Beyond Tuskegee — Vaccine Distrust and Everyday Racism Bajaj, Simar Singh; Stanford, Fatima Cody
New England journal of medicine/The New England journal of medicine,
02/2021, Letnik:
384, Številka:
5
Journal Article
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When we hyperfocus on a few historical racist atrocities, we ascribe current Black health experiences to past racism, rooting our present in immovable past events and undermining efforts to combat ...mistrust. Everyday racism, by contrast, can be tackled in the present.
Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. ...BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
FatCamera/Getty Images A paucity of Black women in academic leadership and medicine not only limits the role models students can take inspiration from but may also contribute to inadequate care for ...Black patients, particularly given the importance of racial and gender concordance in health care. ...if they do speak up about inequities, advocate for reform, or seek to advance institutional diversity, these physicians can be caricatured as just another angry Black woman and dismissed as being unreasonable and melodramatic. At New York University School of Medicine, Uché Blackstock resigned due to a perceived inhospitable environment for Black trainees seeking professional mentorship and for Black faculty seeking promotion. ...the National Institute of Health's Faculty Institutional Recruitment for Sustainable Transformation programme is a career-development initiative that fosters cultures of inclusive excellence through the hiring and retention of diverse faculty, integrated systems to address bias, and the development of a Data Coordination and Evaluation Center for the evaluation and measurement of systemic cultural change.
Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic ...glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes
and spontaneous metastatic melanoma
. In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1-activated (GRM1
) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1
melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death
and
. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation
and tumor progression
. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion. SIGNIFICANCE: These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.
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