Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Archive for the ‘Biomarkers & Medical Diagnostics’ Category

Pull at Cancer’s Levers

Posted in Anticancer Resistance, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biomarkers & Medical Diagnostics, BioTechnology - Venture Creation, Cancer and Current Therapeutics, Cell Biology, Clinical Diagnostics, Clinical Genomics, CT, Diagnostic Immunology, Disease Biology, Epigenetics and Environmental Factors, Immuno-Oncology & Genomics, Immunology, Immunotherapy, tagged Cancer - General, gene expression profiling, Immunotherapy, mRNA and miRNA expression, on target, transcriptome, translocation, tumor immune microenvironment on April 2, 2016| Leave a Comment »

Pull at Cancer’s Levers

Curator: Larry H. Bernstein, MD, FCAP

 

Driving Cancer Immunotherapy 

The Stakes in Immuno-Oncology Are Too High for Researchers to Pull at Cancer’s Levers Blindly. Researchers Need a System.

• Ian Clift, Ph.D      GEN  Apr 1, 2016 (Vol. 36, No. 7)     http://www.genengnews.com/gen-articles/driving-cancer-immunotherapy/5726/

• Within the past decade or so, a revolutionary idea has emerged in the minds of scientists, physicians, and medical experts. Instead of using man-made chemicals to treat cancer, let us instead unleash the power of our own bodies upon the malignancy.

  This idea is the inspiration behind cancer immunotherapy, which is, according to most experts, a therapeutic approach that involves training the immune system to fight off cancer. In the words of one expert, cancer immunotherapy means “taking the immune system’s inherent properties and turbo charging those to fight cancer.”

  Cancer immunotherapy technologies are being developed to accomplish
  several tasks:

  • Enhance the molecular targeting of cancer cells
  • Report the rate of killing by specific immune agents
  • Direct immune cells toward tumor destruction.

  Since its inception, the field has evolved, and it continues to do so. It began with in vivo investigations of tumor growth and development, and it progressed through laboratory investigations of cellular morphology and survival curves. And now it is adopting pathway analysis to guide therapeutic development and improve patient care.

  To begin to understand cancer immunotherapy, one must understand how the immune system targets tumor cells. One of the prominent adaptive components of the immune system is the T cell, which responds to perceived threats through the massive increase in clonal T cells targeted in some way toward the diseased cell or pathogen.

• The T-Cell Repertoire

  

  Adaptive Biotechnologies’ immunoSEQ Assay, a high-throughput research platform for immune system profiling, is designed to generate sequencer-ready libraries using highly optimized primer sets in a multiplex PCR format that targets T- and B-cell receptor genes. This image depicts how the assay’s two-step PCR process can be used to quantify the clonal diversity of immune cells.

  Immunologists call this process VJD rearrangement. It happens during T-lymphocyte development and affects three gene regions, the variable (V), the diversity (D), and the joining (J) regions. This rearrangement of the genetic code allow for the structural diversity in T-cell receptors responsible for antigenic specificity including antigenic targets on tumor cells. In the case of cancer, specificity is complicated because the tumor is actually part of the body itself, one of the reasons cancers naturally evade detection.

  The specificity problem would always hinder attempts to goad the immune system into attacking cancer, scientists realized, unless technologies emerged that could efficiently track the clonal diversity of T cells inside patients. Existing technologies, such as spectratyping, were inadequate.  In 2007, when Dr. Robins and his collaborators began developing the technology, only 10,000 T-cell receptor sequences had been reported in all the literature using older methodologies.

  “The immunology field of the time had no connection with high-throughput sequencing,” notes Dr. Robins, recalling his days as a computational biologist for the Fred Hutchinson Cancer Research Center. “It became clear that instead of using this old technology to look at T-cell receptors, we could just directly sequence them—if we could amplify them correctly.”

  With its first experiment, Dr. Robins’ team ended up with six million T-cell receptor sequences. “Our approach,” Dr. Robins modestly suggests, “kind of changed the scale of what we were able to do.” The team went on to develop advanced multiplex sequencing technology, doing work that essentially started the field of immune sequencing. “Previously,” maintains Dr. Robins, “no one had ever been able to quantitatively do a multiplex PCR.”

  Adaptive Biotechnologies’ product, the ImmunoSEQ^® assay, uses several hundred primer pairs to quantify the clonal diversity of T cells. Using this technology, researchers and clinicians can focus on T-cell clones that are expanded specifically in or near a tumor or that are circulating in the blood stream.

  “You obviously can’t get a serial sample of the tumor,” explains Dr. Robins, “but you can get serial samples of blood,” allowing for immune cell repertoire tracking during the progression of a disease. The technology is already being used to assess leukemias in the clinic, directly tracking the leukemia itself based on the massive clonal expansion of a single cancerous B or T cell.

  Eventually, Dr. Robins’ team hopes to monitor serial changes in T cell clones before, during, and after therapeutic intervention. The team has even developed a tumor infiltrating lymphocyte (TIL) assay to examine clones that are attracted to tumors.

   

Circulating Tumor Cells

“Years ago, they were just interested in what was happening in the tumor,” says Daniel Adams, senior research scientist at Creatv MicroTech. “Now people have realized that the immune system is reacting to the tumor.”

Scientists such as Adams have been tracking tumor cells and tumor-modified stromal cells, as well as components of the non-adaptive immune system, directly within the bloodstream to examine changes that occur over time.

“We can’t go back in to re-biopsy the patient every year, or every time there is a recurrence,” says Adams, “It’s just not feasible.”

That is why Creatv MicroTech, with locations in Maryland and New Jersey, has developed the CellSieve, a mechanical cell filter. The CellSieve, which improves on older technology through better polymers and engineering, isolates circulating tumor cells (CTCs) and stromal cells in order to capture them for further clinical analysis.

Isolation, culture and expansion of cells isolated on CellSieve™. (A) MCF-7 cells spiked into vacutainers, isolated by filtration and cultured on CellSieve for 2-3 weeks. A 3 dimensional cluster attributed to this cell line is seen on the filter. (green=anti-cytokeratin, blue=DAPI) (B) PANC-1 cells spiked into vacutainers, isolated by filtration and grown on CellSieve for 2-3 weeks. PANC-1 is seen growing as a monolayer on the filter. (C) SKBR3 cells are spiked into blood, filtered by CellSieve. The CTCs are identified by presence of anti-cytokeratin and anti-EpCAM, and absence of anti-CD45. After CTCs are counted, cells are subtyped by HER2 FISH. (D) SKBR3 cells are spiked into vacutainers, isolated by filtration and grown on CellSieve for 2-3 weeks. Expanded colonies were directly analyzed as a whole colony and as individual cells, molecularly by HER2/CR17 FISH probes. (E) Circulating stromal cell, e.g. a 70 µm giant cancer associated macrophage can be identified for clinical use, myeloid marker in red. (F) A cell of interest can be identified and restained with immunotherapeutic biomarkers, e.g. PD-L1 (green) and PD-1 (purple). (G) After filtration, cells were identified with histopathological stains (e.g. H&E) for cytological analysis. (H) After H&E, external cell structures were analyzed by SEM. [Creatv MicroTech].

 

“As a patient goes through therapy, the patient’s resistance builds, and the cancer recurs in different subpopulations,” states Adams. “And after a few years, the original tumor mass is no longer applicable to what is growing in the patient farther down the road.”

Although CTCs are exceedingly rare in the bloodstream, with just one or two in every 5 to 10 mL of blood, and although these cells have a very low viability, the surviving CTCs have a high prognostic value.

“We looked at 30 to 40 breast cancer patients over two years,” reports Adams. “And we showed that if you have a dividing CTC, you have a 90% chance of dying in two years and a 100% chance of dying within two and half years.”

Furthermore, the immune system response can be tracked, says Adams, by examining stromal cells, which can also be collected with the CellSieve filtration device. That is, these cells can be collected serially. Much recent evidence supports the conclusion that stromal cells in the tumor environment co-evolve with the tumor, suggesting that stromal marker changes reflect tumor changes.

“There is this plethora of stromal cells and tumor cells out there in the circulation for you to look at,” declares Adams. “Once the cells are isolated, you can subject them to pathological approaches, biomarker approaches, or molecular approaches—or all of the above.”

A MicroTech Creatv study published in the Royal Society of Chemistry showed the efficacy of following up CTC isolation with techniques such as fluorescence in situ hybridization (FISH), histopathological analysis, and cell culture.

Cancer-Killing Assays

Diverse mechanisms are at play in cancer biology. Our understanding of these mechanisms contributes to a couple of virtuous cycles. It strengthens and is strengthened by diagnostic approaches, such as immune- and tumor-cell monitoring. The same could be said of therapeutic approaches. Cancer biology will inform and be informed by cancer immunotherapies such as adoptive cell transfer. To maintain the virtuous cycle, however, it will be necessary to conduct in vitro testing.

“There is no doubt that immunotherapy is going to play a major role in the treatment of cancer,” says Brandon Lamarche, Ph.D., technical communicator and scientist at ACEA Biosciences. “Regardless of what the route is, what is going to have to happen in terms of the research area is that you need an effective cell-killing assay.”

ACEA Biosciences, a San Diego-based company, has developed a microtiter plate that is coated with gold electrodes across 75% of the well bottoms. When the microtiter plates are placed in the company’s xCELLigence plate reader, the electrodes enable the detection of changes in cell morphology and viability through electrical impedance.

“The instrument provides a weak electric potential to the electrodes on the plate, so you get electrons flowing between these electrodes,” explains Dr. Lamarche. Researchers can then apply reagents or non-adherent immune cell suspensions to adherent cancer cells and examine the effect.

Dr. Lamarche asserts that the xCELLigence system overcomes problems that bedevil competing cell-killing assays. These problems include leaky and radioactive labels, such as chromium 51, and assays that can only provide users with an endpoint for cell killing. “With xCELLigence,” he insists, “you’re getting the full spectrum of what’s happening, and there’s all kinds of subtleties in the cell-killing curves that are very informative in terms of the biology.”

ACEA would like to see the xCELLigence system become the new standard in cell-killing assays from standard research to clinical testing on patient tumors. Dr. Lamarche envisions a day when patient tumor cells are quickly screened with therapeutic scenarios to determine the most efficacious killing option. “xCELLigence technology,” he suggests, “enables you to quickly sample a broad spectrum of conditions with a very simple workflow.”

Bioinformatics of Immuno-Oncology

From monitoring to treatment modalities, the field of cancer immunotherapy is aided by bioinformatics-minded data-mining experts, such as the analysts at Thompson-Reuters who are compiling data archives and applying advanced analytics to find new targets. “Essentially,” says Richard Harrison Ph.D., the company’s chief scientific officer for the life science division, “for every stage within pharmaceutical drug development, we have a database associated with that.”

The analysts at Thompson-Reuters curate and compile databases such as MedaCore and Cortellis, which they provide to their clients to help them with their research and clinical studies. “We can take customer data, and using our tools and our pathway maps, we can help them understand what their data is telling them,” explains Dr. Harrison.

Matt Wampole, Ph.D., a solutions scientist at Thompson-Reuters, spends his days reaching out and working with customers to help them understand and better use the company’s products. “Bench researchers,” he points out, “don’t necessarily know what is upstream of whatever expression change might be leading to a particular change in regulation.” Dr. Wampole indicates that he is part of a “solution team” that aids clients in determining important signaling cascades, regulators, and so on.

“We have a group of individuals who are very ‘skilling’ experts in the field,” Dr. Wampole continues, “including experts in the areas such as biostatistics, data curation, and data analytics. These experts help clients identify models, stratify patients, understand mechanisms, and look into disease mechanisms.”

Dr. Harrison sums up the Thompson-Reuters approach as follows: “We look for master regulators that can serve as both targets and biomarkers.” By examining the gene signatures from both the patient and from curated datasets, in the case of cancer immunotherapy, they hope to segregate patients according to what drugs will work best for them.

• “We are working with a number of pharmaceutical companies to put our approach into practice for clinical trials,” informs Dr. Harrison. The approach has already been applied in several studies, including one that used data analysis of cell lines to help predict drug response in patients. Another study helped stratify glioblastoma patients.

• Tumor-Targeted Delivery Platform

  PsiOxus Therapeutics, which is focused on immune therapeutics in oncology, has developed a patented platform for tumor-targeted delivery based on its oncolytic vaccine, Enadenotucirev (EnAd), which can be delivered systemically via intravenous administration.

  According to company officials, EnAd’s anti-cancer scope can be expanded by adding new genes, thereby enabling the creation of a broad range of unique immuno-oncology therapeutics. In a recent study conducted at the University of Oxford, researchers led by Philip G. Jakeman, Ph.D., sought to improve the models for evaluating cancer therapeutics by introducing ex vivo methodologies for research into colorectal cancer.

  The ex vivo approach utilized was able to exploit a major advantage by preserving the three-dimensional architecture of the tumor and its associated compartments, including immune cells. The study, which was presented at the International Summit on Oncolytic Viral Therapeutics in Quebec, showed the tissue slice model can provide a novel means to assessing an oncolytic vaccine in a system that more accurately recapitulates human tumors, provide a more stringent test for oncolytic viruses, such as EnAd, and allow study of the human immune cells within the tumor 3D context.

  By maintaining the components of the tumor immune microenvironment, this new methodology could become useful in analyzing anti-viral responses within tumors, or even in evaluating therapeutics that target immunosuppressive tumor micro-environments, noted the Oxford team.

   

 

Deciphering the Cancer Transcriptome

A Rogue’s Gallery of Malignant Outliers May Hide in Transcriptome Profiles That Emphasize Averages

• Richard A. Stein, M.D., Ph.D                                     GEN  Apr 1, 2016 (Vol. 36, No. 7)

http://www.genengnews.com/gen-articles/deciphering-the-cancer-transcriptome/5729/

 

The key link between genomic instability and cancer progression is transcriptome dynamics. The shifts in transcriptome dynamics that contribute to cancer evolution may come down to statistical outliers. [iStock/zmeel]

• In recent years, scientists have adopted a gene-centric view of cancer, a tendency to see each malignant transformation as the consequence of alterations in a discrete number of genes or pathways. These alterations are, fortunately, absent from healthy cells, but they pervert malignant cells.

  The gene-centric view takes in molecular landscapes illuminated by genomic and transcriptomic technologies. For example, genomes can be cost-effectively sequenced within hours. Such capabilities have made it possible to interrogate associations between genotypes and phenotypes for increasing numbers of conditions, and to collect data from progressively larger patient groups.

  As genomic and transcriptomic technologies rise, they reveal much—but much remains hidden, too. Perhaps these technologies are less like the sun and more like the proverbial streetlight, the one that narrows our searches because we’re inclined to stay in the light, even though what we hope to find may lie in the shadows.

  “Each individual study that looks at the cancer transcriptome is impressive and tells a convincing story, but if we put several high-quality papers together, there are very few genes that overlap,” says Henry H. Heng, Ph.D., professor of molecular medicine, genetics, and pathology at Wayne State University. “This shows that something is wrong.”

• Distinct Karyotypes

  One of the major observations in Dr. Heng’s lab is that the intra- and intertumor cellular heterogeneity results in nearly every cancer cell having a unique, distinct karyotype, that is, an important but often ignored genotype. “Biological systems need a lot of heterogeneity,” notes Dr. Heng. “People like to think that this is noise, but heterogeneity is a fundamental buffer system for biological function to be achievable. Moreover, it is the key agent for cellular adaptation.”

  To capture the degree of genomic heterogeneity at the genome level and its impact on cancer cell growth, Dr. Heng and colleagues performed serial dilutions to isolate single mouse ovarian surface epithelial cells that had undergone spontaneous transformation. Spectral karyotyping revealed that within a short timeframe each of these unstable cells exhibited a very distinct karyotype. In these unstable cells, cloning at the level of the karyotype was not possible.

  Stable cells exhibited a normal growth distribution, i.e., no subset of stable cells contributed disproportionately to the overall growth of the cell population. In contrast, unstable cell populations showed a non-normal growth distribution, with few cells contributing most to the cell population’s growth. For example, a single unstable colony contributed more than 70% to the cell population’s growth. This finding suggests that although average profiles can be used to describe non-transformed cells, they cannot be taken to represent the biology of malignant cells.

  “Most people who study the transcriptome want to get rid of the noise, but the noise is in fact the strategy that cancer uses to be successful,” explains Dr. Heng. “Each individual cancer cell is very weak but together the entity becomes very robust.”

  In a recent model that Dr. Heng and colleagues proposed, system inheritance visualizes chromosomes not merely as the vehicle for transmitting genetic information, but as the genetic network organizer that shapes the physical interactions between genes in the three-dimensional space. Based on this model, individual genes represent parts of the system. The same genes can be reorganized to form different systems, and chromosomal instability becomes more important than the contribution of individual genes and pathways to cancer biology.

  The vital link between genomic instability and cancer progression is transcriptome dynamics, and the shifts in those dynamics that contribute to cancer evolution may come down to statistical outliers.

  “Transcriptome studies rarely focus on single-cell analyses, which means important outliers are frequently ignored,” declares Dr. Heng. “This preoccupation with uninformative averages explains why we have learned so little despite having examined so many transcriptomes.”

• Chimeras and Fusion Genes

  “Our focus is on chimeric RNA molecules,” says Laising Yen, Ph.D, assistant professor of pathology at Baylor College of Medicine. “This category of RNAs is very special because their sequences come from different genes.”

  In a study that was designed to capture chimeric RNAs in prostate cancer, Dr. Yen and his colleagues performed high-throughput sequencing of the transcriptomes from human prostate cancer samples. “We found far more chimeric RNAs, in terms of abundance, and a number of species that are not seen in normal tissue,” reports Dr. Yen. This approach identified over 2,300 different chimeric RNA species. Some of these chimeras were present in prostate cancer cell lines, but not in primary human prostate epithelium cells, which points toward their relevance in cancer.

  “Most of these chimeric RNAs do not have a genomic counterpart, which means that they could be produced by trans-splicing,” explains Dr. Yen. During trans-splicing, individual RNAs are generated and trans-spliced together as a single RNA, which provides a mechanism for generating a chimera.

  “The other possibility is that in cancer cells, where gene–gene boundaries are known to become broken, chimeras can be formed by cis-splicing from a very long transcript that encodes several neighboring genes located on the same chromosome,” informs Dr. Yen. Chimeric RNAs formed by either of these two mechanisms can potentially translate into fusion proteins, and these aberrant proteins may have oncogenic consequences.

  Another effort in Dr. Yen’s laboratory focuses on chromosomal aberrations in ovarian cancer. One of the hallmarks of ovarian cancer is the high degree of genomic rearrangement and the increased genomic instability.

  “When we looked at ovarian cancers, we did not find as many chimeric RNAs,” notes Dr. Yen. “But we found many fusion genes.” Gene fusions, similarly to chimeric RNAs, increase the diversity of the cellular proteome, which could be used selectively by cancer cells to increase their rates of proliferation, survival, and migration.

  A recent study in Dr. Yen’s lab identified BCAM-AKT2, a recurrent fusion gene that is specific and unique to high-grade serous ovarian cancer. BCAM-AKT2 is the only fusion gene in this malignancy that was proved to be translated into a fusion kinase in patients, which points toward its functional significance and potential therapeutic value.

  “Recurrent fusion genes, which are repeatedly found in many patients in precisely made forms, indicate that there is a reason that they are present,” concludes Dr. Yen. “This might have important therapeutic implications.”

• Context-Specific Patterns

  “We contributed to a study of tumor gene expresssion that we are currently revisiting because so much more data has become available,” says Barbara Stranger, Ph.D., assistant professor, Institute for Genomics and Systems Biology, University of Chicago. “The data is being processed in homogenized analytic pipelines, and we can look at many more tumor types across the Cancer Genome Atlas than a few years ago.”

  Previously, Dr. Stranger and colleagues performed expression quantitative trait loci (eQTL) analyses to examine mRNA and miRNA expression in breast, colon, kidney, lung, and prostate cancer samples. This approach identified 149 known cancer risk loci, 42 of which were significantly associated with expression of at least one transcript.

  Causal alleles are being prioritized using a fine-mapping strategy that integrated the eQTL analysis with genome-wide DNAseI hypersensitivity profiles obtained from ENCODE data. These analyses are focusing on capturing differences across tumors and on performing comparisons with normal tissue, and one of the challenges is the lack of normal tissue from the same patients.

  “But still there is a lot of power in these analyses because they are based on large-scale genomic datasets. Also, these tumor datasets can be compared with large-scale normal tissue genomics datasets, such as the NIH’s Genotype-Tissue Expression (GTEx) project,” clarifies Dr. Stranger. “This helps us characterize differences between those tumors and normal tissue in terms of the genetics of gene regulation.”

  An ongoing effort in Dr. Stranger’s laboratory involves elucidating how the effect of genetic polymorphisms is shaped by context. Stimulated cellular states, cell-type differences, cellular senescence, and disease are some of the contexts that are known to impact genetic polymorphisms.

  “We have seen a lot of context specificity,” states Dr. Stranger. “Our observations suggest that a genetic polymorphism can have a specific effect in regulating a particular gene or transcript in one context, and another effect in another context.”

  Another example of cellular context is sex, and an active area of investigation in Dr. Stranger’s lab proposes to dissect the manner in which sex differences shape the regulatory effects of genetic polymorphisms.

  “Thinking about sex-specific differences is not very different from thinking about a different cellular environment,” notes Dr. Stranger.

  The expression of specific transcription factors can be determined by sex; consequently, a polymorphism that interacts with a transcription factor may have functional outcomes that can be seen in only one of the sexes.

  “There are gene-level and gene-splicing differences that we see in normal tissues between males and females, and we want to take the same approach and look at the cancer context to see whether the genetic regulation of gene expression and transcript splicing is different between individuals and whether it has a sex bias,” concludes Dr. Stranger. “Finally, we want to see how that differs in cancer relative to normal tissues.”

  Early Clinical Impact

  

An increasing number of clinicians are adding the cancer transcriptome to their precision medicine program. They have found that the transcriptome is important in identifying clinically impactful results. [iStock/DeoSum]

“Over the last two years,” says Andrew Kung, M.D., Ph.D., chief of the Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation at Columbia University Medical Center, “we have included the cancer transcriptome as part of our precision medicine program.” Dr. Kung and colleagues developed a clinical genomics test that includes whole-exome sequencing of tumors and normal tissue and RNA-seq of the tumor.

“Our results show that the transcriptome is very important in identifying clinically impactful results,” asserts Dr. Kung. “The technology has really moved from a research tool to real clinical application.” In fact, the test has been approved by New York State for use in cancer patients.

The data from transcriptome profiling has enabled identification of translocations, verification of somatic alterations, and assessment of expression levels of cancer genes.  Dr. Kung and his colleagues are using genomic information for initial diagnosis and prognostic decisions, as well as the investigation of potentially actionable alterations and the monitoring of disease response.

To gain insight into gene-expression changes, transcriptome analysis usually compares two different types of tissues or cells. For example, analyses may attempt to identify differentially expressed genes in cancer cells and normal cells.

“In patients with cancer, we usually do not have access to the normal cell of origin, making it harder to identify the genes that are over- or under-expressed,” explains Dr. Kung. “Fortunately, the vast amounts of existing gene-expression data allow us to identify genes whose expression are most changed relative to models built on the expression data aggregated across large existing datasets.”

These genomic technologies were first used to augment the care of pediatric patients at Columbia. The technologies were so successful that they attracted philanthropic funding, which is being used to expand access to genomic testing to all children with high-risk cancer across New York City.

Other related articles published in this Open Access Online Scientific Journal include the following:

Immunotherapy in Combination, 2016 MassBio Annual Meeting  03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA

Live Press Coverage: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2016/04/01/plenary-session-immunotherapy-in-combination-2016-massbio-annual-meeting-03312016-800-am-04012016-300-pm-royal-sonesta-hotel-cambridge-ma/

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

Next Generation Sequencing in Clinical Laboratory

Posted in Biomarkers & Medical Diagnostics, Cancer and Current Therapeutics, Diagnostics and Lab Tests, Disease Biology, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genomic Testing: Methodology for Diagnosis, Next Generation Sequencing (NGS), tagged Clinical, clinical research, diagnostics, DNA analysis, Insights, next generation sequencing on March 22, 2016| Leave a Comment »

Next Generation Sequencing in Clinical Laboratory

Curator: Larry H. Bernstein, MD, FCAP

INSIGHTS on Next-Generation Sequencing

Next-generation (NGS) sequencing brings scalability and sensitivity to diagnostics in ways that traditional DNA analysis could not

By Angelo DePalma | March 11, 2016   http://www.labmanager.com/insights/2016/03/insights-on-next-generation-sequencing

Enabling Technology for Diagnosis, Prognosis, and Personalized Medicine

Significantly higher speed, lower cost, smaller sample size, and higher accuracy compared with conventional Sanger sequencing make next-generation sequencing (NGS) an attractive platform for medical diagnostics. By practically eliminating cost and time barriers, NGS allows testing of virtually any gene or genetic mutation associated with diseases.

Scalability and Sensitivity

NGS brings scalability and sensitivity to diagnostics in ways that traditional DNA analysis could not. “NGS analyzes hundreds of gene variants or biomarkers simultaneously. Traditional sequencing is better suited for analysis of single genes or fewer than 100 variants,” notes Joseph Bernardo, president of next-generation sequencing and oncology at Thermo Fisher Scientific (Waltham, MA).

Related Article: Computational Changes in Next-Generation Sequencing

Thermo Fisher’s Oncomine Focus Assay for NGS, for example, analyzes close to 1,000 biomarkers associated with the 52-gene panel. These biomarkers constitute about 1,000 different locations on the 52 genes that correlate with the efficacy of certain drugs. The assay allows single-workflow concurrent analysis of DNA and RNA, enabling sequencing of 35 hot-spot genes, 19 genes associated with copy number gain, and 23 fusion genes.

NGS is also better suited to detect lower levels of variants present in heterogeneous material, such as tumor samples. And while both NGS and Sanger sequencing are versatile, NGS can analyze both DNA and RNA, including RNA fusions, at a much more cost-efficient price point.

“When interrogating a limited number of analytes, Sanger sequencing is the standard for many laboratory- developed tests, offering fast turnaround times and lower cost than NGS,” Bernardo says. “We view the two methods as complementary.”

Diagnostic NGS is moving inexorably toward targeted sequencing, particularly for tumor analysis. The targets are specific regions within a tumor’s DNA or individual genes, or specific locations on single genes.

“Targeted sequencing lends itself to diagnostic testing, particularly in oncology, as the goal is to analyze multiple genes associated with cancer using a platform that offers high sensitivity, reliability, and rapid turnaround time,” Bernardo tells Lab Manager. “It is simply more cost-effective.”

That is why the National Cancer Institute (NCI) chose Thermo Fisher’s Ion Torrent sequencing system and the Oncomine reagents for NCI-MATCH, the most ambitious trial to date of NGS oncology diagnostics.

NCI-MATCH will use a 143-gene panel to test submitted tumor samples at four centers (NCI, MD Anderson Cancer Center, Massachusetts General Hospital, and Yale University). The centers then provide sequencing data that helps direct appropriate treatments.

The NCI test protocol ensures consistency across multiple instruments and sites.

Personalized Treatments

Another great opportunity for NGS-based diagnostics is in personalized or precision medicine for both new and existing drugs. Companion diagnostics—co-approved with the relevant drug—drive this entire business. “The only way personalized medicine can succeed commercially is if pharmaceutical companies incorporate a universal assay philosophy in their development programs instead of developing a unique assay for each new drug,” Bernardo explains. For example, in late 2015, Thermo Fisher partnered with Pfizer and Novartis to develop a universal companion diagnostic with the goal of identifying personalized therapy selection from a menu of drugs targeting non-small-cell lung cancer, which annually causes more deaths than breast, colon, and prostate cancer combined.

While advances in sequencing have been remarkable in recent years, the eventual success of NGS-based diagnostics will not depend on instrumentation alone. “What [ensures] ease of use and commonality of results is the cohesiveness of the entire workflow, from sample prep to rapid sequencing systems and bioinformatics,” Bernardo says. “Those components working together will drive NGS into a realizable solution for the clinical market.”

In addition to confirming a disease condition (diagnosis), NGS also provides valuable information on disease susceptibility, prognosis, and the potential effect of drugs on individual patients. The latter idea, known as precision medicine or personalized medicine, uses an individual’s molecular profile to guide treatment. The idea is to differentiate diseases into subtypes based on molecular (usually genetic) characteristics and tailor therapies accordingly.

Precision medicine is still in its infancy, but dozens of pharmaceutical, diagnostics, and genetics firms have bought into the idea.

“We are just at the beginning of connecting genomic and genetic information to target specific therapies for patients,” says T.J. Johnson, president and CEO of HTG Molecular Diagnostics (Tuscon, AZ). “Precision medicine will have a bright future as we gain better understanding of the root causes of disease.”

In 2013, HTG commercialized its HTG Edge instrument platform and a portfolio of RNA assays, which fully automate the company’s proprietary nuclease protection chemistry. This chemistry measures mRNA and miRNA gene expression levels from very small quantities of difficult-to-handle samples.

HTG entered the NGS market in 2014 with the launch of the first HTG EdgeSeq product, an assay that targets and digitally measures the expression of more than 2,000 microRNAs. The assay utilizes the HTG Edge for sample and library preparation, and it uses a suitable NGS instrument (from either Illumina or Thermo Fisher) for quantitation. The data is imported back into the HTG EdgeSeq instrument for analytics and reporting.

In 2015, the company launched four additional HTG EdgeSeq panels: immuno- oncology and pan-oncology biomarker panels, a lymphoma profiling panel, and a classifier for subtyping diffuse large B-cell lymphomas (DLBCL).

Eliminating Biopsies?

Traditional biopsies for tumor DNA analysis are invasive, risky, and often impossible to obtain, and they may not uncover the heterogeneity often present in tumors. It was recently discovered that dying tumor cells release small pieces of DNA into the bloodstream. This cell-free circulating tumor DNA (ctDNA) is detectable in samples through NGS.

In September 2015, Memorial Sloan Kettering Cancer Center (MSK) and NGS leader Illumina (San Diego, CA) entered a collaboration to study ctDNA for cancer diagnosis and monitoring. The aim is to establish ctDNA as a relevant cancer biomarker.

Heterogeneity as it pertains to cancer traditionally refers to multiple tissues located within a tumor, as determined histologically. A number of recent studies suggest that tumor heterogeneity occurs at the genetic level as well. “In particular, there appears to be a tremendous variety of sequence variants within the same tumor, even resulting in situations where one tumor can have multiple mutated genes that have been demonstrated to drive cancer,” says John Leite, PhD, vice president, oncology—market development and product marketing at Illumina.

Heterogeneity challenges the search for treatments that target a specific gene product or pathway. Once the patient is treated, biopsies tell very little about how that patient is responding. “Our hope is that ctDNA provides clinicians with a real-time measure of the abundance of those mutated genes and that a decrease in the relative abundance is synonymous with a lower tumor burden,” Leite adds.

Clinical trials are needed to demonstrate that patients whose therapy was selected using ctDNA versus traditional tissue biopsy testing had a significantly improved outcome or that the analysis might be informative for prognosis.

What about cancer cells that do not release DNA? “Studies show that tumors from different organs or tissues release more or less ctDNA into the peripheral blood,” Leite explains, “but in general the possibility that some cells might not release ctDNA is an open area of research.”

For the MSK-Illumina collaboration, the cancer center will collect samples, and Illumina will apply its sequencing technology to detect ctDNA in those samples. The big draw here is the potential to reduce the number of invasive, expensive diagnostic and monitoring procedures with a simple blood test. This would not be possible without deep next-generation sequencing—the genomics vernacular for sequencing at great depths of coverage.

“Whereas sequencing to identify germline variants can be performed at a nominal depth of coverage—for example, reading a DNA strand 30 times—sequencing rare variants such as in ctDNA requires a much higher level of sensitivity, which is driven by increasing depth of coverage [as much] as 25,000 times,” Leite tells Lab Manager.

In addition to the Illumina MSK collaboration and the work of Thermo Fisher Scientific described above, many more studies involving research consortia and pharmaceutical companies are under way.

“This is a really exciting time for oncology,” Leite says.

Reducing Sample Size

Similarly, in November 2015, Circulogene Theranostics (Birmingham, AL) launched its cfDNA (cell-free DNA) liquid biopsy products for testing ten tumor types, including breast, lung, and colon cancers. The company claims the ability to enrich circulating cfDNA from a single drop of blood.

“While all liquid biopsy companies are focusing on the downstream novel technologies to selectively enrich or amplify tumor-specific cfDNA from a dominantly normal population, the upstream 40 to 90 percent material loss during cfDNA extraction leads to potential false negative results of cancer mutation detection,” explains Chen Yeh, Circulogene’s chief scientific officer. “This is why 10 to 20 mL of blood [are] generally required for conventional cfDNA liquid biopsies.”

Related Article: Researcher Using Next-Generation Sequencing, Other New Methods to Rapidly Identify Pathogens

Released cfDNA fragments often complex with proteins and lipids, which shift their densities to values much lower than those of pure DNA or protein while protecting the corresponding cfDNA from attack by circulating nucleases. Circulogene’s cfDNA breakthrough concentrates and enriches these genetic fragments through density fractionation followed by enzyme-based DNA modification and manipulation, eliminating extraction-associated loss. The technology ensures near-full recovery of both small-molecular-weight (apoptotic cell death) and high-molecular-weight (necrotic cell death) cell-free DNA species from droplet volumes of plasma, serum, or other body fluids.

“The 50-gene panel is our first offering,” says Yeh. “We will continue to develop and cover more comprehensive, informative, and actionable genes and tests.”

The current bottleneck in personalized and precision medicine is the severe shortage of anticancer drugs. Yeh provides perspective, saying, “We have about 60 FDA-approved drugs for cancer-targeted therapies on market, while there are approximately 150 cancer driver genes to aim for. If counting all mutations within these 150 genes, the numbers will be overwhelming.”

Circulogene’s cell-free DNA enrichment technology may be followed up with NGS, conventional Sanger sequencing, or any DNA assay based on PCR or mass spectrometry. However, the sensitivity of Sanger sequencing is insufficient for detecting variants with volumes below 15 percent. Moreover, the company’s multiplex NGS liquid biopsy test captures and monitors real-time, longitudinal tumor heterogeneity or tumor clonal dynamic evolution, which goes well beyond testing of a single mutation on a single sample in traditional sequencing.

 

Gene Editing Casts a Wide Net 

With CRISPR, Gene Editing Can Trawl the Murk, Catching Elusive Phenotypes amidst the Epigenetic Ebb and Flow

• Kate Marusina, Ph.D.

http://www.genengnews.com/gen-articles/gene-editing-casts-a-wide-net/5713/

• Genome editing, a much-desired means of accomplishing gene knockout, gene activation, and other tasks, once seemed just beyond the reach of most research scientists and drug developers. But that was before the advent of CRISPR technology, an easy, versatile, and dependable means of implementing genetic modifications. It is in the process of democratizing genome editing.

  CRISPR stands for “clustered, regularly interspaced, short palindromic repeats,” segments of DNA that occur naturally in many types of bacteria. These segments function as part of an ancient immune system. Each segment precedes “spacer DNA,” a short base sequence that is derived from a fragment of foreign DNA. Spacers serve as reminders of past encounters with phages or plasmids.

  The CRISPR-based immune system encompasses several mechanisms, including one in which CRISPR loci are transcribed into small RNAs that may complex with a nuclease called CRISPR-associated protein (Cas). Then the RNA guides Cas, which cleaves invading DNA on the basis of sequence complementarity.

  In the laboratory, CRISPR sequences are combined with a short RNA complementary to a target gene site. The result is a complex in which the RNA guides Cas to a preselected target.

  Cas produces precise site-specific DNA breaks, which, with imperfect repair, cause gene mutagenesis. In more recent applications, Cas can serve as an anchor for other proteins, such as transcriptional factors and epigenetic enzymes. This system, it seems, has almost limitless versatility.

• Edited Stem Cells

  The Sanger Institute Mouse Genetic Program, along with other academic institutions around the world, provides access to thousands of genetically modified mouse strains. “Genetic engineering of mouse embryonic stem (ES) cells by homologous recombination is a powerful technique that has been around since the 1980s,” says William Skarnes, Ph.D., senior group leader at the Wellcome Trust Sanger Institute.

  “A significant drawback of the ES technology is the time required to achieve a germline transmission of the modified genetic locus,” he continues. “While we have an exhaustive collection of modified ES cells, only about 5,000 knockout mice, or a quarter of mouse genome, were derived on the basis of this methodology.”

  The dominant position of the mouse ES cell engineering is now effectively challenged by the CRISPR technology. Compared with very low rates of homologous recombination in fertilized eggs, CRISPR generates high levels of mutations, and off-target effects may be so few as to be undetectable.

  “We used the whole-genome sequencing to thoroughly assess off-target mutations in the offspring of CRISPR-engineered founder animals,” informs Dr. Skarnes. “A mutated Cas9 nuclease was deployed to increase specificity, resulting in nearly perfect targeting.”

  Dr. Skarnes explains that the major mouse genome centers are now switching to CRISPR to complete the creation of the world-wide repository of mouse knockouts. His own research is now focused on genetically engineered induced pluripotent stem cells (iPSCs). These cells are adult cells that have been reprogrammed to an embryonic stem cell–like state, and are thus devoid of ethical issues associated with research on human embryonic stem cells. The ultimate goal is to establish a world-wide panel of reference iPSCs created by high-throughput genetic editing of every single human gene.

  “We are poised to begin a large-scale phenotypic analysis of human genes,” declares Dr. Skarnes. His lab is releasing the first set of functional data on 100 DNA repair genes. “By knocking out individual proteins involved in DNA repair and sequencing the genomes of mutant cells,” declares Dr. Skarnes, “we hope to better understand the mutational signatures that occur in cancer.”

• Pooled CRISPR Libraries

  Researchers hope to gain a better understanding of the mutational signatures found in cancers by using CRISPR techniques to knock out individual proteins involved in DNA repair and then sequencing the genomes of mutant cells. [iStock/zmeel]

  Connecting a phenotype to the underlying genomics requires an unbiased screening of multiple genes at once. “Pooled CRISPR libraries provide an opportunity to cast a wide net at a reasonably low cost,” says Donato Tedesco, Ph.D., lead research scientist at Cellecta. “Screening one gene at a time on genome scale is a significant investment of time and money that not everyone can afford, especially when looking for common genetic drivers across many cell models.”

  Building on years of experience with shRNA libraries, Cellecta is uniquely positioned to prepare pooled CRISPR libraries for genome-wide or targeted screens of gene families. While shRNA interferes with gene translation, CRISPR disrupts a gene and the genomic level due to imperfections in the DNA repair mechanism.

  To determine if these different mechanisms for inactivating genes affect the results of genetic screens, the team conducted a side-by-side comparison of Cellecta’s Human Genome-Wide Module 1 shRNA Library, which expresses 50,000 shRNA targeting 6,300 human genes, with the library of 50,000 gRNA targeting the same gene set. The concordance between approaches was very high, suggesting that these technologies may be complementary and used for cross-confirmation of results.

  Also, a recently completed Phase I NIH SBIR Grant was used to create and test guiding strand RNA (sgRNA) structures to drastically improve efficiency of gene targeting. For this work, Cellecta used a pool library strategy to simultaneously test multiple sgRNA structures for their efficiency and specificity. An early customized Cellecta pooled gRNA library was successfully utilized for screening for epigenetic genes. This particular screen is highly dependent on a complete loss of function, and could not have been accomplished by shRNA inhibition.

  Scientists from Epizyme interrogated 600 genes in a panel of 100 cell lines and, in addition to finding many epigenetic genes required for proliferation in nearly all cell lines, were able to identify validate several essential epigenetic genes required only in subsets of cells with specific genetic lesions. In other words, pooled cell line screening was able to distinguish targets that are likely to produce toxic side effects in certain types of cancer cells from gene targets that are essential in most cells.

  “A more complicated application of CRISPR technology is to use it for gene activation,” adds Dr. Tedesco. “Cellecta plans to optimize this application to bring forth highly efficient, inexpensive, high-throughput genetic screens based on their pooled libraries.

• Chemically Modified sgRNA

  Scientists based at Agilent Research Laboratories and Stanford University worked together to demonstrate that chemically modified single guide RNA can be used to enhance the genome editing of primary hepatopoietic stem cells and T cells. This image, which is from the Stanford laboratory of Matthew Porteus, M.D., Ph.D., shows CD34+ human hematopoietic stem cells that were edited to turn green. Editing involved inserting a construct for green fluorescent protein. About 1,000 cells are pictured here.

  Researchers at Agilent Technologies applied their considerable experience in DNA and RNA synthesis to develop a novel chemical synthesis method that can generate long RNAs of 100 nucleotides or more, such as single guide RNAs (sgRNAs) for CRISPR genome editing. “We have used this capability to design and test numerous chemical modifications at different positions of the RNA molecule,” said Laurakay Bruhn, Ph.D., section manager, biological chemistry, Agilent.

  Agilent Research Laboratories worked closely with the laboratory of Matthew Porteus, M.D., Ph.D., an associate professor of pediatrics and stem cell transplantation at Stanford University. The Agilent and Stanford researchers collaborated to further explore the benefits of chemically modified sgRNAs in genome editing of primary hematopoetic stem cells and T cells.

  Dr. Porteus’ lab chose three key target genes implicated in the development of severe combined immunodeficiency (SCID), sickle cell anemia, and HIV transmission. Editing these genes in the patient-derived cells offers an opportunity for novel precision therapies, as the edited cells can renew, expand, and colonize the donor’s bone marrow.

  Dr. Bruhn emphasized the importance of editing specificity, so that no other cellular function is affected by the change. The collaborators focused on three chemical modifications strategically placed at each end of sgRNAs that Agilent had previously tested to show they maintained sgRNA function. A number of other optimization strategies in cell culturing and transfection were explored to ensure high editing yields.

  “Primary cells are difficult to manipulate and edit in comparison with cell lines already adapted to cell culture,” maintains Dr. Bruhn. Widely varied cellular properties of primary cells may require experimental adaptation of editing techniques for each primary cell type.

  The resulting data showed that chemical modifications can greatly enhance efficiency of gene editing. The next step would translate these findings into animal models. Another advantage of chemical synthesis of RNA is that it can potentially be used to make large enough quantities for therapeutics.

  “We are working with Agilent’s Nucleic Acid Solution Division—a business focused on GMP manufacturing of oligonucleotides for therapeutics—to engage with customers interested in this capability and better understand how we might be able to help them accomplish their goals,” says Dr. Bruhn.

• Customized Animal Models

  “Given their gene-knockout capabilities, zinc-finger-based technologies and CRISPR-based technologies opened the doors for creation of animal models that more closely resemble human disease than mouse models,” says Myung Shin, Ph.D., senior principal scientist, Merck & Co. Dr. Shin’s team supports Merck’s drug discovery and development program by creating animal models mimicking human genetics.

  For example, Dr. Shin’s team has worked with the Dahl salt-sensitive strain of rats, a widely studied model of hypertension. “We used zinc-finger nucleases to generate a homozygous knockout of a renal outer medullary potassium channel (ROMK) gene,” elaborates Dr. Shin. “The resulting model represents a major advance in elucidating the role of ROMK gene.”

  According to Dr. Shin, the model may also provide a bridge between genetics and physiology, particularly in studies of renal regulation and blood pressure. In one study, the model generated animal data that suggest ROMK plays a key role in kidney development and sodium absorption. Work along these lines may lead to a pharmacological strategy to manage hypertension.

  In another study, the team applied zinc-finger nuclease strategy to knockout the coagulation Factor XII, and thoroughly characterize them in thrombosis and hemostasis studies. Results confirmed and extended previous literature findings suggesting Factor XII as a potential target for antithrombotic therapies that carry minimal bleeding risk. The model can be further utilized to study safety profiles and off-target effects of such novel Factor XII inhibitors.

  “We use one-cell embryos to conduct genome editing with zinc-fingers and CRISPR,” continues Dr. Shin. “The ease of this genetic manipulation speeds up generation of animal models for testing of various hypotheses.”

  A zinc finger–generated knockout of the multidrug resistance protein MDR 1a P-glycoprotein became an invaluable tool for evaluating drug candidates for targets located in the central nervous system. For example, it demonstrated utility in pharmacological analyses.

  Dr. Shin’s future research is directed toward preclinical animal models that would contain specific nucleotide changes corresponding to those of humans. “CRISPR technology,” insists Dr. Shin, “brings an unprecedented power to manipulate genome at the level of a single nucleotide, to create gain- or loss-of-function genetic alterations, and to deeply understand the biology of a disease.”

• Transcriptionally Active dCas9

  “Epigenome editing is important for several reasons,” says Charles Gersbach, Ph.D., an associate professor of biomedical engineering at Duke University. “It is a tool that helps us answer fundamental questions about biology. It advances disease modeling and drug screening. And it may, in the future, serve as mode of genetic therapy.”

  “One part of our research focuses on studying the function of epigenetic marks,” Dr. Gersback continues. “While many of these marks are catalogued, and some have been associated with the certain gene-expression states, the exact causal link between these marks and their effect on gene expression is not known. CRISPR technology can potentially allow for targeted direct manipulation of each epigenetic mark, one at a time.”

  Dr. Gersback’s team mutated the Cas9 nuclease to create deactivated Cas9 (dCas9), which is devoid of endonuclease activity. Although the dCas9 protein lacks catalytic activity, it may still serve as an anchor for a plethora of other important proteins, such as transcription factors and methyltransferases.

  In an elegant study, Dr. Gersbach and colleagues demonstrated that recruitment of a histone acetyltransferase by dCas9 to a genomic site activates nearby gene expression. Moreover, the activation occurred even when the acetyltransferase domain was targeted to a distal enhancer. Similarly, recruitment of KRAB repressor to a distant site silenced the target gene in a very specific manner. These findings support the important role of three-dimensional chromatin structures in gene activation.

  “Genome regulation by epigenetic markers is not static,” maintains Dr. Gersbach. “It responds to changes in the environment and other stimuli. It also changes during cell differentiation. We designed an inducible system providing us with an ability to execute dynamic control over the target genes.”

  In a light-activated CRISPR-Cas9 effector (LACE) system, blue light may be used to control the recruitment of the transcriptional factor VP64 to target DNA sequences. The system has been used to provide robust activation of four target genes with only minimal background activity. Selective illumination of culture plates created a pattern of gene expression in a population of cells, which could be used to mimic what is observed in natural tissues.

  Together with collaborators at Duke University, Dr. Gersbach intends to carry out the high-throughput analysis of all currently identified regulatory elements in the genome. “Our ultimate goal,” he declares, “is to assign function to all of these elements.”

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

« Newer Posts - Older Posts »

• Follow Blog via Email

  Enter your email address to follow this blog and receive notifications of new posts by email.

  Email Address

  Follow

  Join 2,037 other subscribers

• Recent Posts

  • Novartis and Bristol Myers Squibb halt CAR-T trial for autoimmune diseases over patient deaths: a potential issue with cell-based manufacturing September 15, 2026
  • FDA Contemplates Changes in Trial Design, Drug Development, and Use of AI in Clinical Trials September 15, 2026
  • FDA Moves Forward With Its Guidance Framework for Rare Disease Trials: 2026 August 3, 2026
  • Artificial Intelligence TRANSFORMS Medicine, Biotech and Healthcare, How? August 3, 2026
  • In Memoriam: Nobel Laureate J. Michael Bishop for discovery of Retroviral Oncogenes July 31, 2026
  • Companies Actively Engaging Artificial Intellegence for Drug Design: 2026 July 31, 2026
  • AI-Native Drug Discovery Landscape 2026 – How LPBI Group Differentiates in the New Era of Foundation Models July 19, 2026
  • In Memoriam: In Remembrance of Cancer Researchers who passed in 2026 July 13, 2026
  • Urgent Request for Action on Proposed Rule Affecting Federal Funding Grant Review July 7, 2026
  • 2026 Tang Prize in Biopharmaceutical Science Awarded to Three Pioneers of Cellular Immunotherapy Revolutionizing Treatments for Blood Cancers and Solid Tumors July 5, 2026

• Archives

  Archives Select Month September 2026  (2) August 2026  (2) July 2026  (6) June 2026  (4) May 2026  (1) January 2026  (10) December 2025  (8) November 2025  (8) October 2025  (12) September 2025  (2) July 2025  (4) June 2025  (8) May 2025  (4) April 2025  (2) March 2025  (1) February 2025  (2) January 2025  (3) December 2024  (1) November 2024  (5) October 2024  (7) September 2024  (7) August 2024  (1) June 2024  (1) May 2024  (2) April 2024  (2) January 2024  (1) November 2023  (1) October 2023  (3) September 2023  (3) August 2023  (2) July 2023  (2) June 2023  (7) May 2023  (4) April 2023  (2) March 2023  (5) February 2023  (2) January 2023  (3) December 2022  (2) October 2022  (6) September 2022  (2) August 2022  (1) July 2022  (3) June 2022  (3) May 2022  (8) April 2022  (10) March 2022  (7) February 2022  (7) January 2022  (3) December 2021  (3) November 2021  (4) October 2021  (11) September 2021  (5) August 2021  (8) July 2021  (21) June 2021  (8) May 2021  (10) April 2021  (8) March 2021  (15) February 2021  (17) January 2021  (20) December 2020  (10) November 2020  (12) October 2020  (26) September 2020  (17) August 2020  (22) July 2020  (27) June 2020  (33) May 2020  (26) April 2020  (42) March 2020  (22) February 2020  (11) January 2020  (7) December 2019  (20) November 2019  (13) October 2019  (11) September 2019  (3) August 2019  (8) July 2019  (25) June 2019  (47) May 2019  (40) April 2019  (27) March 2019  (29) February 2019  (17) January 2019  (50) December 2018  (14) November 2018  (17) October 2018  (18) September 2018  (17) August 2018  (8) July 2018  (20) June 2018  (22) May 2018  (17) April 2018  (12) March 2018  (20) February 2018  (26) January 2018  (16) December 2017  (6) November 2017  (20) October 2017  (13) September 2017  (16) August 2017  (16) July 2017  (19) June 2017  (20) May 2017  (32) April 2017  (21) March 2017  (10) February 2017  (24) January 2017  (21) December 2016  (43) November 2016  (8) October 2016  (40) September 2016  (67) August 2016  (59) July 2016  (75) June 2016  (37) May 2016  (95) April 2016  (152) March 2016  (175) February 2016  (196) January 2016  (139) December 2015  (90) November 2015  (287) October 2015  (237) September 2015  (115) August 2015  (96) July 2015  (63) June 2015  (44) May 2015  (53) April 2015  (76) March 2015  (95) February 2015  (83) January 2015  (75) December 2014  (75) November 2014  (88) October 2014  (135) September 2014  (117) August 2014  (88) July 2014  (88) June 2014  (109) May 2014  (60) April 2014  (85) March 2014  (58) February 2014  (72) January 2014  (107) December 2013  (104) November 2013  (136) October 2013  (62) September 2013  (32) August 2013  (46) July 2013  (74) June 2013  (110) May 2013  (112) April 2013  (86) March 2013  (92) February 2013  (63) January 2013  (63) December 2012  (46) November 2012  (71) October 2012  (84) September 2012  (82) August 2012  (122) July 2012  (59) June 2012  (34) May 2012  (46) April 2012  (2)

• Categories

  Categories Select Category 3D Printing for Medical Application  (240)    3D Plotting Scaffolds  (44)    BioInks  (34)       Biopolymer Blend Open Porous  (18)       Dental Applications  (10)    BioPrinting in Regenerative Medicine  (77)       Cell Level  (16)       MicroEngineering Cell-Tissue & Systems  (31)       Tissue Engineering  (37)    Cardiovascular and Vascular Systems  (30)       Artificial Vascular Structures  (9)       Cardiovascular Tissue  (8)    Drug Development using MultiOrgan Chip  (12)    Drug Development/Formulation using 3D Printing  (10)    MEMS  (16)       Bio-MEMS  (12)    Organ-on-a-Chip  (11)    Programmable Sensors (Carbon Nano Tubes)  (5) 3rd Party IP: Drug DIscovery  (1) 4D Printing and Meta Materials  (10) Academic Publishing  (223)    Key Opinion Leaders in eScientific Publishing – Interviews with  (8) Advanced Drug Manufacturing Technology  (97)    Antimalarial Preparation  (8)    Autologous Cell Therapy  (14)    Automated Cell Processing  (13) Allergy and Infectious Diseases  (12) Alzheimer’s Disease  (163)    Etiology  (77)    Medical Device Therapies for Altzheimer’s Disease  (15)    Pharmacotherapy and Cell Activity  (51) Anticancer Resistance  (31) Art Exhibits on the Human Condition  (1) Art Inspires Science  (4) Article Type  (2)    Authored  (1)    Curated  (2)    Scientific report  (1) Artificial Heart  (2) Artificial Intelligence – General  (240)    An executive’s guide to AI  (11)    Artificial Intelligence – Breakthroughs in Theories and Technologies  (119)    Artificial Intelligence Applications in Health Care  (131)       Artificial Intelligence in CANCER  (42)       Artificial Intelligence in Health Care – Tools & Innovations  (77)    Artificial Intelligence in Medicine – Application for Diagnosis  (72)       Artificial intelligence applications for cardiology  (33)          AI-assisted Cardiac MRI  (10)       Artificial Intelligence in Psychiatry  (7)       Deep Learning in Pathology  (19)    Artificial Intelligence in Medicine – Applications in Therapeutics  (71)    ChatGPT, GPT-4  (7)       ChatGPT at LPBI Group  (3)       ChatGPT in Academic Education  (3)    Machine Learning  (73)       Deep Learning  (26)       Natural Language Processing (NLP)  (45)    Machine learning in predicting type 2 diabetes  (6) Auditory and vision  (13) Autism Spectrum Disorders  (10) Autoimmune Inflammatory DIseases  (25)    Crohn’s disease  (5)    Tolerance-inducing Autoimmune Disease Therapeutics  (7)    Ulcerative Colitis  (3) Autophagosome  (4) Bacterial Resistance  (25) Behavior  (26) Behavioral Genetics  (21) Big Data  (88)    Intelligent Information Systems  (51) Bio Instrumentation in Experimental Life Sciences Research  (368)    Analytical Instruments Industry  (5)    Microfuidics  (8) Bio-Ethics  (16) BioBanking  (36) Biodegradable Drug-eluting Material  (8) Bioengineering & reverse engineering design  (43) BioIT: BioInformatics  (147) BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics  (135)    Advanced Computing Platform  (32)       Blockchain Transactions System  (6)          Platform for Content Monetization embedded Content Promotion  (1)    Pancreatic adenocarcinoma classifier  (4)    Simulation Modeling in NGS  (5) Biological Engineering  (43) Biological Networks  (193) Biological Networks, Gene Regulation and Evolution  (479)    Virology  (10) Biomarkers & Medical Diagnostics  (572)    VOC – Volatile Organic Compounds as BioMarkers  (2) Biomedical Measurement Science  (173) BioSimilars  (112) BioTechnology – Venture Creation  (133)    Foundations for supporting Science and Education  (14)    Philanthropy to Academic Institution  (3) BioTechnology – Venture Creation, Venture Capital  (110)    Seeking Talent  (3) BiVAD  (1) Blindness  (6) Bone Disease and Musculoskeletal Disease  (82) Brain Basis of Emotion  (5) Business Career Consideration  (1) Ca2+ triggered activation  (61) Calcium  (21) Calcium Signaling  (71) Calmodulin Kinase and Contraction  (36) Cancer – General  (186) Cancer and Current Therapeutics  (412)    interventional oncology  (49)       Breast Cancer – impalpable breast lesions  (20)       Prostate Cancer: Monitoring vs Treatment  (9) CANCER BIOLOGY & Innovations in Cancer Therapy  (1,127)    Anaerobic Glycolysis  (51)    Cachexia  (18)    Cancer Genomics  (85)       Circulating Tumor Cells (CTC)  (27)          Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood  (17)             mRNA  (6)          MagSifter chip  (1)       KRAS Mutation  (9)       Li-fraumeni syndrome.  (4)       TP53 – Germline mutations  (9)    cancer metabolism  (28)    Funding Opportunities for Cancer Research  (13)    Genomic Expression  (150)    Glioblastoma  (7)    Hexokinase  (14)    Loss of function gene  (18)    Metabolic Immuno-Oncology  (21)    Metastasis Process  (15)    Methylation  (33)    Microbiome and Responses to Cancer Therapy  (10)    Monoclonal Immunotherapy  (29)    mtDNA  (13)    Oxidative phosphorylation  (56)    Pancreatic cancer  (10)    Pyruvate Kinase  (27)    The NCI Formulary  (1)    tumor microenvironment  (16)    Warburg effect  (50) Cancer Informatics  (104) Cancer Prevention: Research & Programs  (132) Cancer Screening  (108) Cancer Vaccines: Targeting Cancer Genes for Immunotherapy  (30)    Engineering Enhanced Cancer Vaccines  (3) cancer-general  (7) Cardiac and Cardiovascular Surgical Procedures  (328)    Aortic Valve: TAVR, TAVI vs Open Heart Surgery  (91)       Prosthesis-Patient Mismatch (PPM) in TAVI vs SAVR  (2)       TAVI vs Open Heart Surgery  (6)       Transcatheter Aortic Valve Replacement via the Transcarotid Access  (3)       Transcaval TAVR Procedure  (3)       Valve-in-Valve Procedure  (5)    Atrial Fibrilation (a-Fib), Cardiac Pacing and Arrhythmias  (18)    BackBeat’s Cardiac Neuromodulation Therapy (CNT) bioelectronic therapy  (1)    CABG  (47)    Cancer Surgery of the Heart  (10)    Cardiovascular Fluid Management: algorithms  (1)    Heart Transplant  (16)    Heart-Lung Transplant  (11)    Implantation  (3)    Left Main Coronary Artery Disease (LMCAD)  (3)    Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart  (22)    Mitral Valve: Repair and Replacement  (64)       TMVR – Transcatheter Mitral Valve Repair  (5)    PCI  (108)       Bioresorbable Vascular Scaffold (BVS)  (4)       Invasive FFR for PCI  (2)       Multivessel PCI FFR Guidance  (1)       Robotic-assisted percutaneous coronary intervention  (2)       Stent Retriever in endovascular thrombectomy  (3)    Peripheral Arterial Disease & Peripheral Vascular Surgery  (65)       Abdominal Aorta  (20)       Carotid Artery  (15)       Limb ischemia  (4)       Thoracic Aorta  (16)    Pulmonary Valve Replacement and Repair  (3)    Renal Denervation  (20)    Replacement  (1)    Robotically assisted Cardiothoracic Surgery  (2)    Tricuspid Valve Repair  (7)    Vena Caval Filters: Device for Prevention of Pulmonary Embolism and Thrombosis  (2) Cardiovascular Pharmacogenomics  (171) Cargo  (3) Cell Biology  (323) Cell Biology, Signaling & Cell Circuits  (673)    Apoptosis  (17)    Autophagy-Modulating Proteins  (6)    “Antibody–enzyme conjugates”  (6)    Cell Processing System in Cell Therapy Process Development  (28)    Endoplasmic reticulum  (3)    Enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)  (3)    Ubiquitin  (11) Cerebrovascular and Neurodegenerative Diseases  (123)    Stroke  (9) Chemical Biology and its relations to Metabolic Disease  (464)    #BIGAxisSummit  (1)    Gut Microbiome and Obesity  (8) Chemical Genetics  (350) Child and Adolescent Psychiatry  (13) Childhood cancer  (17) Childhood malnutrition  (3) children  (4) Circulating Progenitor Cells  (27)    Bone marrow derived cells  (17)    Endothelial cells  (7)    Umbilical cord cells  (6) Clinical & Translational  (239) Clinical Diagnostics  (220)    Mass automation of plasma proteins  (13) Clinical Genomics  (144) Coagulation Therapy and Internal Bleeding  (83) Cognition  (47) Commercialization  (20) Components and IRB related issues  (4) Computational Biology/Systems and Bioinformatics  (471)    Computational Histopathology  (3)    Meta-analysis of transcriptome data  (10) Conference Coverage with Social Media  (494)    MassBio  (3) coronavirus  (18) COVID-19  (20) CRISPR/Cas9 & Gene Editing  (192)    CRISPR alternative for editing genes without cutting  (14)       CAST – Alternative to CRISPR/Cas9  (3)       Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration  (4)    CRISPR applied to Human Germ Line  (13)       Gene Editing Impact on Longevity  (6) CT  (20) Cytokines  (21) Cytoskeleton  (85) Developmental biology  (107) Diabetes Mellitus  (146)    Artificial Pancreas for Type 2 Diabetes  (4)    Artificial Pancreas for Type1 Diabetes  (8)    Gestational diabetes  (5) Diagnostic Immunology  (61) Diagnostics and Lab Tests  (128)    Liquid Biopsy: Circulating Tumor Cells in Urine and Blood  (9) Digital HealthCare – biotech & internet joint ventures  (47) Disease Biology  (334) Disease Biology, Small Molecules in Development of Therapeutic Drugs  (488) DNA repair  (73)    Apoptosis  (13)    Autophagy  (13)    Cell death pathways  (19)    Proteolysis  (8)    Proteosome  (8) Drug Delivery Platform Technology  (159)    Drug Carrier Design  (21)       Medication Remote Compliance Monitoring  (3)    Exosomes: Natural Carriers for siRNA Delivery  (9) Drug Toxicity  (74) Ecosystems & Industrial Concentration in the Medical Device Sector  (172)    Cardiac & Vascular Repair Tools Subsegment  (128)    Exec Compensation in the Cardiac & Vascular Repair Tools Subsegment  (14)    Massachusetts Niche Suppliers and National Leaders  (20) Electronic Health Record  (10) Embryology  (24) Empathy  (6) Endocrine Diseases  (60) Enzyme Induction  (46)    ion-transporting enzyme  (2)    K + -ATPase.  (1)    Na +  (2) Epigenetics and Environmental Factors  (35) Ethics and Leadership  (10) Executive Compensation – Big Pharma  (3) Fat soluble vitamins  (4) FDA  (73) FDA Regulatory Affairs  (360)    FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP, GLP, ISO 14155  (52)    ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics  (30) Fetal Ultrasound  (2) Fiction and medicine  (5) Frontiers in Cardiology and Cardiovascular Disorders  (929)    Acute Myocardial Infarction  (63)       Cardiogenic Shock  (5)    Anemia in CVD Patients  (6)    Cardio-Oncology  (4)    Cardiomyopathy  (57)    Cardiovascular Research  (187)       Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism  (64)       Pre-Clinical Animal Model Development  (23)    Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH)  (20)    Cost of Inpatient Stay for Cardiovascular Diagnosis for Admission  (1)    Electrophysiology  (111)       Ablation Procedure vs Drug Therapy  (2)       Arrhythmia Detection with Machine Learning Algorithms  (7)       Cardiotoxic Risks of Immune Checkpoint Inhibitors  (1)       Genomic Analysis of EKG Electrophysiology Genomics  (3)       implantable cardioverter defibrillator (ICD) and External Defibrillation  (1)       implantable pacemaker  (2)       Rare heart rhythm disorders and Long QT syndrome (LQTS)  (7)    Epigenetics and Cardiovascular Risks  (57)    Heart Failure (HF)  (51)       Acute coronary syndrome  (7)       congestive heart failure  (19)       Hypertensive Disorders of Pregnancy  (1)    Medical Devices R&D and Inventions  (212)       Assist Devices: LV  (3)       RV  (1)       Stents & Tools  (90)       Valves & Tools  (67)    Origins of Cardiovascular Disease  (422)       Atherogenic Processes & Pathology  (180)       Congenital Heart Disease  (34)          Genetic Mutations in Congenital Heart Disease  (4)       inflammation independent of lipid levels  (13)       Systemic Inflammatory Diseases as CVD Risk  (12)    Pharmacotherapy of Cardiovascular Disease  (356)       HTN  (176)       HTN in Youth  (8)       Resident-cell-based  (43)       Subarachnoid Hemorrhage (SAH)  (1)       Transthyretin amyloid cardiomyopathy (ATTR-CM)  (1)    Spontaneous Coronary Artery Dissection (SCAD)  (6)    Stroke  (15)       endovascular thrombectomy  (6)    Vascular Diseases  (21)       mesenteric ischemia  (3) Future Pandemics Inform-graphics  (1) Gastroenterology  (38) Gene Regulation  (233) Gene Regulation and Evolution  (137) Genetics & Innovations in Treatment  (176) Genetics & Pharmaceutical  (204) Genome Biology  (967)    Exosomes  (25)    Gene Therapy & Gene Editing Development  (42)    mRNA Therapeutics  (20)    Mutagenesis  (27)    Single Cell Genomics  (25)    Single-cell sequencing  (20)    Variation in human protein-coding regions  (35) Genomic Endocrinology  (42) Genomic Testing: Methodology for Diagnosis  (416) Genomics Pharmacy  (40) Global Market of Medical Devices Technology  (3) Global Medical Publishers by Country  (3) Global Partnering & Biotech Investment  (48) GLP  (4) Glycobiology: Biopharmaceutical Production  (16) Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics  (28) Health Care System by Country  (58)    AI Models in Healthcare  (12)    Centers for Medicare & Medicaid Services  (8)    Health in Israel  (2)    India  (1)    United States  (27)       Hospital-based Medical Innovations  (10)       Medical Recertification and Maintenance of Certification (MOC)  (1) Health Economics and Outcomes Research  (384)    Women Health  (18)       Heart and Brain Disease in Women  (3) Health Law & Patient Safety  (165)    and Bioethics  (14)    Biotechnology  (12)    Health Law Policy  (13) HealthCare IT  (139) Healthcare Reform  (118)    Accountable Care Organizations  (26)    Affordable Care Act  (29)       Repair  (1)       Repeal ACA  (1)       Replace  (1)    Federal Budget Appropriations  (27)    Healthcare costs and reimbursement  (59)    Indigent Nutrition  (14)    Medicare and Medicaid  (20)    Prescription Drugs Costs  (21)    Skilled Nursing Facilities  (6)    Technology Capital Expenses  (15)    Uninsured and Underinsured  (20) Hematology  (100)    Acute lymphocytic leukemia  (18)    Acute myelocytic leukemia  (21)    Hematopoiesis  (48)    Lymphoma  (21) History and physical exam  (6) Human aging  (27) Human Immune System in Health and in Disease  (246) Human Sensation and Cellular Transduction: Physiology and Therapeutics  (21) Image Processing/Computing  (41) Imaging-based Cancer Patient Management  (116) Immuno-Oncology & Genomics  (133)    mRNA platform in Drug DIscovery  (6) Immunodiagnostics  (141)    Cancer-Immune Interactions  (31)    CNS-Immune Interface  (5)    Neuronal Circuits  (4) Immunology  (123)    Adaptive Immune Response to Biomaterials and Tissue Repair  (13)    Antibody Responses Predict Antigen Exposure  (17)    Cytokine Receptor Structure  (8)    Human Antibody Response  (18)    Human Circulating Antibody Repertoire  (11)    Human Naive B Cell Repertoire  (8)    MHC Repertoires for Antigen Prediction  (8)    Protection Against Autoimmune Disease  (11)    Synthetic Immunology: Hacking Immune Cells  (15) Immunotherapy  (137)    CAR-T  (16)    combination immunotherapies.  (15)    Efficacy of Anti-Tumor T Cells  (15)    Engineering Better T Cells  (11)    Immune Engineering  (18)    Immune Modulatory  (16)    Integrin-targeted Combination Immunotherapy  (6)    Modulating Macrophages in Cancer Immunotherapy  (17)    NK Cell-Based Cancer Immunotherapy  (20)    Synergistic Innate and Adaptive Immunotherapy  (14) Income Disparity  (2) Infectious Disease & New Antibiotic Targets  (162)    Antibiotic resistance  (7)    Viral diseases  (37)       Myocarditis  (1) Infectious Disease Immunodiagnostics  (58)    Virology – Vector-borne DIsease  (17) Inflammasome  (29)    Anti-tumor necrosis factor drugs (TNF inhibitors)  (3) Innovation in Immunology Diagnostics  (111)    Universal Immune Cell Therapies (uICT)  (11) Innovations  (186)    R&D Expenditure  (8) Innovations in Neurophysiology & Neuropsychology  (145)    Age and Life Expectancy  (3)    autism spectrum disorder  (1)    Circadian Rhythm and Sleep  (6)    hNPCs  (1)    Nervous System Function  (2)    Relapsing Multiple Sclerosis  (1) Intellectual Property  (85)    Disputes and Settlements  (9)    IP Valuation Models – Pricing Intangible Assets  (7)    Patent Law in Biotech  (12) Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough  (121) International Global Work in Pharmaceutical  (191) Interventional Oncology: Radiofrequency Ablation, Transarterial Chemoembolization, Microwave Ablation and Irreversible Electroporation (IRE)  (12) Interviews with Scientific Leaders  (319)    Albany Medical Center Prize in Medicine and Biomedical Research  (3)    Annual Breakthrough Prize  (4)    Annual Lewis S. Rosenstiel Award  (2)    Awards in Cardiology and Cardiovascular Medicine  (6)    CEOs of Biotech Companies  (3)    Gerald D Aurbach Award for Outstanding Translational Research  (2)    Interviews with Key Opinion Leaders (KOLs)  (11)    James Prize in Science and Technology Integration  (2)    Jessie Stevenson Kovalenko Medal – Medical Sciences  (2)    Lemelson-MIT Prize  (2)    Life Sciences Breakthrough Prize  (6)    Mosteller Statistician of the Year Award  (2)    Mourning the Loss of a Scientific Leader  (6)    National Academy of Sciences AWARDS  (4)    Nobel Prize Winners  (30)    Noble Prize (Not Nobel Prize)  (2)    Paul Marks Prize for Cancer Research  (2)    Russ Prize recognizes bioengineering achievements worldwide  (2)    The Dan David Prize  (6)    Warren Alpert Foundation Prize Recipients  (4)    Wolf Prize  (2)    Wolf Prize in Medicine  (2)    women in science  (5) Investment in Technological Breakthrough  (60) Ionic Transporters Na+  (25) IP Development by LPBI Group Team  (14) IP Development by LPBI Group Team & Other Organizations  (8) ISO 14155  (3) Joint Venture – SBH & M3DP: SOP and Arrangements  (1) Justice & Law  (1) K  (15) Lab-on-a-chip  (2) Landscape  (1) Lasers and photonics  (18)    Midrange IR spectroscopy  (1) Law and Medicine Conflicts  (15) Leadership, Power, Social Interlocking Connections  (13) Lipid metabolism  (109)    Fatty acids  (38)    Lipids  (38)    PCSK9 Inhibitor Therapy  (19) Lipidomics  (11) Liposome  (4) Liver & Digestive Diseases Research  (122) LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management  (143)    Award Nominations  (5)    BioMed e-Books e-Series by LPBI Group  (9)    Feedback from Investors: LPBI Portfolio of Five Businesses  (2)    LPBI Group Founder – Aviva Lev-Ari  (27)    PhD  (1)    RN  (1) LPBI Management  (23) Massachusetts Academy of Sciences (MAS)    (2) Materials Science & Engineering  (37)    Organic BioElectronics  (2) Math  (13)    Great Discoveries  (7) Mechanical Assist Devices: LVAD  (4) Medical and Population Genetics  (193) Medical Devices R&D Investment  (242)    21st Century Cures Act  (2)    CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP  (14)    Rhythm management device hardware: dual-chamber pacemakers  (1)       Systolic HTN  (1) Medical Imaging Technology  (59) Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound  (164)    Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI)  (3)    Echocardiography  (3)    MRI  (18)    Noninvasive Diagnostic Fractional Flow Reserve (FFR) CT  (6)    Ultra Sound  (10) Melatonin & Circadian Regulation  (9) memory loss  (1) Metabolism  (239)    Biochemical pathways  (144)       Enzymes and isoenzymes  (73)          Dehydrogenase  (16)          Kinase  (28)          Phosphatase  (9)          Phosphorylase  (22)          tyrosine decarboxylases  (3)    Inosine nucleotides  (9)    Leloir pathway  (6)    microbiome  (7)    Pentose monophosphate shunt  (14)    Pyridine nucleotides  (28)       Pyridine nucleotide transhydrogenase  (7) Metabolomics  (321) Methods  (37) Mg++  (10) Microbiologial genetics  (36) Microbiology  (68)    Virology  (14) Micronutrients  (16) Microvesicle  (7) Microwave Ablation and Irreversible Electroporation (IRE)  (1) Mobile Healthcare  (5) Molecular Genetics & Pharmaceutical  (377)    Organoids  (3) Monoclonal antibody therapy  (14) Mutant Gene Expression  (42) Myocardial adenine nucleotide metabolism  (6) Myocardial Ischemia  (26) Myocardial Metabolism  (36) Na-K transport  (40) Na-K-ATPase  (27) Nanotechnology for Drug Delivery  (99) Nephrology  (46) Nephrology & Regenerative medicine  (9) Neurodegenerative Diseases  (89)    hNPCs  (3)    MS  (5) Neurohumoral Transmission  (68)    Ca2+ triggered activation  (21)    Calmodulin  (13)    Parkinson’s disease dyskinesia levodopa  (3)    PKC  (13)    Synaptic vesicle  (20) Neurological Diseases  (121) Neuroscience  (126) Next Generation Sequencing (NGS)  (27)    Nanopore sequencing  (1) NIH Common Fund  (1) Nitric Oxide in Health and Disease  (136) Nuclear Medicine  (11) Nutrigenomics  (68) Nutrition  (195)    Nutritional Supplements: Atherogenesis, lipid metabolism  (50) Nutrition and Phytochemistry  (62)    Minerals in Medicine  (4)    Plant extract  (22) Nutrition Disorders  (31) Nutritional Supplements: Atherogenesis  (31) Obesity  (19) Oligonucleotide Therapeutics & Delivery  (7) Oncolytic virus & OncoViro-Therapy  (23)    Synthetic Virology  (1) Organ-on-a-Chip & 3D Printing in Life Sciences  (7) Pain: Etiology, Genetics & Innovations in Treatment  (24) Parasitology  (5)    Malaria  (4)    Tropical diseases  (1) Patents  (35) Patient Experience  (66)    Art therapy  (1)    Hospital reputation  (7)    Humor  (1)    Music therapy  (2)    Pain Alleviation  (7)    Patient Outlook  (28)    Reputation of Interventionist  (4)    Support Staff  (13)    Supportive therapies  (6)       laughfter  (1)    Surgical Procedure  (9) Patient Experience: Personal Memories of Invasive Medical Intervantion  (30) Patient’s Voice: Personal Experience with Invasive Medical Procedures  (18) Perioperative Statins at Noncardiac Surgery  (2) Personal Health Applications: Tech Innovations serves HealhCare  (43) Personalized and Precision Medicine & Genomic Research  (740)    Longevity  (3)    New Drug Approval  (7)    Patient-centered Medicine  (39)       cell-based therapy  (9)       stem cell biology and patient-specific  (7)    Personalized Medicine Coalition  (10)    Precision Cancer Medicine  (33) Phagophore  (2) Pharmaceutical Analytics  (262)    Pharmacologic toxicities  (63) Pharmaceutical Discovery  (112)    Rapid automation of plasma protein pools  (18) Pharmaceutical Drug Discovery  (207)    Drug Development Process  (62)       Drug Discovery Chemistry  (33)    drug repurposing  (11) Pharmaceutical Industry Competitive Intelligence  (347)    Pharmacovigilance  (8)    Value-based Drug Pricing  (8) Pharmaceutical R&D Informatics  (45) Pharmaceutical R&D Investment  (301) Pharmacodynamics and Pharmacokinetics  (24) Pharmacogenomics  (161) Photography Collection  (1) Physics  (12) Placenta  (7) Population genetics  (27) Population Health Management  (205)    Evolution of Biology Through Culture  (14)    U.S. Employment-to-Population Ratio  (8) Population Health Management, Genetics & Pharmaceutical  (643)    COVID-19  (157)       Biomarkers: Inflammation  (37)       Cancer Researchers Fighting COVID-19  (14)       COVID-19 effects on Human Heart  (15)       COVID-19: Pandemic Surgery Guidance  (19)       Economic Impact of Coronavirus Pandemic  (41)       number of asymptomatic infections  (27)       Treatment Protocols for COVID-19  (62)    SARS-CoV-2  (141)       Coronavirus Gene Expression  (66)          SARS-CoV-2 circulating variants   (14)          SARS-CoV-2 Viral Variants  (19)       Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis  (2)       Immune-Mediation (independent immunopathology: lung and reticuloendothelial system)  (30)       Mechanisms of infection by SARS-CoV-2  (21)       SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus  (35)          SARS-COV2 Hijacking the Complement and Coagulation Systems  (19)       Seasonality & Environmental Factors in Resurgence  (26)       Serology tests for coronavirus antibodies  (44)       T-cell response to SARS-CoV-2 infection  (14)       Vaccinology  (51)          Mechanism of Thrombosis with AZ & J&J COVID-19 Vaccines  (5)       Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins  (8)    Virus Infective Acute Respiratory Syndrome: SARS-CoV  (92) Population Health Management, Nutrition and Phytochemistry  (162) Preimplantation Genetic Diagnosis and Reproductive Genomics  (13) Protein-energy malnutrition  (12) Proteomics  (367)    Amino acids  (54)    Proteins  (138) Pulmonary diseases  (16)    Lung and pulmonology  (15) Pulmonary pathology  (8) Radio Frequency (RF)-based Surgical Solutions  (2) REAL TIME Conference Coverage Twitter’s Hashtags and Handles per Presentation/session  (50) Regenerative Biology and Medicine  (92) Regulated Clinical Trials: Design, Methods, Components and IRB related issues  (265) Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics  (113) Reproductive Biology & Bio Instrumentation  (78) RNA Biology  (81)    RNA interference (RNAi) therapeutic  (4) RNA Biology, Cancer and Therapeutics  (64) RVAD  (1) SBIR, SBA, NIH, NSF  (3) Schizophrenia  (16) Scientific & Biotech Conferences: Press Coverage  (182) Scientific Publishing  (609)    Curation  (585)       Curation methodology  (40)       De novo synthesis  (16)       Dialectic  (17)       Discovery process  (72)       Evolutionary cognition  (52)       Experimental validation  (91)       Explanatory  (91)       Historical relevance  (71)       Technology Advance Assessment of  (69)       Theoretic convergence  (27)    Open Access Journals  (37) Scientist: Career considerations  (198)    Big Data & Analytics  (17)    Data Science  (13)    Women in Life Sciences  (12) Scoop.it  (19) Sensors & Analytics  (18) Sepsis  (2) Severe Autism  (3) Signaling  (102)    Phosphorylation  (43)    S-nitrosylation  (13)    Ubiquitinylation  (34) Signaling & Cell Circuits  (130) single cell sequencing  (3) Small Molecules in Development of Therapeutic Drugs  (71) Social Development  (15) Specialized 3D BioPrinters (Cornea  (1) Statistical Methods for Research Evaluation  (137) Stem Cells for Regenerative Medicine  (177)    Cardiac muscle regeneration  (19)    Competition in regenerative stem cell science  (18)    Human neural progenitor cells  (8)    Skeletal muscle regeneration  (9) STORM  (2) Stress Disorders  (19) Substance Abuse  (4) Systemic Inflammatory Response Related Disorders  (161)    Inflammatory Pathophysiology  (9) Technology Transfer: Biotech and Pharmaceutical  (354) therapeutics  (3) Tissue Engineering and Regenerative Medicine  (22) Tissue Microenvironment  (5) Transarterial Chemoembolization  (2) Transcriptomics  (47) Transformative Technologies in Healthcare  (23) Translational Science  (230)    Best evidence  (52)    Bias measurement tools  (2)    Evidence-based decision-making  (29)    Inferential analysis  (25)    Intra-rater error  (1)    Quality Assurance  (8)    Random Error  (2)    Systematic Error (Bias)  (6)    Total error  (2)    Translational Effectiveness  (49)    Translational Research  (92) Trends in Global Economy  (6) Uncategorized  (1,019) Unfolded Protein Response (UPR)  (6) US and Global Economy: Trends and Findings  (9) Venture Capital  (47)    Income Geographic Distribution  (3)    Institutional Capital Raised by Female Founders  (6) virology  (10) Vision  (7) Voices of Patients and Healthcare Providers  (22) Water Transporters  (8) Wearable Tech + Digital Health  (5) Anemia  (22) Neutropenia  (8) Neutrophilia  (9) Platelet count disorder  (9) Folate and B12  (7) Iron deficiency  (5) Myelodysplasia  (13) Myelofibrosis  (10)

• Meta

  • Log in
  • Entries feed
  • Comments feed
  • WordPress.org

• • 2012pharmaceutical
  • sjwilliamspa