The researchers also found that certain molecules, when added to cancer drugs, can prevent chromosome shattering from occurring in a discovery that may be useful to pathologists and oncologists
Anatomic pathologists who diagnose tissue and closely monitor advances in cancer diagnostics and therapy will be interested in a recent study into how a mutational process known as chromothripsis (chromosome shattering) can promote cancer cell growth in humans and increase resistance to cancer drug therapies.
The study, which was published in the journal Nature, titled, “Chromothripsis Drives the Evolution of Gene Amplification in Cancer,” provides insights into how cancer cells can adapt to different environments and also may suggest potential solutions to drug resistance among cancer patients.
Led by researchers from the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, the discovery could open up a new field in cancer diagnostic testing, where the pathology laboratory analyzes a cancer patient’s tumor cells to determine where chromosomal damage exists. This knowledge could then inform efforts to repair damaged chromosomes or to identify which therapeutic drugs would be most effective in treating the patient, a key element of precision medicine.
“Drug resistance is the most problematic part of cancer therapy. If not for drug resistance, many cancer patients would survive,” said Ofer Shoshani, PhD (above right) postdoctoral fellow at the Cleveland Lab at UC San Diego School of Medicine and the study’s first author, in a news release. He’s shown with Don Cleveland, PhD (above left), head of the Cleveland Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, another author of the study. Cleveland is also Chair of the Department of Cellular and Molecular Medicine, and Distinguished Professor of Cellular and Molecular Medicine, Medicine, and Neurosciences at UC San Diego School of Medicine. (Photo copyright: Ludwig Institute for Cancer Research.)
Shattered Chromosomes
Chromosomes that undergo chromothripsis shatter or fragment into several pieces and then are stitched back together by a DNA repair processes. However, not all of the fragments make it back into the repaired chromosome, and this can be a problem.
“During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order,” Shoshani told Genetic Engineering and Biotechnology News (GEN News). “Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called double minutes.”
Studies have shown that up to half of all cancer cells contain cancer-promoting ecDNA chromosome fragments.
Some Cancer Drugs Could be Fueling Drug Resistance
To perform their study, the UC San Diego/Ludwig scientists sequenced entire genomes of cancer cells that had developed drug resistance. Their research revealed that chromothripsis prompts and drives the formation of ecDNA and that the process can also be induced by some chemotherapeutic drugs. The researchers also discovered that the particular type of damage these drugs may cause can provide an opening for ecDNA to reintegrate back into chromosomes.
“We show that when we break a chromosome, these ecDNAs have a tendency to jump into the break and seal them, serving almost like a DNA glue,” Shoshani said in the news release. “Thus, some of the very drugs used to treat cancers might also be driving drug resistance by generating double-stranded DNA breaks.”
Preventing DNA Shattering and Reducing Drug Resistance
The scientists also discovered that ecDNA formation could be halted by pairing certain cancer drugs with molecules that prevent DNA shattering from occurring in the first place, thus reducing drug resistance.
“This means that an approach in which we combine DNA repair inhibitors with drugs such as methotrexate or vemurafenib could potentially prevent the initiation of drug resistance in cancer patients and improve clinical outcomes,” Shoshani said.
“Our identifications of repetitive DNA shattering as a driver of anticancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome,” Don Cleveland, PhD, Head of the Cleveland Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and one of the authors of the paper, told GEN News.
This research from the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research is the latest example of how scientists have gained useful insights into how human genomes operate. More research and clinical studies are needed to solidify the advantages of this study, but the preliminary results are promising and could lead to new cancer diagnostics and therapies.
Government prosecutors allege destruction of LIS database and point to Holmes’ extravagant lifestyle as evidence of fraud motive
There is a new twist in the federal criminal fraud trial of Elizabeth Holmes, co-founder and former CEO of now defunct clinical laboratory testing company Theranos. Once again, the trial has been delayed. In the meantime, however, dueling court filings between prosecutors and defense lawyers have shed additional light on the allegations against Holmes and co-defendant Ramesh Balwani, the company’s chief operating officer. The revelations will be of interest to medical laboratory leaders.
According to The Mercury News, United States District Judge Edward J. Davila cited the ongoing COVID-19 pandemic in his December 18 ruling that postponed the start of Holmes’ trial to July 13, 2021.
In his ruling, Judge Davila wrote, “The court notes sadly, the impact on our lives is grim. California is in the midst of an unprecedented surge in cases and hospitalizations.”
The judge also noted the prospects for widespread public vaccination in the coming months. “All of this supports continuing the trial [of Holmes] to a time when our community is safer,” he added. “The court recognizes that a continuance of the trial will cause great inconvenience to victims who would like their day in court, as well as Defendant, who wishes a speedy opportunity to defend against the charges. All of these rights are important, but paramount to the court is the safety and health of the community.”
On February 9, Law360 reported that Balwani’s trial was delayed even further, with jury selection now set to begin on January 11, 2022.
Wall Street Journal Exposé of Theranos and its Flawed Clinical Lab Testing
In “Elizabeth Holmes: The Breakthrough of Instant Diagnosis,” the Wall Street Journal (WSJ) put Holmes squarely in the public eye. It could be credibly asserted that the paper’s fawning coverage helped boost her credibility when no one knew who she was. Thus, it is ironic that just two years later it was the WSJ that, in a series of articles, exposed the alleged misrepresentation and fraud committed by Holmes, Balwani, and Theranos.
By 2015, the company had a stock valuation of $9 billion, but it all came crashing down after WSJ investigative journalist John Carreyrou revealed serious problems with the company’s management and technology.
In a public notification from the US Attorney’s Office Northern District of California, the government alleged that Holmes and former Theranos president Balwani promoted the company’s blood-testing technology despite knowing that it was likely to produce unreliable results.
The defendants now face 12 federal felony counts related to wire fraud. They have pleaded not guilty. According to The Mercury News, if found guilty of all charges, “Holmes faces a potential 20-year prison sentence, up to $2.75 million in fines, and possible restitution to investors the government alleges lost more than $700 million.”
Elizabeth Holmes (above), former CEO of now defunct clinical laboratory testing company Theranos, will now stand trial starting in July. Due to risk of infection from the SARS-CoV-2 coronavirus, jurors will be required to wear masks and to socially distance during the trial, CNBC reported. What will be of great interest to clinical laboratories are statements by federal prosecutors that testing data stored on the company’s laboratory information system was destroyed before it could be accessed by investigators, even though it had been subpoenaed months earlier by a federal grand jury. (Photo copyright: Forbes/Yichuan Cao/NurPhoto via Getty Images.)
Missing Clinical Laboratory Data
Though the trial has been delayed, attorneys on both sides have been busy. Last November, after failing to have the charges dismissed, defense attorneys filed a flurry of motions seeking to exclude much of the government’s evidence, The Mercury News reported. This included expert witnesses, testimony about inaccurate test results, and numerous news articles about the company and its tests.
Prosecutors responded to the motions in January, further illuminating their case while providing more fodder for media coverage.
In a January 11 filing [doc-682], the government alleged that a Theranos laboratory information system (LIS) containing patient test results and quality control data was destroyed “on or about August 31, 2018—three months after a federal grand jury issued a subpoena requesting a working copy of this database.” News of the allegation was first reported by The Register, a UK-based IT publication.
Previously, the prosecutors alleged, Theranos, with assistance from an IT contractor, had provided a backup copy of the database to the government but without a password needed for decryption. “All subsequent efforts by the government to access the data on this hard drive have failed,” even with assistance from a computer forensics expert, they wrote.
Then, the original database was permanently destroyed in August when Theranos moved out of its facility in Newark, Calif., the government alleged in its filing. “On or about August 31, 2018—three months after a federal grand jury issued a subpoena requesting a working copy of this database—the LIS was destroyed. The government has never been provided with the complete records contained in the LIS, nor been given the tools, which were available within the database, to search for such critical evidence as all Theranos blood tests with validation errors,” the filing read.
The January 11 filing was in response to a Theranos motion [doc-563] seeking to exclude evidence of “anecdotal test results.”
“The data disappeared. Defendant should be barred from arguing the government’s case is anecdotal when Theranos (and others) destroyed this data,” the prosecutors argued.
Furthermore, prosecutors wrote, “the government’s case is hardly ‘anecdotal.’ The reliability and accuracy problems in Theranos’ clinical lab were well-documented when the Centers for Medicare and Medicaid Services (CMS) investigated the lab, discovered the accuracy and reliability problems, and determined Theranos could not safely administer its tests on patients. Whistleblowers will also testify about Theranos’ accuracy and reliability problems. And patients themselves experienced these problems, receiving incorrect results that affected their treatment and deprived them of the benefit of the purportedly reliable blood tests for which they had paid.”
And Then There’s Her Lifestyle
Prosecutors also claimed in their filing that Holmes’ activities—which included “travel on private jets, stays in luxury hotels, and access to multiple assistants … [who] handled a range of non-business tasks for Defendant, including personal clothes and jewelry shopping, home decorating, food and grocery buying, and other items”—shows that Holmes was “funding an extravagant lifestyle … through company money,” CNBC reported.
And so, the saga of Theranos continues. Will Elizabeth Holmes succeed in her defense? Could a clinical laboratory phoenix bird rise from the ashes of this failed lab test company? Who knows? Probably not. But until there is a resolution, we will keep reporting on the case.
Researchers find declining antibody levels in SARS-CoV-2 patients are offset by T cells and B cells that remain behind to fight off reinfection
Questions remain regarding how long antibodies produced by a COVID-19 vaccine or natural infection will provide ongoing protection against SARS-CoV-2. However, a new study showing COVID-19 immunity may be “robust” and “long lasting” may signal important news for clinical laboratories and in vitro diagnostics companies developing serological tests for the coronavirus disease.
The LJI research team analyzed blood samples from 188 COVID-19 patients, 7% of whom had been hospitalized. They measured not only virus-specific antibodies in the blood stream, but also memory B cell infections, T helper cells, and cytotoxic (killer) T cells.
While antibodies eventually disappear from the blood stream, T cells and B cells appear to remain to fight future reinfection.
“As far as we know, this is the largest study ever for any acute infection that has measured all four of those components of immune memory,” Crotty said in a La Jolla Institute news release.
The LJI researchers found that virus-specific antibodies remained in the blood stream months after infection while spike-specific memory B cells—which could trigger an accelerated and robust antibody-mediated immune response in the event of reinfection—actually increased in the body after six months. In addition, COVID-19 survivors had an army of T cells ready to halt reinfection.
“Our data show immune memory in at least three immunological compartments was measurable in ~95% of subjects five to eight months post symptom onset, indicating that durable immunity against secondary COVID-19 disease is a possibility in most individuals,” the study concludes. The small percentage of the population found not to have long-lasting immunity following COVID-19 infection could be vaccinated in an effort to stop reinfection from occurring on the way to achieving herd immunity, the LJI researchers maintained.
Do COVID-19 Vaccines Create Equal Immunity Against Reinfection?
Whether COVID-19 vaccinations will provide the same immune response as an active infection has yet to be determined, but indications are protection may be equally strong.
“It is possible that immune memory will be similarly long lasting similar following vaccination, but we will have to wait until the data come in to be able to tell for sure,”
LJI Research Professor Daniela Weiskopf, PhD, said in the LJI statement. “Several months ago, our studies showed that natural infection induced a strong response, and this study now shows that the response lasts. The vaccine studies are at the initial stages, and so far, have been associated with strong protection. We are hopeful that a similar pattern of responses lasting over time will also emerge for the vaccine-induced responses.”
The study’s authors cautioned that people previously diagnosed with COVID-19 should not assume they have protective immunity from reinfection, the Washington Post noted. In fact, according to the LJI news release, researchers saw a “100-fold range in the magnitude of immune memory.”
Alessandro Sette, Doctor of Biological Sciences (above), an Italian immunologist, Professor at the Center for Autoimmunity and Inflammation/Center for Infectious Disease and Vaccine Research at La Jolla Institute for Immunology, and co-author of the study, told the Washington Post that people should act responsibly. “If I had COVID, I would still not throw away my masks, I would not go to rave parties … It’s like driving a car where you know you have 90% probability that the brakes work.” (Photo copyright: La Jolla Institute for Immunology.)
Previous Studies Found Little Natural Immunity Against SARS-CoV-2 Reinfection
The Scientist reported that several widely publicized previous studies raised concerns that immunity from natural infection was fleeting, perhaps dwindling in weeks or months. And a United Kingdom study published in Nature Microbiology found that COVID-19 generated “only a transient neutralizing antibody response that rapidly wanes” in patients who exhibited milder infection.
Daniel M. Davis, PhD, Professor of Immunology at the University of Manchester, says more research is needed before scientists can know for certain how long COVID-19 immunity lasts after natural infection.
“Overall, these results are interesting and provocative, but more research is needed, following large numbers of people over time. Only then, will we clearly know how many people produce antibodies when infected with coronavirus, and for how long,” Davis told Newsweek.
While additional peer-reviewed studies on the body’s immune response to COVID-19 will be needed, this latest study from the La Jolla Institute for Immunity may help guide clinical laboratories and in vitro diagnostic companies that are developing serological antibody tests for COVID-19 and lead to more definitive answers as to how long antibodies confer protective immunity.
By training a computer to analyze blood samples, and then automating the expert assessment process, the AI processed months’ worth of blood samples in a single day
New technologies and techniques for acquiring and transporting biological samples for clinical laboratory testing receive much attention. But what of the quality of the samples themselves? Blood products are expensive, as hospital medical laboratories that manage blood banks know all too well. Thus, any improvement to how labs store blood products and confidently determine their viability for transfusion is useful.
One such improvement is coming out of Canada. Researchers at the University of Alberta (U of A) in collaboration with scientists and academic institutions in five countries are looking into ways artificial intelligence (AI) and deep learning can be used to efficiently and quickly analyze red blood cells (RBCs). The results of the study may alter the way donated blood is evaluated and selected for transfusion to patients, according to an article in Folio, a U of A publication, titled, “AI Could Lead to Faster, Better Analysis of Donated Blood, Study Shows.”
Improving Blood Diagnostics through Precision Medicine and Deep Learning
“This project is an excellent example of how we are using our world-class expertise in precision health to contribute to the interdisciplinary work required to make fundamental changes in blood diagnostics,” said Jason Acker, PhD, a senior scientist at Canadian Blood Services’ Centre for Innovation, Professor of Laboratory Medicine and Pathology at the University of Alberta, and one of the lead authors of the study, in the Folio article.
The research took more than three years to complete and involved 19 experts from 12 academic institutions and blood collection facilities located in Canada, Germany, Switzerland, the United Kingdom, and the US.
“Our study shows that artificial intelligence gives us better information about the red blood cell morphology, which is the study of how these cells are shaped, much faster than human experts,” said Jason Acker, PhD (above), Senior Research Scientist, Canadian Blood Services, and Professor of Laboratory Medicine and Pathology at the University of Alberta, in an article published on the Canadian Blood Services website. “We anticipate this technology will improve diagnostics for clinicians as well as quality assurance for blood operators such as Canadian Blood Services in the coming years,” he added. Clinical laboratories in the US may also benefit from this new blood viability process. (Photo copyright: University of Alberta.)
To perform the study, the scientists first collected and manually categorized 52,000 red blood cell images. Those images were then used to train an algorithm that mimics the way a human mind works. The computer system was next tasked with analyzing the shape of RBCs for quality purposes.
Removing Human Bias from RBC Classification
“I was happy to collaborate with a group of people with diverse backgrounds and expertise,” said Tracey Turner, a senior research assistant in Acker’s laboratory and one of the authors of the study, in a Canadian Blood Services (CBS) article. “Annotating and reviewing over 52,000 images took a long time, however, it allowed me to see firsthand how much bias there is in manual classification of cell shape by humans and the benefit machine classification could bring.”
According to the CBS article, a red blood cell lasts about 115 days in the human body and the shape of the RBC reveals its age. Newer, healthier RBCs are shaped like discs with smooth edges. As they age, those edges become jagged and the cell eventually transforms into a sphere and loses the ability to perform its duty of transporting oxygen throughout the body.
Blood donations are processed, packed, and stored for later use. Once outside the body, the RBCs begin to change their shape and deteriorate. RBCs can only be stored for a maximum of 42 days before they lose the ability to function properly when transfused into a patient.
Scientists routinely examine the shape of RBCs to assess the quality of the cell units for transfusion to patients and, in some cases, diagnose and assess individuals with certain disorders and diseases. Typically, microscope examinations of red blood cells are performed by experts in medical laboratories to determine the quality of the stored blood. The RBCs are classified by shape and then assigned a morphology index score. This can be a complex, time-consuming, and laborious process.
“One of the amazing things about machine learning is that it allows us to see relationships we wouldn’t otherwise be able to see,” Acker said. “We categorize the cells into the buckets we’ve identified, but when we categorize, we take away information.”
Human analysis, apparently, is subjective and different professionals can arrive at different results after examining the same blood samples.
“Machines are naive of bias, and AI reveals some characteristics we wouldn’t have identified and is able to place red blood cells on a more nuanced spectrum of change in shape,” Acker explained.
The researchers discovered that the AI could accurately analyze and categorize the quality of the red blood cells. This ability to perform RBC morphology assessment could have critical implications for transfusion medicine.
“The computer actually did a better job than we could, and it was able to pick up subtle differences in a way that we can’t as humans,” Acker said.
“It’s not surprising that the red cells don’t just go from one shape to another. This computer showed that there’s actually a gradual progression of shape in samples from blood products, and it’s able to better classify these changes,” he added. “It radically changes the speed at which we can make these assessments of blood product quality.”
More Precision Matching Blood Donors to Recipients
According to the World Health Organization (WHO), approximately 118.5 million blood donations are collected globally each year. There is a considerable contrast in the level of access to blood products between high- and low-income nations, which makes accurate assessment of stored blood even more critical. About 40% of all blood donations are collected in high-income countries that home to only about 16% of the world’s population.
More studies and clinical trials will be necessary to determine if U of A’s approach to using AI to assess the quality of RBCs can safely transfer to clinical use. But these early results promise much in future precision medicine treatments.
“What this research is leading us to is the fact that we have the ability to be much more precise in how we match blood donors and recipients based on specific characteristics of blood cells,” Acker stated. “Through this study we have developed machine learning tools that are going to help inform how this change in clinical practice evolves.”
The AI tools being developed at the U of A could ultimately benefit patients as well as blood collection centers, and at hospitals where clinical laboratories typically manage the blood banking services, by making the process of matching transfusion recipients to donors more precise and ultimately safer.
Called the Geographic Direct Contracting Model (GEO), CMS’ new “voluntary payment model” aims at giving providers of Medicare Part A and Part B services “a direct incentive to improve care across entire geographic regions,” according to a CMS press release.
“The Geographic Direct Contracting Model is part of the Innovation Center’s suite of Direct Contracting models and is one of the Center’s largest bets to date on value-based care,” Brad Smith, Deputy Administrator and Director of the Center for Medicare and Medicaid Innovation (CMMI), told RevCycleIntelligence. Smith is also the former CEO and co-founder of Aspire Health.
According to a CMS Fact Sheet, the GEO model “will test whether a geographic-based approach to value-based care can improve quality of care and reduce costs for Medicare beneficiaries across an entire geographic region.”
“This model allows participating entities to build integrated relationships with healthcare providers and invest in population health in a region to better coordinate care, improve quality, and lower the cost of care for Medicare beneficiaries in a community, said CMS Administrator Seema Verma in the CMS press release. Clinical laboratories may find opportunities as well, to collaborate with physicians in the clinical decision-making process. (Photo copyright: Business Insider.)
“Leveraging best practices and lessons learned from prior Innovation Center models, Geo will enable Direct Contracting Entities (DCEs) to build integrated relationships with healthcare providers and community organizations in a region to better coordinate care and address the clinical and social needs of Medicare beneficiaries,” the CMS Fact Sheet states.
“If we’re successful, we’ll move value-based care from something that might be 10 or 20% of somebody’s revenue to something that’s 80 or hopefully 100% of somebody’s revenue (in five to 10 years),” Smith told MedPage Today.
Healthcare providers and health plans that participate in the Geographic Direct Contracting model must be covered entities under the Health Insurance and Portability Accountability Act (HIPAA) and submit applications by April 2, 2021, the CMS fact sheet states.
The first performance period starts Jan. 1, 2022, and participation is voluntary. Direct contracting entities take “100% shared savings and shared losses for Medicare Part A and B services for aligned Medicare fee for service beneficiaries in a defined region,” the CMS fact sheet explained.
CMS is considering implementing the GEO model in Atlanta, Dallas, Denver, Detroit, Houston, Los Angeles, Miami, Minneapolis, Orlando, Phoenix, Philadelphia, Pittsburgh, Riverside, San Diego, and Tampa.
“By initially testing the model in a small number of geographies, we will be able to thoughtfully learn how these flexibilities are able to impact quality and costs,” Smith told RevCycleIntelligence.
How Will Value-Based Care Programs Affect Clinical Laboratories?
Value-based payment arrangements require doctors to accept changes to how they are reimbursed for their services. In kind, doctors are examining how clinical laboratories can take on an enhanced role in clinical decision making.
“Physicians and hospitals in a value-based environment need a different level of service and professional consultation from the lab and pathology group because they are being incented to detect disease earlier and be active in managing patients with chronic conditions to keep them healthy and out of the hospital,” said Robert Michel, Publisher and Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
Michel explained that value-based care providers are calling on labs to go beyond reporting accurate test results within allotted turnaround times. “They want collaboration in identifying at-risk patients and in finding and closing gaps in care by using laboratory test results.”
Medical laboratory leaders may want to reach out to healthcare providers participating in value-based care models to explore areas of interest relating to patient population, chronic conditions, and severity of illness.
Clinical laboratories that offer testing and reporting and additionally collaborate with healthcare providers and health plans in ways that contribute to improved patient outcomes and lowered costs, may be in a position to earn any financial rewards from these and other new value-based arrangements.
