Opposing Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Forkhead BoxO 1/3 is Responsible for Sepantronium Bromide's Poor Efficacy and Resistance in Cancer cells: Opportunity for Combination Therapy in Triple Negative Breast Cancer.

Survivin, a cancer-cell-specific multifunctional protein, is regulated by many oncogenic signaling pathways and an effective therapeutic target. Although, several types of survivin-targeting agents have been developed over the past few decades, none of them received clinical approval. This could be because survivin expression is tightly controlled by the feedback interaction between different signaling molecules. Of the several signaling pathways that are known to regulate survivin expression, the phosphatidylinositol 3-kinase/AKT serine-threonine kinase/forkhead boxO (PI3K/AKT/FoxO) pathway is well-known for feedback loops constructed by cross-talk among different molecules. Using sepantronium bromide (YM155), the first of its class of survivin-suppressant, we uncovered the existence of an interesting cross-talk between Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and FoxO transcription factors that also contributes to YM155 resistance in triple negative breast cancer (TNBC) cells. Pharmacological manipulation to interrupt this interaction not only helped restore/enhance the drug-sensitivity but also prompted effective immune clearance of cancer cells. Because the YM155-induced reactive oxygen species (ROS) initiates this feedback, we believe that it will be occurring for many ROS-producing chemotherapeutic agents. Our work provides a rational explanation for the poor efficacy of YM155 compared to standard chemotherapy in clinical trials. Finally, the triple drug combination approach used herein might help reintroducing YM155 into the clinical pipeline, and given the high survivin expression in TNBC cells in general, it could be effective in treating this subtype of breast cancer.

Design, synthesis, molecular docking and anti-proliferative activity of novel phenothiazine containing imidazo[1,2-a]pyridine derivatives against MARK4 protein.

A series of novel phenothiazine-containing imidazo[1,2-a]pyridine derivatives were designed and synthesized under metal-free conditions in excellent yield. These derivatives were effectively transformed further into N-alkyl, sulfoxide, and sulfone derivatives. Derivatives were deployed against human microtubule affinity regulating kinase (MARK4), some molecules play crucial roles in cell-cycle progression such as G1/S transition and regulator of microtubule dynamics. Hence, molecules have shown excellent MARK4 inhibitory potential. Molecules with excellent IC50 values were selected for further studies such as ligand interactions using fluorescence quenching experiments for the binding constant. The highest binding constant was calculated as K = 0.79 × 105 and K = 0.1 × 107 for compounds 6a and 6h, respectively. Molecular docking, cell cytotoxicity, mitochondrial reactive oxygen species measurement and oxidative DNA damage were also studied to understand the mechanism of action of the molecules on cancer cells. It was found that the designed and synthesized compounds played anti-cancer roles by binding and inhibiting MARK4 protein.

Pre-implementation perceptions of clinicians regarding a patient portal in inpatient addictions settings: A qualitative descriptive study.

BACKGROUND: Patient portals have been implemented in many organizations to support patient engagement and empowerment. However, their use in inpatient mental health and addiction settings is relatively new and has not been extensively studied. To address this gap, this study explored clinician perspectives of implementing a patient portal in inpatient addiction settings. METHODS: The study followed qualitative descriptive methodology and used the Consolidated Framework for Implementation Research (CFIR) to guide the research. Interviews were conducted with clinicians working in an inpatient addictions service at a large mental health and addictions teaching hospital in Toronto, Canada. Data analysis was performed using directed content analysis and the CFIR domains. RESULTS: Twelve clinicians participated in semi-structured interviews. Participants included prescribers (such as physicians and nurse practitioners), registered nurses, allied health clinicians, and leadership. Participants had positive attitudes toward the patient portal, believing it would benefit patients and support consistency in healthcare. However, they also expressed reservations about its relevance and value during short inpatient admissions. Clinicians perceived the patient portal as compatible with existing workflows, enhancing patient empowerment and facilitating access to medical documentation. Concerns were raised about potential negative impacts on therapeutic rapport, particularly if patients disagreed with or were upset by the contents of their notes. Adaptations to the portal, such as improving documentation templates and providing detailed medication information, were suggested. Participants also highlighted advantages of the portal, including secure communication and access to laboratory results. CONCLUSIONS: Clinicians generally had positive attitudes toward implementing a patient portal. However, concerns about maintaining therapeutic rapport and the relevance of information to patients were identified, and adaptations were suggested to improve the utility of a portal in the context of short inpatient stays. The findings provide insights into clinician perspectives and can inform the implementation of patient portals in inpatient addiction settings.