Stem Cell Clinic

This Womans Toothache Medication Actually Turned Her Blood Blue – Prevention.com

The New England Journal of Medicine 2019.

When you take medication, you expect that it will work to make you feel better. What you dont expect is that it will turn you blue. Unfortunately, thats what happened to one woman in Rhode Islandand she ended up in a case report.

The 25-year-old woman, who was not publicly identified, went to an emergency room in Providence, Rhode Island, with generalized weakness, fatigue, shortness of breath, according to The New England Journal of Medicine. She was also concerned about the fact that she was, you know, turning blue.

After evaluating her, the womans doctors determined that she was turning blue thanks to a numbing agent she had used. She reported having used large amounts of topical benzocaine the night before for a toothache, the case report authors wrote.

The woman was diagnosed with methemoglobinemia, a blood disorder where an abnormal amount of methemoglobin is produced. Methemoglobin is a form of hemoglobin, the protein in red blood cells that carries and distributes oxygen to the body, according to the U.S. National Library of Medicine. However, it is a dark pigment that causes blood to appear very dark in color, says Jamie Alan, PhD, an assistant professor of pharmacology and toxicology at Michigan State University.

There is normally a small percentage of this compound in the red blood cells, however it is kept very low, she explains. But certain compounds like benzocaine can accelerate the formation of methemoglobin. The result? Hemoglobin cannot successfully release critical oxygen to the tissues, so the body turns blue.

Methemoglobinemia is usually either inherited from your family or caused by exposure to certain chemicals, medicines, or foods, the U.S. National Library of Medicine says. Those can include anesthetics like benzocaine, nitrobenzene (which is used in some drugs, pesticides, and dyes), certain antibiotics like dapsone and chloroquine, and nitrates (which are used as additives to keep meat from spoiling).

Benzocaine and similar compounds used to be in infant and childrens teething gels, but it was taken out of those products because of this exact thing, Alan says.

A bluish tint to the skin is a major symptom of methemoglobinemia, but a person can also have a headache, giddiness, altered mental state, fatigue, shortness of breath, and lack of energy.

Methemoglobinemia is very harmful, Alan says. The problem is that methemoglobinemia reduces the ability of your red blood cells to carry oxygen. This can lead to heart attack, stroke, organ damage, and death, she adds.

A medication called methylene blue is used to treat severe cases of methemoglobinemia and ascorbic acid (aka vitamin C) can also be used to reduce the amount of methemoglobin in a patients blood, the U.S. National Library of Medicine says. Undergoing hyperbaric oxygen therapy, a blood cell transfusion, and exchange transfusions (where a persons blood is removed and replaced) can also be helpful.

People dont usually need treatment for mild cases of methemoglobinemia, thoughthey should just avoid the medication or chemical that caused their condition in the first place. The half life of methemoglobin is 55 minutes, meaning the condition will usually reverse in hours, Alan says. In the meantime, the patient needs supportive care with oxygen.

If you suspect youve developed methemoglobinemia, see a doctor immediately.

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SCD: Hypertension Tablet May Prevent Vaso-Occlusive Crisis, Study Says – Sickle Cell Anemia News

A medication used to treat high blood pressure, called valsartan, may help decrease the stickiness of red blood cells and reduce the risk of vaso-occlusive crisis in people with sickle cell disease (SCD), a research study suggests.

The study, Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells, was published in the journal PLOS One.

SCD is characterized by the production of abnormal hemoglobin proteins, resulting in red blood cells (RBCs) that are stickier and more prone to aggregate together and to blood vessel walls. When such RBC clumps are formed, they can cause painful blockage of blood vessels, a condition that is called vaso-occlusive crisis(VOC).

This blockage process is in part due to abnormally high activation of cell surface proteins, including the intercellular adhesion molecule-4 (or ICAM-4) that mediates RBC clumps binding to blood vessel walls.

Previous studies have suggested that the hormone epinephrine (commonly known as adrenaline) can also contribute to the increased production of ICAM-4 molecules at the surface of RBCs in response to physical stress.

This research led scientists from the University of Connecticut to explore whether using an inhibitor to block the signals of epinephrine could be beneficial in preventing vaso-occlusive episodes. They evaluated the impact of valsartan, an approved oral therapy to reduce blood pressure and treat congestive heart failure, which is sold with the brand name Diovan by Novartis.

The study enrolled five healthy volunteers, three patients with sickle cell trait (SCT, who have both normal and mutated hemoglobin variants), and six patients with diagnosed SCD, who provided blood samples for analysis.

The team used a technique called atomic force microscopy to collect information on the stickiness status of blood cells. This approach can specifically determine the binding force between ICAM-4 at the surface of RBCs to the blood vessel walls.

The researchers found that the binding frequency of ICAM-4 to vessel walls increased in the presence of epinephrine in all three groups. We observed that epinephrine significantly increased the surface percentage of active ICAM-4 receptors, they wrote.

Treatment with valsartan significantly decreased ICAM-4-binding to 10.41% from 17% in RBC samples of healthy volunteers. Similar results were seen in both SCT and SCD samples, with valsartan lowering epinephrine-induced levels of ICAM-4 to 6.87% from 17.11% in SCT blood samples, and to 10.07% from 20.58% in SCD samples.

Supported by these findings, the researchers said that administration of valsartan could mitigate the vaso-occlusive consequences of SCD and may open new avenues for the development of novel therapeutic targets.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

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Celsius Therapeutics Signs Multiple Agreements with Academic Institutions to Access Samples for the Identification of Novel Targets in Immune…

Sept. 19, 2019 12:30 UTC

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Celsius Therapeutics, a company focused on bringing personalized medicine to patients with cancer, autoimmunity and other complex diseases, today announced the signing of collaboration agreements with the Parker Institute for Cancer Immunotherapy (San Francisco, USA), Institut Gustave Roussy (Paris, France) and the University Health Network (Toronto, Canada). Under these three agreements, Celsius will apply its proprietary single-cell genomics platform to tissue samples from patients receiving immune checkpoint inhibitor therapies for triple negative breast cancer, bladder cancer and kidney cancer, respectively. The goal of these collaborations is the discovery of novel molecular mechanisms and targets for drug discovery.

We are delighted to collaborate with these premier academic groups, given their disease expertise and their commitment to cutting-edge research and improving the lives of cancer patients, said Tariq Kassum, M.D., chief executive officer of Celsius. The heterogeneity of response in immunotherapy studies suggests that a deeper understanding of disease biology and patient subpopulations is needed to fully realize the potential of this approach. These new partnerships highlight our interest in broadly engaging the academic community to better elucidate the cellular ecosystem of cancer, with the ultimate goal of translating new insights into novel precision medicines for patients.

Under these agreements, Celsius will apply its platform approach to generate single-cell data from patient biopsy samples taken pre- and post-treatment with checkpoint inhibitors. In each case, Celsius retains the ability to integrate the clinical information and single-cell genomics data generated from the studies into its growing database. The company plans to utilize its machine learning algorithms and functional genomics capabilities to rapidly identify and prioritize targets for drug discovery.

Our integrated platform allows Celsius to obtain samples from anywhere in the world, process them in a highly industrialized manner and rapidly deploy a suite of machine learning algorithms to identify new drug targets in relevant cell types, said Christoph Lengauer, Ph.D., co-founder and chief scientific officer of Celsius. Across just these three collaborations, we expect to analyze more than 300 longitudinal samples from over 150 patients, a scale that is unprecedented for single-cell genomics. Combined with the associated clinical data that is being gathered from these studies, we are building a massive database that will be leveraged to develop novel precision medicines.

About Celsius Therapeutics

Celsius Therapeutics is charting a new course of target and drug discovery by applying a systematic approach to single-cell sequencing of patient tissue, combining massive datasets, complex algorithms, and machine learning to discover first-in-class precision therapies with a transformative impact on the lives of patients with autoimmune diseases and cancer. Celsius was launched in 2018, is backed by Third Rock Ventures and GV (formerly Google Ventures), and is based in Cambridge, Mass. For more information, please visit http://www.celsiustx.com.

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A compound may improve pancreatic cancer survival rate, scientists find – PhillyVoice.com

Scientists have discovered a compound could help slow down pancreatic cancer by targeting proteins that promote metastatic cells.

Researchers at Johns Hopkins Medicine found that the compound, 4-HAP, reduced tumors in mice and could improve survival for pancreatic cancer patients.

According to the National Cancer Institute, 73,554 people in the U.S. have pancreatic cancer and only 9.3 percent of those diagnosed survive five or more years.

The study, published in the journal Cancer Research, examined two types of proteins, mechanoresponsive proteins and non-mechanoresponsive proteins.

Scientists looked at a total of seven proteins, including nonmuscle myosin IIA, IIB and IIC; alpha-actinin 1 and 4; and filamin A and B. The mechanoresponsive proteins IIA, IIC, active actinin 4 and filamin B increased cancer tissue in the pancreas by over-producing the cancer cells.

Scientists found that even though the protein nonmuscle myosin IIC was found to be low in the cancer cells it had a profound impact on the cell's overall function. When they exposed these proteins to 4-HAP, it increased the cells' overall structure and stiffened the cells.

The group then tested 4-HAP as a treatment for pancreatic cancer by using a mouse model that had human pancreatic tissue implanted in the mouse's liver. They found that the tumors reduced by 50 percent.Researchers believe that treating the cells with the compound will allow scientists to target cancerous cells while protecting the healthy cells in the pancreas.

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Making Sense of Medicine: The meaning of life | Lifestyles – The Daily News of Newburyport

Ancient Greek philosopher Aristotle made what may be the first known attempt to define life. He said that something is alive if it grows, is animated and nourishes itself. A more recent definition suggests the important characteristics being the capacity for growth, reproduction, functional activity and continual change preceding death.

There are other attempts, but they all fail in some way. Both of these definitions, for example, would consider fire to be alive and mules, which are born sterile, not to be alive. All that said, most of us have an instinctive understanding of what it means to be alive. If you see a bug or a bird or even an amoeba, you are certain it possesses life.

None of this, however, tells us anything about how life first started or whence it came. Again, there are countless thoughts about this, such as life resulting from a stroke of lightning zapping just the right elements at the right time. Some believe radiation was the instigator, and some suggest that early life forms arrived on Earth aboard rocks from outer space. No one knows for sure.

However, there is research that shows the possibility of creating the basic building blocks of life, amino acids and proteins, from basic inorganic compounds by simulating the conditions that must have prevailed at Earths beginning. And research in cell biology has established some remarkably likely facts about how we became human.

Its all about cells?

A cell is the smallest functional unit of every living thing; we are made from trillions of them. The cell has a jelly-like liquid called cytoplasm enclosed in a membrane. Within the cytoplasm are structures with functions similar to our organs, and they are called organelles, or little organs, with names like mitochondria, lysosomes and others. With these, the cell can perform for itself all the same functions that we need for life: respiration, reproduction, waste removal, energy conversion and more.

Some cells have an organelle called the nucleus inside the membrane, as well. These are called eukaryotes, meaning to have a true (eu) nucleus (kary). A nucleus is important, as it contains most of the cells genes that are part of its DNA molecules; DNA is packaged in the form of chromosomes in order to fit into the nucleus. Other cells are called prokaryotes, meaning to exist before (pro) a nucleus occurs; bacteria are prokaryotes. They, too, have DNA, but its located directly in the cytoplasm.

The organelles are like computer programs, apps, in that they can perform specific functions, but they have to be started by a brain. The important fact is that cells are intelligent, and their brain is the cell membrane. The membrane includes tens of thousands of IMPs (integral membrane proteins) that receive and send signals from and to their environment, directing the organelles to do their thing and so create the complex behavior of a living cell.

A brief timeline

Earth was created about 41/2 billion years ago, but it wasnt until 3.8 billion years ago that single-cell prokaryotes appeared. That is, the bacteria have been here a seriously long time.

The eukaryotes evolved from prokaryotes, appearing about 21/2 billion years ago, and the kind of life forms we experience today are only about 600 million years old. There were no mammals until about 200 million years ago, and we, Homo sapiens, have been around for a mere 200,000 years. So, what happened to get from the first eukaryotes to us?

Community building

For the first 3 billion years that there was life on Earth, it consisted of independent single cells, monads. They were bacteria, they were algae, they were protozoans and some fungi. It was long thought that they were solitary.

Research has shown, however, that the signals they use to organize their own physiology can be released into their environment, creating a kind of long-distance communication. For example, amoebas consuming food release a particular molecule that informs other amoebas of a supply of food to which many are then drawn. Other signal molecules like hormones were in use by these single-cell critters, as well.

As time passed, monads learned to increase the number of IMPs in their membrane and started to assemble themselves into close-knit cellular communities for survival. As the size and complexity of these multicellular communities grew, they became highly organized and parceled out specific functions to specialized groups of cells: forming body tissues and organs, building nervous and immune systems, etc. And so there evolved the complex organisms we recognize as plants and animals.

As the more complex animals evolved, there were specialized cells that became responsible for monitoring and regulating the flow of signaling among other cells. This central information processor became the brain that controls the overall interaction and behavior of all the cells in the body. We commonly believe that our mind is the same as our brain and is located our head. However, neuroscientist and pharmacologist Candace Perts elegant experiments showed that the mind is distributed throughout the body.

We as humans, and, in fact, all mammals and some others, are an advanced stage of this kind of community organization. Of special interest is the development of a region of the brain called the prefrontal cortex. In this, we find the capacity for thinking, planning and decision-making, as well as the seat of self-consciousness.

And so ...

Cellular communities continue to evolve, giving new perspectives on what it means to be alive.

Bob Keller maintains a holistic practice in Newburyport. He offers medical massage therapy for pain relief, as well as psychological counseling, dream work and spiritual direction. Many patients call him Dr. Bob and accuse him of doing miracles, but he is not a medical doctor nor a divinity. His expertise is medical massage therapy, understanding this miracle we call the human being. He can be reached at 978-465-5111 or rk2name@gmail.com.

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#E#ECTRIMS2019 – In Progressive MS, ATA188 Showing Safety and Hints of Effectiveness in Phase 1 Trial – Multiple Sclerosis News Today

People with progressive forms of multiple sclerosis (MS) and past exposure to the Epstein-Barr virus are responding to a potentialimmunotherapy known as ATA188, tolerating the treatment well and with signs that suggest effectiveness, early updated data from an ongoing Phase 1 trial show.

The research, Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis, was presented at the 35thCongress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)held in Stockholm (Sept. 1113).

Infection with the Epstein-Barr virus (EBV)is linked to a greater susceptibility to MS. EBV promotes the expansion of immune B-cells, which can produce autoantibodies against myelin, the protective coating of nerve fibers that is progressively damaged in this disease.

People with MS are believed to be deficient in T-cells, which would normally kill EBV-infected B-cells.

ATA188, byAtara Biotherapeutics, is designed to overcome this deficiency by providing allogeneic immune T-cells that target EBV in B-cells. (Allogeneic cells are from donors with no family or genetic relationship to the recipient; an advantage is that these cells are available immediately, or off-the-shelf.)

The Phase 1 study (NCT03283826), taking place in the U.S. and Australia, is assessing the safety and efficacy of ATA188 in progressive MS patents here, a near equal mix of secondary progressive disease (SPMS) and primary progressive MS (PPMS) ages 18 to 66. Patients are assigned to four groups, each testing a different cell dose: 5 x 106, 1 x 107, 2 x 107, and 4 x 107.

Clinically recognized MS scales are assessing ATA188 effectiveness at baseline (study start), and at roughly 3, 6, and 12 months after initial treatment. These include the Expanded Disability Status Scale(EDSS), the Fatigue Severity Score, the MS Impact Scale, the Timed 25-Foot Walk (T25FW) where patients walk 25 feet as quickly and safely as possible the 9-Hole Peg Test of hand and finger skills, 12-Item MS Walking Scale, and tests of visual acuity.

Early data previously reportedshowed that treatment with ATA188 was well-tolerated across the four groups, with no evidence of cytokine release syndrome(a form of systemic inflammatory response), graft versus host disease(which refers to the attack of the hosts cells by transplanted stem cells), or dose-limiting toxicities.

Preliminary data now reported at ECTRIMS, collected through July 29, 2019, covered the four groups of six patients each (median age, 56).

Results found no dose-limiting toxicities. There were also no reports ofclinically significant laboratory abnormalities in any of the groups.

One patient in group 4 (using 4 x 107cells) dropped out of the study due to aMS relapse that took place in the setting of an ongoing URI [upper respiratory tract infection] and possible dental infection, the researchers reported at ECTRIMS.

Safety results showed that across the four planned dose cohorts, ATA188 was well tolerated in patients with progressive forms of MS, with no evidence of cytokine release syndrome, graft versus host disease, or dose-limiting toxicities, they added.

Efficacy data were available from the first two groups, and hints of benefit were seen.

Four of the six patients in group 1 the lowest dose group showed clinical decline at 6 and 12 months, defined as worsening in two or moreMS scales compared to baseline. The other two showed at least partial improvement in these scales at month six, with one of these showing stable disease at 12 months.

In group 2 (1 x 107),all six patients showed either clinical improvement (two people) or partial clinical improvement (four people) at six months, or improvements in two or more or more MS scales. Data for this group did not stretch out 12 months.

Better results in terms of lesser disability were seen in people in group 2, where only one person experienced clinical decline compared to four of the six patients in group 1.

These preliminary results support continuing the trial to identify the dose for both the OLE [open-label extension] and the randomized, double-blind, placebo-controlled portion (part 2) of the study, the researchers wrote.

I am encouraged by the well tolerated safety profile, as well as early findings of potential efficacy in the ongoing ATA188 Phase 1 study, Amit Bar-Or, MD, a principal investigator in the trial and chief of MS Divisionat thePerelman School of Medicine at the University of Pennsylvania, said in apress release.

He also favored this studys innovative approach, that of using multiple MS scales to measure benefit.

I look forward to advancing the study alongside my colleagues for progressive MS patients who have limited treatment options,and where continual clinical decline is expected, Bar-Or added.

These early data support the potential of a T-cell immunotherapy targeting EBV-infected B-cells in progressive MS, said AJ Joshi, MD, Ataras senior vice president and chief medical officer.

Our recent completion of enrollment in the fourth and final dose escalation cohort moves us closer to identifying the dose to be used in the studys placebo-controlled Phase 1b part, Joshi added.We are committed to advancing ATA188 for MS patients, and look forward to presenting additional efficacy and safety results from this study in 2020, including from cohorts 3 and 4.

Of note, eight of the studys 14 authors are employees and stockholders of Atara. One other is a member of the companys Neurology Clinical Advisory Panel.

Jos is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimers disease.

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Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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