Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder (Medicine)

Findings show that LMNA gene mutations can disrupt the “identity” of heart muscle cells

Scientists in the Perelman School of Medicine at the University of Pennsylvania have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCM — which affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failure — is one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In the study, published this week in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cells — but not two other cell types studied — leading to the abnormal activation of non-heart muscle genes.

“We’re now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types,” said study co-senior author Rajan Jain, MD, an assistant professor of Cardiovascular Medicine and Cell and Developmental Biology at the Perelman School of Medicine.

“Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause,” said study co-senior author Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine and Genetics, and Director of the Genetic and Epigenetic Origins of Disease Program at Penn Medicine.

Inherited LMNA mutations have long puzzled researchers. The LMNA gene encodes proteins that form a lacy structure on the inner wall of the cell nucleus, where chromosomes full of coiled DNA are housed. This lacy structure, known as the nuclear lamina, touches some parts of the genome, and these lamina-genome interactions help regulate gene activity, for example in the process of cell division. The puzzle is that the nuclear lamina is found in most cell types, yet the disruption of this important and near-ubiquitous cellular component by LMNA mutations causes only a handful of relatively specific clinical disorders, including a form of DCM, two forms of muscular dystrophy, and a form of progeria — a syndrome that resembles rapid aging.

To better understand how LMNA mutations can cause DCM, Jain, Musunuru, and their colleagues took cells from a healthy human donor, and used the CRISPR gene-editing technique to create known DCM-causing LMNA mutations in each cell. They then used stem cell methods to turn these cells into heart muscle cells — cardiomyocytes — and, for comparison, liver and fat cells. Their goal was to discover what was happening in the mutation-containing cardiomyocytes that wasn’t happening in the other cell types.

The researchers found that in the LMNA-mutant cardiomyocytes — but hardly at all in the other two cell types — the nuclear lamina had an altered appearance and did not connect to the genome in the usual way. This disruption of lamina-genome interactions led to a failure of normal gene regulation: many genes that should be switched off in heart muscle cells were active. The researchers examined cells taken from DCM patients with LMNA mutations and found similar abnormalities in gene activity.

A distinctive pattern of gene activity essentially defines what biologists call the “identity” of a cell. Thus the DCM-causing LMNA mutations had begun to alter the identity of cardiomyocytes, giving them features of other cell types.

The LMNA-mutant cardiomyocytes also had another defect seen in patients with LMNA-linked DCM: the heart muscle cells had lost much of the mechanical elasticity that normally allows them to contract and stretch as needed. The same deficiency was not seen in the LMNA-mutant liver and fat cells.

Research is ongoing to understand whether changes in elasticity in the heart cells with LMNA mutations occurs prior to changes in genome organization, or whether the genome interactions at the lamina help ensure proper elasticity. Their experiments did suggest an explanation for the differences between the lamina-genome connections being badly disrupted in LMNA-mutant cardiomyocytes but not so much in LMNA-mutant liver and fat cells: Every cell type uses a distinct pattern of chemical marks on its genome, called epigenetic marks, to program its patterns of gene activity, and this pattern in cardiomyocytes apparently results in lamina-genome interactions that are especially vulnerable to disruption in the presence of certain LMNA mutations.

“The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome,” Jain said. “This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.”

Other co-authors of the study were co-first authors Parisha Shah and Wenjian Lv; and Joshua Rhoades, Andrey Poleshko, Deepti Abbey, Matthew Caporizzo, Ricardo Linares-Saldana, Julie Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam Stanton, Kenneth Bedi, Michael Morley, Thomas Cappola, Anjali Owens, Kenneth Margulies, David Frank, Joseph Wu, Daniel Rader, Wenli Yang, and Benjamin Prosser.

Funding was provided by the Burroughs Wellcome Career Award for Medical Scientists, Gilead Research Scholars Award, Pennsylvania Department of Health, American Heart Association/Allen Initiative, the National Institutes of Health (DP2 HL147123, R35 HL145203, R01 HL149891, F31 HL147416, NSF15-48571, R01 GM137425), the Penn Institute of Regenerative Medicine, and the Winkelman Family Fund for Cardiac Innovation.

Featured image: A iPSC-cardiomyocyte harboring an LMNA mutation resulting in the loss of nuclear morphology. Parisha Shah and Wenjian Lv in the Jain and Musunuru laboratories at Penn studied how mutations in LMNA impact how DNA is organized in the cell. © Penn Medicine


Reference: Parisha P. Shah, Wenjian Lv et al., “Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes”, Cell Stem Cell, 2021. https://doi.org/10.1016/j.stem.2020.12.016


Provided by Penn Medicine

Scientists Develop Method to Detect Fake News (Engineering)

Researchers develop robust approach for detecting market manipulation

Social media is increasingly used to spread fake news. The same problem can be found on the capital market – criminals spread fake news about companies in order to manipulate share prices. Researchers at the Universities of Göttingen and Frankfurt and the Jožef Stefan Institute in Ljubljana have developed an approach that can recognise such fake news, even when the news contents are repeatedly adapted. The results of the study were published in the Journal of the Association for Information Systems.

In order to detect false information – often fictitious data that presents a company in a positive light – the scientists used machine learning methods and created classification models that can be applied to identify suspicious messages based on their content and certain linguistic characteristics. “Here we look at other aspects of the text that makes up the message, such as the comprehensibility of the language and the mood that the text conveys,” says Professor Jan Muntermann from the University of Göttingen.

The approach is already known in principle from its use by spam filters, for example. However, the key problem with the current methods is that to avoid being recognised, fraudsters continuously adapt the content and avoid certain words that are used to identify the fake news. This is where the researchers’ new approach comes in: to identify fake news despite such strategies to evade detection, they combine models recently developed by the researchers in such a way that high detection rates and robustness come together. So even if “suspicious” words disappear from the text, the fake news is still recognised by its linguistic features. “This puts scammers into a dilemma. They can only avoid detection if they change the mood of the text so that it is negative, for instance,” explains Dr Michael Siering. “But then they would miss their target of inducing investors to buy certain stocks.”

The new approach can be used, for example, in market surveillance to temporarily suspend the trading of affected stocks. In addition, it offers investors valuable information to avoid falling for such fraud schemes. It is also possible that it could be used for criminal prosecutions in the future.

Featured image: Professor Jan Muntermann Photo: Frank Lemburg/Fotostudio Wilder


Reference: Michael Siering, Jan Muntermann, Miha Grčar. Design Principles for Robust Fraud Detection: The Case of Stock Market Manipulations. Journal of the Association for Information Systems (2021). Doi: 10.17705/1jais.00657, or https://aisel.aisnet.org/jais/vol22/iss1/4


Provided by Georg-August-Universität Göttingen

Oncotarget: The Pro-apoptotic Actions of 2-methoxyestradiol Against Ovarian Cancer (Medicine)

Oncotarget published “The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer involve catalytic activation of PKCδ signaling” which reported that the authors have previously shown that a flaxseed-supplemented diet decreases both the incidence and severity of ovarian cancer in laying hens, also induces CYP1A1 expression in liver.

Recently, they have shown that as a biologically derived active component of flax diet, 2MeOE2 induces apoptosis in ovarian cancer cells which is partially dependent on p38 MAPK.

The objective of this Oncotarget study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors.

The objective of this Oncotarget study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors

2MeOE2 induces γH2Ax expression and apoptotic histone modifications in ovarian cancer cells, which are predicted downstream targets of protein kinase Cδ during apoptosis.

Overexpressing full length PKCδ alone does not induce apoptosis but potentiates 2MeOE2-mediated apoptosis.

Dr. Dale Buchanan Hales from The Southern Illinois University said, “With an estimated 22,530 cases reported and 13,980 estimated deaths in the year 2019, ovarian cancer is the deadliest gynecological disease accounting for more deaths than any other cancer in the female reproductive tract.

With an estimated 22,530 cases reported and 13,980 estimated deaths in the year 2019, ovarian cancer is the deadliest gynecological disease accounting for more deaths than any other cancer in the female reproductive tract.

Their laboratory studies epithelial ovarian cancer in laying hens, the only known natural animal model that spontaneously develops the disease over its lifespan.

The research has shown that dietary ingestion of flaxseed reduces the onset and severity of ovarian cancer in laying hens.

Recently they have shown that 2MeOE2 induces apoptosis in human ovarian cancer cells.

The objective of this study was to investigate the epigenetic modifications exerted by 2MeOE2 and assess the role of PKCδ in 2MeOE2 actions in order to gain an in-depth mechanistic understanding of its molecular and cellular pro-apoptotic actions.

The Hales Research Team concluded in their Oncotarget Research Paper, “Our findings indicate that 2MeOE2 -mediated anti-tumor actions involve the catalytic activation of PKCδ in the pro-apoptotic pathway. The catalytic fragment of PKCδ is responsible for the apoptotic histone modifications and acceleration of the apoptotic cascade through p38 MAPK pathway. Dietary flaxseed supplementation activates PKCδ secondary to increasing endogenous production of 2MeOE2 which drives apoptosis in ovarian cancer cells (Figure 7). This study offers new insight into the molecular underpinnings of dietary flaxseed’s chemopreventative actions in ovarian cancer.

Featured image: Schematic diagram of the molecular action of 2MeOE2. 2MeOE2 -mediated pro-apoptotic actions involve the catalytic activation of PKCδ by cellular caspases. The catalytic fragment of PKCδ is responsible for the apoptotic histone modifications in the nucleus and activates p38 MAPK pathway in the cytosol, which induces more activation of caspases that consequently cleave and activate more PKCδ. Therefore this cycle accelerates and amplifies the 2MeOE2-mediated apoptotic signal.


Reference: Pal P., Hales K., Hales D. Buchanan The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer involve catalytic activation of PKCδ signaling. Oncotarget. 2020; 11: 3646-3659. Retrieved from https://www.oncotarget.com/article/27760/text/


Provided by Impact Journals LLC

Searching for Dark Matter Through the Fifth Dimension (Astronomy)

A discovery in theoretical physics could help to unravel the mysteries of dark matter

Theoretical physicists of the PRISMA+ Cluster of Excellence at Johannes Gutenberg University Mainz (JGU) are working on a theory that goes beyond the Standard Model of particle physics and can answer questions where the Standard Model has to pass – for example, with respect to the hierarchies of the masses of elementary particles or the existence of dark matter. The central element of the theory is an extra dimension in spacetime. Until now, scientists have faced the problem that the predictions of their theory could not be tested experimentally. They have now overcome this problem in a publication in the current issue of the European Physical Journal C.

Already in the 1920s, in an attempt to unify the forces of gravity and electromagnetism, Theodor Kaluza and Oskar Klein speculated about the existence of an extra dimension beyond the familiar three space dimensions and time – which in physics are combined into 4-dimensional spacetime. If it exists, such a new dimension would have to be incredible tiny and unnoticeable to the human eye. In the late 1990s, this idea has seen a remarkable renaissance when it was realized that the existence of a fifth dimension could resolve some of the profound open questions of particle physics. In particular, Yuval Grossman of Stanford University and Matthias Neubert, then a professor at Cornell University in the US, showed in a highly cited publication that the embedding of the Standard Model of particle physics in a 5-dimensional spacetime could explain the so far mysterious patterns seen in the masses of elementary particles.

Another 20 years later, the group of Professor Matthias Neubert – since 2006 on the faculty of Johannes Gutenberg University Mainz and spokesperson of the PRISMA+ Cluster of Excellence – made another unexpected discovery: they found that the 5-dimensional field equations predicted the existence of a new heavy particle with similar properties as the famous Higgs boson but a much heavier mass – so heavy, in fact, that it cannot be produced even at the highest-energy particle collider in the world, the Large Hadron Collider (LHC) at the European Center for Nuclear Research CERN near Geneva in Switzerland. “It was a nightmare,” recalled Javier Castellano Ruiz, a PhD student involved in the research. “We were excited by the idea that our theory predicts a new particle, but it appeared to be impossible to confirm this prediction in any foreseeable experiment.”

The detour through the fifth dimension

In a recent paper published in the European Physical Journal C, the researchers found a spectacular resolution to this dilemma. They discovered that their proposed particle would necessarily mediate a new force between the known elementary particles of our visible universe and the mysterious dark matter, the dark sector. Even the abundance of dark matter in the cosmos, as observed in astrophysical experiments, can be explained by their theory. This offers exciting new ways to search for the constituents of the dark matter – literally via a detour through the extra dimension – and obtain clues about the physics at a very early stage in the history of our universe, when dark matter was produced. “After years of searching for possible confirmations of our theoretical predictions, we are now confident that the mechanism we have discovered would make dark matter accessible to forthcoming experiments, because the properties of the new interaction between ordinary matter and dark matter – which is mediated by our proposed particle – can be calculated accurately within our theory,” said Professor Matthias Neubert, head of the research team. “In the end – so our hope – the new particle may be discovered first through its interactions with the dark sector.” This example nicely illustrates the fruitful interplay between experimental and theoretical basic science – a hallmark of the PRISMA+ Cluster of Excellence.

Featured image: Prof. Dr. Matthias Neubert © JGU


Reference:
A. Carmona, J. Castellano, M. Neubert, A warped scalar portal to fermionic dark matter, The European Physical Journal C 81, 20 January 2021,
DOI:10.1140/epjc/s10052-021-08851-0


Provided by JGU

Discovery Could Lead to Self-propelled Robots (Engineering)

Army-funded researchers discovered how to make materials capable of self-propulsion, allowing materials to move without motors or hands.

Researchers at the University of Massachusetts Amherst discovered how to make materials that snap and reset themselves, only relying upon energy flow from their environment. This research, published in Nature Materials and funded by the U.S. Army, could enable future military robots to move from their own energy.

“This work is part of a larger multi-disciplinary effort that seeks to understand biological and engineered impulsive systems that will lay the foundations for scalable methods for generating forces for mechanical action and energy storing structures and materials,” said Dr. Ralph Anthenien, branch chief, Army Research Office, an element of the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, Army Research Laboratory. “The work will have myriad possible future applications in actuation and motive systems for the Army and DOD.”

Researchers uncovered the physics during a mundane experiment that involved watching a gel strip dry. The researchers observed that when the long, elastic gel strip lost internal liquid due to evaporation, the strip moved. Most movements were slow, but every so often, they sped up.

Scientists discover how to make materials that snap and reset themselves, only relying upon energy flow from their environment. This research could enable future military robots that are able to move off their own energy. © Yongjin Kim, UMass Amherst

These faster movements were snap instabilities that continued to occur as the liquid evaporated further. Additional studies revealed that the shape of the material mattered, and that the strips could reset themselves to continue their movements.

“Many plants and animals, especially small ones, use special parts that act like springs and latches to help them move really fast, much faster than animals with muscles alone,” said Dr. Al Crosby, a professor of polymer science and engineering in the College of Natural Sciences, UMass Amherst. “Plants like the Venus flytraps are good examples of this kind of movement, as are grasshoppers and trap-jaw ants in the animal world.”

Snap instabilities are one way that nature combines a spring and a latch and are increasingly used to create fast movements in small robots and other devices as well as toys like rubber poppers.

“However, most of these snapping devices need a motor or a human hand to keep moving,” Crosby said. “With this discovery, there could be various applications that won’t require batteries or motors to fuel movement.”

Scientists discover how future military robots may be able to move off just their own energy. © Yongjim Kim, UMass Amherst

After learning the essential physics from the drying strips, the team experimented with different shapes to find the ones most likely to react in expected ways, and that would move repeatedly without any motors or hands resetting them. The team even showed that the reshaped strips could do work, such as climb a set of stairs on their own.

“These lessons demonstrate how materials can generate powerful movement by harnessing interactions with their environment, such as through evaporation, and they are important for designing new robots, especially at small sizes where it’s difficult to have motors, batteries, or other energy sources,” Crosby said.

The research team is coordinating with DEVCOM Army Research Laboratory to transfer and transition this knowledge into future Army systems.

Featured image: Army-funded researchers discover how to make materials capable of self-propulsion, allowing materials to move without motors or hands. © Yongjin Kim, UMass Amherst


Reference: Kim, Y., van den Berg, J. & Crosby, A.J. Autonomous snapping and jumping polymer gels. Nat. Mater. (2021). https://doi.org/10.1038/s41563-020-00909-w


Provided by US Army Research Laboratory

Oncotarget: Neuroendocrine Carcinoma of Uterine Cervix Findings Shown by MRI (Medicine)

Oncotarget recently published “Neuroendocrine carcinoma of uterine cervix findings shown by MRI for staging and survival analysis – Japan multicenter study” which reported that to investigate neuroendocrine carcinoma of the uterine cervix cases for MRI features and staging, as well as pathological correlations and survival.

In 50 patients who underwent a radical hysterectomy and lymphadenectomy without neoadjuvant chemotherapy, intrapelvic T staging by MRI overall accuracy was 88.0% with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for metastatic pelvic lymph node detection was 38.5%, 100%, and 83.3%, respectively.

Three-year progression-free and overall survival rates for FIGO I, II, III, and IV were 64.3% and 80.9%, 50% and 64.3%, 0% and 0%, and 0% and 0%, respectively.

Sixty-two patients with histologically surgery-proven uterine cervical NEC were enrolled.

The Oncotarget author’s findings show that MRI is reliable for T staging of cervical NEC.

“The Oncotarget author’s findings show that MRI is reliable for T staging of cervical NEC”

Dr. Kazuhiro Kitajima from The Department of Radiology at The Hyogo College of Medicine said, “Neuroendocrine carcinomas (NECs) of the female genital tract are aggressive uncommon tumors that usually involve the uterine cervix and ovaries, though are very rarely seen in the endometrium.

According to the World Health Organization classification, neuroendocrine tumors in the uterine cervix are categorized into 4 categories; typical carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma.

Cervical NEC has a higher frequency of lymphovascular invasion, lymphatic and distal metastasis, and recurrence as compared to other subtypes of uterine cervical malignancies, e. g., squamous cell carcinoma and adenocarcinoma.

However, findings obtained in smear and cervical biopsy analyses are insensitive and inconclusive for diagnosis of cervical NEC in some patients, due to limited sample size or tumor heterogeneity.

To the best of these researcher’s knowledge, 2 different reports have been presented that include discussion of MRI characteristics of uterine cervical SCNEC, with a small number of patients in each, while no known reports discussing MRI findings of cervical LCNEC are available.

The aim of this study was to identify the distinct features and staging accuracy of uterine cervical NEC, including SCNEC and LCNEC, using MRI, as well as pathological correlations.

The Kitajima Research Team concluded in their Oncotarget Research Paper that NEC of the uterine cervix is rare and affected patients have a poor prognosis, especially advanced stage cases.

A definitive diagnosis based on preoperative MRI results seems to be difficult. Nevertheless, the present as well as other previous findings indicate that a homogeneous lesion texture with an obvious restricted diffusion throughout the tumor are suggestive of uterine cervical NEC.

Furthermore, they found pelvic MRI to provide reliable imaging findings for T staging in these patients.

Featured image: Kaplan-Meier overall survival curves for 62 uterine cervical neuroendocrine carcinoma patients according to FIGO stage. Advanced FIGO staging disease (III, IV) patients (n = 6) showed significantly worse OS as compare to those (n = 56) with early FIGO staging disease (I, II) (p < 0.0001). © Kitajima et al.


Reference: Kitajima K., Kihara T., Kawanaka Y., Kido A., Yoshida K., Mizumoto Y., Tomiyama A., Okuda S., Jinzaki M., Kato F., Takahama J., Takahata A., Fukukura Y., et al Neuroendocrine carcinoma of uterine cervix findings shown by MRI for staging and survival analysis – Japan multicenter study. Oncotarget. 2020; 11: 3675-3686. Retrieved from https://www.oncotarget.com/article/27613/text/


Provided by Impact Journals LLC

Oncotarget: Simvastatin is a Potential Candidate Drug in Ovarian Clear Cell Carcinomas (Medicine)

Oncotarget recently published “Simvastatin is a potential candidate drug in ovarian clear cell carcinomas” which reported that based on previous studies, the authors assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer cell line, Caov3. The authors used the Rho GTPase interfering drug CID-1067700 as a control.

All OCCC cell lines were more sensitive to single-agent simvastatin than the HGSOC cells, while all cell lines were less sensitive to CID-1067700 than to simvastatin.

Most treatments inhibited migration, while only simvastatin and CID-1067700 also disrupted actin organization in the OCCC cell lines.

Treatments with simvastatin consistently reduced c-Myc protein expression in all OCCC cell lines and displayed evidence of causing both caspase-mediated apoptotic cell death and autophagic response in a cell line dependent manner.

Conclusively, simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.

“Simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.”

Dr. Ingrid Hedenfalk from The Lund University said, “Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) accounting for 5–10% of cases diagnosed in Europe and America, while the incidence in Asia is reported to be higher (10–20%).

The Oncotarget authors recently reported Rho GTPases and their associated pathways to be differentially expressed between OCCC compared to the other major EOC subtypes.

Rho GTPases have been studied as targets for cancer treatment in various settings due to their role in regulating key cellular functions including the maintenance of cytoskeletal integrity, cell migration and proliferation, but also in metastasis and progressive disease in many cancer types.

However, targeting Rho GTPases directly is challenging due to their high binding affinity for GTP/GDP, and indirect strategies such as targeting the localization of Rho GTPases to the cell membrane are promising alternatives.

CID-1067700 is a pan-GTPase inhibitor that inhibits binding of GTP/GDP and downstream binding of Rho GTPases to their targets and is used as a comparator for Rho GTPase interference as a druggable target in OCCC.

Based on the deregulated expression of both Rho GTPases and cytoskeletal pathways in primary human OCCC tumors in our previous work, they investigated the potential of simvastatin, a lipophilic statin, as a targeted treatment in OCCC cell lines with CID-1067700 as a comparator in the present study.

The Hedenfalk Research Team concluded in their Oncotarget Research Paper that while HGSOC has been studied intensively, OCCC remains a rare subtype with poor prognosis, but this study, although investigative, demonstrates a potential for simvastatin treatment in OCCC.

Simvastatin could act through Rho GTPase interference as simvastatin affects the cytoskeletal integrity of OCCC cells at levels which can be achieved in plasma.

However, the mechanism is different from Rho GTPase inhibition by CID-1067700.

Furthermore, caution should be given, as this data suggest that a combination with standard chemotherapy may elicit an antagonistic response.

Whether this is of clinical relevance for patients receiving statin treatment remains unclear and needs to be investigated further, but simvastatin holds promise as a potential drug candidate in OCCC and warrants further investigation in the clinical setting.

Featured image: Down-regulation of AKT2 decreases tumorigenic capacity (A) Tumorigenic capacity in vivo. 1 × 106 cells were injected into the right flank of female Balb/c mice. Representative photo shows differential volume of tumor at 30 days after cisplatin treatment and tumor burden was assessed after every 3 days in injected animals, for a total of 30 days. Error bars represent mean ± S. D. versus control.


Reference: Arildsen N. Skovbjerg, Hedenfalk I. Simvastatin is a potential candidate drug in ovarian clear cell carcinomas. Oncotarget. 2020; 11: 3660-3674. Retrieved from https://www.oncotarget.com/article/27747/text/


Provided by Impact Journals LLC

NIH Study Shows Hyaluronan is Effective in Treating Chronic Lung Disease (Medicine)

Naturally produced by the body, hyaluronan represents a new class of biologic that significantly improves lung health in patients with severe COPD.

Researchers at the National Institutes of Health and their collaborators found that inhaling unfragmented hyaluronan improves lung function in patients suffering from severe exacerbation of chronic obstructive pulmonary disease (COPD). Hyaluronan, a sugar secreted by living tissue that acts as a scaffold for cells, is also used in cosmetics as a skin moisturizer and as a nasal spray to moisturize lung airways. Utilized as a treatment, hyaluronan shortened the amount of time COPD patients in intensive care needed breathing support, decreased their number of days in the hospital, and saved money by reducing their hospital stay.

The study, published online in Respiratory Research, is a good example of how examining the impacts of environmental pollution on the lungs can lead to viable treatments. Several years ago, co-senior author Stavros Garantziotis, M.D., medical director of the Clinical Research Unit at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, showed that exposure to pollution causes hyaluronan in the lungs to break down into smaller fragments. These fragments irritate lung tissue and activate the immune system, leading to constriction and inflammation of the airways. He determined that inhalation of healthy, unfragmented hyaluronan reduces inflammation by outcompeting the smaller hyaluronan fragments.

Garantziotis offered an analogy for how the inflammation occurs. He said hyaluronan surrounds cells like mortar surrounds bricks. Introducing pollution causes cracks in the mortar, breaking it into smaller chunks.

“These smaller chunks irritate the body and activate the immune system, leading to inflammation,” Garantziotis said. “Reintroducing the full-length hyaluronan, like a fresh coat of mortar, means it is less irritating and reduces the amount of inflammation.”

Since hyaluronan was approved in Italy for airway moisturization, Garantziotis worked with colleagues in Rome to see if inhalation of full-size hyaluronan could improve lung function in critically ill COPD patients. He explained that the patients were using a breathing apparatus similar to a continuous positive airway pressure (CPAP) machine to treat their acute exacerbation of COPD. This apparatus provided breathing support by blowing air into the airways through a mask.

“Inhaled hyaluronan qualifies as a stimulating aid for patients with exacerbated COPD, as it is safe and easy to administer,” said co-senior author Raffaele Incalzi, M.D., Department of Medicine, Campus Bio-Medico University and Teaching Hospital, Rome. “Furthermore, it acts locally, only in the bronchial tree, and, thus, cannot interfere with any systemic drug.”

Garantziotis also wanted to know what was producing airway constriction in the lungs of COPD patients. He theorized that thick mucus may be involved. Collaborating with scientists at the University of Alabama at Birmingham (UAB), they grew airway cells from emphysema patients in culture and looked at how mucus moved in the cells. They saw that mucus flowed more easily after administering hyaluronan.

Co-author Steven Rowe, M.D., director of the Gregory Fleming James Cystic Fibrosis Research Center at UAB, said if patients with severe COPD took hyaluronan, the treatment would improve mucus transport and aid their recovery.

Current treatments for lung disease include inhaled steroids, antibiotics, and bronchodilators, so using a molecule that is already found in the body is a new concept. The goal now for Garantziotis is to study this treatment in more patients in the U.S., so he can understand the optimal conditions and dosing that will produce the most benefit.

Featured image: The research shows that inhaling hyaluronan interferes at almost every step of the COPD cycle, making it a potent treatment for chronic lung disease. © Stavros Garantziotis, M.D.


Reference: Galdi, F., Pedone, C., McGee, C.A. et al. Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study. Respir Res 22, 30 (2021). https://doi.org/10.1186/s12931-020-01610-x https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01610-x


Provided by NIH/NEIHS

The First Steps Toward a Quantum Brain (Nanotechnology)

An intelligent material that learns by physically changing itself, similar to how the human brain works, could be the foundation of a completely new generation of computers. Radboud physicists working toward this so-called “quantum brain” have made an important step. They have demonstrated that they can pattern and interconnect a network of single atoms, and mimic the autonomous behaviour of neurons and synapses in a brain. They report their discovery in Nature Nanotechnology on 1 February.

Considering the growing global demand for computing capacity, more and more data centres are necessary, all of which leave an ever-expanding energy footprint. ‘It is clear that we have to find new strategies to store and process information in an energy efficient way’, says project leader Alexander Khajetoorians, Professor of Scanning Probe Microscopy at Radboud University.

‘This requires not only improvements to technology, but also fundamental research in game changing approaches. Our new idea of building a ‘quantum brain’ based on the quantum properties of materials could be the basis for a future solution for applications in artificial intelligence.’

Quantum brain

For artificial intelligence to work, a computer needs to be able to recognise patterns in the world and learn new ones. Today’s computers do this via machine learning software that controls the storage and processing of information on a separate computer hard drive. ‘Until now, this technology, which is based on a century-old paradigm, worked sufficiently. However, in the end, it is a very energy-inefficient process’, says co-author Bert Kappen, Professor of Neural networks and machine intelligence.

The physicists at Radboud University researched whether a piece of hardware could do the same, without the need of software. They discovered that by constructing a network of cobalt atoms on black phosphorus they were able to build a material that stores and processes information in similar ways to the brain, and, even more surprisingly, adapts itself.

Self-adapting atoms

In 2018, Khajetoorians and collaborators showed that it is possible to store information in the state of a single cobalt atom. By applying a voltage to the atom, they could induce “firing”, where the atom shuttles between a value of 0 and 1 randomly, much like one neuron. They have now discovered a way to create tailored ensembles of these atoms, and found that the firing behaviour of these ensembles mimics the behaviour of a brain-like model used in artificial intelligence.

In addition to observing the behaviour of spiking neurons, they were able to create the smallest synapse known to date. Unknowingly, they observed that these ensembles had an inherent adaptive property: their synapses changed their behaviour depending on what input they “saw”. ‘When stimulating the material over a longer period of time with a certain voltage, we were very surprised to see that the synapses actually changed. The material adapted its reaction based on the external stimuli that it received. It learned by itself’, says Khajetoorians.

Exploring and developing the quantum brain

The researchers now plan to scale up the system and build a larger network of atoms, as well as dive into new “quantum” materials that can be used. Also, they need to understand why the atom network behaves as it does. ‘We are at a state where we can start to relate fundamental physics to concepts in biology, like memory and learning’, says Khajetoorians.

‘If we could eventually construct a real machine from this material, we would be able to build self-learning computing devices that are more energy efficient and smaller than today’s computers. Yet, only when we understand how it works – and that is still a mystery – will we be able to tune its behaviour and start developing it into a technology. It is a very exciting time.’


Reference: ‘An atomic Boltzmann machine capable of self-adaption’, Nature Nanotechnology, 2021. DOI: 10.1038/s41565-020-00838-4 https://www.nature.com/articles/s41565-020-00838-4


Provided by Radboud University