out how to meet other community needs, says Ohuabunwo. For example, while working in Nigeria, he and his colleagues made progress with nomadic populations. It meant sometimes combining vaccinating their children with vaccinating their animals. The nomads cattle would be immunized against brucellosis and anthrax bacterial infections. Protecting the animals also protected the nomads from these infections, he says, and motivated their cooperation towards having their children receive polio vaccine: a win-win.

Polio eradication has been a long journey, but were getting close, Ohuabunwo says. The new oral polio vaccine is another light in the tunnel.

More:
A new polio vaccine joins the fight to vanquish the paralyzing disease - Science News Magazine