The FASER particle detector, located deep underground at CERN’s Large Hadron Collider, was mostly built out of spare parts from other experiments at CERN. Credit: CERN
In a scientific first, a team led by physicists at the University of California, Irvine has detected neutrinos created by a particle collider. The discovery promises to deepen scientists’ understanding of the subatomic particles, which were first spotted in 1956 and play a key role in the process that makes stars burn.
The work could also shed light on cosmic neutrinos that travel large distances and collide with the Earth, providing a window on distant parts of the universe.
It’s the latest result from the Forward Search Experiment, or FASER, a particle detector designed and built by an international group of physicists and installed at CERN, the European Council for Nuclear Research in Geneva, Switzerland. There, FASER detects particles produced by CERN’s Large Hadron Collider.
“We’ve discovered neutrinos from a brand-new source—particle colliders—where you have two beams of particles smash together at extremely high energy,” said UC Irvine particle physicist and FASER Collaboration Co-Spokesman Jonathan Feng, who initiated the project, which involves over 80 researchers at UCI and 21 partner institutions.
Brian Petersen, a particle physicist at CERN, announced the results Sunday on behalf of FASER at the 57th Rencontres de Moriond Electroweak Interactions and Unified Theories conference in Italy.
Neutrinos, which were co-discovered nearly 70 years ago by the late UCI physicist and Nobel laureate Frederick Reines, are the most abundant particle in the cosmos and “were very important for establishing the standard model of particle physics,” said Jamie Boyd, a particle physicist at CERN and co-spokesman for FASER. “But no neutrino produced at a collider had ever been detected by an experiment.”
Since the groundbreaking work of Reines and others like Hank Sobel, UCI professor of physics & astronomy, the majority of neutrinos studied by physicists have been low-energy neutrinos. But the neutrinos detected by FASER are the highest energy ever produced in a lab and are similar to the neutrinos found when deep-space particles trigger dramatic particle showers in our atmosphere.
“They can tell us about deep space in ways we can’t learn otherwise,” said Boyd. “These very high-energy neutrinos in the LHC are important for understanding really exciting observations in particle astrophysics.”
FASER itself is new and unique among particle-detecting experiments. In contrast to other detectors at CERN, such as ATLAS, which stands several stories tall and weighs thousands of tons, FASER is about one ton and fits neatly inside a small side tunnel at CERN. And it took only a few years to design and construct using spare parts from other experiments.
“Neutrinos are the only known particles that the much larger experiments at the Large Hadron Collider are unable to directly detect, so FASER’s successful observation means the collider’s full physics potential is finally being exploited,” said UCI experimental physicist Dave Casper.
Beyond neutrinos, one of FASER’s other chief objectives is to help identify the particles that make up dark matter, which physicists think comprises most of the matter in the universe, but which they’ve never directly observed.
FASER has yet to find signs of dark matter, but with the LHC set to begin a new round of particle collisions in a few months, the detector stands ready to record any that appear.
“We’re hoping to see some exciting signals,” said Boyd.
Scientists have gleaned new insights into how psychedelics alter conscious experience via their action on brain activity.
In a study at Imperial College London, detailed brain imaging data from 20 healthy volunteers revealed how the potent psychedelic compound DMT (dimethyltryptamine), alters brain function. During the immersive DMT experience, there was increased connectivity across the brain, with more communication between different areas and systems. The changes to brain activity were most prominent in areas linked with “higher level” functions, such as imagination.
DMT is a potent psychedelic found naturally in certain plants and animals. It occurs in trace amounts in the human body and is the major psychoactive compound in ayahuasca—the psychedelic brew prepared from vines and leaves and used in ceremonies in south and central America.
The study, published in the Proceedings of the National Academy of Sciences, is the first to track brain activity before, during and after the DMT experience in such detail.
Dr. Chris Timmerman, from the Center for Psychedelic Research at Imperial College London, and first author on the study, said, “This work is exciting as it provides the most advanced human neuroimaging view of the psychedelic state to-date.
“One increasingly popular view is that much of brain function is concerned with modeling or predicting its environment. Humans have unusually big brains and model an unusually large amount of the world. For example, like with optical illusions, when we’re looking at something, some of what we’re actually seeing is our brainfilling in the blanks based on what we already know. What we have seen with DMT is that activity in highly evolved areas and systems of the brain that encode especially high-level models becomes highly dysregulated under the drug, and this relates to the intense drug ‘trip.'”
Unlike other classic psychedelics, such as LSD or psilocybin, DMT’s effects on the brain are relatively brief, lasting a matter of minutes, rather than hours. DMT can produce intense and immersive altered states of consciousness, with the experience characterized by vivid and bizarre visions, a sense of “visiting” alternative realities or dimensions, and similarities with near death experiences. But exactly how the compound alters brain function to account for such effects has been unclear.
In the latest study, 20 healthy volunteers were given an injection of the drug while researchers from Imperial’s Center for Psychedelic Research captured detailed imagery of their brains, enabling the team to study how activity changes before, during and after the trip.
Volunteers received a high dose of DMT (20mg, given intravenously), while simultaneously undergoing two types of brain imaging: functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). The total psychedelic experience lasted about 20 minutes, and at regular intervals, volunteers provided a rating of the subjective intensity of their experience (on a 1 to 10 scale).
The fMRI scans found changes to activity within and between brain regions in volunteers under the influence of DMT. Effects included increased connectivity across the brain, with more communication between different areas and systems. These phenomena, termed “network disintegration and desegregation” and increased “global functional connectivity,” align with previous studies with other psychedelics. The changes to activity were most prominent in brain areas linked with “higher level,” human-specific functions, such as imagination.
The researchers highlight that while their study is not the first to image the brain under the influence of psychedelics or the first to show the signatures of brain activity linked to psychedelics, it is the first to combine imaging techniques to study the brain during a highly immersive psychedelic experience. They explain the work provides further evidence of how DMT, and psychedelics more generally, exert their effects by disrupting high level brain systems.
Prof Robin Carhart-Harris, founder of the Center for Psychedelic Research at Imperial College London, and senior author on the paper (now working at the University of California, San Francisco), stated, “Motivated by, and building on our previous research with psychedelics, the present work combined two complementary methods for imaging the brain imaging. fMRI allowed us to see the whole of the brain, including its deepest structures, and EEG helped us view the brain’s fine-grained rhythmic activity.
“Our results revealed that when a volunteer was on DMT there was a marked dysregulation of some of the brain rhythms that would ordinarily be dominant. The brain switched in its mode of functioning to something altogether more anarchic. It will be fascinating to follow-up on these insights in the years to come. Psychedelics are proving to be extremely powerful scientific tools for furthering our understanding of how brain activity relates to conscious experience.”
The Imperial team is now exploring how to prolong the peak of the psychedelic experience through continuous infusion with DMT, and some are also advising on a commercially run trial to assess DMT for patients with depression.
Johns Hopkins University School of Medicine Illustration of bacteria in the human gut. Credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health
In experiments with mice and humans, a team led by Johns Hopkins Medicine researchers says it has identified a particular intestinal immune cell that impacts the gut microbiome, which in turn may affect brain functions linked to stress-induced disorders such as depression. Targeting changes mediated by these immune cells in the gut, with drugs or other therapies, could potentially bring about new ways to treat depression.
The findings of the study were published March 20, 2023 in the journal Nature Immunology.
“The results of our study highlight the previously unrecognized role of intestinal gamma delta T cells (γδ T cells) in modifying psychological stress responses, and the importance of a protein receptor known as dectin-1, found on the surface of immune cells, as a potential therapeutic target for the treatment of stress-induced behaviors,” says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study’s senior author.
Dectin-1 binds to certain antigens, or proteins, to signal immune cells to activate in specific ways. This receptor, the researchers say, may be involved in the microbiome alteration and immune-inflammatory responses in the colon of mice, which suggests that it may be involved in stress responses via γδ T cells in the intestinal immune system.
On the basis of previous studies suggesting that immune inflammatory responses in the gut are related to depression, Kamiya and his team designed experiments to focus on understanding stress-induced behaviors produced by an imbalance in the gut microbiota—types of microorganisms found in a specific environment, such as bacteria, fungi and viruses.
To this end, the team examined the effects of chronic social defeat stress (CSDS) on the gut microbiota in mice. CSDS is a standard rodent test to study stress-induced disorders such as depression. In a series of experiments, the researchers simulated potential stress inducing environments that could mimic similar responses in human environments. After each exposure, the mice were assessed and classified as stress-resilient (stress did not diminish social interactions) or stress-susceptible (stress increased social avoidance).
Fecal samples were then collected and put through genetic analysis to identify the diversity of bacteria in the gut microbiota of the mice. The analysis showed that the intestinal organisms were less diverse in stress-susceptible mice than in stress-resilient mice. It specifically revealed that there were less Lactobacillus johnsonii (L. johnsonii)—a type of probiotic, or “good” bacteria—in stress-susceptible mice compared to stress-resilient mice.
“We found that stress increased the γδ T cells, which in turn increased social avoidance,” says Xiaolei Zhu, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study’s lead author. “However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes.”
Looking for potential natural approaches for prevention of depression rooted somehow in the gut, the researchers explored how changes in dectin-1 on CSDS-induced elevation of γδ T cells responded to pachyman. A compound extracted from wild mushrooms, pachyman is used as a natural anti-inflammatory agent and for treating depression in Eastern medicine.
For this experiment, mice were fed a dose of pachyman, which was shown in previous research to affect immune function. Data from flow cytometry analysis—a technology used to measure the physical and chemical characteristics of a population of cells—provided evidence that dectin-1 binds to pachyman, inhibiting CSDS-induced γδ17 T cell activity and easing social avoidance behavior.
To gain insight into how the alterations in the gut microbiota could impact the human brain, the researchers investigated the makeup of gut organisms in people with major depressive disorder (MDD) compared to people without MDD. From June 2017 to September 2020, 66 participants, ages 20 or older, were recruited at Showa University Karasuyama Hospital, Keio University Hospital and Komagino Hospital in Tokyo, Japan. Of the study participants, 32 had MDD (17 women and 15 men). The other 34 participants (18 women and 16 men) who did not have MDD formed the control group.
Stool samples were collected from all study participants, who had comprehensive evaluations including psychiatric history and standard screening assessments for depression and anxiety. In these assessments, higher scores indicate greater depressive symptoms. Genetic analysis of the stool samples showed no difference in the diversity of intestinal bacteria between the subjects with MDD and the control group. However, the relative abundance of Lactobacillus was inversely related to higher depression and anxiety scores in the MDD group, meaning that the more Lactobacillus found in the gut, the lower the potential for depression and anxiety, the researchers say.
“Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety,” says Kamiya.
The investigators say more research is needed to further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in other cell types along the gut-brain connection under stress conditions.
“These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression,” says Kamiya.
The concept of cancer vaccination has generated excitement in the scientific community for decades.
Preventive vaccines, such as those against HPV and hepatitis B virus, have helped to reduce rates of virus-associated malignancies, such as cervical and liver cancer. In January, American Cancer Society researchers credited HPV vaccination with a 65% decline in cervical cancer incidence among women aged 20 to 24 years between 2012 and 2019.
Cancer vaccine researchers have learned over the past 5 to 10 years that simply inducing an immune response is not enough, according to Jay A. Berzofsky, MD, PhD. “You also need to block these negative regulatory mechanisms that are suppressing the immune system,” he said.
Meanwhile, the development of therapeutic vaccines against nonviral cancers has been fraught with setbacks.
To date, only a few vaccines have received FDA approval. In 2010, the agency approved sipuleucel-T (Provenge, Dendreon Pharmaceuticals), a dendritic cell-based vaccine for prostate cancer. Five years later, the oncolytic viral therapy talimogene laherparepvec, or T-VEC (Imlygic, Amgen), received FDA approval for certain patients with advanced melanoma. Many other vaccines remain under investigation in clinical trials.
“People have been skeptical about cancer vaccines because historically they haven’t really worked in advanced cancer,” Neeha Zaidi, MD, assistant professor of oncology at Johns Hopkins University, told Healio | HemOnc Today.
Neeha Zaidi
The success of COVID-19 vaccines, however, has helped draw attention to the potential of mRNA vaccines against cancer.
Among them is the investigational personalized cancer vaccine mRNA-4157/V940, co-developed by Moderna and Merck. A combination of the vaccine and anti-PD-1 therapy pembrolizumab (Keytruda, Merck) conferred a statistically significant and clinically meaningful improvement in RFS among patients with stage III or stage IV melanoma who underwent surgical resection, according to topline data from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial released in December. The data, which showed a reduction in the risk for recurrence or death of 44% (HR = 0.56; 95% CI, 0.31-1.08), represent “the first demonstration of efficacy for an investigational mRNA cancer treatment in a randomized clinical trial,” the manufacturers stated in a news release.
In June, results of a phase 1 study by Balachandran and colleagues presented at ASCO Annual Meeting showed autogene cevumeran (BioNTech, Genentech), an mRNA-based individualized neoantigen-specific immunotherapy vaccine, activated T cells that recognized pancreatic cancer in eight of 16 patients with resected disease. Responders to the vaccine also had longer RFS than nonresponders (median, not reached vs. 13.7 months; HR = 0.08; 95% CI, 0.01-0.5).
“There has been renewed interest in cancer vaccines, partly due to mRNA technology but also the fact that we can identify unique, patient-specific antigens to develop personalized vaccines and treatments,” Zaidi said. “The mRNA technology allows for more flexibility in the types of antigens or targets we can encode, and vaccines can be developed more rapidly in real time.”
Healio | HemOnc Today spoke with experts about the various types of cancer vaccines, ongoing challenges and recent advances in their development, and potential directions for future research.
Types of vaccines
In a paper published in Vaccines, Lollini and colleagues described three broad categories of cancer vaccines: cell-based, protein/peptide based and gene-based (DNA/RNA). Although some vaccines aim for primary cancer prevention, many are designed for secondary prevention of progression or tertiary prevention of cancer recurrence. These vaccines activate the immune system to attack tumor cells through delivery of tumor-associated or tumor-specific antigens.
“At least until now, cancer vaccines have been intended to be therapeutic rather than prophylactic, but they are still vaccines,” Jay A. Berzofsky, MD, PhD, head of the Vaccine Branch at NCI’s Center for Cancer Research, told Healio | HemOnc Today. “A vaccine is something that induces the immune system to make a response against a specific target. In this case, that target would be a tumor antigen, but one doesn’t necessarily want to risk adverse events by immunizing a whole population against one specific type of cancer. So, what they were originally designed to do was to eradicate a cancer that already exists.”
Jay A. Berzofsky
Exposure to tumor-associated and tumor-specific antigens stimulates the immune system to recognize these antigens as foreign and distinct from the body’s native cells.
“The immune system is very good at rejecting foreign organisms, and we believe there are many cancers that start to develop but are sufficiently different from the host that they get rejected before they are ever detected,” he said. “It’s only the ones that escape this rejection that become clinically evident cancers.”
Development challenges
Unlike treatments such as chemotherapy and radiation that are associated with off-target adverse effects, therapies that trigger immune response are capable of targeting only the tumor while sparing the adjacent normal tissue, Berzofsky said.
Although early cancer vaccines successfully induced an immune response measurable in an immunologic assay, they nevertheless failed to kill the cancer, he said.
“People didn’t know why they weren’t succeeding, because the immune response was being developed — this was true in mice, as well as people,” he said. “Researchers could even make a vaccine, immunize mice and transplant the cancer, and the immune system would reject it. However, you couldn’t treat them once they had the cancer. So, you couldn’t treat an established cancer.”
Cancers have evolved to exploit immune mechanisms designed to control overreactions such as cytokine storms that lead to autoimmune disease, Berzofsky said.
“The immune system has mechanisms to keep itself under control, such as checkpoint molecules, but there are many other mechanisms,” he said. “There are also regulatory T cells and natural killer T cells that suppress, as well as cancer-associated macrophages and other suppressive myeloid cells, and then there are cytokines that suppress, like TGF-beta or interleukin-13. All of those can be exploited by the cancer to turn off those T cells before they can reject the cancer.”
This immunosuppressive tumor microenvironment is so hostile to T cells that even when a vaccine triggers an immune response, the T cells are not always able to effectively destroy the cancer.
“What we’ve learned over the past 5 to 10 years is that you need not only to have the vaccine to induce the immune response, but you also need to block these negative regulatory mechanisms that are suppressing the immune system,” he said. “Ideally, you want to block all of these mechanisms, and each one has different subsets.”
Eliminating these suppressive mechanisms enables the T cells to work and reject the cancer. This is why anti-CTLA-4 and anti-PD-1 drugs have shown efficacy in melanoma and in a subset of patients with lung cancer.
“Then there are other tumors, like prostate cancer, where you don’t see any T cells in the first place,” Berzofsky said. “Even if you use, say, anti-PD-1, it doesn’t help because the T cells aren’t there to work. So, now you need the vaccine to induce a T-cell response, which the tumor itself wasn’t capable of inducing.”
Personalized vaccines
Berzofsky and colleagues demonstrated the feasibility and safety of custom-made peptide vaccination for patients with cancer in a study published in 2005 in Journal of Clinical Oncology.
“We found that if we immunized against KRAS and p53 mutations with the peptides corresponding to the patient’s own mutation, the patients who made a good T-cell response tended to live more than a year longer than those who didn’t make an immune response to the vaccine,” he said.
However, the correlation did not prove causation, and the patients who made a strong immune response may have been healthier in the first place, he noted.
“More recently, in the past 5 years, we’ve discovered that there are many mutant genes and that many tumors have somatic mutations,” Berzofsky said. “Tumors that have a lot of mutations that are unique to the tumor are more likely be immunogenic and are therefore more likely to respond to checkpoint inhibitors such as PD-1, even without a vaccine.”
From this, researchers have extrapolated that these mutations could create epitopes that could be targeted with a cancer vaccine.
“So, there has been a flurry of activity toward making cancer vaccines against neoepitopes,” he said. “Now, it’s 17 years after we published our study, and everyone is trying to do this type of thing. It was an idea before its time.”
Zaidi said her group is among those working on development of personalized vaccines in the lab.
“Each patient gets a biopsy, and a small amount of tissue is retrieved that gets sent for sequencing,” she said. “Computerized algorithms can predict which mutations are more likely to generate an immune response. Based on this information, a vaccine is designed.”
Zaidi said her research group is also currently investigating “off-the-shelf” vaccines, which differ from vaccines that are tailored specifically to the patient’s tumor.
“In the off-the-shelf approach, each patient gets the same vaccine but we’re targeting common mutations that result from driver genes,” she said, “There are certain genes, such as KRAS, that drive the growth of the cancer and occur very early on in the development of the cancer. We are targeting those mutations because they are so critical for cancer cell growth and development, as a way to teach the immune system to recognize these mutations and mount a response against the cancer.”
Zaidi and colleagues have developed a long peptide vaccine targeting the six most prevalent KRAS mutation proteins in patients with pancreatic ductal adenocarcinoma. They have evaluated the initial safety and immunogenicity of the vaccine in 11 patients so far in a phase 1 clinical trial. The patients, who underwent surgery and chemotherapy, received the vaccine in combination with checkpoint blockade.
“We’re measuring the immune response in the blood after these patients get the vaccine and looking for T cells that are responding to the targets we’re vaccinating against,” she said. “This is a very small study, but we do have several patients enrolled and many of them are generating immune responses in the blood. However, in terms of efficacy and outcomes, it’s just too early to say.”
Based on their findings, Zaidi and her colleagues have begun enrolling a second clinical trial testing their KRAS peptide vaccine in those at high risk for developing pancreatic cancer.
“These are patients who already have a known risk because of a strong family history or genetic mutation,” she said. “Pancreatic cancer is an ideal cancer [for vaccines] because most of the time it presents when the disease is so far advanced, there are no curative options. Catching it in the earliest stages, even in the precancer stage, is key.”
Promising research
Research into vaccines against breast, ovarian, lung, prostate, colon and bladder cancers has shown a great deal of promise, according to Mary L. “Nora” Disis, MD, director of University of Washington’s Cancer Vaccine Institute.
Mary L. “Nora” Disis
“We’ve been working on cancer vaccines for probably the past 25 years, and our most advanced programs are in breast cancer and ovarian cancer,” Disis told Healio. “We’re in randomized phase 2 clinical trials, and both of these programs are looking at single-antigen vaccines. We’re trying to target driver proteins in a subtype of malignancy. Our new vaccines, which encode multiple antigens and target biologic pathways that define a cancer subtype, are in early-stage clinical trials.”
Disis and colleagues evaluated the long-term safety of a plasmid-based breast cancer vaccine that encodes the ERBB2 cellular domain in a phase 1 trial of 66 patients with advanced ERBB2-positive breast cancer. At a follow-up of 10 years, the DNA-based vaccine appeared safe and associated with generation of ERBB2-specific type 1 T cells in most patients, prompting the researchers to initiate phase 2 trials.
In a separate phase 1 study, Disis and colleagues assessed the safety of T-helper 1 selective insulin-like growth factor binding protein-2 (IGFBP-2) vaccination among 25 women with advanced ovarian cancer. Researchers administered the plasmid-based vaccine monthly for 3 months and assessed toxicity using NCI criteria. Results showed the vaccine appeared well-tolerated and induced high levels of IGFBP-2-specific interferon gamma-secreting T cells among half of the women.
“The early results of those phase 1 and single-arm phase 2 studies are very promising and showed a progression-free survival and overall survival benefit, although they weren’t powered for those endpoints,” Disis said. “That has now led to large, randomized clinical trials looking at preventing disease recurrence in those patients.”
Looking ahead
Future vaccine research will likely focus on interrupting the development of cancer for people at high risk, particularly for malignancies such as pancreatic cancer, Zaidi said.
“I think moving earlier and earlier, even to a premalignant setting, is where we believe vaccines may be important in intercepting the development of cancer in high-risk individuals,” Zaidi said.
Advances in technology have helped to brighten the future for cancer vaccines, according to Berzofsky.
“The technology to sequence and look for mutations in the patient’s tumor has improved by many orders of magnitude,” he said. “Back in 2005, it was very laborious to sequence RAS and p53 in a patient’s tumor. It took weeks to get the sequence and then months to make the synthetic peptide. Now, the technology is so much better, and you can do it much faster, more easily and more cheaply. So, it’s become more practical to do.”
Zaidi agreed that the science and the technology are steadily catching up to the promise of developing an effective cancer vaccine.
“Not only do we know what to target better in each patient’s tumor, we also are getting better at knowing how to deliver these vaccines with mRNA technologies, with nanoparticles,” she said. “Now, we can take the patient’s tumor and sequence it in a matter of days, and it’s not that expensive. We can use that information to develop personalized vaccines. So, all this technology is helping to drive better cancer vaccines and strategies.”
Disis said she believes cancer vaccine development has reached “a tipping point” for three reasons.
“The first reason is that we now know the type of immune response we need to stimulate,” Disis said. “The second is we now know many proteins are immunogenic in specific types of cancers, so we’re able to put together vaccines quickly that will train the immune system to recognize those proteins. Finally, vaccine technologies have advanced dramatically and nucleic acid vaccines, such as mRNA and DNA vaccines, have shown to be superior in terms of generating high levels of immunity very safely. Considering all of this together, I think we’re there in terms of being able to move ahead extremely quickly.”
Eating foods that are rich in vitamin C and vitamin D while taking calcium supplements can aid in the absorption of calcium.
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Calcium is the most abundant mineral in the human body, yet it is also one of the nutrients that modern people often lack. Calcium deficiency can cause osteoporosis and other health issues, so it is important to include sufficient amounts of calcium intake in the daily diet.
Calcium Deficiency Leads to Osteoporosis and Night Cramps
Calcium is predominantly stored in bones and teeth, making up 99 percent of the body’s calcium, with the remaining 1 percent distributed throughout the rest of the body. Bones serve as the body’s calcium reservoir. According to Dr. Chen Yitzu, an attending physician at Rong-Xin Orthopedic Clinic, when blood calcium levels drop, the parathyroid hormone and vitamin D will stimulate the release of calcium from bones to maintain a balance in the blood. Long-term calcium deficiency in the blood can lead to osteoporosis and other health issues.
Common symptoms of calcium deficiency are:
Osteoporosis
Anxiety
Insomnia
Night cramps
Chen pointed out that knee pain or other body aches can often be mistaken as a symptom of osteoporosis. However, this disease is usually asymptomatic and may only be discovered during a health checkup or after a fracture has occurred.
People who are deficient in calcium may also experience anxiety and insomnia. However, similar symptoms can also be caused by a deficiency in potassium, as both calcium and potassium are important elements for stabilizing the nerves.
If a person experiences night leg cramps, it is likely due to a calcium deficiency. Chen explained that after a day of walking and the effect of gravity, metabolic waste can accumulate in the calves, which, when combined with a lack of calcium, can cause nerve instability and cramping at night. For those experiencing these symptoms, it is recommended to have a bone density checkup at the hospital, as it may indicate osteoporosis.
Sudden leg cramps at night may indicate calcium deficiency.
4 Types of People Prone to Calcium Deficiency
According to the International Osteoporosis Foundation, increasing bone density by 10 percent during youth can delay the onset of osteoporosis by 13 years (pdf). Hence, individuals of all ages should maintain their bone health through a balanced diet. Four types of individuals should be particularly mindful of their calcium intake:
1. Elderly: Bone density typically peaks between the ages of 20 and 30, and gradually declines thereafter. The older one gets, the more bone mass one loses.
2. Menopausal women: After menopause, bone loss speeds up due to the decrease in hormones.
3. Patients with thyroid and parathyroid disorders: The thyroid and parathyroid glands are responsible for regulating the levels of calcium and phosphate ions in the body. Both overactivity and under-activity of these glands can lead to calcium loss in the blood.
4. Patients with kidney disease:Declining kidney function can lead to phosphate buildup in the blood. This triggers the parathyroid gland to secrete more hormones to eliminate the excess phosphate, but the increased levels of parathyroid hormones will then lead to calcium loss in the bones.
Key Nutrients for Calcium Absorption: Vitamins C and D
Calcium is present in many foods, and some examples of calcium-rich foods include fresh milk, beans, dried bean curd, tofu, dark green vegetables, nuts, and more.
Chang I-Ting, a nutritionist from Cofit Healthcare Inc., pointed out that drinking a glass of milk before bed can help relax the mind and promote better sleep due to the calcium content. Furthermore, the growth hormone secreted during sleep can also aid in the absorption of calcium.
In addition to consuming high-calcium foods, it is also important to consume two major nutrients that can enhance the body’s absorption of calcium.
Vitamin C
Eating fruits or drinking juices that are rich in vitamin C, such as guava, kiwi, papaya, tomatoes, strawberries, and citrus fruits, after meals can enhance calcium absorption. This is because the acidic nature of these fruits aids in the absorption rate of calcium.
Vitamin D
When ingested, calcium requires the assistance of vitamin D3 in the stomach to penetrate the gastric mucosa and enter the bloodstream. If there is a deficiency of vitamin D3, even consuming a large amount of calcium will not help, as it cannot be absorbed in the stomach and will instead be excreted through the small intestine.
People who regularly expose themselves to sunlight and have normal liver and kidney function can synthesize vitamin D3 on their own, and therefore will not experience a deficiency. However, in modern times, people often have limited exposure to sunlight or experience a decrease in liver and kidney function as they age, and both things can negatively impact the synthesis of vitamin D3.
In addition to getting moderate sun exposure, consuming foods that are rich in vitamin D, such as salmon, egg yolks, and buckwheat is also necessary to enhance the efficacy of calcium.
Chen mentioned that magnesium is also a crucial nutrient that needs to be taken into account. People may assume they do not have osteoporosis because their blood calcium levels appear normal during health checkups, but that is not necessarily the case. She explained that although magnesium deficiency is not directly linked to osteoporosis, maintaining a 2:1 calcium-to-magnesium ratio in the blood is crucial, as long-term magnesium deficiency can lead to calcium loss. Some calcium supplements on the market now not only contain vitamin D3, but also trace amounts of magnesium ions.
Consuming salmon, which is rich in vitamin D, along with high-calcium foods, can aid in the absorption of calcium in the body.
4 Types of Foods That Can Impair the Effectiveness of Calcium Supplements
Chang pointed out that for calcium obtained through diet to be truly utilized by the body, one should also avoid certain foods and eating habits that can affect calcium absorption.
Foods high in salt: Avoid excessively salty meals and processed foods with high sodium content.
High-protein foods: Consuming too much protein, such as meat, which also contains high amounts of phosphorus, can cause an imbalance in the calcium-phosphorus ratio and lead to poor calcium absorption.
High-fat foods: Excessively oily meals can interfere with calcium absorption, as the calcium may bind with the fats.
Oxalate and caffeine-containing beverages: Consumption of oxalate and caffeine can reduce the absorption rate of calcium. Examples of such beverages include strong tea, coffee, carbonated drinks, and energy drinks. Therefore, it is recommended to wait at least one hour after a meal before consuming these beverages and avoid excessive consumption.
Cell Press Bacterial communities in the penile urethra.
Contrary to common beliefs, your urine is not germ-free. In fact, a new study shows that the urethra of healthy men is teeming with microbial life and that a specific activity—vaginal sex—can shape its composition. The research, being published March 24 in the journal Cell Reports Medicine, provides a healthy baseline for clinicians and scientists to contrast between healthy and diseased states of the urethra, an entrance to the urinary and reproductive systems.
“We know where bugs in the gut come from; they primarily come from our surroundings through fecal-oral transfer,” says co-senior author David Nelson, a microbiologist at Indiana University. “But where does genital microbiology come from?”
To flush out the answer, the team of microbiologists, statisticians, and physicians sequenced the penile urethra swabs of 110 healthy adult men. These participants had no urethral symptoms or sexually transmitted infections (STIs) and no inflammation of the urethra. DNA sequencing results revealed that two types of bacterial communities call the penile urethra home—one native to the organ, the other from a foreign source.
“It is important to set this baseline,” says co-senior author Qunfeng Dong, a bioinformatician at Loyola University Chicago. “Only by understanding what health is can we define what diseases are.”
The researchers found that most of the healthy men had a simple, sparse community of oxygen-loving bacteria in the urethra. In addition, these bacteria probably live close to the urethral opening at the tip of the penis, where there is ample oxygen. The consistent findings of these bacteria suggest that they are the core community that supports penile urethra health.
But some of the men also had a more complex secondary group of bacteria that are often found in the vagina and can disturb the healthy bacterial ecosystem of the vagina. The team speculates that these bacteria reside deeper in the penile urethra because they thrive in oxygen-scarce settings. Only men who reported having vaginal sex carry these bacteria, hinting at the microbes’ origins.
Delving into the participant’s sexual history, the team found a close link between this second bacterial community and vaginal sex but not other sexual behaviors, such as oral sex and anal sex. They also found evidence that vaginal sex has lasting effects. Vagina-associated bacteria remained detectable in the participants for at least two months after vaginal sex, indicating that sexual exposure to the vagina can reshape the male urinary-tract microbiome.
“In our study, one behavior explains 10% of the overall bacterial variation,” says Nelson, when discussing the influence of vaginal sex. “The fact that a specific behavior is such a strong determinant is just profound.”
Although current findings from the study show that vaginal bacteria can spread to the penile urethra, the team’s next plan is to test whether the reverse is true. Using the newly established baseline, the researchers also hope to offer new insights into bacteria’s role in urinary- and reproductive-tract diseases, including unexplained urethral inflammation and STIs.
“STIs really impact people who are socioeconomically disadvantaged; they disproportionately impact women and minorities,” says Nelson. “It’s a part of health care that’s overlooked because of stigma. I think our study has a potential to dramatically change how we handle STI diagnosis and management in a positive way.”
More magnesium in our daily diet leads to better brain health as we age, according to scientists from the Neuroimaging and Brain Lab at The Australian National University (ANU).
The researchers say increased intake of magnesium-rich foods such as spinach and nuts could also help reduce the risk of dementia, which is the second leading cause of death in Australia and the seventh biggest killer globally.
The study of more than 6,000 cognitively healthy participants in the United Kingdom aged 40 to 73 found people who consume more than 550 milligrams of magnesium each day have a brain age that is approximately one year younger by the time they reach 55 compared with someone with a normal magnesium intake of about 350 milligrams a day.
“Our study shows a 41 percent increase in magnesium intake could lead to less age-related brain shrinkage, which is associated with better cognitive function and lower risk or delayed onset of dementia in later life,” lead author and Ph.D. researcher Khawlah Alateeq, from the ANU National Centre for Epidemiology and Population Health, said.
“This research highlights the potential benefits of a diet high in magnesium and the role it plays in promoting good brain health.”
It’s believed the number of people worldwide who will be diagnosed with dementia is expected to more than double from 57.4 million in 2019 to 152.8 million in 2050, placing a greater strain on health and social services and the global economy.
“Since there is no cure for dementia and the development of pharmacological treatments have been unsuccessful for the past 30 years, it’s been suggested that greater attention should be directed towards prevention,” study co-author Dr. Erin Walsh, who is also from ANU, said.
“Our research could inform the development of public health interventions aimed at promoting healthy brain aging through dietary strategies.”
The researchers say a higher intake of magnesium in our diets from a younger age may safeguard against neurodegenerative diseases and cognitive decline by the time we reach our 40s.
“The study shows higher dietary magnesium intake may contribute to neuroprotection earlier in the aging process and preventative effects may begin in our 40s or even earlier,” Ms Alateeq said.
“This means people of all ages should be paying closer attention to their magnesium intake.
“We also found the neuroprotective effects of more dietary magnesium appears to benefit women more than men and more so in post-menopausal than pre-menopausal women, although this may be due to the anti-inflammatory effect of magnesium.”
Participants completed an online questionnaire five times over a period of 16 months. The responses provided were used to calculate the daily magnesium intake of participants and were based on 200 different foods with varying portion sizes. The ANU team focused on magnesium-rich foods such as leafy green vegetables, legumes, nuts, seeds and wholegrains to provide an average estimation of magnesium intake from the participants’ diets.
Our case is about a 73-year-old man with a history of GERD and diabetes mellitus who presented with a 1-week history of hematochezia with associated nausea, vomiting, diarrhea, and epigastric pain.
His CT imaging showed a pulmonary mass and a duodenocolonic fistula in the second part of the duodenum. Upper GI endoscopy displayed a 10-mm fistula in the first and second portions of the duodenum with opening into the right side of the colon and an infiltrative mass past the duodenal bulb with biopsy positive for invasive adenocarcinoma.
Considering a palliative approach, we placed a Niti-S (Taewoong Medical, Los Angeles, CA) bare-type covered metal luminal esophageal stent under fluoroscopic guidance that was anchored proximally by the endoscopic placement of 2 interrupted sutures to prevent distal migration.
The patient was seen 3 weeks postprocedure with improvement in symptoms, and imaging revealed a second primary lung malignancy.
This video highlights a palliative and endoscopic approach to stenting a duodenocolonic fistula in a patient with metastatic disease. Malignant duodenocolonic fistulas can cause rapid nutritional deficiencies and severe symptoms, including diarrhea and abdominal pain. An endoscopic approach by placing a covered duodenal stent with stent fixation would allow for a less-invasive alternative to surgery while providing symptom relief, especially in a palliative situation.
Our study demonstrates a palliative approach to treating patients with significant disease burden from malignant duodenocolonic fistulas. Although alternative endoscopic approaches, such as through-the-scope or over-the-scope clips, can be used for enteral fistula closure, they have a higher likelihood of dislodging given their smaller size relative to the fistula.
In addition, primary endoscopic suturing of the defect can have a higher probability of the sutures to fail and dehisce given the friability associated with the tumor, and it can ultimately provide minimal relief.
A, A medium fistula found in the first portion of the duodenum and in the second portion of the duodenum, opening into the right side of the colon, at the region of hepatic flexure. B, Medium-sized fungating mass in the first and second portion of the duodenum.
New research from the Dana-Farber Cancer Institute demonstrates that the cells in the lining of the colon can go through a transition before cancer develops. Using mouse models and tumor models called patient-derived organoids, researchers discovered that the cells undergo a type of molecular time travel that reverts them back to an embryonic state. The researchers also uncovered that this “time travel” depends on a protein called Sox9.
“Cell state plasticity is carefully regulated in adult epithelia to prevent cancer,” the researchers wrote. “The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development.”
The current study looks at what happens before the emergence of these mutations and finds not only evidence of fetal reprogramming that can initiate cancer, but also a protein, Sox9, that fuels that reprogramming. This and previous research from the lab of Nilay Sethi, MD, PhD, suggest Sox9 is a promising therapeutic target for colorectal cancer.
“Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq,” noted the researchers. “Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.”
Researchers say they have found out how some skin cancers stop responding to treatment at the end of life. An analysis of 14 patients who died from incurable melanoma has revealed that changes to the order, structure, and number of copies of tumor DNA could cause some skin cancers to resist treatment. These changes also explain how melanoma can spread to other parts of the body.
“Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy program, including 222 exome, 493 panel-sequenced, 161 RNA-seq, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients,” write the investigators.
“We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. “Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.”
The study analysis showed that immune checkpoint inhibitor drugs had stopped working in all 14 patients who had died from advanced melanoma. [Andrew Brookes/Getty Images]
In the study, the scientists took 573 samples from 387 tumors from 14 patients with advanced melanoma. All of the patients in the study had been treated with immune checkpoint inhibitor (ICI) drugs, which help the immune system to recognize and attack cancer cells. In all 14 patients, ICI drugs had stopped working by the time of their deaths.
The scientists read the genetic code of individual cells within the tumor samples, looking for patterns in how the code changed when the tumors spread and resisted treatment.
They found that 11 out of the 14 patients in the study had lost functioning genes that enable ICI drugs to help the immune system recognize and attack the cancer. This loss occurs because the cancer can either make multiple copies of defective versions of the genes, or use extrachromosomal DNA to override normal copies of the genes.
“Treatment options for patients whose melanoma that returned or spread have improved dramatically in the last decade. But sadly, almost half of melanoma patients still lose their lives to their cancer,” says Samra Turajlic, PhD, consultant medical oncologist in the melanoma unit at the Royal Marsden and Research Group Leader at the Francis Crick Institute. “To understand why existing treatments sometimes fail, we need to know what happens in the final stages of their cancer. It’s difficult, but the only practical way to do this is to analyze tumor samples after people have died from their cancer.
“We found that melanoma can profoundly alter its genome to hide from the immune system and spread around the body. These profound changes are highly complex, but we’re hopeful that we can now find ways to target them in the clinic.”
The researchers involved are currently analyzing samples from people who died from other types of incurable cancer to find out how cancers spread and why they stop responding to treatment.
“These results present the most detailed picture yet of what melanoma looks like at the final stages of life. We can now see how the cancer evolves to spread to the brain and the liver, and how it can beat the most common treatment currently available for people with advanced disease,” notes Mariam Jamal-Hanjani, PhD, clinical associate professor at University College London. “We now have a huge opportunity to look for new ways to treat advanced cancer.”
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