Chemotherapy may impair cognition and contribute to accelerated aging. The purpose of this study was to assess the effects of chemotherapy on the connectivity of the default mode network (DMN) in older women with breast cancer. This prospective longitudinal study enrolled women aged ≥ 60 years with stage I-III breast cancer (CTx group) and matched healthy controls (HC group). Study assessments, consisting of resting-state functional MRI (rs-fMRI) and the Picture Sequence Memory (psm) test for episodic memory from the NIH Toolbox for Cognition, were obtained at baseline and within one month after the completion of chemotherapy for the CTx group and at matched intervals for the HC group. Two-sample t-test and FDR multiple comparison were used for statistical inference. Our analysis of the CTx group (N = 19; 60-82 years of age, mean = 66.6, SD = 5.24) compared to the HC group (N = 14; 60-78 years of age, mean = 68.1, SD = 5.69) revealed weaker DMN subnetwork connectivity in the anterior brain but stronger connectivity in the posterior brain at baseline. After chemotherapy, this pattern was reversed, with stronger anterior connectivity and weaker posterior connectivity. In addition, the meta-level functional network connectivity (FNC) among the DMN subnetworks after chemotherapy was consistently weaker than the baseline FNC as seen in the couplings between anterior cingulate cortex (ACC) and retrosplenial (rSplenia) region, with ΔFNC(ACC,rSplenia)=-0.14, t value=-2.44, 95 %CI=[-0.27,-0.10], pFDR<0.05). The baseline FNC matrices of DMN subnetworks were correlated with psm scores (corr = 0.58, p < 0.05). Our results support DMN alterations as a potential neuroimaging biomarker for cancer-related cognitive impairment and accelerated aging.

OBJECTIVE: We aimed to use diffusion tensor imaging (DTI) to detect alterations in white matter microstructure in older patients with breast cancer receiving chemotherapy. METHODS: We recruited women age ≥60 years with stage I-III breast cancer (chemotherapy [CT] group; n = 19) to undergo two study assessments: at baseline and within one month after chemotherapy. Each assessment consisted of a brain magnetic resonance imaging scan with DTI and neuropsychological (NP) testing using the National Institutes of Health (NIH) Toolbox Cognition Battery. An age- and sex-matched group of healthy controls (HC, n = 14) underwent the same assessments at matched intervals. Four DTI parameters (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], and radial diffusivity [RD]) were calculated and correlated with NP testing scores. RESULTS: For CT group but not HCs, we detected statistically significant increases in MD and RD in the genu of the corpus callosum from time point 1 to time point 2 at p < 0.01, effect size:0.3655 and 0.3173, and 95% confidence interval: from 0.1490 to 0.5821, and from 0.1554 to 0.4792, for MD and RD respectively. AD values increased for the CT group and decreased for the HC group over time, resulting in significant between-group differences (p = 0.0056, effect size:1.0215, 95% confidence interval: from 0.2773 to 1.7657). There were no significant correlations between DTI parameters and NP scores (p > 0.05). CONCLUSIONS: We identified alterations in white matter microstructures in older women with breast cancer undergoing chemotherapy. These findings may potentially serve as neuroimaging biomarkers for identifying cognitive impairment in older adults with cancer.

As the number of older adults in the U.S. increases, so too will the incidence of cancer and cancer-related cognitive impairment (CRCI). However, the exact underlying biological mechanism for CRCI is not yet well understood. We utilized susceptibility-weighted imaging with quantitative susceptibility mapping, a non-invasive MRI-based technique, to assess longitudinal iron deposition in subcortical gray matter structures and evaluate its association with cognitive performance in women age 60+ with breast cancer receiving adjuvant chemotherapy and age-matched women without breast cancer as controls. Brain MRI scans and neurocognitive scores from the NIH Toolbox for Cognition were obtained before chemotherapy (time point 1) and within one month after the last infusion of chemotherapy for the patients and at matched intervals for the controls (time point 2). There were 14 patients age 60+ with breast cancer (mean age 66.3 ± 5.3 years) and 13 controls (mean age 68.2 ± 6.1 years) included in this study. Brain iron increased as age increased. There were no significant between- or within- group differences in neurocognitive scores or iron deposition at time point 1 or between time points 1 and 2 (p > 0.01). However, there was a negative correlation between iron in the globus pallidus and the fluid cognition composite scores in the control group at time point 1 (r = -0.71; p < 0.01), but not in the chemotherapy group. Baseline iron in the putamen was negatively associated with changes in the oral reading recognition scores in the control group (r = 0.74, p < 0.01), but not in the chemotherapy group. Brain iron assessment did not indicate cancer or chemotherapy related short-term differences, yet some associations with cognition were observed. Studies with larger samples and longer follow-up intervals are warranted.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.