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XLSX file - 24K, PCR Primer sequences.

PDF file - 113K, Bcl2 protein expression in wild-type and Tyk2 knockout mice.

PDF file - 74K, Knockdown efficiency and BCL2 expression in JURKAT cells.

XLSX file - 525K, Summary of inducible shRNA screen on three T-ALL cell lines.

PDF file - 138K

PDF file - 32K, Expressions of IL-10 and IL-10 receptors, and effect of an anti-IL10 neutralizing antibody on growth of T-ALL cell lines.

XLSX file - 30K, Targeting sequences for shRNAs.

PDF file - 68K, Cell cycle distribution after TYK2 knockdown in T-ALL cells.

XLSX file - 14291K, TYK2 genotype in 17 T-ALL cell lines.

XLSX file - 35K, Sensitivities to TYK2 knockdown and JAK Inhibitor I treatment, and phosphorylation status of downstream signaling molecules in T-ALL cell lines and Ba/F3 clones.

PDF file - 61K, Validation of shRNA constructs.

XLSX file - 36K, Cell viability profile by RAPID assay.

PDF file - 273K, Confirmation of CD3 expression on OP9 DL1 outgrowth cells.

PDF file - 24K, Effect of JAK kinase inhibitors with varying TYK2-specificity on growth and viability of T-ALL cells.

XLSX file - 23K, Clinical, biologic and molecular characteristics of the T-ALL patient samples analyzed. See separate file.

PDF file - 105K, Signaling and cell cycle distribution after JAK inhibitor I treatment.

Background: Children with relapsed CNS tumors, neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. Here we describe a study to determine the feasibility of leveraging genomic profiling results within a molecular tumor board (MTB) to make real-time treatment decisions for children with relapsed/refractory solid tumors. Methods: Subjects were divided to 3 strata: Strata 1: Relapsed/refractory neuroblastoma, Strata 2: Relapsed/refractory CNS tumors, and Strata 3: Relapsed/refractory rare solid tumors. Samples were sent for tumor/normal whole exome (WES) and tumor whole transcriptome sequencing, and the genomic data were used in a MTB to make real-time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of CR, PR, SD, NED, and PD subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. Results: 144 eligible subjects were enrolled with 144 evaluable for safety and 124 evaluable for response. Tumor types included neuroblastoma (n=31), CNS tumors (n=41), and rare tumors (n=72). Sarcomas (n=40) were the most common tumor type in the rare tumor stratum. The average time from biopsy to completion of DNA/RNA sequencing was 10 days (range 2-31 days); to completed analysis and drug prediction report, 17 days (8-41); 23 days (10-66) to MTB decisions; and 38 days (18-146) to initiation of the 4-drug combination agreed upon by the MTB. Treatments were selected on DNA and RNA findings in 19.5% of cases and in 80.5% on RNA alone. Patient benefit was exhibited in 70% of all subjects, 85% of neuroblastoma subjects, 73% of CNS tumor subjects, and 62% of rare tumor subjects. AEs occurred in Conclusions: It has been well-established that comprehensive genomic sequencing is the future of precision medicine. Here, we have demonstrated the feasibility, efficacy, and safety of a comprehensive sequencing model to guide targeted therapy for patients with any relapsed/refractory solid malignancies. Targeted therapy was well tolerated, and the response benefit rate of 70% in these heavily pretreated populations suggests that this treatment could be an effective option for relapsed and refractory pediatric cancers. Citation Format: Giselle L. Saulner Sholler, Jacqueline Kraveka, Genevieve Bergendahl, Elizabeth Lewis, William Ferguson, Abhinav Nagulapally, Karl Dykema, Valerie Brown, Michael Isakoff, Joseph Junewick, Deanna Mitchell, Don Eslin, Virginia Harrod, William Roberts, Javier Oesterheld, Randy Wada, Jawhar Rawwas, Devang Pastakia, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang, Gina Hanna, Daniel Enriquez, Tyler Izatt, Rebecca Halperin, Sara Byron, William Hendricks, Jeffrey Trent. Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT089.

Objectives This study examined the effects of sacubitril/valsartan on N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. Background NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). Methods Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline. Results In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p Conclusions In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217)

Counting bands via the gastric mill is a potential direct approach for ageing crayfish; however, the validity of ageing crustaceans using the gastric mill is unknown. Our study objectives were to 1) compare gastric mill age estimates to a traditional aging technique, 2) compare ageing precision among the ossicles, and 3) examine the effects of temperature on gastric mill band formation. From 2017–2018, we collected 681 ringed crayfish Faxonius neglectus neglectus (Faxon) from ten Ozark Highland streams. Our length-frequency analysis reflected seven age classes, whereas gastric mill age estimates indicated individuals were up to 10 yr of age. The length-frequency analysis age estimates showed good congruence (± 1 yr) with age estimates from the gastric mill 78% of the time. The coefficient of variation (CV) of age estimates from gastric mill bands between our readers was 29.7%. Ageing precision was highest when using the zygocardiac ossicles (CV = 12.4%). Gastric mill age estimates for known age-1 crayfish from a thermally stable laboratory were not significantly different from one, whereas age estimates from a thermally varying laboratory were greater than one. Our results indicate molting frequency does not control gastric mill band formation, and temperature plays a role in band formation.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.

Background Survival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients. Procedure The biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research. Results Originally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals. Conclusions These samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma. Pediatr Blood Cancer 2015;62:450–455. © 2014 Wiley Periodicals, Inc.

Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications.

Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications.

Survival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients.The biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research.Originally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals.These samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma.

ILLiad is an interlibrary loan borrowing system designed and implemented in the University Libraries at Virginia Tech. ILLiad models the ILL borrowing process so as to track the status of an ILL request as it is processed, either by the staff or by software. This process approach to automating interlibrary loan is leading to fundamental improvements in ILL management and service. The process approach allows continued expansion and modification of the system, including the addition of electronic delivery of articles. The process approach results in substantial improvements in customer service by allowing customers to intervene directly in the borrowing process without staff assistance.

10053 Background: Survival rates of osteosarcoma patients have remained stagnant over the last twenty years. Predictive biomarkers of response to treatment and likelihood of recurrence are yet to be developed. In order to develop new therapeutics and better risk-stratified regimens, a greater understanding of osteosarcoma biology is needed. The Children’s Oncology Group (COG) addressed this need by banking more than 10,000 tumor and tissue samples from over 1500 patients with osteosarcoma, but many samples lacked clinically relevant data. Methods: 1105 eligible patients enrolled on the COG osteosarcoma biology study P9851. Of those, 510 patients were not enrolled on a concurrent therapeutic trial, which limited the clinical annotation of those samples. 589 patients have enrolled on the successor study AOST06B1. The lack of clinical annotation of the P9851 specimens limited their value, and the lack of statistical support slowed the analysis of several biology studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) in 2008 to link clinically annotated patient data to the samples and to provide statistical support. Results: In 2008, only 5.3% of samples from the 510 P9851 patients not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses. As a result, 18 biology studies in osteosarcoma are completed, with 11 published in peer-reviewed journals. Samples were provided to the TARGET program (for gene expression arrays, copy number analysis, and sequencing data); the resulting data will be available to the scientific community for in silico studies. Conclusions: The efforts of the CSBAO have led to a substantial increase in the value of a large osteosarcoma biospecimen repository by clinically annotating the specimens and providing statistical resources for analyses of planned and completed studies. These samples with annotated patient information are available by request to the research community for basic and translational science projects to improve the biological understanding of, and the treatment of patients with osteosarcoma. Clinical trial information: NCT00899275.