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Archive for the ‘Innovation in Immunology Diagnostics’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

One of the most contagious diseases known to humankind, measles killed an average of 2.6 million people each year before a vaccine was developed, according to the World Health Organization. Widespread vaccination has slashed the death toll. However, lack of access to vaccination and refusal to get vaccinated means measles still infects more than 7 million people and kills more than 100,000 each year worldwide as reported by WHO. The cases are on the rise, tripling in early 2019 and some experience well-known long-term consequences, including brain damage and vision and hearing loss. Previous epidemiological research into immune amnesia suggests that death rates attributed to measles could be even higher, accounting for as much as 50 percent of all childhood mortality.

 

Over the last decade, evidence has mounted that the measles vaccine protects in two ways. It prevents the well-known acute illness with spots and fever and also appears to protect from other infections over the long term by giving general boost to the immune system. The measles virus can impair the body’s immune memory, causing so-called immune amnesia. By protecting against measles infection, the vaccine prevents the body from losing or “forgetting” its immune memory and preserves its resistance to other infections. Researchers showed that the measles virus wipes out 11% to 73% of the different antibodies that protect against viral and bacterial strains a person was previously immune to like from influenza to herpes virus to bacteria that cause pneumonia and skin infections.

 

This study at Harvard Medical School and their collaborators is the first to measure the immune damage caused by the virus and underscores the value of preventing measles infection through vaccination. The discovery that measles depletes people’s antibody repertoires, partially obliterating immune memory to most previously encountered pathogens, supports the immune amnesia hypothesis. It was found that those who survive measles gradually regain their previous immunity to other viruses and bacteria as they get re-exposed to them. But because this process may take months to years, people remain vulnerable in the meantime to serious complications of those infections and thus booster shots of routine vaccines may be required.

 

VirScan detects antiviral and antibacterial antibodies in the blood that result from current or past encounters with viruses and bacteria, giving an overall snapshot of the immune system. Researchers gathered blood samples from unvaccinated children during a 2013 measles outbreak in the Netherlands and used VirScan to measure antibodies before and two months after infection in 77 children who’d contracted the disease. The researchers also compared the measurements to those of 115 uninfected children and adults. Researchers found a striking drop in antibodies from other pathogens in the measles-infected children that clearly suggested a direct effect on the immune system resembling measles-induced immune amnesia.

 

Further tests revealed that severe measles infection reduced people’s overall immunity more than mild infection. This could be particularly problematic for certain categories of children and adults, the researchers said. The present study observed the effects in previously healthy children only. But, measles is known to hit malnourished children much harder, the degree of immune amnesia and its effects could be even more severe in less healthy populations. Inoculation with the MMR (measles, mumps, rubella) vaccine did not impair children’s overall immunity. The results align with decades of research. Ensuring widespread vaccination against measles would not only help prevent the expected 120,000 deaths that will be directly attributed to measles this year alone, but could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system.

 

References:

 

https://hms.harvard.edu/news/inside-immune-amnesia?utm_source=Silverpop

 

https://science.sciencemag.org/content/366/6465/599

 

www.who.int/immunization/newsroom/measles-data-2019/en/

 

https://www.ncbi.nlm.nih.gov/pubmed/20636817

 

https://www.ncbi.nlm.nih.gov/pubmed/27157064

 

https://www.ncbi.nlm.nih.gov/pubmed/30797735

 

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Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Immunotherapy may help in glioblastoma survival


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.

 

A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.

 

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

 

Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.

 

In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.

 

References:

 

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

 

https://www.ncbi.nlm.nih.gov/pubmed/30742122

 

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

 

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

 

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

 

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Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders at https://www.amazon.com/dp/B078313281 – electronic Table of Contents 

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Available on Kindle Store @ Amazon.com since 12/9/2017

List of Contributors & Contributors’ Biographies

Volume Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Preface, all Introductions, all Summaries and Epilogue

Part One:

1.4, 1.5, 1.6, 2.1.1, 2.1.2, 2.1.3, 2.1.4, 2.2.1, 2.2.2, 2.2.3, 2.3, 2.4, 2.4.1, 2.4.2, 2.5, 2.6.1, 2.6.2, 2.6.3, 2.6.4, 2.7, 2.8, 2.9, 2.10, 3.1, 3.2, 3.3, 3.4, 4.1, 4.2, 4.3

Part Two:

5.2, 5.3, 5.6, 6.1.2, 6.1.4, 6.2.1, 6.2.2, 6.3.2, 6.3.4, 6.3.5, 6.3.6, 6.3.8, 6.3.10, 6.4.1, 6.4.2, 6.5.1.2, 6.5.1.3, 6.5.2.2, 7.1, 7.2, 7.3, 7.4, 7.5, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 8.9.1, 8.9.3, 8.9.4, 8.9.5, 8.9.6, 8.10.1, 8.10.2, 8.10.3, 8.10.4, 9.2, 9.3, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10, 9.11, 9.12, 9.13, 9.14, 9.15, 9.16, 10.2, 10.5, 10.6, 10.7, 10.8, 10.10, 10.11, 11.1, 11.2, 11.3, 11.5, 11.6, 11.7, 12.1, 12.2, 12.3, 12.4, 12.5, 12.7, 12.8, 12.9, 12.10, 12.11, 12.12, 13.1, 13.2, 13.3, 13.6, 13.12, 13.13, 14.1, 14.2

Guest Authors:

Pnina Abir-Am, PhD Part Two: 6.1.1

Stephen J Williams, PhDPart Two: 6.2.6, 6.5.2.2, 10.4, 10.9, 13.4

Aviva Lev-Ari, PhD, RN:

Part One:

1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2.2.1, 2.3

Part Two:

5.1, 5.4, 5.5, 5.7, 5.8, 5.9, 5.10, 5.11, 6.1.3, 6.2.3, 6.2.4, 6.2.5, 6.3.1, 6.3.3, 6.3.7, 6.3.9, 6.4.3, 6.5.1.1, 6.5.2.1, 6.5.2.2, 6.5.3.1, 6.5.4, 6.5.5, 6,5,6, 8.9.2, 8.10.2, 9.1, 9.4, 10.1, 10.3, 11.4, 12.6, 13.5, 13.7, 13.8, 13.9, 13.10, 13.11

Adam Sonnenberg, BSC, MSc(c)Part Two: 13.9

 

electronic Table of Contents

PART ONE:

Physician as Authors, Writers in Medicine and Educator in Public Health

 

Chapter 1: Physicians as Authors

Introduction

1.1  The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – Best writers Among the WRITERS

1.2 Atul Gawande: Physician and Writer

1.3 Editorial & Publication of Articles in e-Books by  Leaders in Pharmaceutical Business Intelligence:  Contributions of Larry H Bernstein, MD, FCAP

1.4 Abraham Verghese, MD, Physician and Notable Author

1.5 Eric Topol, M.D.

1.6 Gregory House, MD

1.7 Peter Mueller, MD  Professor of Radiology @MGH & HMS – 2015 Synergy’s Honorary Award Recipient

Summary

Chapter 2: Professional Recognition

Introduction

2.1 Proceedings

2.1.1 Research Presentations

2.1.2 Proceedings of the NYAS

2.1.3 Cold Spring Harbor Conference Meetings

2.1.4 Young Scientist Seminars

2.2 Meet Great Minds

2.2.1 Meet the Laureates

2.2.2 Richard Feynman, Genius and Laureate

2.2.3 Fractals and Heat Energy

2.3 MacArthur Foundation Awards

2.4 Women’s Contributions went beyond Rosie the Riveter

2.4.1 Secret Maoist Chinese Operation Conquered Malaria

2.4.2 Antiparasite Drug Developers Win Nobel

2.5 Impact Factors and Achievement

2.6   RAPsodisiac Medicine

2.6.1 Outstanding-achievements-in-radiology-or-radiotherapy

2.6.2 Outstanding-achievement-in-anesthesiology

2.6.3 Outstanding-achievement-in-pathology

2.6.4 Topics in Pathology – Special Issues from Medscape Pathology

2.7 How to win the Nobel Prize

2.8 Conversations about Medicine

2.9 Current Advances in Medical Technology

2.10 Atul Butte, MD, PhD

Summary

Chapter 3:  Medical and Allied Health Sciences Education

Introduction

3.1 National Outstanding Medical Student Award Winners

3.2 Outstanding Awards in Medical Education

3.3 Promoting Excellence in Physicians and Nurses

3.4 Excellence in mentoring

Summary

Chapter 4: Science Teaching in Math and Technology (STEM)

Introduction

4.1 Science Teaching in Math and Technology

4.2 Television as a Medium for Science Education

4.2.1 Science Discovery TV

4.3 From Turing to Watson

Summary

PART TWO:

Medical Scientific Discoveries Interviews with Scientific Leaders

Chapter 5: Cardiovascular System

Introduction

5.1 Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

5.2 Mitochondrial Dysfunction and Cardiac Disorders

5.3 Notable Contributions to Regenerative Cardiology

5.4 For Accomplishments in Cardiology and Cardiovascular Diseases: The Arrigo Recordati International Prize for Scientific Research

5.5 Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

5.6 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

5.7 CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin

5.8 2013 as A Year of Revolutionizing Medicine and Top 11 Cardiology Stories

5.9 Bridging the Gap in Medical Innovations – Elazer Edelman @ TEDMED 2013

5.10 Development of a Pancreatobiliary Chemotherapy Eluting Stent for Pancreatic Ductal Adenocarcinoma PIs: Jeffrey Clark (MGH), Robert Langer (Koch), Elazer Edelman (Harvard:MIT HST Program)

5.11 Publications on Heart Failure by Prof. William Gregory Stevenson, M.D., BWH

Summary

Chapter 6: Genomics

Introduction
6.1 Genetics before the Human Genome Project

6.1.1 Why did Pauling Lose the “Race” to James Watson and Francis Crick? How Crick Describes his Discovery in a Letter to his Son

6.1.2 John Randall’s MRC Research Unit and Rosalind Franklin’s role at Kings College

6.1.3 Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin

6.1.4 The Initiation and Growth of Molecular Biology and Genomics, Part I

6.2 The Human Genome Project: Articles of Note  @ pharmaceuticalintelligence.com by multiple authors

6.2.1 CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

6.2.2 What comes after finishing the Euchromatic Sequence of the Human Genome?

6.2.3 Human Genome Project – 10th Anniversary: Interview with Kevin Davies, PhD – The $1000 Genome

6.2.4 University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

6.2.5 Exceptional Genomes: The Process to find them

6.2.6 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

6.3 The Impact of Genome Sequencing on Biology and Medicine

6.3.1 Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data

6.3.2 Modification of genes by homologous recombination – Mario Capecchi, Martin Evans, Oliver Smithies

6.3.3 AAAS February 14-18, 2013, Boston: Symposia – The Science of Uncertainty in Genomic Medicine

6.3.4 The Metabolic View of Epigenetic Expression

6.3.5  Pharmacogenomics

6.3.6 Neonatal Pathophysiology

6.3.7 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

6.3.8 3D mapping of genome in combine FISH and RNAi

6.3.9 Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

6.3.10 DNA mutagenesis and DNA repair

6.4 Scientific Leadership Recognition for Contributions to Genomics

6.4.1 Interview with Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak (44 minutes)

6.4.2 DNA Repair Pioneers Win Nobel – Tomas Lindahl, Paul Modrich, and Aziz Sancar 2015 Nobel Prize in Chemistry for the mechanisms of DNA repair

6.4.3  Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

6.5 Contemporary Field Leaders in Genomics

6.5.1 ROBERT LANGER

6.5.1.1 2014 Breakthrough Prizes Awarded in Fundamental Physics and Life Sciences for a Total of $21 Million – MIT’s Robert Langer gets $3 Million

6.5.1.2 National Medal of Science – 2006 Robert S. Langer

6.5.1.3  Confluence of Chemistry, Physics, and Biology

6.5.2 JENNIFER DOUDNA

6.5.2.1 Jennifer Doudna, cosmology teams named 2015 Breakthrough Prize winners

6.5.2.2 UPDATED – Medical Interpretation of the Genomics Frontier – CRISPR – Cas9: Gene Editing Technology for New Therapeutics

6.5.3 ERIC LANDER

6.5.3.1  2012 Harvey Prize in April 30: at the Technion-Israel Institute of Technology to Eric S. Lander @MIT & Eli Yablonovitch @UC, Berkeley

6.5.4 2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

6.5.5 Recognitions for Contributions in Genomics by Dan David Prize Awards

6.5.6   65 Nobel Laureates meet 650 young scientists covering the fields of physiology and medicine, physics, and chemistry, 28 June – 3 July, 2015, Lindau & Mainau Island, Germany

Summary

Chapter 7: The RNAs

Introduction

7.1 RNA polymerase – molecular basis for DNA transcription – Roger Kornberg, MD

7.2  One gene, one protein – Charles Yanofsky

7.3 Turning genetic information into working proteins – James E. Darnell Jr.

7.4 Small but mighty RNAs – Victor Ambros, David Baulcombe, and Gary Ruvkun, Phillip A. Sharp

7.5 Stress-response gene networks – Nina V. Fedoroff

Summary

Chapter 8: Proteomics, Protein-folding, and Cell Regulation
Introduction.

8.1 The Life and Work of Allan Wilson

8.2 Proteomics

8.3 More Complexity in Protein Evolution

8.4 Proteins: An evolutionary record of diversity and adaptation

8.5 Heroes in Basic Medical Research – Leroy Hood

8.6 Ubiquitin researchers win Nobel – Ciechanover, Hershko, and Rose awarded for discovery of ubiquitin-mediated proteolysis

8.7 Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeostatic regulation

8.8 Dynamic Protein Profiling

8.9 Protein folding

8.9.1 Protein misfolding and prions – Susan L. Lindquist, Stanley B. Prusiner

8.9.2 A Curated Census of Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy

8.9.3 Voluntary and Involuntary S-Insufficiency

8.9.4 Transthyretin and Lean Body Mass in Stable and Stressed State

8.9.5 The matter of stunting in the Ganges Plains

8.9.6 Proteins, Imaging and Therapeutics

8.10 Protein Folding and Vesicle Cargo

8.10.1 Heat Shock Proteins (HSP) and Molecular Chaperones

8.10.2 Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and sub epithelial myofibroblasts

8.10.3 Biology, Physiology and Pathophysiology of Heat Shock Proteins

8.10.4 The Role of Exosomes in Metabolic Regulation 


Summary

Chapter 9:  Neuroscience

Introduction

9.1 Nobel Prize in Physiology or Medicine 2013 for Cell Transport: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University

9.2 Proteins that control neurotransmitter release – Richard H. Scheller

9.3 Heroes in Basic Medical Research – Robert J. Lefkowitz

9.4 MIND AND MEMORY: BIOLOGICAL AND DIGITAL – 2014 Dan David Prize Symposium

9.5 A new way of moving – Michael Sheetz, James Spudich, Ronald Vale

9.6 Role the basal ganglia

9.7 The Neurogenetics of Language – Patricia Kuhl – 2015 George A. Miller Award

9.8 The structure of our visual system

9.9 Outstanding Achievement in Schizophrenia Research

9.10 George A. Miller, a Pioneer in Cognitive Psychology, Is Dead at 92

9.11 – To understand what happens in the brain to cause mental illness

9.12 Brain and Cognition

9.13 – To reduce symptoms of mental illness and retrain the brain

9.14 Behavior

9.15 Notable Papers in Neurosciences

9.16 Pyrroloquinoline quinone (PQQ) – an unproved supplement

Summary

Chapter 10: Microbiology & Immunology

Introduction

10.1 Reference Genes in the Human Gut Microbiome: The BGI Catalogue

10.2 Malnutrition in India, high newborn death rate and stunting of children age under five years

10.3 In His Own Words: Leonard Herzenberg, The Immunologist Who Revolutionized Research, Dies at 81

10.4 Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

10.5 Tang Prize for 2014: Immunity and Cancer

10.6 Halstedian model of cancer progression

10.7 The History of Hematology and Related Sciences

10.8 Pathology Emergence in the 21st Century

10.9 Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

10.10  T cell-mediated immune responses & signaling pathways activated by TLRs – Bruce A. Beutler, Jules A. Hoffmann, Ralph M. Steinman

10.11 Roeder – the coactivator OCA-B, the first cell-specific coactivator, discovered by Roeder in 1992, is unique to immune system B cells

Summary

Chapter 11: Endocrine Hormones

Introduction

11.1 Obesity – 2010 Douglas L. ColemanJeffrey M. Friedman

11.2 Lonely Receptors: RXR – Jensen, Chambon, and Evans – Nuclear receptors provoke RNA production in response to steroid hormones

11.3 The Fred Conrad Koch Lifetime Achievement Award—the Society’s highest honor—recognizes the lifetime achievements and exceptional contributions of an individual to the field of endocrinology

11.4 Gerald D Aurbach Award for Outstanding Translational Research

11.5 Roy O. Greep Award for Outstanding Research in Endocrinology – Martin M. Matzuk

11.6 American Physiology Society Awards

11.7 Solomon Berson and Rosalyn Yalow

Summary

Chapter 12. Stem Cells

Introduction

12.1 Mature cells can be reprogrammed to become pluripotent – John Gurdon and Shinya Yamanaka

12.2 Observing the spleen colonies in mice and proving the existence of stem cells – Till and McCulloch

12.3 McEwen Award for Innovation: Irving Weissman, M.D., Stanford School of Medicine, and Hans Clevers, M.D., Ph.D., Hubrecht Institute

12.4 Developmental biology

12.5  CRISPR/Cas-mediated genome engineering – Rudolf Jaenisch

12.6 Ribozymes and RNA Machines –  Work of Jennifer A. Doudna

12.7 Ralph Brinster, ‘Father of Transgenesis’

12.8 Targeted gene modification

12.9 Stem Cells and Cancer

12.10 ALPSP Awards

12.11 Eppendorf Award for Young European Investigators

12.12 Breaking news about genomic engineering, T2DM and cancer treatments

Summary
Chapter 13: 3D Printing and Medical Application

Introduction

13.1 3D Printing

13.2 What is 3D printing?

13.3 The Scientist Who Is Making 3D Printing More Human

13.4 Join These Medical 3D Printing Groups on Twitter and LinkedIn for great up to date news

13.5 Neri Oxman and her Mediated Matter group @MIT Media Lab have developed a technique for 3D-printing Molten Glass

13.6 The ‘chemputer’ that could print out any drug

13.7 3-D-Bioprinting in use to Create Cardiac Living Tissue: Print your Heart out

13.8 LPBI’s Perspective on Medical and Life Sciences Applications – 3D Printing: BioInks, BioMaterials-BioPolymer

13.9 Medical MEMS, Sensors and 3D Printing: Frontier in Process Control of BioMaterials

13.10 NIH and FDA on 3D Printing in Medical Applications: Views for On-demand Drug Printing, in-Situ direct Tissue Repair and Printed Organs for Live Implants

13.11 ‘Pop-up’ fabrication technique trumps 3D printing

13.12 Augmentation of the ONTOLOGY of the 3D Printing Research

13.13 Superresolution Microscopy

Summary

Chapter 14: Synthetic Medicinal Chemistry

Introduction

14.1 Insights in Biological and Synthetic Medicinal Chemistry

14.2 Breakthrough work in cancer

Summary to Part Two

Volume Summary and Conclusions

EPILOGUE

 

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Scientists at the Stanford University School of Medicine have completed the first-ever characterization of the meticulously timed immune system changes in women that occur during pregnancy. The findings were published in Science Immunology revealed that there is an immune clock of pregnancy and suggest it may help doctors predict preterm birth.

 

The timing of immune system changes follows a precise and predictable pattern in normal pregnancy. Although physicians have long known that the expectant mother’s immune system adjusts to prevent her body from rejecting the fetus, no one had investigated the full scope of these changes, nor asked if their timing was tightly controlled.

 

Nearly 10 percent of U.S. infants are born prematurely, arriving three or more weeks early, but physicians lack a reliable way to predict premature deliveries. Previous research at Stanford and other places suggested that inflammatory immune responses may help in triggering early labor. It suggested that if scientists identify an immune signature of impending preterm birth, they should be able to design a blood test to detect it.

 

The researchers used mass cytometry, a technique developed at Stanford, to simultaneously measure up to 50 properties of each immune cell in the blood samples. They counted the types of immune cells, assessed what signaling pathways were most active in each cell, and determined how the cells reacted to being stimulated with compounds that mimic infection with viruses and bacteria.

 

The researchers developed an algorithm that captures the immunological timeline during pregnancy that both validates previous findings and sheds new light on immune cell interaction during gestation. By defining this immunological chronology during normal term pregnancy, they can now begin to determine which alterations associate with pregnancy-related pathologies.

 

With an advanced statistical modeling technique, introduced for the first time in this study, the scientists then described in detail how the immune system changes throughout pregnancy. Instead of grouping the women’s blood samples by trimester for analysis, the model treated gestational age as a continuous variable, allowing the researchers to account for the exact time during pregnancy at which each sample was taken. The mathematical model also incorporated knowledge from the existing scientific literature of how immune cells behave in nonpregnant individuals to help determine which findings were most likely to be important.

 

The study confirmed immune features of pregnancy that were already known. Such as the scientists saw that natural killer cells and neutrophils have enhanced action during pregnancy. The researchers also uncovered several previously unappreciated features of how the immune system changes, such as the finding that activity of the STAT5 signaling pathway in CD4+T cells progressively increases throughout pregnancy on a precise schedule, ultimately reaching levels much higher than in nonpregnant individuals. The STAT5 pathway is involved in helping another group of immune cells, regulatory T cells, to differentiate. Interestingly, prior research in animals has indicated that regulatory T cells are important for maintaining pregnancy.

 

The next step will be to conduct similar research using blood samples from women who deliver their babies prematurely to see where their trajectories of immune function differ from normal.

 

This study revealed a precisely timed chronology of immune adaptations in peripheral blood over the course of a term pregnancy. This finding was enabled by high-content, single-cell mass cytometry coupled with a csEN algorithm accounting for the modular structure of the immune system and previous knowledge. The study provided the conceptual backbone and the analytical framework to examine whether disruption of this chronology is a diagnostically useful characteristic of preterm birth and other pregnancy-related pathologies.

 

References:

 

http://immunology.sciencemag.org/content/2/15/eaan2946.full

 

http://med.stanford.edu/news/all-news/2017/09/immune-system-changes-during-pregnancy-are-precisely-timed.html

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078586/

 

http://www.nature.com/nm/journal/v19/n5/full/nm.3160.html?foxtrotcallback=true

 

https://www.ncbi.nlm.nih.gov/pubmed/14758358

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