Preclinical models of soft tissue sarcomas - generation and applications to enhance translational research.

Soft tissue sarcomas (STS) represent a large group of rare and ultra-rare tumors distinguished by unique morphological, molecular and clinical features. Patients with such rare cancers are generally underrepresented in clinical trials which has limited the introduction of new treatment options and subsequent improvement of patient outcomes. Preclinical models of STS that recapitulate the human disease can aid progress in identifying new effective treatments.

Diagnostic accuracy of Ages and Stages Questionnaire, Third Edition to identify abnormal or delayed gross motor development in high-risk infants.

Aim: To investigate the diagnostic accuracy of parent-completed Ages and Stages Questionnaire, Third Edition (ASQ-3) to identify abnormal or delayed gross motor development in infants born less than 1000 g or less than 28 weeks gestation.

Methods: Prospective cohort study of high-risk infants comparing ASQ-3 as the index test with concurrent score on Alberta Infant Motor Scale (AIMS) as the reference standard, at 4-, 8- and 12-month corrected (post-term) age. Reference standard positivity cut-offs were 'Abnormal motor development' (AIMS Clinical Range) and 'Motor delay' (AIMS score >1 SD below mean, not captured in Clinical Range).

Development of a Clinical Framework for the Assessment of Dyskinesia and Function in the Upper Limb in Children with Cerebral Palsy.

Objective: Dyskinesia in cerebral palsy (CP) is a complex movement disorder that can significantly impact upper limb function. Despite a range of available tools, there is no consensus on best practice assessment of upper limb function in children with CP and dyskinesia. This study aimed to develop a clinical framework for the assessment of the impact of dyskinesia on upper limb function in children with CP.

'Low-normal' motor skills in infants at high risk for poor developmental outcomes: A prevalence and prognostic study.

Aim: To investigate the prevalence and prognostic value of 'low-normal' motor skills in infants at high-risk for poor developmental outcomes.

Method: Infants born extremely low-birthweight and extremely preterm discharged from neonatal intensive care between 2015 and 2018 completed the Alberta Infant Motor Scale (AIMS), Neuro-Sensory Motor Developmental Assessment (NSMDA) at corrected age 4, 8, and 12 months, and Griffiths Mental Development Scale at corrected age 12 months.

Results: Participating infants (n = 191) with a mean gestational age (95% confidence interval [CI]) of 26.

A New Interprofessional Community-Service Learning Program, HATS (Health Ambassador Teams for Seniors) to Improve Older Adults Attitudes about Telehealth and Functionality.

Senior population health often is underrepresented in curricula for medical and allied health students. Furthermore, entrenched and dense curricular schedules preclude interprofessional teams from clinical experiences related to senior population health. Community service learning potentially offers the opportunity to engage interprofessional students with a panel of older adults to assess health promotion metrics over time.

Modeling mycorrhizal fungi dispersal by the mycophagous swamp wallaby ().

Despite the importance of mammal-fungal interactions, tools to estimate the mammal-assisted dispersal distances of fungi are lacking. Many mammals actively consume fungal fruiting bodies, the spores of which remain viable after passage through their digestive tract. Many of these fungi form symbiotic relationships with trees and provide an array of other key ecosystem functions.

Unmasking the complexity of species identification in Australasian flying-foxes.

Pteropus (flying-foxes) are a speciose group of non-echolocating large bats, with five extant Australian species and 24 additional species distributed amongst the Pacific Islands. In 2015, an injured flying-fox with unusual facial markings was found in Sydney, Australia, following severe and widespread storms. Based on an initial assessment, the individual belonged to Pteropus but could not be readily identified to species.

Are behaviour problems in extremely low-birthweight children related to their motor ability?

Aim: To investigate whether behaviour problems are independently related to mild motor impairment in 11-13-year-old children born preterm with extremely low birthweight (ELBW).

Methods: The cross-sectional study included 48 (27 males) non-disabled, otherwise healthy ELBW children (<1000 g) and 55 (28 males) term-born peers. Parents reported behaviour using the Child Behaviour Checklist (CBCL).

Fitness limitations in non-disabled extremely low birthweight adolescents.

Aim: This study aims to compare non-disabled otherwise healthy extremely low birthweight (ELBW) (<1000 g) children and term-born peers in an investigation of relationship between cardiorespiratory endurance and parent report of competence.

Methods: Forty-eight of 105 eligible ELBW 11- to 13-year-old children (27 male) and 55 term-born school peers (28 male) completed a 20-m shuttle run, anthropometric measures, respiratory function tests and the Motor Assessment Battery for Children. Parents completed the Child Behavior Checklist (CBCL).

Perinatal events and motor performance of children born with ELBW and nondisabled.

Purpose: To explore the relationship between perinatal variables and motor performance in children who were born with extremely low birth weight (ELBW) and were nondisabled at 1 and 4 years.

Methods: Children without neurological or cognitive impairment (n = 48) born weighing less than 1000 g between 1992 and 1994 were assessed at 1 and 4 years corrected age using the Neurosensory Motor Developmental Assessment (NSMDA). Scores were used to categorize motor performance as normal or abnormal.

Perinatal factors in non-disabled ELBW school children and later performance.

Aim: To determine the association between perinatal events and subsequent motor performance, cardiorespiratory endurance and respiratory function in non-disabled extremely low birthweight (ELBW) school children at 12 years of age.

Methods: Forty-eight ELBW infants were included in this study. The Movement Assessment Battery for Children (MABC), VO(2) max score as a measure of cardiorespiratory endurance and respiratory function testing were performed and perinatal variables were extracted from the children's hospital files.

The long-term predictive validity of early motor development in "apparently normal" ELBW survivors.

Background: Within the able majority of ELBW survivors, there is a lack of identified predictors of which children will require extra support despite having escaped significant disability.

Aims: Investigate the predictive validity of early motor scores, compared to that of perinatal descriptors or early growth, on long-term motor impairment in non-disabled ELBW (<1000g) children.

Study Design: Prospective longitudinal study.

'Cort short on a mountaintop' - Eight new species of sequestrate Cortinarius from sub-alpine Australia and affinities to sections within the genus.

During the course of research on mammal mycophagy and movement in the Northern Tablelands of New South Wales, Australia, extensive collections of sequestrate fungi were made, including numerous cortinarioid taxa. Historically any novel taxa would have been described in the cortinarioid sequestrate genera Descomyces, Hymenogaster, Protoglossum, Quadrispora, Thaxterogaster or Timgrovea based on broad morphological similarities of the sporocarps and spore ornamentation. However, consistent with other recent analyses of nuclear DNA regions, taxa from sequestrate genera were found to have affinities with Cortinarius and Descolea or Hebeloma, and to be scattered across many sections within Cortinarius.

New therapeutic targets for the treatment of high-risk neuroblastoma.

High-risk neuroblastoma remains a major problem in pediatric oncology, accounting for 15% of childhood cancer deaths. Although incremental improvements in outcome have been achieved with the intensification of conventional chemotherapy agents and the addition of 13-cis-retinoic acid, only one-third of children with high-risk disease are expected to be long-term survivors when treated with current regimens. In addition, the cost of cure can be quite high, as surviving children remain at risk for additional health problems related to long-term toxicities of treatment.

Cell adhesion molecules as targets for therapy of neuroblastoma.

Cell adhesion molecules (CAMs) are glycoproteins expressed on the surface of cell membranes. In normal cells, CAMs participate in a variety of biological processes including cell proliferation, migration and differentiation. In tumor cells, CAMs have been reported to function as oncogenes or tumor suppressors, in signal transduction and as regulators of tumor progression and metastasis.

Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis.

Purpose: Osteoprotegerin (OPG) inhibits osteoclast activation and reduces osteolysis in bone tumors. We hypothesized that tumor-tropic neural progenitor cells (NPCs) engineered to express OPG would reduce neuroblastoma disease burden in the bone.

Methods: Stable expression of green fluorescent protein (NPC-GFP) and OPG (NPC-OPG) was established in human NPCs by lentivirus-mediated transduction.

Motor coordination difficulties and physical fitness of extremely-low-birthweight children.

Motor coordination difficulties and poor fitness exist in the extremely low birthweight (ELBW) population. This study investigated the relative impact of motor coordination on the fitness of ELBW children aged 11 to 13 years. One hundred and nine children were recruited to the study: 54 ELBW participants (mean age at assessment 12y 6mo; 31 male, 23 female; mean birthweight 769g, SD 148g; mean gestational age 26.

Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide.

Background: We have shown that continuous systemic delivery of interferon beta (IFN-beta) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-beta could also effect maturation of tumor vasculature without generating high systemic levels of IFN-beta.

Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-beta only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-beta in combination with CTX.

Stem and progenitor cell-mediated tumor selective gene therapy.

The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX).

An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11.

CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE.

Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report.

Purpose: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O(6)-benzylguanine in patients < or =21 years with recurrent brain tumors.

Experimental Design: Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.

Planarity and constraint of the carbonyl groups in 1,2-diones are determinants for selective inhibition of human carboxylesterase 1.

Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics, including numerous clinically used drugs. Therefore, the selective inhibition of these proteins may prove useful in modulating drug half-life and bioavailability. Recently, we identified 1,2-diones as potent inhibitors of CEs, although little selectivity was observed in the inhibition of either human liver CE (hCE1) or human intestinal CE (hiCE).

Targeting methylguanine-DNA methyltransferase in the treatment of neuroblastoma.

Purpose: The combination of temozolomide and irinotecan has preclinical schedule-dependent synergy against neuroblastoma but is not curative for relapsed high-risk patients. We hypothesized that the DNA repair protein methylguanine-DNA methyltransferase (MGMT) is an important resistance factor, and that inactivation of MGMT would sensitize neuroblastoma cells to these agents.

Experimental Design: MGMT protein expression was assessed in 74 primary neuroblastoma tumors.

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo.

Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma.

Neural stem cells and progenitor cells migrate selectively to tumor loci in vivo. We exploited the tumor-tropic properties of HB1.F3.