Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways Show more
Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407. Show less
The purpose of this population-based study was to examine whether sedentary behavior (SB) and light physical activity intensity (LPA) are associated with pain in older adults. A further aim is to inve Show more
The purpose of this population-based study was to examine whether sedentary behavior (SB) and light physical activity intensity (LPA) are associated with pain in older adults. A further aim is to investigate the psychosomatic complaints as mediators between SB and pain. Individuals aged ≥50 from the 2018 Study on Aging, Health, and Health-seeking Behavior reported on SB and LPA using the International Physical Activity Questionnaire and pain severity using a cross-culturally validated item from the bodily pain subscale of the MOS SF-36. Multivariable logistic regression models evaluated the associations of SB and LPA with pain. Bootstrapping analyses assessed whether psychosomatic complaints mediate the association between SB and pain. Among 1201 participants (mean ± SD age = 66.1 ± 11.9 years; women = 63.3%), the prevalence of SB and pain was 21.4% and 43.0%, respectively. Compared with <8 h/d, ≥8 h/d of SB was positively associated with pain (OR = 2.42, 95% CI = 1.71-3.42). However, LPA was associated with 11% lower odds of reporting pain (OR = 0.89, 95% CI = 0.81-0.98). Self-rated health (41.2%), anxiety (23.5%), comorbidity (20.6%), functional limitations (17.6%), depression (13.2%), and sleep problems (11.8%) were associated with pain and mediated the SB-pain link. The present study observed that SB and LPA were associated with pain in older adults residing in Ghana, and psychosomatic complaints were identified as potential mechanisms in the pathway between SB and pain. Managing the pain burden in old age may require shifting the 24-hour behavior from SB to LPA and addressing the inherent psychosomatic complaints. Show less