Red onions pack a cancer-fighting punch, study reveals

The next time you walk down the produce aisle of your grocery store, you may want to reach for red onions if you are looking to fight off cancer. In the first study to examine how effective Ontario-grown onions are at killing cancer cells, University of Guelph researchers have found that not all onions are created equal.

Engineering professor Suresh Neethirajan and PhD student Abdulmonem Murayyan tested five onion types grown in Ontario and discovered the Ruby Ring onion variety came out on top. Onions as a superfood are still not well known. But they contain one of the highest concentrations of quercetin, a type of flavonoid, and Ontario onions boasts particularly high levels of the compound compared to some parts of the world.

The Guelph study revealed that the red onion not only has high levels of quercetin, but also high amounts of anthocyanin, which enriches the scavenging properties of quercetin molecules, said Murayyan, study’s lead author.

Anthocyanin is instrumental in providing colour to fruits and vegetables so it makes sense that the red onions, which are darkest in colour, would have the most cancer-fighting power.

Published recently in Food Research International, the study involved placing colon cancer cells in direct contact with quercetin extracted from the five different onion varieties.

We found onions are excellent at killing cancer cells,” said Murayyan. “Onions activate pathways that encourage cancer cells to undergo cell death. They promote an unfavourable environment for cancer cells and they disrupt communication between cancer cells, which inhibits growth.”

The researchers have also recently determined onions are effective at killing breast cancer cells. “The next step will be to test the vegetable’s cancer-fighting powers in human trials,” said Murayyan.

These findings follow a recent study by the researchers on new extraction technique that eliminates the use of chemicals, making the quercetin found in onions more suitable for consumption. Other extraction methods use solvents that can leave a toxic residue which is then ingested in food, said Neethirajan.

This new method that we tested to be effective only uses super-heated water in a pressurized container,” he said. “Developing a chemical-free extraction method is important because it means we can use onion’s cancer-fighting properties in nutraceuticals and in pill form.”

While we can currently include this superfood in salads and on burgers as a preventative measure, the researchers expect onion extract will eventually be added to food products such as juice or baked goods and be sold in pill form as a type of natural cancer treatment.

Murayyan et al. Antiproliferative activity of Ontario grown onions against colorectal adenocarcinoma cells. Food Res Int. 2017;96:12-18. doi: 10.1016/j.foodres.2017.03.017 [Abstract]

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Balance, gait negatively impacted after chemotherapy treatment

A single chemotherapy treatment can result in a significant negative impact on walking gait and balance, putting patients at an increasing risk for falls, according to a new study involving breast cancer patients conducted by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). Up to 60 percent of patients experience chemotherapy-induced peripheral neuropathy (CIPN), nerve damage that impacts feeling in the hands or feet; however, when and to what extent this damage impacts functional abilities has been largely unknown.

This new study is the first to objectively measure the functional abilities of cancer patients during and after taxane-based chemotherapy. Researchers followed 33 patients with stage I-III breast cancer, assessing functional performance (standing balance and gait) and patient-reported outcomes at five timepoints spanning before treatment began up to three months post-treatment completion.

Researchers observed a 28 percent increase in side-to-side sway (medial-lateral) after just one chemotherapy treatment. That increased to 48 percent with cumulative chemotherapy exposure. Patients also demonstrated a 5 percent reduction in walking speed after three cycles of chemotherapy.

This is not simply a quality of life concern – CIPN can impact a patient’s ability to receive treatment at all, limiting the potential for a cure. For patients who have great difficulty with neuropathy, we often have to modify their treatment regimen to make it tolerable – sometimes the therapy has to be ceased entirely,” says Maryam Lustberg, MD, MPH, senior author of the study and director of breast cancer survivorship services at the OSUCCC – James. “We need to make these treatments more tolerable to patients so they can get the full benefit of the treatments.”

Lustberg and her colleagues report that taxane exposure is also associated with worsened sensory symptoms and poorer postural control. There was also an association between patients’ balance and self-reported sensory symptoms.

Significant Clinical Problem

CIPN leads to pain, falls and difficulty walking as well as performing activities of daily living. Although symptoms can improve with time, up to 30 percent of patients have persistent symptoms that last at least six months.

Researchers say the study provides initial support for the feasibility and potential utility of implementing objective measures of physical function into the oncology clinic.

Cancer survivors are at a significant increased risk for falls, and the incidence rate of falling after chemotherapy is a serious concern for survivors’ long-term quality of life,” adds Lustberg. “Our study provides new insights on how taxane-based chemotherapy can impact fundamental aspects of patient function. These new insights can help us develop better strategies to help patients combat these challenges and, in some cases, choose a different therapy to treat the disease but with reduced side effects.”

The OSUCCC – James is expanding this research to assess CIPN in colorectal cancer patients receiving taxane-based chemotherapy.

Integrating Gait, Balance Testing Into Clinical Practice

Study co-author Ajit Chaudhari, PhD, associate professor of physical therapy, orthopedics, mechanical engineering and biomedical engineering at The Ohio State University Wexner Medical Center says the study was an important first step in achieving better long-term outcomes after cancer and provides a new tool for integrating gait and balance screening into clinical care.

We have created an easy-to-use clinical tool that has strong potential to quickly help clinicians identify patients – very early on – who are developing a chemotherapy reaction that impacts gait and balance,” says Chaudhari. “It’s no longer good enough for someone to just ‘survive’ cancer because many patients have decades of life ahead of them. It is critical to do everything we can to make the rest of their lives as productive and enjoyable as they want it to be.

Monfort et al. Gait, balance, and patient-reported outcomes during taxane-based chemotherapy in early-stage breast cancer patients. Breast Cancer Res Treat. 2017; doi: 10.1007/s10549-017-4230-8 [Abstract]

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Are wealthier people more likely to receive a diagnosis of cancer?

Picture

CREDIT The Dartmouth Institute

Do wealthier people receive too much medical care? In a Perspective article recently published in the New England Journal of Medicine, H. Gilbert Welch, MD, and Elliott Fisher, MD, of The Dartmouth Institute for Health Policy and Clinical Practice examine the association between income level and cancer diagnosis.

Using data from the Surveillance, Epidemiology, and End Results (SEER) program, Welch and Fisher examined incidence and mortality trends for four types of cancers: breast cancer, prostate cancer, thyroid cancer and melanoma. They chose these specific cancers because the likelihood of diagnosis is sensitive to the intensity with which physicians look for these cancers – the combined effect of factors, including the frequency of screening and diagnostic exams, the ability of exams to detect small irregularities, and the threshold used to label results as abnormal. As Welch and Fisher note, these factors can have a dramatic effect on the apparent amount of disease. In simple terms, the harder doctors look for these cancers, the more they find.

Using 2000 U.S. census data, Welch and Fisher compared incidence and mortality of the four cancers in high- vs. low-income counties (median incomes greater than $75,000 and less than $40,000, respectively). Among their findings:

  • High-income counties have recorded a much greater increase in the incidence of these four cancers than low-income counties.
  • The combined death rate from the four cancers is similar in high- and low-income counties, which Welch and Fisher say suggests that the underlying burden of disease is actually similar in high- and low-income counties.
  • Mortality from these cancers hasn’t been increasing (as one might expect given the increase in diagnosis), but rather decreasing-due largely to improved treatments for breast and prostate cancer.

What accounts for the higher incidence of cancer in high-income counties? Welch and Fisher say there could be several contributing factors: affluent people may expect and demand more testing. Also, health systems serving relatively wealthy and healthy populations may see offering more testing “as a good way to produce more patients and increase business.”

If we want to move toward more sustainable and affordable health care systems, we’re going to have to understand what’s driving the overutilization of care and develop better ways to address it,” Fisher said.

Among the remedies Welch and Fisher suggest are moving toward alternative payment models, such as accountable care organizations, that move us away from the traditional fee-for-service model; reducing, or at least disclosing, financial conflicts of interest (such as doctors who receive payments from breast and prostate care centers); and promoting a more nuanced and balanced view of medical care.”Doctors and other health care professionals tend to overstate the role of medical testing in promoting health – particularly in people who aren’t sick,” Welch said. “A healthy diet, regular exercise, and a sense of purpose are very often the best tools people, at every income level, have to maintain good health.

Welch and Fisher. Income and Cancer Overdiagnosis – When Too Much Care Is Harmful. N Engl J Med. 2017;376(23):2208-2209. doi: 10.1056/NEJMp1615069 [Abstract]

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Using a genetic signature to overcome chemotherapy-resistant lung cancer

Patients with non-small cell lung cancer (NSCLC) often respond to standard chemotherapy, only to develop drug resistance later, and with fatal consequences. But what if doctors could identify those at greatest risk of relapse and provide a therapy to overcome or avoid it?

Researchers at UT Southwestern Medical Center believe they have an answer: a 35-gene signature that identifies tumor cells most likely to develop resistance to treatment. The study, published today in Cell Reports, points to a new pharmacologic approach to target chemo-resistant lung cancer and even prevent development of such resistance in the first place.

Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure,” said study co-author Dr. John Minna, a Professor and Director of in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. “These findings provide new insights into why resistance develops and how to overcome it.

Dr. Minna, with additional appointments in Pharmacology and Internal Medicine, also holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. Investigators studied mouse and cellular models of NSCLC, a type of lung cancer that the American Cancer Society estimates accounts for 85 percent of all lung cancer cases in the United States.

Previous studies have shown that up to 70 percent of those cancers develop resistance to standard therapy, such as the platinum-taxane two-drug combo that is often given,” said study senior author Dr. Elisabeth D. Martinez, Assistant Professor of Pharmacology and in the Hamon Center. Both she and Dr. Minna are also members of UTSW’s Harold C. Simmons Comprehensive Cancer Center.

Using long-term on/off drug cycles, lead author and former postdoctoral researcher Dr. Maithili Dalvi developed a series of cellular models of progressive tumor resistance to standard chemotherapy that ranged from very sensitive to highly insensitive. Next, the researchers identified genes commonly altered during the development of resistance across multiple cell line and mouse models and identified a 35-gene signature that indicated a higher genetic likelihood of chemotherapy resistance.

It’s like a fingerprint for resistance,” Dr. Martinez said, adding that it was predictive in both cells and mouse models.

Next, they compared this resistance biomarker using genetic profiles from human tumors in their National Cancer Institute (NCI) lung cancer Specialized Programs of Research Excellence (SPORE) database at UT MD Anderson Cancer Center in Houston. The database contained information on patient outcomes and those who had been treated with the two-drug chemotherapy. The genetic fingerprint for resistance correlated with cancer relapse in NSCLC patients in the database, she said.

Researchers discovered that as cancer cells developed greater resistance to chemotherapy, they progressively made higher amounts of enzymes called JumonjiC lysine demethylases. Dr. Martinez said these enzymes facilitate resistance by changing the expression of – or turning on and off – genes.
Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy. By changing the expression of genes, the tumor cells can adapt and survive the toxins,” she said.

Investigators then tested two potential drugs, both JumonjiC inhibitors. One of them, JIB-04, was found by UT Southwestern researchers in the Martinez lab during a small-molecule screen conducted at the National Center for Advancing Translational Sciences’ Chemical Genomics Center in Bethesda, Maryland.

I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress. In addition, and this is the most fascinating part: Dr. Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitors,” she said. “The cancer cells develop a new Achilles’ heel that we can hit.”

Because the chemo-resistant cancer cells are dependent on JumonjiC enzymes for survival, inhibiting those enzymes returns cancer cells to mortality and vulnerability to cell death, she explained.
We think these JumonjiC inhibitors have the potential to be used either to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether,” she said. “In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells.”

Later, researchers tested whether the Jumonji inhibitors JIB-04 or GSK-J4 prevented chemotherapy resistance. This strategy succeeded in cell cultures and partially prevented resistance in animal models, Dr. Martinez said.

Dalvi et al. Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors.Cell Reports, 2017;19:1669–1684 [Article]

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High doses of vitamin C to improve cancer treatment passes human safety trial

Clinical trials found that it is safe to regularly infuse brain and lung cancer patients with 800-1000 times the daily recommended amount of vitamin C as a potential strategy to improve outcomes of standard cancer treatments. In a work presented March 30, 2017 in Cancer Cell, University of Iowa researchers also show pathways by which altered iron metabolism in cancer cells, and not normal cells, lead to increased sensitivity to cancer cell death caused by high dose vitamin C

This image shows differential susceptibility of normal cells (left) and cancer cells (right) to vtamin C.
Credit: Schoenfeld, et al.

This paper reveals a metabolic frailty in cancer cells that is based on their own production of oxidizing agents that allows us to utilize existing redox active compounds, like vitamin C, to sensitize cancer cells to radiation and chemotherapy,” says co-author Garry Buettner, who was one of the first to propose that cancer cells might have a vulnerability to redox active compounds over 40 years ago. Buettner, along with study senior authors Bryan Allen and Douglas Spitz, are faculty members at the University of Iowa’s Department of Radiation Oncology, Free Radical and Radiation Biology Program, in the Holden Comprehensive Cancer Center.

The 11 evaluable patients enrolled in the brain cancer safety trial received three infusions of vitamin C a week for 2 months followed by two infusions per week for 7 months while receiving standard care radiation and chemotherapy. The goal of each infusion was to raise the concentration of vitamin C in a patient’s blood to 20,000 μM, as compared to a blood level of about 70 μM found in most adults. The high dose is necessary because vitamin C has a half-life of about two hours in the circulation of humans. The treatment was generally well tolerated; with modest side effects including frequent trips to the bathroom and dry mouth. Rarely, some patients developed high blood pressure that subsided quickly following infusion.

Why is this approach safe? Vitamin C, even at high levels, isn’t toxic to normal cells. The research group at Iowa found, however, that tumor tissue’s abnormally high levels of redox active iron molecules (a by-product of abnormal mitochondrial metabolism) react with vitamin C to form hydrogen peroxide and free radicals derived from hydrogen peroxide. These free radicals are believed to cause DNA damage selectively in cancer cells (versus normal cells) leading to enhanced cancer cell death as well as sensitization to radiation and chemotherapy in cancer cells.

This is a significant example of how knowing details of potential mechanisms and the basic science of redox active compounds in cancer versus normal cells can be leveraged clinically in cancer therapy,” says co-senior author Douglas Spitz, who focused on the biochemical studies. “Here, we verified convincingly that increased redox active metal ions in cancer cells were responsible for this differential sensitivity of cancer versus normal cells to very high doses of vitamin C.”

The safety study sets the stage for phase II clinical trials looking at whether high dose vitamin C is effective at extending overall lifespan and quality of life for patients undergoing radiation and chemotherapy. The researchers are currently enrolling patients with stage 4 lung cancer and will soon begin enrolling people with glioblastoma multiforme (brain cancer) in these phase II trials. They are hopeful that brain cancer responses to radiation and chemotherapy can be enhanced in these phase II trials. This guarded optimism is based on the phase I trial data showing an increase in overall survival of 4-6 months in 11 glioblastoma multiforme patients (18-22 months) versus the 14-16 months survival typically seen with the standard treatment.

The majority of cancer patients we work with are excited to participate in clinical trials that could benefit future patient outcomes down the line,” says co-senior author Bryan Allen, who led the clinical side of the study. “Results look promising but we’re not going to know if this approach really improves therapy response until we complete these phase II trials.”

The cost per patient above standard insurance billing for the phase II vitamin C glioblastoma multiforme protocol is approximately $8000 spread over 9 months of test infusions. This cost can be less than a single dose of some immunotherapy and/or chemotherapy drugs.

Schoenfeld et al. O2 and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell, 2017; DOI: 10.1016/j.ccell.2017.02.018 [Abstract]

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The intestine has a reservoir of stem cells that are resistant to chemotherapy

These comprise a small group of passive stem cells -quiescent- that are activated when needed and have the capacity to produce any kind of intestinal cell. Quiescent cells are relevant for tissue regeneration and for participation in tumor development.

After Chemotherapy, these cells change their behaviour, become active and regenerate all cell types in the intestine (in green). CREDIT Franscisco Barriga, IRB Barcelona


The intestine has a high rate of cellular regeneration due to the wear and tear originated by its function degrading and absorbing nutrients and eliminating waste. The entire cell wall is renewed once a week approximately. This explains why the intestine holds a large number of stem cells in constant division, thereby producing new cell populations of the various types present in this organ.

Researchers at the Institute for Research in Biomedicine (IRB Barcelona) headed by ICREA investigator Eduard Batlle, head of the Colorectal Cancer Laboratory, have discovered a new group of intestinal stem cells with very different characteristics to those of the abundant and active stem cells already known in this organ. Performed in collaboration with the Centro Nacional de Análisis Genómico (CNAG-CRG), the study has been published in Cell Stem Cell. These new group of stem cells are quiescent, that is to say, they do not proliferate and are apparently dormant.

The researchers describe them as a reservoir of stem cells–it is estimated that there is one quiescent cell for every 10 active intestinal stem cells. In healthy conditions, these cells have no apparent relevant function. However, they are important in situations of stress, for example, after chemotherapy, in inflammatory processes, and in tissue infections–all conditions in which the population of “normal/active” stem cells is depleted. These quiescent cells would serve to regenerate the organ by giving rise to the various types of cells present in the intestine, renewing the population of “normal/active” stem cells, and restoring balance to the tissue.

Eduard Batlle explains that the discovery of quiescent stem cells in the intestine reveals that stem cell biology is more complex that previously appreciated and that it does not follow ahierarchical model of cell organisation. “In intestinal cell hierarchy, there are no cells above others, so the two populations are in a continual balance to ensure the proper function of the organ“.

Most drugs against cancer have a secondary effect on the cells that are dividing in our tissues. “Because quiescent stem cells divide infrequently, they are resistant to many types of chemotherapy and they regenerate the tissue that this treatment has damaged,” explains Eduard Batlle, head of one of the labs of international prestige in research into intestinal stem cells and their involvement in colorectal cancer.

Quiescent cells are present in many kinds of tissue. However, in spite of their relevance in tissue regeneration, increasing evidence points to their involvement in tumour development. “It is difficult to study these cells, mainly because they are scarce and there are technical limitations with respect to monitoring, straining and distinguishing them from the others,” explains Francisco Barriga, first author of the study and current postdoctoral fellow at the Memorial Sloan Kettering Cancer Center in New York.

Using advanced techniques, such as genetic tracing of cell lineages and transcriptomic analysis of individual cells, performed by CNAG-CRG and the Bioinformatics and Biostatistics Unit at IRB Barcelona, the group has identified the distinct genetic programme used by quiescent stem cells with respect to normal intestinal ones. This work has been done over six years.

The researchers have labelled this cell population with a specific marker, the Mex3a protein, which has allowed them to track it over time. “We intend to continue studying quiescent stem cells in health and disease and to discover the function of the genes that distinguish them in the colon and in other organs,” says Batlle.

Barriga et al. Mex3a marks a slowly dividing subpopulation of Lgr5+ intestinal stem cells. Cell Stem Cell (2017). doi: 10.1016/j.stem.2017.02.007 [Abstract]

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Early deaths from childhood cancer up to 4 times more common than previously reported

Treatments for childhood cancers have improved to the point that 5-year survival rates are over 80 percent. However, one group has failed to benefit from these improvements, namely children who die so soon after diagnosis that they are not able to receive treatment, or who receive treatment so late in the course of their disease that it is destined to fail.

A study published in the Journal of Clinical Oncology explores this challenging population, finding that death within a month of diagnosis is more likely in very young children and those from minority racial and ethnic groups even independent of low socioeconomic status. The study uses a large national database to find that the rate of deaths within one month of diagnosis has been previously under-reported in clinical trial data, with early deaths from some pediatric cancer subtypes up to four times as common as had been implied by clinical trial reports.

During my pediatric residency a teenager came in with leukemia, but had so much cancer when he presented that he had multi-organ failure and died within about 24 hours of coming to our attention, before we could even start treatment. I wanted to find out who these kids are in hopes that as a system we could learn to spot them earlier, when treatment still has a chance of success,” says Adam Green, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children’s Hospital Colorado. Green originated this study during his clinical fellowship at Dana Farber Cancer Institute, working with Carlos Rodriguez Galindo, MD.

Green and colleagues used data from the Surveillance, Epidemiology and End Results (SEER) database, finding 36,337 cases of pediatric cancer between the years 1992 and 2011. Of these young patients, 555 or 1.5 percent died within one month of cancer diagnosis. Overall, the strongest predictor of patients who would die soon after diagnosis was age below one year.

In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling. Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic. Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study,” Green says.

Additionally, black race and Hispanic ethnicity predicted early death, even beyond the influence of socioeconomic status. Green hopes that future studies will be able to discover whether biologic or cultural factors may be responsible for these disparities, or if higher rates of early death in minority populations could be due to factors built into insurance and health care systems.

He also points out that the rate of early deaths due to pediatric cancers is higher than previously reported.

Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials. However, these kids in our study aren’t surviving long enough to join clinical trials,” Green says.

For example, the paper shows that a clinical trial against childhood Acute Myeloid Leukemia (AML) reported early death in 16 of 1,022 young patients, or 1.6 percent of these cases. In contrast, the SEER database, which collects about 15 percent of all cancer outcomes across the United States (representing a geographic and socioeconomic cross-section), shows 106 early deaths in 1,698 diagnoses, or 6.2 percent of all cases, almost four times as high as previously reported. When comparing the rates of early deaths seen in the SEER database to rates of early deaths reported in clinical trial data, early death was higher for all cancer subtypes (0.7 versus 1.3 percent in non-infant ALL; 2.0 versus 5.4 percent in infant ALL; 1.4 versus 3.8 percent in hepatoblastoma; 0.04 versus 0.5 percent in Wilms tumor).

I had a hunch this was a bigger problem than we thought. Now we see that is indeed the case,” says Green.

Now that Green has shown the fact of early death in this population, he hopes to work with CU Cancer Center colleagues to design a national prospective study that could more closely examine the factors associated with this outcome. “So that whenever a family has a child who dies of cancer within a month of diagnosis, we could contact the family to gather information about timing of symptoms and their experience accessing care. We can already act on our findings in this current study to improve early identification of these patients. But with prospective, patient-level data, we can move from understanding the scope and risk factors for early death to identifying problems in the diagnostic process we can fix,” Green explains.

The overall goal of this ongoing line of research is to change potential early deaths to long-term survivors.

This is a population that deserves our attention,” Green says.

Green et al.  Death Within 1 Month of Diagnosis in Childhood Cancer: An Analysis of Risk Factors and Scope of the Problem. Journal of Clinical Oncology (2017) DOI: 10.1200/JCO.2016.70.3249 [Article]

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