There are two forms of vitamin D supplements available: vitamin D2 and vitamin D3. Researchers have found that taking vitamin D2 supplements can lead to a drop in the body's concentration of vitamin D3, which is the form our bodies naturally produce from sunlight and use most effectively to raise overall vitamin D levels.

The study, published in Nutrition Reviews, analysed data from randomised controlled trials and found that vitamin D2 supplementation resulted in a reduction in vitamin D3 levels compared to those not taking a vitamin D2 supplement. In many of the studies, the vitamin D3 levels went lower than in the control group.

Emily Brown, PhD Research Fellow and Lead Researcher of the study from the University of Surrey's Nutrition, Exercise, Chronobiology & Sleep Discipline, said:

"Vitamin D supplements are important, especially between October and March, when our bodies cannot make vitamin D from sunlight in the UK. However, we discovered that vitamin D2 supplements can actually decrease levels of vitamin D3 in the body, which is a previously unknown effect of taking these supplements. This study suggests that subject to personal considerations, vitamin D3 supplements may be more beneficial for most individuals over vitamin D2."

Professor Cathie Martin, Group Leader at the John Innes Centre, said:

"This meta-analysis highlights the importance of ensuring plant-based vitamin D3 is accessible in the UK."

This research supports a previous study published in Frontiers in Immunology, led by Professor Colin Smith from the University of Surrey, which suggests that vitamin D2 and D3 do not have identical roles in supporting immune function. Vitamin D3 has a modifying effect on the immune system that could fortify the body against viral and bacterial diseases.

Professor Colin Smith said:

"We have shown that vitamin D3, but not vitamin D2, appears to stimulate the type I interferon signalling system in the body -- a key part of the immune system that provides a first line of defence against bacteria and viruses. Thus, a healthy vitamin D3 status may help prevent viruses and bacteria from gaining a foothold in the body."

Further research into the different functionalities of vitamin D2 and D3 should be a priority in deciding whether vitamin D3 should be the first-line choice of vitamin D supplement, subject to individual requirements.

Professor Martin Warren, Chief Scientific Officer at the Quadram Institute, said:

"Vitamin D deficiency represents a significant public health concern, especially during the winter months with significant deficiency across the UK population. This collaborative research effort aligns well with the Quadram Institute's mission to deliver healthier lives through food innovation to enhance the nutrient density of the food we eat. Tackling this with the most effective form of vitamin D supplementation or fortification is of the utmost importance to the health of the nation."

"Metastasis is the main reason patients with triple negative breast cancer face poor survival odds," said senior author Dr. Vivek Mittal, Ford-Isom Research Professor of Cardiothoracic Surgery and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "Our study suggests a new therapeutic approach to block metastasis before it starts and help patients overcome this deadly cancer."

The findings, published Oct. 2 in Cancer Discovery, challenge the popular notion that cancer treatments should boost cell division errors already occurring in tumor cells beyond the breaking point to induce cell death. When normal cells divide, the chromosomes -- DNA "packages" carrying genes -- are duplicated and split evenly into two daughter cells. This process goes haywire in many cancer cells, leading to chromosomal instability: too many, too few, or jumbled chromosomes in multiple daughter cells.

"I find the attempt to drive cancer cells over the edge with more chromosomal instability a little concerning because if you don't reach the right level, it may paradoxically lead to aggressive disease," Dr. Mittal said. "Instead, our findings suggest that restoring order to cell division by targeting EZH2 can stop them from spreading."

First author Dr. Shelley Yang Bai began this work as a graduate student and is now a postdoctoral associate with Dr. Mittal in cardiothoracic surgery at Weill Cornell Medicine. Dr. Samuel Bakhoum, who was at Memorial Sloan Kettering Cancer Center at the time, co-led this study.

Linking Epigenetics and Metastasis

About 5% of cells in a TNBC primary tumor are highly likely to metastasize, and these cells have unique features such as different metabolism, increased chromosomal instability and altered epigenetics -- modifications to DNA or its associated proteins that do not directly change the genetic code.

Dr. Mittal's team found a suspicious culprit that could be triggering metastasis in these particular cancer cells: EZH2. This protein normally modifies how DNA is packaged in cells. But cancers often hijack EZH2 by increasing its production. In TNBC, this overproduction leads to the silencing of key genes needed for chromosomes to segregate properly during cell division and to rampant errors.

When analyzing data from breast cancer patients, Dr. Bai found that patients with higher levels of EZH2 also had tumor cells with more chromosomal alterations. This provided clues for further lab experiments. While inhibiting EZH2 with tazemetostat, an FDA-approved drug to treat certain cancers, reduced chromosomal instability in cell lines, boosting EZH2 levels genetically increased errors in cell division.

Furthermore, mouse models with elevated EZH2 and chromosomal instability in primary tumors showed increased lung metastases compared to tumors lacking EZH2, confirming a direct link between EZH2 levels, chromosomal instability and metastasis. But how was EZH2 driving instability?

Chromosomal Chaos

The team discovered that EZH2 silences the tankyrase 1 gene, which normally ensures the chromosome-separating machinery works properly during cell division. This triggers a chain reaction -- the decrease in tankyrase 1 causes another protein called CPAP to build up excessively. This prompts the cell's centrosomes -- structures that pull chromosomes apart -- to multiply uncontrollably, leading to faulty divisions into three or more daughter cells.

The team showed that inhibiting EZH2 restored balance, significantly reducing metastasis in preclinical models. "For the first time, we have linked EZH2, which is an epigenetic regulator, with chromosomal instability in a mechanistic fashion," Dr. Bai said.

EZH2 inhibitors may be the first drugs that can suppress chromosomal instability directly. "This study provides a promising new approach to treating triple-negative breast cancer by targeting the root cause of metastases," said Dr. Magdalena Plasilova, associate professor of clinical surgery (pending appointment at rank), a surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and an author on the study. "I see firsthand the devastating impact of metastases on patients, and this offers hope for improved outcomes and survival rates."

While Tazemetostat could be repurposed as a treatment for TNBC, other drugs might have similar or better effects. "Our discovery opens the door for clinical trials to test EZH2 inhibitors in high-risk breast cancer and potentially other cancers that are also marked by chromosomal instability, such as lung adenocarcinoma," said Dr. Mittal, who is also a member of the Englander Institute of Precision Medicine at Weill Cornell. Currently, he is planning collaborations to conduct safety tests in a clinical trial.

MASLD occurs when fat builds up in the liver and is associated with one or more of five conditions: obesity, Type 2 diabetes, high blood pressure, high blood sugar and low HDL cholesterol, known as "good" cholesterol. These conditions are characterized as cardiometabolic risk factors because they affect the heart or metabolism.

MASLD can lead to serious illness, such as advanced liver, heart and kidney disease, but little research has been done to examine if certain cardiometabolic risk factors for those with MASLD are more associated with death than others.

The deadliest cardiometabolic risk factors

Now, a new study from Keck Medicine of USC published in Clinical Gastroenterology and Hepatology reveals that three of the cardiometabolic risk factors carry the greatest risk of death for those with MASLD: high blood pressure, pre-diabetes or Type 2 diabetes, and low HDL, which raise the risk of death by 40%, 25% and 15%, respectively.

These results were independent of how many or which combination of cardiometabolic risk factors patients had, and held steady despite individuals' gender, sex, race or ethnicity.

"MASLD is a complicated disease, and this study sheds new light on where doctors may want to focus their efforts when treating patients," said Norah A. Terrault, MD, a hepatologist with Keck Medicine and a senior author of the study. "Knowing which aspects of MASLD might lead to poorer outcomes can help us offer patients the best possible care."

Researchers were especially surprised to discover that high blood pressure was associated with a higher chance of death than diabetes, said Matthew Dukewich, MD, PharmD, MS, a USC transplant hepatology fellow and lead author of the study. "Until now, it was commonly thought that diabetes was the most pressing health problem for MASLD patients, which is a key insight."

The study also found that obesity, the most common cardiometabolic risk factor of MASLD, can substantially raise the risk of mortality depending on a patient's body mass index (BMI), which is a formula used to estimate body fat percentage based on an individual's height and weight. The higher a patient's BMI, the higher the association with death.

Additionally, the research adds to the growing body of research that patients with more cardiometabolic risk factors have poorer outcomes. The study found that the risk of death in MASLD patients increased by 15% for each additional cardiometabolic risk factor present.

How the study was conducted

Researchers used data from the National Health and Nutrition Examination Survey (NHANES), which collected health information about children and adults in the United States from 1988-2018, the most current year for which data was available for their study. Out of 134,515 participants 20 years or older, some 21,000 patients qualified as having MASLD.

The study authors tracked all-cause mortality rates by individual cardiometabolic risk factors to reach their conclusions.

Looking ahead, the study authors hope to conduct further studies examining patients' genetic background, dietary habits and alcohol use in relation to MASLD outcomes to provide more comprehensive risk profiles. "The more we can understand about the drivers of the disease, the more we can identify those most in need of interventions and prioritize our resources for enhanced outcomes," said Terrault.

Liyun Yuan, MD, a transplant hepatologist with Keck Medicine, is also a study author.