Day: May 4, 2021

Categories : Metabolic DisordersTags :

Enzyme’s Role in Kidney Disease Could Unlock New Therapies

On By ModernMedia
Anatomic model of a kidney. Photo by Robina Weermeijer on Unsplash

University of South Australia (UniSA) researchers have discovered that a certain enzyme may help to curb chronic kidney disease, which affects nearly 10% of the world’s population.

This enzyme, known as NEDD4-2, is critical for kidney health, said UniSA Centre for Cancer Biology scientist Dr Jantina Manning.

Chronic kidney disease (CKD) is defined as the presence of kidney damage or reduced filtration rate, persisting for three months or more. It is a state of progressive loss of kidney function ultimately resulting in the need for dialysis or transplantation. 

Dr Manning and her colleagues, including Professor Sharad Kumar, Chair of the UniSA Centre for Cancer Biology, have shown in an animal study that there is a link between a high salt diet, low levels of NEDD4-2 and advanced kidney disease.

While a high salt diet can worsen some forms of kidney disease, it was not previously known that NEDD4-2 is involved in promoting this salt-induced kidney damage.

“We now know that both a high sodium diet and low NEDD4-2 levels promote renal disease progression, even in the absence of high blood pressure, which normally goes hand in hand with increased sodium,” says Dr. Manning.

The NEDD4-2 enzyme regulates the pathway required for sodium reabsorption in the kidneys to ensure correct levels of salt are maintained. If this enzyme is reduced or inhibited, increased salt absorption can result in kidney damage.

Even if people are on a low salt diet, they can get kidney damage if their levels of NEDD4-2 are low due to genetic causes.

Prof Kumar said the goal is to eventually to develop a drug that can raise NEDD4-2 levels in people who have CKD.

“We are now testing different strategies to make sure this protein is maintained at a normal level all the time for overall kidney health,” Prof Kumar said. “In diabetic nephropathy—a common cause of kidney disease—levels of NEDD4-2 are severely reduced. This is the case even when salt is not a factor.”

The study also revealed one other unexpected finding: that kidney disease induced by high salt diets is not always the result of high blood pressure.

“In a lot of cases, kidney disease is exacerbated by hypertension, so we wanted to investigate that link in our study. In fact, we found the complete opposite—that a high salt diet caused excessive water loss and low blood pressure. This is significant because it means that kidney disease can also happen in people who don’t have high blood pressure,” Dr Manning said.

A Lancet paper from 2020 estimated that about 700 million people—about 10% of the world’s population—suffer from chronic kidney disease, and has seen a 29% increase in the past 30 years. This massive surge in CKD is mainly due to the global obesity epidemic. Overweight and obesity lead to diabetes, one of the leading causes of CKD, along with high blood pressure. Between 1980 and 2014 there was a 300% increase in diabetes, according to World Health Organization statistics. This makes it one of the top 10 causes of death worldwide.

“Obesity and lifestyle are two main factors driving chronic kidney disease but there are other things at play as well,” said Dr Manning. “Acute kidney injuries, drugs taken for other conditions, high blood pressure and a genetic predisposition can also cause it.”

Source: Medical Xpress

Journal information: Jantina A. Manning et al. The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease, Cell Death & Disease (2021). DOI: 10.1038/s41419-021-03688-7

Categories : Cancer GeneticsTags :

‘Chemical Nose’ Sniffs Out Cancer-causing DNA Folds

On By ModernMedia
Artistic depiction of DNA double helix. Image by lisichik from Pixabay

Small folds in DNA structure have been implicated in breast cancer and other diseases have been elusive until a team of researchers developed a “chemical nose” to seek them out.

In the journal Nature Chemistry, chemists at  UC Riverside describe the development and testing of a “chemical nose” enabling them to “smell” unusual folds in DNA.

“If a DNA sequence is folded, it could prevent the transcription of a gene linked to that particular piece of DNA,” explained study author and UCR chemistry professor Wenwan Zhong. “In other words, this could have a positive effect by silencing a gene with the potential to cause cancer or promote tumors.”

DNA folding could also have a negative effect, however.

“DNA folds could potentially keep viral proteins from being produced to minimize immune response,” Prof Zhong said.

DNA folds have also been examined as potential targets for chemotherapy.   

To date, scientists have been unable to easily determine the effects of DNA folding on living organisms, as they lacked the proper tools to study them. In order to create one that can study the tiny structures, TUCR organic chemistry professor Richard Hooley and colleagues modified an existing concept that has previously been used to detect other things, such as chemical components in different vintages of wine.

The chemical system could be configured to seek out any kind of molecule, but it could not detect DNA in the way it was currently used. The addition of nonstandard components Prof Hooley’s group enabled the nose to sniff out its DNA target.

“Humans detect smells by inhaling air containing odor molecules that bind to multiple receptors inside the nose,” explained Prof Hooley. “Our system is comparable because we have multiple receptors able to interact with the DNA folds we’re looking for.”

The chemical nose consists of three parts: host molecules, fluorescent guest molecules, and DNA, which is the target. The guest molecules glow when the sought-after folds are present in a sample.

DNA is made of four nucleic acids: guanine, adenine, cytosine and thymine which are combined into the familiar double helix of DMA. Sections that are rich in guanine sometimes fold differently and create what’s called a G-quadruplex.

The parts of the genome that make these quadruplex structures are extremely complex, though the researchers have found that their folds are known to regulate gene expression, and aid in maintaining cell health.

The researchers sought to demonstrate that they could detect a single type of quadruplex composed of four guanines. Prof Zhong said that having accomplished this, the research team will try to build on their success.

“Now we think we can do more,” she said. “There are other three-dimensional structures in DNA, and we want to understand those as well.”

For their next step, the researchers will examine how effects that damage DNA influence the ways they fold. In addition, they also plan to study RNA folding since RNA is also important for cellular functioning.

“RNA has even more complex structures than DNA, and is more difficult to analyze, but understanding its structure has great potential for disease research,” Prof Zhong said. 

Source: UC Riverside News

Categories : Genetics Obstetrics & GynaecologyTags :

Foetal Genetics Drive Birth Defects and Pregnancy Loss

On By ModernMedia
Pregnant belly with ultrasound image superimposed. Image by Rudy and Peter Skitterians from Pixabay

A study by Yale researchers has shown that the genetics of the foetus and placenta drive developmental abnormalities, including those that lead to pregnancy loss and autism.

In the US, a birth defect is diagnosed in about 3% of children born every year, according to the Centers for Disease Control and Prevention. Birth defects also occur in most cases of pregnancy loss, and also result in many deaths in the first year of life. The causes are thought to be a complex interplay of environmental and biological factors.

“Mothers often feel that they are responsible for these defects,” explained senior author Dr Harvey Kliman,  Research Scientist at the Department of Obstetrics, Gynecology & Reproductive Services, Yale School of Medicine. “But it’s not their fault. This new research points to the genetics of these children as being the most important cause.”

Dr Kliman and his team examined placental data for nearly 50 sets of identical and non-identical twins. They discovered identical twins had similar numbers of abnormal cell growths called trophoblast inclusions (TIs), which are markers for a number of developmental abnormalities, while non-identical twins showed a markedly different TI count.

While identical twins share the same DNA, non-identical twins only share half of their DNA. Identical twins were found to often have the same number of TIs or were within one of having the same TI count. Non-identical twins had TI counts that differed by four or five on average.

“This work suggests that developmental abnormalities are much more likely to be due to the genetics of the child, and not the mother’s fault,” Dr Kliman explained.

The findings were reported in the journal Placenta.  

First author Julia Katz, a former Yale undergraduate and now medical student at Hofstra University, provided the inspiration for the study.

Katz and her brother, Jesse, who was born underweight and with several congenital abnormalities, are non-identical twins. “I had a lot of guilt, growing up, about why my twin had certain conditions that I didn’t,” Katz explained. “I think mothers also tend to blame themselves.”

After a lecture,  Katz approached Dr Kliman and asked him what causes babies to be born undersized, a conversation which led to a discussion about developmental abnormalities and Katz’s desire to find out more about her and her twin’s genetics — including looking at her own placental slides from birth.

It also led Dr Kliman, Katz, and co-author Parker Holzer, a graduate student in the Yale Department of Statistics and Data Science, to conduct the new study.

“Julia’s need to resolve this burden is what propelled our study,” Dr Kliman said. “Hopefully, this finding will help many other people, as well.”

“This experience has shown me that if you have a question, ask it,” Katz added. “And if you don’t get an answer, try to answer it yourself.”

Source: News-Medical.Net

Journal information: Katz, J., et al. (2021) Genetics, not the uterine environment, drive the formation of trophoblast inclusions: Insights from a twin study. Placenta. doi.org/10.1016/j.placenta.2021.04.010.

Categories : CancerTags :

New Radiotherapy Treatment for Metastatic Cancers is Safe

On By ModernMedia
MRI machine. Image by Michal Jarmoluk from Pixabay

A phase I trial showed that stereotactic body radiotherapy (SBRT) proved safe for treating cancer patients with multiple metastases. However, some late adverse effects underscored the need for long-term follow-up.

SBRT is a new radiotherapy treatment method that delivers high doses of ionising radiation to tumours with great precision, minimising damage to other parts of the body while killing tumour cells.

Increasingly used by clinicians, SBRT can improve survival in cancer patients with multiple metastases, explained first author Steve Chmura, MD, PhD, of University of Chicago Medicine, and colleagues, but there is little evidence as to its safety in this application.

“Existing data include mostly treatment of 1 or 2 metastases separated widely from each other and use of differing radiation doses, toxicity reporting, image guidance, and normal tissue constraints,” they wrote. “Given the critical need, NRG Oncology NRG-BR001 trial sought to determine the safety of delivering curative-intent SBRT to patients with 3 to 4 metastases or 2 metastases within close proximity to each other.”

Patients in the study had metastatic breast, prostate, or non-small-cell lung carcinoma (NSCLC). Each metastasis was assigned to a metastatic location based on the potential for toxicity.

Dose-limiting toxicity (DLT; side effects severe enough to discontinue treatment) was the primary study outcome, defined as specific AEs of grades 3 to 5 related to SBRT within 180 days of treatment. Dose levels were considered to be safe if DLTs were seen in no more than one of six patients per location with metastases.

Of the evaluable 35 patients, 12 (34.3%) had breast cancer, 10 NSCLC (28.6%), and 13 (37.1%) prostate cancer, with a median of three metastases per patient.

DLT analysis WAS based on six evaluable patients in all of the metastatic locations save the liver (five evaluable patients). The authors reported there were no protocol-specified DLTs in any of the seven metastatic locations within 180 days of the initiation of treatment.

There were 50 grade 3 or 4 AEs reported in 18 patients, and eight were deemed to be linked to the treatment. Of those eight, six (including bone pain, pulmonary fibrosis, bronchial fistula, bronchial stenosis, spinal fracture, and humeral fracture) were reported in six patients over 180 days from the start of the treatment. No treatment-related deaths occurred, according to the authors.

The authors suggested that, with the number of late AEs reported in this trial, patients should be monitored closely for late toxic effects.

“Given the potential for ablative radiotherapy to improve outcomes of patients with oligometastatic cancer, the finding that SBRT is safe when delivered to 3 to 4 metastases or 2 metastases in close proximity to one another is important, and serves as the foundation for ongoing randomized trials,” wrote the authors. They noted that these include studies such as the phase II/III NCI-sponsored NRG-BR002 trial.

Source: MedPage Today

Journal information: Chmura S, et al “Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases” JAMA Oncol 2021; DOI: 10.1001/jamaoncol.2021.0687.

Categories : Obstetrics & GynaecologyTags :

‘Absolutely Amazing’ Results of Baby’s Surgery in the Womb

On By ModernMedia
Baby's hand holding on to an adult's finger. Image by RitaE from Pixabay

When her mother learned of her condition while still pregnant with her, baby Mila became one of dozens of babies with spina bifida who have been treated in the womb with a revolutionary procedure, according to the Great Ormond Street Hospital (GOSH) for Children in London.

Spina bifida is a congenital malformation which occurs in the 4th week post-fertilisation where the embryonic neural tube fails to close, leaving the spinal column split (bifid) and open, exposing the spinal cord. Below the level of the damage on exposed spinal cord, there can be motor and sensory neurological deficit. Orthopaedic abnormalities such as clubfoot are possible. Additionally, the higher up the damage is on the spine, the higher the mortality rate. 

Helena, a mother from the UK who had become pregnant after six IVF attempts, at 20 weeks discovered her baby had spina bifida. A scan showed a huge open lesion on her baby’s lumbar sacral region, exposing her spinal cord. But Helena was aware of pioneering open foetal surgery carried out by the NHS following a diagnosis with a previous pregnancy, and was determined to apply for it.

“I knew if I didn’t get the operation the quality of her life would be very different,” Helena told BBC News.

“It was a very large lesion on her back and half of her spine was exposed. They said that it was likely she will be paralysed, incontinent and will need a shunt to drain the fluid from her brain later on.”

A US study, as reported previously on QuickNews, showed that the benefits of foetal repair surgery continued into later childhood, with those having had foetal repair being six times more likely to go to the toilet unaided than those who had surgery after birth, and were 70% more likely to walk unaided, and twice as likely to walk without braces. They were also more likely to use self-care skills such as brushing teeth and using a fork.  

“The procedure is complex, time-sensitive and not without its risks, but the significant and life-changing impact on babies … and their families, cannot be overstated,” explained Dr Dominic Thompson, lead neurosurgeon at GOSH. “This makes all the difference to the quality of their lives.”

Twenty-five clinicians from GOSH and University College London Hospitals, as well as University Hospitals Leuven in Belgium, were involved in Helena’s surgery, according to BBC News.

The procedure generally involves administering an anaesthetic to the mother, which passes to the foetus through the placenta, and then cutting through the abdomen and uterus to reach the foetus’s spine. Neurosurgeons then take off any skin attached to the exposed spinal cord and place the cord inside the spinal canal before stitching the tissues closed.

In her 23rd week of pregnancy, she received surgery at a specialist hospital in Belgium, and three months later, she gave birth to her daughter Mila at University College London Hospital. According to GOSH, some excess fluid still remains on the newborn’s brain, but Mila is showing signs of healthy development.

“She can move her legs, and she’s got feeling to her toes so it’s absolutely amazing,” Helena told BBC News. “I’m just so grateful to the surgeons who’ve done this operation because her life would look very different without it.” Including Mila, the team has performed the same operation on 32 babies since January 2020.

“We’re very excited about the next phase of the prenatal surgery for babies with spina bifida, including less invasive approaches,” Dr. Paolo De Coppi, part of the fetal surgical team for spina bifida, said in the statement.

“As with any new approach, we first need to fully understand the benefits and risks involved to mother and baby,” De Coppi noted. “While we look to make these future procedures as safe as possible, what is clear is that prenatal surgery for patients with spina bifida leads to better outcomes.”

Source: Live Science

Categories : Cardiovascular Disease Diet and NutritionTags :

A Daily Cup of Leafy Vegetables Can Slash Heart Disease Risk

On By ModernMedia

Eating just one cup of nitrate-rich vegetables each day can significantly reduce the risk of heart disease by up to 26%, according to research from New Edith Cowan University (ECU).

The study sought to find out whether people eating a diet with higher quantities of nitrate-rich vegetables, such as leafy greens and beetroot, had lowered blood pressure, and it also examined whether these same people were less likely to have a heart disease diagnosis in later years.

Cardiovascular diseases are a leading cause of deaths around the world, attributed to some 13 million deaths in 2010 and making up one in every four deaths.

The study examined the diets of over 50 000 people in Denmark, who took part in the Danish Diet, Cancer, and Health Study over a 23-year period. People who consumed the greatest amounts of nitrate-rich vegetables had about a 2.5 mmHg lower systolic blood pressure, and their risk of heart disease was 12 to 26% lower.

The results were published in the European Journal of Epidemiology. It is a collaboration between Edith Cowan University, the Danish Cancer Society and The University of Western Australia.  

Lead researcher Dr Catherine Bondonno from ECU’s Institute for Nutrition Research said that it was a priority to identify diets that prevent heart disease.

“Our results have shown that by simply eating one cup of raw (or half a cup of cooked) nitrate-rich vegetables each day, people may be able to significantly reduce their risk of cardiovascular disease,” Dr Bondonno said.

“The greatest reduction in risk was for peripheral artery disease (26 percent), a type of heart disease characterized by the narrowing of blood vessels of the legs, however we also found people had a lower risk of heart attacks, strokes and heart failure.”

The study found that only one cup of nitrate-rich vegetables was needed for optimum results, and it didn’t seem that there were any more benefits from eating more.

“People don’t need to be taking supplements to boost their nitrate levels because the study showed that one cup of leafy green vegetables each day is enough to reap the benefits for heart disease,” Dr Bondonno said. “We did not see further benefits in people who ate higher levels of nitrate rich vegetables.”

Dr Bondonno added that some shortcuts such as adding a cup of spinach when making a banana or berry smoothie could be an easy way to include more daily leafy greens.

“Blending leafy greens is fine, but don’t juice them. Juicing vegetables removes the pulp and fiber,” Dr Bondonno said.

The research adds to a growing body of evidence linking vegetables generally and leafy greens specifically with improved cardiovascular health and muscle strength.

Source: Medical Xpress

Journal information: Catherine P. Bondonno et al, Vegetable nitrate intake, blood pressure and incident cardiovascular disease: Danish Diet, Cancer, and Health Study, European Journal of Epidemiology (2021). DOI: 10.1007/s10654-021-00747-3