Small cell lung cancer: Scientists identify two new approaches for therapy

Small cell lung cancer: Scientists identify two new approaches for therapy

Using samples of small cell lung tumors, a research team led by biologist Dr. Silvia von Karstedt has discovered two new ways to induce tumor cell death. One of two subsets of tumor cells can be targeted by activating ferroptosis: iron-dependent cell death caused by oxidative stress. In the second subtype, oxidative stress—and hence cell death—can also be induced in a different way. Both types of cell death must be triggered simultaneously by drugs to kill the majority of the tumor mass. The results of the study have been published in Nature Communications.

Despite many advances in treatment, a diagnosis of small cell lung cancer means a particularly poor prognosis. In Germany, up to 8000 new cases of small cell lung cancer (SCLC) are diagnosed each year. At the time of diagnosis, cancer has already found many loopholes to escape the body’s immune system. “Traditional’ cell death mechanisms, such as regulated cell death by apoptosis, are usually already inactivated at this stage. That way, tumor cells can continue to divide and spread almost unperturbed.

A high cell division rate is characteristic of small cell lung cancer, which initially promises a good response to chemotherapy. “Unfortunately, in many cases the success of chemotherapy is short-lived because tumor cells rapidly develop resistance to therapy. In addition, a tumor consists not only of one, but of several cell types—the so-called subtypes—each of which uses unique strategies to escape lethal therapy,” said von Karstedt, research group leader at the CECAD Cluster of Excellence for Aging Research, the Department of Translational Genomics at the University of Cologne and the Center for Molecular Medicine Cologne (CMMC). This is where her research comes in. The biologist explores which cell death mechanisms are already inactivated in cancer cells and which ones can still be targeted by therapies to kill the tumor.

The research team used patient samples taken at the time of diagnosis, thus depicting the treatment-naïve tumor. To find out which pathways of cell death are still available, the scientists compared gene activity between patient cells taken inside and outside the tumor. Signaling pathways important for traditional cell death mechanisms were already switched off inside the tumor at this early stage, before therapy. In contrast, genes important for the activation of iron-dependent cell death by oxidative damage (ferroptosis) were strongly activated in the cancer cells.

Put in simple terms, small cell lung cancer cells can be divided into two subtypes: neuroendocrine cells and non-neuroendocrine cells. In the neuroendocrine cell subtype, more genes are active which are otherwise typically found in nerve cells that produce hormones. Cells belonging to the other subtype do not have this property and are therefore grouped as non-neuroendocrine cells. “Several experiments showed that cells of the non-neuroendocrine type can be killed using buthionine sulfoximine, which induces ferroptosis. In cells belonging to the neuroendocrine subtype, we found that they protect themselves from oxidative stress—and thus cell death—by producing antioxidants. However, by adding the antioxidant inhibitor Auranofin, we were able to kill these cells as well,” explains doctoral researcher Christina Bebber, the lead author of the paper.

Regarding a possible application of these findings to the therapy of small cell lung cancer, the biologists made an important observation: When targeting just one of the two pathways—i.e., either activating ferroptosis or inhibiting antioxidant production—in a tumor consisting of cells of both subtypes, cancer cells were able to evade the lethal therapy. They did so by adjusting their gene expression to switch to the subtype that could resist the respective single pathway-targeting treatment.

“When we applied a combination therapy, we took away this route of escape. What is also special about the study is that we used drugs that have already been tested in extensive clinical trials or even approved for the treatment of other diseases,” von Karstedt explained. Buthionine sulfoximine, which triggers ferroptosis, is already in clinical trials for cancer treatment. The gold salt Auranofin, which blocks the production of protective antioxidants in cancer cells, has been in use for decades to treat rheumatoid arthritis.

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Researchers show how stem cell depletion leads to recurring pregnancy loss

pregnancy

Depletion of a certain type of stem cell in the womb lining during pregnancy could be a significant factor behind miscarriage, according to a study released today in STEM CELLS. The study, by researchers at Warwick Medical School, University of Warwick, Coventry, England, reports on how recurrent pregnancy loss is a result of the loss of decidual precursor cells prior to conception.

“This raises the possibility that they can be harnessed to prevent pregnancy disorders,” said corresponding author Jan J. Brosens, M.D., Ph.D., professor of obstetrics and gynecology at Warwick Medical School (WMS).

The womb lining—or endometrium—is a highly regenerative tissue capable of adopting different physiological states during the reproductive years. In the second half of the menstrual cycle when progesterone levels are high, the endometrium starts remodeling intensively, heralding the start of a short window during which an embryo can implant. Pregnancy depends on this transformation, a process called decidua, as it is driven by the differentiation of endometrial stromal cells into specialized decidual cells. These cells impart the plasticity needed for tissue to accommodate an embryo’s rapid growth.

“While the magnitude of tissue remodeling required for pregnancy makes it likely that poised progenitor and highly proliferative decidual precursor cells are critical for the formation of a robust maternal-fetal interface, the underlying mechanisms behind this are unclear,” Dr. Brosens said.

The same team had recently described the presence of a discrete population of highly proliferative mesenchymal cells (hPMC) during the window of implantation. Mesenchymal stem/stromal cells can be isolated from bone marrow, adipose and other tissue sources, and can differentiate into a variety of cell types depending on the conditions of the culture they are grown in. In this latest study, the research team set out to characterize these hPMCs.

“Our findings indicate that hPMC are derived from circulating bone marrow-derived stem cells and recruited into the lining of the womb at the time of embryo implantation. These cells appear critical in pregnancy to accommodate the rapidly growing placenta.” Dr. Brosens said. “We also found that these rare but highly specialist cells are depleted in the womb lining of women with recurrent pregnancy.”

Siobhan Quenby, M.D., FRCOG, professor of obstetrics and Honorary Consultant at University Hospitals Coventry and Warwickshire and the University of Warwick, was part of the research team. “These are very exciting findings,” she said. “We have already demonstrated that we can increase these highly proliferative cells in the lining of womb before pregnancy. These new findings explain why these highly proliferative cells are so important for the prevention of miscarriage and possibly spontaneous preterm labor, two devasting pregnancy disorders that affect many women and couples all over the world.”

Dr. Jan Nolta, Editor-in-Chief of STEM CELLS, said, “this key study begins to find answers to a very concerning problem in pregnancy disorders and gives insight into understanding factors that could contribute to pregnancy loss. We are very excited to be able to publish these important results.”

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Identification of specific anti-SARS-CoV-2 antibodies with cross-neutralization potency

A team of scientists from the USA and Canada recently characterized the cross-neutralizing potency of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies isolated from coronavirus disease 2019 (COVID-19) patients. The findings reveal that some of the isolated antibodies targeting the spike receptor-binding domain (RBD) and the S2 subunit are capable of cross-neutralizing other members of the human beta-coronavirus family. The study is currently available on the bioRxiv* preprint server.

Study: Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects. Image Credit: Corona Borealis Studio / Shutterstock

Background

SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped, positive-sense, single-stranded RNA virus of the Coronaviridae family. The viruses belonging to the Coronaviridae family are capable of zoonotic transmission as observed in the current COVID-19 pandemic, as well as in previous outbreaks of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).

Given the 54% sequence similarity between different coronavirus strains, many studies have been conducted to investigate the cross-reactive potency of anti-SARS-CoV-2 antibodies. In this context, it has been observed that only a small fraction of antibodies isolated from SARS-CoV-2 infected patients are capable of cross-neutralizing SARS-CoV, MERS-CoV, or other beta (OC43 and HKU1) and alpha (229E and NL63) coronaviruses.

In the current study, the scientists have isolated and characterized a total of 198 monoclonal antibodies targeting SARS-CoV-2 spike protein. Specifically, they have explored the cross-neutralizing potency of these antibodies against different strains of coronaviruses.  

For antibody isolation, serum samples and peripheral blood mononuclear cells have been collected from four COVID-19 positive patients 3 to 7 weeks after the symptom onset.

Important observations

The analysis of serum samples using Enzyme-linked Immunosorbent assay (ELISA) revealed that all enrolled patients developed significant levels of anti-RBD bindings and neutralizing antibodies in response to SARS-CoV-2 infection. The highest virus neutralization potency was observed in samples collected at later timepoints.

By conducting a series of experiments using patient-obtained spike+ and RBD+ B cells (IgG+), the scientists finally isolated 198 anti-SARS-CoV-2 monoclonal antibodies. Moreover, they isolated 59 monoclonal antibodies from healthy individuals as experimental controls. By comparing relative frequencies of each heavy and light chain variable region sequence of patients and healthy controls, they observed that naïve B cell clones preferentially recognized the viral spike protein at the initial stages of infection. In contrast, the anti-spike B cell response predominated 3 – 7 weeks after the symptom onset. Moreover, they noticed that the sequences of heavy and light chain variable regions derived from later-timepoint samples harbored higher amino acid mutations than early-timepoint samples. This indicates that the evolution of B cells occurs continuously during SARS-CoV-2 infection.

Cross-reactive potency of anti-SARS-CoV-2 antibodies

Using various recombinant proteins, including spike S1 and S2 subunits, RBD, and N-terminal domain (NTD), the scientists observed that only a small fraction of isolated monoclonal antibodies recognized and bound the RBD. While exploring the cross-reactivity against SARS-CoV, MERS-CoV, OC43 and HKU1 beta-coronaviruses, and NL63 and 229E alpha-coronaviruses, they noticed that 81 out of 198 monoclonal antibodies bound various subdomains of SARS-CoV spike protein, with RBD being the highly recognized region. In contrast, a significantly lower cross-reactivity was observed against other coronaviruses.

Cross-neutralizing potency of anti-SARS-CoV-2 antibodies

Of 198 monoclonal antibodies, only 14 showed SARS-CoV-2 neutralization potency; of which, one targeted the NTD, one targeted the S2 subunit, and 12 targeted the RBD. Regarding cross-neutralization, only 4 out of 14 antibodies were found to effectively neutralize SARS-CoV. Of all cross-neutralizing antibodies, three were specific to the RBD, and one was specific to the S2 subunit. Importantly, all cross-neutralizing antibodies were found to effectively neutralize the South African variant of SARS-CoV-2 (lineage: B.1.351).  

The mechanistic analysis conducted in the study revealed that the most potent anti-RBD antibodies neutralized SARS-CoV-2 by blocking the angiotensin-converting enzyme 2 (ACE2)-RBD interaction. Moreover, there was an association between the degree of ACE2-RBD binding inhibition and the robustness of neutralization. A similar mechanism was observed for SARS-CoV neutralization.

Interestingly, the analysis revealed that the two most potent anti-SARS-CoV-2 neutralizing antibodies failed to neutralize SARS-CoV. This could be because these two antibodies interacted with the receptor-binding motif in the RBD, which is structurally not similar to that of SARS-CoV RBD.

To explore the infection preventing abilities of neutralizing antibodies, the scientists initially immunized the mice with a panel of neutralizing antibodies with different epitope specificities, followed by experimental infection with SARS-CoV-2. By analyzing the viral RNA in lung samples two days post-infection, they observed that only antibodies with high neutralization efficiency could provide protection against infection.

Study significance

The study reveals that the expansion of B cell populations expressing particular pairs of variable domains is not a prerequisite for generating SARS-CoV-2 and SARS-CoV cross-neutralizing antibodies. The study also identifies one epitope in the spike S2 subunit that is specific to at least four human beta-coronaviruses. Monoclonal antibodies targeting this S2 epitope have cross-neutralization potency.  

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Jennewein M. 2021. Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects. BioRxiv. doi: https://doi.org/10.1101/2021.03.23.436684, https://www.biorxiv.org/content/10.1101/2021.03.23.436684v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Assay, Blood, Cell, Coronavirus, Coronavirus Disease COVID-19, Enzyme, Evolution, MERS-CoV, Pandemic, Pathogen, Protein, Receptor, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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Researchers identify new drug candidates for treating patients with severe COVID-19

University of Maryland School of Medicine (UMSOM) researchers have identified the most toxic proteins made by SARS-COV-2–the virus that causes COVID-19 – and then used an FDA-approved cancer drug to blunt the viral protein's detrimental effects.

In their experiments in fruit flies and human cell lines, the team discovered the cell process that the virus hijacks, illuminating new potential candidate drugs that could be tested for treating severe COVID-19 disease patients. Their findings were published in two studies simultaneously on March XX in Cell & Bioscience, a Springer Nature journal.

Our work suggests there is a way to prevent SARS-COV-2 from injuring the body's tissues and doing extensive damage."

Zhe "Zion" Han, PhD, Study Senior Author and Associate Professor of Medicine, Director of Center for Precision Disease Modeling, University of Maryland School of Medicine

He notes that the most effective drug against Covid-19, remdesivir, only prevents the virus from making more copies of itself, but it does not protect already infected cells from damage caused by the viral proteins.

Prior to the pandemic, Dr. Han had been using fruit flies as a model to study other viruses, such as HIV and Zika. He says his research group shifted gears in February 2020 to study SARS-COV-2 when it was clear that the pandemic was going to significantly impact the U.S.

SARS-COV-2 infects cells and hijacks them into making proteins from each of its 27 genes. Dr. Han's team introduced each of these 27 SARS-CoV-2 genes in human cells and examined their toxicity. They also generated 12 fruit fly lines to express SARS-CoV-2 proteins likely to cause toxicity based on their structure and predicted function.

The researchers found that a viral protein, known as Orf6, was the most toxic killing about half of the human cells. Two other proteins (Nsp6 and Orf7a) also proved toxic, killing about 30-40 percent of the human cells. Fruit flies that made any one of these three toxic viral proteins in their bodies were less likely to survive to adulthood. Those fruit flies that did live had problems like fewer branches in their lungs or fewer energy-generating power factories in their muscle cells.

For the remaining experiments, the researchers focused on just the most toxic viral protein, so they could figure out what cell process the virus hijacks during infection. Dr. Han's team found that the virus' toxic Orf6 protein sticks to multiple human proteins that have the job of moving materials out of the cell's nucleus–the place in the cell that holds the genome, or the instructions for life.

They then discovered that one of these human moving proteins, targeted by the virus, gets blocked by the cancer drug selinexor. The researchers tested selinexor on human cells and fruit flies making the toxic viral protein to see if the drug could help reverse the damage.

Selinexor, like many cancer drugs is itself toxic. However, after accounting for its toxic effects, the drug improved human cell survival by about 12 percent. Selinexor prevented early death in about 15 percent of the flies making the toxic viral protein. The drug also restored branches in the lungs and the energy-generators in the muscle cells. Selinexor is FDA-approved to treat certain blood cancers.

"More than 1,000 FDA-approved drugs are in clinical trials to test as treatments for Covid-19, and luckily a trial testing selinexor, the drug used in our study, is being performed already," says Dr. Han. "If this trial proves to be successful, our data will have demonstrated the underlying mechanism for why the drug works."

Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, commented, "Although we now have vaccines, it may still be a while before we will have Covid-19 infections under control, especially with the new variants emerging. We will need to tap into every tool in the arsenal available to protect people from needless sickness, disability or even death, and this study guides us towards a new target for potential therapeutics."

Source:

University of Maryland School of Medicine

Journal reference:

Lee, J-G., et al. (2021) Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor. Cell & Bioscience. doi.org/10.1186/s13578-021-00568-7.

Posted in: Medical Research News | Disease/Infection News

Tags: Blood, Cancer, Cell, Disability, Disease Modeling, Drugs, Fruit, Genes, Genome, HIV, Lungs, Mass Spectrometry, Medical Research, Medical School, Medicine, Muscle, Pandemic, Pharmacy, Protein, Remdesivir, Research, SARS, SARS-CoV-2, Spectrometry, Therapeutics, Virus

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VHIO-born spin-off receives approval to initiate Phase I/II clinical trial of novel Myc inhibitor

Co-founded back in 2014 by VHIO's Laura Soucek, CEO of the enterprise, and Marie-Eve Beaulieu, Chief Scientific Officer (CSO) of the company, VHIO-born spin-off Peptomyc S.L. has just announced that it has received approval from the Spanish Agency of Medicines and Medical Devices for conducting clinical trials in Spain (AEMPS), to initiate the first-in-human Phase I/II clinical trial with its first compound – a disruptive Myc inhibitor, Omomyc (OMO-103).

Building on the proven preclinical efficacy and safety of the Omomyc cell-penetrating peptide (CCP) in mouse models, and Peptomyc's company's successful development of anti-Myc peptides for the treatment of several tumor types, this latest milestone represents a greatly anticipated 'leap' into the clinical research setting and an important step forward in becoming the first ever clinically viable and direct inhibitor of Myc – a protein implicated in the formation of most tumor types.

Commenting for VHIO's Global Communications, Laura Soucek, Principal Investigator of VHIO's Mouse Models of Cancer Therapies and an ICREA Research Professor said, "MYC has been considered an 'undruggable' cancer target for many years. We have previously shown that Myc blockade has an excellent therapeutic effect in several mouse models, with mild side effects that are well tolerated and reversible. Now that we have received approval to initiate our early phase clinical trial, we can further progress in testing the safety and efficacy of our Omomyc-based therapy for the benefit of those who matter the most – our patients."

Over the last 20 years Laura's determined research efforts have centered on proving countless cynics wrong in her ambitions to combat resistance to therapy and combat cancer cell spread through clinically inhibiting the Myc oncogene. Found deregulated in most, if not all tumor types, and as a key driver of cancer progression and maintenance, Myc is consequently a major contender as a cancer target and yet, promise of its inhibition has not yet been successfully translated into benefits at the patient level.

While several factors including Myc's nuclear localization, lack of identified ligand binding site, and its function in maintaining normal tissues, are responsible for both this frustrating scenario as well as the sustained belief that it is in fact an impossible cancer target, Laura and her team are now silencing the sceptics by finally pushing Myc inhibition into the clinic.

At the preclinical level, we have reported the efficacy of Omomyc as a cell penetrating peptide – essentially, a mini-protein with the ability to enter cells and reach its target compartment, namely, the nucleus. The successful intravenous systemic administration of our mini-protein MYC inhibitor against lung cancer and other malignancies, has led to this week's exciting development."

Marie-Eve Beaulieu, Peptomyc's Chief Scientific Officer

She added, "Our strategy differs immensely from other previous approaches aimed at inhibiting Myc. Our Omomyc mini-protein is large enough to accurately fold and adapt to Myc's disordered structure, which determines the specificity of inhibition. At the same time, it is small enough to penetrate tumor cells and nuclei in order to reach its target. By conducting our first-in-human early phase clinical trial, we hope to drive this novel therapy into the clinic for the more effective treatment of multiple tumor types".

Twenty patients with advanced solid tumors across various cancer types, whose disease has progressed after previous treatments, will be enrolled in the Phase I study. This clinical trial will be carried out at three different Spanish sites: our Vall d'Hebron University Hospital (HUVH), also located within the Vall d'Hebron Barcelona Hospital Campus, the HM Sanchinarro University Hospital, and the Fundación Jiménez Díaz University Hospital (Madrid).

VHIO's Elena Garralda, Director of our Research Unit for Molecular Therapy of Cancer (UITM) – "la Caixa" Foundation, and Head of Early Clinical Drug Development at our Institute, is the Principal Investigator of Peptomyc's clinical study at Vall d'Hebron. She noted, "I am honored and privileged to participate in this study of a VHIO-developed molecule. Since Myc has traditionally been considered as an impossible drug target, this clinical trial represents a pivotal development. Confirmation of OMO-103's safety and efficacy in patients would be extremely important for the future treatment of cancer".

"To get to where we are today has been a long and challenging journey. While we have had to overcome many obstacles, we have successfully proven our hypothesis about Myc by achieving amazing results in animal models. We very much hope that Omomyc will meet the same expectations in clinical research so that we can ultimately provide new hope for cancer patients, particularly for those suffering from advanced disease," concluded Laura Soucek.

The preclinical development of Omomyc was possible thanks to the support received from Worldwide Cancer Research (WCR/AICR), European Research Council (ERC) – one Consolidator and two Proof of Concept grants – Instituto de Salud Carlos III (Institute of Health Carlos III), Fondo de Investigación en Salud (FIS) grants, Fero Foundation, and the BBVA Foundation, among other funding entities.

Source:

Vall d'Hebron Institute of Oncology

Posted in: Drug Trial News | Medical Condition News

Tags: Cancer, Cell, Clinical Trial, Compound, Efficacy, Hospital, Ligand, Lung Cancer, Molecule, Oncogene, Peptides, Preclinical, Protein, Research, Tumor

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New AI-based decision support system can help prevent anemia in hemodialysis patients

Anemia, a condition characterized by the lack of healthy red blood cells in the body, is common in patients with chronic kidney disease who need to undergo routine hemodialysis (a process that helps to "clean" the blood when the kidneys don't function well). Thus, red blood cell-stimulating agents (called "erythropoiesis-stimulating agents" or ESAs) and iron supplements (ISs) are administered as part of this process. But, complications can arise if the patients have an altered iron metabolism or poor response to medications.

Moreover, the medications tend to be expensive and impose a heavy financial burden on public health. Thus, with such patients currently on the rise but not enough physicians suitably trained to administer treatment, additional support systems with smart decision-making capabilities are highly sought after. One option is to turn to artificial intelligence (AI), which seems promising but demands a large dataset and is not practical owing to diverse health conditions of patients.

So, can something be done to improve the situation? In a recent study published in the International Journal of Medical Sciences, medical researchers from Japan tried to find the answer. They came up with a new approach: instead of making the AI learn from the complex physiology of the patient's body, they opt for a prediction model based on the decisions of experienced physicians.

We got the idea while contemplating the thought process of seasoned physicians. After all, they do not calculate detailed values of vital reactions in a patient's body when deciding dosages, which means prediction models based on biochemistry are not necessary."

Toshiaki Ohara,  Lead Scientist, Assistant Professor, Okayama University

The researchers started off by collecting clinical data at two hospitals in Japan and then preparing two datasets for each hospital: one for training their model and the other for testing and validating its predictions. Simultaneously, they recorded the dosage directions of physicians at both hospitals and considered responses for the two medications used during hemodialysis: ESAs and ISs.

Based on these, they constructed an AI-based model called an "artificial-intelligence-supported anemia control system" (AISACS), which received a total of five inputs (four items of blood examination and dosage history) and churned out dosage direction probabilities for the two medications as outputs. In addition, to make the training process more efficient, they compensated for the time lag between blood examination and dosage decisions by using "data rectification" to match the decision dates with the examination dates.

To the researchers' delight, AISACS showed a high prediction accuracy with correct classification (directions matching those of physicians) rates of 72%-87%. But what was even more interesting was that it provided "clinically appropriate" classifications at even higher rates (92%-97%). These were directions that didn't match those of physicians (and were sometimes provided ahead of them) but were still considered appropriate from a medical viewpoint.

With these results, researchers are hopeful about AISAC's future prospects. "By preventing anemia, our system can help alleviate the burdens on physicians and medical insurance systems. Moreover, it has the potential to share the knowledge and experiences related to medications," comments an excited Dr. Ohara.

Hopefully, this new AI-based approach provides some hope to both patients undergoing hemodialysis and physicians treating them.

Source:

Okayama University

Journal reference:

Ohara, T., et al. (2021) Artificial intelligence supported anemia control system (AISACS) to prevent anemia in maintenance hemodialysis patients. International Journal of Medical Sciences. doi.org/10.7150/ijms.53298.

Posted in: Device / Technology News | Medical Research News | Medical Condition News

Tags: Anemia, Artificial Intelligence, Biochemistry, Blood, Cell, Chronic, Chronic Kidney Disease, Erythropoiesis, Hospital, Kidney, Kidney Disease, Metabolism, Physiology, Public Health, Red Blood Cells, Supplements

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Electromagnetic fields may slow or stop the spread of breast cancer cells

Electricity may slow – and in some cases, stop – the speed at which breast cancer cells spread through the body, a new study indicates.

The research also found that electromagnetic fields might hinder the amount of breast cancer cells that spread. The findings, published recently in the journal Bioelectricity, suggest that electromagnetic fields might be a useful tool in fighting cancers that are highly metastatic, which means they are likely to spread to other parts of the body, the authors said.

"We think we can hinder metastasis by applying these fields, but we also think it may be possible to even destroy tumors using this approach," said Vish Subramaniam, senior author of the paper and former professor of mechanical and aerospace engineering at The Ohio State University. Subramaniam retired from Ohio State in December.

"That is unclear at this stage, but we are working on understanding that – how big should the electromagnetic field be, how close should it be to the tumor? Those are the next questions we hope to answer."

The study is among the first to show that electromagnetic fields could slow or stop certain processes of a cancer cell's metabolism, impairing its ability to spread. The electromagnetic fields did not have a similar effect on normal breast cells.

Travis Jones, lead author of the paper and a researcher at Ohio State, compared the effects to what might happen if something interfered with a group running together down a path.

The effect, Subramaniam said, is that some of the cancer cells slow down when confronted with electromagnetic fields.

It makes some of them stop for a little while before they start to move, slowly, again. As a group, they appear to have split up. So how quickly the whole group is moving and for how long they are moving becomes affected."

Vish Subramaniam, Senior Author

The electromagnetic fields are applied to cancerous cells without touching them, said Jonathan Song, co-author of the paper, associate professor of mechanical and aerospace engineering at Ohio State and co-director of Ohio State's Center for Cancer Engineering.

Song compared the cancer cells with cars. Each cell's metabolism acts as fuel to move the cells around the body, similar to the way gasoline moves vehicles.

"Take away the fuel, and the car cannot move anymore," Song said.

The work was performed on isolated human breast cancer cells in a lab and has not been tested clinically.

The electromagnetic fields appear to work to slow cancer cells' metabolism selectively by changing the electrical fields inside an individual cell. Accessing the internal workings of the cell, without having to actually touch the cell via surgery or another more invasive procedure, is new to the study of how cancer metastasizes, Subramaniam said.

"Now that we know this, we can start to answer other questions, too," Subramaniam said. "How do we affect the metabolism to the point that we not only make it not move but we choke it, we completely starve it. Or can we slow it down to the point where it will always remain weak?"

This research is an extension of two previous pioneering studies, published in 2015 and 2019, that showed electromagnetic fields could hinder breast cancer metastasis.

Source:

Ohio State University

Journal reference:

Jones, T.H., et al. (2021) Directional Migration of Breast Cancer Cells Hindered by Induced Electric Fields May Be Due to Accompanying Alteration of Metabolic Activity. Bioelectricity. doi.org/10.1089/bioe.2020.0048.

Posted in: Medical Science News | Medical Research News | Women's Health News

Tags: Breast Cancer, Cancer, Cell, Electromagnetic, Metabolism, Metastasis, Research, Running, Surgery, Tumor

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The bald truth—altered cell divisions cause hair thinning

The bald truth - altered cell divisions cause hair thinning

Hair grows from stem cells residing in hair follicles. During aging, the capability of hair follicles to grow hair is successively lost, leading to hair thinning and ultimately hair loss. In a new study, researchers from Tokyo Medical and Dental University (TMDU) and the University of Tokyo identified a novel mechanism by which hair follicles lose their regenerative capabilities.

Hair follicles are mini-organs from which new hair constantly grows. The basis for new hair growth is the proper function of hair follicle stem cells (HFSCs). HFSCs undergo cyclic symmetric and asymmetric cell divisions (SCDs and ACDs). SCDs generate two identical cells that go on to have the same fate, while ACDs generate a differentiating cell and a self-renewing stem cell. The combination ensures that the stem cell population continues to exist, yet how those contribute to the loss of HFSC function due to aging is not yet completely understood.

“For proper tissue function, symmetric and asymmetric cell divisions have to be in balance,” says corresponding author of the study Emi Nishimura. “Once stem cells preferentially undergo one of either or, worse yet, deviate from the typical process of either type of cell division, the organ suffers. In this study, we wanted to understand how stem cell division plays into hair grows during aging.”

To achieve their goal, the researchers investigated stem cell division in HFSCs in young and aged mice by employing two different types of assays: Cell fate tracing and cell division axis analyses. In the former, HFSCs were marked with a fluorescent protein so they could be followed over time, while in the latter the angle of HFSC division was measured. Strikingly, the researchers were able to show that while HFSCs in young mice underwent typical symmetric and asymmetric cell divisions to regenerate hair follicles, during aging they adopted an atypical senescent type of asymmetric cell division.

But why does the mode of cell division change so drastically during aging? To answer this question, the researchers focused on hemidesmosomes, a class of protein that connect the cells to the extracellular matrix (ECM; proteins surrounding cells). Cell-ECM have long been known to confer polarity to cells, i.e., that the cells can sense their localization within a given space through the action of specific proteins. The researchers found that during aging both hemidesmosomal and cell polarity proteins become destabilized, resulting in the generation of aberrantly differentiating cells during division of HFSCs. As a result, HFSCs become exhausted and lost (leading to hair thinning and hair loss) over time.

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Cannabis compound inhibits SARS-CoV-2 replication in human lung cells

Researchers in the United States have conducted a study showing that a cannabis plant compound inhibited infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung cells.

SARS-CoV-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that continues to sweep the globe posing a threat to global public health and the worldwide economy.

Marsha Rosner from the University of Chicago in Illinois and colleagues found that cannabidiol (CBD) and its metabolite 7-OH-CBD potently blocked SARS-CoV-2 replication in lung epithelial cells.

The CBD inhibited viral gene expression and reversed many of the effects the virus has on host gene transcription.

The compound also induced the expression of interferons – cell signaling proteins that are produced by host cells as an early response to viral invasion.

Furthermore, the incidence of SARS-CoV-2 infection was up to an order of magnitude lower in a cohort of patients who had been taking CBD, compared with matched patients who had not been taking CBD.

“This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection,” says Rosner and the team.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

Study: Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response. Image Credit: Stokkete / Shutterstock

Rapid spread of SARS-CoV-2 highlights the need for new treatments

Since the COVID-19 outbreak first began in Wuhan, China, in late December 2019, the rapid spread of SARS-CoV-2 has led to more than 119.5 million infections and caused more than 2.64 million deaths.

Although recently-approved vaccines are now being rolled out in many countries, the virus is still spreading rapidly. Rosner and colleagues say this highlights the need for alternative approaches, particularly among populations with limited access to vaccines.

However, “to date, few therapies have been identified that block SARS-CoV-2 replication and viral production,” write the researchers.

More about SARS-CoV-2 and CBD

The SARS-CoV-2 virus primarily enters host cells through the binding of a surface viral protein called spike to the human host cell receptor angiotensin-converting enzyme 2 (ACE2).

The viral genome is then translated into two large polypeptides that are cleaved by the viral proteases MPro and PLPro to produce the proteins required for viral replication, assembly, and budding.

Rosner and colleagues say that, although limited, some studies have reported that certain cannabinoids have antiviral effects against hepatitis C virus and other viruses.

Furthermore, an oral solution of CBD is already approved by the US food and Drug Administration for the treatment of epilepsy.

High Dose CBD usage in patients is significantly correlated with a reduction in COVID-19 positivity. Associations between reported cannabinoid medication use and COVID-19 test results among adults tested at the University of Chicago Medicine (total n=93,565). P*: p-values of percent positivity of the specified patient population compared to percent positivity of all patients (10% COVID-19 positive among 93,565 patients). Middle right: 85 patients took CBD before their COVID test date. Upper right: 82 of the 85 patients took FDA-approved CBD (Epidiolex®) and were matched to 82 of the 93,167 patients (Matched Controls) with a nearest neighbor propensity score model that scored patients according to their demographics and their recorded diagnoses and medications from the two years before their COVID-19 test. P-values were calculated using Fisher’s exact test two-sided.

What did the current study involve?

To test the effect of CBD on SARS-CoV-2 replication, the researchers pretreated A549 human lung carcinoma cells expressing ACE-2 (A549-ACE2) with 0-10μM CBD for 2 hours before infecting them with SARS-CoV-2.

Analysis of the cells 48 hours later showed that CBD had potently inhibited viral replication in the cells.

Since CBD is often consumed as part of a Cannabis sativa extract, the team investigated whether other cannabinoids could also inhibit SARS-CoV-2 infection, especially those with closely related structures.

Remarkably, the only agent that potently inhibited viral replication was CBD; limited or no antiviral activity was exhibited by the other structurally similar cannabinoids tested.

Furthermore, the CBD metabolite 7-OH-CBD, the active ingredient in the CBD treatment of epilepsy, also effectively inhibited SARS-CoV-2 replication in the A549-ACE2 cells.

CBD effectively eliminated viral RNA expression

When the researchers assessed whether CBD might prevent proteolytic cleavage by Mpro or PLpro, they found CBD had no effect on the activity of either protease.

This led the team to hypothesize that CBD targets host cell processes.

Consistent with this hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours revealed significant suppression of SARS-CoV-2-induced changes in gene expression.

The CBD effectively eliminated viral RNA expression, including RNA coding for the spike protein.

Both SARS-CoV-2 and CBD triggered significant changes in cellular gene expression, including the expression of several transcription factors.

Further analysis of host cell RNA showed that the virus-induced changes were almost completely reversed, but rather than the cells returning to a normal cell state, the CBD+virus-infected cells resembled those treated with CBD alone.

What about interferon signaling?

Given that infection with SARS-CoV-2 is known to suppress the interferon signaling pathway, the researchers tested whether CBD could suppress viral infection by introducing this pathway.

Some genes were induced by CBD in both the absence and presence of SARS-CoV-2, including genes that encode interferon receptors and mediators of the interferon signaling pathway.

In addition, CBD effectively reversed the viral induction of cytokines that can trigger a deadly hyperinflammatory response called the “cytokine storm” during the later stages of infection.

“Thus, CBD has the potential not only to act as an antiviral agent at early stages of infection but also to protect the host against an overactive immune system at later stages,” says Rosner and the team.

SARS-CoV-2 incidence was lower in patients who took CBD

Finally, the team assessed the incidence of SARS-CoV-2 infection among 82 patients who had been prescribed CBD prior to SARS-C0V-2 testing and matched patients who had not been prescribed CBD.

Strikingly, the incidence of SARS-CoV-2 was only 1.2% among the patients prescribed CBD, compared with 12.2% among the matched patients who had not been taking CBD.

“The substantial reduction in SARS-CoV-2 infection risk of approximately an order of magnitude in patients who took FDA-approved CBD highlights the potential efficacy of this drug in combating SARS-CoV2 infection,” says Rosner and colleagues.

“We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly-characterized formulations in order to define CBD’s role in preventing and treating early SARS-CoV-2 infection,” they conclude.  

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Rosner M, et al. Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response. bioRxiv, 2021. doi: https://doi.org/10.1101/2021.03.10.432967, https://www.biorxiv.org/content/10.1101/2021.03.10.432967v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Cannabidiol, Cannabinoid, Cannabis, Carcinoma, Cell, Cell Signaling, Compound, Coronavirus, Coronavirus Disease COVID-19, Cytokine, Cytokines, Efficacy, Enzyme, Epilepsy, Gene, Gene Expression, Genes, Genome, Hepatitis C, Immune Response, Immune System, Medicine, Metabolite, Pandemic, Placebo, Protein, Public Health, Receptor, Research, Respiratory, RNA, RNA Sequencing, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Signaling Pathway, Spike Protein, Syndrome, Transcription, Transcription Factors, Virus

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Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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