The 15 species of small carnivorous marsupials that comprise the genus Antechinus exhibit semelparity, a rare life-history strategy where death occurs after one breeding season. Antechinus males, but not females, age rapidly (demonstrate organismal senescence) during the breeding season and show promise as new animal models of ageing. Some antechinus species are also threatened or endangered. Here, we report chromosome-level genomes of the yellow-footed antechinus Antechinus flavipes. The genome assembly has a total length of 3.2 Gb with a contig N50 of 51.8 Mb and a scaffold N50 of 636.7 Mb. We anchored and oriented 99.7% of the assembly on seven pseudochromosomes and found that repetitive DNA sequences occupy 51.8% of the genome. Draft genome assemblies of three related species in the subfamily Phascogalinae, two additional antechinus species (A. argentus and A. arktos) and the iteroparous sister species Murexia melanurus were also generated. Preliminary demographic analysis supports the hypothesis that climate change during the Pleistocene isolated species in Phascogalinae and shaped their population size. A transcriptomic profile across the A. flavipes breeding season allowed us to identify genes associated with aspects of the male die-off. The chromosome-level A. flavipes genome provides a steppingstone to understanding an enigmatic life-history strategy and a resource to assist the conservation of antechinuses.

The 15 species of small carnivorous marsupials that comprise the genus Antechinus exhibit semelparity, a rare life-history strategy in mammals where synchronized death occurs after one breeding season. Antechinus males, but not females, age rapidly (demonstrate organismal senescence) during the breeding season and show promise as new animal models of ageing. Some antechinus species are also threatened or endangered. Here, we report a chromosome-level genome of a male yellow-footed antechinus Antechinus flavipes. The genome assembly has a total length of 3.2 Gb with a contig N50 of 51.8 Mb and a scaffold N50 of 636.7 Mb. We anchored and oriented 99.7% of the assembly on seven pseudochromosomes and found that repetitive DNA sequences occupy 51.8% of the genome. Draft genome assemblies of three related species in the subfamily Phascogalinae, two additional antechinus species (Antechinus argentus and A. arktos) and the iteroparous sister species Murexia melanurus, were also generated. Preliminary demographic analysis supports the hypothesis that climate change during the Pleistocene isolated species in Phascogalinae and shaped their population size. A transcriptomic profile across the A. flavipes breeding season allowed us to identify genes associated with aspects of the male die-off. The chromosome-level A. flavipes genome provides a steppingstone to understanding an enigmatic life-history strategy and a resource to assist the conservation of antechinuses.

Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM response. Mesenchymal breast cancer cell lines, as well as the mesenchymal variant in an isogenic EMT/MET human breast cancer cell system (PMC42-ET/LA), were more sensitive to PAM treatment than their epithelial counterparts, contrary to their responses to other therapies. The same trend was seen in luminal muscle-invasive bladder cancer model (TSU-Pr1/B1/B2) and the non-muscle-invasive basal 5637 bladder cancer cell line. Three-dimensional spheroid cultures of the bladder cancer cell lines were less sensitive to the PAM treatment compared to their two-dimensional counterparts; however, incrementally better responses were again seen in more mesenchymally-shifted cell lines. This study provides evidence that PAM preferentially inhibits mesenchymally-shifted carcinoma cells, which have been associated with resistance to other therapies. Thus, PAM may represent a novel treatment that can selectively inhibit triple-negative breast cancers and a subset of aggressive bladder cancers, which tend to be more mesenchymal. Our approach may potentially be utilized for other aggressive cancers exhibiting EMT and opens new opportunities for CAP and PAM as a promising new onco-therapy.

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 ( CUX1 ) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1 -deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.

PURPOSE:Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS:ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS:PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION:We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

Reprogramming of cellular pathways is a crucial mechanism of drug resistance and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, we performed an unbiased gene expression analysis and identified a dysfunctional mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within the electron transport chain was significantly downregulated, correlated with decreased mitochondrial mass and ATP production in drug-resistant ALL cells. To validate mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in several ALL cell lines grown alone or in co-culture with BMSC. To increase the bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar to PP on the mitochondrial respiration. Importantly, PP’s cell death activity was found to be specific for leukemic cells as primary normal immune cells were resistant to PP-mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells.

On the 14th of September 2018, we lost a colleague, mentor, teacher, and friend, Giulio D'Angio, the father of pediatric radiation oncology and 1999 American Society for Radiation Oncology Gold Medal recipient. He died peacefully at home surrounded by his family. Dr D'Angio's impact on and influence in the fields of pediatric oncology and pediatric radiation oncology were unmatched. During his long and fruitful life, Dan achieved much, encouraged many, and passed his knowledge and wisdom to countless students, residents, and colleagues. This is in addition to the countless patients who have benefited from his knowledge. Born on May 2, 1922, Dan was a true giant in several medical specialties: diagnostic radiology, radiation oncology, pediatric oncology, and cancer survivorship. The second son of Italian immigrants, Dan was raised in Brooklyn, New York, and earned an undergraduate degree at Columbia University. He applied for admission to Harvard Medical School (HMS) during the era of widespread anti-Semitic and anti-Italian Roman Catholic restrictive admissions quotas. After an interview with Harvard's director of medical school admissions, Dr Worth Hale, where he was advised that there were restrictions on admitting “too many students whose names end in vowels” he was admitted to HMS, where, as he said, he was “the only Italian-American in his class.” His training was interrupted by World War II; he served in the Pacific theatre and had a brief stint in Florence to study the classics before returning to Boston. He was trained by world-renowned surgeons, radiologists, and other physicians and then joined the nascent efforts at Boston Children's Hospital with Sidney Farber to usher in the era of chemotherapy for cancer. One of Dan's most important early contributions was demonstrating how radiation therapy and chemotherapy can act synergistically, and he was responsible for some of the first cures of metastatic Wilms tumor in children. In an interview with Dr Edward C. Halperin for the American Society for Radiation Oncology History Committee, Dan was asked how he became interested in radiation oncology as he had been orientated toward diagnostic radiology. He replied“Yes, that was the training. You did both diagnostic and therapeutic radiology. There was no such thing as separate training in radiation oncology. It didn't exist. In those days, radiation therapy in Boston, as in most major cities, was a black hole. It was really terrible. If you got cutaneous erythema with 250 kV x-rays with large-field radiation, it was evidence of malpractice. So you can imagine what happened to the skin of a lady who had postoperative chest wall radiation therapy after a radical mastectomy, she got a lot of radiation and a lot of erythema! Anyhow, the Korean War broke out and the man who was in charge of radiation therapy was called to the colors to go off into the Navy. Dr Max Ritvowe, who was the chief of the program, called me in one day and said, “D'Angio, I've been watching you.” “Yes, sir,” he said. “You hate radiation therapy the least among all the residents, so you're in charge.” That was it. That was absolutely it. We had truly only a smattering of exposure. And then through complicated false reports that I was leaving the Boston City Hospital, Dick Wittenborg [Martin “Dick” Wittenborg, 1914-1969, published important papers on the effect of radiation therapy on the growing spines of children and on the management of neuroblastoma], who was one of the real pioneers in pediatric radiation therapy, called me and said, “How would you like to do radiation therapy at the Children's Hospital?” and I loved the Children's. I had done my internship there in surgery with Dr Robert E. Gross [Robert E. Gross, 1905-1988, served on the HMS faculty for over 40 years and was a pioneer in pediatric surgery], so going back to the Children's was almost a dream. In many ways, the lack of training was a help because you had no precedents, you had no fixed ideas as to what to do. It was all new. And just at that time, effective chemotherapy was just coming into the picture, so the development of the combined therapy was due largely to Dr Sidney Farber who believed in coordinated care, total care and that dictum about cure not being enough for children. So all of that just was part of the air I breathed. I didn't have to manufacture anything personally; it was the way things were done. And it turned out to be quite successful—not because of me, but because of the model.” When Dr Halperin asked what gave him the most satisfaction in his professional life, Dr D'Angio replied, without hesitation, “To get a letter from one of my patients saying that she's had a baby.” Perhaps Dan's most important professional achievements arose from his humble and collegial spirit. Dan had the vision to bring multidisciplinary investigators together by founding the National Wilms Tumor Study Group in 1969. Although combination therapy was able to bring about cures in this pediatric tumor, Dan recognized the harmful effects of radiation therapy on young children and courageously organized the first randomized clinical trial that reduced the use of this curative, but sometimes harmful, modality. He was proven correct, and subsequent clinical trials adhered to his famous admonition to oncologists: “Cure is not enough.” As pediatric oncologists became more successful, he led the efforts to understand the harmful consequences of cancer therapy in young children and organized efforts to avoid them. Early in his career, he learned from Dr Farber that families with a sick child require consideration of total care and sought ways to reduce the psychosocial and economic burdens of childhood cancer. The lessons from his leadership have been applied across the landscape of pediatric cancers and have had an impact on the care of patients and families. Dan became the Chairman of Radiation Therapy at the University of Minnesota in 1964 and then served as Chairman of Radiation Therapy at the Memorial Sloane Kettering Cancer Center in 1968. After being recruited to the University of Pennsylvania and Children's Hospital of Philadelphia in 1976, he solidified his life-long collaboration with Dr Audrey Evans and had an immeasurable impact on children and families in the Philadelphia region. Working with Dr C. Everett Koop, they described the remarkable spontaneous regression of an identifiable subset of neuroblastoma in infants, and together they developed the Evans-D'Angio staging system for neuroblastoma that is the basis for the staging system we use today. Drs D'Angio and Evans were married just before her 80th birthday, and they were inseparable partners. Dan led the Childhood Cancer Research Center at Children's Hospital of Philadelphia and built the foundation for the current “bench-to-bedside and back” research efforts across our campus today. He was the founder of several currently robust organizations, including the Society for Pediatric Radiology, the Pediatric Radiation Oncology Society, the Histiocyte Society, and the Late Effects Study Group, which ultimately led to the Office of Cancer Survivorship at the National Institutes of Health. He mentored hundreds of young investigators from across the world, creating what could be called Dan and Audrey's international family, and published over 500 manuscripts, some of which remain absolute classics in the field. Dan had an international impact. He became a full member of International Society of Pediatric Oncology (SIOP) during the 4th SIOP Annual Meeting held in Manchester in 1972, 4 years after the Society was founded. He was among the first North American doctors accepted as a full member in the Society. Since then, the story of this society has been marked by his presence, by his extraordinary stature as a clinical scientist, by his vision, by his determination and commitment, but above all, by his unique capacity for building global human and scientific networks, which represent one of his main legacies to the Society. He served SIOP as president between 1986 and 1988, edited for many years its international journal, and promoted a series of worldwide collaborative research and education efforts. His last contribution to SIOP is dated in 2015, at the age of 93, when he published in a special 50-page edition of Pediatric Blood and Cancer, the “History of SIOP.” Finally, on October 12, 2017, in Washington, during the opening ceremony of the 48th Annual Meeting, SIOP acknowledged his tremendous contribution to the field of pediatric oncology and to the life of the Society with a special prize: the Lifetime Achievement Award. Needless to say, Dr Audrey Evans was a co-recipient. Although he had many professional achievements, Dan was internationally known as the ultimate bow-tied gentleman—kind, polite, and always most interested in what others had to say. His family always came first, and he was blessed with 2 sons, 2 grandchildren, and 2 great-grandchildren who enjoyed visits to his Rittenhouse Square balcony. A voracious reader, he could hold court on a remarkable breadth of subjects, from the arts to military history, and readily shared his books with others. Dr Evans composed a fitting epitaph: “Dan's eyes have closed. They will open in a better world than this. Our love travels with him. He will be greatly missed.”

“Determine that the thing can and shall be done, and then we will find the way.”—Abraham Lincoln Moody Wharam graduated cum laude from Harvard in 1963 and entered the United States Naval Reserve with service on the U.S.S. Blandy. He received his medical degree from the University of Virginia in 1969. He served a combined medicine/pediatrics internship at Georgetown University that foreshadowed his academic career as an adult and pediatric radiation oncologist. From 1970 to 1973, he served as a National Institutes of Health fellow in radiation oncology at the University of California at San Francisco (UCSF), working with many luminaries in our field, including J. Franz Bushske, Theodore Phillips, Karen Fu, and William Wara. During this time he also served as a visiting resident at the University of Virginia. He remained as a clinical instructor at UCSF from 1973 to 1974, and after a year at Duke University, he became a faculty member at Johns Hopkins (JH), where he remained for the balance of his career. As an exceptionally respected member of the JH medical community, Moody held professorships in the departments of radiation oncology, radiological science, neurosurgery, and pediatrics. During his residency at UCSF he published several articles demonstrating his longstanding interest in science and applied science to clinical care. In 1973, he published articles on tumor models evaluating the response to chemotherapy and radiation therapy in mammary carcinomas both in vitro and in vivo. In 1974 he published a well-recognized article demonstrating unintended euoxic and hypoxic tumor protection with thiophosphate compounds. In 1975, he published one of the first articles demonstrating modification of radiation injury with chemotherapy, including pulmonary metastasis from both sarcoma and germ cell tumors of the testis. His work with the excellent team at UCSF established a disciplined pathway for his academic work, well recognized throughout his career.1Wharam M.D. Phillips T.L. Kane L. Utley J.F. Response of a murine tumor model to in vivo combined chemotherapy and irradiation.Radiology. 1973; 109: 451-455Crossref PubMed Scopus (50) Google Scholar, 2Utley J.F. Phillips T.L. Kane L.J. Wharam M.D. Wara W.M. Differential radioprotection of euoxic and hypoxic mouse mammary tumors by a thiophosphate compound.Radiology. 1974; 110: 213-216Crossref PubMed Scopus (31) Google Scholar, 3Wharam M.D. Phillips T.L. Jacobs E.M. Combination chemotherapy and whole lung irradiation for pulmonary metastases from sarcomas and germinal cell tumors of the testis.Cancer. 1974; 34: 136-142Crossref PubMed Scopus (15) Google Scholar, 4Phillips T.L. Wharam M.D. Margolis L.W. Modification of radiation injury to normal tissues by chemotherapeutic agents.Cancer. 1975; 35: 1678-1684Crossref PubMed Scopus (211) Google Scholar, 5Fu K.K. Phillips T.L. Wharam M.D. Radiation response of artificial pulmonary metastases of the EMT6 tumor.Int J Radiat Oncol Biol Phys. 1976; 1: 257-260Abstract Full Text PDF PubMed Scopus (27) Google Scholar Moody's expertise in adult and pediatric oncology was well acknowledged at JH. He published articles with colleagues in central nervous system cancer, head/neck carcinoma, prostate cancer, endometrial cancer, and hepatic malignancies treated with systemic radiation therapy. He was one of the first investigators to publish on the relationship between transurethral resection of the prostate and patient outcome and to describe postprostatectomy radiation therapy as adjuvant and definitive treatment. He was one of the first investigators to advocate for fractionation of total body irradiation for bone marrow transplantation to ameliorate negative sequelae of overall management. He published articles identifying risk factors for pneumonitis associated with bone marrow transplantation.6Kaiser H. Leventhal B.G. Wharam M.D. et al.Cryopreserved autologous bone marrow transplantation in the treatment of selected pediatric malignancies: A preliminary report.Transplant Proc. 1979; 11: 208-211PubMed Google Scholar, 7Lichter A.S. Tutschka P.J. Wharam M.D. et al.The use of fractionated radiotherapy as preparation for allogeneic bone marrow transplantation.Transplant Proc. 1979; 11: 1492-1494PubMed Google Scholar, 8Pino Y. Torres J.L. Bross D.S. et al.Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation.Int J Radiat Oncol Biol Phys. 1982; 8: 1301-1307Abstract Full Text PDF PubMed Scopus (81) Google Scholar, 9Wharam M.D. Phillips T.L. Bagshaw M.A. The role of radiation therapy in clinical stage I carcinoma of the endometrium.Int J Radiat Oncol Biol Phys. 1976; 1: 1081-1089Abstract Full Text PDF PubMed Scopus (34) Google Scholar, 10Lee D.J. Wharam M.D. Kashima H. Order S.E. Short course high fractional dose irradiation in advanced and recurrent head and neck cancer.Int J Radiat Oncol Biol Phys. 1979; 5: 1829-1832Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 11Leibel S.A. Wharam M.D. Vaginal and paraaortic lymph node metastases in carcinoma of the endometrium.Int J Radiat Oncol Biol Phys. 1980; 6: 893-896Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 12Taxy J.B. Ettinger D.S. Wharam M.D. Primary small cell carcinoma of the skin.Cancer. 1980; 46: 2308-2311Crossref PubMed Scopus (99) Google Scholar, 13Forman J.D. Zinreich E. Lee D.J. Wharam M.D. Baumgardner R.A. Order S.E. Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate.Int J Radiat Oncol Biol Phys. 1985; 11: 2073-2080Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 14Forman J.D. Order S.E. Zinreich E.S. Lee D.J. Wharam M.D. Mellits E.D. The correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and disease-free survival. A univariate and multivariate analysis.Cancer. 1986; 58: 1770-1778Crossref PubMed Scopus (44) Google Scholar, 15Order S.E. Klein J.L. Leiclmer P.K. Wharam M.D. Ettinger D.S. Siegelman S.S. Advances in iodine 131-labeled antiferritin immunoglobulin cancer therapy.Cancer Bull. 1982; 34: 264-267Google Scholar, 16Williams J.A. Wessels B.W. Edwards J.A. et al.Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies.Cancer Res. 1980; 50: 974s-979sGoogle Scholar He was one of the first investigators to publish the importance of volumetric imaging for planning of radiation therapy.17Wharam M.D. Order S.E. Treatment planning in radiation therapy: Maximization by CT.Appl Radiol. 1980; 9: 50-55Google Scholar, 18Rostock R.A. Giangreco A. Wharam M.D. Lenhard R. Siegelman S.S. Order S.E. CT scan modification in the treatment of mediastinal Hodgkin’s disease.Cancer. 1982; 49: 2267-2275Crossref PubMed Scopus (39) Google Scholar Supporting the academic development of many residents and students from multiple oncology-related disciplines, Moody provided significant value to the JH medical community and the entire radiation oncology community. His national and international recognition as an oncology leader and radiation oncologist was in the field of pediatrics. He published seminal articles in pediatric oncology on liquid and solid tumor diseases with key investigators in all disciplines.19Sullivan M.P. Fuller L.M. Chen T. et al.Intergroup Hodgkin’s disease in children study of stages I and II: A preliminary report.Cancer Treat Rep. 1982; 66: 937-947PubMed Google Scholar, 20Hays D.M. Turnberg J.L. Chen T.T. et al.Complications related to 234 staging laparotomies performed in the Intergroup Hodgkin’s Disease in Childhood study.Surgery. 1984; 96: 471-478PubMed Google Scholar, 21Gehan E.A. Sullivan M.P. Fuller L.M. et al.The intergroup Hodgkin’s disease in children: A study of stages I and II.Cancer. 1990; 65: 1429-1437Crossref PubMed Scopus (48) Google Scholar, 22Strauss L.C. Killmond T.M. Carson B.S. Maria B.L. Wharam M.D. Leventhal B.G. Efficacy of postoperative chemotherapy using cisplatin plus etoposide in young children with brain tumors.Pediatr Blood Cancer. 1991; 19: 16-21Google Scholar, 23Castleberry R.P. Kun L.E. Shuster J.J. et al.Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma.J Clin Oncol. 1991; 9: 789-795Crossref PubMed Scopus (93) Google Scholar, 24Bunin N.J. Hvizdala E. Link M. et al.Mediastinal nonlymphoblastic lymphomas in children: A clinicopathologic study.J Clin Oncol. 1986; 4: 154-159Crossref PubMed Scopus (29) Google Scholar, 25Horowitz M.E. Ewing’s sarcoma: Current status of diagnosis and treatment.Oncology (Williston Park). 1989; 3 (discussion 106-109): 101-106PubMed Google Scholar In this early era, when there were two pediatric oncology groups, it was recognized that to conduct successful studies, harmonization among the groups and oncology disciplines was essential for successful accrual and trial management. At the inception of the Pediatric Oncology Group, Moody served the critical role representing radiation oncology as chairman of the Radiation Discipline Committee from 1981 to 1991. His leadership was insightful and impressive, ensuring objective understanding of the role of radiation therapy in pediatric cancers and the importance of carefully assessing the late effects that determined the therapeutic ratio. Moody's thoughtful approach, thorough demeanor, and apt management style allowed the groups to succeed in an integrated model for multiple disease sites. His leadership skill supported and brought together diverse groups and medical disciplines for a common purpose with the singular goal of improving outcome for patients. He was part of the Intergroup publication on Hodgkin lymphoma in 1982,19Sullivan M.P. Fuller L.M. Chen T. et al.Intergroup Hodgkin’s disease in children study of stages I and II: A preliminary report.Cancer Treat Rep. 1982; 66: 937-947PubMed Google Scholar with several important publications evaluating therapeutic augmentation and titration in selected circumstances based on stage and response to induction therapy. Moody advocated for two arms in the Pediatric Oncology Group 8625 trial that randomly assigned patients to either radiation therapy or no radiation therapy for Hodgkin disease. This predecessor trial led to the design of the Children's Oncology Group paradigm of response-based, risk-adapted therapy for pediatric Hodgkin disease. In the field of pediatric soft tissue sarcoma, including rhabdomyosarcoma, his expertise in building bridges between groups and medical disciplines became essential to the harmonization and success of the Intergroup effort. Of his 159 total publications, he published no fewer than 30 articles in this area, including outcome analysis and complications of therapy. Within the Intergroup Rhabdomyosarcoma Study Group, Moody's leadership with his good friend Sarah Donaldson enhanced collaboration with pediatric colleagues from all disciplines and increased respect for radiation oncology as a discipline. Together they let facts drive the conversation and friendly compromise define the final protocol. The publications generated by the Intergroup Rhabdomyosarcoma Study Group established the standard of care for children affected by this disease. Cooperation among the disciplines became the model within the soon to be formed Children's Oncology Group. Moody understood that to succeed in clinical trial management in the cooperative group environment, the whole had to become greater than the sum of the parts, and patients would benefit from this effort. His quiet leadership brought unparalleled success to our discipline.26Wharam Jr., M.D. Foulkes M.A. Lawrence Jr., W. et al.Soft tissue sarcoma of the head and neck in childhood: Nonorbital and nonparameningeal sites. A report of the Intergroup Rhabdomyosarcoma Study (IRS)-I.Cancer. 1984; 53: 1016-1019Crossref PubMed Scopus (56) Google Scholar, 27Crist W.M. Raney R.B. Ragab A. et al.Intensive chemotherapy including cisplatin with or without etoposide for children with soft-tissue sarcomas.Med Pediatr Oncol. 1987; 15: 51-57Crossref PubMed Scopus (20) Google Scholar, 28Lawrence Jr., W. Hays D.M. Heyn R. et al.Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study.Cancer. 1987; 60: 910-915Crossref PubMed Scopus (102) Google Scholar, 29Wharam M.D. Beltangady M.S. Heyn R.M. et al.Pediatric orofacial and laryngopharyngeal rhabdomyosarcoma. An Intergroup Rhabdomyosarcoma Study Report.Arch Otolaryngol Head Neck Surg. 1987; 113: 1225-1227Crossref PubMed Scopus (36) Google Scholar, 30Wharam M. Beltangady M. Hays D. et al.Localized orbital rhabdomyosarcoma. An interim report of the Intergroup Rhabdomyosarcoma Study Committee.Ophthalmology. 1987; 94: 251-254Abstract Full Text PDF PubMed Scopus (73) Google Scholar, 31Maurer H.M. Crist W. Lawrence W. et al.The Intergroup Rhabdomyosarcoma Study-I. A final report.Cancer. 1988; 61: 209-220Crossref PubMed Scopus (802) Google Scholar, 32Crist W.M. Garnsey L. Beltangady M.S. et al.Prognosis in children with rhabdomyosarcoma: A report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee.J Clin Oncol. 1990; 8: 443-452Crossref PubMed Scopus (233) Google Scholar, 33Heyn R. Haeberlen V. Newton W.A. et al.Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Committee.J Clin Oncol. 1993; 11: 262-270Crossref PubMed Scopus (169) Google Scholar, 34Maurer H.M. Gehan E.A. Beltangady M. et al.The Intergroup Rhabdomyosarcoma Study-II.Cancer. 1993; 71: 1904-1922Crossref PubMed Scopus (492) Google Scholar, 35Crist W. Gehan E.A. Ragab A.H. et al.The Third Intergroup Rhabdomyosarcoma Study.J Clin Oncol. 1995; 13: 610-630Crossref PubMed Scopus (825) Google Scholar As a leader in the cooperative groups, Moody was important in the career development of many of our contemporary leaders, including Jeff Michalski, Suzanne Wolden, John Breneman, Lynn Million, and Stephanie Terezakis, and many trainees in the JH community, including Drs Jabbour, Timmerman, Raben, and DeWeese.36Breneman J.C. Lyden E. Pappo A.S. et al.Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma—A report from the Intergroup Rhabdomyosarcoma Study IV.J Clin Oncol. 2003; 21: 78-84Crossref PubMed Scopus (349) Google Scholar, 37Wharam M.D. Meza J. Anderson J. et al.Failure pattern and factors predictive of local failure in rhabdomyosarcoma: A report of group III patients on the third Intergroup Rhabdomyosarcoma Study.J Clin Oncol. 2004; 22: 1902-1908Crossref PubMed Scopus (63) Google Scholar, 38Michalski J.M. Meza J. Breneman J.C. et al.Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV.Int J Radiat Oncol Biol Phys. 2004; 59: 1027-1038Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 39Million L. Anderson J. Breneman J. et al.Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: A report from the Children’s Oncology Group.Int J Radiat Oncol Biol Phys. 2011; 80: 333-338Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 40Terezakis S.A. Wharam M.D. Radiotherapy for rhabdomyosarcoma: Indications and outcome.Clin Oncol. 2013; 25: 27-35Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar He was an outstanding mentor and supported young investigators pursuing secondary and tertiary analyses. These articles were very important because they often identified issues and limitations in outcome that were then addressed in the next series of sarcoma protocols. Moody believed there was value in sound, validated databases to be used as translational research libraries for generations of investigators. In the later part of his career, Moody was selected as one of a few experts to write appropriateness criteria guidelines for radiation therapy and radiosurgery for patients with central nervous system diseases. This elite group of investigators, including Edward Shaw and Jay Loeffler, wrote criteria and guidelines for all of us to follow. Many of these criteria and guidelines remain valid today.41Simpson J.R. Mendenhall W.M. Schupak K.D. et al.Follow-up and retreatment of brain metastasis.Radiology. 2000; 215 (American College of Radiology. ACR Appropriateness Criteria): 1129-1135PubMed Google Scholar He served on many important committees for the American Society for Radiation Oncology, including Constitution and Bylaws, Awards, and the Annual Meeting Program. He was an examiner for the American Board of Radiology and a member of the Radiation Oncology Residency Review Committee of the Accreditation Council for Graduate Medical Education. Moody was a strong advocate for quality assurance. He understood that successful clinical trial execution could only be of value if patients were treated in a uniform manner. This is especially important in pediatrics; this population does not easily lend itself to randomization because radiation techniques require alternative strategies to validate the importance of radiation therapy with this patient population. He advocated for uniform queryable databases to draw the information needed to support clinical trial management. Moody was one of the longstanding advisors to the Quality Assurance Review Center (QARC) and would monitor activities at QARC for continuous process improvements in data acquisition and data management. His advice was prescient, and he would help prepare QARC for the challenges of data management for future studies. He attended every QARC site visit and often spoke of his own experience in quality assurance to the National Institutes of Health review panels. QARC is indebted to Moody for his indefatigable support, and QARC is a better organization because of the longstanding relationship with Moody Wharam. Although his contributions in national and international forum are well documented, Moody was most noted for his work with his own patients. He personally provided calm direction, warmth, and gentle honesty to patients and parents to help them process the impact of disease on outcome. He was a student of these situations and would follow the trajectory of both disease and impact of treatment on normal tissue. Moody had a wonderful way with young patients, with a kind smile and a warm laugh. He would often walk into an examination room with his long white coat, remove his Harvard class ring, and toss it gently into his other hand and place it into his pocket before examining the patient. Residents would often in a humorous but respectful way emulate this action and toss their own rings into the air and into their pockets. He was the consummate professional. Patients and families with routine would contact Moody years after his care to express thanks and gratitude for his support during their treatment. In his emeritus status, Moody was always in support of and available to JH faculty for coverage and to provide advice for academic issues. He remained a well-respected member of the faculty. Everyone in the JH radiation oncology community and our community at large was affected when he received the diagnosis of the life-altering and life-threatening illness, amyotrophic lateral sclerosis. In his poem “Dignity,” Bob Dylan states that an Englishman is staring into a “blackheart wind/Combin’ his hair back, his future looks thin/Bites the bullet and looks within/For dignity.” The verse parallels Moody's response to his situation: He accepted his fate with a dignity this disease did not deserve. In a later verse, Dylan states that someone gave him a photograph and Dylan simply had to laugh as he was told that “Dignity had never been photographed.” Dylan was perceptive and correct. Dignity had been photographed, and Dignity's name is Moody Wharam.42Dylan B. Bob Dylan’s Greatest Hits Volume 3 [compact disc]. Columbia Records, New York1994Google Scholar Moody met several of his goals, including seeing his 77th birthday and his 50th wedding anniversary). When his nervous system could no longer support life, carbon dioxide exacted its final toll. Moody was immediately brought to the place most of us can and will only imagine. He was greeted by relatives and friends congratulating him for a job well done and a race well run. Among the first to greet him was his good friend, Larry Kun. Out of the background came a man with a snow-colored beard, above-average height with a stocky build wearing a pressed tropical beige khaki suit. As he approached Moody, he spoke in a melodious, powerful voice well known in public places of refreshment from Spain to Cuba and from Nantucket to Key West. He shook Moody's hand with his right hand while supporting a gin martini in his left. He said his name was Hemingway. As he drew Moody close, he said “Dr Wharam, although these words were directed to Santiago, you were the individual I imagined when I wrote that ‘real courage is grace under pressure.’”43Hemingway E. Maxwell C. The Old Man and the Sea. 1st ed. Life Magazine, New York1952Google Scholar As we say goodbye to Moody, we will remember his academic discipline, patient care excellence, and personable, dignified demeanor we all try to emulate.Sheila and Moody Wharam celebrating their 50th wedding anniversary. Image courtesy of Sheila Wharam.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Purpose To improve the event-free survival (EFS) and overall survival (OS) for patients with clear cell sarcoma of the kidney (CCSK) by incorporating cyclophosphamide and etoposide into treatment on National Wilms Tumor Study (NWTS)-5. Patients and methods Results Patients less than 16 years of age with a centrally confirmed pathological diagnosis of CCSK were eligible for treatment on this prospective single-arm study conducted between August 1995 and June 2002. Staging consisted of CT scans of chest, abdomen, pelvis, bone scan, skeletal survey, and CT or MRI of the head. Treatment consisted of vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide for 24 weeks and radiation to sites of disease. One hundred eight eligible patients were enrolled on study (69% males, 63% Caucasian), with a median age of 22 months. Stage distribution was as follows: stage I, 12; II, 44; III, 45; IV, 7. Median follow-up was 9.7 years. Five-year EFS and OS were 79% (95% CI: 71%-88%) and 90% (95% CI: 84%-96%). Five-year EFS for stage I-IV was 100%, 88%, 73%, and 29%, respectively. Twenty of the 23 disease-related events occurred within three years of initial treatment. The most common site of recurrence was brain (12/23). Conclusion The outcome for patients with CCSK treated on NWTS-5 was similar to NWTS-4 and accomplished over a shorter treatment duration. Stage was highly predictive of outcome. Brain metastases occurred more frequently than on NWTS-4. Regimen I showed more benefit for patients with stage I and II disease as compared with higher stages of disease where new therapies are needed.

Abstract Long non-coding RNA (lncRNA) genes are abundant in the human genome, and many are now recognized as oncogenes and/or tumor suppressors. We previously characterized the structure of GHRLOS, an antisense gene on the opposite strand of the multifunctional ghrelin gene (GHRL), however, its expression and function in disease has not been described. To this end, using The Cancer Genome Atlas (TCGA) data set, we revealed that GHRLOS is differentially expressed in a number of cancers. In particular, expression was elevated in endometrial cancer (1.2 - fold; P = 7.1 x 10-3 Welch's two-sample t-test; n = 24 vs. n = 175) and prostate cancer (1.2-fold; P = 3.7 x 10-6; n = 52 vs. n = 498) compared to normal tissues. Using qRT-PCR (and commercial cDNA panels) we confirmed that GHRLOS expression was upregulated in endometrial cancer (1.96-fold, P = 0.005 Welch’s two-sample t-test, n = 5 vs. n = 17) and prostate cancer (2.46-fold, P = 0.0045 Welch’s two-sample t-test, n = 5 vs. n = 21) compared to normal tissues. Initial studies, using siRNA designed to silence endogenous GHRLOS expression, significantly reduced cell migration in the PC3 prostate cancer cell line (0.47-fold change, P = 0.042 Kruskal-Wallis test, n = 2) conversely, preliminary data using forced GHRLOS overexpression increased migration and proliferation. Taken together, we show that the long non-coding RNA GHRLOS is differentially expressed in tumor tissue and regulates cell migration and proliferation; possibly by modulating alternative splicing of the overlapping, multifunctional ghrelin gene locus. Targeting GHRLOS could provide a valuable and novel way to target the ghrelin axis in disease. Ongoing studies aim to validate in vitro functional results in complementary mouse xenograft models and identify genes and pathways regulated by this novel lncRNA. Citation Format: Esha T. Shah, Penny Jeffery, Patrick Thomas, Inge Seim, Lisa Chopin. A role for the long non-coding RNA GHRLOS in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3491. doi:10.1158/1538-7445.AM2017-3491

Long non-coding RNAs (lncRNAs) play key regulatory roles in cancer progression and are novel therapeutic targets. We recently discovered an lncRNA termed GHSROS (GHSR opposite strand) on the antisense strand of the ghrelin receptor gene (GHSR). Using quantitative RT-PCR, we demonstrated that GHSROS is highly expressed in a subset of high-grade prostate cancers. GHSROS over-expression significantly increased cell proliferation and migration in the PC3 (1.76 ± 0.18 fold, P<0.01; 1.54 ± 0.35 fold, P<0.05) and DU145 prostate cancer cell lines (1.74 fold ± 0.73 P<0.01; 1.94 ± 0.43 fold, P<0.01). Tumour volumes were significantly increased in both PC3 and DU145 GHSROS over-expressing prostate cancer cell line xenografts in NOD/SCID mice (P<0.05). Preliminary studies indicate that up-regulation of GHSROS confers resistance to the androgen receptor (AR) antagonist enzalutamide and the chemotherapeutic drug docetaxel, both of which are used to treat advanced prostate cancer. Through high-throughput transcriptome sequencing (RNA-seq) ~400 differentially expressed genes were identified in GHSROS over-expressing PC3 cells, demonstrating enrichment of genes associated with motility, survival, and regulation of cell growth. From this gene set, concept mapping and interrogation of publicly-available clinical prostate cancer data sets revealed a 34-gene signature associated with poorer disease outcome and metastatic progression in patients. Analysis of The Cancer Genome Atlas (TCGA) data suggests that the signature has potential as a prognostic indicator for disease free- or overall survival for numerous cancers. Finally, locked nucleic acid antisense oligonucleotide (LNA-ASO) inhibition of endogenous GHSROS expression reciprocally regulated cell growth (RNV124: -1.14 ± 0.06, P = 0.049 and RNV104L: -1.18 ± 0.05, P = 0.030), migration (RNV124: -1.96 ± 0.11, P = 0.004) and gene expression changes. Taken together, we therefore propose that GHSROS has clinical significance as a potential target for novel antisense therapy.

Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established "site of sanctuary" for ALL, as well as myeloid-lineage hematopoietic disease, with signals in this unique anatomic location contributing to drug resistance. Several models have been developed to recapitulate the interactions between the BMM and ALL cells. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant subset of leukemic cells during coculture with BMM elements. Preclinical in vivo models have advantages, but can be costly, and are often not fully informed by optimal in vitro studies. We describe an innovative extension of 2-D coculture wherein ALL cells uniquely interact with bone marrow-derived stromal cells. Tumor cells in this model bury beneath primary human bone marrow-derived stromal cells or osteoblasts, termed "phase dim" ALL, and exhibit a unique phenotype characterized by altered metabolism, distinct protein expression profiles, increased quiescence, and pronounced chemotherapy resistance. Investigation focused on the phase dim subpopulation may more efficiently inform preclinical design and investigation of the minimal residual disease and relapse that arise from BMM-supported leukemic tumor cells. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

BACKGROUND:Despite advancements in our understanding of the importance of stress reduction in achieving good health, we still only have limited insight into the impact of stress on cellular function. Recent studies have suggested that exposure to prolonged psychological stress may alter an individual's physiological responses, and contribute to morbidity and mortality. This paper presents an overview of the study protocol we are using to examine the impact of life stressors on lifestyle factors, health-related quality of life and novel and established biomarkers of stress in midlife and older Australian women.The primary aim of this study is to explore the links between chronic psychological stress on both subjective and objective health markers in midlife and older Australian women. The study examines the extent to which exposure frightening, upsetting or stressful events such as natural disasters, illness or death of a relative, miscarriage and relationship conflict is correlated with a variety of objective and subjective health markers.METHODS/DESIGN:This study is embedded within the longitudinal Healthy Aging of Women's study which has collected data from midlife and older Australian women at 5 yearly intervals since 2001, and uses the Allostastic model of women's health by Groër and colleagues in 2010. The current study expands the focus of the HOW study and will assess the impact of life stressors on quality of life and clinical biomarkers in midlife and older Australian women to explain the impact of chronic psychological stress in women.DISCUSSION:The proposed study hypothesizes that women are at increased risk of exposure to multiple or repeated stressors, some being unique to women, and the frequency and chronicity of stressors increases women's risk of adverse health outcomes. This study aims to further our understanding of the relationships between stressful life experiences, perceived quality of life, stress biomarkers, chronic illness, and health status in women.