Do Measures of Real-World Physical Behavior Provide Insights Into the Well-Being and Physical Function of Cancer Survivors? Cross-Sectional Analysis.

BACKGROUND: As the number of cancer survivors increases, maintaining health-related quality of life in cancer survivorship is a priority. This necessitates accurate and reliable methods to assess how cancer survivors are feeling and functioning. Real-world digital measures derived from wearable sensors offer potential for monitoring well-being and physical function in cancer survivorship, but questions surrounding the clinical utility of these measures remain to be answered. OBJECTIVE: In this secondary analysis, we used 2 existing data sets to examine how measures of real-world physical behavior, captured with a wearable accelerometer, were related to aerobic fitness and self-reported well-being and physical function in a sample of individuals who had completed cancer treatment. METHODS: Overall, 86 disease-free cancer survivors aged 21-85 years completed self-report assessments of well-being and physical function, as well as a submaximal exercise test that was used to estimate their aerobic fitness, quantified as predicted submaximal oxygen uptake (VO2). A thigh-worn accelerometer was used to monitor participants' real-world physical behavior for 7 days. Accelerometry data were used to calculate average values of the following measures of physical behavior: sedentary time, step counts, time in light and moderate to vigorous physical activity, time and weighted median cadence in stepping bouts over 1 minute, and peak 30-second cadence. RESULTS: Spearman correlation analyses indicated that 6 (86%) of the 7 accelerometry-derived measures of real-world physical behavior were not significantly correlated with Functional Assessment of Cancer Therapy-General total well-being or linked Patient-Reported Outcomes Measurement Information System-Physical Function scores (Ps≥.08). In contrast, all but one of the physical behavior measures were significantly correlated with submaximal VO2 (Ps≤.03). Comparing these associations using likelihood ratio tests, we found that step counts, time in stepping bouts over 1 minute, and time in moderate to vigorous activity were more strongly associated with submaximal VO2 than with self-reported well-being or physical function (Ps≤.03). In contrast, cadence in stepping bouts over 1 minute and peak 30-second cadence were not more associated with submaximal VO2 than with the self-reported measures (Ps≥.08). CONCLUSIONS: In a sample of disease-free cancer survivors, we found that several measures of real-world physical behavior were more associated with aerobic fitness than with self-reported well-being and physical function. These results highlight the possibility that in individuals who have completed cancer treatment, measures of real-world physical behavior may provide additional information compared with self-reported and performance measures. To advance the appropriate use of digital measures in oncology clinical research, further research evaluating the clinical utility of real-world physical behavior over time in large, representative samples of cancer survivors is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT03781154; https://clinicaltrials.gov/ct2/show/NCT03781154.

Measuring What Is Meaningful in Cancer Cachexia Clinical Trials: A Path Forward With Digital Measures of Real-World Physical Behavior.

PURPOSE: The burden of cancer cachexia on patients' health-related quality of life, specifically their physical functioning, is well documented, but clinical trials thus far have failed to show meaningful improvement in physical functioning. The purpose of this review is to summarize existing methods of assessing physical function in cancer cachexia, outline a path forward for measuring what is meaningful to patients using digital measures derived from digital health technologies (DHTs), and discuss the current landscape of digital measures from the clinical and regulatory standpoint. DESIGN: For this narrative review, peer-reviewed articles were searched on PubMed, clinical trials records were searched on clinicaltrials.gov, and records of digital measures submitted for regulatory qualification were searched on the US Food and Drug Administration's Drug Development Tool Qualification Program database. RESULTS: There are gaps in assessing aspects of physical function that matter to patients. Existing assessment methods such as patient-reported outcomes and objective performance outcomes have limitations, including their episodic nature and burden to patients. DHTs such as wearable sensors can capture real-world physical behavior continuously, passively, and remotely, and may provide a more comprehensive picture of patients' everyday functioning. Recent regulatory submissions showcase potential clinical implementation of digital measures in various therapeutic areas. CONCLUSION: Digital measures of real-world physical behavior present an opportunity to detect and demonstrate improvements in physical functioning in cancer cachexia, but evidence-based development is critical. For their use in clinical and regulatory decision making, studies demonstrating meaningfulness to patients as well as feasibility and validation are necessary.

Predicting Subjective Recovery from Lower Limb Surgery Using Consumer Wearables.

INTRODUCTION: A major challenge in the monitoring of rehabilitation is the lack of long-term individual baseline data which would enable accurate and objective assessment of functional recovery. Consumer-grade wearable devices enable the tracking of individual everyday functioning prior to illness or other medical events which necessitate the monitoring of recovery trajectories. METHODS: For 1,324 individuals who underwent surgery on a lower limb, we collected their Fitbit device data of steps, heart rate, and sleep from 26 weeks before to 26 weeks after the self-reported surgery date. We identified subgroups of individuals who self-reported surgeries for bone fracture repair (n = 355), tendon or ligament repair/reconstruction (n = 773), and knee or hip joint replacement (n = 196). We used linear mixed models to estimate the average effect of time relative to surgery on daily activity measurements while adjusting for gender, age, and the participant-specific activity baseline. We used a sub-cohort of 127 individuals with dense wearable data who underwent tendon/ligament surgery and employed XGBoost to predict the self-reported recovery time. RESULTS: The 1,324 study individuals were all US residents, predominantly female (84%), white or Caucasian (85%), and young to middle-aged (mean age 36.2 years). We showed that 12 weeks pre- and 26 weeks post-surgery trajectories of daily behavioral measurements (steps sum, heart rate, sleep efficiency score) can capture activity changes relative to an individual's baseline. We demonstrated that the trajectories differ across surgery types, recapitulate the documented effect of age on functional recovery, and highlight differences in relative activity change across self-reported recovery time groups. Finally, using a sub-cohort of 127 individuals, we showed that long-term recovery can be accurately predicted, on an individual level, only 1 month after surgery (AUROC 0.734, AUPRC 0.8). Furthermore, we showed that predictions are most accurate when long-term, individual baseline data are available. DISCUSSION: Leveraging long-term, passively collected wearable data promises to enable relative assessment of individual recovery and is a first step towards data-driven intervention for individuals.

Multidimensional pooled shRNA screens in human THP-1 cells identify candidate modulators of macrophage polarization.

Macrophages are key cell types of the innate immune system regulating host defense, inflammation, tissue homeostasis and cancer. Within this functional spectrum diverse and often opposing phenotypes are displayed which are dictated by environmental clues and depend on highly plastic transcriptional programs. Among these the 'classical' (M1) and 'alternative' (M2) macrophage polarization phenotypes are the best characterized. Understanding macrophage polarization in humans may reveal novel therapeutic intervention possibilities for chronic inflammation, wound healing and cancer. Systematic loss of function screening in human primary macrophages is limited due to lack of robust gene delivery methods and limited sample availability. To overcome these hurdles we developed cell-autonomous assays using the THP-1 cell line allowing genetic screens for human macrophage phenotypes. We screened 648 chromatin and signaling regulators with a pooled shRNA library for M1 and M2 polarization modulators. Validation experiments confirmed the primary screening results and identified OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) as a novel mediator of M2 polarization in human macrophages. Our approach offers a possible avenue to utilize comprehensive genetic tools to identify novel candidate genes regulating macrophage polarization in humans.

YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers.

YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting.

The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment.

The pH-sensing receptor ovarian cancer G protein-coupled receptor 1 (OGR1; GPR68) is expressed in the gut. Inflammatory bowel disease is typically associated with a decrease in local pH, which may lead to altered epithelial barrier function and subsequent gastrointestinal repair involving epithelial cell adhesion and migration. As the mechanisms underlying the response to pH changes are not well understood, we have investigated OGR1-mediated, pH-dependent signaling pathways in intestinal epithelial cells. Caco-2 cells stably overexpressing OGR1 were created and validated as tools to study OGR1 signaling. Barrier function, migration, and proliferation were measured using electric cell-substrate impedance-sensing technology. Localization of the tight junction proteins zonula occludens protein 1 and occludin and the rearrangement of cytoskeletal actin were examined by confocal microscopy. Paracellular permeability and protein and gene expression analysis using DNA microarrays were performed on filter-grown Caco-2 monolayers. We report that an acidic pH shift from pH 7.8 to 6.6 improved barrier function and stimulated reorganization of filamentous actin with prominent basal stress fiber formation. Cell migration and proliferation during in vitro wound healing were inhibited. Gene expression analysis revealed significant upregulation of genes related to cytoskeleton remodeling, cell adhesion, and growth factor signaling. We conclude that acidic extracellular pH can have a signaling function and impact the physiology of intestinal epithelial cells. The deconstruction of OGR1-dependent signaling may aid our understanding of mucosal inflammation mechanisms.

A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation.

Increasing evidence suggests that long non-coding RNAs (LncRNAs) represent a new class of regulators of stem cells. However, the roles of LncRNAs in stem cell maintenance and myogenesis remain largely unexamined. For this study, hundreds of intergenic LncRNAs were identified that are expressed in myoblasts and regulated during differentiation. One of these LncRNAs, termed LncMyoD, is encoded next to the Myod gene and is directly activated by MyoD during myoblast differentiation. Knockdown of LncMyoD strongly inhibits terminal muscle differentiation, largely due to a failure to exit the cell cycle. LncMyoD directly binds to IGF2-mRNA-binding protein 2 (IMP2) and negatively regulates IMP2-mediated translation of proliferation genes such as N-Ras and c-Myc. While the RNA sequence of LncMyoD is not well conserved between human and mouse, its locus, gene structure, and function are preserved. The MyoD-LncMyoD-IMP2 pathway elucidates a mechanism as to how MyoD blocks proliferation to create a permissive state for differentiation.

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling.

The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.