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The available data suggest that among cellular constituents, proteins are the major target for oxidation primarily because of their quantity and high rate of interactions with ROS. Proteins are susceptible to ROS modifications of amino acid side chains which alter protein structure. Among the amino acids, Cysteine (Cys) is more prone to oxidation by ROS because of its high nucleophilic property. The reactivity of Cys with ROS is due to the presence of thiol group. In the oxidised form, Cys forms disulfide bond, which are primary covalent cross-link found in proteins, and which stabilize the native conformation of a protein. Indirect evidence suggests that thiol modifications by ROS may be involved in neurodegenerative disorders, but the significance and precise extent of the contributions are poorly understood. Here, we review the role of oxidized Cys in different pathological consequences and its biochemistry may increase the research in the discovery of new therapies. The purpose of this review is to re-examine the role and biochemistry of oxidised Cys residues.

Tumor progression to metastasis is not cancer cell autonomous, but rather involves the interplay of multiple cell types within the tumor microenvironment. Here we identify asporin (ASPN) as a novel, secreted mesenchymal stromal cell (MSC) factor in the tumor microenvironment that regulates metastatic development. MSCs expressed high levels of ASPN, which decreased following lineage differentiation. ASPN loss impaired MSC self-renewal and promoted terminal cell differentiation. Mechanistically, secreted ASPN bound to BMP-4 and restricted BMP-4-induced MSC differentiation prior to lineage commitment. ASPN expression was distinctly conserved between MSC and cancer-associated fibroblasts (CAF). ASPN expression in the tumor microenvironment broadly impacted multiple cell types. Prostate tumor allografts in ASPN-null mice had a reduced number of tumor-associated MSCs, fewer cancer stem cells, decreased tumor vasculature, and an increased percentage of infiltrating CD8 þ T cells. ASPNnull mice also demonstrated a significant reduction in lung metastases compared with wild-type mice. These data establish a role for ASPN as a critical MSC factor that extensively affects the tumor microenvironment and induces metastatic progression. Significance: These findings show that asporin regulates key properties of mesenchymal stromal cells, including selfrenewal and multipotency, and asporin expression by reactive stromal cells alters the tumor microenvironment and promotes metastatic progression.

PURPOSE Androgen receptor ( AR) gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate AR gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC. METHODS Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies—enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n = 2) —and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in AR and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS). RESULTS Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; P = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; P = .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; P = .004). AR ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; P = .020) were associated with a shorter PFS in multivariable models. AR CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; P = .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; P = .026) were associated with a worse OS in multivariable models. CONCLUSION These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. AR status associations with outcomes were not robust, and additional validation is needed.

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Hydroxyurea is an efficacious treatment for sickle cell disease (SCD), but adoption is low among individuals with SCD. The objective of this study was to examine barriers to patients’ adherence to hydroxyurea use regimens by using the intentional and unintentional medication nonadherence framework. We interviewed individuals with SCD age 15 to 49.9 years who were participants in the Sickle Cell Disease Implementation Consortium (SCDIC) Needs Assessment. The intentional and unintentional medication nonadherence framework explains barriers to using hydroxyurea and adds granularity to the understanding of medication adherence barriers unique to the SCD population. In total, 90 semi-structured interviews were completed across 5 of the 8 SCDIC sites. Among interviewed participants, 57.8% (n = 52) were currently taking hydroxyurea, 28.9% (n = 26) were former hydroxyurea users at the time of the interview, and 13.3% (n = 12) had never used hydroxyurea but were familiar with the medication. Using a constructivist grounded theory approach, we discovered important themes that contributed to nonadherence to hydroxyurea, which were categorized under unintentional (eg, Forgetfulness, External Influencers) and intentional (Negative Perceptions of Hydroxyurea, Aversion to Taking Any Medications) nonadherence types. Participants more frequently endorsed adherence barriers that fell into the unintentional nonadherence type (70%) vs intentional nonadherence type (30%). Results from this study will help SCD health care providers understand patient choices and decisions as being either unintentional or intentional, guide tailored clinical discussions regarding hydroxyurea therapy, and develop specific, more nuanced interventions to address nonadherence factors.

Background Sickle cell disease (SCD) is an inherited blood disorder causing acute complications and chronic progressive end organ damage. SCD is associated with significant morbidity, early mortality, impaired health-related quality of life, and increased acute health care utilization. Hydroxyurea is a US Food and Drug Administration–approved medication that reduces disease complications, acute health care utilization, and costs. However, adherence to hydroxyurea is suboptimal. Mobile health (mHealth) interventions have the potential to improve hydroxyurea adherence, but few examples exist that are specific to the SCD population. Objective This study aimed to design a mHealth intervention for individuals with SCD to improve adherence to hydroxyurea, using a user-centered design that was informed by specific barriers to hydroxyurea adherence and utilization in this population. Methods This study consisted of 4 phases. In phase 1, individuals with SCD and health care providers participated in an optimization digital workshop. In phase 2, patients completed surveys pertaining to their interest in mHealth use, barriers and facilitators to hydroxyurea use, and health literacy. Phases 3 and 4 involved semistructured interviews and focus groups, respectively, and used the Health Belief Model (HBM) as the framework to investigate drivers of poor hydroxyurea adherence and to inform the development of an app prototype. In addition, in phase 4, we have incorporated the patients’ feedback on the preliminary app prototype and its features. Results Barriers to hydroxyurea adherence were consistent with the literature and included forgetfulness and several specific thoughts and emotions associated with hydroxyurea use (eg, fear of side effects, depression, stigma, and hopelessness). In addition, more than half of the participants reported potentially low health literacy. Preferred patient app features included 7 key components, namely (1) medication reminders and tracker, (2) disease education, (3) communication, (4) personalization, (5) motivation, (6) support during pain episodes, and (7) social support. Utilizing a user-centered design approach, data obtained from patients and providers were translated into features within the app, mapping to components of the HBM and the specific drivers of hydroxyurea adherence and matching the literacy level of the population, resulting in the development of a novel mobile app called InCharge Health. Conclusions The InCharge Health app is an mHealth intervention developed with substantial input from users and by mapping the HBM as the framework that guided the choice for its components. InCharge Health is a customized product for the SCD population aimed at optimizing medication adherence, with the end goal of improving quality of life and health outcomes among patients with SCD. The efficacy and implementation of the InCharge Health app as an mHealth intervention to promote hydroxyurea adherence will be tested in a future stepped-wedge multicenter trial for adolescents and adults with SCD.