Body

From March 2020, when COVID-19 spread throughout Europe, GPs had to rely on clinical information collected in hospitals, the only official information available, when dealing with potential infections. "However, we also heard, from colleagues or even through social media, of other and unconfirmed information that reported very different clinical pictures encountered by GPs," explains Dr Hubert Maisonneuve, a lecturer and researcher in the research group led by Professor Dagmar Haller at the Primary Care Unit of the UNIGE Faculty of Medicine, and a GP in the Lyon region. "Since it was extremely difficult to test our patients, we decided, with a few colleagues and in collaboration with two ambulatory laboratories, to set up studies that would allow us to better understand the symptomatology of COVID-19 in its mild forms, and potentially develop a clinical evaluation tool." To this end, clinical data from more than 1,500 patients who underwent a PCR test were collected between March 24 and May 7, 16% of whom tested positive for COVID-19.

Significantly different symptoms

The medical researchers were able to establish a clinical picture for these patients that was significantly different from that described in the hospital setting, but consistent with the informal information collected previously. "Very early on, we detected that loss of taste and smell were among the most predictive symptoms of the disease, unlike fever or cough, which are not specific enough," explains Dr. Benoît Tudrej, a general practitioner and member of the Collège universitaire de médecine générale at the Claude Bernard University in Lyon, who participated in this work. In addition, rarer symptoms that were thought to be strongly related to COVID-19, such as shortness of breath, were found to have very little correlation with a positive test. Because the ambulatory population is different from the population arriving at the hospital, the clinical picture is also different. "However, this is a good indication that you cannot base an entire public health policy in managing an epidemic on hospital data alone, especially when there is a lack of tests to screen for people with light symptoms,» adds Dr. Tudrej.

A poor clinical prediction score

Many research teams have sought to develop a clinical prediction score, a technique commonly used that, by combining various clinical signs and symptoms, allows a statistical estimate of a patient's risk for a particular disease. "We thus tested the model published by an Anglo-American team in Nature Medicine based on data collected through an application," explains Dr Maisonneuve. "But on our data, this score doesn't work. Why? Probably because of a selection bias in the Anglo-American study, where respondents - mostly young women - did not have the same demographic profile as our patients.»

The clinical prediction score does indeed seem to work better for a subgroup, women in their 40s to 60s, whose symptoms seem more pronounced, and therefore easier to detect. "However, this aspect of our work needs to be confirmed on larger samples or with more powerful analysis tools," adds Dr. Paul Sebo of UIGP, who was in charge of this part of the study.

GPs are essential to an efficient health policy

These studies carried out in the urgency of an exceptional situation highlight two important points: firstly, the fact that GPs often remain on the sidelines of political decisions, to the detriment of a large part of the population for whom their usual doctor remains the sole contact person for health matters. In a situation where triage of patients is problematic, but where the threat is spreading rapidly, this can lead to a delay in care or a lack of subtlety in analysing the situation. "This is especially true when, as it is currently the case, the aim is to identify new clusters as quickly as possible in order to contain the spread of the virus", the authors point out. Secondly, research in primary care is still underdeveloped. It is through such work, which is based on strong evidence, that it will be able to take its full place in the construction of academic and medical knowledge.

Pancreatic cancer is a life-threatening disease with very poor survival rates in patients, and--despite various efforts--its treatment remains challenging. This is because pancreatic cancer is characterized by the presence of "fibrosis," a pathological scarring process that occurs when the physiological wound healing process goes awry. Thus, to tackle pancreatic cancer, it is crucial to understand the mechanisms driving fibrosis in detail. However, experimental models that are used to study pancreatic cancer have not yet been able to fully replicate the extent of fibrosis in human tissue.

To this end, researchers at Okayama University, Japan, including Professor Mitsunobu R. Kano and Assistant Professor Hiroyoshi Y. Tanaka, found a way to recreate pancreatic cancer tissue "in vitro" (in the laboratory). Using a three-dimensional (3D) cell culture technique, they devised a method to mix pancreatic cancer cells together with fibrotic components to generate tissues that resemble human pancreatic cancer. Their findings are published in Biomaterials. Prof Kano, who supervised the study, explains, "No cancer is an island entire of itself. In pancreatic cancer, fibrotic tissue often occupies much more space than the cancer cells themselves. While numerous 3D models of pancreatic cancer have been reported, ours is the first to allow the tuning of the amount of fibrosis in the model."

But, why does the presence of fibrosis hinder cancer treatment in the first place? Specifically, the dense and thick fibrotic tissue obstructs the penetration of drugs into the tumor and limits anti-tumor immunity. Assistant Professor Tanaka, who led the study, explains, "With the 5-year survival rate of pancreatic cancer at approximately 9% despite decades of intensive research, a deeper understanding of the mechanisms that underlie fibrosis in pancreatic cancer, as well as its pathophysiological and therapeutic ramifications, is necessary." Thus, the scientists set out to find ways of understanding fibrotic mechanisms in pancreatic cancer.

But, this was no easy task, as currently used experimental models of pancreatic cancer, especially in vitro models, fail to replicate the fibrotic components that are seen in pancreatic cancer. Thus, the scientists reasoned that it was important to establish relevant pancreatic cancer models that comprise not only cancer cells but also cells involved in fibrosis. There were other challenges as well: an analysis by the research team revealed that the area occupied by fibrosis in human pancreatic cancer tissues ranges from 40 to 80% among patients. Prof Kano says, "There was considerable heterogeneity among patients, and for our 3D cell culture model to fully resemble human pancreatic cancer, we wanted to make sure that we could recreate tissue with any given amount of fibrosis."

Fibrosis consists mainly of cells called "fibroblasts" and other extracellular matrix components secreted by fibroblasts. Considering this, the research team came up with a simple strategy: mix and culture pancreatic cancer cells and fibroblasts at various ratios. "The strategy seemed too simple to work," Tanaka recollects with a laugh, "But much to our pleasant surprise, it did!" The team successfully showed that by varying the ratio of pancreatic cancer cells seeded against a fixed number of fibroblasts, they could create pancreatic cancer tissues in vitro with different amounts of fibrosis. Importantly, they showed that the area occupied by fibrosis in these tissues can be experimentally tuned to match the amount of fibrosis in the clinically observed range. The team also went on to use the model to successfully understand the molecular mechanisms by which a particular "phenotype" of fibroblasts, characteristic to pancreatic cancer, occurs.

The scientists are optimistic that this novel model can complement other well-established models of pancreatic cancer, especially with regard to fibrosis. "The great thing about our model is that it is fairly simple to create," concluded Prof Kano. "We believe it will be useful in mechanistic studies as well as in screening for drugs that target fibrosis. This is just the beginning, but we hope to make a real difference in the treatment of pancreatic cancer."

Doctors have traditionally avoided prescribing nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen to patients with fractures. This belief is based on basic science research that supports delayed bone healing in some animal models, as well as in some spinal fusion cases. However, a new study from the University of Missouri School of Medicine and MU Health Care shows ibuprofen is an effective medication for fracture pain in children and its use does not affect fracture healing.

The study examined 95 skeletally immature children with fractures. Forty-six patients in the control group received acetaminophen for pain, while 49 patients in the NSAID group received ibuprofen. Six weeks after surgery, 82% of the control group and 92% of the ibuprofen group had healed fractures. At 10-to-12 week follow-ups, 98% of the control group and 100% of the ibuprofen group had healed.

"The findings of this study are relevant for a wide variety of practitioners," said study co-author Sumit Gupta, MD, an associate professor of orthopaedic surgery at the MU School of Medicine. "I think this study will be especially important when the patient first presents to the emergency department. The physician there should feel comfortable prescribing ibuprofen in addition to acetaminophen as a safe and effective pain reliever that won't hinder a child's bone healing."

Patients in the control and ibuprofen groups reported similar pain management scores during the first three days after injury and at each follow-up interval. For the control group, acetaminophen was used for 3.9 days on average while the ibuprofen group average was 4.3 days.

"We often find that pain management is not adequate with just acetaminophen," Gupta said. "Patients respond better to having two medications at the same time. So if that second medication can be ibuprofen instead of a narcotic, that's a much safer alternative."

Gupta believes the results from this study warrant further investigation to examine the effectiveness of other NSAID drugs besides ibuprofen, how NSAIDs work on specific types and locations of fractures and the effectiveness of this treatment on specific patient profiles, including adults.

Sophia Antipolis, 23 July 2020: Eating chocolate at least once a week is linked with a reduced risk of heart disease, according to research published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

"Our study suggests that chocolate helps keep the heart's blood vessels healthy," said study author Dr. Chayakrit Krittanawong of Baylor College of Medicine, Houston, Texas.

"In the past, clinical studies have shown that chocolate is beneficial for both blood pressure and the lining of blood vessels," he continued. "I wanted to see if it affects the blood vessels supplying the heart (the coronary arteries) or not. And if it does, is it beneficial or harmful?"

The researchers conducted a combined analysis of studies from the past five decades examining the association between chocolate consumption and coronary artery disease (the blockage of the coronary arteries). The analysis included six studies with a total of 336,289 participants who reported their chocolate consumption.

During a median follow-up of nearly nine years, 14,043 participants developed coronary artery disease and 4,667 had a heart attack (when coronary artery disease progresses and the flow of blood to the heart is suddenly blocked).

Compared with consuming chocolate less than once a week, eating chocolate more than once a week was associated with an 8% decreased risk of coronary artery disease.

Dr. Krittanawong said: "Chocolate contains heart healthy nutrients such as flavonoids, methylxanthines, polyphenols and stearic acid which may reduce inflammation and increase good cholesterol (high-density lipoprotein or HDL cholesterol)."

He noted that the study did not examine whether any particular type of chocolate is more beneficial and whether there is an ideal portion size. "Chocolate appears promising for prevention of coronary artery disease, but more research is needed to pinpoint how much and what kind of chocolate could be recommended," he said.

While it's not clear how much chocolate is optimal, Dr. Krittanawong warned against overeating. He said: "Moderate amounts of chocolate seem to protect the coronary arteries but it's likely that large quantities do not. The calories, sugar, milk, and fat in commercially available products need to be considered, particularly in diabetics and obese people."

The cover for issue 29 of Oncotarget features Figure 5, "In vivo effects of treatment with L-Grb2 in combination with anti-angiogenic therapy in an ovarian tumor model," by Lara, et al. which reported that adaptor proteins such as growth factor receptor-bound protein-2 play important roles in cancer cell signaling. In the present study, the authors examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression in gynecologic cancer models.

Murine orthotopic models of ovarian and uterine cancer were used to study the biological effects of L-Grb2 on tumor growth.

In vitro experiments were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2. Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight.

Reverse-phase protein array analysis identified significant dysregulation of metabolites in ovarian cancer cells after Grb2 downregulation.

L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer.

"L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer."

Dr. Anil K. Sood and Dr. Cristian Rodriguez-Aguayo from The University of Texas MD Anderson Cancer Center said, "Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation."

Druggable targets have often been proteins with enzymatically active sites to which small molecules could bind.

However, the ability to target previously undruggable targets is evolving. Small-molecule inhibitors rely on intracellular targets or antibodies to inhibit the activity of growth factors, cell surface receptors, and cytokines.

The development of nucleic acid interference-based therapeutics has allowed for regulation of gene expression to inhibit elusive targets.

Nucleic acid-based therapeutics involves a process in which RNA molecules or antisense oligonucleotides inhibit gene expression or translation by neutralizing targeted mRNA molecules.

After crossing the cell membrane, ASOs target mRNA directly through complementary base pair interactions, in the nucleus or cytosol, thus blocking and neutralizing targeted mRNAs.

The Sood/Rodriguez-Aguayo Research Team concluded in their Oncotarget Research Paper, "we report that L-Grb2 has promising antitumor activity in preclinical models of ovarian and uterine carcinoma.

Whereas the evidence of L-Grb2's activity against hematological malignancies is promising, whether it is active in clinical trials against solid tumors has yet to be tested.

Therapies targeting the ErbB2 receptor have had limited success in ovarian cancer, but L-Grb2 may be a better target given its status as an important converging point for cancer cell signaling pathways."

Sign up for free Altmetric alerts about this article

DOI - https://doi.org/10.18632/oncotarget.27667

Full text - https://www.oncotarget.com/article/27667/text/

Correspondence to - Anil K. Sood - asood@mdanderson.org and Cristian Rodriguez-Aguayo - CRodriguez2@mdanderson.org

Keywords -
ovarian cancer,
nucleic-acid based therapeutics,
therapeutic approaches,
uterine cancer

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
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

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

Journal

Oncotarget

DOI

10.18632/oncotarget.27667

PROVIDENCE, R.I. [Brown University] -- The epidemic of opioid-related overdose death persists across the United States, and people released from jails and prisons are at particular risk.

While the benefits of life-saving medications for opioid use disorder (MOUD) -- such as methadone, buprenorphine and extended-release (XR) naltrexone -- has been documented across hospitals and treatment centers, its uptake has been extremely limited in U.S. prisons and jail settings.

In a new study published in the International Journal of Drug Policy on July 22, researchers from the Brown University School of Public Health led by Alexandria Macmadu, a doctoral candidate in epidemiology, found that expanding access to all three MOUD in prisons and jails can reduce overdose deaths by 31.6% in certain circumstances.

The researchers developed a microsimulation model -- a computer program that mimics the operation of government programs and demographic processes on individual members of a population -- to simulate a population of 55,000 people at risk of opioid-related overdose death in Rhode Island. The primary calibration targets for the model were the observed overdose mortality rates in Rhode
Island in 2015. The model proceeds in two-week time-steps; therefore, incarceration was defined as being incarcerated in Rhode Island's unified prison and jail system for a period of at least two weeks.

They then studied the potential effects of providing access to all three MOUD in a combined prison and jail setting to at-risk people in Rhode Island over eight years and compared that to an XR-naltrexone-only intervention and the standard of care.

In the standard of care scenario, which accounts for limited or no access to MOUD, the model predicted 2,385 opioid-related overdose deaths between 2017 and 2024. An XR-naltrexone intervention averted 103 deaths, for a 4.3% reduction, and access to all three MOUD averted 139 deaths, for a 5.8% reduction. Among those with prior-year incarceration, those numbers rose to 22.8% and 31.6%, respectively.

According to previous studies, the first two weeks following release from incarceration are associated with a 129-fold increase in overdose risk relative to the general population. During incarceration, tolerance to opioids is diminished or lost, which -- combined with disrupted social support networks, limited access to MOUD, medical comorbidities and various other socioeconomic conditions -- places individuals at a much higher risk for overdose upon release.

"We found that the most overdose deaths were averted when the computer model was set up such that persons initiating therapy at release were retained in care for longer periods," said Brandon Marshall, corresponding author on the paper and associate professor of epidemiology at Brown. "This finding suggests that, to maximize public health impact, programs should ensure continuity of care by addressing known barriers to accessing treatment for opioid use disorder, such as unstable housing and medical insurance interruptions that often occur as persons are released from prison and jails."

The findings align with similar studies conducted in other countries such as the United Kingdom and Australia that found that increased access to MOUD in prisons and jails is associated with a lower overdose rate.

The researchers say that the Rhode Island results suggest that other states would see similarly large mortality reductions with increased access to MOUD. However, Rhode Island stands out from other states when it comes to prisons.

First, Rhode Island has one of the lowest incarceration rates in the country. It also implemented diversion programming, which offers the dismissal of criminal charges to those with nonviolent felonies through participation in drug treatment and mental health programs. Finally, the pre-2016 standard of care in Rhode Island allowed for the provision of methadone on a 30-day taper protocol among those who were prescribed methadone prior to incarceration -- the majority of prisons and jails in the U.S. offer MOUD only to women who are pregnant.

These characteristics likely underestimate the potential reduction in overdose mortality that would be observed if all three MOUD were implemented in correctional facilities elsewhere.

"As it stands, most prisons and jails that provide any access to treatment only offer extended-release naltrexone," Macmadu said. "Our findings suggest that if all prisons and jails in the U.S. expanded access to MOUD to all persons who are indicated for treatment, overdose mortality in this highly vulnerable population would plummet."

Concussions can have a compounding effect on children, leading to long-term cognitive, behavioral, and emotional health consequences, according to researchers at The University of Texas Health Science Center at Houston (UTHealth), who published their findings in the American Journal of Sports Medicine.

In 2017, approximately 2.5 million high school students in the United States reported suffering at least one concussion related to sports or physical activity in the last 12 months, according to information from the U.S. Centers for Disease Control and Prevention (CDC).

The UTHealth researchers analyzed survey data from more than 13,000 high school students in the United States. According to the authors, it is the first study to report on the association between sports-related concussions and negative health implications based on a representative sample of U.S. high school students.

"We have previously speculated that children who suffer a concussion have more behavioral problems, so this study was able to provide a more comprehensive analysis on the various cognitive and behavioral health issues that this population faces in connection with this type of brain injury," said Gregory Knell, PhD, the study's first and corresponding author. Knell is an assistant professor at UTHealth School of Public Health in Dallas and is research faculty at Children's Health Andrews Institute for Orthopaedics and Sports Medicine.

A concussion is the most common form of traumatic brain injury, caused by a mild blow to the head. Common symptoms include a headache, ringing in the ears, nausea, vomiting, fatigue, drowsiness, and blurry vision.

Participants were asked how many times they had suffered a concussion from playing a sport or during physical activity in the last 12 months. Students were also surveyed on relevant cognitive, emotional, and behavioral factors and related health outcomes, including questions on topics such as academics, suicidal ideation, and substance abuse.

The study revealed that 14.5% of female high school athletes and 18.1% of male high school athletes reported experiencing at least one concussion the previous year. These students also reported at least one factor associated to their behavioral, cognitive, and emotional health. The questions covered topics such as difficulty concentrating, poor grades, drinking and driving, carrying a weapon, getting into a physical altercation, using tobacco or marijuana, binge drinking, feeling depressed, and having suicidal thoughts or actions.

Of the male participants who suffered at least one concussion, 33.8% reported they drank and drove in the last 30 days. For the female athletes who reported suffering more than one concussion, 19% stated they had used marijuana at least once in the last 30 days. Both male and female participants who answered that they had been in at least one physical fight in the last year were significantly more likely to have reported having at least one concussion in that same timeframe.

Other associated factors that were significantly more likely in male students who reported a prior concussion included difficulty concentrating, tobacco/e-cigarette use, and binge drinking. Female students who reported prior concussions were more likely to ride in a car with a driver who had been drinking, and have suicidal thoughts or actions.

"Parents need to understand that a concussion is a very serious brain injury, one which requires treatment every time a concussion is sustained. This study has revealed this type of traumatic brain injury can have a compounding effect on children that could lead to more aggressive behavior, academic problems, and social issues," said study co-author Scott Burkhart, PsyD, a neuropsychologist at Children's Health Andrews Institute for Orthopaedics and Sports Medicine.

The research team encourages future studies to continue the surveillance on the prevalence of concussions among student athletes, as well as the severity of these injuries.

July 22, 2020--(BRONX, NY)-- A new study led by Albert Einstein College of Medicine and Montefiore Health System confirms the findings of the large scale British trial of steroid use for COVID-19 patients and advances the research by answering several key questions: Which patients are most likely to benefit from steroid therapy? Could some of them be harmed? Can other formulations of steroids substitute for the agent studied in the British trial? The research was published today in the Journal of Hospital Medicine.

The U.K. RECOVERY trial, a prospective, randomized, open-label study of the steroid dexamethasone versus standard of care, involved more than 6,000 patients with COVID-19. Dexamethasone reduced deaths by about one-third in patients on ventilators and by about one-fifth among people who needed oxygen but were not on ventilators. However, the study leaves questions about the use of steroids for treating some patients.

"Our study is consistent with the promising findings from Britain, but for the first time, we are able to demonstrate that people can see the same life-saving benefits with steroid formulations other than dexamethasone," said Marla Keller, M.D., vice chair for research in the department of medicine at Einstein and Montefiore and lead author of the study. "We also found that a common blood test may identify the best candidates for steroid treatment." Dr. Keller is also professor of medicine and of obstetrics & gynecology and women's health at Einstein and an infectious disease specialist at Montefiore.

Authors of the Einstein-Montefiore study compared outcomes for two groups selected from nearly 3,000 people hospitalized at Montefiore with a positive COVID-19 test. One group of 140 patients was treated with steroids within 48 hours of hospital admission; and a control group of 1,666 similar patients did not receive steroid therapy. Most of the patients who received steroid therapy received prednisone. Some received dexamethasone and methylprednisolone.

Nearly all patients initially had a blood test to measure levels of C-reactive protein (CRP), which the liver produces in response to inflammation. The higher the CRP level in the blood, the greater amount of inflammation. A normal CRP level reported in the study is below 0.8 milligrams per deciliter of blood.

“We found that in patients with high levels of inflammation, namely a CRP level greater than 20, steroids were associated with a 75% reduction in the risk of going on mechanical ventilation or dying,” said Dr. Keller. “Critically, we also found that for patients with a lower level of inflammation—CRP levels less than 10—steroid use was associated with an almost 200% increased risk of going on mechanical ventilation or death.”

A large percent of the people who succumb to COVID-19 die from the body's intense inflammatory response, which can overwhelm and severely damage the lungs. "Our findings suggest that steroid therapy should be reserved for people with high inflammation, as indicated by markedly elevated CRP levels," said William Southern, M.D., M.S., professor of medicine and chief of the division of hospital medicine at Einstein and Montefiore and the study's senior author. "It's a different story for people who do not have significant inflammation: for them, any benefit is outweighed by the risks from using steroids."

Study co-author Shitij Arora, M.D., associate professor of medicine at Einstein and a hospitalist at Montefiore, noted that the Einstein-Montefiore study included approximately equal numbers of male and female patients. In addition, nearly 40% of patients studied were Black and 36% were Hispanic. "The demographic diversity of the patients in this study suggests that steroid therapy benefits hospitalized COVID-19 patients affected by significant inflammation regardless of their race or ethnicity," he said.

The title of this paper is "Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19." Other Einstein and Montefiore authors were Jen-Ting Chen, M.D., M.S., Elizabeth Kitsis, M.D., M.B.E., Shivani Agarwal, M.D., M.P.H., Michael Ross, M.D., and Yaron Tomer, M.D.

Researchers at Columbia University Irving Medical Center have isolated antibodies from several COVID-19 patients that, to date, are among the most potent in neutralizing the SARS-CoV-2 virus.

These antibodies could be produced in large quantities by pharmaceutical companies to treat patients, especially early in the course of infection, and to prevent infection, particularly in the elderly.

"We now have a collection of antibodies that's more potent and diverse compared to other antibodies that have been found so far, and they are ready to be developed into treatments," says David Ho, MD, scientific director of the Aaron Diamond AIDS Research Center and professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, who directed the work.

The researchers have confirmed that their purified, strongly neutralizing antibodies provide significant protection from SARS-CoV-2 infection in hamsters, and they are planning further studies in other animals and people.

The findings were published today in the journal Nature.

Why look for neutralizing antibodies

One of the human body's major responses to an infection is to produce antibodies--proteins that bind to the invading pathogen to neutralize it and mark it for destruction by cells of the immune system.

Though a number of drugs and vaccines in development for COVID-19 are in clinical trials, they may not be ready for several months. In the interim, SARS-CoV-2 neutralizing antibodies produced by COVID-19 patients could be used to treat other patients or even prevent infection in people exposed to the virus. The development and approval of antibodies for use as a treatment usually takes less time than conventional drugs.

This approach is similar to the use of convalescent serum from COVID-19 patients, but potentially more effective. Convalescent serum contains a variety of antibodies, but because each patient has a different immune response, the antibody-rich plasma used to treat one patient may be vastly different from the plasma given to another, with varying concentrations and strengths of neutralizing antibodies.

Sicker patients produce more potent antibodies

When SARS-CoV-2 arrived and led to a pandemic at the beginning of the year, Ho rapidly shifted the focus of his HIV/AIDS laboratory to work on the new virus. "Most of my team members pretty much have been working nonstop 24/7 since early March," says Ho.

The researchers had easy access to blood samples from patients with moderate and severe disease who were treated at Columbia University Irving Medical Center in New York City, the epicenter of the pandemic earlier this year. "There was plenty of clinical material, and that allowed us to select the best cases from which to isolate these antibodies," Ho says.

Ho's team found that although many patients infected with SARS-CoV-2 produce significant quantities of antibodies, the quality of those antibodies varies. In the patients they studied, those with severe disease requiring mechanical ventilation produced the most potently neutralizing antibodies.

"We think that the sicker patients saw more virus and for a longer period of time, which allowed their immune system to mount a more robust response," Ho says.  "This is similar to what we have learned from the HIV experience."

Antibody cocktails

The majority of anti-SARS-CoV-2 antibodies bind to the spike glycoprotein--a feature that gives the virus its corona--on the virus's surface. Some of the most potent antibodies were directed to the receptor binding domain (where the virus attaches to human cells), but others were directed to the N-terminal region of the spike protein.

The Columbia team found a more diverse variety of antibodies than previous efforts, including new, unique antibodies that were not reported earlier.

"These findings show which sites on the viral spike are most vulnerable," Ho says. "Using a cocktail of different antibodies that are directed to different sites in spike will help prevent the virus becoming resistant to the treatment."

Implications for vaccines

"We discovered that these powerful antibodies are not too difficult for the immune system to generate. This bodes well for vaccine development," Ho says. "Vaccines that elicit strong neutralizing antibodies should provide robust protection against the virus."

Antibodies may also be useful even after a vaccine is available.  For example, a vaccine may not work well in the elderly, in which case the antibodies could play a key role in protection.

Implications for immunity

This research demonstrates that people with severe disease are more likely to have a durable antibody response, however more research needs to be done to answer the critical question about how long immunity to COVID-19 will last.

What's next

The researchers are now designing experiments to test the strategy in other animals, and eventually in humans.

If the animal results hold true in humans, the pure, highly neutralizing antibodies could be given to patients with COVID-19 to help them clear the virus.

Caveats

Although tremendously informative for researchers developing vaccines and antiviral therapies, the findings are early-stage preclinical results and the antibodies are not yet ready for use in people.

Early menstruation increases the likelihood of hot flushes and nights sweats decades later at menopause, according to a University of Queensland study.

School of Public Health researchers analysed data from more than 18,000 middle aged women across the UK, USA and Australia, as part of the Life course Approach to reproductive health and Chronic disease Events (InterLACE) international collaboration.

UQ's Dr Hsin-Fang Chung said the study showed women who started menstruating aged 11 or younger had a 50 per cent higher risk of experiencing frequent hot flushes and night sweats - known as vasomotor symptoms - at menopause.

The group was compared with women who had their first period at 14 or older.

"The risk of the women who menstruated early experiencing both symptoms was greater than having either hot flushes or night sweats alone," Dr Chung said.

She said early menstruation previously had been linked to adverse health conditions later in life, including type 2 diabetes and cardiovascular diseases.

InterLACE project leader Professor Gita Mishra said obesity played a significant role in the findings.

"Women who experienced early menstruation and were overweight or obese in midlife had a two times greater risk of frequent hot flushes and night sweats, compared with women who experienced their first period aged 14 years or older, and had normal weight," she said.

"These findings encourage women with early menstruation to engage in health promotion programs, especially weight management in adulthood," Professor Mishra said.

Research reveals that treatment of heart attack patients for a common condition, underactive thyroid, with levothyroxine does not improve heart muscle function, so is unlikely to be of benefit.

The results of a double-blind randomised clinical trial which was carried out in six UK hospitals and led by experts at Newcastle University, UK are published today in JAMA.

Mild or subclinical hypothyroidism is a condition in which the body doesn't produce enough thyroid hormones and is very common affecting approximately 10% of the adult population. Management of the condition is currently haphazard due to the lack of high quality evidence either for or against treatment. Some clinicians may treat whereas others may not - and this is particularly the case in high risk conditions such as heart attacks.

Observational studies have previously suggested that patients with cardiac problems, including heart attacks, and subclinical hypothyroidism are at higher risk of death. And so, current guidelines suggest that these patients should be treated with levothyroxine.

This clinical trial demonstrates that treatment with levothyroxine does not improve cardiac function in patients who have had a heart attack and therefore is unlikely to be beneficial.

Dr Salman Razvi, Senior Lecturer and Consultant Endocrinologist, Newcastle University and the Queen Elizabeth Hospital in Gateshead, explains: "The results of this trial will help clinicians reconsider offering treatment with levothyroxine to tens of thousands of patients with subclinical hypothyroidism worldwide. The results of this trial demonstrate that there are no significant improvements for patients with heart attacks who are given levothyroxine.

"On this basis, screening for and subsequent treatment of subclinical hypothyroidism in patients who have had a heart attack to preserve or improve heart function is not justified."

The clinical trial

In the trial, 95 patients were recruited with 46 receiving levothyroxine and 49 a placebo. After 12 months, heart function improved in both groups - but there was no greater improvement in those receiving levothyroxine.

Limitations of the trial include the low dose offered initially which may have reduced the therapeutic effect and there may be a more significant improvement in patients were patients to start treatment sooner (average 17 days after heart attack). In addition, 4 in 10 patients with subclinical hypothyroidism on the initial blood test had normalised their levels when rechecked a few days later.

The team will now be making this research available as part of the evidence to change existing guidelines.

Dr Razvi adds: "To any patient who has had a heart attack and has been diagnosed with subclinical hypothyroidism, I would advise that they consult their GP on whether levothyroxine is likely to be of benefit. The results of our trial suggest that all such patients should have their thyroid function rechecked after a few weeks. Treatment with levothyroxine should not be started routinely in such patients. Furthermore, international guidelines should be amended to reflect this finding."

A diverse array of bacteria live in the human mouth as part of a vital ecosystem known as the oral microbiome. Virginia Tech researchers have discovered that one of these common bacteria can leave the mouth and potentially cause existing cancer cells in other parts of the body to spread.

These bacteria are believed to predominantly travel through the blood to different sites in the body where they are associated with serious infections of the brain, liver, and heart; preterm birth in pregnant women; and are present in high levels in colon tumors. Poor oral hygiene could cause the bacteria to migrate to other parts of the body where cancers exist. Also, evidence exists for a link between severe gum disease and colorectal cancer.

"Our team's discovery shows that infection with these bacteria initiates cancer cell migration," said Daniel Slade, who is an assistant professor in the Department of Biochemistry in the College of Agriculture and Life Sciences, and an affiliated researcher in the Fralin Life Sciences Institute. "This is vital information because 90 percent of cancer-related deaths result from nonprimary tumors or sites that have metastasized to somewhere else in the body."

The findings were published July 21 as the cover story in Science Signaling, which is produced by the American Association for the Advancement of Science.

Since 2012, multiple studies have shown this bacterium, Fusobacterium nucleatum, directly invades colon tumors, but questions remained as to how this bacterium is contributing to cancer.

A 2017 study showed that when human colon tumors containing F. nucleatum are put into a mouse, cancer cells containing live bacteria will break off and reattach in the liver, providing the first evidence that F. nucleatum could be directly involved in causing the spread of cancer cells throughout the body.

To address the potential of F. nucleatum driving metastasis, Virginia Tech researchers asked the broad question: How do human cells respond when colon cancer cells are infected with F. nucleatum? Their findings provide a deeper understanding of the critical role bacteria can play in cancer.

Origins of the project

The relatively benign nature of F. nucleatum initially intrigued Slade and his team of researchers. At first glance, Fusobacterium nucleatum appears quite unremarkable and lives in harmony with other bacteria under the gums in the oral microbiome. Despite its role as a common bacterium in the mouth, the correlations with colon cancer were too strong to ignore.

"Dan convinced me that this bacterium was a viable research direction as a bacterium that could directly influence the behavior of cancer cells," said Scott Verbridge, a member of the team, associate professor in the Virginia Tech Department of Biomedical Engineering and Mechanics in the College of Engineering, and principal investigator of the Laboratory of Integrative Tumor Ecology. "He had developed the ability to genetically modify this bacterium. He had some amazing technology to culture this bacterium with cancer cells that was beyond anything that we could do in my lab."

According to Slade and his team, there is no evidence that this bacterium is directly initiating cancer. Also, this bacterium does not appear to be releasing molecules that are causing the cancer cells to migrate.

Instead, F. nucleatum sticks to and even enters cancer cells using the protein Fap2, which docks with sugars overrepresented on the surface of cancer cells. This in turn causes cancer cells to release two proteins known as IL-8 and CXCL1, which are members of the cytokine protein family that play critical roles in immune system activation against infections.

Strikingly, the cytokine combination of IL-8 and CXCL1 was previously shown in multiple studies to induce the spread of cancer cells. However, Slade and his team believe this is the first example of a tumor-associated bacterium producing this distinct cytokine combination.

These cytokines released by an infected cell then can talk back to the same cell or those signals can be sent out to other cancer cells, immune cells, and various other cell types that surround a tumor. In essence, one infected cell could be affecting multiple neighboring cells, so there doesn't have to be a widespread infection within a tumor for it to be influencing a large surrounding area.

In addition to IL-8 and CXCL1 contributing to cellular migration or metastasis, they are also potent immune cell attractants, which can lead to inflammation; a hallmark of cancer. The attraction and subsequent infection of immune cells known as neutrophils and macrophages by F. nucleatum could in turn lead to additional pro-cancerous proteins being released, which Slade and colleagues show in this work. A key contributor to the team in understanding the interactions of F. nucleatum with immune cells was Liwu Li, a professor in the Department of Biological Sciences and an affiliated researcher in the Fralin Life Sciences Institute.

F. nucleatum, a common bacteria that can leave the mouth and potentially cause existing cancer cells in other parts of the body to spread, pictured inside of colon cancer cells.

Eyes on the future

The long-term goal of Slade and his team is to advance cancer treatment by addressing the role bacteria play in disease, which could be a critical piece that has been missing from the puzzle.

Finding pro-metastatic human proteins that are released by cancer cells upon bacterial infections has opened the door for future research. These results provide an insight into potentially blocking the secretion of cytokines to combat metastasis induced by bacteria. This is an attractive alternative to using antibiotics to kill F. nucleatum, which could also clear beneficial bacteria.

"We need to know if there are other important bacteria that could be working in synergy with F. nucleatum to drive cancer. We need to understand the physiological role of these bacteria as we can't just go about clearing them from the body because we need them for some situations. Oftentimes, bacteria are needed for chemotherapy to be fully effective," Verbridge said.

"I also think it's interesting to ask if the bacteria are causing this cellular migration as a way to get around in the human body. There could be a selective advantage for any infectious agent, a virus or bacteria, that could get inside of a host cell and migrate," Verbridge said. This could be particularly important for F. nucleatum as it is classified as a nonmotile bacterium; one that does not possess the ability to move through a lack of molecular appendages like flagella that drive movement.

Together, these results provide a deeper understanding of how bacteria influence cancer. While this process was shown to occur with colorectal cancer cells, the team is exploring if the same process is influencing other types of cancer, including pancreatic cancer, breast cancer, and oral squamous cell carcinoma of the mouth.

An international team of researchers has developed a non-invasive blood test that can detect whether an individual has one of five common types of cancers, four years before the condition can be diagnosed with current methods. The test detects stomach, esophageal, colorectal, lung and liver cancer.

Called PanSeer, the test detected cancer in 91% of samples from individuals who had been asymptomatic when the samples were collected and were only diagnosed with cancer one to four years later. In addition, the test accurately detected cancer in 88% of samples from 113 patients who were already diagnosed when the samples were collected. The test also recognized cancer-free samples 95% of the time. ß

In addition, the test accurately detected cancer in 88% of samples from 113 patients who already diagnosed with five common cancer types. The test also recognized cancer-free samples 95% of the time.

The study is unique in that researchers had access to blood samples from patients who were asymptomatic and had not yet been diagnosed. This allowed the team to develop a test that can find cancer markers much earlier than conventional diagnosis methods. The samples were collected as part of a 10-year longitudinal study launched in 2007 by Fudan University in China.

"The ultimate goal would be performing blood tests like this routinely during annual health checkups," said Kun Zhang, one of the paper's corresponding authors and professor and chair of the Department of Bioengineering at the University of California San Diego. "But the immediate focus is to test people at higher risk, based on family history, age or other known risk factors."

Early detection is important because the survival of cancer patients increases significantly when the disease is identified at early stages, as the tumor can be surgically removed or treated with appropriate drugs. However, only a limited number of early screening tests exist for a few cancer types.

Zhang and colleagues present their work in the July 21, 2020 issue of Nature Communications. The team includes researchers at Fudan University and at Singlera Genomics, a San Diego and Shanghai based startup that is working to commercialize the tests based on advances originally made in Zhang's bioengineering lab at the UC San Diego Jacobs School of Engineering.

The researchers emphasize that the PanSeer assay is unlikely to predict which patients will later go on to develop cancer. Instead, it is most likely identifying patients who already have cancerous growths, but remain asymptomatic for current detection methods. The team concluded that further large-scale longitudinal studies are needed to confirm the potential of the test for the early detection of cancer in pre-diagnosis individuals.

Taizhou Longitudinal Study

Blood samples in the Nature Communications study were collected as part of the Taizhou Longitudinal Study, which has collected plasma samples from over 120,000 individuals between 2007 and 2017. Each individual gave blood samples over a 10-year period and underwent regular check-ins with physicians. In all, over 1.6 million specimens have been collected and archived to date.

Once a person was diagnosed with cancer, the researchers had access to blood samples taken one to four years before these patients even started to show symptoms.

The team was able to examine samples from both healthy and sick individuals from the same cohort. The authors performed an analysis on plasma samples obtained from 605 asymptomatic individuals, 191 of whom were later diagnosed with cancer. They also profile plasma samples from an additional 223 diagnosed cancer patients as well as 200 primary tumour and normal tissue samples.

DNA methylation based diagnosis method

Zhang and his lab have been developing for over a decade methods to detect cancer based on a biological process called DNA methylation analysis. The method screens for a particular DNA signature called CpG methylation, which is the addition of methyl groups to multiple adjacent CG sequences in a DNA molecule. Each tissue in the body can be identified by its unique signature of methylation haplotypes. They did an early-stage proof-of-concept study that was published in a 2017 paper in Nature Genetics.

Zhang cofounded Singlera Genomics, which licensed technology he developed at UC San Diego. In the past few years, Singlera Genomics has been working to improve and eventually commercialize early cancer detection tests, including the PanSeer test, which was used in the Nature Communications study. Zhang is now the company's scientific advisor.

Zhang, Singlera Genomics and additional collaborators have been working to make a formal demonstration that cancer can be detected in the blood prior to conventional diagnosis. The July 2020 Nature Communications publication is the outcome of that effort.

With the lure of online gambling high during COVID-19 lockdowns - and some gambling venues now reopening - partners and families of problem gamblers may be the first to see a problem emerging.

Many problem gamblers do not acknowledge their addiction and do not seek help - and that's when people close to them need support to cope, and potentially even help turn the situation around by motivating a partner to seek help.

"Most people with gambling problems don't seek formal help, so problems often remain hidden within families," says Flinders University expert Ben Riley, an expert therapist with the Statewide Gambling Therapy Service in South Australia.

"As well as evidence-based strategies to help motivate non-help-seeking problem gamblers to acknowledge their problem and seek help, it's clear we also need effective programs to help partners protect their own wellbeing and perhaps help their partner to seek treatment or targeted interventions."

Gambling and addiction experts at the Flinders University and Deakin University warn partners and families of such problem gamblers can suffer from chronic worry, exhaustion, relationship conflict, and an overwhelming sense of isolation.

"They may become hypervigilant as a response to a non-disclosing problem gamblers' activities," adds co-author Professor Sharon Lawn.

"In our in-depth interviews with 15 such partners, they said they found it exceedingly difficult to reliably detect their partners' gambling behaviour, resulting in chronic hypervigilance, and many were reluctant to seek help due to stigma," she says.

"Families are often the first to know something is going on, and they really share the adverse consequences in many ways. Involving families sooner to help identify gambling problems earlier is a missed opportunity."

Mr Riley says new programs could focus on helping family members or partners to motivate their loved one to seek help.

"It's a real gap in knowledge because only a very small proportion of problem gamblers seek help - and that may be only when significant harm has been done to finances, relationships, reputation and employment," he says.

A research team from the SEAaq group at the Universitat Autònoma de Barcelona conducted analyses to determine whether the microplastics contaminating the Mediterranean Sea can also be found inside the organism of the deep-sea shrimp (Aristeus antennatus), and what effects these could have on the animal's health and on human consumption. The study was conducted in three fishing zones off the coasts of Girona, Barcelona and Delta de l'Ebre in Tarragona, during the years 2017 and 2018. Some of these samples, such as the ones from Barcelona, were compared to others from more than 10 years ago, in order to establish the changes in microplastics concentrations within a ten-year period.

The results are clear, three out of every four shrimp analysed contained anthropogenic fibers in their digestive tract. Of these, almost half of them had a good part of the fibers tangled into a ball inside their stomach. In one specific sampling, the shrimp taken from in front of the coast of Barcelona presented up to 30 times as many synthetic fibres than those taken from other fishing zones. However, when the results of 2007 were compared with those of 2017 and 2018, there was no clear increase in the abundance of these fibers. What was found was that the composition had changed, with a reduction in the presence of acrylic polymers and an increase in polyester, similar to the changes seen in consumption habits during the same period.

With regard to the effects these fibers may have on the health of these shrimp, the study shows that even animals with a considerably sized ball of fibers maintain their health condition and no tissular histopathological alterations were observed in the organs analysed, not even in the cuticle or digestive epithelium in direct contact with the artificial fibers. The study did not detect any consistent effect or correlation of these fibers with the health condition of the shrimp, which were considered to be in good health. "The shrimp probably get rid of all of the fibers they ingest and accumulate thanks to the shedding of their exoskeleton which takes place every so often, and this could explain why although an abundance of these fibers have been found in some shrimp, they continue to show signs of being healthy", explains UAB lecturer of the Department of Animal Biology, Plant Biology and Ecology Ester Carreras, one of the researchers participating in the study.

Effects on Human Health

In relation to human health, researchers consider that "the consumption of shrimp is in no way a contaminating agent that should concern us. Other studies show that ingesting micropastics through shrimp is minimal in comparison to the amount of fibers entering our bodies through other means, such as the use of plastic packagings or environmental contamination, or through the synthetic fibers in clothes and also those found in dust and which inevitably also end up in our plates", researcher Carreras highlights. In a study conducted in the United Kingdom, it was estimated that a person could ingest some 14,000 to 68,000 particles of microplastics found in the dust and air each year. This is far superior to the average 22 fibers identified in shrimp, and even more so when considering that more than 90% of the fibers are found in the animal's stomach, a part which is not eaten if we do not eat the shrimp's "head".

"Soon it will be time to discover whether common commercial fish from our coastal waters such as red mullet, surmullet or striped mullet (Mullus barbatus), and anchovy (Engraulis encrasicolus), follow the same path", Ester Carreras predicts.