Solving ‘Peto’s Paradox,’ new model shows selection pressure of healthy tissue keeps cells with cancerous mutations in check
July 21, 2015
University of Colorado Anschutz Medical Campus
A new article argues against the commonly held ‘accumulation of mutations’ model of oncogenesis in favor of a model that depends on evolutionary pressures acting on populations of cells.
A paper published today in the Proceedings of the National Academy of Sciences argues against the commonly held “accumulation of mutations” model of oncogenesis in favor of a model that depends on evolutionary pressures acting on populations of cells. Basically, the paper states that the ecosystem of a healthy tissue landscape lets healthy cells outcompete ones with cancerous mutations; it is when the tissue ecosystem changes due to aging, smoking, or other stressors, that cells with cancerous mutations can suddenly find themselves the most fit, allowing their population to expand over generations of natural selection.
This new thinking about oncogenesis has profound implications for cancer therapy and drug design.
“We’ve been trying to make drugs that target mutations in cancer cells. But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer,” says James DeGregori, PhD, associate director for basic science at University of Colorado Cancer Center, and the paper’s senior author.
The proposed model helps to answer a longstanding question in cancer science known as Peto’s Paradox — if cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing the disease earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?
“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” DeGregori says.
The answer that DeGregori and CU Cancer Center colleague Andrii Rozhok, PhD propose is that in addition to activating mutation, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.
Consider the following two evolutionary scenarios: In a grassy lawn, the health of the lawn is the best defense against dandelions; and in the time of the dinosaurs, the environment selected for giant lizards until the meteor hit at which point the new context favored the evolution of new species better adapted to the changed environment, including larger mammals.
Let’s start with the lawn: “Healthy cells are optimized for the ecosystem of the healthy body. But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape,” DeGregori says. In this scenario, DeGregori’s suggestion to explore the development of interventions supporting the fitness of healthy tissues is like applying fertilizer to the lawn rather than herbicide to the weeds.
DeGregori’s model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness. “In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” DeGregori says.
For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues. In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells; cancer cells are outcompeted and they die, or at least their population is held in check and remains insignificantly small.
But what happens when the tissue landscape changes? This brings us to the dinosaurs. Sixty-five million years ago, a warm, wet planet favored dinosaurs, though a few early mammals scurried among them. Then the giant meteor hit (among other environmental changes happening around this time), altering the basic dynamics of the ecosystem. It was this adjustment to the ecosystem that allowed furry and feathered, warm-blooded creatures to eventually dominate earth.
It seems as if new, successful species are produced by new, successful genetic changes. But in this example, as in cancer, individuals with these “new” genetics may already exist and it is changes to the ecosystem that allow them to flourish. Yet cancer biologists focus on how cancer risk factors like aging and smoking create new mutations, instead of focusing on how these contexts alter tissue landscapes and thus alter selection for already-existing mutations. Supporting this idea, DeGregori points out that studies modeling stem-cell pools show that selection pressure from the tissue landscape is more powerful than mutations at deciding the makeup of a population of stem cells.
“When the body changes due to aging, smoking, inherited genetic differences or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” DeGregori says.
Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer? It may not be that these mutations create accidental “super cells” that immediately run amok. Oncogenic mutations are often or always present in the body, but are kept at bay by selection pressures set against them. That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells, over time allowing the population of cancer cells to overcome that of healthy cells.
We can avoid some of these tissue changes by lifestyle choices, such as by not smoking. Unfortunately, we can’t put off aging forever. But there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways resist cancer better, longer.
- Andrii I. Rozhok, James DeGregori. Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proceedings of the National Academy of Sciences, 2015; 201501713 DOI: 10.1073/pnas.1501713112
Source: University of Colorado Anschutz Medical Campus. “Evolution, not just mutation, drives development of cancer: Solving ‘Peto’s Paradox,’ new model shows selection pressure of healthy tissue keeps cells with cancerous mutations in check.” ScienceDaily. ScienceDaily, 21 July 2015. <www.sciencedaily.com/releases/2015/07/150721134835.htm>.
Heat trapped below the surface will begin moving up kicking off a warming cycle
July 16, 2015
University of California – Los Angeles
A new study of ocean temperature measurements shows that in recent years, extra heat from greenhouse gases has been trapped in the subsurface waters of the Pacific and Indian oceans, thus accounting for the slowdown in the global surface temperature increase observed during the past decade, researchers say.
A new study of ocean temperature measurements shows that in recent years, extra heat from greenhouse gases has been trapped in the subsurface waters of the Pacific and Indian oceans, thus accounting for the slowdown in the global surface temperature increase observed during the past decade, researchers say.
A specific layer of the Indian and Pacific oceans between 300 and 1,000 feet below the surface has been accumulating more heat than previously recognized, according to climate researchers from UCLA and NASA’s Jet Propulsion Laboratory. They also found the movement of warm water has affected surface temperatures. The results were published July 9 in the journal Science.
During the 20th century, as greenhouse gas concentrations increased and trapped more heat on Earth, global surface temperatures also increased. However, starting in the early 2000s though greenhouse gases continued to trap extra heat, the global average surface temperature stopped climbing for about a decade and even cooled a bit.
In the study, researchers analyzed direct ocean temperature measurements, including observations from a global network of about 3,500 ocean temperature probes known as the Argo array. These measurements show temperatures below the surface have been increasing.
The Pacific Ocean is the primary source of the subsurface warm water found in the study, though some of that water now has been pushed to the Indian Ocean. Since 2003, unusually strong trade winds and other climatic features have been piling up warm water in the upper 1,000 feet of the western Pacific, pinning it against Asia and Australia.
“The western Pacific got so warm that some of the warm water is leaking into the Indian Ocean through the Indonesian archipelago,” said Veronica Nieves, lead author of the study and a UCLA researcher with the UCLA Joint Institute for Regional Earth System Science and Engineering, a scientific collaboration between UCLA and NASA’s Jet Propulsion Laboratory.
The movement of the warm Pacific water westward pulled heat away from the surface waters of the central and eastern Pacific, which resulted in unusually cool surface temperatures during the last decade. Because the air temperature over the ocean is closely related to the ocean temperature, this provides a plausible explanation for the global cooling trend in surface temperature, Nieves said.
Cooler surface temperatures also are related to a climatic pattern called the Pacific Decadal Oscillation, which moves in a 20- to 30-year cycle. It has been in a cool phase during the entire time surface temperatures showed cooling, bringing cooler-than-normal water to the eastern Pacific and warmer water to the western side. There currently are signs the pattern may be changing, with observations showing warmer-than-usual water in the eastern Pacific.
“Given the fact the Pacific Decadal Oscillation seems to be shifting to a warm phase, ocean heating in the Pacific will definitely drive a major surge in global surface warming,” Nieves said.
Previous attempts to explain the global surface temperature cooling trend have relied more heavily on climate model results or a combination of modeling and observations, which may be better at simulating long-term impacts over many decades and centuries. This study relied on observations, which are better for showing shorter-term changes over 10 to 20 years.
Pauses of a decade or more in Earth’s average surface temperature warming have happened before in modern times, with one occurring between the mid-1940s and late 1970s.
“In the long term, there is robust evidence of unabated global warming,” Nieves said.
Co-authors are Josh Willis and William Patzert of NASA’s Jet Propulsion Laboratory.
- V. Nieves, J. K. Willis, W. C. Patzert. Recent hiatus caused by decadal shift in Indo-Pacific heating. Science, 2015; DOI:10.1126/science.aaa4521
Source: University of California – Los Angeles. “Oceans slowed global temperature rise, until now: Heat trapped below the surface will begin moving up kicking off a warming cycle.” ScienceDaily. ScienceDaily, 16 July 2015. <www.sciencedaily.com/releases/2015/07/150716160652.htm>.
The Paperless Clinical Trial
As the world goes digital, why not clinical research? FDA has issued 2 critical guidance documents, one final on eSource and one draft onElectronic Informed Consent. There was also an FDA Webinar on eSource back in January, which is a must-see for all. Time for the industry to catch up. What is also gaining traction quite rapidly is the Electronic Trial Master File (eTMF). What a difference it makes to know where everything is. At Target Health, for 10+ years, we have been using Target Document as the eTMF and also have been generating Form FDA 3500A within our EDC system. As a result, there’s no need to hunt for pieces of paper and no need to do an SAE/database reconciliation at the end of the study. We have also been executing clinical trials with our web-based eSource solution, which is truly transformative.
Mountain Top View of the World
This picture was taken by our friend and colleague Brian Yarnell when he was on Quandary Peak, outside of Breckenridge Colorado, in the summer of 2013. Brian now joins James Farley, photographer extraordinaire, as a contributor to On Target.
Mountain Top View of the World©Brian Yarnell 2015
ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
‘Heading’ May Be Riskier For Girls Than For Boys
According to an article published in JAMA Pediatrics (13 July 2015), fewer girls suffer concussion, but the 1) ___ rate is higher for girls. The most severe injuries in high school soccer occur from “heading the ball,” but the risk seems to vary by gender, according to the results of a large longitudinal study of high school sports injuries. While a lower percentage of girls experience concussions from heading compared to boys (25.3% versus 30.2%), the concussion rate from heading is higher for girls (relative risk 15.1) than boys (RR 11.0). And the number is only growing. In the last nine years (2005-2006 to 2013-2014), concussion rates due to heading have increased for girls (P=0.03), but not boys (P=0.10).
While overall, contact with another player still comprises the vast majority of concussions in both genders (68.8% for boys and 51.3% for girls), 2) ___ were more likely to report concussion symptoms from “contact with a playing apparatus” (the ball) as opposed to contact with another player. These symptoms included:
1. Irritability (16.5% versus 8.3%, P<0.01)
2. Drowsiness (43.4% versus 30.7%, P<0.01)
3. Sensitivity to noise (34.1% versus 23.0%, P<0.01)
4. Sensitivity to light or visual disturbances (48.9% versus 39.3%, P=0.04)
Boys were more likely to report transient amnesia from contact with the ball compared to contact with another player (22.0% versus 6.9%, P<0.01). Girls reported a longer symptom resolution time than boys (P=0.02 and P=0.05, respectively), with an overall lengthier recovery time if the concussion was the result of contact with the 3) ___.
Jeffrey Bazarian, MD, professor, emergency medicine at the University of Rochester Medical Center in Rochester, N.Y., who was not involved in this study, said that this study confirmed recent research that girls have a higher rate of concussions than boys, and suggested that understanding this discrepancy could help reduce concussions in 4) ___. “Could this difference be due to different styles of play? For example, do girls head the ball more than boys? Is their heading technique poorer than boys? Does the ball spend more time in the air (and less on the ground) when girls play, compared to boys? Understanding difference in playing style might help us understand how to prevent concussions without eliminating 5) ___ from the game of soccer,” he said.
Overall, concussion rates have increased, regardless of gender. Both boys and girls reported an overall 6) ___ in concussion rates during the past nine years (P=0.002 and P=0.004, respectively), including similar increases in concussions sustained both during competition and practice. Examining overall concussion rates in nine high school sports, girls soccer ranked second, while boys soccer ranked fifth. Co-author Sarah K. Fields, JD, PhD, also of the University of Colorado Denver, told MedPage Today via e-mail that this study arose from her participation in a New York Times debate about the mechanisms of high school concussions in soccer. Comstock contributed data for the analysis, and afterwards, they decided they should write a scientific article on the topic. “In the discussion about banning heading among children under the age of 14, no one had really looked at what was 7) ___ the concussions,” she said. Fields said she was the most surprised about the large number of concussions occurring from player-to-8) ___ contact. “I’ve played recreational level soccer for 40 years and have been a fan of elite soccer for just as long, so I shouldn’t have been surprised by these proportions, but I was,” she said. “I’ve seen player to player concussions occur at all levels over that time, but seeing the numbers was still staggering for me.”
The study examined data from 100 schools in the National High School Sports-Related Injury Surveillance Study’s High School Reporting Information Online. Of the 1,393,753 athletic exposures (AEs) in girls sports, 627 were concussions, for a rate of 4.50 per 10,000 AEs. Of the 1,592,238 AEs in boys sports, 442 were concussions, for a rate of 2.78 concussions per 10,000 AEs. Limitations cited by the authors include that only schools with National Athletic Trainers’ Association-affiliated ATs were eligible to participate, as well as that AEs were based on units of participation rather than time. In addition, ATs only reported AEs of which they were aware. Bazarian also pointed out the study did not distinguish between which of the concussions occurred as the result of fair, legal play and which resulted from illegal plays. “If we knew that many of these heading-related concussions occurred during illegal plays, we might conclude that enforcing the existing 9) ___ — rather than eliminating heading — would be good first step toward reducing concussions,” he said. Fields said that 10) ___ should advise their patients and their parents about participation on teams where rules are closely enforced, and soccer is allowed to be a collision sport as opposed to a contact sport (like football). Comstock and colleagues agreed that reducing contact across phases of play would help prevent more concussions than simply banning heading. “It may be more culturally tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” they concluded.
This study was funded in part by grants from the Centers for Disease Control and Prevention. Research funding was also provided by the National Federation of State High School Associations, National Operating Committee on Standards for Athletic Equipment, DonJoy Orthotics, and EyeBlack. Source: R. Dawn Comstock, MD, University of Colorado Denver; MedPageToday
ANSWERS: 1) concussion; 2) girls; 3) ball; 4) soccer; 5) heading; 6) increase; 7) causing; 8) player; 9) rules; 10) pediatricians
Ann Preston and Marie Equi: American Physicians from the 1800s
Ann Preston MD (1813-1872)
Ann Preston, MD
Born in West Grove, Pennsylvania, as one of eight siblings, Ann Preston was raised as a Quaker by a Quaker minister Amos and his wife Margaret (nee Smith) Preston. Three of the children were girls, but Ann was the only one to survive until adulthood. She was educated in a local school then attended a boarding school in Chester, Pennsylvania. However, she had to return home to care for her mother, who was terminally ill.
Dr. Preston became a member of the temperance movement and the Clarkson Anti-Slavery Society. After her younger brothers were old enough to care for themselves, she worked as a schoolteacher. In 1849, she published a book of nursery rhymes, Cousin Ann’s Stories. By the 1840s, she became interested in educating women about their bodies and taught all-female classes on hygiene and physiology. She was privately educated in medicine by Nathaniel Moseley from 1847-1849. Unable to gain admittance to male medical school because of biases against women, she entered the Quaker-run Female Medical College of Pennsylvania when it first opened, where she was one of eight women awarded an MD in the first graduating class of 1852. Dr. Preston returned to the college the following year for postgraduate work, then ran a series of lectures on hygiene for women. Beginning in 1853 she was a professor of physiology and hygiene at the Female Medical College of Pennsylvania. During the American Civil War, the college was closed due to lack of financial support. Preston began to suffer from rheumatic fever and exhaustion at this time. She was confined to Pennsylvania Hospital for the Insane for three months to recuperate. After the college was re-opened, student Mary Putnam Jacobi was refused a medical degree by Edwin Fussel, even though she met the required qualifications. This resulted in a rift among the staff because most of them, including Dr. Preston, disagreed with the decision. Fussell resigned following the incident and Preston became dean of the college from 1866-1872. She was also the first woman to become the dean of a medical school, a position that allowed her to champion the right of women to become physicians. In 1867 the Philadelphia County Medical Society objected to the practice of medicine by women. Ann Preston’s response in part was we must protest against the injustice which places difficulties in our way, not because we are ignorant or incompetent or unmindful in the code of medical or Christian ethics, but because we are women. Preston’s defense disarmed much of the adverse criticism. In 1871 she suffered from an attack of acute articular rheumatism, which left her in a weakened state. She suffered a relapse the following year and died on April 18, 1872. Marshall, Clara. The Woman’s Medical College of Pennsylvania. An historical outline.
Marie Equi, MD
Marie Diana Equi MD, (1872-1952)
Dr. Marie Equi (April 7, 1872 -July 13, 1952) was an early American medical doctor in the American West devoted to providing care to working-class and poor patients. She regularly provided birth control information and abortions at a time when both were illegal. She became a political activist and advocated civic and economic reforms, including women’s right to vote and an eight-hour workday. After being clubbed by a policeman in a 1913 workers’ strike, Equi aligned herself with anarchists and the radical labor movement. Equi was a lesbian who maintained a primary relationship with Harriet Speckart for more than a decade. The two women adopted an infant and raised the child in an early example of a same-gender alternative family. For her radical politics and same-gender relations, Equi battled discrimination and harassment. In 1919, Equi was convicted under the Sedition Act for speaking against U.S. involvement in World War One. She was sentenced to a three-year term at San Quentin California State Prison. She was the only known lesbian and radical to be incarcerated at the prison.
Equi was the daughter of John Equi, an Italian immigrant, and Sarah Mullins, an Irish immigrant. She was born the fifth child and fifth daughter in a large working-class family in New Bedford, the former whaling capital of the world that became a textile manufacturing powerhouse during Equi’s early years. She attended New Bedford High School for one year before dropping out to work in a textile mill to support herself. In 1892 Equi escaped a grim future in the mills and joined her high school girlfriend, Bessie Holcomb, on an Oregon homestead along the Columbia River. In the late 19th century, little was known or publicly discussed about same-gender affairs between women. Instead in some spheres of society in the United States, people recognized romantic friendships among women. Wealthy and professional women at the time undertook what were called Boston Marriages. These associations entailed varying degrees of emotional and affectionate intimacy between two women and, often, intimate activity as well. Marie Equi once remarked that as a young woman she had spurned the interests of a young man, and she expressed little interest in a heterosexual pairing or marriage. Equi’s lengthy relationship with Bessie Holcomb, from 1892 until 1901, was dissimilar from the Boston Marriages adopted by upper-class women due to Equi’s working-class background. Equi lived much of her adult life with other women, but she was never a separatist. She treated male patients in her medical practice, and she worked closely with men in many of her political activities. She undertook the longest lesbian relationship of her life in 1905 after meeting a younger woman, Harriet Speckart, the niece of Olympia Brewing Company founder Leopold Schmidt. Speckart’s family was vehemently opposed to the two women’s relationship, and Speckart battled in the courts for years with her mother and brother to receive her rightful inheritance. After ten years of sharing a life together, Equi and Speckart adopted an infant girl, Mary, because Speckart wanted to raise a child. As an adult, Mary recalled that she had called Speckart ma and Equi da since everyone called Equi Doc. In later years the two women separated but remained close until Speckart’s death in 1927.
Equi also became involved with other prominent, professional women. When birth control advocate Margaret Sanger lectured in Portland in 1916, Equi became smitten with her. She later wrote letters to Sanger that referred to intimacy between them during Sanger’s earlier visit. Archivist Judith Schwartz has described Equi’s letters to Sanger as love letters. During Equi’s anti-war activity prior to and during World War I, she became romantically involved with the Irish nationalist Kathleen O’Brennan. Although Equi lived openly with several women, she is not known to have publicly spoken of her lesbianism and same-gender desires. Equi and Holcomb lived a quiet life as close companions in a small house on several rocky acres outside the small city of The Dalles, Oregon. On July 21, 1893 a local newspaper, The Dalles Times-Mountaineer, reported the sensational ruckus earlier that day that drew crowds of merchants and shoppers to the center of town. Equi paced back and forth in front of the office of the Reverend Orson D. Taylor, a land developer and also the superintendent of the Wasco Independent Academy. Taylor had reneged on paying Holcomb her full salary for teaching at the institution. Frustrated over the mistreatment of her companion, Equi horsewhipped Taylor when he tried to escape from his office. Many people in The Dalles regarded Taylor a crook who pedaled fraudulent land deals, and they applauded Equi’s assault. They later held a raffle for the whip and gave the proceeds to the two women. The event became the public’s first exposure to Equi’s bold defense of justice. In 1897 the pair moved to San Francisco, California where Equi began studying medicine. She completed two years of coursework, first at the Physicians & Surgeons Medical College and then at the University of California Medical Department. She relocated to Portland, Oregon – without Bessie Holcomb – and completed her studies at the University of Oregon Medical Department in 1903. She was among the first 60 women to obtain medical licenses in the state. In the aftermath of the 1906 San Francisco earthquake and fire, she joined a group of doctors and nurses to provide medical care to people stricken in the disaster, earning her a commendation from the United States Army.
An assistant with a patient at Equi’s Portland, Oregon office
Marie Equi became one of the first 60 women to become a physician in Oregon. She established a general medicine practice in Portland in 1905 with an emphasis on health concerns of women and children. Her role as a physician became widely known to the public once she volunteered to join a group of doctors and nurses who provided medical care to people stricken during the 1906 San Francisco earthquake and fire. That disaster was the largest natural calamity with the most deaths for nearly one hundred years. At the time, the federal government was not prepared to provide the kind of massive relief needed. Equi’s courageous volunteer work was hailed by California’s Governor, San Francisco’s Mayor, and the U.S. Army which awarded her a medal and a commendation.
At some point between 1905 and 1915, Equi began to provide abortions and did so without regard for social class or status. She often charged wealthy women more for the procedure to help cover the costs of poor patients. Although city and state authorities often tried to halt the practice of abortion with prosecutions, Equi never faced legal consequences for her services. Unlike several of her colleagues, she retained her general medical practice and did not focus on abortions alone. Equi was an active member of Portland’s Birth Control League and helped disseminate information about birth control when such activity was illegal. When Margaret Sanger visited Portland in 1916, the authorities arrested her, Equi, and other women and men who distributed Sanger’s Family Limitation booklet. Equi and Sanger spent time in jail together before their trial. The judge found them all guilty, ordered fines for the men (and then suspended them), and no fees for the women. Equi continued her birth control work.
Crowd of women in Portland, Oregon register for jury duty after gaining right to vote, 1912
During the Progressive Era, generally 1895 to 1920, Oregon adopted civic and political reforms that became a model for the nation, including the initiative and referendum process, recall of elected officials, and direct election of U.S. Senators. Equi worked in several campaigns to secure women’s right to vote in Oregon, and celebrated victory in 1912 when women gained suffrage in the state. She also helped organize campaigns for an eight-hour workday, guaranteed state funding for public education, and improvements in working conditions for laborers in the factories, farms, and forests. She registered as a voter in 1913 and declared her affiliation with the Progressive Party. In 1913 Equi visited the site of a strike by cannery workers in east Portland at the Oregon Packing Company. The workers, primarily women, protested poor working conditions, uncertain work hours, and a wage of only five to eight cents an hour. Once Socialists and members of the Industrial Workers of the World (IWW) joined the strike in support of the women, the struggle expanded to include the right to free speech. Equi joined the protest and became one of its leaders, partly due to her professional stature as a physician. After days of picketing, the police stormed the strikers. Equi was clubbed by an officer after she became enraged that a 30-year-old pregnant woman had been dragged away by the police. After several more days, the strike ended on terms unsatisfactory to the women workers. For Equi, the police brutality she witnessed had radicalized here, and she turned from her earlier advocacy of Progressive reforms. Equi became an influential voice in Portland’s unemployment crisis in 1913-1914. She regularly marched with jobless men, demanded better working conditions for them, and she engaged in the IWW’s free speech fights and support for lumber workers in the region’s forests. She declared herself a Radical Socialist and an anarchist, and she aligned herself with the IWW. During the increasingly contentious times leading to the U.S. entering World War I, Equi objected to the nation’s war preparedness campaigns. She believed the war efforts represented a grab for profits by capitalists and an imperialistic adventure for the government. Huge preparedness parades were held in all major U.S. cities in 1915 and 1916.
Portland entered a phase of hyper-nationalism, and Equi became more of a political outsider than before. She protested a pre-war campaign in downtown Portland and unfurled a banner reading Prepare to die, workingmen, JP Morgan & Co. want preparedness for profit. She was attacked by others in the march, and a fight ensued, leading to her arrest. Equi continued to protest once the US entered the war in 1917. The US government believed that Equi was a dangerous threat to national security and charged and convicted her of sedition under the newly revised Espionage Act. Equi attempted appeals to the higher courts, but her arguments were rejected. At the last minute before imprisonment, President Woodrow Wilson commuted her three-year sentence to one year and a day. Equi served her time in San Quentin State Prison in northern California, beginning her term on October 19, 1920 as inmate number 34410. She was forty-eight years old. She shared the women’s quarters with thirty-one other inmates, many of them serving sentences for homicide, theft, and performing abortions. Equi was the only political among them. Equi’s health suffered while in prison with flare-ups of tuberculosis that she had contracted in childhood. She maintained her morale as best she could with the moral support from many visitors and letter writers. She sought early release through a pardon or parole, but it appeared that the US Attorney General repeatedly blocked any leniency for her. Equi left San Quentin on August 9, 1921 with a reduced sentence due to good behavior. She had served nearly ten months. Americans tried to forget the war years, in the 1920s, but they nevertheless were swept into a heightened fear of radicals, labor unionists, and communists that became known as the Red Scare. Equi re-entered public life with her political comrades imprisoned or greatly restricted from protest activity. Equi returned to her medical practice.
For lengthy periods between 1926 and 1936 Equi invited the IWW leader Elizabeth Gurley Flynn to live with her and help care for Equi’s daughter. Mary Equi had come to live with her mother once Harriet Speckart died of a brain tumor in 1927. Elizabeth Flynn suffered serious health problems, including exhaustion from overwork and depression from political setbacks. In 1930 Equi suffered a heart attack, sold her medical practice, and asked Flynn to assist her for several more years. Finally Flynn retreated to the East and resumed her work. She became a national leader of the Communist Party USA. Equi led a quiet life following the departure of Flynn and then the elopement of her daughter. Radical and labor leaders continued to revere her for her courage and compassion during earlier decades; several visited her at her house.
In 1950 Equi fractured her hip in a fall and spent a year at Good Samaritan Hospital in Portland and then to a nursing home outside Portland near the town of Gresham. She died at Fairlawn Hospital on July 13, 1952 at 80 years of age. Her obituaries ran in newspapers across the country, including those in Portland, New Bedford, Massachusetts, and in the New York Times. Equi’s activist friend Julia Ruttila described her as a woman of passion and conviction (and) a real friend of the have-nots of this world.
Futuristic Brain Probe Allows for Wireless Control of Neurons
There are electrical circuits that control a variety of disorders including stress, depression, addiction, and pain. Typically, scientists who study these circuits have to choose between injecting drugs through bulky metal tubes and delivering lights through fiber optic cables. Both options require surgery that can damage parts of the brain and introduce experimental conditions that hinder animals’ natural movements. According to an article published online in Cell (16 July 2015), a study has shown that the path a mouse walks can be wirelessly determined with a press of a button. The authors created a remote controlled, next-generation optofluidic implant that allows neuroscientists to inject drugs and shine lights on neurons deep inside the brains of mice. The device is made out of soft materials that are a tenth the diameter of a human hair and can simultaneously deliver drugs and lights. With a thickness of 80 micrometers and a width of 500 micrometers, the optofluidic implant is thinner than the metal tubes, or cannulas, scientists typically use to inject drugs. When the authors compared the implant with a typical cannula they found that the implant damaged and displaced much less brain tissue.
For the study, the device’s drug delivery potential was tested by surgically placing it into the brains of mice. In some experiments, it was shown that circuits could be precisely mapped by using the implant to inject viruses that label cells with genetic dyes. In other experiments, the authors made mice walk in circles by injecting a drug that mimics morphine into the ventral tegmental area (VTA), a region that controls motivation and addiction. The authors also tested the device’s combined light and drug delivery potential when they made mice that have light-sensitive VTA neurons stay on one side of a cage by commanding the implant to shine laser pulses on the cells. The mice lost the preference when the device was directed to simultaneously inject a drug that blocks neuronal communication. In all of the experiments, the mice were about three feet away from the command antenna.
The authors fabricated the implant using semi-conductor computer chip manufacturing techniques. It has room for up to four drugs and has four microscale inorganic light-emitting diodes. An expandable material was installed at the bottom of the drug reservoirs to control delivery. When the temperature on an electric heater beneath the reservoir rose, then the bottom rapidly expanded and pushed the drug out into the brain.
Mediterranean Diet and Age-Related Cognitive Decline
Oxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline, a strong risk factor for development of dementia. Epidemiologic studies suggest that a Mediterranean diet, an antioxidant-rich cardioprotective dietary pattern, delays cognitive decline, but clinical trial evidence is lacking. As result, a study published in JAMA Internal Medicine (2015;175:1094-1103) was performed to investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet.
The study was a parallel-group randomized clinical trial of 447 cognitively healthy volunteers from Barcelona, Spain (233 women [52.1%]; mean age, 66.9 years), at high cardiovascular risk were enrolled into the Prevencion con Dieta Mediterranea nutrition intervention trial from October 1, 2003, through December 31, 2009. All patients underwent neuropsychological assessment at inclusion, randomly assigned to a Mediterranean diet supplemented with extra virgin olive oil (1 L/wk), a Mediterranean diet supplemented with mixed nuts (30 g/d), or a control diet (advice to reduce dietary fat). Retesting was offered at the end of the study. The main outcomes measures were the rates of cognitive change over time based on a neuropsychological test battery including: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Color Trail Test.
Follow-up cognitive tests were available in 334 participants after intervention (median, 4.1 years). In multivariate analyses adjusted for confounders, participants allocated to a Mediterranean diet plus olive oil scored better on the RAVLT (P=0.049) and Color Trail Test part 2 (P=0.04) compared with controls; no between-group differences were observed for the other cognitive tests. Similarly adjusted cognitive composites (mean z scores) for changes above baseline of the memory composite were 0.04 for the Mediterranean diet plus olive oil, 0.09 (P=0.04 vs controls) for the Mediterranean diet plus nuts, and -0.17 for the control diet. Respective changes from baseline of the frontal cognition composite were 0.23 (P=0.003 vs controls). Changes from baseline of the global cognition composite were 0.05 (P=0.005 vs controls) for the Mediterranean diet plus olive oil, -0.05 for the Mediterranean diet plus nuts, and -0.38 for the control diet. All cognitive composites significantly (P<0.05) decreased from baseline in controls.
According to the authors, in an older population, a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function.
FDA Blog: More Collaboration, Research Needed to Develop Cures
The following is extracted from FDA Voice, authored by Robert Califf, M.D. FDA’s Deputy Commissioner for Medical Products and Tobacco.
The U.S. Food and Drug Administration’s drug approval process is the fastest in the world, which means Americans typically have first access to new drugs when they are demonstrated to be safe and effective. But according to Dr. Califf, even as our agency has transformed the approval process – approving 51 new molecular entities and biological products last year alone, including more new orphan drugs for rare diseases than in any previous year – drug discovery and development is not keeping pace for many diseases.
In many cases, what’s holding back progress is a lack of understanding of the biology of disease, as outlined in a new report FDA has recently released that compares diseases where there is a robust pipeline of new therapies with certain diseases that have few known treatments or cures. For instance, when it comes to cancer, HIV/AIDS, and other viral infections, decades of intense research have given the scientific community and the FDA critical insight on how to develop effective treatments. Ongoing research has led to the discovery ofbiomarkers, which are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or response to a therapeutic intervention. Some types of biomarkers give insight on the genetic and metabolic characteristics that alter patients’ responsiveness to particular drugs, and others give insight into whether drugs in development are likely to work. This deep knowledge has resulted in important breakthroughs, rapid drug development and speedy FDA approvals.
While additional research is needed for all diseases, the paucity of reliable biomarkers in some diseases highlights the critical need for more research if we are to make much needed progress. Examples include Alzheimer’s and many rare diseases, as we outline in the new report. In these cases, the scientific community still lacks basic information about what causes these diseases and how they can be slowed and treated. When research does not offer answers to important scientific questions, cures cannot be developed. And when viable cures are not in the pipeline, focusing on regulation will not improve the situation, since FDA can only approve therapies with evidence for safety and effectiveness.
Once key scientific questions are answered, a variety of tools can be used to reduce the length and cost of initial clinical trials for drug approval for these disease areas, and FDA can provide guidance to industry including advice on how to develop additional reliable biomarkers. For instance, the efficiency and predictability of clinical drug development has been improved by developing tools such as biomarkers and surrogate endpoints – markers of drug effect that do not directly represent an improvement in how a patient feels or functions, but are reasonably likely to predict a clinical benefit. Thus, for example, lowering a patient’s blood pressure can be used as a surrogate for the clinical benefit of preventing heart attack. Such tools have modernized clinical trial designs and may dramatically reduce the length and cost of drug development. They also can help target drugs to specific patients who can benefit most, thereby limiting the number and size of clinical trials.
FDA will continue to work to speed patient access to therapies shown to be safe and effective through existing programs that allow for expedited review, development, and approval of certain medical products. To encourage innovation, FDA will also will continue to work with other government agencies and the healthcare community, including members of patient groups, academia, and industry. It will take a collaborative effort to improve our nation’s understanding of certain diseases and to translate any resulting scientific discoveries into cures.
Mozzarella-Stuffed Eggplant Balls with Whole Wheat Pasta, Marinara & Freshly Grated Parmesan
Your kitchen will smell so-o good while you cook this fabulous veggie meal. ©Joyce Hays, Target Health Inc.
Ingredients for Eggplant Balls
2 Tablespoons extra-virgin olive oil, divided
1 large or 2 medium eggplants, peeled and cubed
1 shallot, finely minced
1 cup fresh mozzarella shredded
1 cup baby spinach, cut in ribbons
1/2 cup jicama, chopped (you can buy it chopped)
3 fresh garlic cloves, minced
Pinch black pepper
Pinch chili flakes
1 Tablespoon fresh parsley, chopped
1 cup Panko + 1/4 cup more for rolling
Marinara Sauce Ingredients or Buy it
2 teaspoons extra virgin olive oil or canola oil
2 shallots, minced
3 garlic cloves, minced
1-28 oz. can of Cento crushed tomatoes
1-28 oz. can of Cento whole or diced tomatoes
Pinch black pepper
Pinch chili flakes
1 teaspoon fresh basil, chopped
1 teaspoon fresh oregano, chopped
1 teaspoon fresh parsley, chopped
Make the marinara sauce first and the pasta (any pasta you wish) and set aside
1. In a large-saucepan, heat the oil over medium-high heat. Add the shallots and saute them for 3 minutes. Add the garlic and saute for about 1 minute. Next, add the crushed tomatoes to the saucepan. Then add the whole or diced tomatoes. If you are using whole tomatoes, gently crush them with a potato masher.
2. Add the salt, pepper, basil, oregano and parsley to the sauce. Stir and let cook. When the sauce starts to bubble, lower the heat to medium-low and cover the pan. Let cook for at least 20 minutes. Taste and adjust for seasonings. Set aside.
First cook the eggplant cubes until soft and brown ©Joyce Hays, Target Health Inc.
Add the kale sprouts or spinach (or your favorite green veggie) to the eggplant cubes and cook them together. ©Joyce Hays, Target Health Inc.
Make the Eggplant Balls
In a large skillet, heat 1 Tablespoon of the oil over medium-high heat. Add the eggplant cubes and saute until they are browned and very soft (8 minutes); then add the kale sprours or spinach to the eggplant cubes and cook for another 10-12 minutes. Make sure they are super-soft because they need to be mashed. You could also roast the eggplant to make it soft, but in the summer, the oven makes the room so hot, even with the a/c on. When you take the eggplant out of the pan, don’t wash the pan. Save any liquid in the pan for later.
Pulsing the cooked eggplant and spinach, then everything else ©Joyce Hays, Target Health Inc.
Transfer the eggplant to the food processor bowl. Mash the eggplant, until there are no whole pieces left and add the spinach and pulse it along with the eggplant. If you don’t have a food processor, use a potato masher. If using a food processor, once the eggplant is all completely mashed into mush, add the shallot, cheese, garlic, salt, pepper and parsley, right into the food processor. Pulse a few times. Be sure all these ingredients are mixed well, into the eggplant.
Mixing ingredients and adding the Panko ©Joyce Hays, Target Health Inc.
1. If you are using a food processor, transfer the eggplant mixture to a bowl; use a spatula to get all the eggplant out.
2. Before adding the bread crumbs, add the egg (whisked ahead of time) and the jicama to the eggplant and stir it in so it’s well distributed in this mixture.
3. Next add the bread crumbs to the eggplant mixture. Don’t add them all at once; you want to feel the mix and see whether you need a whole cup. First add 1/2 cup of bread crumbs and mix it.
4. The best way to mix it, is wet one hand and use it (keep the other hand clean & dry) to gently mix the crumbs into the eggplant. You will probably need more crumbs so add another 1/4 cup and mix it again. You want the consistency to feel firm, so it will hold up as a veggie ball. If it feels too moist, add the last 1/4 cup of bread crumbs. If you end up using all the crumbs, that’s fine.
Here eggplant balls have been formed and rolled in Panko, now ready to cook. ©Joyce Hays, Target Health Inc.
Put the eggplant mixture into the fridge for about 30 minutes. Don’t skip the refrigerator step. Take the bowl out of the fridge and using a spoon, scoop up some of the eggplant mixture and roll it into a ball with your hands. It should be the size of a golf ball. Roll it until it feels sturdy. Place it on a plate and continue making veggie balls until you use up all the eggplant mix. Spread the remaining 1/4 cup bread crumbs onto a plate and roll each veggie ball in the crumbs.
Cooking the eggplant balls ©Joyce Hays, Target Health Inc.
Heat the remaining oil in a large skillet over medium-high heat. Add the eggplant balls to the skillet and fry them. Depending on the size of your skillet, you may need to fry them in batches. Make sure the veggie balls brown on all sides. The way to do this is to pull the pan back and forth by the handle, which makes the veggie balls roll around. By doing this, it covers all the sides better than trying to turn them with a utensil. When you use a spatula, there’s a tendency to flatten the veggie balls. When they are browned, transfer the eggplant balls to a paper towel-lined plate and keep covered and warm. If you have a warming drawer, keep your marinara sauce and pasta there, covered until ready to serve.
If you’re ready to serve, and need to warm up the marinara sauce and pasta, turn a low flame on under the marinara sauce and your pasta. Get out a nice serving dish and arrange the eggplant balls and everything else on it and serve, with some extra freshly grated parmesan. You could consider starting with a salad, which is what we did, along with a lovely chilled New Zealand white wine, Cloudy Bay.
Everything on this serving dish can be enough for a meal; however, if you crave more, all of the above will go well with fish, poultry and meat. We would suggest a white wine with the fish and poultry; however, if you want a good red, for all foods, Hall cabernet sauvignon from Napa, is that wine.
The eggplant balls is a recipe I have experimented a lot with. First, with no greens added, another time with different amounts of garlic, another time with scallions and not shallots. The final experiment is the recipe in this newsletter. We think it’s absolutely delicious. Its fun and a real challenge to get meatless dishes to taste as good, if not better than those with meat type protein.
For dessert we had strawberry cake, a new recipe that needs to be worked on more, before shared in the newsletter.
This weekend we saw the show that won a Tony for best musical, Fun Home. This most celebrated Broadway musical of the year is based on Alison Bechdel’s best-selling graphic memoir, Fun Home (Pulitzer Prize nominee) features music by Jeanine Tesori, book and lyrics by Lisa Kron and direction by Sam Gold, all of whom won 2015 Tony Awards for their work on this production. We’ve seen many plays directed by Sam Gold, and he is a person of interest in the New York theater scene. With good reason this production won so many awards. The subject is extremely hard to present to a general audience. Not only does it deal with a highly dysfunctional family and the way a child is molded by it, as a result, but the script goes back and forth in time on a stage that is in the round (Circle In The Square Theater on Broadway) plus all of this is set to music. This production succeeds brilliantly to all the challenges. You leave the theater, deeply moved. The sets, direction, acting, script, music, lighting are all first rate. I first sat down, thinking negatively that this show was going to be disappointing. It was just the opposite. I thought that being a musical would be banal. It was just the opposite. Music was exactly the right approach with which to present such a difficult subject. Music softens the edges of a harsh reality that no doubt exists in every town, everywhere, and now, bravely presented in a palatable highly artistic form. Theater is such a great communicator. This is worth seeing.
Icy cold Cloudy Bay sauvignon blanc, from New Zealand ©Joyce Hays, Target Health Inc.
From Our Table to Yours!
July 16, 2015
Simon Fraser University
When studying the proteins that underlie electrical signaling in the heart, and subjecting those proteins to conditions that are similar to the stress of exercise, researchers have found that in some cases, temperature can cause changes that trigger arrhythmia.
Scientists, including SFU professor Peter Ruben, have found that sudden death caused by cardiac arrhythmia can be triggered by changes in body temperature. The study is published in the Journal of Physiology.
The soccer player who drops dead in the middle of a game, or the infant who dies during sleep is often a victim of arrhythmia. Sudden cardiac death has several causes, including inheritable mutations in our DNA affecting structure and function of proteins in the heart. Simon Fraser University professor Peter Ruben found when studying the proteins that underlie electrical signaling in the heart, and subjecting those proteins to conditions that are similar to the stress of exercise, in some cases, temperature can cause changes that trigger arrhythmia.
According to Ruben, a professor in the Department of Biomedical Physiology and Kinesiology (BPK), when muscle cells in our hearts contract rhythmically and in a well-coordinated way, the heart efficiently pumps blood throughout our bodies. When the rhythmic pumping action is disrupted by an arrhythmia, our hearts can no longer distribute blood.
In extreme cases, this leads to sudden cardiac death. He adds: “The electrical signal behind muscle contraction is produced by tiny protein molecules in the membrane of our heart cells. Temperature fluctuations modify the way all proteins behave, but some DNA mutations can make proteins especially sensitive to changes in temperature.”
Ruben’s team found a protein that is far more sensitive to temperature than normal. When normal body temperature goes up for example, during exercise, or goes down during sleep, the affected protein no longer functions normally. The disrupted protein function causes the electrical signal in our heart to become erratic, triggering an arrhythmia and, potentially, sudden cardiac death.
The DNA mutation that creates more temperature-sensitive proteins is very rare, but it can produce deadly results when combined with another arrhythmia trigger, such as changes in the acid content of our blood that occur normally as a by-product of exercise and sleep, particularly sleep apnea.
“For many years, we have studied sodium channels, the proteins in our hearts that produce electrical signals. An earlier study of ours found that temperature changes are a trigger for some seizure disorders. We imagined that cardiac arrhythmias are like seizures and wondered whether they might share the same triggers.”
Ruben notes that with this new knowledge, people can examine their family histories and, if sudden cardiac death is part of that family history, or if they suffer from unexplained fainting, they can seek medical advice. Through a combination of electrocardiograms, genetic screening, and lifestyle management, some tragic deaths caused by cardiac arrhythmia may be prevented.
- Mena Abdelsayed, Colin H. Peters, Peter C. Ruben. Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants. The Journal of Physiology, 2015; DOI: 10.1113/JP270139
Source: Simon Fraser University. “Body temperature may trigger sudden cardiac death.” ScienceDaily. ScienceDaily, 16 July 2015. <www.sciencedaily.com/releases/2015/07/150716101526.htm>.