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Surprising new role for lungs: making platelets

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Using video microscopy in the living mouse lung, UC San Francisco scientists have revealed that the lungs play a previously unrecognized role in blood production. As reported online March 22, 2017, in Nature, the researchers found that the lungs produced more than half of the platelets – blood components required for the clotting that stanches bleeding – in the mouse circulation.

In another surprise finding, the scientists also identified a previously unknown pool of blood stem cells capable of restoring blood production when the stem cells of the bone marrow, previously thought to be the principal site of blood production, are depleted.

“This finding definitely suggests a more sophisticated view of the lungs – that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said pulmonologist Mark R. Looney, MD, a professor of medicine and of laboratory medicine at UCSF and the new paper’s senior author. “What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”

The findings could have major implications for understanding human diseases in which patients suffer from low platelet counts, or thrombocytopenia, which afflicts millions of people and increases the risk of dangerous uncontrolled bleeding. The findings also raise questions about how blood stem cells residing in the lungs may affect the recipients of lung transplants.

Lungs produce more than 10 million platelets per hour

The new study was made possible by a refinement of a technique known as two-photon intravital imaging recently developed by Looney and co-author Matthew F. Krummel, PhD, a UCSF professor of pathology. This imaging approach allowed the researchers to perform the extremely delicate task of visualizing the behavior of individual cells within the tiny blood vessels of a living mouse lung.

Looney and his team were using this technique to examine interactions between the immune system and circulating platelets in the lungs, using a mouse strain engineered so that platelets emit bright green fluorescence, when they noticed a surprisingly large population of platelet-producing cells called megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said Emma Lefrançais, PhD, a postdoctoral researcher in Looney’s lab and co-first author on the new paper.

More detailed imaging sessions soon revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature, suggesting that more than half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed. Video microscopy experiments also revealed a wide variety of previously overlooked megakaryocyte progenitor cells and blood stem cells sitting quietly outside the lung vasculature – estimated at 1 million per mouse lung.

Blood stem cells in the lung can restore bone marrow

The discovery of megakaryocytes and blood stem cells in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a clever set of lung transplant studies:

First, the team transplanted lungs from normal donor mice into recipient mice with fluorescent megakaryocytes, and found that fluorescent megakaryocytes from the recipient mice soon began turning up in the lung vasculature. This suggested that the platelet-producing megakaryocytes in the lung originate in the bone marrow.

“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Muñoz, PhD, also a postdoctoral researcher in the Looney lab and the paper’s other co-first author. “It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”

In another experiment, the researchers transplanted lungs with fluorescent megakaryocyte progenitor cells into mutant mice with low platelet counts. The transplants produced a large burst of fluorescent platelets that quickly restored normal levels, an effect that persisted over several months of observation — much longer than the lifespan of individual megakaryocytes or platelets. To the researchers, this indicated that resident megakaryocyte progenitor cells in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy new megakaryocyte cells to restore proper platelet production.

Finally, the researchers transplanted healthy lungs in which all cells were fluorescently tagged into mutant mice whose bone marrow lacked normal blood stem cells. Analysis of the bone marrow of recipient mice showed that fluorescent cells originating from the transplanted lungs soon traveled to the damaged bone marrow and contributed to the production not just of platelets, but of a wide variety of blood cells, including immune cells such as neutrophils, B cells and T cells. These experiments suggest that the lungs play host to a wide variety of blood progenitor cells and stem cells capable of restocking damaged bone marrow and restoring production of many components of the blood.

“To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” said Looney, who is also an attending physician on UCSF’s pulmonary consult service and intensive care units.

Lungs as Resource for Platelet Production

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Looney said. The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

“These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation,” said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of the new study for Nature. “The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation.”

The observation that blood stem cells and progenitors seem to travel back and forth freely between the lung and bone marrow lends support to a growing sense among researchers that stem cells may be much more active than previously appreciated, Looney said. “We’re seeing more and more that the stem cells that produce the blood don’t just live in one place but travel around through the blood stream. Perhaps ‘studying abroad’ in different organs is a normal part of stem cell education.”

The study was supported the UCSF Nina Ireland Program in Lung Health, the UCSF Program for Breakthrough Biomedical Research, and the National Heart, Lung, and Blood Institute (NHLBI), a division of the National Institutes of Health (HL092471, HL107386 and HL130324).

“It has been known for decades that the lung can be a site of platelet production, but this study amplifies this idea by demonstrating that the murine lung is a major participant in the process,” said Traci Mondoro, PhD, project officer at the Translational Blood Science and Resources Branch of the NHLBI. “Dr. Looney and his team have disrupted some traditional ideas about the pulmonary role in platelet-related hematopoiesis, paving the way for further scientific exploration of this integrated biology.”

Additional authors included Axelle Caudrillier, PhD, Beñat Mallavia, PhD, Fengchun Liu, MD, Emily E. Thornton, PhD, Mark B. Headley, PhD, Tovo David, PhD, Shaun R. Coughlin, MD, PhD, Andrew D. Leavitt, MD; David M. Sayah, MD, PhD, of UCLA; and Emmanuelle Passegué, PhD, a former UCSF faculty member who is now director of the Columbia Stem Cell Initiative at Columbia University Medical Center.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.

Source: UCSF

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Exposure to BPA substitute, BPS, multiplies breast cancer cells

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BPS is found in polycarbonate hard plastics, currency bills and thermal paper receipts as well as many products touted to be free of BPA, a known endocrine-disrupting chemical suspected of having multiple possible health risks.

“Despite hopes for a safer alternative to BPA, studies have shown BPS to exhibit similar estrogen-mimicking behavior to BPA,” said the study’s principal investigator, Sumi Dinda, Ph.D., associate professor at Oakland University School of Health Sciences, Rochester, Mich.

Their study confirmed that BPS acts like estrogen in breast cancer cells, Dinda said, adding, “So far, BPS seems to be a potent endocrine disruptor.”

He and his colleagues studied the effects of BPS on estrogen receptor-alpha and the BRCA1 gene. Most breast cancers are estrogen receptor positive, and, according to the National Cancer Institute, 55 to 65 percent of women who inherit a harmful mutation in the BRCA1 gene will develop breast cancer.

Using two commercially available breast cancer cell lines obtained from women with estrogen-receptor-positive breast cancer, the research team exposed the cancer cells to varying strengths of BPS or to an inactive substance as a control.

The investigators also treated the breast cancer cells with estradiol (estrogen) and found that BPS acted like estrogen in multiplying breast cancer cells, Dinda said. Compared with the control, BPS heightened the protein expression in estrogen receptor and BRCA1 after 24 hours, as did estrogen. After a six-day treatment with BPS, the breast cancer cells in both cell lines reportedly increased in number by 12 percent at the lowest dose (4 micromolars) and by 60 percent at 8 micromolars.

The research team then blocked the BPS-induced proliferation of breast cancer cells by treating the cells with anti-estrogen drugs, which are used to block estrogen’s action onto estrogen binding proteins (estrogen receptors) in breast cancer cells.

Dinda said their findings suggest that BPS may cause breast cancer to become more aggressive. Although further study of BPS in breast cancer cells is needed for confirmation, he suggested that “if a woman has a mutated BRAC1 gene and uses products containing BPS, her risk for developing breast cancer may increase further.”

Co-author Katie Aleck, a research assistant at Oakland University, will present the study results at the meeting.

Source: Endrocrine.org

Antimicrobial Susceptibility Testing for new antibiotics: the clinical laboratorian’s dilemma

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In the era of relentlessly increasing antimicrobial resistance, a newly introduced antibiotic is greeted by clinicians not as the latest addition to a rich armamentarium for the fight against infectious diseases (as, for example, tetracycline or vancomycin might have been in the 1950s) but as a desperately needed therapy of last resort for patients infected with organisms against which most, if not all, currently available antibiotics are impotent. The urgent need for new broad-spectrum antibiotics is reflected in government initiatives, such as the Generating Antibiotic Incentives Now (GAIN) provisions, which incentivize the development of new antibiotics and expedite their review process. Even so, clinicians often utilize the compassionate use process to access an antibiotic that is still in investigational status for critically ill patients with few remaining therapeutic options.

As eager as clinicians are to provide a new antibiotic to a patient who may benefit from it, they first want to know whether it will be effective against the particular organism infecting the patient. As they are accustomed to doing, they turn to the clinical microbiology laboratory to provide antimicrobial susceptibility testing (AST) results, but here they are frequently met with a very unpleasant surprise: AST is not yet available for the new antibiotic.

The AST development process

What exactly has to happen before commercial AST for a new antibiotic is introduced, and why does it take so long? First, a test must be developed by an AST manufacturer. While in theory this process can begin while a drug is still until in investigational status, in practice manufacturers often wait until it appears that FDA approval is likely. Furthermore, AST clinical trials can only include pathogens for which a drug has a specific FDA-approved clinical indication, but these indications are not known until the antibiotic’s New Drug Application (NDA) is approved. Once the test is developed,it must be approved by the FDA, and even after it receives FDA clearance it must undergo in-house verification in any clinical laboratory that adopts it, in order to demonstrate that it performs as expected when used by that laboratory.

For single-agent AST tests, such as antimicrobial susceptibility disks or gradient diffusion test strips, development may be fairly straightforward. However, most commercial minimal inhibitory concentration (MIC) test panels have limited physical space for the addition of new antibiotics and can only add wells for a new antibiotic at the expense of antibiotics already in the panel. Similarly, addition of new antibiotics to automated AST test cards requires the introduction of an entirely new card, and for systems such as the VITEK® 2, which use calculated rather than direct MIC measurements, the development process may quite involved. As a result, there is often a significant delay before manufacturers determine the best way to integrate the new drug into their testing platforms.

Once a new test is developed and cleared by the FDA, a process which may take 1-5 years, each laboratory that adopts it must perform a verification before using the test on patient samples. Guidelines for verification of FDA-approved tests are laid out in CLSI’s M52 document.  If a lab already routinely performs disk diffusion testing, they can test as few as 5 isolates to verify a disk for a new antibiotic, although for other test methods the process may involve testing 30 or more isolates with a range of MICs. The difficulty arises in acquiring isolates for which the true MIC is known: since the lab has no established method for performing AST for the new antibiotic, it has no way to establish a comparator MIC. This introduces a circular dilemma: the lab must verify a new test against a verified test, but it can only acquire a verified test by verifying that test against… a verified test.

There are a few options available to  address this problem. The FDA-CDC Antimicrobial Resistance Isolate Bank offers isolates with a range of resistance profiles and known MICs, including strains resistant to recently introduced antibiotics. Another approach is to send clinical isolates that are submitted to the laboratory to a reference laboratory to determine their MICs. As discussed below, this is frequently also how labs obtain clinical AST results before they are able to perform testing in-house. If they save isolates that were sent out for AST and record the MIC results obtained by the reference laboratory, they will gradually acquire a collection of isolates with known MICs, which they can use for an AST verification study. However, the collection of a sufficient number of such isolates takes time, particularly as costly new antibiotics are often used infrequently in the first months or years after their introduction.

What is a lab to do?

The result of the complex process of AST development is a delay (which may last as long as several years) between the introduction of a new antibiotic and completion of in-house verification of commercial, FDA-approved AST for that antibiotic. Clinicians, however, cannot wait several years after an antibiotic’s introduction before they start using it. How, then, can a clinical laboratory provide them with useful information in the interim? There are several possibilities, outlined below.

Laboratory-developed AST

The first option, in-house development and validation of a reference method, such as broth microdilution, or a laboratory-developed test (LDT), may be conceptually the most obvious, but it is often prohibitively difficult to carry out in practice. However, standard dilution testing (broth microdilution or agar dilution) is highly labor-intensive, and most clinical laboratories simply do not have the resources or experience with relevant methods required to develop and perform such tests in a clinically relevant timeframe. Furthermore, obtaining antibiotic powder from a drug manufacturer to prepare these tests is a complex and lengthy process in the first years of a new drug’s availability. Some laboratories may develop LDTs with research-use only (RUO) susceptibility disks or gradient test strips that are made available by the drug manufacturer soon after the drug’s approval. Because the FDA does not allow RUO reagents to be used for patient testing, however, t, laboratories cannot officially report the results of such tests in the clinical record. Regardless of the method used, the development and validation of a reference method or LDT requires testing an even larger number of isolates than are needed for verification of an FDA-approved test, which makes development of AST for the newest antibiotics challenging.

Reference Laboratory AST

Perhaps the most common approach to AST for new antibiotics is to send isolates to a reference laboratory. Unlike most clinical laboratories, reference microbiology laboratories have the capacity to readily develop and validate broth microdilution or agar dilution tests. Nevertheless, there is still usually some delay before the largest reference laboratories begin to offer AST for new antibiotics, and AST may at first be available only at a specialty lab (e.g. Laboratory Specialists, Inc.), often through a program affiliated with the drug manufacturer. In some such cases the drug manufacturer may place restrictions on which isolates can be tested; for example, AST offered through this type of program for  ceftolozane/tazobactam,  was provided only for isolates obtained from body sites corresponding to the drug’s FDA-approved indications (i.e. urinary and intra-abdominal isolates). The main downside of reference laboratory AST is the delayed availability of results.

Surrogate susceptibility testing

In some cases, new antibiotics are introduced that are closely related to existing antibiotics in the same class. In these cases, susceptibility to the new agent may be predictable based on susceptibility to a related antibiotic for which AST is readily available. This is the case for the lipoglycopeptides: telavancin, dalbavancin, and oritavancin. AST options are very limited for these drugs, even at reference laboratories, but susceptibility to vancomycin is highly predictive of susceptibility to the lipoglycopeptides. The studies linked above also noted that lipoglycopeptide resistance in Staphylococcus aureus (the most common organism for which these drugs are used), is extremely rare, as it is for vancomycin, although this is not the case for Enterococcus species. In another example, susceptibility or resistance to linezolid is predictive in the majority of cases of susceptibility or resistance to tedizolid, an oxazolidinone antibiotic introduced in 2014. It should be noted that such surrogate testing is not appropriate for drugs with primarily Gram-negative activity like ceftazidime-avibactam and ceftolozane-tazobactam, which are specifically introduced to overcome existing resistance mechanisms.

AST Future Directions

Clinicians are often confused and frustrated when they learn that their lab can’t immediately perform AST for a newly introduced antibiotic. There are many reasons for the delay between the introduction of a new antibiotic and the availability of AST for that antibiotic, as described above, but the implications for patients of this delay in AST availability are significant. Fortunately, many of the stakeholders in AST development and use are increasingly recognizing the importance of accelerating AST development. In September 2016, the FDA held a workshop on coordination of development of antimicrobials and AST, and CLSI’s Subcommittee on AST frequently addresses these issues and publishes a newsletter through the AST Outreach Working Group to disseminate relevant updates to laboratories. Resources such as the FDA-CDC Antimicrobial Resistance Isolate Bank are also making the process of validating and verifying AST for new antibiotics more practical. It will be essential for all concerned parties–including pharmaceutical companies, AST manufacturers, government agencies, and clinical microbiology laboratories–to continue to prioritize rapid development and adoption of AST for new antibiotics  a critical component in the fight against drug resistance.

The above post reflects the thoughts of its author, Dr. Thea Brennan-Krohn, and not the American Society for Microbiology. 

Source: ASM

Combatting epigenetic effects from outdoor air pollution

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Exhaust from cars and trucks is a significant source of outdoor air pollution. When we breathe in high levels of the particles present in exhaust, these particles can irritate the lungs and cause breathing disorders. Once in the bloodstream, fine particles (2.5 micrometers in diameter or less) may lead to inflammation throughout the body. Outdoor air pollution has been associated with heart attacks, strokes, and cancers.

Not much is known about how fine particles affect the body on a molecular level. However, breathing in fine particles has been associated with epigenetic changes that may increase the risk of disease. Epigenetic changes are alterations in the way genes are switched on and off without a change in the DNA sequence. The type of epigenetic change associated with air pollution is DNA methylation, the attachment of methyl groups to DNA.

An international team led by scientists at Columbia University set out to determine whether the fine particles in air pollution may alter DNA methylation in CD4+ T-helper cells, a type of circulating white blood cell involved in the inflammatory response. They also investigated whether a nutrient involved in DNA methylation, specifically a B vitamin supplement, might counteract the methylation changes. The study was supported by NIH’s National Institute of Environmental Health Sciences (NIEHS). Results appeared online on March 13, 2017, in Proceedings of the National Academy of Sciences.

Ten healthy volunteers, aged 19 to 49 years, took part in the 3-stage study. In the first stage, they were given an inactive placebo for 2 weeks before being exposed to filtered air for 2 hours. They then took the placebo for 4 weeks and were exposed to air containing fine particles from vehicle exhaust for 2 hours. The researchers obtained vehicle exhaust from a busy street in downtown Toronto and concentrated the fine particles before delivering them through an oxygen-type mask. In the final stage of the study, the participants took the vitamin B supplement for 4 weeks and were then exposed to fine particles for 2 hours.

At each stage, the scientists analyzed changes in the genes of CD4+ T-helper cells. They found that exposure to exhaust particles from outdoor air pollution was associated with DNA methylation changes. However, these changes were not observed when the participants took the daily B vitamin supplement before exposure to the particles.

Larger, longer-term studies are needed to validate the findings of this small study. A better understanding of how outdoor air pollution causes epigenetic changes could provide insights to guide the development of future prevention therapies.

“While emission control and regulation is the backbone of prevention, high exposures are, unfortunately, the rule still in many megacities throughout the world,” says senior author Dr. Andrea Baccarelli of Columbia University’s Mailman School of Public Health. “As individuals, we have limited options to protect ourselves against air pollution. Future studies, especially in heavily polluted areas, are urgently needed to validate our findings and ultimately develop preventive interventions using B vitamins to contain the health effects of air pollution.”

Source: NIH

Genetic variant accelerates normal brain aging in older people by up to 12 years

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The findings could point toward a novel biomarker for the evaluation of anti-aging interventions and highlight potential new targets for the prevention or treatment of age-associated brain disorders such as Alzheimer’s disease.

The study was published online in the journal Cell Systems.

“If you look at a group of seniors, some will look older than their peers and some will look younger,” said the study’s co-leader Asa Abeliovich, PhD, professor of pathology and neurology in the Taub Institute for Alzheimer’s Disease and the Aging Brain at CUMC. “The same differences in aging can be seen in the frontal cortex, the brain region responsible for higher mental processes. Our findings show that many of these differences are tied to variants of a gene called TMEM106B. People who have two ‘bad’ copies of this gene have a frontal cortex that, by various biological measures, appears 12 years older that those who have two normal copies.”

Studies have identified individual genes that increase one’s risk for various neurodegenerative disorders, such as apolipoprotein E (APOE) for Alzheimer’s disease. “But those genes explain only a small part of these diseases,” said study co-leader Herve Rhinn, PhD, assistant professor of pathology and cell biology in the Taub Institute. “By far, the major risk factor for neurodegenerative disease is aging. Something changes in the brain as you age that makes you more susceptible to brain disease. That got us thinking, ‘What, on a genetic level, is driving healthy brain aging?'”

In the current study, Drs. Abeliovich and Rhinn analyzed genetic data from autopsied human brain samples taken from 1,904 people without neurodegenerative disease. First, the researchers looked at the subjects’ transcriptomes (the initial products of gene expression), compiling an average picture of the brain biology of people at a given age. Next, each person’s transcriptome was compared to the average transcriptome of people at the same age, looking specifically at about 100 genes whose expression was found to increase or decrease with aging. From this comparison, the researchers derived a measure that they call differential aging: the difference between an individual’s apparent (biological) age and his or her true (chronological) age. “This told us whether an individual’s frontal cortex looked older or younger than expected,” said Dr. Abeliovich.

The researchers then searched the genome of each individual, looking for genetic variants that were associated with an increase in differential age.

“One variant stood out: TMEM106B,” said Dr. Rhinn. “It’s very common. About one-third of people have two copies and another third have one copy.”

“TMEM106B begins to exert its effect once people reach age 65,” said Dr. Abeliovich. “Until then, everybody’s in the same boat, and then there’s some yet-to-be-defined stress that kicks in. If you have two good copies of the gene, you respond well to that stress. If you have two bad copies, your brain ages quickly.”

The researchers found a second variant–inside the progranulin gene–that contributes to brain aging, though less so than TMEM106B. Progranulin and TMEM106B are located on different chromosomes but are involved in the same signaling pathway. Both have also been associated with a rare neurodegenerative disease called frontotemporal dementia.

The study did not address what role the two genetic variants might have in neurodegenerative disease. “We were studying healthy individuals, so it is not about disease, per se,” said Dr. Abeliovich. “But of course, it’s in healthy tissue that you start to get disease. It appears that if you have these genetic variants, brain aging accelerates and that increases vulnerability to brain disease. And vice versa: if you have brain disease, the disease accelerates brain aging. It’s a vicious cycle.”

Source: Eurekalert

Bone markers as screening strategy for patient adherence to osteoporosis medications

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Oral bisphosphonates are common first line treatments for osteoporosis. However, approximately half of patients who begin osteoporosis treatment do not follow their prescribed treatment and/or discontinue treatment within a year. Identifying low adherence to medication – a problem commonly seen with many chronic diseases – is a critical issue as it jeopardizes the efficacy of treatment, leaving osteoporosis patients unprotected against fractures.

A newly published International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) Working Group position paper [1] proposes measuring specific bone turnover markers (BTMs) in patients who have initiated use of oral bisphosphonates for postmenopausal osteoporosis as a clinically feasible and practical way to identify low adherence. BTMs can reflect the early effect of the drug on bone tissue. If a low response is detected shortly after treatment has been started, this can indicate low adherence or point to underlying causes of impaired response to medication.

Using the findings of the TRIO study [2] as the basis for their recommendations, the Working Group recommends measuring serum PINP (procollagen type 1 N-terminal propeptide) and CTX (collagen type 1 C-terminal telopeptide) levels at baseline and after 3 months of initiating treatment. The timing for the assessment at 3 months is optimal because the first weeks after the prescription is given is the critical period of primary non-adherence, when patients are most likely to have discontinued treatment.

The Working Group recommends that in those individuals where the decrease of the two BTMs, PINP and CTX does not exceed the least significant change (38% and 56%, respectively) assessment of adherence, or possibly investigation of secondary osteoporosis, should be carried out.

Professor Adolfo Diez-Perez, Co-Chair of the Joint IOF-ECTS Adherence Working Group, stated, “The use of bone turnover marker measurement to detect a lack of response to oral bisphosphonates is a practical and low-cost screening procedure which helps identify potential non-adherence in patients very early after treatment initiation. The patients benefit as this opens up opportunity for discussion and early intervention with noncompliant patients, or can indicate that secondary causes of osteoporosis need to be assessed.”

Co-Chair of the Working Group, Professor Richard Eastell, emphasized that “It will be interesting to further evaluate if these recommendations have an impact on adherence in a real-life setting.”

Source: Eurekalert

A hormone that is secreted by bone can suppress appetite in mice reports a study

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Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively.

These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood–brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.

Authors: Ioanna Mosialou, Steven Shikhel, Jian-Min Liu, Antonio Maurizi, Na Luo, Zhenyan He, Yiru Huang, Haihong Zong, Richard A. Friedman, Jonathan Barasch, Patricia Lanzano, Liyong Deng, Rudolph L. Leibel, Mishaela Rubin, Thomas Nicholas, Wendy Chung, Lori M. Zeltser, Kevin W. Williams, Jeffrey E. Pessin, Stavroula Kousteni. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature doi:10.1038/nature21697

Source: Nature

Chimeric Antigen Receptor T-Cell Therapy: How it Works

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Lymphocytes, a subtype of white blood cells, comprise a major portion of the immune system. There are three types of lymphocytes

  • B lymphocytes (B cells) make antibodies to fight infection
  • T lymphocytes (T cells) and natural killer (NK) cells directly kill infected or cancerous cells and also talk to other cells of the immune system using chemicals known as “cytokines.”

Immunotherapy

  • Is a type of treatment that utilizes the body’s own immune system to fight cancer
  • Improves the body’s ability to detect and kill cancer cells
  • Is based on the concept that immune cells or antibodies can recognize and kill cancer cells.

Immune cells or antibodies can be produced in the laboratory under tightly controlled conditions and then given to patients to treat cancer. Several types of immunotherapy are either approved for use or are under study in clinical trials to determine their effectiveness in treating various types of cancer.

Chimeric Antigen Receptor T-Cell Therapy: How it Works

T cells are collected from a patient. T cells are collected via apheresis, a process that withdraws blood from the body and removes one or more blood components (such as plasma, platelets or white blood cells). The remaining blood is then returned back into the body.

T cells are reengineered in a laboratory. The T cells are sent to a laboratory or a drug manufacturing facility where they are genetically engineered to produce chimeric antigen receptors (CARs) on their surface.

After this reengineering, the T cells are known as “chimeric antigen receptor (CAR) T cells.” CARs are proteins that allow the T cells to recognize an antigen on targeted tumor cells.

The reengineered CAR T cells are then multiplied. The number of the patient’s genetically modified T cells is “expanded” by growing cells in the laboratory until there are many millions of them. These CAR T cells are frozen and, when there are enough of them, they are sent to the hospital or center where the patient is being treated.

At the hospital or treatment center, the CAR T cells are then infused into the patient. Many patients are given a brief course of one or more chemotherapy agents before they receive the infusion of CAR T cells. CAR T cells that have been returned to the patient’s bloodstream multiply in number. These are the “attacker” cells that will recognize, and kill, cancerous cells that have the targeted antigen on their surface.

The CAR T cells guard against recurrence. CAR T cells may remain in the body long after the infusion has been completed. They guard against cancer recurrence, so the therapy frequently results in long-term remissions.

Dr. Brentjens talks about CAR T therapy.

Dr. Steven Rosenberg discusses saving lives with CAR T.

At this time, CAR T-cell therapy is only available to patients who are participating in a clinical trial. Trial protocols vary. Depending on the clinical trial, care may be provided in either a hospital setting or a treatment center. Patients may have to stay at the treatment facility, or they may need to plan to stay close by before, during or following treatment. Some trial protocols require patients to confirm the availability of a caregiver before they can enroll in the trial..

Possible Side Effects of CAR T-Cell Therapy

Cytokine-Release Syndrome (CRS). A serious side effect associated with CAR T-cell therapy is cytokine-release syndrome (CRS). CRS is the result of T-cell activation, so its presence actually indicates a positive response to therapy. Cytokines are chemical messengers that help the T cells perform their duties. With CAR T-cell therapy, large amounts of cytokines are produced by the activated immune system. CRS in this setting may cause high fevers, low blood pressure or poor lung oxygenation (requiring administration of supplemental oxygen as a temporary measure). Some patients experience delirium, confusion and seizure while undergoing treatment. The onset of these symptoms is typically within the first week of treatment. These symptoms, however, are reversible.

B-Cell Aplasia. CAR T-cell therapy targeting antigens found on the surface of B cells not only destroys cancerous B cells but also normal B cells. Therefore, B cell aplasia (low numbers of B cells or absent B cells) is an expected side effect. This absence of B cells results in less ability to make the antibodies that protect against infection. Intravenous immunoglobulin replacement is used to prevent infection. It is not known how long the decreased number of B cells persists however, no long-term side effects have been noted.

Tumor Lysis Syndrome (TLS). Another known side effect of CAR T-cell therapy is tumor lysis syndrome (TLS), a group of metabolic complications that can occur due to the breakdown of dying cells—usually at the onset of toxic cancer treatments. However, TLS can occur one month or more after CAR T-cell therapy. TLS can be a life-threatening complication of any treatment that causes breakdown of cancer cells, including CAR T cells. The complication has been managed by standard supportive therapy.

Results, Limitations, and the Future of CAR T-cell Therapy

Early results from CAR T-cell trials have generated impressive results and considerable promise in patients with blood cancers.

Acute lymphoblastic leukemia (ALL). CAR T-cell therapy may represent options for ALL patients who have relapsed after intensive chemotherapy or a stem cell transplant. In some studies, up to 90 percent of children and adults with ALL who had either relapsed multiple times, or failed to respond to standard therapies, achieved remission after receiving CAR T-cell therapy.

Other blood cancers. Studies of CAR T-cell therapy in other blood cancers, including chronic lymphocytic leukemia (CLL), some types of non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL) and follicular lymphoma, as well as multiple myeloma, are also very promising.

While data is fast emerging as to the early responses to CAR T-cell therapy, most of the patients participating in these clinical trials have only been followed for a relatively short period of time. Following these trial participants over the long term will provide information as to the length of their responses. It is important for more pediatric and adult patients to be enrolled in clinical trials. Larger study samples, looked at over more extended periods, will help researchers further understand the impact of this type of therapy, ways to reduce its toxicity and also improve toxicity management.

Enrolling in a Trial

Talk with your doctor about whether participation in a CAR T-cell therapy clinical trial is an option for you. Obtaining another opinion from a hematologist–oncologist (a blood cancer specialist), may be helpful in finding additional clinical-trial information as well. When you discuss CAR T-cell therapy as a potential treatment option for you, it may be helpful to have

  • A list of questions to ask concerning risks versus benefits of such a trial (click here for lists of suggested questions).
  • A family member, friend, or another advocate with you for support and to take notes.

In addition to speaking with your doctor, LLS Information Specialists, available at (800) 955-4572, offer guidance on how patients can work with their doctors to determine if a specific clinical trial is an appropriate treatment option. Information Specialists can search for clinical trials on behalf of patients, family members and healthcare professionals.

Source: lls.org

Aspirin may help increase pregnancy chances in women with high inflammation, NIH study finds

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The women who benefited from the aspirin treatment had high levels of C-reactive protein (CRP), a substance in the blood indicating system-wide inflammation, which aspirin is thought to counteract. The study appears in the Journal of Clinical Endocrinology and Metabolism.

Researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) analyzed data originally obtained from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. The trial sought to determine if daily low-dose aspirin could prevent subsequent pregnancy loss among women who had one or two prior losses.

For the current study, researchers classified the women into 3 groups: low CRP (below 0,70 mg per liter of blood), mid CRP (from 0,70 to 1,95) and high CRP (at or above 1,95). Women within each group received either daily low-dose aspirin or a placebo. In their analysis, researchers found no significant differences in birth rates between those receiving aspirin and those receiving placebo in both the low CRP and mid CRP groups. For the high CRP group, those taking the placebo had the lowest rate of live birth at 44 percent, while those taking daily aspirin had a live-birth rate of 59 percent — a 35-percent increase. Aspirin also appeared to reduce CRP levels in the high CRP group when measured during weeks 8, 20, and 36 of pregnancy.

The authors concluded that more research is needed to confirm the findings and to examine the potential influence of inflammation in becoming pregnant and maintaining pregnancy.

Author: Lindsey A. Sjaarda, Ph.D., staff scientist in the NICHD Division of Intramural and Population Health Research.

Sjaarda LA, et al. Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low grade inflammation: a secondary analysis of a randomized trial (link is external). Journal of Clinical Endocrinology and Metabolism.  DOI: https://doi.org/10.1210/jc.2016-2917 (link is external)

Source: NIH

 

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