Accelerating cancer treatments with the power of isotopes

Accelerating cancer treatments with the power of isotopes

Cancer is one of the most dreaded diagnoses most people can imagine receiving.

However, no two cancer patients—even if they have the same kind of cancer—experience exactly the same disease.

Successful treatment requires an approach tailored to the specific nature of an individual’s disease. The more customized the therapy is, the more effective it will be at killing cancer cells and sparing healthy tissue.

One way to deliver a knockout punch to tumor cells is to use medical isotopes or radionuclides—radiologically active atoms that can provide a highly targeted dose directly at a tumor site. While not applicable for all cancers, targeted radionuclide therapy is providing doctors with a new weapon in their arsenal against cancer.

The use of radionuclides in medicine is not new: Every year, doctors perform more than 40 million medical procedures that rely on the use of medical isotopes. However, most of these procedures are currently for diagnosing disease rather than treating it.

Producing radionuclides requires specialized facilities—they can’t be manufactured in just any lab. At the U.S. Department of Energy’s (DOE) Argonne National Laboratory, for example, high-powered linear accelerators are dispatched to generate these radionuclides, and specialized radiological facilities are needed to purify them. Traditionally used for physics experiments, these accelerators have the capability to study and even create radionuclides for use by researchers and doctors.

How medical isotopes work

Once produced, medical radionuclides can fall into three major categories. The first is diagnostic, where the radioisotope allows doctors to visualize a tumor’s precise location and contours within the body with greater clarity than an MRI scan provides. Another is therapeutic, where doctors use the radionuclide to deliver cancer-killing radiation directly to tumor cells. The third is theragnostic, which combines the power of both in such a way that the theragnostic radionuclide agent allows a doctor to both visualize and treat a tumor simultaneously.

When added into new generations of medicines that contain medical isotopes, or radiopharmaceuticals, that selectively seek out cancer cells, or that provide additional benefits in radiotherapy, these theragnostic isotopes will give doctors more options in the fight against disease and will ultimately give patients more hope.

Argonne’s long history of expertise in nuclear physics, nuclear chemistry, chemical separations and accelerator physics has paid dividends in the creation of both a radionuclide research and development program and a specialized process for supplying a particular radionuclide, copper-67, to the medical community.

“Copper-67 is an especially valuable radioisotope because it is theragnostic and because we have a way to produce it in quantities that would be useful to hospitals,” said Dave Rotsch, an Argonne chemist and deputy program manager of Argonne’s radioisotope program. “Because Argonne has unique facilities and expertise that allow us to produce these isotopes, hospitals are expressing interest.”

Argonne’s critical research role

Argonne’s work in radioisotopes is supported by the DOE Isotope Program, which is the global leader in producing and distributing radioactive and enriched stable isotopes that are deemed critical or are in short supply. DOE’s Isotope Program is taking advantage of the capabilities found at national laboratories like Argonne and putting them to use developing advanced production and processing technologies for these much-needed isotopes.

In addition to this effort, the DOE’s National Nuclear Security Administration funds Argonne to support and accelerate the U.S. production of another isotope, molybdenum-99. Argonne continues to provide target testing and development, irradiation, and Monte Carlo calculation services for multiple commercial partners to accelerate domestic production of molybdenum-99. The laboratory also helps develop and optimize separation methods for those partners.

“Argonne has a long history of showing that we can make important contributions in radioisotopes—originally in R&D, but now in actually producing them as well,” said Argonne physicist and deputy program manager Jerry Nolen.

One key facility involved in producing radioisotopes is Argonne’s Low-Energy Accelerator Facility (LEAF). To make medical isotopes, the LEAF delivers a powerful beam of electrons, which are converted to gamma rays, which are highly energetic photons, or packets of light.

These gamma rays, in turn, strike a highly pure, stable target material, like zinc-68. The resulting photo-nuclear reaction ejects one or more protons or neutrons to make the desired radioisotope: copper-67 in this case.

Only a small fraction of the target mass is converted to the isotope of interest, which means that the target can be used over and over again.

“It’s a little bit like doing alchemy,” Rotsch said. “Essentially, by hitting our target with photons, we’re converting one element into another or one isotope into another.”

The copper-67 and other byproduct isotopes are separated in gaseous form in a process that involves vaporizing the zinc in the target material and condensing it on a cold surface. The copper is then dissolved into a solution and further purified through a process that allows researchers to selectively isolate copper-67 (or whatever isotope they might want) based on the chemical differences of the atoms that are present in the solution.

A world of medical isotopes

Copper-67 is not the only isotope of interest being studied by researchers at Argonne. Rotsch and his colleagues are also investigating scandium-47, another exciting theragnostic isotope, and actinium-225, which has shown great promise for treating cancer.

“With most standard treatments, like chemotherapy, you don’t know to which drug, or drugs, a patient will respond the best, so it can sometimes be a guess-and-check game,” Rotsch said.

Radiopharmaceuticals allow doctors to observe a tumor’s uptake of a diagnostic version of the radiopharmaceutical. Based on these results, Rotsch explained, the doctor can more effectively develop and prescribe a treatment plan with a therapeutic or theragnostic radiopharmaceutical.

Artificial intelligence also could help doctors pair radioisotope candidates with individual tumors. Using the genetic profile of a tumor on a computer, researchers and medical professionals could run simulations of how a radiopharmaceutical would attach to and attack the tumor. This would provide a good idea of which therapies would be most effective even before implementing them, said Kawtar Hafidi, Argonne associate laboratory director for Physical Sciences and Engineering.

“Argonne is unique in the suite of facilities and expertise that it offers, from the accelerators to the radiochemical separations to the computing,” she said. “By combining all of these resources, we can really make a range of treatments more effective.”

From Argonne’s perspective, the ultimate goal, Hafidi said, is to create an integrated program that allows scientists to develop isotopes as fluidly as possible and create pathways for new treatments that have yet to be conceived.

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Cancer rates in medieval Britain around ten times higher than previously thought, study suggests

Cancer rates in medieval Britain around ten times higher than previously thought, study suggests

The first study to use X-rays and CT scans to detect evidence of cancer among the skeletal remains of a pre-industrial population suggests that between 9-14% of adults in medieval Britain had the disease at the time of their death.

This puts cancer prevalence in a time before exposure to tumour-inducing chemicals from industry and tobacco at around ten times higher than previously thought, according to researchers.

Prior research into historic cancer rates using the archaeological record has been limited to examining the bone exterior for lesions. It suggested that cancer was rare, affecting less than 1% of the population.

A team led by the University of Cambridge have now coupled visual inspection with radiological imaging to analyse 143 skeletons from six medieval cemeteries in and around the city of Cambridge, UK, dating from the 6th to the 16th century.

The findings of the study are published today in the journal Cancer.

“The majority of cancers form in soft tissue organs long since degraded in medieval remains. Only some cancer spreads to bone, and of these only a few are visible on its surface, so we searched within the bone for signs of malignancy,” said lead author Dr. Piers Mitchell, who conducted the research as part of the ‘After the Plague’ project.

“Modern research shows a third to a half of people with soft tissue cancers will find the tumour spreads to their bones. We combined this data with evidence of bone metastasis from our study to estimate cancer rates for medieval Britain.”

“We think the total proportion of the medieval population that probably suffered with a cancer somewhere in their body was between nine and fourteen percent,” said Mitchell, from Cambridge University’s Department of Archaeology.

“Using CT scans we were able to see cancer lesions hidden inside a bone that looked completely normal on the outside,” said study co-author and After the Plague researcher Dr. Jenna Dittmar.

“Until now it was thought that the most significant causes of ill health in medieval people were infectious diseases such as dysentery and bubonic plague, along with malnutrition and injuries due to accidents or warfare.”

“We now have to add cancer as one of the major classes of disease that afflicted medieval people,” Dittmar said.

However, the researchers point out that in modern Britain some 40-50% of people have cancer by the time they die, making the disease 3-4 times more common today than the latest study suggests it was during medieval times.

They say that a variety of factors likely contribute to contemporary rates of the disease, such as the effects of tobacco, which began to be imported into Britain in the 16th century with the colonising of the Americas.

The researchers also point to the cancerous effects of pollutants that have become ubiquitous since the industrial revolution of the 18th century, as well as the possibility that DNA-damaging viruses are now more widespread with long-distance travel. Moreover, our longer lifespans give cancer much more time to develop.

The skeletal remains investigated for the latest study came from sites near three villages in the vicinity of Cambridge, as well as three cemeteries uncovered within the medieval centre of the university city, including the site of a former Augustinian friary, and the site of a former charitable hospital that cared for the sick and destitute (now part of St. John’s College).

Very few of the excavated remains were complete, so the team limited themselves to individuals with intact spinal column, pelvis and femora (thigh bones). Modern research shows these to be the bones most likely to contain secondary malignancies—or metastases—in people with cancer.

The remains of 96 men, 46 women, and an individual of unknown sex, had their vertebrae, femurs and pelvis inspected and then imaged using X-rays and CT scans. The team found signs of malignancy in the bones of five individuals—a minimum prevalence of 3.5%. These were mostly in the pelvis, although one middle-aged man had small lesions throughout his skeleton suggesting a form of blood cancer.

Research shows that CT scans detect bone metastases around 75% of the time, and only a third to half of cancer deaths involve spread to the bone, so the team projected that 9-14% of medieval Britons developed cancer.

However, they caution that the sample size is inevitably limited and diagnosing cancer in those lain dead for many centuries is somewhat challenging.

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Young people of color with a higher income more likely to participate in cancer clinical trials

People of color, those with a higher income and younger individuals are more likely to participate in clinical trials during their cancer treatment according to a new study from the University of Missouri School of Medicine.

Clinical trials are research studies that involve people who volunteer to take part in tests of new drugs, current approved drugs for a new purpose or medical devices.

The study analyzed data collected from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System Survey, which is an annual national telephone survey designed to collect health-related data from U.S. adults. Survey years selected included the question, "Did you participate in a clinical trial as part of your cancer treatment?" The analysis of 20,053 respondents revealed an average overall clinical trial participation rate of 6.51%. Among 17,600 white respondents, participation was 6.24%; among 445 Hispanic respondents, participation was 11%; and among 943 Black respondents, participation was 8.27%.

This study informs our understanding of who is participating in cancer clinical trials. We found people of color were more likely to participate in cancer clinical trials than white cancer patients when controlling for other demographic factors. It could be that in previous studies, the effects of income, sex or age were muddling the true picture."

Lincoln Sheets, MD, PhD, Assistant Research Professor, MU School of Medicine

Sheets said the analysis also indicated people who earn more than the national median household income of $50,000 annually and the young were more likely to participate in clinical trials during cancer treatment.

"Taken in total, the results of this study help confirm that there are sociodemographic disparities in cancer clinical trials, indicating there are deficiencies in the system as it stands now," Sheets said. "We must lessen financial barriers to participation, improve logistical accessibility of cancer clinical trials and loosen restrictions on the enrollment of patients with comorbidities."

Sheets said improving access to transportation, childcare and health insurance would remove some of the structural and logistical barriers that prevent people from participating in cancer clinical trials.

Sheets collaborated on the study with MU School of Medicine student Shelby Meyer.

Source:

University of Missouri-Columbia

Journal reference:

Meyer, S., et al. (2021) Sociodemographic diversity in cancer clinical trials: New findings on the effect of race and ethnicity. Contemporary Clinical Trials Communications. doi.org/10.1016/j.conctc.2021.100718.

Posted in: Medical Research News | Medical Condition News | Healthcare News

Tags: Cancer, Cancer Treatment, Clinical Trial, Drugs, Health Insurance, Medicine, Research

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Cognitive outcomes in survivors of childhood cancers have been largely understudied

In a new study led by Yale Cancer Center, researchers report many survivors of childhood cancers receive systemic therapies associated with cognitive effects and chronic health conditions that may impact long-term cognitive outcomes with downstream effects on education, employment, and income. The results were published online today in the Journal of Clinical Oncology (JCO).

Cognitive outcomes in survivors of childhood cancers have been largely understudied. In this study, we wanted to explore cognitive functioning after specific extracranial solid tumor and lymphoma diagnoses to discuss possible associated risk factors and highlight research gaps to help provide clinical guidance for affected survivors."

Nina S. Kadan-Lottick, MD, MSPH, Study Senior Author and Associate Professor of Pediatrics (Hematology/Oncology) and Disease Aligned Research Team (DART), Leader for Pediatric Cancer at Yale Cancer Center

Researchers examined previous studies that investigated long-term (>2 years off-therapy and/or 5 years from diagnosis) cognitive outcomes in survivors of childhood (diagnosed <21 years) extracranial solid tumors and lymphomas with at least 10 patients within the diagnostic subcategory back to 1990.

The studies suggested survivors of osteosarcoma, neuroblastoma, Wilms tumor, non-Hodgkin lymphoma, Hodgkin lymphoma, and Langerhans cell histiocytosis have increased risk of cognitive impairment. Co-morbid health conditions were frequently associated with cognition. For pediatric survivors of Ewing Sarcoma, Retinoblastoma, and soft tissue sarcomas, the data was less convincing for similar impairment.

"Given the older age at diagnosis of many childhood extracranial solid tumors and lymphomas as well as toxicities associated with certain therapies, we concluded patients may benefit from vocational services, occupational therapy, physical therapy, and/or hearing or visual rehabilitation in addition to surveillance for cognitive difficulties," added Kadan-Lottick. "However, larger prospective studies are needed that better delineate the severity of cognitive impairment, contributory risk factors, and effective interventions to reduce impairment."

Source:

Yale Cancer Center

Posted in: Child Health News | Medical Research News | Medical Condition News

Tags: Cancer, Cancer Prevention, Cancer Treatment, Cell, Chronic, Diagnostic, Education, Ewing Sarcoma, Hematology, Hodgkin Lymphoma, Hospital, Langerhans Cell Histiocytosis, Lymphoma, Mortality, Neuroblastoma, Non-Hodgkin Lymphoma, Occupational Therapy, Oncology, Osteosarcoma, Pediatrics, Physical Therapy, Research, Retinoblastoma, Sarcoma, Tumor, Wilms Tumor

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Inhibition of Meprin Β enzyme can trigger the development of Alzheimer's disease, cancer

Researchers at Johannes Gutenberg University Mainz (JGU) in Germany and the Institute of Molecular Biology of Barcelona in Spain have discovered how the blood plasma protein fetuin-B binds to the enzyme meprin β and used a computer model to visualize their findings.

These results could lead to the development of new drugs to treat serious diseases such as Alzheimer's and cancer. Meprin β releases proteins from cell membranes, thus controlling important physiological functions in the human body.

However, a dysregulation of this process can trigger the development of Alzheimer's and cancer. Meprin β is regulated by fetuin-B binding to the enzyme when required, thereby preventing the release of other proteins. Presenting their findings in the journal Proceedings of the National Academy of Sciences, the researchers are now the first to describe this binding in detail.

The team at Mainz University produced both meprin β and fetuin-B in insect cells and then allowed them to react with one other in a test tube. By means of measurement of enzyme kinetics and biophysical analyses, the researchers determined that this reaction resulted in an exceptionally stable, high-molecular-mass complex.

Their colleagues in Barcelona subsequently managed to crystallize the complex and determine its three-dimensional structure using X-ray crystallography. This involved X-rays being fired at the protein crystals, which allowed the atomic structure of the crystals to be calculated from the diffraction of the X-rays. A computer model of the structure was then generated.

"Thanks to the model, we can now see exactly how meprin β and fetuin-B bind together," said Professor Walter Stöcker, who conducted the research at JGU together with Dr. Hagen Körschgen and Nele von Wiegen. "This research represents an excellent starting point for gaining a better understanding of diseases such as Alzheimer's and for developing the drugs to combat them."

Meprin β is already known to be involved in the formation of so-called beta-amyloid plaques, which are a characteristic feature of the condition. Moreover, people with Alzheimer's disease have relatively little fetuin-B in their blood, which in turn may lead to a lack of regulation of meprin β.

If it is possible to develop a drug that binds to the enzyme and inhibits it in a similar way to fetuin-B, this could be a new way of treating Alzheimer's."

Walter Stöcker, Professor, Johannes Gutenberg University Mainz (JGU), Germany

Source:

Johannes Gutenberg University Mainz

Journal reference:

Eckhard, U., et al. (2021) The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2023839118.

Posted in: Medical Research News | Medical Condition News

Tags: Alzheimer's Disease, Blood, Cancer, Cell, Crystallography, Diffraction, Drugs, Enzyme, Molecular Biology, Protein, Research, X-Ray

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Hypothesis: Milk and Beef ‘Causally Linked’ to Colorectal Cancer

HEIDELBERG, Germany — Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team is headed by Harald zur Hausen, MD, PhD, Division of Episomal-Persistent DNA in Cancer and Chronic Diseases, German Cancer Research Center, Heidelberg, Germany, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papilloma viruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published by the Proceedings of the National Academy of Sciences of the United States of America on March 23.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Hausen said in a related press statement.

Pathogenic Agents, Found in Vicinity of Tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

They found that the BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of pro-inflammatory macrophages.

They also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep vs just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stress, however, that further study will be required to confirm the results.

They nevertheless believe that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers, via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha (Munich) (to Hausen). Mathias Heikenwalder was supported by the EOS Foundation (Flundern), the SFBTR-179 and 209, and a European Research Council consolidator grant. The authors have disclosed no relevant financial relationships.

PNAS. Published online March 23, 2021. Full text

Translated and adapted from Medscape’s French edition.

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Women seeking help for unmet needs often overdue for cervical cancer screenings

More than half of cervical cancer cases in the United States occur in women who have not had timely Pap smears and/or HPV tests — screenings that allow for detection of precancerous or cancerous cells on the cervix. Encouraging low-income women in particular to participate in such screenings likely would improve cancer detection and save lives, but health-care professionals have been uncertain of how best to improve patient adherence to screenings and follow-ups involving abnormal results.

Women with low incomes sometimes skip Pap smears and other cancer prevention screenings because they are focused on more pressing needs such as housing, food and other necessary expenses. So, researchers at Washington University School of Medicine in St. Louis evaluated efforts to help such women obtain cervical cancer screenings.

The scientists studied a group of female callers in Missouri seeking assistance from a free and confidential phone service that helps people find basic resources. The researchers determined that many female callers were due for cervical cancer screenings but most did not schedule one, even with the support of a health navigator, an individual trained to help people access medical care. Their findings indicate a new, more involved approach is needed to achieve such screenings and, ultimately, lower the number of women treated for advanced cancer.

“Reasons for inadequate screening are many and often deeply rooted to social and structural determinants of health that drive health inequities,” said first author Lindsay Kuroki, MD, an assistant professor of obstetrics & gynecology. “We wanted to determine the need for cervical cancer screening among women seeking assistance with unmet basic needs and to assess different methods of encouraging callers to seek Pap screening. Connecting underserved women to cervical cancer-screening services and assisting them with barriers to access medical care can improve health equity and reduce cancer disparities.“

The findings are available online in the American Journal of Obstetrics & Gynecology.

Participants were recruited from June 2010 through June 2012 from among callers to United Way 2-1-1 Missouri, a telephone helpline for local health and social service resources. Most callers seek help with basic needs such as food, utility bills, shelter and unexpected expenses.

Of 932 callers, 211 were referred for cervical cancer screenings. Callers were randomized to one of three conditions: phone call only; phone call and a print reminder; or a phone call and a personal navigator. The researchers looked at how many women contacted a clinic to schedule a Pap test one month after receiving a referral.

Patients in need of Pap screening had multiple cervical cancer risk factors. These women had a mean age of 48.2 years, were predominantly non-white, poor and unemployed, not married, and actively smoking. Nearly all (94.7%) female callers, regardless of their need for Pap testing, had at least one unmet basic need, with callers reporting an average of two unmet needs.

Women in the group that was assigned health navigators reported higher rates of contacting Pap services (29.6%) than those given phone calls only (15.1%), or phone calls and tailored print reminders (13.4%). Health navigators tripled the likelihood that women made contact with Pap services, and this remained true even among women with multiple unmet needs. Nevertheless, only 41 of 211 (19.4%) women who were overdue for Pap testing and received a referral contacted the referred clinic to schedule cervical cancer screenings.

The scientists said future research is necessary to understand how unmet basic needs pose barriers to cervical screening and how effective interventions to meet basic needs may lead to improved access to cancer prevention services. Some of these interventions might include immediate help such as assisting women with transportation and childcare. Other interventions might focus on redesigning health systems and influencing social policy to provide women at risk for cervical cancer with secure homes free of hunger and tobacco.

“Women contacting 2-1-1 are likely to have health needs that greatly exceed those of the general population, in addition to lacking financial resources and social support required to seek cervical cancer screening,” said senior author Matthew Kreuter, PhD, the Kahn Family Professor of Public Health at the Brown School. “Continuing this line of research is critical to improving outcomes for low-income, medically underserved populations. No woman should die from a preventable cancer.”

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Should You Get Tested for Vitamin D?

  • The U.S. Preventive Services Task Force said there isn’t sufficient evidence to recommend for or against screening most people for vitamin D deficiency.
  • Experts say that vitamin D is essential for health and they’re surprised at the task force’s decision.
  • Experts caution that while vitamin D overdosing is difficult and rare, too little in our bodies is associated with sometimes severe illness.

The U.S. Preventive Services Task Force (USPSTF) has determined there isn’t sufficient evidence to recommend for or against testing for vitamin D deficiency in adults, according to a recent recommendation statement.

However, the USPSTF emphasized that this recommendation does not apply to people who are pregnant, anyone with signs and symptoms of vitamin D deficiency (like muscle weakness or bone pain), and people with conditions that require vitamin D treatment.

But does this mean you shouldn’t bother to be tested at all?

Experts point out importance of vitamin D for health

Rajsree Nambudripad, MD, integrative medicine specialist with Providence St. Jude Medical Center in Orange County, California said she screens all patients with a 25-hydroxy vitamin D test at their initial consultation.

“I consider vitamin D to be one of the most essential vitamins in the body,” she said. “I find that over 50 percent of my patients are low at their initial consultation.”

She added that this is easily correctable with supplementation.

According to Nambudripad, multiple sclerosis is associated with low vitamin D levels, and having low vitamin D can cause many vague symptoms that range from fatigue and low mood to body aches.

“Severe vitamin D deficiency can cause osteoporosis, brittle bones, and fractures. In children, severe vitamin D deficiency can cause rickets, which is a softening or weakening of bones,” she said.

Who is most at risk for deficiency?

Nambudripad said people at risk for deficiency include those who work indoors or anyone who lives in the northern latitudes (due to less sunlight during winter).

She also pointed out that if you’re going out midday but wearing sunblock on all exposed skin, you still may have a deficiency.

“You may be at higher risk of low vitamin D since we get some vitamin D from sunlight. Sunscreen also inhibits the formation of vitamin D from exposure to sunlight,” she explained.

But that doesn’t mean you should avoid sun sunscreen. Instead, you can talk with your physician about the right diet or supplements if your vitamin D levels are low.

According to Nambudripad, other people at risk for deficiency include:

  • those who’ve had gastric bypass surgery
  • people with small intestine bacterial overgrowth
  • anyone with intestinal absorption problems like inflammatory bowel disease
  • people experiencing exocrine pancreatic insufficiency

If you’re following a restricted vegan diet, you might also have a higher risk of vitamin D deficiency, “since vitamin D is most commonly found in foods like dairy, eggs, and salmon,” she said.

USPSTF cautions against broad screening due to ‘uncertainty’

In their statement, the Task Force warned against potential harms of screening the general population for vitamin D deficiency.

“Screening may misclassify persons with a vitamin D deficiency because of the uncertainty about the cutoff for defining deficiency and the variability of available testing assays,” cautioned the USPSTF.

This may result in over or under-diagnosis — and people being inappropriately treated or not treated.

The Task Force also pointed out that one potential harm of treatment with vitamin D is toxicity.

“Vitamin D should be kept at an optimal level of 60–80 ng/mL,” explained Nambudripad. “If your level is greater than 100, you could be at higher risk of developing kidney stones since vitamin D increases your absorption of calcium.”

However, she said she rarely sees this, and even then, it’s usually in people taking over 10,000 IU of vitamin D daily. Standard over-the-counter vitamin D supplements come in 1,000 or 2,000 IU dosage.

Enriched foods and sun are essential for healthy vitamin D levels

Janine Souffront, RDN, supervisor and health educator at L.A. Care Health Plan, the largest publicly operated health plan in the United States, said dietary sources of vitamin D are limited and we rely on certain “enriched” foods to get what we need.

“Some fish does [contain vitamin D], such as salmon, herring, sardines, and canned tuna. Eggs from poultry fed vitamin D-enriched feed or raised outdoors (where they get sun) are high in vitamin D,” she said. “For the most part, we depend on foods enriched with vitamin D for our daily intake.”

Souffront listed milk, alternative milks, orange juice, oatmeal, and cereals as examples of vitamin D-enriched foods.

“In the past we relied on the sun for our vitamin D,” she said. “But because of our change in lifestyle, we do not get the recommended 20 minutes of almost daily mid-morning sun.”

She added that people are using less milk than in the past, meaning the best way to get vitamin D through diet is to make the foods she mentioned part of our regular diet.

Elena Gagliardi, clinical nutrition services manager at Santa Clara Valley Medical Center, emphasized the importance of meeting the Dietary Reference Intake (DRI) of 600 IU per day if you’re 1–70 years old, or at least 800 IU per day if you’re 71 years or older.

She also recommended getting about 5 to 30 minutes of outdoor sun exposure at least twice a day as another way to maintain sufficient vitamin D levels in your body.

“If you are unable to meet the requirement through food intake alone, talk to your doctor about supplementation of vitamin D3,” she advised.

Experts ‘surprised’ by USPSTF statement

“I’m surprised by the results and conclusions of the USPSTF statement,” said Nambudripad. “My practice has a preventive focus and my patients feel a significant improvement in their health when their vitamin D level is optimized.”

She added that she’s seen many patients with body aches, fatigue, and other issues improve as they’ve had their vitamin D levels optimized, along with addressing their diet and lifestyle.

“For most patients, the blood test 25-hydroxyvitamin D is covered by their insurance,” she said. “So I like to be proactive and test, since it’s something we can easily improve with supplementation.”

The bottom line

In a recent draft recommendation, the U.S. Preventive Services Task Force said there isn’t sufficient evidence to recommend for or against screening most people for vitamin D deficiency.

Experts say that vitamin D is essential for overall health and they’re surprised at the decision.

While too much vitamin D is difficult to achieve and rare, too little is much more common and associated with sometimes severe illness.

For many people, a vitamin D test is covered by health insurance, and low levels can easily be improved with supplements.

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Mouse model closely replicates human NAFLD

Human non-alcoholic fatty liver disease (NAFLD) is a little-understood condition that significantly increases the risk of inflammation, fibrosis and liver cancer and ultimately requires liver transplant.

"NAFLD has been difficult to study mainly because we had no good animal model," said corresponding author Dr. Karl-Dimiter Bissig, who was at Baylor during the development of this project and is now at Duke University.

The disease has both genetic and nutritional components, which have been hard to understand in human studies, and murine models until now had not accurately reflected typical characteristics of human livers with the disease.

Part mouse, part human

Our goal was to have a mouse model that would allow us to study the disorder and test potential treatments. Applying our lab's yearslong expertise developing chimeric mouse models, those that combine both human and murine cells, we developed mice with livers that were part human and part murine."

Dr. Beatrice Bissig-Choisat, co-first author, assistant professor at Duke University

The team fed a high-fat diet to the chimeric mice for 12 weeks, then they looked at the livers under the microscope and also studied their metabolic functions and gene expression, comparing them with those of normal mice and of humans with NAFLD.

"We were surprised by the striking differences we observed under the microscope," Bissig said. "In the same liver, the human liver cells were filled with fat, a typical characteristic of the human disease, while the mouse liver cells remained normal."

Next, the researchers analyzed the products of metabolism, in particular the metabolism of fats, of the human liver cells in the mouse model and identified signatures of clinical NAFLD.

"For instance, when mice that received human liver cells fed on a high-fat diet, they started to show features of cholesterol metabolism that looked more like what a patient shows than what other previous animal models showed," said co-first author Dr. Michele Alves-Bezerra, instructor of molecular physiology and biophysics at Baylor. "We made the same observation regarding genes that are regulated after the high-fat diet. All the analyses pointed at cholesterol metabolism being changed in this model in a way that closely replicates what we see in humans."

The researchers also investigated whether the gene expression profiles of the human liver cells in the chimeric model supported the microscopy and metabolic findings.

"We discovered that, compared to the normal mouse liver cells in our model, the fat-laden human liver cells had higher levels of gene transcripts for enzymes involved in cholesterol synthesis," said co-author Dr. Neil McKenna, associate professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "We wanted to see whether this was also the case in human NAFLD livers."

The team used the web-based platform called the Signaling Pathways Project to create a NAFLD consensome, which surveys previously published clinical studies to identify transcripts whose expression is consistently different between NAFLD livers and healthy ones.

"Using the NAFLD consensome we discovered that, indeed, compared to normal livers, NAFLD livers have consistently higher levels of cholesterol synthesis enzyme transcripts," McKenna said. "This is additional confirmation of the clinical accuracy of our NAFLD model."

Together, the microscopy, metabolic and gene transcription evidence support that the chimeric model closely replicates clinical NAFLD. With this model, researchers have an opportunity to advance the understanding and treatment of this serious condition for which there is no effective therapy.

Not quite human

Another important contribution of this work is that it clearly shows that human and murine cells can be quite different in their responses to factors such as diet, and we have to be careful when interpreting mouse studies of human conditions," Bissig said.

"Here we have a model in which human liver cells respond like in humans. We propose that this model can be used to better understand NAFLD and to identify effective therapies."

The study appeared in JHEP Reports.

Source:

Baylor College of Medicine

Journal reference:

Bissig-Choisat, B., et al. (2021) A human liver chimeric mouse model for non-alcoholic fatty liver disease. JHEP Reports. doi.org/10.1016/j.jhepr.2021.100281.

Posted in: Molecular & Structural Biology | Cell Biology

Tags: Animal Model, Blood, Cancer, Cellular Biology, Children, Cholesterol, Diabetes, Diet, Enzyme, Fatty Liver, Fibrosis, Gene, Gene Expression, Genes, Genetic, Heart, Hospital, Inflammation, Kidney, Kidney Disease, Liver, Liver Cancer, Liver Disease, Liver Transplant, Medicine, Metabolism, Microscope, Microscopy, Mouse Model, Physiology, Transcription, Transplant

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Thiazides may up risk for skin cancer in older adults

Thiazides may up risk for skin cancer in older adults

(HealthDay)—Higher exposure to thiazides is associated with increased rates of incident keratinocyte carcinoma and melanoma among older adults, according to a study published online April 12 in CMAJ, the journal of the Canadian Medical Association.

Aaron M. Drucker, M.D., from the University of Toronto, and colleagues conducted a population-based inception cohort study using linked administrative health data from Ontario for 1998 to 2017. Adults aged 66 years and older with a first prescription for an antihypertensive medication were matched by age and sex to two unexposed adults prescribed a nonantihypertensive medication within 30 days of the index date to examine associations with keratinocyte carcinoma and melanoma. The cohorts included 302,634 adults prescribed an antihypertensive medication and 605,268 unexposed adults.

The researchers found that increasing thiazide exposure was associated with increased rates of incident keratinocyte carcinoma, advanced keratinocyte carcinoma, and melanoma (adjusted hazard ratios [95 percent confidence intervals] per one defined annual dose unit, 1.08 [1.03 to 1.14], 1.07 [0.93 to 1.23], and 1.34 [1.01 to 1.78], respectively). No consistent evidence was found for associations between other antihypertensive classes and keratinocyte carcinoma or melanoma.

“We found consistent dose-dependent increases in skin cancer risk associated with thiazides but not with other antihypertensive classes,” the authors write. “Clinicians may consider alternatives to thiazide diuretics to treat hypertension in patients at high risk for skin cancer.”

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