Pharmacodynamic Modeling Identifies Synergistic Interaction Between Chloroquine and Trastuzumab in Refractory HER2- positive Breast Cancer Cells.

BACKGROUND/AIM: Despite improvements in HER2-positive breast cancer (BC) patients' outcomes with trastuzumab, the occurrence of intrinsic or acquired resistance presents a clinical challenge. Here, we quantitatively assess the combinatorial effects of chloroquine, an autophagy inhibitor, with trastuzumab on JIMT-1 cells, a HER2-positive BC cell-line primarily resistant to trastuzumab. MATERIALS AND METHODS: The temporal changes in JIMT-1 cellular viability were assessed using the CCK-8 kit, where JIMT-1 cells were exposed for 72-h to trastuzumab (0.007-17.19 µM) or chloroquine (5-50 µM) as single-agents, in combination (trastuzumab: 0.007-0.688 µM; chloroquine: 5-15 µM), or control (no drug). Concentration-response relationships were built for each treatment arm to determine drugs' concentrations inducing 50% of cell-killing (IC50). Cellular pharmacodynamic models were built to characterize the time-trajectory of JIMT-1 cellular viability under each treatment arm. The nature of trastuzumab and chloroquine interaction was quantified by estimating the interaction parameter (Ψ). RESULTS: The IC50 were estimated at 19.7 and 24.4 µM for trastuzumab and chloroquine. The maximum killing effect was about thrice higher for chloroquine than trastuzumab (0.0405 vs. 0.0125 h-1), validating chloroquine's superior anti-cancer effect on JIMT-1 cells compared to trastuzumab. The time-delay for chloroquine cell-killing was twice longer than that for trastuzumab (17.7 vs. 7 h), suggesting a chloroquine time-dependent anti-cancer effect. The Ψ was determined at 0.529 (Ψ<1), indicating a synergistic interaction. CONCLUSION: This proof-of-concept study on JIMT-1 cells identified chloroquine and trastuzumab synergistic interaction, warranting further in vivo investigations.

Probing the nucleotide-binding activity of a redox sensor: two-component regulatory control in chloroplasts.

Two-component signal transduction systems mediate adaptation to environmental changes in bacteria, plants, fungi, and protists. Each two-component system consists of a sensor histidine kinase and a response regulator. Chloroplast sensor kinase (CSK) is a modified sensor histidine kinase found in chloroplasts-photosynthetic organelles of plants and algae. CSK regulates the transcription of chloroplast genes in response to changes in photosynthetic electron transport. In this study, the full-length and truncated forms of Arabidopsis CSK proteins were overexpressed and purified in order to characterise their kinase and redox sensing activities. Our results show that CSK contains a modified kinase catalytic domain that binds ATP with high affinity and forms a quinone adduct that may confer redox sensing activity.

Validity and responsiveness of the German version of the Motor Activity Log for the assessment of self-perceived arm use in hemiplegia after stroke.

BACKGROUND: Rehabilitation of patients after stroke requires valid and responsive assessments for arm and hand function to determine the effectiveness of rehabilitative interventions. The Motor Activity Log (MAL) aims to assess self-perceived arm and hand use after stroke. Its clinimetric properties are incomplete and contradictory. OBJECTIVE: To investigate internal consistency, concurrent validity and responsiveness of the German MAL-30 in patients after stroke with minimal to moderate arm and hand function. METHODS: 42 patients were included in this longitudinal prospective cohort study. Internal consistency was determined in a complete-case analysis with Cronbach's α. Concurrent validity was assessed with Spearman' rho by comparing the German MAL-30 with Wolf Motor Function Test, Chedoke McMaster Stroke Assessment, isometric elbow, shoulder and grip strength at baseline, post-treatment and 6 month follow-up. Responsiveness was determined separately for lower and higher arm and hand function by calculating the standardized response mean. RESULTS: Internal consistency was excellent (Cronbach's α = 0.94-0.99), concurrent validity good to excellent (Spearman's rho = 0.64-0.99). Responsiveness was high for both functional levels from baseline to discharge (SRM = 0.93-1.43) and to follow-up (SRM = 0.95-1.34). CONCLUSION: The German MAL-30 is a valid and responsive assessment for self-perceived arm and hand use after stroke even when function is low.

The impact of denial on health-related quality of life in patients with HIV.

BACKGROUND/PURPOSE: The purpose of this study was to examine the influence of denial coping on quality of life (QOL) over time among individuals living with HIV, as denial has been understudied as a coping strategy within the literature on HIV/AIDS. METHODS: In a sample of 65 adult men and women, we used multilevel linear modeling to test trajectories of change in physical and mental health-related QOL across baseline, 3, 6, and 12 months, including denial as a predictor and gender as a moderator. RESULTS: The use of denial coping was associated with lower physical and mental health-related QOL at baseline. Denial coping predicted an increase in QOL over time, though QOL remained low in those who practiced denial coping. Men's baseline mental health-related QOL was more negatively affected by denial coping than women's. Women tended to increase in QOL more slowly over time compared to men. CONCLUSION: Reliance on denial as a coping strategy is associated with poorer physical and mental health-related QOL in an HIV-positive population, though participants who engaged in denial also displayed more rapid improvement in their QOL over time. Men and women displayed different rates of improvement in QOL, indicating a need for gender-based treatment approaches. Future research should examine the complex role of denial on change in QOL.

Potential effectiveness of three different treatment approaches to improve minimal to moderate arm and hand function after stroke--a pilot randomized clinical trial.

OBJECTIVE: To test a study design and explore the feasibility and potential effects of conventional neurological therapy, constraint induced therapy and therapeutic climbing to improve minimal to moderate arm and hand function in patients after a stroke. METHOD: A pilot study with six-month follow-up in patients after stroke with minimal to moderate arm and hand function admitted for inpatient rehabilitation was performed. Participants were randomly allocated to one of three treatment approaches. Main outcomes were improvement of arm and hand function and adverse effects. RESULTS: 283 patients with stroke were screened for inclusion over a two-year period, out of which fourtyfour were included. All patients could be treated according to the protocol. Improvement of arm and hand function was significantly higher in conventional neurological therapy and constraint induced therapy compared with therapeutic climbing at discharge, and at six months follow-up (P < 0.05, effect size = 0.56-0.76). No significant differences in arm and hand function were observed between constraint induced therapy and conventional neurological therapy. Constraint induced therapy participants were significantly less at risk of developing shoulder pain at six months follow-up compared with the other participants (P < 0.05, effect size = 0.82 and 1.79, respectively). CONCLUSIONS: The study design needs adaptation to accommodate the stringent inclusion criteria leading to prolonged study duration. Constraint induced therapy seems to be the optimal approach to improve arm and hand function and minimize the risk of shoulder pain for patients with minimal to moderate arm hand function after stroke in the intermediate term.