The humanistic burden of myasthenia gravis: A systematic literature review.

BACKGROUND/OBJECTIVES: While the clinical manifestations of myasthenia gravis (MG) are well understood, its humanistic impact is not. The objective of this systematic literature review (SLR) was to provide a comprehensive understanding of the humanistic burden of MG with regards to psychological symptoms and health-related quality of life (HRQoL) according to patients and caregivers. METHODS: A systematic search was conducted on December 27, 2019, in MEDLINE and Embase to identify English-language studies that were published from January 1, 2009-December 27, 2019 and presented relevant information on the humanistic burden among adults with MG and their caregivers. Title/abstract and full-text screening was performed by two investigators, with any discrepancies resolved by a third investigator. RESULTS: Sixty-seven publications were included in the SLR. Compared with the general population, patients with MG experienced worse HRQoL. Studies reporting on psychological symptoms of MG, including depression, anxiety, fatigue, and sleep, were heterogeneous in terms of the scales and instruments used to assess patients, as well as the patient populations themselves. However, in general those with more severe symptoms and hospitalization days had worse depression and anxiety, and fatigue and sleep improved with disease remission and/or improvement. Scores were worse for females compared with males and where evaluated, HRQoL scores generally improved following treatment. CONCLUSION: While the literature demonstrates that symptoms associated with MG get better with disease improvement and remission, additional options in efficacious therapy that adequately address the disease-related symptoms and also improve HRQoL may contribute to beneficial outcomes in a greater number of patients with MG.

Enhanced immortalization, HUWE1 mutations and other biological drivers of breast invasive carcinoma in Black/African American patients.

Black/African-American (B/AA) breast cancer patients tend to have more aggressive tumor biology compared to White/Caucasians. In this study, a variety of breast tumor molecular expression profiles of patients derived from the two racial groupings were investigated. Breast invasive carcinoma sample data (RNASeq version 2, Reverse Phase Protein Array, mutation, and miRSeq data) from the Cancer Genome Atlas were examined. The results affirm that B/AA patients are more likely than Caucasian patients to harbor the aggressive basal-like or the poor prognosis-associated HER2-enriched molecular subtypes of breast cancer. There is also a higher incidence of the triple-negative breast cancer (TNBC) among B/AA patients than the general population, a fact reflected in the mutation patterns of genes such as PIK3CA and TP53. Furthermore, an immortalization signature gene set, is enriched in samples from B/AA patients. Among stage III patients, TERT, DRAP1, and PQBP1, all members of the immortalization gene signature set, are among master-regulators with increased activity in B/AA patients. Master-regulators driving differences in expression profiles between the two groups include immortalization markers, senescence markers, and immune response and redox gene products. Differences in expression, between B/AA and Caucasian patients, of RB1, hsa-let-7a, E2F1, c-MYC, TERT, and other biomolecules appear to cooperate to enhance entry into the S-phase of the cell cycle in B/AA patients. Higher expression of miR-221, an oncomiR that facilitates entry into the cell cycle S-phase, is regulated by c-MYC, which is expressed more in breast cancer samples from B/AA patients. Furthermore, the cell migration- and invasion-promoting miRNA, miR-135b, has increased relative expression in B/AA patients. Knock down of the immortalization marker TERT inhibited triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) cell viability and decreased expression of TERT, MYC and WNT11. For those patients with available survival data, prognosis of stage II patients 50 years of age or younger at diagnosis, was distinctly poorer in B/AA patients. Also associated with this subset of B/AA patients are missense mutations in HUWE1 and PTEN expression loss. Relative to Caucasian non-responders to endocrine therapy, B/AA non-responders show suppressed expression of a signature gene set on which biological processes including signaling by interleukins, circadian clock, regulation of lipid metabolism by PPARα, FOXO-mediated transcription, and regulation of TP53 degradation are over-represented. Thus, we identify molecular expression patterns suggesting diminished response to oxidative stress, changes in regulation of tumor suppressors/facilitators, and enhanced immortalization in B/AA patients are likely important in defining the more aggressive molecular tumor phenotype reported in B/AA patients.

Enhanced immortalization, HUWE1 mutations and other biological drivers of breast invasive carcinoma in Black/African American patients.

Black/African-American (B/AA) breast cancer patients tend to have more aggressive tumor biology compared to White/Caucasians. In this study, a variety of breast tumor molecular expression profiles of patients derived from the two racial groupings were investigated. Breast invasive carcinoma sample data (RNASeq version 2, Reverse Phase Protein Array, mutation, and miRSeq data) from the Cancer Genome Atlas were examined. The results affirm that B/AA patients are more likely than Caucasian patients to harbor the aggressive basal-like or the poor prognosis-associated HER2-enriched molecular subtypes of breast cancer. There is also a higher incidence of the triple-negative breast cancer (TNBC) among B/AA patients than the general population, a fact reflected in the mutation patterns of genes such as PIK3CA and TP53. Furthermore, an immortalization signature gene set, is enriched in samples from B/AA patients. Among stage III patients, TERT, DRAP1, and PQBP1, all members of the immortalization gene signature set, are among master-regulators with increased activity in B/AA patients. Master-regulators driving differences in expression profiles between the two groups include immortalization markers, senescence markers, and immune response and redox gene products. Differences in expression, between B/AA and Caucasian patients, of RB1, hsa-let-7a, E2F1, c-MYC, TERT, and other biomolecules appear to cooperate to enhance entry into the S-phase of the cell cycle in B/AA patients. Higher expression of miR-221, an oncomiR that facilitates entry into the cell cycle S-phase, is regulated by c-MYC, which is expressed more in breast cancer samples from B/AA patients. Furthermore, the cell migration- and invasion-promoting miRNA, miR-135b, has increased relative expression in B/AA patients. Knock down of the immortalization marker TERT inhibited triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) cell viability and decreased expression of TERT, MYC and WNT11. For those patients with available survival data, prognosis of stage II patients 50 years of age or younger at diagnosis, was distinctly poorer in B/AA patients. Also associated with this subset of B/AA patients are missense mutations in HUWE1 and PTEN expression loss. Relative to Caucasian non-responders to endocrine therapy, B/AA non-responders show suppressed expression of a signature gene set on which biological processes including signaling by interleukins, circadian clock, regulation of lipid metabolism by PPARα, FOXO-mediated transcription, and regulation of TP53 degradation are over-represented. Thus, we identify molecular expression patterns suggesting diminished response to oxidative stress, changes in regulation of tumor suppressors/facilitators, and enhanced immortalization in B/AA patients are likely important in defining the more aggressive molecular tumor phenotype reported in B/AA patients.