Culture

Burkholderia pseudomallei is a bacterium in the soil that causes melioidosis, a tropical disease with high morbidity and mortality. Recently, researchers at the NUS Yong Loo Lin School of Medicine discovered that Burkholderia infection sets off a series of events that provoke the host's immune system and cause the infected cells to self-destruct. The work was published on 22 June in the prestigious journal Proceedings of the National Academy of Sciences U.S.A.

When Burkholderia pseudomallei infects cells, it can cause the infected cells to fuse with other cells around them, forming giant cells with many nuclei. Dr Joanne Wei-Kay Ku and Associate Professor Gan Yunn Hwen, both from the Department of Biochemistry and the NUSMed Infectious Disease Programme, as well as their co-authors found that this cell fusion event stimulated the type 1 interferon (IFN) signaling pathway, which modulates the immune system to fight against invading pathogens such as bacteria and viruses.

Interestingly, the act of the cells fusing, rather than the bacterial infection, was the trigger to the immune system because the type 1 IFN signaling pathway was also stimulated when cell fusion was induced by the addition of a chemical. The researchers found that the giant cells did not behave like normal cells. Firstly, they started to divide but could not complete the process (Images 1 and 2; Video). Secondly, the DNA in the giant cells was damaged, making it more unstable (prone to changes such as mutations). These are ripe conditions for the cells to transform into cancer cells.

One of the hallmarks of damaged, unstable DNA is the presence of micronuclei, which form when bits of DNA fail to segregate properly during cell division. When these micronuclei rupture (which they are prone to do), the DNA is made accessible to factors in the cytosol. A/Prof Gan and team observed micronuclei in the giant cells and a corresponding activation of the cGAS-STING pathway of the immune system, which senses the out-of-place DNA and is known to lead to type 1 IFN signaling.

However, under the onslaught of extensive cell fusion, the activated cGAS-STING pathway turns on an unusual death program known as autophagy instead of producing type 1 IFN. This causes these abnormal giant cells to self-destruct. Since unnatural cell fusion is often accompanied with DNA damage and instability, the killing mechanism could be a powerful way to destroy cells before they become cancerous.

The ability of our immune system to "sense" different forms of danger such as viral or bacterial invaders is well known. However, it took an unusual pathogen like Burkholderia bacteria for researchers to discover that abnormal cell fusion is a novel danger signal sensed by the immune system. These findings add to our understanding of how the immune system resists abnormally fused cells, whether a result of infections or through exposure to chemicals, from turning into cancer cells.

A/Prof Gan further explained the importance of knowing your enemy, "Our microbial adversaries are often our best teachers. Learning how to cure and control infections are critically important. However, understanding the interactions between pathogen and host is equally important, because it allows us to discover what our immune system is capable or incapable of, and these fundamental discoveries can give us new perspectives in maintaining health and treating disease."

The cover for issue 27 of Oncotarget features Figure 4, "(A) Bimodal imaging examples of control and treated tumors (red) before and after the treatment period," by Browning, et al. and reported that the authors developed a 3-dimensional bioprinted skin model of cutaneous squamous cell carcinoma (cSCC) tumors together with a microscopy assay to test chemotherapeutic effects in tissue.

Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls.

The imaging biomarkers also showed that normal keratinocytes were less affected by treatment than the untreated tissue, which had no significant killing effect.

Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes.

The authors' 3DBPS assay platform provides the cellular-level measurement of cell viability and can be adapted to achieve non-destructive high-throughput screening in bio-fabricated tissues.

"The authors' 3DBPS assay platform provides the cellular-level measurement of cell viability and can be adapted to achieve non-destructive high-throughput screening in bio-fabricated tissues"

Dr. Daniel S. Gareau from The Laboratory for Investigative Dermatology at The Rockefeller University, New York said, "Global incidence of cSCC is 2.2 million people and accounts for most of the ~10,000 annual non-melanoma skin cancer deaths in the United States."

Drug discovery for small molecule therapies to treat locally advanced/inoperable or metastatic cSCC and other cancers can be accelerated using patient-specific, physiologically relevant models amenable to high-throughput screening.

Models should mimic the tumor microenvironment, given its influence on tumor progression and metastasis, and should reproduce in vivo tumor cell physiochemical signaling and mechanical cues from the surrounding tissue extracellular matrix.

Animal models may not be readily translatable to human cancer treatment, and three-dimensional tissue culture models offer a viable alternative for pre-clinical screening of small molecule therapeutics.

3D models using human-derived cell lines offer increased complexity and physiological fidelity compared with two-dimensional monocultures and have been developed for several cancer models, including melanoma, pancreatic cancer, and cervical cancer.

In the disease model presented here, A431 cSCC spheroids were introduced into the tissue, and histopathology and cDNA microarray analysis was used to confirm the biological fidelity of the cancer model.

The authors' objective was to quantify the therapeutic efficacy of a standard of care treatment for a cSCC skin tissue model that recapitulates the microenvironment in which this cancer grows.

The Gareau Research Team concluded in their Oncotarget Research Paper that the model described provides a higher degree of clinical relevance because it enables the testing of chemotherapeutics against tumor cell growth in a tissue-specific context, thus capturing any potential interactions between the tumor and its microenvironment.

They envision that this model could be adopted in a “bedside” manner and applied to cells from cSCC patient tumor biopsies.

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DOI - https://doi.org/10.18632/oncotarget.27570

Full text - https://www.oncotarget.com/article/27570/text/

Correspondence to - Daniel S. Gareau - dgareau@rockefeller.edu.

Keywords -
squamous cell carcinoma,
screening,
3D printing,
in vitro model,
confocal microscopy

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Journal

Oncotarget

DOI

10.18632/oncotarget.27570

Oncotarget Volume 11, Issue 27 published "Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT" by Jia et al. which reported that Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition are central to metastatic aggressiveness and therapy resistance in solid tumors.

While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies.

Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals.

While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging.

Here, the authors' identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division.

Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, the authors' use mechanistic mathematical models to show how GRHL2 can be involved in both the above mentioned processes, thus driving an irreversible MET. This study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

Dr. Herbert Levine from The Center for Theoretical Biological Physics at Rice University as well as The Department of Physics at Northeastern University and Dr. Mohit Kumar Jolly from The Centre for BioSystems Science and Engineering at The Indian Institute of Science said "Epithelial-Mesenchymal Transition (EMT) is a cell biological process involved in driving cancer metastasis and therapy resistance?the two grand clinically unsolved challenges."

These hybrid E/M phenotypes may drive collective cell migration as clusters of tumor cells and can be more aggressive than cells in pure epithelial or mesenchymal phenotypes.

Recent experiments decoding the dynamics of EMT/MET using live-cell imaging and/or induction and withdrawal of various EMT-inducing external signals such as TGF? or tuning the levels of EMT-specific transcription factors have provided important insights into the reversibility of EMT and MET. Cells induced to undergo EMT for shorter durations may revert to an epithelial state after withdrawal of the signal/stimulus.

However, similar investigations about the irreversibility of MET, or in other words, the resistance of epithelial cells to undergo EMT in response to EMT-inducing signals, remain to be done.

Here, the authors' propose two independent mechanism that may explain the resistance of epithelial tumor cells to undergo EMT:

1) epigenetic feedback mediated via GRHL2?an MET-inducing transcription factor ; and
2) stochastic partitioning of parent cell biomolecules among the daughter cells at the time of cell division.

Conversely, here, the authors' show that incorporating this epigenetic feedback loop acting on the inhibition of ZEB1 by GRHL2 can cause an irreversible MET. Cells undergoing irreversible MET may exhibit resistance in undergoing EMT when exposed to EMT-inducing signals.

The Levine/Jolly Research Team concluded in their Oncotarget Research Paper that their results offer mechanistic insights into two possible mechanisms that may drive varying degrees of susceptibility and resistance to undergoing EMT in response to an EMT-inducing signal in a given isogenic population.

"Results offer mechanistic insights into two possible mechanisms that may drive varying degrees of susceptibility and resistance to undergoing EMT in response to an EMT-inducing signal in a given isogenic population."

Future efforts should decode the molecular mechanisms of any such epigenetic feedback of GRHL2 on ZEB1 expression as well as track the distribution of molecules during cell divisions happening while cells are being induced to undergo EMT/MET. Moreover, this study calls for concerted efforts to map the single-cell dynamics of MET induction.

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DOI - https://doi.org/10.18632/oncotarget.27651

Full text - https://www.oncotarget.com/article/27651/text/

Correspondence to - Herbert Levine - h.levine@northeastern.edu and Mohit Kumar Jolly - mkjolly@iisc.ac.in.

Keywords -
epithelial-mesenchymal transition,
mesenchymal-epithelial transition,
GRHL2,
epigenetics,
asymmetric cell division

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

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Journal

Oncotarget

DOI

10.18632/oncotarget.27651

Oncotarget Volume 11, Issue 27 published "Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours" by Lim et al. which reported peptide receptor radionuclide therapy (PRRT) is an approved treatment modality for gastroenteropancreatic neuroendocrine tumours, although Phase III randomised clinical trial data is not available for NETs of other site of origin, in practice, PRRT is used more widely in clinical practice, based on its mechanism of targeting the somatostatin receptor.

A retrospective chart review of patients with TC and AC who received 177Lu-dotatate PRRT between January 2002 and June 2019 in six hospitals across Australia was undertaken.

Forty-eight patients received a median of four 177Lu-dotatate treatments.
The response rate to 177Lu-dotatate was 33%, with a median overall survival of 49 months, at a median follow up of 33 months.
177Lu-dotatate PRRT in patients with lung NETs is used in real world practice, where it appears well-tolerated with some efficacy.

Dr. Lisi Elizabeth Lim from The Department of Medical Oncology at Monash Health said "Neuroendocrine tumours (NETs) are uncommon malignancies, comprising 0.5% of all cancers."

Lung is the primary site for approximately 20?25% of NETs; conversely NETs comprises about 2% of all lung malignancies.

New trials have demonstrated that adequate numbers of patients can be recruited through global collaborations, both for protocols specific to lung NETs and those recruiting patients with NETs from a variety of sites.

PRRT is a firmly established treatment modality for advanced GEP NETs following the publication of the landmark NETTER-1 trial, where patients with progressive midgut NET were randomised to receive 177Lu-dotatate with ongoing octreotide long-acting repeatable therapy, or high dose octreotide LAR alone.

The significant benefit for PRRT in midgut NETs has provoked debate about whether randomised trials are required to prove its efficacy in NETs of other site of origin.

"The significant benefit for PRRT in midgut NETs has provoked debate about whether randomised trials are required to prove its efficacy in NETs of other site of origin."

NET consensus guidelines either omit specific comment on the use of PRRT in lung NETs, or state that imaging with SSTR-PET can assist in identifying patients who may benefit from PRRT. The Lim Research Team concluded in their Oncotarget Research Paper that further data will be forthcoming also from studies of PRRT in patients with SSTR-expressing tumours of histologies other than NET. The randomised phase II LUTHREE trial is inclusive of all SSTR positive tumour types, and is not restricted to NETs. The POLNETS trial is also extending the use of PRRT to paraganglioma and pheochromocytoma, in addition to advanced NETs of any site of origin.

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DOI - https://doi.org/10.18632/oncotarget.27659

Full text - https://www.oncotarget.com/article/27659/text/

Correspondence to - Lisi Elizabeth Lim - elizabeth.lisi.lim@gmail.com.

Keywords -
lung,
carcinoid,
atypical,
neuroendocrine,
peptide receptor radionuclide therapy

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27659

Tiny, 3D printed cubes of plastic, with intricate fractal voids built into them, have proven to be effective at dissipating shockwaves, potentially leading to new types of lightweight armor and structural materials effective against explosions and impacts.

"The goal of the work is to manipulate the wave interactions resulting from a shockwave," said Dana Dattelbaum, a scientist at Los Alamos National Laboratory and lead author on a paper to appear in the journal AIP Advances. "The guiding principles for how to do so have not been well defined, certainly less so compared to mechanical deformation of additively manufactured materials. We're defining those principles, due to advanced, mesoscale manufacturing and design."

Shockwave dispersing materials that take advantage of voids have been developed in the past, but they typically involved random distributions discovered through trial and error. Others have used layers to reverberate shock and release waves. Precisely controlling the location of holes in a material allows the researchers to design, model and test structures that perform as designed, in a reproducible way.

The researchers tested their fractal structures by firing an impactor into them at approximately 670 miles per hour. The structured cubes dissipated the shocks five times better than solid cubes of the same material.

Although effective, it's not clear that the fractal structure is the best shock-dissipating design. The researchers are investigating other void- or interface-based patterns in search of ideal structures to dissipate shocks. New optimization algorithms will guide their work to structures outside of those that consist of regular, repeating structures. Potential applications might include structural supports and protective layers for vehicles, helmets, or other human-wearable protection.

COVID-19 has temporarily shuttered many early childhood education centers across the country, shifting full-time child care and teaching responsibilities largely to parents.

As some of those centers look toward reopening, they can play an important part in ensuring that parents continue to be engaged in their children's education at home, says University of Arizona researcher Melissa Barnett.

In a study conducted before the pandemic began, Barnett and her colleagues looked at the role that early childhood education centers play in encouraging parents to engage in educational activities with their children both at the centers and at home. The researchers also explored how parental engagement can help better prepare young children for kindergarten.

Their findings were recently published in Early Childhood Research Quarterly.

"There's been some research evidence that when parents of preschoolers are more engaged in early childhood education centers, their children may be more prepared for kindergarten. But it's not entirely clear why that's the case," said Barnett, lead study author and an associate professor of family studies and human development in the UArizona Norton School of Family and Consumer Sciences, housed in the College of Agriculture and Life Sciences.

"One of the goals of our study was to understand the extent to which parents perceive that early childhood educators are working with them and engaging them, and whether that is linked to school readiness," said Barnett, who also is director of the Norton School's Frances McClelland Institute for Children, Youth and Families.

Among the researchers' key findings:

When parents perceive that early childhood education centers do a good job of communicating with them and providing information about how their children are doing, they are more likely to engage in educational activities such as reading and singing with their children - both at the center and at home. And the more parents engage in educational activities at home, the better prepared their children are for kindergarten, in terms of language and early reading skills.

The more involved parents are in center activities - such as volunteering in classrooms, attending meetings or chaperoning field trips - the more educational activities they do with their children at home.

Although early childhood education centers appear to influence the quantity of at-home educational activities, they do not influence the quality of those activities. And the quality of at-home educational activities is one of the strongest predictors of a child's school readiness, influencing not only language and early reading skills but also early math skills.

The research is based on data from the Early Childhood Longitudinal Study - Birth Cohort, a nationally representative sample of 10,700 children who were born in the United States in 2001 were followed from birth to kindergarten. The researchers homed in on the 17% of those children who were enrolled in early childhood education centers at age 4.

Those children's parents rated a series of statements designed to measure how well they thought their early childhood education centers did at keeping them informed and involved. The parents also answered questions about how often they engaged in educational activities with their children, both at the center and at home.

The children completed assessments to measure their language, reading and early math skills prior to entering kindergarten.

"For children who are enrolled in early childhood education centers, what parents did at home was a good predictor of how well children were prepared for school, in terms of the quantity of what parents were doing and the quality of what they were doing," Barnett said. "We found that more engagement in the early childhood education centers was related to doing more at home, and that seemed to be especially true for lower-income households."

The researchers also observed parents and children engaging in learning activities and assessed the quality of those interactions based on how much cognitive stimulation they provided. They found that quality matters even more than quantity for school readiness.

"It's important that parents read with their kids and sing to their kids. But the quality of what parents are doing also is really critical and perhaps harder to change," Barnett said.

That's an area where early childhood education centers could make a difference in the future, she said.

"Parents who are able to engage and volunteer at those centers are getting the message that they need to read with their kids and sing songs with their kids, but they may not be getting messages about how best to do that," Barnett said.

Some best practices, she said, include thinking about ways to build activities around a child's unique interests and abilities, and making activities such as reading more meaningful by stopping to ask questions that help children relate stories to their own experiences.

Pandemic Could Impact Access

Unfortunately, Barnett said, many families don't have access to early childhood education centers and the support they provide, especially in lower-income areas, where, according to her findings, they might have the most impact. The problem could be made even worse by COVID-19, she said, as some centers hit hard financially may be forced to close permanently.

"We know that many families in many communities didn't have access to high-quality early childhood education, even before the pandemic, and it's become an increasingly significant problem as centers have closed and may need to remain closed," she said. "In part, our findings point to the value of those opportunities for lower-income parents to be involved in early childhood education centers, so this potentially could even further increase what we see as a socioeconomic gap in school readiness."

For now, with many parents of all socioeconomic backgrounds at home with their kids, Barnett stresses the importance of focusing on quality activities as much as possible.

"This may be an especially challenging time to do that, as parents are juggling multiple potential stressors and time crunches," she said, "but those home learning activities really are important to prepare children for school."

A new study by MIT neuroscientists into how seemingly similar neuronal subtypes drive locomotion in the fruit fly revealed an unexpected diversity as the brain's commands were relayed to muscle fibers. A sequence of experiments revealed a dramatic difference between the two nerve cells - one neuron scrambled to adjust to different changes by the other, but received no requital in response when circumstances were reversed.

The findings published in the Journal of Neuroscience suggest that these subclasses of neurons, which are also found abundantly in people and many other animals, exhibit a previously unappreciated diversity in their propensity to respond to changes, a key property known as "synaptic plasticity." Synaptic plasticity is considered an essential mechanism of how learning and memory occur in the brain, and aberrations in of the process are likely central to disorders such as autism.

"By seeing that these two different types of motor neurons actually show very distinct types of plasticity, that's exciting because it means it's not just one thing happening," said senior author Troy Littleton, a member of The Picower Institute for Learning and Memory and Menicon Professor of Neuroscience in MIT's Departments of Biology and of Brain and Cognitive Sciences. "There's multiple types of things that can be altered to change connectivity within the neuromuscular system."

Tonic and phasic neurons

Both of the neurons work in the same way, by emitting the neurotransmitter glutamate onto their connections, or synapses, with the muscles. But these two neurons do so with different styles. The "tonic" neuron, which connects only to a single muscle, emits its glutamate at a constant but low rate while the muscle is active. Meanwhile, the "phasic" neuron connects to a whole group of muscles and jumps in with a strong quick pulse of activity to spring the muscles into action.

Heading into the study Littleton and lead author Nicole Aponte-Santiago were curious to explore whether these different neurons compete or cooperate to drive the muscle fibers, and if they exhibited different plasticity when their functions were altered. To get started on what ultimately became her dissertation research, Aponte-Santiago developed the means to tailor genetic alterations specifically in each of the two neurons.

"The reason we were able to answer these questions in the first place was because we produced tools to start differentially manipulating one neuron versus the other one, or label one versus the other one," said Aponte-Santiago, who earned her PhD in Littleton's lab earlier this spring and is now a postdoc at the University of California at San Francisco.

With genetic access to each neuron, Aponte-Santiago distinctly labeled them to watch each one grow in fly larvae as they developed. She saw that the tonic neuron reached the muscle first and that the phasic one connected to the muscle later. She also observed that unlike in mammals, the neurons did not compete to control the muscle but remained side by side, each contributing in its characteristic way to the total electrical activity needed to drive movement.

To study the neurons' plasticity, Aponte-Santiago employed two manipulations of each neuron. She either wiped them out completely by making them express a lethal protein called "reaper" or she substantially tamped down their glutamate activity via expression of tetanus toxin.

When she wiped out the phasic neuron with reaper, the tonic neuron quickly stepped up its signaling, attempting to compensate as much as it could. But in flies where she wiped out the tonic neuron, the phasic neuron didn't budge at all, continuing as if nothing had changed.

Similarly when Aponte-Santiago reduced the activity of the phasic neuron with the toxin, the tonic neuron increased the number of boutons and active zone structures in its synapses to respond to the loss of its partner. But when she reduced the activity of the tonic neuron the phasic neuron again didn't appear to respond.

In all the experiments, the muscle received less overall drive from the neurons than when everything was normal. And while the phasic neuron apparently didn't bother to make up for any loss on the part of the tonic neuron, the tonic neuron employed different means to compensate - either increasing its signaling or by enhancing the number of its connections on the muscle - depending on how the phasic neuron was diminished.

"It was quite intriguing that Nicole found that when the phasic input wasn't there, there was a unique form of plasticity that the tonic neuron showed," Littleton said, "but if the phasic neuron was there and wasn't working, the tonic neuron behaved in a very different way."

Another intriguing aspect of the study is the role of the muscle itself, which may be an active intermediary of the plasticity, Littleton said. The neurons may not sense when each other have been wiped out or inactivated. Instead the muscle appears to call for those changes.

"Even though a muscle has two distinct inputs, it can sort of uniquely control those two," Littleton said. "When the muscle is getting glutamate, does it know whether it is coming from the tonic or the phasic neuron and does it care? It appears that it does care, that it really needs the tonic more than the phasic. When the phasic is gone it shifts some of the plasticity, but when the tonic is gone the phasic can't do much about it."

In new work, the lab is now looking at differences in gene expression between the two neurons to identify which proteins are responsible for the unique properties and plasticity of the tonic and phasic neurons. By defining the genetic underpinnings of their unique properties, the lab hopes to begin to get a handle on the molecular underpinnings of neuronal diversity in the brain.

Highlights

A recent study found that most kidney transplant recipients with COVID-19 do not need to be hospitalized.

Another study found that patients on dialysis who develop COVID-19 may have symptoms that are different from other patients with the infectious disease.

Washington, DC -- Two new studies examine the health and outcomes of patients with COVID-19 who have undergone kidney transplantation or are receiving hemodialysis. The findings appear in an upcoming issue of CJASN.

During the global COVID-19 pandemic, it's important to identify individuals who are at high risk of developing severe forms of the disease. Kidney transplant recipients--who take life-long immunosuppressive drugs and tend to have additional illnesses--may be especially vulnerable. Early reports indicate that kidney transplant recipients who are hospitalized for COVID-19 have similar symptoms and outcomes as other patients, but little is known about how they fare in the outpatient setting, when they are not admitted to a hospital.

To provide insights, clinicians led by Sumit Mohan, MD, MPH and S. Ali Husain, MD, MPH (Columbia University Medical Center) described their early experience with outpatient kidney transplant recipients with established or suspected COVID-19 seen at their medical center.

Of 41 patients who were included, 22 (54%) had confirmed COVID-19 and 19 (46%) were suspected cases. Patients most commonly reported fever, cough, and shortness of breath. Most patients' symptoms went away without the need for hospitalization. Thirteen (32%) patients required hospitalization, and these patients were more likely to have shortness of breath and higher levels of a blood marker for impaired kidney function. There were no differences in demographics or medical illnesses between those who were or were not admitted to the hospital.

"In the midst of the pandemic surge in New York, many transplant recipients needed to be monitored remotely. Our report underscores the fact that a comprehensive outpatient monitoring protocol could provide adequate clinical care and excellent outcomes for outpatient kidney transplant recipients with COVID-19 by allowing identification of those individuals who would benefit from inpatient care," said Dr. Husain.

Of note, the study revealed a wide variation in the amount of time it took patients to improve. Among the patients who were hospitalized, the average time between symptom onset and admission was 8 days (similar to the general US population), but one patient was admitted 16 days after symptoms started. Among the patients with outpatient management, the average time from symptom onset to improvement was 12 days, with one patient taking 23 days before symptoms improved. "These findings show that patients must be followed until improvement to watch for late worsening of symptoms requiring hospitalization," Dr. Husain said.

Another study led by Xiangyou Li, PhD (Tongren Hospital of Wuhan University) investigated the clinical features of patients with kidney failure on hemodialysis who developed COVID-19. The study included 49 hospitalized dialysis patients and 52 hospitalized patients without kidney failure (controls) with confirmed COVID-19 in Wuhan, China from January 30th to March 10th.

Fever, fatigue, and dry cough were the dominant symptoms in controls, whereas the most common symptoms in patients on dialysis were fatigue and anorexia, with fever and cough being less common.

Common complications including shock, acute respiratory distress syndrome, arrhythmia, and acute cardiac injury were significantly higher in patients on dialysis. Also, 14% of patients on hemodialysis died, compared with 4% of controls.

An accompanying editorial stresses the need for more research and guidance related to COVID-19 in these patient populations. "As time passes, a treatment protocol based on patient characteristics, phase of illness, and disease severity using antivirals, anti-coagulation, immunomodulators, and immunosuppressive agents will be formulated," the authors wrote. "However, there are concrete steps that the nephrology community can take immediately to optimize the safety of our patients and ourselves."

UNIVERSITY PARK, Pa. -- A unique nanoparticle to deliver a localized cancer treatment inhibits tumor growth in mice, according to a team of Penn State researchers.

The nanoparticles, developed by Daniel Hayes, associate professor of biomedical engineering, have a specific chemistry that allows a microRNA (miRNA) to attach to it. A miRNA is a molecule that when paired to a messenger RNA (mRNA) prevents it from operating. In this case, it prohibits the mRNA in a cancer cell from creating proteins, which are essential for that cancer cell to survive.

In their study, the researchers delivered nanoparticles to the cancer cells of mice through an IV. Once the nanoparticles built up in the cancerous area, they used a specific wavelength of light to separate the miRNA from the nanoparticles. The miRNA then pairs with a mRNA in the cancer cell, causing the mRNA to stop making proteins. Eventually, the cancer cell dies.

Their paper appeared on June 22 in the journal Biomaterials.

"This delivery method gives you temporal and spatial specificity," said Adam Glick, professor of molecular toxicology and carcinogenesis. "Instead of having systemic delivery of a miRNA and the associated side effects, you are able to deliver the miRNA to a specific area of tissue at a specific time by exposing it to light."

Hayes said having temporal and spatial specificity is important when dealing with cancer treatments.

"miRNA can have vastly different effects in different types of tissue which can lead to unwanted side effects and toxicity," Hayes said. "Delivering and activating miRNA only at the site of the tumor reduces these side effects and can increase the overall effectiveness of the treatment."

Using this method, Yiming Liu, a biomedical engineering graduate student in the Hayes Laboratory, was able to show that skin tumors in about 20 mice that were given the miRNA coupled nanoparticle and exposed to light completely regressed within 24 to 48 hours and did not regrow.

Additionally, the specific miRNA that Hayes and Glick are using may be more effective in killing cancer cells than other similar methods.

"What is different about this as a therapeutic is that the miRNA that we are using can regulate a broad set of genes and is particularly powerful to treat a heterogenous disease such as cancer," said Liu.

This could mean that the overall effectiveness of killing a cancer cell is higher because the treatment is attacking multiple points in that cell. It may also lead to a decrease of a cancer cell's ability to become resistant to the treatment because the miRNA is able to pair with different mRNAs in the cancer cell, diversifying the ways in which it can stop the cell from producing proteins.

The types of cancer that might be responsive to this type of treatment include cancers in the oral cavity, the gastrointestinal system or the skin -- anywhere that could be exposed to light via a fiber optic cable.

"We would like to develop this further for internal tumors that are more significant in terms of mortality, such as esophageal cancer," Glick said.

MIAMI--Climate change--from rising temperatures and more severe heavy rain, to drought--is increasing risks for economies, human security, and conflict globally. Scientists at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science are leading an effort to better assess the climate-conflict link to help societies manage the complex risks of increased violence from a changing climate.

The links between climate and the risk of violent conflict are well studied; however, scientists in varying research disciplines often disagree about the scope and severity of possible climate change impacts. Some of the open research questions are about the links between climate change and violence, including large-scale armed conflict.

In a new report in Earth's Future, a group of scholars, with backgrounds including environmental and political science, geography, and economics, analyze the relationship between climate and organized armed conflict to define crosscutting priorities for future directions of research. In a previous assessment published in 2019 by the group, it was estimated that over the last century between 3-20 percent of organized armed conflict risk has been influenced by climate.

In this new assessment, the scholars suggest that future directions for climate-conflict research include deepening insight on what the links are, when they matter, and how they manifest. They suggest that future research can use data from diverse sources, including satellite and drone imagery, social media, and population surveys.

"Our changing climate poses threats for human security," said Katharine Mach, an associate professor at the UM Rosenstiel School and lead author of the assessment. "In this commentary perspective, we provide a roadmap for future research that is supportive of appropriate societal responses. The options include deepening our understanding of how climate shapes security and conflict risks, as well as the ways in which research can prioritize ethical, interactive, and ongoing engagement with the many organizations and governments promoting peace and stability in societies."

Changes in Earth's climate are already impacting societies and economies and will further increase the risks of a range of outcomes, including civil conflict, which is profoundly and enduringly destructive for societies. Comprehensive and transdisciplinary efforts are needed to fully understand the multifaceted links between climate and conflict and appropriate responses by governments and humanitarian assistance organizations.

"This research topic is controversial and contested," said Caroline Kraan, a PhD student in the Abess Graduate Program in Environmental Science and Policy. "We came together to provide a full range of expert views to establish a way forward for research that can serve decision-making needs."

According to the authors, priorities for future directions of research include (1) deepening insight into climate-conflict linkages and conditions under which they manifest, (2) ambitiously integrating research designs, (3) systematically exploring future risks and response options, responsive to ongoing decision-making, and (4) evaluating the effectiveness of interventions to manage climate-conflict links.

Typically, there aren't a lot of positive thoughts when E. coli, generally found in animal and human intestines, is mentioned. It's been blamed for closing beaches and swimming pools and shuttering restaurants because of contamination in salad bars, meats or other food items.

But for more than a century, one strain of the bacteria, E. coli Nissle 1917, has been used as a probiotic and therapeutic agent. Currently, it is used in some countries to treat intestinal inflammation.

Now researchers at the University of Cincinnati College of Medicine say E. coli Nissle may also protect human cells against other more pathogenic strains of E. coli such as E. coli 0157:H7, which is commonly associated with contaminated hamburger meat.

Alison Weiss, PhD, professor, and Suman Pradhan, PhD, research associate, both in in the UC Department of Molecular Genetics, Biochemistry and Microbiology, used stem cell-derived human intestinal organoid tissues to evaluate the safety of Nissle and its ability to protect from pathogenic E. coli bacteria 0157:H7.

They found that human intestinal tissues (HIO) were not harmed by the Nissle bacteria introduced into human intestinal organoids while pathogenic E. coli bacteria destroyed the epithelial layer of the HIO. More importantly, Nissle protected the HIOs when added prior to pathogenic E. coli bacterial infection.

The study's findings are available online in mBio, the scholarly journal of the American Society for Microbiology.

"Nissle did not kill pathogenic E. coli, but rather ramps up your intestinal responses and prepares you for possible pathogens attacking the intestine," explains Weiss, corresponding author of the study. "We don't know how it does this, but our study confirms its effectiveness in human cells. Our hope is to figure out how this is happening."

"There are all sorts of flavors of E. coli," says Weiss. "They gather genes from all over the place and channel a whole bunch of other pathogens. There are E.coli which can also cause urinary tract infections. What is special is that bad E. coli have a chunk of extra genes that allow them to cause problems. The good E. coli are stripped down of these genes and they don't have the capacity to do bad things."

Weiss says they hope to learn more about the abilities of Nissle in order to develop a treatment of E. coli infections that often result from the production of Shiga toxins. The Centers for Disease Control and Prevention estimates that 265,000 such infections occur annually causing stomach cramps, diarrhea and vomiting. Cases can be mild to severe and affect people of all ages, though the illness can be particularly hard on smaller children, who are more likely to die from an infection, says Weiss. Moreover, antibiotic treatment of children with E. coli 0157:H7 infection increases the risk of hemolytic-uremic syndrome.

"Right now there is no cure for an E. coli infection," says Weiss. "We can give individuals fluids, but it can be really deadly and it would be really nice for us to figure out how to cure it."

"E. coli is carried asymptotically by all sorts of animals and released into their fecal matter and then leading to possible contamination if it comes into contact with food items or is ingested," says Weiss. "It is difficult though still possible to screen meat for E. coli. The best possible protection is to cook meat properly before consuming it. E. coli is also found in raw vegetables such as lettuce and it can be difficult to detect and remove."

From movies to museum exhibits, the dinosaur Dilophosaurus is no stranger to pop culture. Many probably remember it best from the movie "Jurassic Park," where it's depicted as a venom-spitting beast with a rattling frill around its neck and two paddle-like crests on its head.

The dinosaur in the movie is mostly imagination, but a new comprehensive analysis of Dilophosaurus fossils is helping to set the record straight. Far from the small lizard-like dinosaur in the movies, the actual Dilophosaurus was the largest land animal of its time, reaching up to 20 feet in length, and it had much in common with modern birds.

The analysis was published open access in the Journal of Paleontology on July 7.

Dilophosaurus lived 183 million years ago during the Early Jurassic. Despite big-screen fame, scientists knew surprisingly little about how the dinosaur looked or fit into the family tree, until now.

"It's pretty much the best, worst-known dinosaur," said lead author Adam Marsh. "Until this study, nobody knew what Dilophosaurus looked like or how it evolved."

Seeking answers to these questions, Marsh conducted an analysis of the five most-complete Dilophosaurus specimens while earning his Ph.D. from The University of Texas at Austin's Jackson School of Geosciences. He is now the lead paleontologist at Petrified Forest National Park.

The analysis is co-authored by Jackson School Professor Timothy Rowe, who discovered two of the five Dilophosaurus specimens that were studied.

The study adds clarity to a muddled research record that reaches back to the first Dilophosaurus fossil to be discovered, the specimen that set the standard for all following Dilophosaurus discoveries. That fossil was rebuilt with plaster, but the 1954 paper describing the find isn't clear about what was reconstructed - a fact that makes it difficult to determine how much of the early work was based on the actual fossil record, Marsh said.

Early descriptions characterize the dinosaur as having a fragile crest and weak jaws, a description that influenced the depiction of Dilophosaurus in the "Jurassic Park" book and movie as a svelte dinosaur that subdued its prey with venom.

But Marsh found the opposite. The jawbones show signs of serving as scaffolding for powerful muscles. He also found that some bones were mottled with air pockets, which would have helped reinforce the skeleton, including its dual crest.

"They're kind of like bubble wrap - the bone is protected and strengthened," Marsh said.

These air sacs are not unique to Dilophosaurus. Modern birds and the world's most massive dinosaurs also have bones filled with air. In both cases, the air sacs lighten the load, which helped big dinosaurs manage their bulky bodies and birds take to the skies.

Many birds use the air sacs to perform other functions, from inflating stretchy areas of skin during mating rituals, to creating booming calls and dispersing heat. The intricate array of air pockets and ducts that extend from Dilophosaurus' sinus cavity into its crests means that the dinosaur may have been able to perform similar feats with its headgear.

All the specimens Marsh examined came from the Kayenta Formation in Arizona and belong to the Navajo Nation. The University of California Museum of Paleontology holds in trust three of the specimens. The Jackson School Museum of Earth History holds the two discovered by Rowe.

"One of the most important responsibilities of our museum is curation," said Matthew Brown, director of the Vertebrate Paleontology Collections. "We are very excited to help share these iconic Navajo Nation fossils with the world through research and educational outreach, as well as preserve them for future generations."

To learn more about how the fossils compared with one another, Marsh recorded hundreds of anatomical characteristics of each fossil. He then used an algorithm to see how the specimens compared with the first fossil - which confirmed that they were indeed all Dilophosaurus.

The algorithm also revealed that there's a significant evolutionary gap between Dilophosaurus and its closest dinosaur relatives, which indicates there are probably many other relatives yet to be discovered.

The revised Dilophosaurus record will help paleontologists better identify specimens going forward. Marsh said that the research is already being put into action. In the midst of his analysis, he discovered that a small braincase in the Jackson School's collections belonged to a Dilophosaurus.

"We realized that it wasn't a new type of dinosaur, but a juvenile Dilophosaurus, which is really cool," Marsh said.

A newly-identified, fast-growing species of algae poses a major threat to coral reefs and the ocean ecosystem. It was previously discovered in Papahānaumokuākea Marine National Monument by a team of researchers from the University of Hawaiʻi, Western Australian Herbarium, College of Charleston and National Oceanic and Atmospheric Administration (NOAA).

Newly-named Chondria tumulosa by UH researchers, the alga has no known origin and has been observed smothering entire reefs and the corals, native algae and other organisms that live in one of the northern atolls. It also has a "tumbleweed-like" growth and appears to easily detach and spread.

"I think this is a warning of the kinds of changes that are to come for the northwestern Hawaiian Islands," said UH Manoa College of Natural Sciences Interim Associate Dean and Professor Alison Sherwood, the lead researcher on the project. "We have, not until now, seen a major issue like this where we have a nuisance species that's come in and made such profound changes over a short period of time to the reefs."

It was not widespread when first detected by NOAA divers in 2016 but a 2019 visit to the same area revealed that it is now covering up to several thousand square meters at the Pearl and Hermes Atoll.

"Until we understand whether it is native or introduced, and until we better understand what is driving this outbreak, it is critically important that research divers and research ships do not inadvertently transport this species to other islands," said Randall Kosaki, NOAA research coordinator at Papahānaumokuākea Marine National Monument. "Thus, all of our dive gear was soaked in bleach, and all of our dive boats were sprayed down with bleach prior to returning to Honolulu."

The findings were featured in a PLOS ONE article, "Taxonomic determination of the cryptogenic red alga, Chondria tumulosa sp. nov., (Rhodomelaceae, Rhodophyta) from Papahānaumokuākea Marine National Monument, Hawaiʻi, USA: a new species displaying invasive characteristics."

'Nuisance' not 'invasive'

Although Chondria tumulosa displays invasive characteristics, researchers are calling it a "nuisance alga" because they have not identified it as being introduced from another region.

"The main Hawaiian Islands are impacted by several well-known invasive seaweeds, but reports of nuisance algae in Papahānaumokuākea Marine National Monument are far fewer, and none have been present at the level of abundance seen in this new alga," Sherwood said.

Next steps

Researchers will conduct mapping and molecular analyses, and will develop mitigation strategies to assist in the development of appropriate management actions.

"This is a highly destructive seaweed with the potential to overgrow entire reefs," College of Charleston Assistant Professor Heather Spalding said. "We need to figure out where it's currently found, and what we can do to manage it. This type of research needs trained divers in the water as quickly as possible. The sooner we can get back to Papahānaumokuākea Marine National Monument, the better."

Scientists at Cold Spring Harbor Laboratory (CSHL) have found that they can stop the growth of pancreatic cancer cells by interfering with the way the cells store cholesterol. Their findings in mice and lab-grown pancreas models point toward a new strategy for treating the deadly disease.

The study, reported in the Journal of Experimental Medicine, was led by CSHL Professor David Tuveson. Tuveson's team wanted to know why pancreatic cancer cells, like many cancer cells, manufacture abundant amounts of cholesterol. Cholesterol is an essential component of cell membranes, but the research team determined that pancreatic cancer cells make far more of it than they need to support their own growth. "This is unusual, because the cholesterol pathway is one of the most regulated pathways in metabolism," says Tobiloba Oni, a graduate student in Tuveson's lab.

Most cells make only as much cholesterol as they need, quickly shutting down the synthesis pathway once they have enough, Oni explains. But he and his colleagues, including Giulia Biffi, a former postdoctoral fellow in Tuveson's lab, found that cancer cells convert most of the cholesterol they make into a form that can be stored within the cell. Free cholesterol never accumulates, and the synthesis pathway keeps churning out more.

Cancer cells in the pancreas seem to thrive off this hyperactive cholesterol synthesis. The team thinks this is probably because they are taking advantage of other molecules generated by the same pathway. They're able to keep the pathway running and maintain their supply thanks to an enzyme called sterol O-acyltransferase 1 (SOAT1), which converts free cholesterol to its stored form and which pancreatic cancer cells have in abundance.

When the researchers eliminated the SOAT1 enzyme through genetic manipulation, preventing cells from converting and storing their cholesterol, cancer cells stopped proliferating. In animal experiments, eliminating the enzyme stalled tumor growth.

Importantly, the team found that eliminating SOAT1 only impacted cells that harbored mutations in both copies of a tumor suppressor gene known as p53. This genetic alteration promotes cancer growth and is exceedingly common in patient tumors. Normal pancreas cells functioned just fine without the enzyme in the team's experiments, and that makes SOAT1 a promising therapeutic target, Oni says. The hope, he says, is that researchers will be able to develop a drug that selectively blocks the enzyme, impairing cancer cells but leaving normal cells healthy.

7 July 2020: Couples embarking on IVF to treat their infertility tend to overestimate their chance of success, according to a prospective study of 69 couples having at least their second treatment attempt. Such over-optimism, suggest the authors, may be a source of distress or even a reason to discontinue their IVF treatment.

The results of the study will be presented today by embryologist Johanna Devroe from the University Hospital of Leuven, Belgium, during ESHRE's online Annual Meeting.

Reports in the past have suggested that couples usually have some degree of optimism when embarking on treatment, but, says Ms Devroe, "to the best of our knowledge, the live birth rates expected by patients during their IVF cycle have yet to be studied and compared to their individual prognosis. In addition, it is not known whether these expected birth rates are affected by factors like gender and an individual's general level of optimism."

The study thus measured a couple's individual expectations about their treatment and their natural disposition to optimism according to a validated questionnaire. In addition, the study used a mathematical model to calculate each couple's IVF prognosis by taking account of clinical and IVF laboratory factors. This allowed the study to calculate the degrees of mis-estimation for both the male and female partner of each couple.

The mean calculated prediction of live birth among the study participants was 32%, after treatments with both fresh and frozen embryo transfers. However, 85% of the female partners overestimated their chances (by 34% on average), with almost half of them expecting their birth rate to be more than double their treatment prognosis. Similarly, 88% of men overestimated their outcomes, with 54% expecting their birth rate to be more than double their calculated prognosis. When comparisons were made between the female and male partners, it was found that the men generally had significantly higher expectations than their female partners (64% vs 59%), although partners did not differ in their overall levels of optimism. Indeed, the correlation between their anticipated success rates and their general level of optimism was generally weak, suggesting that personal disposition does not fully explain the results of this study.

While this was a single-centre study and no study has as yet compared patient expectations with prognosis in this way, Ms Devroe notes that studies in several countries have all indicated that future IVF patients (and the general public) have high expectations of success shaped by the press and internet, besides their own clinics.

"Clinics do share average success rates on their websites," says Ms Devroe, "but these are often only relevant to a reference population of younger patients. And many patients do not think that average success rates apply to them. They expect greater success, thinking of their healthy lifestyle or their experienced doctors. So the message to clinics is, work on setting realistic expectations. We are now investigating this, to see if disclosing an individual's predicted success rate rather than a clinic's average success rate helps to set realistic expectations."

There is already some evidence from other researchers that unrealistic expectations do result in greater disappointment, which in turn may lead some patients to drop out of treatment. "We are currently following up the couples from our study group to correlate levels of unrealistic expectations with levels of disappointment and uptake of another IVF cycle," explains Ms Devroe.