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News Article | February 16, 2017
Site: www.eurekalert.org

CINCINNATI - Genomic testing of biopsies from patients with deadly, treatment-resistant cancerous blood syndromes called histiocytoses allowed doctors to identify genes fueling the ailments and use targeted molecular drugs to successfully treat them. Researchers from the Cincinnati Children's Cancer and Blood Diseases Institute report their data in Journal of Clinical Investigation Insight (JCI Insight). They recommend the regular use of comprehensive genomic profiling at diagnosis to positively impact clinical care, as well as rigorous clinical trials to verify and extend the diagnostic and treatment conclusions in their study. Histiocytoses are a group of disorders in which abnormal accumulations of white blood cells form tumors on vital organs, leading to systemic organ damage or death. About half of the patients can be treated successfully with chemotherapy, but others are treatment resistant. Study authors conducted genomic profiling of biopsies from 72 child and adult patients with a variety of treatment-resistant histiocytoses, including the most common one in children, Langerhans cell histiocytosis (LCH), according to the lead investigator, Ashish Kumar, MD, PhD. Twenty-six patients with treatment-resistant disease had gene mutations involving either BRAF or MAP2K1 that directly activate the MAP-kinase cancer pathway. Researchers determined such patients would benefit from the targeted molecular therapies dabrafenib or trametinib, which block the MAP kinase pathway. The approved cancer drugs were prescribed off label to the histiocytosis patients. "In the last year, three patients we treated were infants with disease that was resistant to several rounds of intense chemotherapy. In the past, these children either would have suffered serious complications including death or would have had to endure more intensive treatments and the ensuing toxicities, including the risk of death," Kumar said. "All three are thriving now on one oral medication that put their disease into remission." In their JCI Insight paper, the researchers also offer detailed case summaries involving four histiocytosis patients between the ages of 9 months and 36 years. In one case a 22-month-old child was referred to Cincinnati Children's for treatment-resistant LCH that was complicated by a secondary diagnosis of HLH (hemophagocytic lymphohistiocytosis). HLH is a difficult-to-treat and often-fatal autoimmune disorder in which an overheated immune system causes uncontrolled inflammation and organ damage. The little girl, whose condition was worsening with organ failure, had a mutation in the BRAF gene. Two days after starting targeted treatment with oral dabrafenib (which blocks the MAP-kinase pathway) the little girl's fever disappeared and a week later her organ function returned to normal, according to study authors. For their JCI Insight research project, in addition to their own laboratory tests, study authors drew from data in previous research papers by a number of institutions, which examined genetic and molecular processes affecting white blood cell expansion in different types of histiocytosis. As Kumar and his colleagues continue their research, they plan to test methodologies that could expand the use of genomic profiling of patient biopsies and targeted molecular therapies in more patients with recurrent, treatment-resistant disease. "It's important for physicians and patients to know that LCH and other forms of histiocytosis are not that mysterious anymore," Kumar said. "We now have new treatments that dramatically improve outcomes for these patients." The JCI Insight study is a collaborative effort of investigators in several divisions at Cincinnati Children's, including first author and oncologist Lynn H. Lee, MD. Kumar is a member of the Division of Bone Marrow Transplant and Immune Deficiency and director of the Langerhans Cell Histiocytosis Center at Cincinnati Children's. Funding support for the research came from the National Heart, Lung, and Blood Institute (R01-HL111192) and the Leukemia and Lymphoma Society (TRP-6076-14).


News Article | February 22, 2017
Site: www.eurekalert.org

CINCINNATI - Scientists propose in Nature blocking a molecule that drives inflammation and organ damage in Gaucher and maybe other lysosomal storage diseases as a possible treatment with fewer risks and lower costs than current therapies. An international research team led by Cincinnati Children's Hospital Medical Center, which also included investigators from the University of Lübeck in Germany, report their data Feb. 22. The study was conducted in mouse models of lysosomal storage disease and in cells from blood samples donated by people with Gaucher disease. Current treatments for Gaucher and other lysosomal storage diseases (LSDs) include enzyme replacement therapy or substrate reduction therapy. These break down or prevent the accumulation of certain fatty molecules and other waste particles that clog cells to cause inflammation, cell and organ damage and, in some cases, death. People with LSDs lack enzymes that break down used-up proteins and other spent particles, preventing their cells from shedding these waste materials and functioning normally. Individually, the 50 genetic diseases characterized as LSDs are considered rare. But collectively they have a frequency of one in 8,000 births, making LSDs a major challenge for the health care system, according to information from the National Institutes of Health. Study authors stress there is a need for new therapies. "Current enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of malignancies and Parkinson's disease," says Manoj Pandey, PhD, study first author and a scientist in the Division of Human Genetics at Cincinnati Children's. "We suggest that targeting a molecule called C5aR1 may serve as a viable treatment option for patients with Gaucher disease and possibly other LSDs." Pandey is co-corresponding author on the paper along with Jörg Köhl, MD, director of the Institute for Systemic Inflammation Research at the University of Lübeck, and adjunct professor in the Division of Immunobiology at Cincinnati Children's. In laboratory mouse models and human cells, researchers show that C5aR1 is a critical part of a molecular pathway that drives pro-inflammatory processes in Gaucher disease, which is initiated by mutations of a gene known as GBA1. GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), which degrades the fatty molecule glucosylceramide (GC). C5aR1 is a receptor for a small peptide (a protein component) that is derived from the complement system (part of the immune system) called C5a, which drives inflammation in several different types of immune cells. The disease process starts by GBA1 mutation driving extensive accumulation of glucosylceramide in immune cells. Before the current study, the molecular process that connects glucosylceramide accumulation to inflammation was unknown, as was the role of inflammation in disease development. Pandey and colleagues show inflammatory glucosylceramide accumulation in spleen, liver, lung and bone marrow immune cells in Gaucher mouse models drives the induction of auto-antibodies against glucosylceramide, which form immune complexes. These immune complexes promote the production of C5a and activation of its receptor C5aR1. In organ tissues from disease mouse models, the researchers found evidence of abundant and active C5aR1, which fuels glucosylceramide accumulation through its control of an enzyme that produces the fatty molecule. According to the authors, C5aR1 activation is what tips the balance between glucosylceramide formation and its degradation. The researchers also found similar evidence of C5aR1 and related pro-inflammatory molecules in cells from the donated blood samples of Gaucher patients. Based on evidence of C5aR1's involvement in the Gaucher disease process, the researchers decided to test targeting the molecule pharmacologically in laboratory mouse models. Taking advantage of a C5aR antagonist (C5aRA) developed by Köhl (patent owned by Cincinnati Children's), the scientists injected C5aRA into the peritoneal cavities of mice. The infiltration of pro-inflammatory immune cells (macrophages) was substantially reduced in the lungs, livers and spleens of mice, and glucosylceramide accumulation was almost completely abolished, as was overall disease burden, the authors report. Because the current project was conducted in mouse models and human blood cells, Pandey and his colleagues stress that additional study is needed before determining whether targeting C5aR1 would be effective and safe enough to test in human patients. Pandey said researchers will continue testing the C5aRA molecule used in the mouse study (which is effective in targeting human and mouse C5aR). They also will test a commercially available anti-C5 monoclonal antibody called eculizumab, which is produced by Alexion Pharmaceuticals (which helped fund the current study). This will allow the researchers to test these compounds as a novel adjunctive therapeutic approach for human patients with Gaucher, and as a possible therapy for other lysosomal storage diseases. Funding support for the study came from Division of Human Genetics at Cincinnati Children's, the German Research Foundation (EXC 306/2, CL XII, IRTG 1911) and the Alexion Rare Disease Innovation Fund (31-91910-584000).


News Article | March 2, 2017
Site: www.eurekalert.org

CINCINNATI - As people get older so do the hematopoietic stem cells (HSCs) that form their blood, creating an increased risk for compromised immunity and certain blood cancers. Now researchers are reporting in the scientific journal EMBO that the bone marrow niche where HSC's form also ages, contributing to the problem. In a study published March 2, scientists from the University of Ulm in Germany and Cincinnati Children's Hospital Medical Center in the United States propose rejuvenating the bone marrow niche where HSCs are created. This could mean younger acting HSCs that form healthier blood cells, boosted immunity in older people, and a better defense mechanism against certain cancers, according to study authors. Conducting their study in mouse models, the scientists point to cells in the bone marrow called osteoblasts, which help form bone. Osteoblasts make a protein called osteopontin, which is important to supporting a vibrant bone marrow environment in the creation of blood-forming HSCs. "We show that the place where HSCs form in the bone marrow loses osteopontin upon aging, but if you give back the missing protein to the blood-forming cells they suddenly rejuvenate and act younger," says Hartmut Geiger, PhD, study lead investigator at the Institute for Molecular Medicine and Aging Research Center at the University of Ulm, and the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. "Our study points to exciting novel ways to have a better immune system and possibly less blood cancer upon aging by therapeutically targeting the place where blood stem cells form." Because the study was in mice, its findings cannot at this stage be extended to clinical treatment of human patients, the authors say. But the data provide interesting leads that one day could benefit human health. The researchers conducted a number of experiments to test the formation and vitality of cells in and near the bone marrow microenvironment. One test in aging mice looked at the formation of endosteum stroma cells, which form a thin layer of connective tissue on the inner surface of bones. Another experiment monitored levels of osteopontin and other proteins linked to distinct cells in bone marrow during the aging process. Study authors say they observed reduced production of osteoblasts and other stroma cells in the endosteum of older mice. They also saw decreased osteopontin protein levels in the bone marrow of older animals, which they note was associated with reduced vigor and function of blood-forming HSCs. Scientists followed up the earlier experiments by transplanting bone marrow cells from older mice (19-21 months) into young mice (8 to 10 weeks). In two other experiments, the authors also transplanted aged HSCs from older mice into younger mice, and they treated aged HSCs with a recombinant form of the osteopontin protein. Transplantation into the younger animals caused cells to act in a younger more vital manner, the authors report. This includes the presence of smaller numbers of HSCs with greater potential for forming different types of blood cells, which included larger populations of B and T cells and smaller production of myeloid cells. The authors also saw aged HSCs treated with recombinant osteopontin regain their youthful characteristics and capacity to form different blood-cell types. Also observed was diminished signaling of the protein Cdc42, a protein that Geiger and his team previously showed causes HSCs to age. Osteopontin levels are not only low in the bone marrow niche, but also in the blood upon aging. As a follow up to the current study, the researchers are investigating the possibility to use osteopontin replacement therapy in mice to counter the influence of an aging niche directly in the animals. First author on the paper was Novella Guidi, a PhD student and member of the Geiger laboratory. Funding support for the study came from the Deutsche Forschungsgemeinschaft (KFO 142 and SFB 1074), the BMBF-funded Program SyStaR, and the National Institutes of Health (HL076604, DK077762, AG040118).


News Article | November 18, 2016
Site: www.eurekalert.org

CINCINNATI -- One of every four children admitted to pediatric intensive care units around the world develops acute kidney injury (AKI), which increases the risk of death as well as longer and more intensive hospitalizations, according to a study published online in The New England Journal of Medicine. Moreover, the nearly 12 percent who develop more severe AKI have a further increased risk of death within 28 days, according to lead author Stuart L. Goldstein, MD, director of the Center for Acute Care Nephrology at Cincinnati Children's Hospital Medical Center. "The common and early occurrence of acute kidney injury reinforces the need for systematic surveillance for AKI at the time patients are admitted to intensive care," says Dr. Goldstein. "Severe AKI was associated with an increased need for mechanical ventilation to assist breathing, and with renal replacement therapy (acute dialysis). Since children who survive AKI are at risk for developing chronic kidney disease, long-term follow up of these survivors is warranted." Dr. Goldstein and his colleagues collected data from 5,297 patients admitted to 32 pediatric intensive care units in nine countries around the world. To determine AKI, the researchers measured both urine output volumes and levels of creatinine in the blood. Creatinine is a chemical waste molecule transported through the bloodstream to the kidneys, which filter most of the waste and deposit it in the urine. The researchers discovered that severe AKI based on decreased urine output increases the risk of death compared to AKI based on creatinine levels. Assessment using blood creatinine levels alone missed AKI in two thirds of patients with oliguria (a particular measured volume of decreased urine output), and oliguria alone conferred increased mortality risk, according to Dr. Goldstein. This reinforces the importance of using both measures to detect AKI, which he says is not commonly done. The AWARE (Assessment of Worldwide AKI, Renal angina and Epidemiology in children) study was coordinated by the Center for Acute Care Nephrology at Cincinnati Children's. Working closely with other divisions within Cincinnati Children's, the center monitors, detects and treats kidney injury before it causes irreparable damage. The study is being published in conjunction with presentation of the data at Kidney Week 2016, the American Society of Nephrology's annual meeting, in Chicago. The study was supported, in part, by funding from the National Institutes of Health (NIH P50 DK096418). Rajit Basu, MD, a physician in the division of Critical Care Medicine at Cincinnati Children's, was co-lead author of the study. Fourteen subsequent manuscripts are planned for the AWARE dataset. These will include the assessment of novel AKI biomarkers and an early AKI risk scoring system to improve early detection and prediction of severe AKI.


News Article | February 16, 2017
Site: globenewswire.com

CINCINNATI, Feb. 16, 2017 (GLOBE NEWSWIRE) -- The Hyatt Regency Cincinnati announced that Phase Two of its multi-million dollar renovation has commenced, making it the newest full-service, renovated hotel in Cincinnati. Perched in the heart of downtown, The Hyatt Regency Cincinnati sits across the street from the Duke Energy Convention Center, close to many of Cincinnati's largest employers, and a short walk to Over-the-Rhine (OTR), The Banks and the Riverfront Sports Complex, home of the Cincinnati Bengals and Cincinnati Reds stadiums. The hotel includes over 40,000 square feet of versatile meeting space, including the largest hotel ballroom in the city, the Red Roost Tavern, The Market (proudly serving Starbucks® Coffee), a 24-hour full service fitness facility, and an indoor heated saline pool – the first in downtown Cincinnati. www.cincinnati.hyatt.com completed Phase One of their renovation in the summer of 2013 that included all public and meeting spaces (now equipped with electronic reader boards), the restaurant, market, guest room carpet, vinyl, and curtains. New artwork was added throughout the hotel, many of which are Cincinnati inspired themes. Hyatt's complimentary 24-hour StayFit™ gym features the latest high-tech cardio and strength-training equipment, complete with flat-screen televisions from industry leader, Life Fitness®. Every one of the hotel's 491 guest rooms are being refurbished and updated to include crisp white stone finish vanities and desk tops with contemporary gray earth tone furniture, spacious desks, blue tooth docking iHome® clock radios, bedside lighting and will feature the new Hyatt Grand Bed II. The renovation also includes all guest room baths, which are being revitalized with new tile, fixtures, counters, and lights. Recharge after a long day with multiple electrical outlets conveniently located for today's discerning traveler. Included are wall mounted swivel HD televisions. Complimentary phone chargers are available upon request. In addition, the hotel will be converting twelve hospitality suites to studio suites to better meet the needs of guests who need a more functional space during their stay. Many rooms boast stunning river or city views. Meeting planners will enjoy the new features offered with this update, including the new bandwidth control and monitoring platform in the 40,000 square feet of meeting space that is housed in redundant data centers featuring: For more information about The Hyatt Regency Cincinnati, visit www.cincinnati.hyatt.com. Photos accompanying this release are available at:


News Article | February 16, 2017
Site: www.prnewswire.com

CINCINNATI, Feb. 16, 2017 /PRNewswire-USNewswire/ -- Genomic testing of biopsies from patients with deadly, treatment-resistant cancerous blood syndromes called histiocytoses allowed doctors to identify genes fueling the ailments and use targeted molecular drugs to successfully treat...


CINCINNATI, Feb. 16, 2017 /PRNewswire/ -- Home Care Assistance of Cincinnati, the leading provider of in-home care for seniors, announced today that the company received the distinguished Best of Home Care Leader in Excellence Award from Home Care Pulse, the leading firm in quality...


News Article | December 16, 2016
Site: www.prnewswire.com

CINCINNATI, Dec. 16, 2016 /PRNewswire-USNewswire/ -- Cincinnati Children's Hospital Medical Center has appointed Andrew Wooten, M.S., M.B.A., to the position of vice president of its Center for Technology Commercialization (CTC). Wooten will begin his position on Jan. 3, 2017. As...


News Article | November 7, 2016
Site: www.prnewswire.com

CINCINNATI, Nov. 7, 2016 /PRNewswire-USNewswire/ -- Using a person's spoken or written words, new computer tools can identify with great accuracy whether that person is suicidal, mentally ill but not suicidal, or neither. A new study shows that computer technology known as machine...


News Article | February 22, 2017
Site: www.prnewswire.com

CINCINNATI, Feb. 22, 2017 /PRNewswire-USNewswire/ -- Scientists propose in Nature blocking a molecule that drives inflammation and organ damage in Gaucher and maybe other lysosomal storage diseases as a possible treatment with fewer risks and lower costs than current therapies....

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