Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast-phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multi-center analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. Two-hundred two patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the three most common approaches were intensive chemotherapy (IC) (n=65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n=65), and DNMTi + venetoclax (VEN)-based regimens (n=54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet (ELN) AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HCT); median OS was 2.30 years from time of allo-HCT. Our study demonstrates that survival amongst patients with MPN-AP/BP is limited in the absence of allo-HCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

An octameric PqiC toroid stabilises the outer-membrane interaction of the PqiABC transport system.

The E. coli Paraquat Inducible (Pqi) Pathway is a putative Gram-negative phospholipid transport system. The pathway comprises three components: an integral inner membrane protein (PqiA), a periplasmic spanning MCE family protein (PqiB) and an outer membrane lipoprotein (PqiC). Interactions between all complex components, including stoichiometry, remain uncharacterised; nevertheless, once assembled into their quaternary complex, the trio of Pqi proteins are anticipated to provide a continuous channel between the inner and outer membranes of diderms. Here, we present X-ray structures of both the native and a truncated, soluble construct of the PqiC lipoprotein, providing insight into its biological assembly, and utilise neutron reflectometry to characterise the nature of the PqiB-PqiC-membrane interaction. Finally, we employ phenotypic complementation assays to probe specific PqiC residues, which imply the interaction between PqiB and PqiC is less intimate than previously anticipated.

Socioeconomic determinants of the biology and outcomes of acute lymphoblastic leukemia in adults.

ABSTRACT: Various socioeconomic and biologic factors affect cancer health disparities and differences in health outcomes. To better characterize the socioeconomic vs biologic determinants of acute lymphoblastic leukemia (ALL) outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL treated at the University of Chicago (UChicago) from 2010 to 2022 and compared our outcomes with the US national data (the Surveillance, Epidemiology, and End Results [SEER] database). Among 221 adult patients with ALL treated at UChicago, BCR::ABL1 was more frequent in patients with higher body mass index (BMI; odds ratio [OR], 7.64; 95% confidence interval [CI], 1.17-49.9) and non-Hispanic Black (NHB) ancestry (59% vs 24% in non-Hispanic White (NHW) and 20% in Hispanic patients; P = .001). In a multivariable analysis, age (hazard ratio [HR], 6.93; 95% CI, 2.27-21.1) and higher BMI at diagnosis (HR, 10.3; 95% CI, 2.56-41.5) were independent predictors of poor overall survival (OS). In contrast, race or income were not predictors of OS in the UChicago cohort. Analysis of the national SEER database (2010-2020) demonstrated worse survival outcomes in Hispanic and NHB patients than in NHW patients among adolescent and young adults (AYAs) but not in older adults (aged >40 years). Both AYA and older adult patients with higher median household income had better OS than those with lower income. Therefore, multidisciplinary medical care coupled with essential supportive care services offered at centers experienced in ALL care may alleviate the socioeconomic disparities in ALL outcomes in the United States.

Practical and customizable study strategies for clerkship year success.

The transition from a pre-clerkship curriculum to the clerkship year presents a need to re-examine and modify study strategies for clinical subject examinations and ultimately the United States Medical License Examination STEP 2 Clinical Knowledge. Efficient and effective learning are keys in balancing the significantly increased responsibility of patient care and decreased time for examination preparation. We describe several customizable study approaches, advice on selecting resources, and methods for applying the educational framework of deliberate practice and corrective feedback to learning during a medical student's clerkship years. These strategies focus on intentional and outcome-driven self-assessments to identify and patch knowledge gaps tailored to the clerkship year that will empower learners.

Le passage du programme de préexternat à l'année d'externat exige que les étudiants revoient leurs stratégies d'étude pour les examens de matières cliniques et, à terme, pour l'examen STEP 2 Clinical Knowledge du United States Medical License Examination. Un apprentissage efficace et efficient est essentiel pour trouver un équilibre entre l'importante augmentation des responsabilités de soins aux patients et la diminution du temps consacré à la préparation des examens.Nous proposons aux étudiants en médecine plusieurs approches d'étude personnalisables, ainsi que des conseils sur la sélection de ressources et méthodes pour appliquer le modèle éducatif de la pratique délibérée et de la rétroaction corrective à leur apprentissage pendant les années d'externat. Ces stratégies, adaptées à l'année d'externat, sont focalisées sur l'autoévaluation intentionnelle et axée sur les résultats pour repérer et combler les lacunes en matière de connaissances. Elles aideront les apprenants à se sentir en confiance de leurs moyens.

Hydrogen Peroxide Disproportionation Activity Is Sensitive to Pyridine Substitutions on Manganese Catalysts Derived from 12-Membered Tetra-Aza Macrocyclic Ligands.

The abundance of manganese in nature and versatility to access different oxidation states have made manganese complexes attractive as catalysts for oxidation reactions in both biology and industry. Macrocyclic ligands offer the advantage of substantially controlling the reactivity of the manganese center through electronic tuning and steric constraint. Inspired by the manganese catalase enzyme, a biological catalyst for the disproportionation of H2O2 into water and O2, the work herein employs 12-membered tetra-aza macrocyclic ligands to study how the inclusion of and substitution to the pyridine ring on the macrocyclic ligand scaffold impacts the reactivity of the manganese complex as a H2O2 disproportionation catalyst. Synthesis and isolation of the manganese complexes was validated by characterization using UV-vis spectroscopy, SC-XRD, and cyclic voltammetry. Potentiometric titrations were used to study the ligand basicity as well as the thermodynamic equilibrium with Mn(II). Manganese complexes were also produced in situ and characterized using electrochemistry for comparison to the isolated species. Results from these studies and H2O2 reactivity showed a remarkable difference among the ligands studied, revealing instead a distinction in the reactivity regarding the number of pyridine rings within the scaffold. Moreover, electron-donating groups on the 4-position of the pyridine ring enhanced the reactivity of the manganese center for H2O2 disproportionation, demonstrating a handle for control of oxidation reactions using the pyridinophane macrocycle.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. METHODS: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. RESULTS: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. CONCLUSIONS: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate in vitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

Synthesis and characterization of two piperazine containing macrocycles and their transition metal complexes.

Rigidification of the ligand scaffolds has been a particular mechanism of interest employed to achieve properties suitable for MRI contrast, catalysis, or other applications of metal complexes. Towards the goal of targeting a 15-anePyN5Pip type ligand, a serendipitous isolation of a 30-anePy2N10Pip2 aza-macrocycle was achieved, instead. X-ray diffraction and determination of pKa events were carried out and compared to 17-anePyN5Pip. Furthermore, the X-ray diffraction of the Cu(II) and Zn(II) complexes of 17-anePyN5Pip was achieved and compared to previous reports of other first-row transition metal derivatives of this ligand. Determination of the log ß with both 30-anePy2N10Pip2 and 17-anePyN5Pip with the divalent MnZn metal-ion series was used to demonstrate the impact that the piperazine ring plays compared to other, less rigid macrocycles reported to date.

Targeted Therapy for MPNs: Going Beyond JAK Inhibitors.

PURPOSE OF REVIEW: JAK inhibition is an effective means of controlling symptom burden and improving splenomegaly in patients with myeloproliferative neoplasms (MPNs). However, a majority of patients treated with JAK inhibition will have disease progression with long-term use. In In this review, we focus on the investigation of novel targeted agents beyond JAK inhibitors both in the chronic phase of disease and in the accelerated/blast phase of disease. RECENT FINDINGS: Relevant targeted therapies in MPNs include BET inhibitors, BCL inhibitors, LSD1 inhibitors, PI3K inhibitors, IDH inhibitors, telomerase inhibitors, and MDM2 inhibitor. Agents within these classes have been investigated either as monotherapy or in combination with a JAK inhibitor. We summarize the prospective data for these agents along with detailing the ongoing phase III trials incorporating these agents. While JAK inhibition has been a mainstay of therapy in MPNs, a majority of patients will have disease of progression. JAK inhibitors also have limited anti-clonal effect and do not impact the rate of progression to the blast phase of disease. The novel therapies detailed in this review not only show promise in ameliorating the symptom burden of MPNs but may be able to alter the natural history of disease.

Upfront immunotherapy leads to lower brain metastasis velocity in patients undergoing stereotactic radiosurgery for brain metastases.

Background: While immunotherapy has been shown to improve survival and decrease neurologic death in patients with brain metastases, it remains unclear whether this improvement is due to prevention of new metastasis to the brain. Method: We performed a retrospective review of patients presenting with brain metastases simultaneously with the first diagnosis of metastatic disease and were treated with upfront immunotherapy as part of their treatment regimen and stereotactic radiosurgery (SRS) to the brain metastases. We compared this cohort with a historical control population (prior to the immunotherapy era) who were treated with pre-immunotherapy standard of care systemic therapy and with SRS to the brain metastases. Results: Median overall survival time was improved in the patients receiving upfront immunotherapy compared to the historical cohort (48 months vs 8.4 months, p=0.001). Median time to distant brain failure was statistically equivalent (p=0.3) between the upfront immunotherapy cohort and historical control cohort (10.3 vs 12.6 months). Brain metastasis velocity was lower in the upfront immunotherapy cohort (median 3.72 metastases per year) than in the historical controls (median 9.48 metastases per year, p=0.001). Cumulative incidence of neurologic death at one year was 12% in the upfront immunotherapy cohort and 28% in the historical control cohort (p=0.1). Conclusions: Upfront immunotherapy appears to improve overall survival and decrease BMV compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent immunotherapy with SRS.

Manganese (III/IV) µ-Oxo Dimers and Manganese (III) Monomers with Tetraaza Macrocyclic Ligands and Historically Relevant Open-Chain Ligands.

The oxygen-evolving complex (OEC) located in photosystem II (PSII) of green plants is one of the best-known examples of a manganese-containing enzyme in nature, but it is also used in a range of other biological processes. OEC models incorporate two multi-dentate nitrogen-containing ligands coordinated to a bis-µ-oxo Mn(III,IV) core. Open-chain ligands were the initial scaffold used for biomimetic studies, but their macrocyclic counterparts have proven to be particularly appropriate due to their enhanced stability. Dimer and monomer complexes with such ligands have shown to be useful for a wide range of applications, which will be reviewed herein. The purpose of this review is to state with some clarity the different spectroscopic and structural characteristics of the Mn complexes formed with tetraaza macrocyclic ligands both in solution and solid-state that allow the reader to successfully identified the species involved when dealing with similar complexes of Mn.

Co-design with aboriginal and torres strait islander communities: A journey.

AIM: This paper explores the principles of co-design with Aboriginal and Torres Strait Islander communities by reflecting on the literature, learning from experiences of allied health professionals, and considering how co-design can be applied in rural and remote allied health practice. CONTEXT: This paper has been authored by a working group from Services for Rural and Remote Allied Health (SARRAH). SARRAH is a member-based allied health organisation, working to improve health outcomes for rural and remote Australians. SARRAH has been representing and supporting allied health professionals in rural and remote Australia for over 20 years, with a member base that includes students, practitioners, programme managers, policy makers and academics. As a non-Indigenous organisation, SARRAH works in partnership and receives guidance from the peak organisation, Indigenous Allied Health Australia (IAHA). APPROACH: Over a period of 3 months, a group of eleven SARRAH members and staff came together to review available literature, seek member perspectives and share their experiences and understandings of co-design. Working group discussions were grounded in the knowledge and experiences shared by two Aboriginal and Torres Strait Islander group members. CONCLUSION: This paper proposes that successful co-design with Aboriginal and Torres Strait Islander communities places legitimate value on different knowledge systems, is built on strong and trusting relationships, promotes inclusive involvement and requires authentic partnerships. Using these principles, SARRAH will engage with members and stakeholders to influence meaningful change in allied health practice in rural and remote Australia.

Utilising fluorescent reporters to probe the mode of action of norbornen-7-one CO releasing molecules.

The synthesis of the fluorescent organic carbon monoxide releasing molecules oCOm-57, oCOm-58, and oCOm-66 are reported. These oCOms are water soluble and exhibit a "turn-on" fluorescent behaviour when CO is released under physiological conditions. oCOm-66 also contains an additional nitro-naphthalimide moiety that functions as a fluorescent reporter. Delivery of CO released from these oCOms to the mitochondria of AC-16 cardiomyocytes was confirmed using confocal microscopy in conjuction with MitoTracker Red. While the neutral, PEGylated oCOm-57 was found to remain in the extracellular environment releasing CO to diffuse into the cellular compartments, the positively charged oCOm-58 and -66 are targeted to the mitochondria where they release CO. Notably, the use of the fluorescent oCOms in live cellular imaging, allows the intracellular CO delivery and oCOm localisation to be characterised. This cellular confocal study also shows that, subtoxic concentrations of CO released from these molecules preserved mitochondrial energetics as indicated by the membrane potential dependent MitoTracker Red.

Associations Between Physical Activity and Alcohol Consumption in Rural Cancer Survivors.

Purpose: Rural adults and cancer survivors are more likely to be physically inactive and exceed recommendations for alcohol use. Physical activity and alcohol use are positively associated in adults and cancer survivors but associations between physical activity and alcohol use in rural cancer survivors is unknown. This cross-sectional study explored associations between physical activity, sitting time, and alcohol use in rural cancer survivors. Methods: Cancer survivors residing in central Pennsylvania were recruited to the Partnering to Prevent and Control Cancer (PPCC) study and completed mailed questionnaires assessing physical activity (low, moderate, high), sitting time (<6 or ≥6 hours/day), and alcohol use (0 or ≥1 drinks/week). Binary logistic regression models tested associations between physical activity, sitting time, and alcohol use, adjusting for age, gender, and education. Results: Participants (N=219) were in their mid-60s (M age=64.5 ± 12.2 years, 60.7% female), overweight (M BMI=29.6 ± 6.9 kg/m2), and 50.5% were college graduates. Nearly half of participants were breast (22.8%) or prostate (20.5%) cancer survivors and 90.4% were >12 weeks but <5 years post-treatment. Participants self-reported meeting physical activity recommendations (79.5%), sitting <6 hours/day (53.3%), and consuming ≥1 alcoholic drinks/week (54.1%). Participants who reported being moderately (OR=5.0, 95% CI: 1.9-12.9) or highly (OR=4.5, 95% CI: 1.9-10.9) active had higher odds of reporting alcohol use, after adjusting for covariates. Conclusion: Results mirror positive associations seen in adults and other subgroups (e.g., racial/ethnic minority adults). Cancer control efforts should stress being physically active while emphasizing messaging to curtail increases in alcohol use among rural cancer survivors.

Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.

Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.

Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases.

BACKGROUND: Previous series have demonstrated CNS activity for immune checkpoint inhibitors, yet no prior data exists regarding whether this activity can improve outcomes of stereotactic radiosurgery. METHODS: In this single institution retrospective series, the clinical outcomes of 80 consecutive lung cancer patients treated with concurrent immune checkpoint inhibitors and stereotactic radiosurgery were compared to 235 in the historical control cohort in which patients were treated prior to immune checkpoint inhibition being standard upfront therapy. Overall survival was estimated using the Kaplan Meier method. Cumulative incidence of local progression was estimated using a competing risk model. RESULTS: Median overall survival time was improved in patients receiving upfront immunotherapy compared to the historical control group (40 months vs 8 months, p < 0.001). Factors affected overall survival include concurrent immunotherapy (HR 0.23, p < 0.0001) and KPS (HR 0.97, p = 0.0001). Cumulative incidence of local failure in the historical control group was 10% at 1 year, compared to 1.1% at 1 year in the concurrent immunotherapy group (p = 0.025). Factors affected local control included use of concurrent immunotherapy (HR 0.09, p = 0.012), and lowest margin dose delivered to a metastasis (HR 0.8, p = 0.0018). CONCLUSION: Local control and overall survival were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent use of immunotherapy with SRS.

Feasibility and Effectiveness of a Worksite-Weight-Loss Program for Cancer Prevention among School-District Employees with Overweight and Obesity.

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, the VLB (n = 131), VLP (n = 87), and VLP + S (n = 88) groups had average weight losses of 2.5, 2.5, and 3.4 kg, respectively, and average increases in weekly PA of 40.4, 35.8, and 65.7 min, respectively. The VLP + S participants were more likely than the other participants to have clinically significant weight loss (≥3%; p = 0.026). Compared with the VLB participants, the VLP participants were less likely to meet the recommendations for consuming fast food (p = 0.022) and sugar-sweetened beverages (p = 0.010). The VLP and VLP + S participants reported higher program satisfaction than the VLB participants. The VL program facilitates weight loss among school-district employees with overweight and obesity by increasing their PA and healthy diet.

Hydrogen Peroxide Disproportionation with Manganese Macrocyclic Complexes of Cyclen and Pyclen.

The catalase family of enzymes, which include a variety with a binuclear manganese active site, mitigate the risk from reactive oxygen species by facilitating the disproportionation of hydrogen peroxide into molecular oxygen and water. In this work, hydrogen peroxide disproportionation using complexes formed between manganese and cyclen or pyclen were investigated due to the spectroscopic similarities with the native MnCAT enzyme. Potentiometric titrations were used to construct speciation diagrams that identify the manganese complex compositions at different pH values. Each complex behaves as a functional mimic of catalase enzymes. UV-visible spectroscopic investigations of the H2O2 decomposition reaction yielded information about the structure of the initial catalyst and intermediates that include monomeric and dimeric species. The results indicate that rigidity imparted by the pyridine ring of pyclen is a key factor in increased TON and TOF values measured compared to cyclen.

Practitioners' perceptions of the ASQ-TRAK developmental screening tool for use in Aboriginal children: A preliminary survey.

AIM: To determine health practitioners' experience of using the culturally adapted Ages and Stages Questionnaire - Talking about Raising Aboriginal Kids (ASQ-TRAK) and the Ages and Stages Questionnaire-3 (ASQ-3) with Australian Aboriginal families and their perception about parents' acceptability and understanding of the instruments. METHODS: We surveyed a convenience sample of practitioners who had used both the ASQ-TRAK and the ASQ-3 developmental screening tools with Aboriginal children in the Northern Territory and South Australia. We compared their experience and perception about parents' acceptability and understanding of both instruments. RESULTS: All 38 respondents used the ASQ-3 and 35 the ASQ-TRAK; 100% rated the ASQ-TRAK as more acceptable and easier to understand for parents compared with 68% (P < 0.001) and 52.6% (P < 0.001), respectively, for the ASQ-3. A greater proportion of respondents were satisfied using the ASQ-TRAK (100%) than the ASQ-3 (65.7%) (P = 0.003). A higher proportion indicated that the ASQ-TRAK was respectful (85.3% compared with ASQ-3 27.8%, P < 0.001), culturally relevant (70.6% compared to 16.2%, P < 0.001) and engaging (76.5% compared to 16.2%, P < 0.001). Qualitative exploration of respondents' comments supported the quantitative findings. The ASQ-TRAK was considered more culturally appropriate, engaging and useful. CONCLUSIONS: Our findings demonstrate that the culturally adapted ASQ-TRAK is preferred to the ASQ-3 by health practitioners in the Australian Aboriginal context. Failing to address cultural and linguistic factors and applying measurement tools developed for one population to another, is problematic in any setting. While further research is required to explore parents' experience directly, these data provide support for the ASQ-TRAK to be used in this context.

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules.

Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12-membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H2O2)-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H2O2 cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.