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Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Reporter: Amandeep Kaur

In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011.  The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.

Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.

Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.

During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.

  • MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
  • MEPAN syndrome is a rare genetic neurological disorder
  • MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
  • The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
  • The prevalence rate of MEPAN syndrome is 1 in 1 million
  • Currently, there are 17 patients of MEPAN syndrome worldwide

The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.

Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.

The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.

Reference: Danny Miller, The diagnostic odyssey: our family’s story, The American Journal of Human Genetics, Volume 108, Issue 2, 2021, Pages 217-218, ISSN 0002-9297, https://doi.org/10.1016/j.ajhg.2021.01.003 (https://www.sciencedirect.com/science/article/pii/S0002929721000033)

Sources:

https://www.variantyx.com/2020/02/26/in-silico-panel-expansion/

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=508093

https://www.mepan. org

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Effect of mitochondrial stress on epigenetic modifiers

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/05/07/effect-of-mitochondrial-stress-on-epigenetic-modifiers/

The Three Parent Technique to Avoid Mitochondrial Disease in Embryo

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

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/04/20/new-insights-into-mtdna-mitochondrial-proteins-aging-and-metabolic-control/

Mitochondrial Isocitrate Dehydrogenase and Variants

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/02/mitochondrial-isocitrate-dehydrogenase-and-variants/

Update on mitochondrial function, respiration, and associated disorders

Larry H. Benstein, MD, FCAP, Gurator and writer

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-disorders/

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Papers citing PharmaceuticalIntelligence.com

Reporter: Stephen J. Williams, PhD

(10 papers, 5 peer reviewed, 2 web page, 2 teaching lectures, 1 preprint) Search from years 2012 – 2018

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777453/

Chin J Cancer. 2012 Oct; 31(10): 463–470.

doi: 10.5732/cjc.012.10216

PMCID: PMC3777453

PMID: 22980418

Application of next-generation sequencing in clinical oncology to advance personalized treatment of cancer

Yan-Fang GuanGai-Rui LiRong-Jiao WangYu-Ting YiLing YangDan JiangXiao-Ping Zhang, and Yin Peng

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

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Abstract

With the development and improvement of new sequencing technology, next-generation sequencing (NGS) has been applied increasingly in cancer genomics research over the past decade. More recently, NGS has been adopted in clinical oncology to advance personalized treatment of cancer. NGS is used to identify novel and rare cancer mutations, detect familial cancer mutation carriers, and provide molecular rationale for appropriate targeted therapy. Compared to traditional sequencing, NGS holds many advantages, such as the ability to fully sequence all types of mutations for a large number of genes (hundreds to thousands) in a single test at a relatively low cost. However, significant challenges, particularly with respect to the requirement for simpler assays, more flexible throughput, shorter turnaround time, and most importantly, easier data analysis and interpretation, will have to be overcome to translate NGS to the bedside of cancer patients. Overall, continuous dedication to apply NGS in clinical oncology practice will enable us to be one step closer to personalized medicineWith the development and improvement of new sequencing technology, next-generation sequencing (NGS) has been applied increasingly in cancer genomics research over the past decade. More recently, NGS has been adopted in clinical oncology to advance personalized treatment of cancer. NGS is used to identify novel and rare cancer mutations, detect familial cancer mutation carriers, and provide molecular rationale for appropriate targeted therapy. Compared to traditional sequencing, NGS holds many advantages, such as the ability to fully sequence all types of mutations for a large number of genes (hundreds to thousands) in a single test at a relatively low cost. However, significant challenges, particularly with respect to the requirement for simpler assays, more flexible throughput, shorter turnaround time, and most importantly, easier data analysis and interpretation, will have to be overcome to translate NGS to the bedside of cancer patients. Overall, continuous dedication to apply NGS in clinical oncology practice will enable us to be one step closer to personalized medicine.

  1. Lev-Ari A. Sunitinib brings Adult acute lymphoblastic leukemia (ALL) to Remission-RNA Sequencing-FLT3 Receptor Blockade. 2012. Available at: https://pharmaceuticalintelligence.com/2012/07/09/sunitinib-brings-adult-all-to-remission-rna-sequencing/

http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0123-30332014000100011

Ingeniería y competitividad

Print version ISSN 0123-3033

Ing. compet. vol.16 no.1 Cali Jan./June 2014

 

Bioinformática multifractal: Una propuesta hacia la interpretación no-lineal del genoma

Multifractal bioinformatics: A proposal to the nonlinear interpretation of genome

Pedro A. Moreno
Escuela de Ingeniería de Sistemas y Computación, Facultad de Ingeniería, Universidad del Valle, Cali, Colombia
E-mail: pedro.moreno@correounivalle.edu.co

Eje temático: Ingeniería de sistemas / System engineering
Recibido: 19 de septiembre de 2012
Aceptado: 16 de diciembre de 2013

Resumen

El primer borrador de la secuencia completa del genoma humano (GH) se publicó en el año 2001 por parte de dos consorcios competidores. Desde entonces, varias características estructurales y funcionales de la organización del GH han sido reveladas. Hoy en día, más de 2000 genomas humanos han sido secuenciados y todos estos hallazgos están impactando fuertemente en la academia y la salud pública. A pesar de esto, un gran cuello de botella llamado la interpretación del genoma persiste; esto es, la falta de una teoría que integre y explique el complejo rompecabezas de características codificantes y no codificantes que componen el GH como un todo. Diez años después de secuenciado el GH, dos trabajos recientes, abordados dentro del formalismo multifractal permiten proponer una teoría no-lineal que ayuda a interpretar la variación estructural y funcional de la información genética de los genomas. El presente artículo de revisión trata acerca de este novedoso enfoque, denominado: “Bioinformática multifractal”.

Palabras clave: Ciencias ómicas, bioinformática, genoma humano, análisis multifractal.

Abstract

The first draft of the human genome (HG) sequence was published in 2001 by two competing consortia. Since then, several structural and functional characteristics for the HG organization have been revealed. Today, more than 2.000 HG have been sequenced and these findings are impacting strongly on the academy and public health. Despite all this, a major bottleneck, called the genome interpretation persists. That is, the lack of a theory that explains the complex puzzles of coding and non-coding features that compose the HG as a whole. Ten years after the HG sequenced, two recent studies, discussed in the multifractal formalism allow proposing a nonlinear theory that helps interpret the structural and functional variation of the genetic information of the genomes. The present review article discusses this new approach, called: “Multifractal bioinformatics”.

  1. Introduction

Omic Sciences and Bioinformatics

In order to study the genomes, their life properties and the pathological consequences of impairment, the Human Genome Project (HGP) was created in 1990. Since then, about 500 Gpb (EMBL) represented in thousands of prokaryotic genomes and tens of different eukaryotic genomes have been sequenced (NCBI, 1000 Genomes, ENCODE). Today, Genomics is defined as the set of sciences and technologies dedicated to the comprehensive study of the structure, function and origin of genomes. Several types of genomic have arisen as a result of the expansion and implementation of genomics to the study of the Central Dogma of Molecular Biology (CDMB), Figure 1 (above). The catalog of different types of genomics uses the Latin suffix “-omic” meaning “set of” to mean the new massive approaches of the new omics sciences (Moreno et al, 2009). Given the large amount of genomic information available in the databases and the urgency of its actual interpretation, the balance has begun to lean heavily toward the requirements of bioinformatics infrastructure research laboratories Figure 1 (below).

The bioinformatics or Computational Biology is defined as the application of computer and information technology to the analysis of biological data (Mount, 2004). An interdisciplinary science that requires the use of computing, applied mathematics, statistics, computer science, artificial intelligence, biophysical information, biochemistry, genetics, and molecular biology. Bioinformatics was born from the need to understand the sequences of nucleotide or amino acid symbols that make up DNA and proteins, respectively. These analyzes are made possible by the development of powerful algorithms that predict and reveal an infinity of structural and functional features in genomic sequences, as gene location, discovery of homologies between macromolecules databases (Blast), algorithms for phylogenetic analysis, for the regulatory analysis or the prediction of protein folding, among others. This great development has created a multiplicity of approaches giving rise to new types of Bioinformatics, such as Multifractal Bioinformatics (MFB) that is proposed here.

1.1 Multifractal Bioinformatics and Theoretical Background

MFB is a proposal to analyze information content in genomes and their life properties in a non-linear way. This is part of a specialized sub-discipline called “nonlinear Bioinformatics”, which uses a number of related techniques for the study of nonlinearity (fractal geometry, Hurts exponents, power laws, wavelets, among others.) and applied to the study of biological problems (https://pharmaceuticalintelligence.com/tag/fractal-geometry/). For its application, we must take into account a detailed knowledge of the structure of the genome to be analyzed and an appropriate knowledge of the multifractal analysis.

https://www.biorxiv.org/content/biorxiv/early/2017/04/24/129742.full.pdf

Genome-wide differential gene network analysis R software and its application in LnCap prostate cancer

Gökmen Altay1* and David E. Neal2 1*La Jolla Institute for Allergy and Immunology, CA, USA 2Nuffield Department of Surgical Sciences, University of Oxford, Headington, OX3 7DQ , Oxford, United Kingdom *Corresponding author altay@lji.org Abstract We introduce an R software package for condition-specific gene regulatory network analysis based on DC3NET algorithm. We also present an application of it on a real prostate dataset and demonstrate the benefit of the software. We performed genome-wide differential gene network analysis with the software on the LnCap androgen stimulated and deprived prostate cancer gene expression datasets (GSE18684) and inferred the androgen stimulated prostate cancer specific differential network. As an outstanding result, CXCR7 along with CXCR4 appeared to have the most important role in the androgen stimulated prostate specific genome-wide differential network. This blind estimation is strongly supported from the literature. The critical roles for CXCR4, a receptor over-expressed in many cancers, and CXCR7 on mediating tumor metastasis, along with their contributions as biomarkers of tumor behavior as well as potential therapeutic target were studied in several other types of cancers. In fact, a pharmaceutical company had already developed a therapy by inhibiting CXCR4 to block non-cancerous immuno-suppressive and pro-angiogenic cells from populating the tumor for disrupting the cancer environment and restoring normal immune surveillance functions. Considering this strong confirmation, our inferred regulatory network might reveal the driving mechanism of LnCap androgen stimulated prostate cancer. Because, CXCR4 appeared to be in the center of the largest subnetwork of our inferred differential network. Moreover, enrichment analyses for the largest subnetwork of it appeared to be significantly enriched in terms of axon guidance, fc gamma R-mediated phagocytosis and endocytosis. This also conforms with the recent literature in the field of prostate cancer. We demonstrate how to derive condition-specific gene targets from expression datasets on genome-wide level using differential gene network analysis. Our results showed that differential gene network analysis worked well in a prostate cancer dataset, which suggest the use of this approach as essential part of current expression data processing. Availability: The introduced R software package available in CRAN at https://cran.r-project.org/web/packages/dc3net and also at https://github.com/altayg/dc3net

  1. Discussion By employing differential gene network analysis approach, the present study aims to investigate the molecular mechanisms that may drive disease progression in prostate cancer using our presented software dc3net. Top four hub nodes, identified in the present study, have been strongly associated with prostate cancer metastatic process, including CXCR7, STK39, ELOVL7 and ACSL3. Hub nodes are genes that are highly connected with other genes and they were proposed to have important roles in biological development. Since hub nodes have more complex interactions than other genes, they may have crucial roles in the underlying mechanisms of disease (Guo, 2015). Identification of hub genes involved in progression of prostate cancer may lead to the development of better diagnostic methods and providing therapeutic approaches. According to our analysis, CXCR7 (chemokine (C-X-C motif) receptor 7) is by far the top hub gene in the androgen stimulated differential network and it is also part of the largest independent subnetwork as seen in Figure 3. In (Wang, 2008), it is reported that staining of high-density tissue microarrays shows that the levels of CXCR7/RDC1 expression increase as the tumors become more aggressive. Also, In vitro and in vivo studies with prostate cancer cell lines propose that alterations in CXCR7/RDC1 expressions are associated with enhanced invasive and adhesive activities in addition to a survival advantage. Along other papers on CXCR7 (Zheng, 2010), it was shown that increased CXCR7 expression was found in hepatocellular carcinoma (HCC) tissues. Knockdown of CXCR7 expression by transfected with CXCR7shRNA significantly inhibited SMMC-7721 angiogenesis, adhesion and cells invasion. Moreover, down-regulation of CXCR7 expression leads to a reduction of tumor growth in a xenograft model of HCC (Zheng, 2010). Another study demonstrated that the IL8–regulated Chemokine Receptor CXCR7 stimulates EGFR Signaling to promote prostate cancer growth (Singh, 2011). In a study conducted by Yun et al., it is reported that CXCR7 expression is increased in most of the tumor cells compared with the normal cells and is involved in cell proliferation, migration, survival, invasion and angiogenesis during the initiation and progression of many cancer types including prostate cancer (Yun, 2015). A more recent study indicated that there appeared to be disconnect of the effect of DHT on CXCL12/CXCR4/CXCR7 chemokine axis between transcriptional and translation machinery in androgen-responsive LnCaP cell line. There are many other studies that showed the strong role of CXCR7 in metastatic type cancer that strongly validates our blind foremost prediction is very likely to be true and thus needs further experimental work on its targets that we inferred in this study. However, available under aCC-BY-NC 4.0 International license. not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made bioRxiv preprint doi: https://doi.org/10.1101/129742; this version posted April 24, 2017. The copyright holder for this preprint (which was 11 It was also observed that CXCR7/RDC1 levels are regulated by CXCR4 (Singh, 2011). This is a very interesting supporting information from literature for our blind estimation because in our predicted largest independent subnetwork, as shown in Figure 3, CXCR7 and CXCR4 appear to be very close and interacting over only one gene. Although CRCX4 is not a hub gene, it appears to be as a bridge that connects both halves of the largest subnetwork. According to KEGG analysis, CXCR4 was found in the gene list of two different significantly enriched KEGG pathways, axon guidance and endocytosis which are strongly associated with prostate cancer (Table 3). Considering the prediction was made on global level, this literature confirmation seems assuring but not a coincidence. Therefore, this relation is worth experimenting in LnCap cancer too. It is also reported (Shanmugam, 2011) that inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model and CXCR4 induced a more aggressive phenotype in prostate cancer (Miki, 2007). In another study, it is reported that CXCR4 and CXCR7 have critical roles on mediating tumor metastasis in various types of cancers as both being a receptor for an important α-chemokine, CXCL12 (Sun, 2010). Furthermore, a more recent study concluded that CXCR4 plays a crucial role in cancer proliferation, dissemination and invasion and the inhibition of CXCR4 strongly affects prostate cancer metastatic disease (Gravina, 2015). The chief officer of Massachusetts based X4 Pharmaceuticals company recently stated that CXCR4 protein “acts as a beacon to attract cells to surround a tumor, effectively hiding the tumor from the body’s T cells that would otherwise destroy them”. He indicated that X4 company is beginning human trials using CXCR4 inhibitors which aims to develop a therapy to block the protein, CXCR4 (https://pharmaceuticalintelligence.com/2015/12/15/are-cxc4-antagonists-making-a-comebackin-cancer-chemotherapy, 2015).

https://www.slideshare.net/dsairamsairam/warburg-effect

  1. 1. Warburg Effect Presented By: D.Sairam Course : Fundamentals of Biology- Life Sciences Course Code: BSBT-201 Course Instructor: Dr. Subhabrata Kar Presentation Code: U3P1
  2. 2. Overview Ø Introduction Ø Causes of Warburg Effect Ø Significance of Warburg Effect ØReferences
  3. 3. Introduction • Warburg, considered by many the pre-eminent bio chemist of the first half of the twentieth century, made vital contributions to many other areas of biochemistry, including respiration, photosynthesis, and the enzymology of intermediary metabolism. • In the mid 1920s Warburg and co-workers showed that, under Aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues. • This phenomenon later came to be known as “Warburg Effect”. • Warburg purified and crystallized seven of the enzymes of glycolysis. He used a tool called as “ Warburg Manometer” which measured directly the consumption of oxygen by monitoring changes in gas volume, and therefore allowed quantitative measurement of any enzyme with oxidase activity.
  4. 4. Note: Warburg Effect in Plant Physiology and Oncology are different • In Plant physiology, Warburg Effect refers to the phenomenon in which Oxygen acts as a competitive inhibitor to Carbon dioxide fixation under the influence of RuBisCO, which initiates photosynthesis. Source : Bild-1928
  5. 5. Comparison of Glycolysis between a Normal Tissue and Tumour/ Proliferated Tissue • https://pharmaceuticalintelligence.com/2012/10/17/is-the- warburg-effect-the-cause-or-the-effect-of-cancer-a-21st- century-view/

https://prezi.com/rbtv_450s3wd/eml4-alk-fusion-gene/

EML4-ALK fusion gene

CK

Published with reusable license by Camille Kawawa-Beaudan

July 2, 2015

Sasaki, Takaaki, Scott J. Rodig, Lucian R. Chirieac, and Pasi A. Janne. “The Biology and Treatment of EML4-ALK Non-Small Cell Lung Cancer.” NCBI. US National Library of Medicine, 24 Apr. 2010. Web. 30 June 2015. <http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC2888755%2F>.

Shaw, Alice T., and Benjamin Solomon. “Targeting Anaplastic Lymphoma Kinase in Lung Cancer.” Clinical Cancer Research. N.p., 2 Feb. 2011. Web. 30 June 2015. <http%3A%2F%2Fclincancerres.aacrjournals.org%2Fcontent%2F17%2F8%2F2081.full>.

Webb, Thomas R., Jake Slavish,et al. “Anaplastic Lymphoma Kinase: Role in Cancer Pathogenesis and Small-molecule Inhibitor Development for Therapy.” Expert Review of Anticancer Therapy. U.S. National Library of Medicine, 1 Jan. 2010. Web. 30 June 2015. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780428/&gt;.

Webb, Thomas R., Jake Slavish, et al. “Anaplastic Lymphoma Kinase: Role in Cancer Pathogenesis and Small-molecule Inhibitor Development for Therapy.” Expert Review of Anticancer Therapy. U.S. National Library of Medicine, 1 Jan. 2010. Web. 30 June 2015. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780428/&gt;.

https://pharmaceuticalintelligence.files.wordpress.com/2014/08/membrane_receptor_tk.jpg?w=500&h=326

https://github.com/arquivo/Research-Websites-Preservation/blob/master/classifier/projects_classification.csv.3

GENEREGULATION,Deciphering the code of gene regulation using massively parallel assays of designed sequence libraries,https://pharmaceuticalintelligence.com/tag/transcription/page/2/,0
EXACTA,

https://tginnovations.wordpress.com/2012/05/08/cancer/

Cancer

MAY 8, 2012 · TGI – BIOMARKERSTGI – CANCERTGI – EPIGENETICSTGI – HEALTHTGI – INTEGRATIVE MEDICINETGI – MASS SPECTROMETRY

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2 Votes

Cancer is a broad group of various diseases involving unregulated cell growth. It is medically known as a malignant neoplasm. In cancer, cells divide and grow uncontrollably and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream, it is called metastasis. However, not all tumors are cancerous. Some tumors do not grow uncontrollably, do not invade neighboring tissues, and do not spread throughout the body which are called Benign tumors.

There are more than 100 types of Cancers. Follow the link to know more:

http://www.cancer.gov/cancertopics/types/alphalist

Main sites of metastases for some common cancer types. Primary cancers are denoted by “…cancer” and their main metastasis sites are denoted by “…metastases”. List of included entries and references is found on main image page in Commons: (Photo credit: Wikipedia)

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https://www.minipiginfo.com/mini-pig-cancer.html

Cancer and pigs

Pig cancer has been widely studied because pigs cancer advantages include the resemblance in anatomy, physiology, and genetic makeup with the human, as well as new methods to manipulate the pig genome. So there is alot of research that continues to be done with regards to pigs and cancer. Some of the articles are older and additonal research has been done, but the studies have not been published publicly, so I am including links to studies that can be viewed by anyone. I do have access to some studies that are published on sites only healthcare personnel can access. These are just a few things you should be aware of when adding a pig to your family. This does not mean your pig may get cancer, but it is certainly a possibility. In the past 15 years (2001–2016), the incidence of reported neoplasia in pet pot-bellied pigs has increased, mostly as a consequence of increased life spans resulting from improved veterinary medical care.

Pigs are predisposed to some genetic cancers as well as other types of cancer. Reproductive cancer is extremely common in pigs that were never spayed/neutered, but especially in the females. I have seen research studies indicating a percentage as high as 75% of ALL females will develop some kind of neoplasm or tumor in the reproductive organs as they age, which is why we let others know the importance of spaying and neutering your pig. These pigs age data were available for 27 of the 32 pigs and ranged from 4 months to 19 years. The study is linked below from Sage Pub.

Sources:
​https://www.ccsi.ca/reports/Melanoma_article.pdf

https://pharmaceuticalintelligence.com/2013/10/10/the-scid-pig-how-pigs-are-becoming-a-great-alternate-model-for-cancer-research/
​http://journals.sagepub.com/uterine-cancer-in-pigs/full
​https://www.ncbi.nlm.nih.gov/pigs-in-research-article
http://pubmedcentralcanada.ca/lukemia-in-mini-pigs/articles
https://www.ncbi.nlm.nih.gov/pmc/hepatocellular-carcinoma-potbellied-pig/articles
http://journals.sagepub.com/full/hepatocelluar-carcinoma-potbellied-pigs
http://journals.sagepub.com/doi/full/oral-squamous-cell-carcinoma-in-potbellied-pig
http://journals.sagepub.com/doi/pdf/gastric-carcinoma-in-mini-pigs

http://illinoisjltp.com/journal/wp-content/uploads/2014/12/Mehta.pdf

But, one key distinction between the Biologics Price Act and the HatchWaxman Act that deserves some attention is that even though the current FDA Draft guidelines are silent on the issue of labeling requirements for follow-on biologic drugs, it is most likely that the FDA will not only permit, but will require follow-on biologic drug manufacturers to maintain warning labels that are unique. (117) What this means is that brand-name biologic drug

  1. It is worth emphasizing that there is a normative debate amongst industry as to whether follow-on biologics should have unique names. See Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers, LEADERS IN PHARMACEUTICAL BUS. INTELLIGENCE, https://pharmaceuticalintelligence.com/tag/BiologicsPriceAct/ (last visited Oct. 27, 2014) (“Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriberpatient decision making . . . .”). However, the debate seems to be tipping in favor of requiring unique labeling as opposed to identical labeling. See id (“[W]hile all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products.

https://www.pharmatutor.org/articles/breakthroughs-in-epigenetics

ABOUT AUTHORS:
Shashi Shekhar Anand, Navgeet, Balraj Singh Gill*
Centre for Biosciences,
School of Basic and Applied Sciences,
Central University of Punjab, Bathinda, India
gillsinghbalraj@gmail.com

ABSTRACT
The word ‘epigenetic’ was first coined by Conrad Waddington in 1946. It deals with functionally relevant modifications to the genome that do not include a change in the nucleotide sequence. Till date observation has focused on the functions of genome sequences and how their regulation occurs. The emerging epigenetic changes and the interactions between cis-acting elements with protein factors  plays a central role in gene regulation as well as give insight to various diseases. To evaluate the crosstalk of DNA and protein by taking account of the whole genome, one new evolving technique which is called as ChIP-chip, works on the principle of combining chromatin immunoprecipitation with microarray. ChIP-chip has been recently used in basic biological studies and may be improved further and can be useful for other to aspects, like human diseases. Now a days large amount of discoveries by ChIP-chip and other high-throughput techniques like this   may be connected with evolving bioinformatics to add to our knowledge of life and diseases.

Histone Phosphorylation
Histone Phosphorylation is the modification in which there is an addition of a phosphate  group. Phosphorylation is catalyzed by the various specific protein kinases, whereas phosphatases mediate removal of the phosphate group (Figure 5). The most studied sites of histone phosphorylation are the serine. Phosphorylation of histones can also be a vital regulatory signal. H2A variant, H2AX that helps in the DNA repair by the process of phosphorylation. It has an important role in DNA damage response and DNA repair.

Fig 5. Phosphorylation of serine chain
Fig.source:pharmaceuticalintelligence.com

Histone H3 phosphorylation has been reported to play important roles in both transcription and chromatin condensation during mitosis.

https://www.archivesofmedicine.com/medicine/ca2stimulated-exocytosis-the-role-of-calmodulin-and-protein-kinase-c-in-ca2-regulation-of-hormone-and-neurotransmitter.php?aid=7058

Archives of Medicine

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Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein*

New York Methodist Hospital, Brooklyn, New York, USA

Corresponding Author:

Larry H Bernstein
New York Methodist Hospital
Brooklyn, New York, USA
Tel: 2032618671
E-mail: larry.bernstein@gmail.com

Visit for more related articles at Archives of Medicine

Abstract

This is a review of the role of calmodulin and protein kinase C inregulation of Ca++ – stimulated secretion. The molecular mechanisms underlying the Ca2+ regulation of hormone and neurotransmitter release are largely unknown. Using a reconstituted [3H] norepinephrine release assay in permeabilized PC12 cells, we found essential proteins that support the triggering stage of Ca2+-stimulated exocytosis are enriched in an EGTA extract of brain membranes. Fractionation of this extract allowed purification of two factors that stimulate secretion in the absence of any other cytosolic proteins. These are calmodulin and protein kinase Ca (PKCa). Their effects on secretion were confirmed using commercial and recombinant proteins. Calmodulin enhances secretion in the absence of ATP, whereas PKC requires ATP to increase secretion, suggesting that phosphorylation is involved in PKC-mediated stimulation but not calmodulin mediated stimulation. Both proteins modulate the half-maximal increase was elicited by 3 nM PKC and 75 nM calmodulin. These results suggest that calmodulin and PKC increase Ca2+-activated exocytosis by directly modulating the membrane- or cytoskeleton-attached exocytic machinery downstream of Ca2+ elevation.

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP
and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

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Multiple Major Scientific Journals Will Fully Adopt Open Access Under Plan S

Curator: Stephen J. Williams, PhD

More university library systems have been pressuring major scientific publishing houses to adopt an open access strategy in order to reduce the library system’s budgetary burdens.  In fact some major universities like the California system of universities (University of California and other publicly funded universities in the state as well as Oxford University in the UK, even MIT have decided to become their own publishing houses in a concerted effort to fight back against soaring journal subscription costs as well as the costs burdening individual scientists and laboratories (some of the charges to publish one paper can run as high as $8000.00 USD while the journal still retains all the rights of distribution of the information).  Therefore more and more universities, as well as concerted efforts by the European Union and the US government are mandating that scientific literature be published in an open access format.

The results of this pressure are evident now as major journals like Nature, JBC, and others have plans to go fully open access in 2021.  Below is a listing and news reports of some of these journals plans to undertake a full Open Access Format.

 

Nature to join open-access Plan S, publisher says

09 APRIL 2020 UPDATE 14 APRIL 2020

Springer Nature says it commits to offering researchers a route to publishing open access in Nature and most Nature-branded journals from 2021.

Richard Van Noorden

After a change in the rules of the bold open-access (OA) initiative known as Plan S, publisher Springer Nature said on 8 April that many of its non-OA journals — including Nature — were now committed to joining the plan, pending discussion of further technical details.

This means that Nature and other Nature-branded journals that publish original research will now look to offer an immediate OA route after January 2021 to scientists who want it, or whose funders require it, a spokesperson says. (Nature is editorially independent of its publisher, Springer Nature.)

“We are delighted that Springer Nature is committed to transitioning its journals to full OA,” said Robert Kiley, head of open research at the London-based biomedical funder Wellcome, and the interim coordinator for Coalition S, a group of research funders that launched Plan S in 2018.

But Lisa Hinchliffe, a librarian at the University of Illinois at Urbana–Champaign, says the changed rules show that publishers have successfully pushed back against Plan S, softening its guidelines and expectations — in particular in the case of hybrid journals, which publish some content openly and keep other papers behind paywalls. “The coalition continues to take actions that rehabilitate hybrid journals into compliance rather than taking the hard line of unacceptability originally promulgated,” she says.

 

 

 

 

What is Plan S?

The goal of Plan S is to make scientific and scholarly works free to read as soon as they are published. So far, 17 national funders, mostly in Europe, have joined the initiative, as have the World Health Organization and two of the world’s largest private biomedical funders — the Bill & Melinda Gates Foundation and Wellcome. The European Commission will also implement an OA policy that is aligned with Plan S. Together, this covers around 7% of scientific articles worldwide, according to one estimate. A 2019 report published by the publishing-services firm Clarivate Analytics suggested that 35% of the research content published in Nature in 2017 acknowledged a Plan S funder (see ‘Plan S papers’).

PLAN S PAPERS

Journal Total papers in 2017 % acknowledging Plan S funder
Nature 290 35%
Science 235 31%
Proc. Natl Acad. Sci. USA 639 20%

Source: The Plan S footprint: Implications for the scholarly publishing landscape (Institute for Scientific Information, 2019)

 

Source: https://www.nature.com/articles/d41586-020-01066-5

Opening ASBMB publications freely to all

 

Lila M. Gierasch, Editor-in-Chief, Journal of Biological Chemistry

Nicholas O. Davidson

Kerry-Anne Rye, Editors-in-Chief, Journal of Lipid Research and 

Alma L. Burlingame, Editor-in-Chief, Molecular and Cellular Proteomics

 

We are extremely excited to announce on behalf of the American Society for Biochemistry and Molecular Biology (ASBMB) that the Journal of Biological Chemistry (JBC), Molecular & Cellular Proteomics (MCP), and the Journal of Lipid Research (JLR) will be published as fully open-access journals beginning in January 2021. This is a landmark decision that will have huge impact for readers and authors. As many of you know, many researchers have called for journals to become open access to facilitate scientific progress, and many funding agencies across the globe are either already requiring or considering a requirement that all scientific publications based on research they support be published in open-access journals. The ASBMB journals have long supported open access, making the accepted author versions of manuscripts immediately and permanently available, allowing authors to opt in to the immediate open publication of the final version of their paper, and endorsing the goals of the larger open-access movement (1). However, we are no longer satisfied with these measures. To live up to our goals as a scientific society, we want to freely distribute the scientific advances published in JBC, MCP, and JLR as widely and quickly as possible to support the scientific community. How better can we facilitate the dissemination of new information than to make our scientific content freely open to all?

For ASBMB journals and others who have contemplated or made the transition to publishing all content open access, achieving this milestone generally requires new financial mechanisms. In the case of the ASBMB journals, the transition to open access is being made possible by a new partnership with Elsevier, whose established capabilities and economies of scale make the costs associated with open-access publication manageable for the ASBMB (2). However, we want to be clear: The ethos of ASBMB journals will not change as a consequence of this new alliance. The journals remain society journals: The journals are owned by the society, and all scientific oversight for the journals will remain with ASBMB and its chosen editors. Peer review will continue to be done by scientists reviewing the work of scientists, carried out by editorial board members and external referees on behalf of the ASBMB journal leadership. There will be no intervention in this process by the publisher.

Although we will be saying “goodbye” to many years of self-publishing (115 in the case of JBC), we are certain that we are taking this big step for all the right reasons. The goal for JBC, MCP, and JLR has always been and will remain to help scientists advance their work by rapidly and effectively disseminating their results to their colleagues and facilitating the discovery of new findings (13), and open access is only one of many innovations and improvements in science publishing that could help the ASBMB journals achieve this goal. We have been held back from fully exploring these options because of the challenges of “keeping the trains running” with self-publication. In addition to allowing ASBMB to offer all the content in its journals to all readers freely and without barriers, the new partnership with Elsevier opens many doors for ASBMB publications, from new technology for manuscript handling and production, to facilitating reader discovery of content, to deploying powerful analytics to link content within and across publications, to new opportunities to improve our peer review mechanisms. We have all dreamed of implementing these innovations and enhancements (45) but have not had the resources or infrastructure needed.

A critical aspect of moving to open access is how this decision impacts the cost to authors. Like most publishers that have made this transition, we have been extremely worried that achieving open-access publishing would place too big a financial burden on our authors. We are pleased to report the article-processing charges (APCs) to publish in ASBMB journals will be on the low end within the range of open-access fees: $2,000 for members and $2,500 for nonmembers. While slightly higher than the cost an author incurs now if the open-access option is not chosen, these APCs are lower than the current charges for open access on our existing platform.

References

1.↵ Gierasch, L. M., Davidson, N. O., Rye, K.-A., and Burlingame, A. L. (2019) For the sake of science. J. Biol. Chem. 294, 2976 FREE Full Text

2.↵ Gierasch, L. M. (2017) On the costs of scientific publishing. J. Biol. Chem. 292, 16395–16396 FREE Full Text

3.↵ Gierasch, L. M. (2020) Faster publication advances your science: The three R’s. J. Biol. Chem. 295, 672 FREE Full Text

4.↵ Gierasch, L. M. (2017) JBC is on a mission to facilitate scientific discovery. J. Biol. Chem. 292, 6853–6854 FREE Full Text

5.↵ Gierasch, L. M. (2017) JBC’s New Year’s resolutions: Check them off! J. Biol. Chem. 292, 21705–21706 FREE Full Text

 

Source: https://www.jbc.org/content/295/22/7814.short?ssource=mfr&rss=1

 

Open access publishing under Plan S to start in 2021

BMJ

2019; 365 doi: https://doi.org/10.1136/bmj.l2382 (Published 31 May 2019)Cite this as: BMJ 2019;365:l2382

From 2021, all research funded by public or private grants should be published in open access journals, according to a group of funding agencies called coALition S.1

The plan is the final version of a draft that was put to public consultation last year and attracted 344 responses from institutions, almost half of them from the UK.2 The responses have been considered and some changes made to the new system called Plan S, a briefing at the Science Media Centre in London was told on 29 May.

The main change has been to delay implementation for a year, to 1 January 2021, to allow more time for those involved—researchers, funders, institutions, publishers, and repositories—to make the necessary changes, said John-Arne Røttingen, chief executive of the Research Council of Norway.

“All research contracts signed after that date should include the obligation to publish in an open access journal,” he said. T……

(Please Note in a huge bit of irony this article is NOT Open Access and behind a paywall…. Yes an article about an announcement to go Open Access is not Open Access)

Source: https://www.bmj.com/content/365/bmj.l2382.full

 

 

Plan S

From Wikipedia, the free encyclopedia

Jump to navigationJump to search

Not to be confused with S-Plan.

Plan S is an initiative for open-access science publishing launched in 2018[1][2] by “cOAlition S”,[3] a consortium of national research agencies and funders from twelve European countries. The plan requires scientists and researchers who benefit from state-funded research organisations and institutions to publish their work in open repositories or in journals that are available to all by 2021.[4] The “S” stands for “shock”.[5]

Principles of the plan[edit]

The plan is structured around ten principles.[3] The key principle states that by 2021, research funded by public or private grants must be published in open-access journals or platforms, or made immediately available in open access repositories without an embargo. The ten principles are:

  1. authors should retain copyrighton their publications, which must be published under an open license such as Creative Commons;
  2. the members of the coalition should establish robust criteria and requirements for compliant open access journals and platforms;
  3. they should also provide incentives for the creation of compliant open access journals and platforms if they do not yet exist;
  4. publication fees should be covered by the funders or universities, not individual researchers;
  5. such publication fees should be standardized and capped;
  6. universities, research organizations, and libraries should align their policies and strategies;
  7. for books and monographs, the timeline may be extended beyond 2021;
  8. open archives and repositories are acknowledged for their importance;
  9. hybrid open-access journalsare not compliant with the key principle;
  10. members of the coalition should monitor and sanction non-compliance.

Member organisations

Organisations in the coalition behind Plan S include:[14]

International organizations that are members:

Plan S is also supported by:

 

Other articles on Open Access on this Open Access Journal Include:

MIT, guided by open access principles, ends Elsevier negotiations, an act followed by other University Systems in the US and in Europe

 

Open Access e-Scientific Publishing: Elected among 2018 Nature’s 10 Top Influencers – ROBERT-JAN SMITS: A bureaucrat launched a drive to transform science publishing

 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

Mozilla Science Lab Promotes Data Reproduction Through Open Access: Report from 9/10/2015 Online Meeting

 

Elsevier’s Mendeley and Academia.edu – How We Distribute Scientific Research: A Case in Advocacy for Open Access Journals

 

The Fatal Self Distraction of the Academic Publishing Industry: The Solution of the Open Access Online Scientific Journals
PeerJ Model for Open Access Scientific Journal
“Open Access Publishing” is becoming the mainstream model: “Academic Publishing” has changed Irrevocably
Open-Access Publishing in Genomics

 

 

 

 

 

 

 

 

 

 

 

 

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Recent Grim COVID-19 Statistics in U.S. and Explanation from Dr. John Campbell: Why We Need to be More Proactive

Reporter: Stephen J. Williams, Ph.D.

In case you have not been following the excellent daily YouTube sessions on COVID-19 by Dr. John Campbell I am posting his latest video on how grim the statistics have become and the importance of using proactive measures (like consistent use of facial masks, proper social distancing) instead of relying on reactive measures (e.g. lockdowns after infection spikes).  In addition, below the video are some notes from his presentation and some links to sites discussed within the video.

 

Notes from the video:

  • approaching 5 million confirmed cases in US however is probably an underestimation
  • 160,00 deaths as of 8/08/2020

From the University of Washington Institute for Health Metrics and Evaluation in Seattle WA

  • 295,000 US COVID-19 related deaths estimated by December 1, 2020
  • however if 95% of people in US consistently and properly wear masks could save 66,000 lives
  • however this will mean a remaining 228,271 deaths which is a depressing statistic
  • Dr. John Campbell agrees with Dr. Christopher Murray, director of the Institute for Health Metrics that “people’s inconsistent use of these measures (face masks, social distancing) is a serious problem”
  • States with increasing transmission like Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia are suggested to have a lockdown when death rate reaches 8 deaths per million population however it seems we should be also focusing on population densities rather than geographic states
  • Dr. Campbell and Dr. Murray stress more proactive measures than reactive ones like lockdowns
  • if mask usage were to increase to 95% usage reimposition to shutdown could be delayed 6 to 8 weeks

 

New IHME COVID-19 Forecasts See Nearly 300,000 Deaths by December 1

SEATTLE (August 6, 2020) – America’s COVID-19 death toll is expected to reach nearly 300,000 by December 1; however, consistent mask-wearing beginning today could save about 70,000 lives, according to new data from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine.The US forecast totals 295,011 deaths by December. As of today, when, thus far, 158,000 have died, IHME is projecting approximately 137,000 more deaths. However, starting today, if 95% of the people in the US were to wear masks when leaving their homes, that total number would decrease to 228,271 deaths, a drop of 49%. And more than 66,000 lives would be saved.Masks and other protective measures against transmission of the virus are essential to staying COVID-free, but people’s inconsistent use of those measures is a serious problem, said IHME Director Dr. Christopher Murray.

“We’re seeing a rollercoaster in the United States,” Murray said. “It appears that people are wearing masks and socially distancing more frequently as infections increase, then after a while as infections drop, people let their guard down and stop taking these measures to protect themselves and others – which, of course, leads to more infections. And the potentially deadly cycle starts over again.”

Murray noted that there appear to be fewer transmissions of the virus in Arizona, California, Florida, and Texas, but deaths are rising and will continue to rise for the next week or two. The drop in infections appears to be driven by the combination of local mandates for mask use, bar and restaurant closures, and more responsible behavior by the public.

“The public’s behavior had a direct correlation to the transmission of the virus and, in turn, the numbers of deaths,” Murray said. “Such efforts to act more cautiously and responsibly will be an important aspect of COVID-19 forecasting and the up-and-down patterns in individual states throughout the coming months and into next year.”

Murray said that based on cases, hospitalizations, and deaths, several states are seeing increases in the transmission of COVID-19, including Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia.

“These states may experience increasing cases for several weeks and then may see a response toward more responsible behavior,” Murray said.

In addition, since July 15, several states have added mask mandates. IHME’s statistical analysis suggests that mandates with no penalties increase mask wearing by 8 percentage points. But mandates with penalties increase mask wearing by 15 percentage points.

“These efforts, along with media coverage and public information efforts by state and local health agencies and others, have led to an increase in the US rate of mask wearing by about 5 percentage points since mid-July,” Murray said. Mask-wearing increases have been larger in states with larger epidemics, he said.

IHME’s model assumes that states will reimpose a series of mandates, including non-essential business closures and stay-at-home orders, when the daily death rate reaches 8 per million. This threshold is based on data regarding when states and/or communities imposed mandates in March and April, and implies that many states will have to reimpose mandates.

As a result, the model suggests which states will need to reimpose mandates and when:

  • August – Arizona, Florida, Mississippi, and South Carolina
  • September – Georgia and Texas
  • October – Colorado, Kansas, Louisiana, Missouri, Nevada, North Carolina, and Oregon.
  • November – Alabama, Arkansas, California, Iowa, New Mexico, Oklahoma, Utah, Washington, and Wisconsin.

However, if mask use is increased to 95%, the re-imposition of stricter mandates could be delayed 6 to 8 weeks on average.

Source: http://www.healthdata.org/news-release/new-ihme-covid-19-forecasts-see-nearly-300000-deaths-december-1

 

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WordCloud Visualization of LPBI’s Top Twelve Articles by Views at All Time and their Research Categories in the Ontology of PharmaceuticalIntelligence.com

Curators: Daniel Menzin, Noam Steiner-Tomer, Zach Day, Ofer Markman, PhD, Aviva Lev-Ari, PhD, RN

 

Article Name
Live Link
Views
All Time
Categories of Research 


#1



Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?





17,140Biological NetworksCANCER BIOLOGY & Innovations in Cancer TherapyCell BiologyDisease BiologyGenome BiologyImaging-based Cancer Patient ManagementInternational Global Work in PharmaceuticalLiver & Digestive Diseases ResearchMetabolomicsMolecular Genetics & PharmaceuticalNutritionPharmaceutical Industry Competitive IntelligencePharmaceutical R&D InvestmentPopulation Health ManagementProteomicsStem Cells for Regenerative MedicineTechnology Transfer: Biotech and Pharmaceutical | Tagged Adenosine triphosphateATPGlycolysisHypoxia-inducible factorsKrebLactate dehydrogenaseMammalian target of rapamycinMitochondrionWarburg Effect


#2



Recent comprehensive review on the role of ultrasound in breast cancer management





14,553Biomarkers & Medical DiagnosticsHealth Economics and Outcomes ResearchHealthcare costs and reimbursementImaging-based Cancer Patient ManagementMedical Device Therapies for Altzheimer’s DiseaseMedical Devices R&D InvestmentMedical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound | Tagged breast biopsiesbreast cancerbreast cancer managementbreast cancer screeningbreast cystbreast lesionsbreast ultrasoundmammographyMRIPersonalized medicinePETsupport breast cancertomosynthesisyale university schoolyale university school of medicine 

#3

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)


13,893Coagulation Therapy and Internal BleedingElectrophysiologyFDA Regulatory AffairsOrigins of Cardiovascular DiseasePharmacotherapy of Cardiovascular Disease | Tagged Academic Medical CenterAmsterdamAnticoagulantApixabanDabigatranDirect thrombin inhibitorDirect Xa inhibitorFood and Drug AdministrationNew England Journal of MedicineNon-steroidal anti-inflammatory drugNortheastern UniversityPRADAXAProthrombin timeRivaroxabanVTEWarfarin 

#4

Paclitaxel vs Abraxane (albumin-bound paclitaxel)cent comprehensive review on the role of ultrasound in breast cancer management


13,878BioSimilarsCANCER BIOLOGY & Innovations in Cancer TherapyDisease Biology, Small Molecules in Development of Therapeutic DrugsNanotechnology for Drug DeliveryPharmaceutical AnalyticsPharmaceutical R&D InvestmentRegulated Clinical Trials: Design, Methods, Components and IRB related issues | Tagged Abraxanealbumin-bound paclitaxelbreast cancerclinical studiesFREE paclitaxellinear PKnon-linear PKPaclitaxelPharmacokineticsPKside effectsTaxol 


#5


Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

8,367Coagulation Therapy and Internal BleedingFrontiers in Cardiology and Cardiovascular DisordersOrigins of Cardiovascular DiseasePharmacotherapy of Cardiovascular Disease, tagged Dabigatranrivaroxaban and apixaban for stroke prevention in atrial fibrillation 

#6

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

8,068Medical Devices R&D InvestmentNitric Oxide in Health and DiseaseTechnology Transfer: Biotech and Pharmaceutical | Tagged ARDSAviva Lev-AriInhaled Nitric Oxidenitric oxideprostacyclinPulmonary hypertensionRespiratory failure 
#7

Our Team

6,553LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management 
#8
Mesothelin: An early detection biomarker for cancer (By Jack Andraka)
6,545Advanced Drug Manufacturing TechnologyBio Instrumentation in Experimental Life Sciences ResearchBiological Networks, Gene Regulation and EvolutionBiomarkers & Medical DiagnosticsBioSimilarsCANCER BIOLOGY & Innovations in Cancer TherapyCancer Prevention: Research & ProgramsCell Biology, Signaling & Cell CircuitsDisease Biology, Small Molecules in Development of Therapeutic DrugsHealth Economics and Outcomes ResearchMedical Devices R&D InvestmentNanotechnology for Drug DeliveryPharmaceutical R&D InvestmentPopulation Health Management, Genetics & PharmaceuticalRegulated Clinical Trials: Design, Methods, Components and IRB related issuesTechnology Transfer: Biotech and Pharmaceutical | Tagged Blood testcarbon nanotubesearly detectionMesothelinPancreatic cancer 




#9






Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects










5,235Aortic Valve: TAVR, TAVI vs Open Heart SurgeryBiomarkers & Medical DiagnosticsCell Biology, Signaling & Cell CircuitsChemical Biology and its relations to Metabolic DiseaseCoagulation Therapy and Internal BleedingDisease Biology, Small Molecules in Development of Therapeutic DrugsMetabolomicsMitral Valve: Repair and ReplacementNitric Oxide in Health and DiseasePersonalized and Precision Medicine & Genomic ResearchPharmaceutical Industry Competitive IntelligencePharmacotherapy of Cardiovascular DiseasePopulation Health Management, Nutrition and PhytochemistryProteomics | Tagged anti-inflammatoryanti-TNFAnticoagulantAntithrombinblood flow resistancecell junctionscellular adhesionCoumadinEndothelial cellsFactor IX and IXaFactor VII and VIIaFactor VIII and Factor VIIIaFactor X and XafibrinogenfibrinolysisheparinHypoxia-inducible factorsNon-steroidal anti-inflammatory drugPartial thromboplastin timePhysiologyplasminplatelet aggregationplateletsprothrombinsoluble fibrinsubendothelial matrixThrombinthrombomodulinThrombustissue factorTNF-aVon Willebrand factorWH Seegers 
#10

Interaction of enzymes and hormones

5,173Cell Biology, Signaling & Cell CircuitsChemical Biology and its relations to Metabolic DiseaseMetabolomicsPopulation Health Management, Genetics & PharmaceuticalPopulation Health Management, Nutrition and PhytochemistryReproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics | Tagged active compoundsenzymehormoneinteractionMetabolismTherapy 

#11

Akt inhibition for cancer treatment, where do we stand today?


4,865CANCER BIOLOGY & Innovations in Cancer TherapyCell Biology, Signaling & Cell Circuits | Tagged Cancer researchcancer therapyCell BiologymTORNF-κBPI3K/AKT pathwayPTENSignal transduction 

 

#12

The History and Creators of Total Parenteral Nutrition

 

4,660

 

Disease BiologyGastroenterologyUncategorized | Tagged Amino acidsenteral nutritionNutritionTPN

 

#1

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Article #1: WordCloud by DM

#2

Recent comprehensive review on the role of ultrasound in breast cancer management

Article #2: WordCloud by NT

#3

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)

Article #3: WordCloud by ZD

#4

Paclitaxel vs Abraxane (albumin-bound paclitaxel)cent comprehensive review on the role of ultrasound in breast cancer management

Article #4: WordCloud by DM

#5

Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

Article #5: WordCloud by ZD

#6

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Article #6: WordCloud by NT

#7

Our Team

Article #7: WordCloud by DM

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The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD.

 

From CNN at https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html

Updated 8:17 AM ET, Sat June 27, 2020

(CNN)Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office. Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life. Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases. But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).
It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.
This effort by Dr. Fajgenbaum’s lab and the resultant collaborative effort shows the power and speed at which a coordinated open science effort can achieve goals. Below is the description of the phased efforts planned and completed from the CORONA website.

CORONA (COvid19 Registry of Off-label & New Agents)

Drug Repurposing for COVID-19

Our overarching vision:  A world where data on all treatments that have been used against COVID19 are maintained in a central repository and analyzed so that physicians currently treating COVID19 patients know what treatments are most likely to help their patients and so that clinical trials can be appropriately prioritized.

 

Phase 1: COMPLETED

Our team reviewed 2500+ papers & extracted data on over 9,000 COVID19 patients. We found 115 repurposed drugs that have been used to treat COVID19 patients and analyzed data on which ones seem most promising for clinical trials. This data is open source and can be used by physicians to treat patients and prioritize drugs for trials. The CDCN will keep this database updated as a resource for this global fight. Repurposed drugs give us the best chance to help COVID19 as quickly as possible! As disease hunters who have identified and repurposed drugs for Castleman disease, we’re applying our ChasingMyCure approach to COVID19.

Read our systematic literature review published in Infectious Diseases and Therapy at the following link: Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

From Fajgenbaum, D.C., Khor, J.S., Gorzewski, A. et al. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infect Dis Ther (2020). https://doi.org/10.1007/s40121-020-00303-8

The following is the Abstract and link to the metastudy.  This study was a systematic review of literature with strict inclusion criteria.  Data was curated from these published studies and a total of 9152 patients were evaluated for treatment regimens for COVID19 complications and clinical response was curated for therapies in these curated studies.  Main insights from this study were as follows:

Key Summary Points

Why carry out this study?
  • Data on drugs that have been used to treat COVID-19 worldwide are currently spread throughout disparate publications.
  • We performed a systematic review of the literature to identify drugs that have been tried in COVID-19 patients and to explore clinically meaningful response time.
What was learned from the study?
  • We identified 115 uniquely referenced treatments administered to COVID-19 patients. Antivirals were the most frequently administered class; combination lopinavir/ritonavir was the most frequently used treatment.
  • This study presents the latest status of off-label and experimental treatments for COVID-19. Studies such as this are important for all diseases, especially those that do not currently have definitive evidence from randomized controlled trials or approved therapies.

Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

Abstract

The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA. Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Read the Press Release from PennMedicine at the following link: PennMedicine Press Release

Phase 2: Continue to update CORONA

Our team continues to work diligently to maintain an updated listing of all treatments reported to be used in COVID19 patients from papers in PubMed. We are also re-analyzing publicly available COVID19 single cell transcriptomic data alongside our iMCD data to search for novel insights and therapeutic targets.

You can visit the following link to access a database viewer built and managed by Matt Chadsey, owner of Nonlinear Ventures.

If you are a physician treating COVID19 patients, please visit the FDA’s CURE ID app to report de-identified information about drugs you’ve used to treat COVID19 in just a couple minutes.

For more information on COVID19 on this Open Access Journal please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

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A Group of Leading Scientists is calling on PNAS to retract a Nobel Laureate’s paper

Reporter: Aviva Lev-Ari, PhD, RN

 

 

Mario Molina, winner of the Nobel Prize in Chemistry in 1995, was the lead author of the paper now being questioned.

A group of leading scientists is calling on PNAS to retract a paper on the effectiveness of masks, saying the study has “egregious errors” and contains numerous “verifiably false” statements.

The scientists wrote a letter to the journal editors on Thursday, asking them to retract the study immediately “given the scope and severity of the issues we present, and the paper’s outsized and immediate public impact.”

The letter follows heated criticism of two other major coronavirus studies in May, which appeared in the New England Journal of Medicine and The Lancet. Both papers were retracted amid concerns that a rush to publish coronavirus research had eroded safeguards at prestigious journals.

The study now under fire was published on June 11 in the journal Proceedings of the National Academy of Sciences. The lead author is Mario Molina, who won the Nobel Prize in Chemistry in 1995, with two other scientists, for finding a link between man-made chemicals and depletion of the atmosphere’s ozone layer.

Read More

REFERENCES

Mario J. Molina

 

Original Article under fire

Identifying airborne transmission as the dominant route for the spread of COVID-19

Renyi ZhangYixin LiAnnie L. ZhangYuan Wang, and Mario J. Molina
  1. Contributed by Mario J. Molina, May 16, 2020 (sent for review May 14, 2020; reviewed by Manish Shrivastava and Tong Zhu)

 

Two major study retractions in one month have left researchers wondering if the peer review process is broken.

SOURCE

https://www.nytimes.com/2020/06/14/health/virus-journals.html

 

Scientists Letter to the Editor of PNAS

Click to access e7ef6fc5-c7c6-42f1-922b-a7788161af37.pdf

SOURCE

From: eScience <escienceinfo@comcast.net>

Subject: A group of leading scientists is calling on PNAS to retract a Nobel Laureate’s paper

Date: June 21, 2020 at 5:30:40 PM PDT

To: mfeldman@stanford.edu

Reply-To: escienceinfo@comcast.net

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MIT, guided by open access principles, ends Elsevier negotiations, an act followed by other University Systems in the US and in Europe

Institute ends negotiations for a new journals contract in the absence of a proposal aligning with the MIT Framework for Publisher Contracts.

MIT Libraries
June 11, 2020

MIT, Elsevier Stop Talking

The Massachusetts Institute of Technology has ended its journal subscription contract negotiations with Elsevier, according to the school.

It adds that the publisher did not provide a contract that was in line with the MIT Framework for Publisher Contracts, which advocates for the open sharing of research and educational material. Part of that policy, Inside Higher Ed notes, is the requirement that researchers must be able to retain copyright of their work, and it suspects that “may have been a sticking point in MIT’s negotiations with Elsevier.”

“I am disappointed that we were not able to reach a contract with Elsevier that honors the principles of the MIT Framework, but I am proud knowing that the MIT community — as well as hundreds of colleagues across the country — stand by the importance of these principles for advancing the public good and the progress of science,” Chris Bourg, director of the MIT Libraries, says in a statement. “In the face of these unprecedented global challenges, equitable and open access to knowledge is more critical than ever.”

Other institutions like the University of California as well as the State University of New York and the University of North Carolina have similarly ended contract negotiations with Elsevier, IHE adds.

https://www.genomeweb.com/scan/mit-elsevier-stop-talking?utm_source=Sailthru&utm_medium=email&utm_campaign=Scan%20Fri%202020-06-12&utm_term=The%20Scan%20Bulletin#.XwykwZNKgdU

http://news.mit.edu/2020/guided-by-open-access-principles-mit-ends-elsevier-negotiations-0611

 

See

University of California accounts for nearly 10% of all published research in the United States. It’s also a significant partner of Elsevier, which publishes about 18% of all UC output and collects more than 25% of the university’s $40-million overall subscription budget.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/12/09/university-of-california-accounts-for-nearly-10-of-all-published-research-in-the-united-states-its-also-a-significant-partner-of-elsevier-which-publishes-about-18-of-all-uc-o/

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US Responses to Coronavirus Outbreak Expose Many Flaws in Our Medical System


US Responses to Coronavirus Outbreak Expose Many Flaws in Our Medical System

Curator: Stephen J. Williams, Ph.D.

The  coronavirus pandemic has affected almost every country in every continent however, after months of the novel advent of novel COVID-19 cases, it has become apparent that the varied clinical responses in this epidemic (and outcomes) have laid bare some of the strong and weak aspects in, both our worldwide capabilities to respond to infectious outbreaks in a global coordinated response and in individual countries’ response to their localized epidemics.

 

Some nations, like Israel, have initiated a coordinated government-private-health system wide action plan and have shown success in limiting both new cases and COVID-19 related deaths.  After the initial Wuhan China outbreak, China closed borders and the government initiated health related procedures including the building of new hospitals. As of writing today, Wuhan has experienced no new cases of COVID-19 for two straight days.

 

However, the response in the US has been perplexing and has highlighted some glaring problems that have been augmented in this crisis, in the view of this writer.    In my view, which has been formulated after social discussion with members in the field ,these issues can be centered on three major areas of deficiencies in the United States that have hindered a rapid and successful response to this current crisis and potential future crises of this nature.

 

 

  1. The mistrust or misunderstanding of science in the United States
  2. Lack of communication and connection between patients and those involved in the healthcare industry
  3. Socio-geographical inequalities within the US healthcare system

 

1. The mistrust or misunderstanding of science in the United States

 

For the past decade, anyone involved in science, whether directly as active bench scientists, regulatory scientists, scientists involved in science and health policy, or environmental scientists can attest to the constant pressure to not only defend their profession but also to defend the entire scientific process and community from an onslaught of misinformation, mistrust and anxiety toward the field of science.  This can be seen in many of the editorials in scientific publications including the journal Science and Scientific American (as shown below)

 

Stepping Away from Microscopes, Thousands Protest War on Science

Boston rally coincides with annual American Association for the Advancement of Science (AAAS) conference and is a precursor to the March for Science in Washington, D.C.

byLauren McCauley, staff writer

Responding to the troubling suppression of science under the Trump administration, thousands of scientists, allies, and frontline communities are holding a rally in Boston’s Copley Square on Sunday.

#standupforscience Tweets

 

“Science serves the common good,” reads the call to action. “It protects the health of our communities, the safety of our families, the education of our children, the foundation of our economy and jobs, and the future we all want to live in and preserve for coming generations.”

It continues: 

But it’s under attack—both science itself, and the unalienable rights that scientists help uphold and protect. 

From the muzzling of scientists and government agencies, to the immigration ban, the deletion of scientific data, and the de-funding of public science, the erosion of our institutions of science is a dangerous direction for our country. Real people and communities bear the brunt of these actions.

The rally was planned to coincide with the annual American Association for the Advancement of Science (AAAS) conference, which draws thousands of science professionals, and is a precursor to the March for Science in Washington, D.C. and in cities around the world on April 22.

 

Source: https://www.commondreams.org/news/2017/02/19/stepping-away-microscopes-thousands-protest-war-science

https://images.app.goo.gl/UXizCsX4g5wZjVtz9

 

https://www.washingtonpost.com/video/c/embed/85438fbe-278d-11e7-928e-3624539060e8

 

 

The American Association for Cancer Research (AACR) also had marches for public awareness of science and meaningful science policy at their annual conference in Washington, D.C. in 2017 (see here for free recordings of some talks including Joe Biden’s announcement of the Cancer Moonshot program) and also sponsored events such as the Rally for Medical Research.  This patient advocacy effort is led by the cancer clinicians and scientific researchers to rally public support for cancer research for the benefit of those affected by the disease.

Source: https://leadingdiscoveries.aacr.org/cancer-patients-front-and-center/

 

 

     However, some feel that scientists are being too sensitive and that science policy and science-based decision making may not be under that much of a threat in this country. Yet even as some people think that there is no actual war on science and on scientists they realize that the public is not engaged in science and may not be sympathetic to the scientific process or trust scientists’ opinions. 

 

   

From Scientific American: Is There Really a War on Science? People who oppose vaccines, GMOs and climate change evidence may be more anxious than antagonistic

 

Certainly, opponents of genetically modified crops, vaccinations that are required for children and climate science have become louder and more organized in recent times. But opponents typically live in separate camps and protest single issues, not science as a whole, said science historian and philosopher Roberta Millstein of the University of California, Davis. She spoke at a standing-room only panel session at the American Association for the Advancement of Science’s annual meeting, held in Washington, D.C. All the speakers advocated for a scientifically informed citizenry and public policy, and most discouraged broadly applied battle-themed rhetoric.

 

Source: https://www.scientificamerican.com/article/is-there-really-a-war-on-science/

 

      In general, it appears to be a major misunderstanding by the public of the scientific process, and principles of scientific discovery, which may be the fault of miscommunication by scientists or agendas which have the goals of subverting or misdirecting public policy decisions from scientific discourse and investigation.

 

This can lead to an information vacuum, which, in this age of rapid social media communication,

can quickly perpetuate misinformation.

 

This perpetuation of misinformation was very evident in a Twitter feed discussion with Dr. Eric Topol, M.D. (cardiologist and Founder and Director of the Scripps Research Translational  Institute) on the US President’s tweet on the use of the antimalarial drug hydroxychloroquine based on President Trump referencing a single study in the International Journal of Antimicrobial Agents.  The Twitter thread became a sort of “scientific journal club” with input from international scientists discussing and critiquing the results in the paper.  

 

Please note that when we scientists CRITIQUE a paper it does not mean CRITICIZE it.  A critique is merely an in depth analysis of the results and conclusions with an open discussion on the paper.  This is part of the normal peer review process.

 

Below is the original Tweet by Dr. Eric Topol as well as the ensuing tweet thread

 

https://twitter.com/EricTopol/status/1241442247133900801?s=20

 

Within the tweet thread it was discussed some of the limitations or study design flaws of the referenced paper leading the scientists in this impromptu discussion that the study could not reasonably conclude that hydroxychloroquine was not a reliable therapeutic for this coronavirus strain.

 

The lesson: The public has to realize CRITIQUE does not mean CRITICISM.

 

Scientific discourse has to occur to allow for the proper critique of results.  When this is allowed science becomes better, more robust, and we protect ourselves from maybe heading down an incorrect path, which may have major impacts on a clinical outcome, in this case.

 

 

2.  Lack of communication and connection between patients and those involved in the healthcare industry

 

In normal times, it is imperative for the patient-physician relationship to be intact in order for the physician to be able to communicate proper information to their patient during and after therapy/care.  In these critical times, this relationship and good communication skills becomes even more important.

 

Recently, I have had multiple communications, either through Twitter, Facebook, and other social media outlets with cancer patients, cancer advocacy groups, and cancer survivorship forums concerning their risks of getting infected with the coronavirus and how they should handle various aspects of their therapy, whether they were currently undergoing therapy or just about to start chemotherapy.  This made me realize that there were a huge subset of patients who were not receiving all the information and support they needed; namely patients who are immunocompromised.

 

These are patients represent

  1. cancer patient undergoing/or about to start chemotherapy
  2. Patients taking immunosuppressive drugs: organ transplant recipients, patients with autoimmune diseases, multiple sclerosis patients
  3. Patients with immunodeficiency disorders

 

These concerns prompted me to write a posting curating the guidance from National Cancer Institute (NCI) designated cancer centers to cancer patients concerning their risk to COVID19 (which can be found here).

 

Surprisingly, there were only 14 of the 51 US NCI Cancer Centers which had posted guidance (either there own or from organizations like NCI or the National Cancer Coalition Network (NCCN).  Most of the guidance to patients had stemmed from a paper written by Dr. Markham of the Fred Hutchinson Cancer Center in Seattle Washington, the first major US city which was impacted by COVID19.

 

Also I was surprised at the reactions to this posting, with patients and oncologists enthusiastic to discuss concerns around the coronavirus problem.  This led to having additional contact with patients and oncologists who, as I was surprised, are not having these conversations with each other or are totally confused on courses of action during this pandemic.  There was a true need for each party, both patients/caregivers and physicians/oncologists to be able to communicate with each other and disseminate good information.

 

Last night there was a Tweet conversation on Twitter #OTChat sponsored by @OncologyTimes.  A few tweets are included below

https://twitter.com/OncologyTimes/status/1242611841613864960?s=20

https://twitter.com/OncologyTimes/status/1242616756658753538?s=20

https://twitter.com/OncologyTimes/status/1242615906846547978?s=20

 

The Lesson:  Rapid Communication of Vital Information in times of stress is crucial in maintaining a good patient/physician relationship and preventing Misinformation.

 

3.  Socio-geographical Inequalities in the US Healthcare System

It has become very clear that the US healthcare system is fractioned and multiple inequalities (based on race, sex, geography, socio-economic status, age) exist across the whole healthcare system.  These inequalities are exacerbated in times of stress, especially when access to care is limited.

 

An example:

 

On May 12, 2015, an Amtrak Northeast Regional train from Washington, D.C. bound for New York City derailed and wrecked on the Northeast Corridor in the Port Richmond neighborhood of Philadelphia, Pennsylvania. Of 238 passengers and 5 crew on board, 8 were killed and over 200 injured, 11 critically. The train was traveling at 102 mph (164 km/h) in a 50 mph (80 km/h) zone of curved tracks when it derailed.[3]

Some of the passengers had to be extricated from the wrecked cars. Many of the passengers and local residents helped first responders during the rescue operation. Five local hospitals treated the injured. The derailment disrupted train service for several days. 

(Source Wikipedia https://en.wikipedia.org/wiki/2015_Philadelphia_train_derailment)

What was not reported was the difficulties that first responders, namely paramedics had in finding an emergency room capable of taking on the massive load of patients.  In the years prior to this accident, several hospitals, due to monetary reasons, had to close their emergency rooms or reduce them in size. In addition only two in Philadelphia were capable of accepting gun shot victims (Temple University Hospital was the closest to the derailment but one of the emergency rooms which would accept gun shot victims. This was important as Temple University ER, being in North Philadelphia, is usually very busy on any given night.  The stress to the local health system revealed how one disaster could easily overburden many hospitals.

 

Over the past decade many hospitals, especially rural hospitals, have been shuttered or consolidated into bigger health systems.  The graphic below shows this

From Bloomberg: US Hospital Closings Leave Patients with Nowhere to go

 

 

https://images.app.goo.gl/JdZ6UtaG3Ra3EA3J8

 

Note the huge swath of hospital closures in the midwest, especially in rural areas.  This has become an ongoing problem as the health care system deals with rising costs.

 

Lesson:  Epidemic Stresses an already stressed out US healthcare system

 

Please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

for more up-to-date scientific, clinical information as well as persona stories, videos, interviews and economic impact analyses

and @pharma_BI

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Lesson 7 of Cell Signaling 7 Motility: Tubulin and Tutorial Quizes for #TUBiol3373

Stephen J. Williams, Ph.D.

This lesson (lesson 7) will discuss the last type of cytoskeletal structure: microtubules and tubulin.  In addition I want to go over the last quiz answers and also introduce some new poll quizes.

I had given the lecture 7 over Canvas and each of you can download and go over the lecture but I will highlight a few slides in the lecture.

Let’s first review:

Remember that microtubules are the largest of the three cytoskeletal structures:

actin microfilaments < intermediate filaments < microtubules

This is very important to understand as the microtubules, as shown later, shuttle organelles and cellular structures like synaptic vesicles, as well as forming the centrisome and spindle fibers of mitosis.

 

 

 

 

 

 

 

 

 

 

 

 

 

Now remember the quiz question from last time

Remember that actin monomers (the G actin binds ATP)  while tubulin, the protein which makes up the microtubules binds GTP {although it is a little more complex than that as the following diagram shows}

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

See how the growth at the plus end is dependent on tubulin heterodimer GTP while when GDP is only bound to tubulin (both forms) you get a destabilization of the plus end and removal of tubulin dimers (catastrophe) if there is no source of tubulin GTP dimers (alpha tubulin GTP with beta tubulin GTP).

 

 

 

 

Also remember that like actin microfilaments you can have treadmilling (the plus end  continues growing while minus end undergoes catasrophe).  The VIDEO below describes these processes:

 

 

 

Certain SNPs and mutants of tubulin are found and can result in drastic phenotypic changes in microtubule stability and structure. Below is an article where a mutation in tubulin can result in microtubule catastrophe or destabilization of microtubule structures.

 

From: A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics;, E.A. Geyer et al..; elife 2015;4:e10113

Abstract

Microtubule dynamic instability depends on the GTPase activity of the polymerizing αβ-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in αβ-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized αβ-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of αβ-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking.

https://doi.org/10.7554/eLife.10113.001

 

Remember the term allosterism: change in the affinity for binding of a ligand or substrate that is caused by the binding of another ligand away from the active site (for example like 2,3 DPG effect on oxygen binding to hemoglobin

 

Cellular transport of organelles and vesicles: a function of microtubules

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Now the above figure (figure 9 in your Powerpoint) shows the movement of organelles and vesicles in two different types of cells along microtubules.

Note the magenta arrow which goes from the nucleus toward the plus end of the microtubule (at cell membrane) is referred to as anterograde transport and is movement away from center of cell to the periphery.  Retrograde transport is movement of organelles and vesicles from periphery of cell to the center of the cell.

Note that kinesin is involved in anterograde transport while dyenin is involved in retrograde transport

Also refer to the Wiki page which shows a nice cartoon of this walking down a microtubule on the right hand side of the page

https://en.wikipedia.org/wiki/Axonal_transport

 

 

 

 

 

 

 

Cilia; a cellular structure of microtubules (we will talk about cilia later)

for more information on structure of Cillia please see https://www.ncbi.nlm.nih.gov/books/NBK21698/

This is from a posting by Dr. Larry Bernstein of Yale University at https://pharmaceuticalintelligence.com/2015/11/04/cilia-and-tubulin/

 

RESEARCHERS VIDEO AND MEASURE TUBULIN TRANSPORT IN CILIA FOR THE FIRST TIME.

http://health-innovations.org/2015/01/27/researchers-image-and-measure-tubulin-transport-in-cilia/

 

 

https://michellepetersen76.files.wordpress.com/2015/01/uga-researchers-image-and-measure-tubulin-transport-in-cilia-healthinnovations1.png

 

Defective cilia can lead to a host of diseases and conditions in the human body, from rare, inherited bone malformations to blindness, male infertility, kidney disease and obesity. It is known that these tiny cell organelles become deformed and cause these diseases because of a problem related to their assembly, which requires the translocation of vast quantities of the vital cell protein tubulin. What they didn’t know was how tubulin and another cell organelle known as flagella fit into the process.

Now, a new study from University of Georgia shows the mechanism behind tubulin transport and its assembly into cilia, including the first video imagery of the process. The study was published in the Journal of Cell Biology.

Cilia are found throughout the body, so defects in cilia formation affect cells that line airways, brain ventricles or the reproductive track.  One of the main causes of male infertility is the cilia won’t function properly.

The team used total internal reflection fluorescence microscopy to analyze moving protein particles inside the cilia of Chlamydomonas reinhardtii, a green alga widely used as a model for cilia analysis.

The team exploited the natural behaviour of the organism, which is to attach by its cilia to a smooth surface, such as a microscope glass cover. This positions the cilia within the 200-nanometer reach of the total internal reflection fluorescence microscope allowing for the imaging of individual proteins as they move inside the cilia.  A video explaining the process was published along with the study.

Tubulin is transported by this process called intraflagellar transport, or IFT.  Though it has long been suspected in the field and there was indirect evidence to support the theory, this is the first time it has been shown directly, through live imaging, that IFT does function as a tubulin pump.  The team observed that about 400,000 tubulin dimers need to be transported within 60 minutes to assemble a single cilium. Being able to see tubulin moving into cilia allowed for first insights into how this transport is regulated to make sure cilia will have the correct size.

The new findings are expected to have wide implications for a variety of diseases and conditions related to cilia defects in the body.  The team state that they are on the very basic side of this research.  But because more and more diseases are being connected to cilia-related conditions, including obesity and even diabetes, the number of people working on cilia has greatly expanded over the last few years.

 

So here are the answer to last weeks polls

  1. Actin filaments are the SMALLEST of the cytoskeletal structures.  As shown in this lecture it is tubulin that binds GTP.  Actin binds ATP.
  2.  ARP2/3 or actin related proteins 2 and 3 are nucleating proteins that assist in initiating growth of branched chain micofiliment networks.  Formins are associated with unbranched actin formations.
  3.  The answer is GAPs or GTPase activating proteins.  Remember RAS in active state when GTP is bound and when you hydrolyze the GTP to GDP Ras is inactive state

 

 

 

 

 

4.  Okay so I did a type here but the best answer was acetylcholinesterase (AchE) degrading acetylcholine.  Acetylcholinesterase degrades the neurotransmitter acetylcholine into choline and acetate not as I accidentally put into acetylCoA.  The freed choline can then be taken back up into the presynaptic neuron and then, with a new acetyl group (with Coenzyme A) will form acetylcholine.

 

Synthesis of the neurotransmitter acetylcholine

 

 

 

The neuromuscular junction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thanks to all who took the quiz.  Remember it is for your benefit.

 

 

 

 

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