Enhanced mitochondrial fission inhibits triple-negative breast cancer cell migration through an ROS-dependent mechanism.

Mitochondria produce reactive oxygen species (ROS), which function in signal transduction. Mitochondrial dynamics, encompassing morphological shifts between fission and fusion, can directly impact ROS levels in cancer cells. In this study, we identified an ROS-dependent mechanism for how enhanced mitochondrial fission inhibits triple negative breast cancer (TNBC) cell migration. We found that enforcing mitochondrial fission in TNBC resulted in an increase in intracellular ROS levels and reduced cell migration and the formation of actin-rich migratory structures. Consistent with mitochondrial fission, increasing ROS levels in cells inhibited cell migration. Conversely, reducing ROS levels with either a global or mitochondrially targeted scavenger overcame the inhibitory effects of mitochondrial fission. Mechanistically, we found that the ROS sensitive SHP-1/2 phosphatases partially regulate inhibitory effects of mitochondrial fission on TNBC migration. Overall, our work reveals the inhibitory effects of ROS in TNBC and supports mitochondrial dynamics as a potential therapeutic target for cancer.

Multiparametric MRI to quantify disease and treatment response in mice with myeloproliferative neoplasms.

Histopathology, the standard method to assess BM in hematologic malignancies such as myeloproliferative neoplasms (MPNs), suffers from notable limitations in both research and clinical settings. BM biopsies in patients fail to detect disease heterogeneity, may yield a nondiagnostic sample, and cannot be repeated frequently in clinical oncology. Endpoint histopathology precludes monitoring disease progression and response to therapy in the same mouse over time, missing likely variations among mice. To overcome these shortcomings, we used MRI to measure changes in cellularity, macromolecular constituents, and fat versus hematopoietic cells in BM using diffusion-weighted imaging (DWI), magnetization transfer, and chemical shift-encoded fat imaging. Combining metrics from these imaging parameters revealed dynamic alterations in BM following myeloablative radiation and transplantation. In a mouse MPLW515L BM transplant model of MPN, MRI detected effects of a JAK2 inhibitor, ruxolitinib, within 5 days of initiating treatment and identified differing kinetics of treatment responses in subregions of the tibia. Histopathology validated the MRI results for BM composition and heterogeneity. Anatomic MRI scans also showed reductions in spleen volume during treatment. These findings establish an innovative, clinically translatable MRI approach to quantify spatial and temporal changes in BM in MPN.

The relationship between teen-reported nocturnal asthma symptoms and daily functioning.

OBJECTIVE: This study aims to identify associations between nocturnal asthma awakenings and functional health outcomes in a cohort of teenagers with asthma. METHODS: We analyzed baseline data from teenagers enrolled in SB-ACT, an NIH-funded RCT. During an at-home baseline survey, teenagers with asthma answered questions about demographics, recent asthma symptoms, and functional health outcomes. We conducted regression analyses to explore the relationship between persistent nocturnal asthma symptoms (≥2 nights of nocturnal asthma awakenings in the past 14 days) and functional health measures. RESULTS: Of the 430 teens enrolled (Participation rate = 79%, Mean Age = 13.4), 30% reported persistent nocturnal asthma symptoms. Compared to teens with intermittent nocturnal asthma symptoms, teens with persistent nocturnal asthma symptoms were more likely to report physical limitation during strenuous activities (OR = 1.9, 1.3-3.0), moderate activities (OR = 1.9, 1.2-3.1), and school gym (OR = 2.4, 1.5-3.8). They were also more likely to report depressive symptoms (OR = 2.3, 1.5-3.6), more asthma-related school absenteeism in the past 14 days (0.81 vs 0.12, p < 0.01) and poorer quality of life (4.6 vs 5.9, p < 0.01). These findings remained significant when controlling for daytime asthma symptoms, weight status, race, ethnicity, gender, age, and smoke exposure. CONCLUSIONS: In this cross-sectional study, persistent nighttime asthma symptoms were associated with poor functional health outcomes among teens, independent of day-time symptoms. Identifying nighttime symptoms and improving asthma control at night may positively impact daily functioning for these teens.

Development and Interrater Reliability of an Observational School Environment Checklist: A Practical, Comprehensive Tool to Assess Healthy Eating and Physical Activity Opportunities in Schools.

INTRODUCTION: Comprehensive, objective assessment of schools' eating and physical activity environments is critical to developing and evaluating policies and interventions to reduce pediatric obesity inequities; however, few tools exist that describe the entire school comprehensively and are feasible with restricted resources. This study describes development and reliability of the observational school environment checklist (OSEC), a comprehensive observational audit tool. METHOD: We developed the OSEC through iterative adaptations of existing instruments and pilot testing. The tool assesses four focus areas: cafeteria, lobby/hallway, gym, and outdoor areas. For reliability testing, two trained auditors independently completed the OSEC and met to resolve disagreements. For items with poor agreement, a third independent coder coded photographs taken during auditing. Percent agreement and Cohen's kappa were calculated for all items and across four evidence-based constructs: atmosphere, accessibility, attractiveness, and advertising. RESULTS: After iterative development, the 88-item OSEC was tested for reliability in 18 schools. Items with poor (<80%) agreement or redundancy were discarded or reworded (n = 16 items). All four constructs had acceptable agreement, ranging by focus area: 72.3% (attractiveness), 86.3% to 97.1% (atmosphere), 82.9% to 100% (accessibility), and 92.9% (advertising). Cohen's kappa ranges were acceptable: 0.66-0.91 (atmosphere), 0.60-1.00 (accessibility), 0.46 (attractiveness), and 0.77 (advertising). After adding similar items across domains (n = 49) to improve comprehensiveness, the final tool contained 121 binary items. IMPLICATIONS: The OSEC reliably and comprehensively captures the school environment. It requires few resources or expertise to administer, has acceptable reliability, and can assess atmosphere, accessibility, attractiveness, and advertising in school areas where students engage in eating and physical activity.

Prognostic and therapeutic TILs of cervical cancer-Current advances and future perspectives.

Cervical cancer is a top lethal cancer for women worldwide. Although screening and vaccination programs are available in many countries, resulting in the decline of new cases, this is not true for developing countries where there are many new cases and related deaths. Cancer immunotherapy through adaptive cell therapy (ACT) has been applied in clinics, but now much attention is focused on autogenic tumor-infiltrating lymphocyte (TIL)-based therapy, which has shown more specificity and better ability to inhibit tumor growth. Data from melanoma and cervical cancers confirm that tumor-specific T cells in TILs can be expanded for more specific and effective ACT. Moreover, TILs are derived from individual patients and are ready to home back to kill tumor cells after patient infusion, aligning well with personalized and precision medicine. In addition to therapy, TIL cell types and numbers are good indicators of host immune response to the tumor, and thus they have significant values in prognosis. Because of the special relationship with human papillomavirus (HPV) infection, cervical cancer has some specialties in TIL-based prognosis and therapy. In this review, we summarize the recent advances in the prognostic significance of TILs and TIL-based therapy for cervical cancer and discuss related perspectives.

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice.

Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.