All posts by uncoverrealityyy

Surgery May Offer Survival Advantage in Certain Metastatic Breast Cancers (Medicine)

Surgery, in addition to treatments like chemotherapy and radiation therapy, may increase the length of survival for metastatic breast cancer patients, according to Penn State College of Medicine and Penn State Cancer Institute researchers. They studied nearly 13,000 stage four breast cancer patients and found that those who had surgery in addition to their other treatments had a survival advantage over those who had other treatments alone.

Surgery, in addition to treatments like chemotherapy and radiation therapy, may increase the length of survival for metastatic breast cancer patients, according to a study of 13,000 stage four breast cancer patients by Penn State College of Medicine and Penn State Cancer Institute researchers. Image: GETTY IMAGES | praetorianphoto

Stage four breast cancer accounts for 6% of newly diagnosed breast cancer cases. Systemic therapy, which may include treatments like chemotherapy, hormone therapies and immunotherapies, is routinely part of treatment plans for those patients. The benefits of surgery to remove the primary breast cancer are currently only recommended for relieving symptoms of advanced breast cancer such as pain and bleeding.

Surgery is the standard of care for some other types of cancers that have spread from the site of origin to another part of the body, known as metastatic cancers. Dr. Kelly Stahl, surgical resident and lead author of the study published in the Annals of Surgical Oncology, said that previous studies evaluating surgical interventions for metastatic breast cancer had conflicting results which has led to a lack of consensus among clinicians and researchers.

“Results from previous trials evaluating surgical benefit in metastatic breast cancer patients have been questioned because of the small number of participants or the fact that patients weren’t also receiving chemotherapy or other systemic therapies,” Stahl said. “We felt another key factor missing from those studies was whether the biologic subtype of breast cancer affected the survival rates in relation to surgical intervention.”

Stahl worked with Dr. Daleela Dodge and Chan Shen to identify 12,838 stage four breast cancer patients from the National Cancer Database from 2010-2015 and whether these patients’ cancer cells had a growth-promoting protein called HER2 and hormone receptors for estrogen and progesterone, which can fuel cancer growth. The researchers said knowing these characteristics of a cancer’s biological subtype can help determine which treatment plans may be effective.

Stahl studied patients who either had systemic therapy alone, had systemic therapy and surgery, or had systemic therapy, surgery and radiation. She and her coauthors then evaluated whether certain biologic subtypes and timing of chemotherapy were associated with survival advantages.

“We evaluated whether the hormone status had an influence on surgical benefit in these treatment-responsive breast cancer patients,” said Dodge, an associate professor of surgery and humanities. “Some types of breast cancer, especially like triple negative, where the cancer is hormone receptor and HER2 negative, are not very responsive to treatment. So our goal was to see if surgery made a difference in metastatic breast cancers that were responsive to treatment.”

The researchers excluded patients who died within six months of their diagnoses, in order to ensure that treatment-responsive cancers were being studied. They found that patients with a surgical intervention tended to have a longer length of survival compared to patients with other treatment plans. Patients whose cancers were HER2 positive especially saw prolonged survival when their treatment plan included surgery.

Stahl and her coauthors further analyzed the patients who received surgery to see whether receiving chemotherapy before or after surgery had an impact on their length of survival. They found that regardless of hormone receptor or HER2 status, patients who received systemic therapy — including chemotherapy and targeted treatments — before surgery tended to live longer than those who had surgery before systemic treatment.

“Not only did we find that surgery may be beneficial for treatment-responsive metastatic breast cancer patients, we also uncovered that getting chemotherapy before that surgery had the greatest survival advantage in patients with positive HER2 and estrogen and progesterone receptor status,” said Shen, associate professor of surgery.

The researchers said that randomized, controlled trials evaluating the role of surgery after systemic therapy in a younger demographic with minimally metastatic cancers could be used to confirm their results, but said that patient resistance to randomization in trials like this have resulted in poor study recruitment. Therefore, they encourage clinicians to evaluate real-world evidence, including their study, to choose optimal treatment for metastatic breast cancer patients.

“Stage four breast cancer patients who are responsive to systemic therapy may be able to benefit from the addition of surgery regardless of their biologic subtype,” Stahl said.

William Wong, Ashton Brooks, Christopher McLaughlin, Elizabeth Olecki, Joseph Lewcun, Kristina Newport and Monali Vasekar of Penn State College of Medicine also contributed to this research.

The authors declare no conflicts of interest or specific financial support.

Reference: Stahl, K., Dodge, D. & Shen, C. ASO Author Reflections: Surgery Offers Survival Advantage in Treatment-Responsive Metastatic Breast Cancer. Ann Surg Oncol (2020). https://link.springer.com/article/10.1245%2Fs10434-020-09286-9 https://doi.org/10.1245/s10434-020-09286-9

Provided by Penn State

The Brain’s Protein Factories At Work (Neuroscience)

Protein synthesis is a finely tuned process in the cell by macromolecules known as ribosomes. Which regulators are responsible for controlling protein synthesis in the brain, and how do they exert their control on the ribosome? To address this question, a team of researchers from Charité – Universitätsmedizin Berlin studied the structure of the brain’s ribosomal complexes in great detail. The team was able to identify a new factor which is also involved in controlling brain development. Details of this research have been published in Molecular Cell.

A snapshot of protein synthesis in action inside the developing brain. Image: M.L. Kraushar/Charité

Proteostasis refers to maintaining a delicate balance of protein levels in the cell, which is of particularly crucial importance to neurons. Abnormal protein production is a characteristic feature of many brain disorders. High precision protein production is of immense importance during the early development of a complex part of the cerebral cortex known as the neocortex. It is particularly important in the production of membrane proteins, which play an important role in cell-to-cell sites of synaptic contact between nerve cells. As the cell’s ‘molecular protein factories’, ribosomes are at the heart of the regulatory processes involved in proteostasis. A range of molecules can influence ribosome function, and are responsible for controlling the production of specific proteins in different tissues and at different developmental stages. The way in which these various factors interact with the ribosome during development remains widely unknown. However, a group of Charité researchers has successfully observed protein production by ribosomes in the developing brain.

“It is the first time the ribosomal complex has been visualized in action inside the brain at near atomic-level resolution,” says Prof. Dr. Christian Spahn, Director of Charité’s Institute of Medical Physics and Biophysics. “While the structure of the ribosomal complex has been mapped in other tissues and organisms, our approach enabled us to identify Ebp1 as the new key factor responsible for controlling both ribosome function and the synthesis of specific proteins during brain development.” The interaction between the regulatory protein Ebp1 (short for ErbB3 binding protein 1) and the ribosome takes place at the ribosome’s exit tunnel, through which the newly formed protein chain emerges from the ribosome. Through this interaction, Ebp1 influences the production of membrane proteins that play an important role in neuronal interactions, thus maintaining neuronal proteostasis.

As part of a multidisciplinary project linking aspects of structural biology and neuroscience, the researchers used cryo-electron microscopy (cryo-EM) as their main investigative tool, combining it with mass spectrometry, RNA sequencing and genetic techniques. The cryo-EM imaging technique enables scientists to determine protein structures – particularly larger complexes comprising multiple molecules – at extremely low temperatures and near-physiological conditions. The study’s first author, Dr. Dr. Matthew L. Kraushar (a neuroscientist at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin and previously a member of Prof. Spahn’s laboratory), explains: “We could therefore visualize the molecular architecture of the ribosome at high resolution, as it would be found inside brain cells. We were able to capture snapshots of the ribosome in action.”

“Protein production in various types of brain cells is subject to finely tuned control mechanisms. Small changes can lead to big consequences, such as neurodegenerative diseases or disrupted development. Our findings on the role of ribosomes during normal brain development will help us to better understand pathological changes affecting the brain,” says Prof. Spahn. As a next step, the researchers are conducting a large-scale study to understand the way ribosomes translate messages from the genetic code (mRNA) into numerous essential proteins throughout brain development.

Reference:- Kraushar ML et al. Protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit. Mol Cell. 2020 Dec 22. doi: 10.1016/j.molcel.2020.11.037 https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30837-6

Provided by Universitätsmedizin Berlin

Scientists Suggested A Way to Measure Soil Properties at Any Depth Without Digging (Engineering)

A team of scientists from RUDN University and the Dokuchyaev Soil Science Institute developed a method for identifying the color of soil at different depths and the structure of soil profile using ground-penetrating radar. With this methodology, scientists can identify the chemical composition of the soil and classify it for potential use in construction, agriculture, or mining without digging soil sections. The results of the study were published in the Eurasian Soil Science journal.

A team of scientists from RUDN University and the Dokuchyaev Soil Science Institute developed a method for identifying the color of soil at different depths and the structure of soil profile using ground-penetrating radar. With this methodology, scientists can identify the chemical composition of the soil and classify it for potential use in construction, agriculture, or mining without digging soil sections. © RUDN University

Color is one of the main indicators of soil properties. Based on it, a specialist can identify the type of soil, humus content, soil density, humidity, salinity, and so on. For example, black soil is rich in humus, and soils with increased iron content usually have a reddish hue. To analyze the color of the soil, scientists have to dig a soil section which is quite a labor-intensive process. A team of scientists from RUDN University together with their colleagues from the Dokuchyaev Soil Science Institute suggested using ground-penetrating radar to determine the color of the soil at different depths. A GPR sends electromagnetic waves to the soil and registers a reflected signal.

“Color is one of the main properties of soils that has been used for their classification for a long time. That is why many names of soils are associated with color. Moreover, color is an integral indicator of many other characteristics of soils. Theoretically, this parameter could be measured with GPR. We wanted to confirm a correlation between the colors of soil layers and GPR profiling data,” said Prof. Igor Savin, an Academician of the Russian Academy of Sciences and a Ph.D. in Agricultural Sciences from the Faculty of Ecology, RUDN University.

The team conducted an experiment in Kamennaya Steppe (Voronezh Region) because this area is known for a large variety of soil types and conditions. The scientists chose seven sites and probed the soils there with ground-penetrating radar. They also took 30 soil samples from each site: one from each 10 cm deep layer down to the depth of 3 m. The samples were dried and ground to identify the color. To do so, the team analyzed their reflective capacity that was averaged to three wavelength ranges: red (610-700 nm), green (520-540 nm), and blue (450-475 nm). After that, the team compared the radar readings with the colors of soil samples and developed a correlation model. The colors calculated with the use of the model matched the actual ones in 80% of cases. Therefore, the new method can be used to determine soil color on other sites in the territory of the study without digging soil sections.

Currently, the model is only applicable to the territory of Kamennaya Steppe because it was calibrated based on the samples collected there. In the future, the team hopes to adapt it to other areas.

“Our models cannot be used in territories with different soil covering. However, it is not a disadvantage, but rather a peculiarity of our method. To secure modeling accuracy, the model should include information about soil colors that are typical for the area of the study. In the initial stages, control soil sections would still have to be made using traditional methods. However, as soon as we accumulate enough field data, we would be able to eliminate this step, and no digging would be required to identify soil color at any depth,” added Prof. Igor Savin from RUDN University.

Reference: Voronin, A.Y., Savin, I.Y. Correlation between Color of Subsurface Soil Horizons and Ground-Penetrating Radar Data. Eurasian Soil Sc. 53, 1119–1131 (2020). https://link.springer.com/article/10.1134%2FS1064229320080165 https://doi.org/10.1134/S1064229320080165

Provided by RUDN University

Volcanic Eruptions Directly Triggered Ocean Acidification During Early Cretaceous (Earth Science)

First study to use stable calcium and strontium isotopes to examine oceanic anoxic event.

  • Study supports hypothesis that Ontong Java Plateau large igneous province eruptions led to oceanic anoxic event 1a
  • This event is associated with a minor mass extinction in the Early Cretaceous
  • Researchers analyzed stable calcium and strontium isotopes in prehistoric fossils 
  • Fossils were obtained from a core, drilled in the middle of the Pacific Ocean
  • By studying ancient greenhouse periods, researchers can better predict the effects of human carbon emissions

Around 120 million years ago, the earth experienced an extreme environmental disruption that choked oxygen from its oceans.

Calcium carbonate samples from a sediment core drilled from the mid-Pacific Mountains show evidence of ocean acidification 127 to 100 million years ago. © Northwestern University

Known as oceanic anoxic event (OAE) 1a, the oxygen-deprived water led to a minor — but significant — mass extinction that affected the entire globe. During this age in the Early Cretaceous Period, an entire family of sea-dwelling nannoplankton virtually disappeared.

By measuring calcium and strontium isotope abundances in nannoplankton fossils, Northwestern earth scientists have concluded the eruption of the Ontong Java Plateau large igneous province (LIP) directly triggered OAE1a. Roughly the size of Alaska, the Ontong Java LIP erupted for seven million years, making it one of the largest known LIP events ever. During this time, it spewed tons of carbon dioxide (CO2) into the atmosphere, pushing Earth into a greenhouse period that acidified seawater and suffocated the oceans.

“We go back in time to study greenhouse periods because Earth is headed toward another greenhouse period now,” said Jiuyuan Wang, a Northwestern Ph.D. student and first author of the study. “The only way to look into the future is to understand the past.”

The study was published online last week (Dec. 16) in the journal Geology. It is the first study to apply stable strontium isotope measurements to the study of ancient ocean anoxic events.

Andrew Jacobson, Bradley Sageman and Matthew Hurtgen — all professors of earth and planetary sciences at Northwestern’s Weinberg College of Arts and Sciences — coauthored the paper. Wang is co-advised by all three professors.

Clues inside cores

Nannoplankton shells and many other marine organisms build their shells out of calcium carbonate, which is the same mineral found in chalk, limestone and some antacid tablets. When atmospheric CO2 dissolves in seawater, it forms a weak acid that can inhibit calcium carbonate formation and may even dissolve preexisting carbonate.

Calcium carbonate samples from a sediment core drilled from the mid-Pacific Mountains show evidence of ocean acidification 127 to 100 million years ago. © Northwestern University

To study the earth’s climate during the Early Cretaceous, the Northwestern researchers examined a 1,600-meter-long sediment core taken from the mid-Pacific Mountains. The carbonates in the core formed in a shallow-water, tropical environment approximately 127 to 100 million years ago and are presently found in the deep ocean.

“When you consider the Earth’s carbon cycle, carbonate is one of the biggest reservoirs for carbon,” Sageman said. “When the ocean acidifies, it basically melts the carbonate. We can see this process impacting the biomineralization process of organisms that use carbonate to build their shells and skeletons right now, and it is a consequence of the observed increase in atmospheric CO2 due to human activities.”

Strontium as corroborating evidence

Several previous studies have analyzed the calcium isotope composition of marine carbonate from the geologic past. The data can be interpreted in a variety of ways, however, and calcium carbonate can change throughout time, obscuring signals acquired during its formation. In this study, the Northwestern researchers also analyzed stable isotopes of strontium — a trace element found in carbonate fossils — to gain a fuller picture.

“Calcium isotope data can be interpreted in a variety of ways,” Jacobson said. “Our study exploits observations that calcium and strontium isotopes behave similarly during calcium carbonate formation, but not during alteration that occurs upon burial. In this study, the calcium-strontium isotope ‘multi-proxy’ provides strong evidence that the signals are ‘primary’ and relate to the chemistry of seawater during OAE1a.”

“Stable strontium isotopes are less likely to undergo physical or chemical alteration over time,” Wang added. “Calcium isotopes, on the other hand, can be easily altered under certain conditions.”

The team analyzed calcium and strontium isotopes using high-precision techniques in Jacobson’s clean laboratory at Northwestern. The methods involve dissolving carbonate samples and separating the elements, followed by analysis with a thermal ionization mass spectrometer. Researchers have long suspected that LIP eruptions cause ocean acidification. “There is a direct link between ocean acidification and atmospheric CO2 levels,” Jacobson said. “Our study provides key evidence linking eruption of the Ontong Java Plateau LIP to ocean acidification. This is something people expected should be the case based on clues from the fossil record, but geochemical data were lacking.”

Modeling future warming

By understanding how oceans responded to extreme warming and increased atmospheric CO2, researchers can better understand how earth is responding to current, human-caused climate change. Humans are currently pushing the earth into a new climate, which is acidifying the oceans and likely causing another mass extinction.

“The difference between past greenhouse periods and current human-caused warming is in the timescale,” Sageman said. “Past events have unfolded over tens of thousands to millions of years. We’re making the same level of warming (or more) happen in less than 200 years.”

“The best way we can understand the future is through computer modeling,” Jacobson added. “We need climate data from the past to help shape more accurate models of the future.”

Reference: Jiuyuan Wang, Andrew D. Jacobson, Bradley B. Sageman, Matthew T. Hurtgen; Stable Ca and Sr isotopes support volcanically triggered biocalcification crisis during Oceanic Anoxic Event 1a. Geology doi: https://doi.org/10.1130/G47945.1 https://pubs.geoscienceworld.org/gsa/geology/article-abstract/doi/10.1130/G47945.1/593341/Stable-Ca-and-Sr-isotopes-support-volcanically?redirectedFrom=fulltext

Provided by Northwestern University

The Achilles’ Heel of Cancer Stem Cells (Medicine)

Since colonoscopies were introduced in Germany for early cancer detection, the number of diagnoses of advanced cancer every year has decreased, as precancerous lesions can now be detected and immediately removed as part of the examination. As a result, the death rate from colon cancer has also gone down – by 26 percent in women and 21 percent in men. Nevertheless, it remains the fourth deadliest cancer in the Western world – just behind lung, prostate and breast cancer. This is because the slow-growing tumors only become noticeable in the advanced stages of the disease and are therefore often diagnosed too late. Survival rate for advanced colorectal cancer is just five percent.

Expanding cancer stem cells (green) in a colon tumor with an oncogenic activated Wnt/beta-catenin signaling pathway (red). © Birchmer Lab, MDC

“Treatment options are very limited – not least because the cancer can return even after successful chemotherapy,” explains Johanna Grinat, the study’s lead author and a doctoral student in the Signal Transduction in Development and Cancer Lab. “The recurrent cancer is often more aggressive than the original tumor, which is thought to be caused by cancer stem cells. So we took a closer look at these cells.”

Molecular switch found in cancer stem cells

The researchers led by Professor Walter Birchmeier identified Mll1, a protein that regulates stem cell genes in mice and in human colon cancer cells. In mice, the team was able to genetically trigger the formation of intestinal tumors. However, if the mice lacked the gene for Mll1, no tumors were able to be induced. And this seems to be the case in humans as well: Human colon cancer cell cultures that the scientists enriched with cancer stem cells lost some of their stem cell properties and behaved less aggressively when Mll1 was blocked. Together with Professor Eduard Batlle and bioinformaticians at the IRB in Barcelona, the MDC group used clinical data to show that colon cancer patients whose tumors have a large amount of this protein have a worse prognosis than patients with tumors that contain little Mll1.

Mll1 is an enzyme that sits on the DNA and controls the expression of certain genes “epigenetically,” as the researchers say. “It primarily does this in cancer stem cells, where the Wnt signaling pathway is strongly activated,” Grinat explains. “This means that, by deactivating it, we can specifically treat cancer stem cells.”

The Wnt signaling pathway regulates the self-renewal and division of stem cells. If mutations occur that trigger a more active Wnt signaling cascade, the affected stem cells become more resistant than healthy stem cells. They then multiply uncontrollably and form tumors. Although chemotherapy slows down the cell division, it can also increase the selection pressure on cancer stem cells: “They become resistant to the treatment and form new tumors that, due to the mutation, grow more rapidly and are even more aggressive,” says Dr. Julian Heuberger. This is why it is so important, he explains, to understand the regulatory mechanisms of cancer stem cells in particular. The postdoctoral researcher is also lead author and head of the study and now works in the Division of Hepatology and Gastroenterology in the Medical Department of Charité – Universitätsmedizin Berlin. “With Mll1,” he adds, “we have found a molecular switch that primarily controls the self-renewal and division of cancer stem cells in colon cancer”

Hope and more effective therapies

Genetically “knocking out” a gene, as the scientists did with mice, is not possible in humans. In mice, the formation of cancer stem cells can be followed over time and there are always enough stem cells available for experiments. However, MII1 could be blocked with a chemical drug. Small molecules have already been developed for this research, for example, the inhibitors MI-2 and MM-401, which bind to essential Mll1 complexes and thereby inactivate its function. “Understanding the way these molecules work will enable us to develop and test these and even more clinically effective Mll1 inhibitors,” says Birchmeier, who is the study’s last author.

Healthy stem cells in the intestine are apparently not blocked in the process. “We were able to use another system in mice, salivary gland cancer cells, to show that Mll1 only affects cancer cells and not healthy stem cells,” says Birchmeier. This also provides hope for the treatment of other types of cancer, as animal models have shown that head and neck tumors have the same Achilles’ heel. “On the basis of our mouse studies, clinical trials are currently being conducted at the University Hospital of Düsseldorf to evaluate the use of Mll1 inhibitors in the treatment of head and neck tumors.”

If they are successful, patients with colon cancer could be treated in the future with both chemotherapy and Mll1 inhibitors, i.e., therapeutics that specifically impede cancer stem cells. This increases the chances of a successful treatment – even with advanced colon cancer.

Reference: Grinat, J., Heuberger, J., Vidal, R.O. et al. The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness. Nat Commun 11, 6422 (2020). https://www.nature.com/articles/s41467-020-20222-z https://doi.org/10.1038/s41467-020-20222-z

Provided by Max Delbruck Center For Molecular Medicine in the Helmholtz Association

Corona: How The Virus Interacts With Cells (Medicine)

Scientists from Würzburg and the US have charted the first global atlas of direct interactions between SARS-CoV-2 RNA and human host cells. This may provide a starting point for novel treatments.

18 host proteins play an important role during SARS-CoV-2 infection – two of them are particularly interesting. They could open up new ways to treat infections with SARS-CoV-2 and other RNA viruses. © SCIGRAPHIX / S. Westermann

SARS-CoV-2 infections pose a global threat to human health and a formidable research challenge. One of the most urgent tasks is to gain a detailed understanding of the molecular interactions between the virus and the cells it infects. It must also be clarified, whether these interactions favour the multiplication of the virus or – on the contrary – activate defence mechanisms.

In order to multiply, SARS-CoV-2 uses proteins of the host cell. However, thus far no detailed information on the part of the human proteome – i.e. the total of all proteins occurring in human cells – that is in direct contact with the viral RNA existed.

Publication in Nature Microbiology

This void has now been filled. Scientists from the Helmholtz Institute for RNA-based Infection Research (HIRI) Würzburg, the Julius-Maximilians-Universität Würzburg (JMU) and the Broad Institute (Cambridge, USA) have succeeded in creating the first global atlas of direct interactions between the SARS-CoV-2 RNA and the proteome of the human host. In addition, the authors identified important regulators of viral replication. Dr Mathias Munschauer from HIRI and Professor Jochen Bodem from the Institute of Virology and Immunobiology at JMU were responsible for the study. They present the results of their work in the latest issue of the journal Nature Microbiology.

In the biosafety level 3 suite at HIRI, the scientists infected human cells with the new coronavirus, which uses RNA as genetic material. In a second step, they purified the viral RNA and identified the proteins bound to it. “Mass spectrometry allows us to accurately determine the host proteins that directly associate with the viral genome. In this particular case, we were able to perform quantitative measurements to identify the strongest specific binding partners,” says Mathias Munschauer.

18 proteins, 2 key factors and 20 potential inhibitors

“The atlas of RNA-protein interactions created in this way offers unique insights into SARS-CoV-2 infections and enables the systematic breakdown of central factors and defence strategies, a crucial prerequisite for the development of new therapeutic strategies,” says Jochen Bodem. In total, the scientists identified 18 host proteins that play an important role during SARS-CoV-2 infection.

According to them, the two factors CNBP and LARP1 are particularly interesting. Using genetic tools, the authors identified the exact binding sites of these two host proteins in the viral genome and showed that they can specifically inhibit the replication of the virus. According to Mathias Munschauer, the characterisation of LARP1 as an antiviral factor is a major finding: “The way LARP1 binds to viral RNA is very interesting, because it is similar to the way LARP1 regulates certain cellular messenger RNAs that we already know. This in turn provides insights into possible mechanisms of action.”

The multidisciplinary nature of the study also enabled the identification of 20 small molecule inhibitors of host proteins that bind SARS-CoV-2 RNA. The authors show that three out of four inhibitors tested actually inhibit viral replication in different human cell types. This result could open up new ways to treat infections with SARS-CoV-2 and other RNA viruses.

Reference: Schmidt N, Lareau C, Keshishian H, Ganskih S, Schneider C, Hennig T, Melanson R, Werner S, Wei Y, Zimmer M, Ade J, Kirschner L, Zielinski S, Dölken L, Lander ES, Caliskan N, Fischer U, Vogel J, Carr SA, Bodem J, Munschauer M (2020) The SARS-CoV-2 RNA-protein interactome in infected human cells. Nature Microbiology in press, https://www.nature.com/articles/s41564-020-00846-z https://doi.org/10.1038/s41564-020-00846-z

Provided by University of Wurzburg

How Fear of the Unknown Influences Decision-making (Psychology)

Fear of unknown is a risk factor for addiction.

The dictionary definition of uncertainty is experiencing an unknown, unpredictability, and unfamiliarity. We live in a world filled with uncertainty. It is hard to predict what will happen to us in the future.

©Stockmarket

The capacity to tolerate unknowns fuel the experience of anxiety and worry. Individuals with high intolerance of uncertainty (IU) are vulnerable to increased worry and distress in the face of uncertainty. Experiencing “what if” questions are common among those who experience severe anxiety, which is a source of impairments in their lives (Carleton, 2016).

Anxiety is an emotion caused by unpredictable potential threats that may occur in the future. Anxiety is potential harm rather than certain harm. Uncertainty impairs our ability to prepare for future events. Anxiety felt in the face of uncertainty can result in maladaptive behaviors such as impulsive decision making and unhealthy behaviors.

Intolerance of uncertainty is a cognitive bias that affects how a person perceives, interprets, and responds to uncertain situations. For example, if you have social anxiety, you are uncertain how you may look asking a question. The negative experience of uncertainty could lead you to exaggerate the threat (e.g., I am going to look stupid and will be humiliated). People who are the most intolerant of uncertainty are more likely to take efforts to try to control the situation or avoid uncertainty (McEvoy & Mahoney, 2012). This explains why a shy student may not volunteer to ask questions.  

Higher IU is associated with a tendency to make hasty decisions to alleviate distress in stressful situations. Waiting in uncertain situations tends to be perceived as highly unpleasant, leading to poor choices (Luhmann et al., 2011). Not surprisingly, IU has been linked to indecisiveness.

Higher IU is a risk factor for developing an addiction if substance abuse is used as a way of coping in the face of unavoidable uncertainty. For example, drinking alcohol is used as an avoidance strategy to cope with worry and distress (Gorka, et al., 2016). Those who have the tendency to find uncertain outcomes distressing and unpleasant are likely to find alcohol use to be highly motivating which sets the stage for continued and escalated drinking (Kraemer et al., 2015).

IU can also lead to an eating disorder in attempts to control the anxiety (Kesby et al., 2109). For instance, women with Anorexia Nervosa (AN) experience significantly higher degrees of IU compared to women with other types of eating disorders. Food restriction in AN may, in part, represent an attempt to avoid the fear of gaining weight and/or obsession with thinness. Thus, the fear of the unknown in individuals with AN represents a vulnerability factor for the inflexible mindset.

The capacity to tolerate unknowns is likely to be determined and maintained by a complex interplay of many factors, such as genes, temperament, and self-efficacy (McEvoy and Mahoney, 2012). Intolerance to uncertainty is a personality trait that runs in the family. A meta-analysis found that 40% of individual differences in personality traits have genetic origins. It is possible that genetic factors predispose one to develop IU. These genes may also interact with environmental factors such as stressful life events, parental neglect, and abusive parenting styles.  

The intolerance of uncertainty also varies with control (or self-efficacy). Control can be thought of as the belief that one has at one’s disposal a response that can influence the aversiveness of an event. People with a high level of fear of unknowns will likely have limited perceptions of self-efficacy, and a greater need for predictability.

In sum, the presence of uncertainty is often unpleasant, and individuals’ reactions vary along a continuum in terms of the extent to which they are comfortable with uncertainty. Research shows that treatments designed to increase acceptance of uncertainty and exposure to uncertainty are successful in increasing tolerance for uncertainty (Olatunji, 2019).

References: (1) Carleton RN (2016). Into the unknown: a review and synthesis of contemporary models involving uncertainty, Journal of Anxiety Disorders, vol. 39, pp. 30–43. (2) Gorka SM, Hee D, Lieberman L, Mittal VA, Phan KL, Shankman SA (2016) Reactivity to uncertain threat as a familial vulnerability factor for alcohol use disorder. Psychol Med 46:3349–3358. (3) Kesby, A., Maguire, S., Vartanian, L.R., Grisham, J.R (2018), Intolerance of uncertainty and eating disorder behaviour: Piloting a consumption task in a non-clinical sample. Journal of Behavior Therapy and Experimental Psychiatry; 65:101492. (4) Kraemer KM, McLeish AC, O’Bryan EM (2105). The role of intolerance of uncertainty in terms of alcohol use motives among college students. Addict. Behav. 42:162–166. (5) Luhmann C, Ishida K, Hajcak G (2011). Intolerance of uncertainty and decisions about delayed, probabilistic rewards. Behav Ther. 42(3):378. (6) McEvoy PM, Mahoney AEJ (2012). To be sure, to be sure: Intolerance of uncertainty mediates symptoms of various anxiety disorders and depression. Behav Ther.;43(3):533–45. (7) Olatunji BO (2019). The Cambridge Handbook of Anxiety and Related Disorders. Cambridge University Press.

This article is originally written by Shahram Heshmat, who is an associate professor emeritus of health economics of addiction at the University of Illinois at Springfield. This article is republished here from psychology today under common creative licenses

New Drug Molecules Hold Promise For Treating Rare Inherited Terminal Childhood Disease (Medicine)

Scientists at the University of Exeter have identified a way to “rescue” cells that have genetically mutated, paving the way to a possible new treatment for rare terminal childhood illness such as mitochondrial disease.

Mitochondria. Credit: Wikipedia commons

The research, funded by the United Mitochondrial Disease Foundation in the U.S., was led by Professors Matt Whiteman and Tim Etheridge. In the study, published in the Journal of Inherited Metabolic Disease, the team used novel drugs being developed at the University of Exeter, which “metabolically reprogramme” mitochondria—the cellular energy production centers in cells, by providing them with an alternative fuel source to generate metabolic energy in the form of minute quantities of hydrogen sulfide.

The team used microscopic worms (C. elegans) with specific genetic mutations affecting energy production, that match mutations that cause human diseases such as Leigh Syndrome. The team found that administering the new compounds to these animals successfully normalized or improved energy production needed to keep them healthy and active.

Professor Tim Etheridge, of the University of Exeter, one of the study authors, said: “Worms are a very powerful genetic tool to study human health and disease and offer an ideal platform to quickly identify new potential therapeutics. The worms used in this study had genetic defects in how their mitochondria regulate cellular energy production to model different human mitochondrial diseases. The novel compounds we are developing at the University of Exeter are able to bypass some of these defects and keep the worms, and their mitochondria healthy. We know this because we saw improvements in physical activity and improvements in muscle and mitochondrial integrity. The animals also lived for longer after treatment but more importantly, they remained active for longer, because of metabolic reprogramming.”

The team had previously shown that the compounds had potent therapeutic effects in mammalian models with defective mitochondria. In those studies, the animals’ mitochondria became defective as result of a disease process. In the latest study however, the defective mitochondria were the direct cause of the disease, as in human mitochondrial disease and were still successfully treated with the Exeter compounds. The fact that the compounds could reverse some of these inherited defects in energy metabolism strongly suggest that their effect will translate to humans, and the team is confident this can be tested in the near future.

Lead author Professor Matt Whiteman, of the University of Exeter, said: “Mitochondrial diseases, and their related conditions, are areas of huge and desperate unmet clinical need. Our study is an important first step and a lot of work still needs to be done. For the first time, we have demonstrated that our new molecules have successfully metabolically reprogrammed, or rescued, cells in animals with genetic defects in their mitochondria. We’re currently testing newer and more potent molecules able to do the same task, through slightly different approaches, and we’re looking for commercial partners to help our efforts to progress our molecules through to clinical testing.”

The paper is titled “The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.”

Reference: Bridget C. Fox et al. The Mitochondria‐targeted Hydrogen Sulfide Donor Ap39 Improves Health and Mitochondrial Function in A C. Elegans Primary Mitochondrial Disease Model, Journal of Inherited Metabolic Disease

Provided by University of Exeter

Unravelling The Multifaceted Mechanisms Of Cancer Cell Death By Mutant p53 Targeting Compound APR-246 (Medicine)

Sophia Ceder and Klas Wiman and their colleagues at Department of Oncology-Pathology have together with researchers from Peter MacCallum Cancer Center, University of Melbourne, University of Cambridge and Aprea Therapeutics published a study in EMBO Molecular Medicine that provides novel understanding on the mechanisms of mutant p53 targeting compound APR-246.

Around half of all tumors carry mutations in the tumor suppressor gene TP53 which is often associated with poor prognosis. The molecule APR-246 (Eprenetapopt) was discovered by Wiman and colleagues around 20 years ago (Bykov et al 2002) and is today the clinically most advanced compound that targets mutant p53. Currently, APR-246 is undergoing a Phase III clinical trial in mutant TP53 myelodysplastic syndrome (MDS) and several Phase II studies in various indications. Earlier this year APR-246 received FDA Breakthrough Therapy Designation for the combination with Azacitidine for the treatment of mutant TP53 MDS and recently also received FDA Fast Track Designation in mutant TP53 acute myeloid leukemia (AML).

The study investigates the multifaceted mechanisms of action of APR-246 to improve therapeutic efficacy and increase our understanding of APR-246 pharmacodynamics in cancer cells. APR-246 targets mutant p53 and also induces oxidative stress by binding glutathione (GSH) or inhibiting antioxidant enzymes, both major mechanisms of APR-246-mediated cancer cell death. MQ, the active conversion product of APR‐246, forms reversible conjugates with the major antioxidant GSH. The study shows that this complex (GSH bound-MQ) can be exported through the multidrug resistance‐associated protein 1 (MRP1) efflux pump and that blocking MRP1 traps MQ inside cancer cells. This forms an intracellular drug reservoir that may enhance targeting of mutant p53 and disrupt the intracellular redox balance. Blocking MRP1 in combination with APR-246 expands the therapeutic window and leads to pronounced synergistic cancer cell death in vitro in cancer cell lines, ex vivo in patient-derived organoids and in vivo in mice with tumor xenografts.

In conclusion, the study explains the dynamics of APR‐246 and MQ in cancer cells and indicates that MRP1 can play a key role in the sensitivity to APR‐246. Altogether our findings suggest that combination treatment with APR‐246 and drugs that target the redox balance may allow more efficient cancer therapy.

Reference: Sophia Ceder et al. A thiol‐bound drug reservoir enhances APR‐246‐induced mutant p53 tumor cell death, EMBO Molecular Medicine (2020). DOI: 10.15252/emmm.201910852

Provided by Karolinska Institutet