Characterization of Balance Control and Postural Stability in Patients With Alzheimer Disease.

Balance in Alzheimer disease (AD) patients is not rigorously understood. In this study, we characterize balance using qualitative [Berg Balance Scale (BBS)] and quantitative measures (posturography) and assess relationships between qualitative and quantitative balance measures in AD. Patients with mild-moderate AD (n=48) were recruited. BBS scores and posturography metrics, including medial-lateral sway range, anterior-posterior sway range, sway area, and sway velocity, were assessed in eyes-open and eyes-closed conditions. Adjusted linear regressions were used to assess relationships between posturography and BBS score. Mean BBS score was 50.4±5.3. In eyes-open conditions, posturography and BBS score were not significantly associated. In eyes-closed conditions, better BBS score was significantly associated with lower sway area (ß=-0.91; P =0.006). Better scores of BBS items involving turning and reduced base of support were associated with greater eyes-closed sway area. Posturography in the more challenging eyes-closed condition may predict functional balance deficits in AD patients.

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis.

Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1.

Double-strand breaks (DSBs) due to genotoxic stress represent potential threats to genome stability. Dysfunctional telomeres are recognized as DSBs and are repaired by distinct DNA repair mechanisms. RAP1 and TRF2 are telomere binding proteins essential to protect telomeres from engaging in homology directed repair (HDR), but how this occurs remains unclear. In this study, we examined how the basic domain of TRF2 (TRF2B) and RAP1 cooperate to repress HDR at telomeres. Telomeres lacking TRF2B and RAP1 cluster into structures termed ultrabright telomeres (UTs). HDR factors localize to UTs, and UT formation is abolished by RNaseH1, DDX21 and ADAR1p110, suggesting that they contain DNA-RNA hybrids. Interaction between the BRCT domain of RAP1 and KU70/KU80 is also required to repress UT formation. Expressing TRF2∆B in Rap1-/- cells resulted in aberrant lamin A localization in the nuclear envelope and dramatically increased UT formation. Expressing lamin A phosphomimetic mutants induced nuclear envelope rupturing and aberrant HDR-mediated UT formation. Our results highlight the importance of shelterin and proteins in the nuclear envelope in repressing aberrant telomere-telomere recombination to maintain telomere homeostasis.

Quantitative vestibular assessment: The development and validation of a novel, remote video head impulse test against in-clinic measurements.

Objectives: To develop a novel remote head impulse test (rHIT), and to provide preliminary data validating the rHIT vestibular-ocular reflex (VOR) gains against the in-clinic vHIT. Methods: A convenience sample of 10 patients referred for vestibular assessment at our institution was recruited. In-clinic vHIT was used to quantify lateral VOR gains. Patients subsequently underwent an rHIT protocol, whereby patients performed active, lateral head rotations while their eyes and heads were recorded using a laptop camera and video-conferencing software. The vHIT and rHIT VOR gains were compared using paired t-tests, and a Pearson correlation coefficient between the gains was calculated. Absolute accuracy, sensitivity, and specificity of the rHIT were additionally calculated. Results: Of the 10 patients recruited, 4 were male, and the average ± standard deviation (SD) age was 61.4 ± 15.3 years. As determined by the vHIT, 2 patients had normal bilateral VOR gains, 6 with unilateral vestibular hypofunction, and 2 with bilateral vestibular hypofunction. The correlation between the rHIT and vHIT gains was 0.73 (p < .001). The rHIT exhibited an absolute accuracy of 75.0%, sensitivity of 70.0%, and specificity of 80.0%. When ears had a vHIT VOR gain less than 0.40, the rHIT exhibited 100.0% accuracy. Conversely, 60.0% of deficient ears with vHIT VOR gains greater than 0.40 were incorrectly categorized by the rHIT. Conclusion: The rHIT may be better suited for detecting more severe vestibular deficiencies. Future iterations of the rHIT should aim to increase the video frame-rate capabilities to detect subtler VOR impairments. Level of Evidence: 4.

Vestibular Function Predicts Balance and Fall Risk in Patients with Alzheimer's Disease.

BACKGROUND: Patients with Alzheimer's disease (AD) are at high risk for falls. Vestibular dysfunction predicts balance impairment in healthy adults; however, its contribution to falls in patients with AD is not well known. OBJECTIVE: The objective of this study was to assess whether vestibular function contributes to balance and fall risk in patients with AD. METHODS: In this prospective observational study, we assessed vestibular function using measures of semicircular canal (vestibulo-ocular reflex (VOR) gain) and saccular function (cervical vestibular-evoked myogenic (cVEMP) response), and we assessed balance function using the Berg Balance Scale and quantitative posturography. We evaluated falls incidence for a mean 1-year follow-up period (range 3-21 months) in 48 patients with mild-moderate AD. RESULTS: Relative to matched controls, AD patients exhibited increased medio-lateral (ML) sway in eyes-open (0.89 cm versus 0.69 cm; p = 0.033) and eyes-closed (0.86 cm versus 0.65 cm; p = 0.042) conditions. Among AD patients, better semicircular canal function was associated with lower ML sway and antero-posterior (AP) sway in the eyes-closed condition (ß= -2.42, 95% CI (-3.89, -0.95), p = 0.002; ß= -2.38, 95% CI (-4.43, -0.32), p = 0.025, respectively). Additionally, better saccular function was associated with lower sway velocity (ß= -0.18, 95% CI (-0.28, -0.08); p = 0.001). Finally, we observed that better semicircular canal function was significantly associated with lower likelihood of falls when adjusted for age, sex, and MMSE score (HR = 0.65; p = 0.009). CONCLUSION: These results support the vestibular system as an important contributor to balance and fall risk in AD patients and suggest a role for vestibular therapy.

Self-Reported Sense of Direction and Vestibular Function in the Baltimore Longitudinal Study of Aging (BLSA).

Sense of direction is an individual's ability to navigate within an environment and generate a mental map of novel environments. Although sense of direction is correlated with psychometric tests of spatial ability, it also reflects an individual's real-world spatial ability that is not fully captured by laboratory-based assessments. Sense of direction is known to vary widely in the population and has been shown to decline with age. However, other factors that contribute to an individual's sense of direction have not been well-characterized. Vestibular impairment has been linked to reduced spatial cognitive ability, which encompasses spatial memory and navigation skills. Several studies have shown that vestibular input is necessary for effective spatial cognition, notably accurate spatial navigation ability. These studies have typically considered laboratory-based spatial navigation assessments; however, the influence of vestibular function on variation in real-world sense of direction is unknown. In this study, we evaluated whether vestibular function is associated with self-reported sense of direction. Participants for this cross-sectional study were recruited from the Baltimore Longitudinal Study of Aging, a longstanding cohort study of healthy aging. In a modified version of the Santa Barbara Sense-of-Direction (SBSOD) Scale, participants rated statements about spatial and navigational abilities. A lower average score indicates poorer self-reported sense of direction. Vestibular function testing included cervical vestibular-evoked myogenic potential (VEMP) to assess saccular function, ocular VEMP to assess utricular function, and the video head-impulse test to assess semicircular canal function based on vestibular ocular reflex. The study sample included 82 participants with mean age of 71.0 (± 16.9) years and mean SBSOD score of 4.95(± 1.07). In a multivariate linear regression model, female sex and bilateral saccular loss were associated with a lower average SBSOD score. These data suggest that vestibular impairment contributes to the known variation in spatial navigation ability.

The Impact of Surgical Delays on Short- and Long-Term Survival Among Colon Cancer Patients.

BACKGROUND: The purpose of this study was to assess the impact of surgical delays on short- and long-term survival among colon cancer patients. METHODS: Adult patients undergoing surgery for stage I, II, or III colon cancer were identified from the National Cancer Database (2010-2016). After categorization by wait times from diagnosis to surgery (<1 week, 1-3 weeks, 3-6 weeks, 6-9 weeks, 9-12 weeks, and >12 weeks), 30-day mortality, 90-day mortality, and 5-year overall survival were compared between patients both overall and after stratification by pathological disease stage. RESULTS: Among 187 394 colon cancer patients, 24.2% waited <1 week, 30.5% waited 1-3 weeks, 29.0% waited 3-6 weeks, 9.7% waited 6-9 weeks, 3.3% waited 9-12 weeks, and 3.3% waited >12 weeks for surgery. Patients undergoing surgery 3-6 weeks after colon cancer diagnosis exhibited the best 30-day mortality (1.3%), 90-day mortality (2.3%), and 5-year overall survival (71.8%) (P < .001 for all). After risk-adjusting for confounders, all wait times beyond 6 weeks were associated with worse 5-year overall survival (6-9 weeks: HR 1.10, 95% CI 1.06-1.15; 9-12 weeks: HR 1.25, 95% CI 1.18-1.33; >12 weeks: HR 1.43, 95% CI 1.35-1.52; P < .001 for all). Subgroup analysis after stratification by disease stage demonstrated that patients with stage III colon cancer were able to wait up to 9 weeks before exhibiting worse 5-year overall survival, compared to 6 weeks for patients with stage I or II disease. CONCLUSIONS: Colon cancer patients should undergo surgery 3-6 weeks after diagnosis, as all surgical delays beyond 6 weeks were associated with worse 30-day mortality, 90-day mortality, and 5-year overall survival.

Impact of Treatment Coordination on Overall Survival in Rectal Cancer.

BACKGROUND: Rectal cancer treatment is often multimodal, comprising of surgery, chemotherapy, and radiotherapy. However, the impact of coordination between these modalities is currently unknown. We aimed to assess whether delivery of nonsurgical therapy within same facility as surgery impacts survival in patients with rectal cancer. METHODS: A patient cohort with rectal cancer stages II to IV who received multimodal treatment between 2004 and 2016 from National Cancer Database was retrospectively analyzed. Patients were categorized into three groups: (A) surgery + chemotherapy + radiotherapy at same facility (surgery + 2); (B) surgery + chemotherapy or radiotherapy at same facility (surgery + 1); or (C) only surgery at reporting facility (chemotherapy + radiotherapy elsewhere; surgery + 0). The primary outcome was 5-year overall survival (OS), analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional-hazards models. RESULTS: A total of 44,716 patients (16,985 [37.98%] surgery + 2, 12,317 [27.54%] surgery + 1, and 15,414 [34.47%] surgery + 0) were included. In univariate analysis, we observed that surgery+2 patients had significantly greater 5-year OS compared to surgery + 1 or surgery + 0 patients (5-year OS: 63.46% vs 62.50% vs 61.41%, respectively; P= .002). We observed similar results in multivariable Cox proportional-hazards analysis, with surgery + 0 group demonstrating increased hazard of mortality when compared to surgery + 2 group (HR: 1.09; P< .001). These results held true after stratification by stage for stage II (HR 1.10; P= .022) and stage III (HR 1.12; P< .001) but not for stage IV (P= .474). CONCLUSION: Greater degree of care coordination within the same facility is associated with greater OS in patients with stage II to III rectal cancer. This finding illustrates the importance of interdisciplinary collaboration in multimodal rectal cancer therapy.

Performance in Real World- and Virtual Reality-Based Spatial Navigation Tasks in Patients With Vestibular Dysfunction.

OBJECTIVE: This study evaluated whether vestibular dysfunction is associated with reduced spatial navigation performance. STUDY DESIGN: Cross-sectional study. SETTING: Otolaryngology Clinic in the Johns Hopkins Outpatient Center and an analogous virtual reality (VR) environment. PATIENTS: Eligible patients had diagnosis of unilateral or bilateral vestibular loss. Matched healthy controls were recruited at 1:1 ratio. INTERVENTIONS: The navigation task involved a route-based or place-based strategy in both real world and VR environments. MAIN OUTCOME MEASURES: Navigation performance was measured by distance travelled relative to optimal distance (i.e., path ratio) and the Judgments of Relative Direction (JRD) task, whereby participants had to recall relative angular distances between landmarks. RESULTS: The study sample included 20 patients with vestibular loss (mean age: 61 yrs, SD: 10.2 yrs) and 20 matched controls (mean age: 60 yrs, SD: 10.4 yrs). Patients with vestibular loss travelled significantly greater distance using both route-based (path ratio 1.3 vs. 1.0, p = 0.02) and place-based (path ratio 2.6 vs. 2.0, p = 0.03) strategies in the real world. Overall, participants performed worse in virtual reality compared to real world in both path ratio (2.2 vs. 1.7; p = 0.04) and JRD error (78° vs. 67°; p < 0.01). Furthermore, while controls exhibited significant positive correlations between real world and VR performance in place-based (ß = 0.75; p < 0.001) and JRD tasks (ß = 0.70; p < 0.001), patients with vestibular loss exhibited no similar correlations. CONCLUSIONS: The vestibular system appears to play a role in navigation ability during both actual and virtual navigation, suggesting a role for static vestibular signals in navigation performance.

Feedback circuitry between miR-218 repression and RTK activation in glioblastoma.

Receptor tyrosine kinase (RTK) signaling promotes the growth and progression of glioblastoma (GBM), a highly aggressive type of brain tumor. We previously reported that decreased miR-218 expression in GBM directly promotes RTK activity by increasing the expression of key RTKs and their signaling mediators, including the RTK epidermal growth factor receptor (EGFR), phospholipase C-γ1 (PLCγ1), and the kinases PIK3CA and ARAF. However, increased RTK signaling usually activates negative feedback mechanisms to maintain homeostasis. We found that decreased miR-218 expression in GBM cells also increased the expression of genes encoding additional upstream and downstream components of RTK signaling pathways, including the RTK platelet-derived growth factor receptor α (PDGFRα) and the kinases ribosomal S6 kinase 2 (RSK2) and S6 kinase 1 (S6K1), that collectively overrode the negative feedback mechanism. Furthermore, increased RTK signaling itself suppressed miR-218 expression. Mass spectrometry and DNA pull-down identified binding of signal transducer and activator of transcription 3 (STAT3) along with the transcriptional repressor BCL2-associated transcription factor 1 (BCLAF1) directly to the miR-218 locus. These data identify previously unknown feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.