An immunotherapy harnessing the immune system’s “natural killer” cells has proven effective in treating acute myeloid leukemia (AML) in some adults whose cancers return. Now, researchers at Washington University School of Medicine in St. Louis have shown, in a small clinical trial, that the same natural killer cells also can help some children and young adults with recurrent AML and few other treatment options.
Results from the phase 1 trial, which included eight patients ages 1 to 30 years, are published online in the journal Blood.
All of the patients enrolled in this study had very aggressive AML. For all of them, their leukemia recurred after stem cell transplantation and was not responsive to several treatment regimens before they were referred to this study. This is a very challenging disease to treat — none of the patients had any curative options. The survival expectation for these patients was essentially zero. That three patients are still alive is very encouraging for this really challenging disease.”
Jeffrey J. Bednarski, MD, PhD, first author, assistant professor of pediatrics
Acute myeloid leukemia is a cancer of the blood and bone marrow that results in the overproduction of immature white blood cells, which crowd out healthy blood cells. Standard therapy involves chemotherapy and a stem cell transplant from a donor, which can result in a long-term remission. But for patients whose cancers return after stem cell transplantation, the disease becomes extremely difficult to treat, and most patients ultimately die from progression of their disease within a few months to a year.
Of the eight patients who received the investigational treatment, four achieved complete remission by day 28 after therapy. Two of the four stayed in remission for more than three months. One of these patients remains in remission today, more than two years after the treatment. Three patients who went into remission later relapsed. Of those three, two were able to receive a second stem cell transplant, and they’re still alive and doing well. Two other patients had a partial response to the therapy, in that their disease decreased, but they did not go into remission. The remaining two patients did not respond to the therapy.
“We found that the donor’s natural killer cells expanded, persisted and remained highly active against the leukemia in most of the patients for over three months,” said Bednarski, who treats patients in the pediatric cancer program at Siteman Kids at St. Louis Children’s Hospital and Washington University School of Medicine. “This therapy also was very well tolerated by the patients, who experienced almost no toxicities.”
Natural killer cells are a type of immune cell that attacks foreign or compromised cells, including bacteria, virus-infected cells and even cancer cells. Past work from Washington University researchers has shown that natural killer cells’ ability to attack cancer cells can be enhanced by exposing them to a specific cocktail of chemicals called cytokines. The natural killer cells are collected from a donor and then exposed in the lab to three cytokines called interleukins 12, 15 and 18. This exposure activates the cells and prompts them to remember this activation. When such “cytokine-induced memory-like” natural killer cells are given to the patient, they are more aggressive in attacking the cancer because of this pre-activation.
“A unique angle to this study is that we’re using the patient’s original stem cell donor’s cells to generate the memory-like natural killer cells, so the cells won’t be rejected by the patient’s immune system but are still able to fight the leukemia,” said senior author Todd A. Fehniger, MD, PhD, a professor of medicine who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “We’re also pleased to see evidence that these cells are extremely safe. They do not have the severe side effects that are sometimes seen in cellular therapies based on T cells. Using cutting-edge science within this trial, we also now understand these memory-like natural killer cells are very unique, even compared with conventional natural killer cells.”
Fehniger’s lab developed the methods for producing the cytokine-induced memory-like natural killer cells and led the original clinical trial of these cells in adults with AML.
Based on the experience of these eight patients, the investigators are making some changes to the protocol in an effort to make the treatment more effective for future patients. Bednarski said they will combine the memory-like natural killer cells with different chemotherapies to investigate whether that can optimize the killing of leukemia cells. They also will add a second infusion of the memory-like natural killer cells to extend the amount of time that the cells have to expand in the body and kill the leukemia cells.
“We plan to treat a larger group of pediatric and adult patients using this approach in an ongoing study,” Fehniger said. “Memory-like natural killer cells also are being explored as an experimental treatment for other cancers, including solid tumors such as melanoma and head and neck cancers, which are really exciting advancements in the field.”
Unraveling How Strigoractone Hormone Regulates Massive Gene Networks Controlling Plant Growth
As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.
New research from Nitzan Shabek’s laboratory at the UC Davis College of Biological Sciences, published in Nature Plants, unravels the underlying mechanism of protein targeting and destruction in a specific plant hormone signaling pathway.
Our lab aims at deciphering sensing mechanisms in plants and understanding how specific enzymes function can be regulated at the molecular levels. We have been studying a new plant hormone signal, strigolactone, that governs numerous processes of growth and development including branching and root architecture.”
Nitzan Shabek, assistant professor of biochemistry and structural biology, Department of Plant Biology
The work stems from a study by Shabek, published in Nature in 2018, unravelling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that “tag” other proteins for destruction within a cell.
To find the key to unlock MAX2 and to better understand its molecular dynamics in plants, postdoctoral fellows Lior Tal and Malathy Palayam, with junior specialist Aleczander Young, used an approach that integrated advanced structural biology, biochemistry, and plant genetics.
“We leveraged structure-guided approaches to systemically mutate MAX2 enzyme in Arabidopsis and created a MAX2 stuck in an unlocked form”, said Shabek, “some of these mutations were made by guiding CRISPR/Cas9 genome editing thus providing us a discovery platform to study and analyze the different signaling outputs and illuminate the role of MAX2 dynamics.”
They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed – activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.
Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only target the repressors proteins, but once it is locked the strigolactone sensor itself gets destroyed, returning the system to its original state.
Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch.
“Beyond the implication in plants signaling, this is the first work that placed a primary metabolite as a direct new regulator of this type of ubiquitin ligase enzymes and will open new avenues of study in this direction,” Shabek said.
Additional coauthors on the paper are specialist Mily Ron and Professor Anne Britt, Department of Plant Biology. The study was supported by NSF CAREER and EAGER grants to Shabek. X-ray crystallography data was obtained at the Advanced Light Source, Lawrence Berkeley National Laboratory, a U.S. Department of Energy user facility.
Tal, L., et al. (2022) A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature Plants. doi.org/10.1038/s41477-022-01145-7.
Original Article: news-medical.net
UrFU Sociologists Identify Digital Fears Among Young People
Sociologists at the Ural Federal University (UrFU) have identified digital fears among young people. According to experts, these are additional fears that do not replace, but complement and reinforce traditional ones. They emerged against the background of uncertainty, the growth of forces beyond human control. Developed emotional intelligence, creativity, and the ability to collaborate help to overcome them.
In the study, sociologists interviewed 1,050 people aged 18-30. Respondents were asked to assess which digital risks concern them most. The study was launched in 2020 and the results were published in April 2022 in the Changing Societies & Personalities journal.
The first group of fears is influence and control. It touches on the problem of interference with privacy by technical means. This category is the most significant for young people: 55.8% are afraid of total control by means of video-surveillance and monitoring software on their mobile devices. 48.5% of respondents believe they are at risk of wiretapping, tracking content in social networks, and inability to keep correspondence secret.”
Natalia Antonova, Professor, Department of Applied Sociology, UrFU
45.8% of young people fear the manipulative influence of the media and an increase in fake news. At the same time, only 27.8% and 18.1% of respondents are concerned about microchipping and genetic manipulation, respectively. It is likely that these threats seem more controllable, both from the individual (through control of food choices, medical procedures, etc.) and from government programs, the researchers believe.
The second group of concerns is crime and security. Here young people are wary of illegal actions using digital technology.
“One of the main fears of 56% of young people is the security of personal data. This is related both to the growth of personal information in social networks and messengers, and to the growth of hacker attacks and viruses. 42.9% of young citizens are afraid of Internet fraudsters, and 25.8% are afraid of losing important information, including smashing their phones, not saving data, forgetting their passwords, or being without an Internet connection,” explains Sofia Abramova, Associate Professor at the Department of Applied Sociology at UrFU.
The third group of fears is based on changes in the way and pace of life, ways of interaction. Thus, 28.4% of respondents indicate a constant lack of time, the acceleration of communications, and worries about not being able to complete all tasks in time. Respondents are also concerned about the growth of online communications and communications with electronic systems (bots, autoresponders, product systems, etc.).
“As a result, 15.3% of young people raise problems related to increasing social distrust against the background of increasing dependence of human life and health on other people and electronic systems: in public transport, planes, elevators, medical intervention,” explains Sofia Abramova.
Respondents also fear the negative consequences of technological development. For example, 22.2% of young citizens fear the robotization of labor processes and the displacement of humans by robots. 14.6% speak directly about negative emotions in relation to the expansion of artificial intelligence.
The fifth type of fear is social inequality. Young people negatively assess the growth of inequality in access to information resources and technology, the exclusion of citizens from the economy depending on the level of digital competence and education, and age. As a result, they fear that benefits will be distributed more and more unequally, both among the inhabitants of the country and between countries.
“It is noteworthy that young people are simultaneously afraid of total surveillance via phone and afraid of being left without mobile devices. Fears shape the irrational behavior of the digital generation, entailing serious transformations in everyday life,” says Natalia Antonova.
Abramova, S.B., et al. (2022) Digital Fears Experienced by Young People in the Age of Technoscience. Changing Societies & Personalities. doi.org/10.15826/csp.2022.6.1.163.
Original Source: news-medical.net
Study demonstrates increased incidence of SARS-CoV-2 Omicron breakthrough infection in cancer patients
In a recently published article in the journal Cancer Cell, scientists have demonstrated the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients residing in Austria and Italy. The study reveals an induction in Omicron breakthrough infections in patients with hematologic and solid cancers.
Study: Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron. Image Credit: Lightspring/Shutterstock
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has been found to cause severe infections in immunocompromised patients, including cancer patients. Moreover, a relatively lower level of neutralizing antibodies in response to COVID-19 vaccines has also been observed in cancer patients, especially those receiving B cell-targeting therapies.
The emergence of SARS-CoV-2 variants with improved immune fitness, such as delta and Omicron variants, has caused a sharp increase in breakthrough infections even in fully vaccinated individuals. However, the vaccines still show high protective efficacy against severe and fatal infections. COVID-19 vaccines have shown acceptable efficacy against severe disease, even in Omicron-infected cancer patients. However, the isolation and quarantine measures associated with SARS-CoV-2 infection may impair the routine administration of anticancer therapy, which can reduce the survival prognosis in cancer patients.
In the current study, the scientists have assessed the incidence of SARS-CoV-2 infection in cancer patients throughout the pandemic.
The study included 3,959 cancer patients, of whom 77% had solid cancer, and 23% had hematologic cancer. About 69% of the patients did not receive any anticancer treatment at the time of COVID-19 vaccination. Regarding vaccine coverage, about 85% of the patients had received at least one vaccine dose, and 15% remained unvaccinated. The incidence of SARS-CoV-2 infection in these patients was assessed between February 2020 and 2022.
SARS-CoV-2 infection was detected in about 24% of the patients during the study period. During the delta-dominated wave, vaccine breakthrough infection was observed in 43% of the patients. In contrast, a significantly higher percentage of breakthrough infection (70%) was observed among the patients during the Omicron-dominated wave. During both delta and Omicron waves, cancer patients receiving systemic anticancer treatment showed a significantly higher percentage of breakthrough infection than those not receiving treatment (83% vs. 56%).
Regarding disease severity irrespective of vaccination status, a higher frequency of COVID-19-related hospitalization was observed during the delta wave compared to that during the Omicron wave. However, a relatively shorter duration of hospital stay was observed in vaccinated patients compared to that in unvaccinated patients. In addition, only 9% of patients with breakthrough infections were admitted to the intensive care unit (ICU). This highlights the protective efficacy of COVID-19 vaccines against severe disease.
Humoral immune response to vaccination
To determine vaccine-induced antibody response against delta and Omicron variants, the scientists measured blood levels of anti-delta and anti-Omicron spike receptor-binding domain (RBD) antibodies in a total of 78 cancer patients. In the analysis, they also included 25 healthcare workers as controls.
In response to vaccination, healthcare workers showed higher levels of total anti-spike antibodies compared to cancer patients. The lowest level of wildtype RBD-specific antibodies was observed in hematologic cancer patients receiving B cell-targeted treatment, followed by hematologic cancer patients not receiving B cell-targeted treatment and patients with solid tumors. A similar trend was observed for delta- and Omicron-specific spike RBD antibodies.
The serum samples collected from hematologic cancer patients without B cell-targeted treatment and solid tumor patients significantly inhibited the interaction between wildtype/delta RBD and angiotensin-converting enzyme 2 (ACE2; host cell receptor for viral entry). However, a significantly lower level of inhibition was observed for patients receiving B cell-targeted treatment. Importantly, a marked reduction in inhibition of Omicron RBD – ACE2 interaction was observed for all patients with solid tumors and hematologic cancer.
The study demonstrates an increased incidence of vaccine breakthrough infections but a reduced disease severity among patients with solid tumors and hematologic cancer during the Omicron wave compared to the delta wave.
The study also highlights that COVID-19 vaccine-induced antibody response is lower in cancer patients than in healthy individuals. The reduction in antibody response is highest among hematologic patients receiving B cell-targeted treatment. Overall, a significant impairment in vaccine-induced Omicron neutralization has been observed in cancer patients.
Health News5 months ago
New report warns about failure to appreciate the complex nature of environmental risks
Health News5 months ago
New EUR8 million multiyear contribution agreement signed to support equitable access for health products
Family7 months ago
3 Secrets to a Long-Lasting Marriage
News6 months ago
Napoli vs. Atalanta odds, expert picks, how to watch, live stream: Dec. 4 Italian Serie A predictions
Nutrition6 months ago
Meet the Dipped Chocolate Chip Cookie Dough Quest Bar!
Family7 months ago
3 Secrets to a Long-Lasting Marriage
Family7 months ago
3 Secrets to a Long-Lasting Marriage
Family7 months ago
3 Secrets to a Long-Lasting Marriage