Development and Validation of an Assessment-Driven Behavioral Intervention for Primary Complex Motor Stereotypies in Young Children.

Complex motor stereotypies are rhythmic, repetitive, fixed, and non-goal directed movements (e.g., bilateral flapping/waving movements of the hands/arms). Movements typically begin in early childhood and can occur in otherwise normally developing ("primary") or autistic ("secondary") children. Stereotypies persist, occur multiple times a day, have prolonged durations, can be socially stigmatizing, and may lead to bullying and isolation. Prior behavioral treatment studies have focused on older children (ages 6-12) and report modest reductions in stereotypy (i.e., between 14% and 33%). The current study involves the functional assessment and treatment of five children with Primary Complex Motor Stereotypy using a modified awareness training procedure, differential reinforcement of other behavior, and schedule thinning in a nonconcurrent multiple baseline design. Results suggest a 99% reduction of motor stereotypy from baseline across all participants.

The role of task preference in the effectiveness of response interruption and redirection.

Response interruption and redirection (RIRD) is a common treatment for automatically reinforced vocal stereotypy; it involves the contingent presentation of task instructions. Tasks that are included in RIRD are typically selected based on caregiver report, which may affect the efficacy of RIRD. The purpose of the current study was to evaluate the role of task preference in the efficacy of RIRD for four participants who engaged in vocal stereotypy. We conducted task-preference assessments and selected tasks of varying preferences to include in RIRD. For three out of four participants, the results showed that RIRD with higher preference tasks was not effective at reducing vocal stereotypy, whereas RIRD with lower preference tasks was effective for all participants.

Caregiver involvement in applied behavior-analytic research: A scoping review and discussion.

We conducted a scoping review to characterize the role of caregiver involvement in behavior-analytic research. We reviewed eight behavioral-learning journals from 2011-2022 for works that included children or caregivers as participants and characterized caregiver involvement as passive (implications for caregivers, input, social validity) and active (implementation, caregiver behavior, training, caregiver-collected data). The review identified 228 studies, and almost all (96.1%; n = 219) involved caregivers in some capacity; 94.3% (n = 215) had passive involvement (26.8% had only passive involvement; n = 61), 69.3% (n = 158) had active involvement (1.8% had only active involvement; n = 4), and 3.9% (n = 9) had neither passive nor active involvement. Involvement generally increased over publication years. The most common types of involvement were implications for caregivers, implementation, and input; caregiver-collected data were rare. We propose considerations when engaging caregivers in research and suggest new avenues of inquiry related to caregivers' treatment objectives and social validity, treatment implementers, and caregiver-collected data.

Feasibility and Acceptability of a Compressed Caregiver Training Program to Treat Child Behavior Problems.

In an effort to address some of the criticisms of Behavioral Parent Training programs (BPT; high attrition, reliance on caregiver report measures), the current study examined the feasibility, acceptability, and outcome of an intensive behavior treatment program (120-minute sessions for 5 days/week over the course of 2 weeks). Using a changing criterion single case experimental design, 12 children (M child age = 4.9 years) and their primary caregivers completed the 2-week function-based intervention procedure designed to increase children's frustration tolerance via a wait training procedure based on the principles of applied behavior analysis. Using both direct observation and standardized measures, results indicated that the treatment was effective in reducing childhood behavior problems, both within and between appointments (Cohen's ds = 3.2 and 1.37, respectively). Preliminary evidence suggests that a compressed treatment package designed to train caregivers in function-based intervention strategies is feasible and acceptable.

Discovery and development of anticancer agents from marine sponges: perspectives based on a chemistry-experimental therapeutics collaborative program.

A collaborative program was initiated in 1990 between the natural product chemistry laboratory of Dr. Phillip Crews at the University of California Santa Cruz and the experimental therapeutics laboratory of Dr. Fred Valeriote at the Henry Ford Hospital in Detroit. The program focused on the discovery and development of anticancer drugs from sponge extracts. A novel in vitro disk diffusion, solid tumor selective assay was used to examine 2,036 extracts from 683 individual sponges. The bioassay-directed fractionation discovery component led to the identification of active pure compounds from many of these sponges. In most cases, pure compound was prepared in sufficient quantities to both chemically identify the active compound(s) as well as pursue one or more of the biological development components. The latter included IC50, clonogenic survival-concentration exposure, maximum tolerated dose, pharmacokinetics and therapeutic assessment studies. Solid tumor selective compounds included fascaplysin and 10-bromofascaplysin (Fascaplysinopsis), neoamphimedine, 5-methoxyneoamphimedine and alpkinidine (Xestospongia), makaluvamine C and makaluvamine H (Zyzzya), psymberin (Psammocinia and Ircinia), and ethylplakortide Z and ethyldidehydroplakortide Z (Plakortis). These compounds or analogs thereof continue to have therapeutic potential.

Effects of Demand Complexity on Echolalia in Students With Autism.

Echolalia is a linguistic phenomenon common in individuals with autism spectrum disorder. We examined the relationship between demand complexity and immediate echolalia in four students with an autism diagnosis in a university-based academic setting. Mastered and novel antecedent verbal demands that required an intraverbal response were systematically alternated using a multielement design to test whether participants' immediate echolalia was socially mediated. Results showed that immediate echolalia was more likely to occur during complex novel intraverbal tasks than in any other condition. Implications for function-based treatment strategies are discussed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40617-020-00535-7.

Synthesis and Biological Evaluation of Novel N-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer.

A new series of isoxazole derivatives, N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six N-phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the in vitro disk-diffusion assay and IC50 cytotoxicity determination. The results showed that one of the derivatives, compound 3,N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50 of 2.5 µg/mL for both cell lines. Western blot analysis showed that compound 3 significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound 3 may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound 3 is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound 3 is a new N-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound 3 inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer.

Alteration of the bis-tetrahydrofuran core stereochemistries in asimicin can affect the cytotoxicity.

A systematic analysis using 10 synthetic asimicin stereoisomers revealed that the stereochemistry of the bis-tetrahydrofuran core, including the tetrahydrofuran rings and the adjacent hydroxy functions, had significant effect on its cytotoxicity. Our findings set to rest the highly controversial perception that the stereochemistry of the tetrahydrofuran core has little effect on the activity, which is not true for its cytotoxic effect, and also reinforces the previous conclusion that asimicin is a highly potent anticancer compound.

Interrogating the bioactive pharmacophore of the latrunculin chemotype by investigating the metabolites of two taxonomically unrelated sponges.

This study involved a campaign to isolate and study additional latrunculin analogues from two taxonomically unrelated sponges, Cacospongia mycofijiensis and Negombata magnifica. A total of 13 latrunculin analogues were obtained by four different ways, reisolation (1-4), our repository (5, 6), new derivatives (7-12), and a synthetic analogue (7a). The structures of the new metabolites were elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, application of DFT calculations, and the preparation of acetonide derivative 7a. The cytotoxicities against both murine and human cancer cell lines observed for 1, 2, 7, 7a, 8, 9, and 12 were significant, and the IC(50) range was 0.5-10 microM. Among the cytotoxic derivatives, compound 9 did not exhibit microfilament-disrupting activity at 5 microM. The implications of this observation and the value of further therapeutic study on key latrunculin derivatives are discussed.

Preclinical efficacy evaluations of XK-469: dose schedule, route and cross-resistance behavior in tumor bearing mice.

XK-469 is advancing to Phase I clinical trials. Preclinical studies were carried out to assist in clinical applications. DOSE-SCHEDULE ROUTE TESTING: Single dose i.v. treatment with XK-469 produced lethality (LD20 to LD100) above 142 mg/kg. Optimum treatment required total dosages of 350 to 600 mg/kg. Furthermore, high individual i.v. dosages (100 to 142 mg/kg) were poorly tolerated, producing substantial weight loss (8 to 18% of body weight), poor appearance, and slow recovery (8 to 12 days). A 1-hour infusion of dosages more than 140 mg/kg, or BID injections 6 hrs apart, did not reduce lethality. However, lower individual dosages of 40 to 50 mg/kg/injection i.v. were well tolerated and could be given daily to reach an optimum total dose with minimal toxicities. Likewise, 75 mg/kg/injection i.v. could be used every other day to reach optimal treatment. The necropsy profiles of deaths from toxic dosages were essentially identical regardless of schedule (deaths 4 to 7 days post treatment). The profiles were: paralytic ileus or gastroparesis; GI epithelial damage; and marrow toxicity. Interestingly, the key lethal events were rapidly reversible and simple to overcome with lower dosages given daily or every other day. Based on these results, the high dose, Q21 day schedule should be avoided in clinical applications. Instead, a split dose regimen is recommended (e.g., daily, every other day, or twice weekly). XK-469 was also well tolerated by the oral route, requiring 35% higher dosages p.o. to reach the same efficacy and toxicity as produced i.v.. CROSS-RESISTANCE STUDIES: XK-469 resistance was produced by optimum treatments of i.v. implanted L1210 leukemia over seven passage generations. This leukemia subline (L1210/XK469) had reduced sensitivity to VP-16 (with a 4.0 log kill in i.v. implanted L1210/XK469 compared to an 8.0 log kill against i.v. implanted L1210/0). It also had a reduction in the sensitivity to 5-FU (with a 2.0 log kill in the implanted L1210/XK469 compared to a 4.0 log kill against i.v. implanted L1210/0). Other agents were approximately as active against the resistant tumor, including: Ara-C, Gemzar, Cytoxan, BCNU, DTIC, and CisDDPT. No case of collateral sensitivity was observed; i.e., no agent was markedly more active against the resistant subline L1210/XK-469 than against the parent tumor in mice.