ABSTRACT
Background: Consensus has not yet been reached regarding the optimal nonoperative treatment of lateral epicondylitis. Physiotherapy is often utilized, yet the specific modalities used can vary significantly, making this treatment arm quite broad. The role and efficacy of passive physiotherapy by way of transcutaneous electrical nerve stimulation (TENS) and extracorporeal shockwave therapy (ESWT) are not well understood. The purpose of this systematic review and meta-analysis was to compare transcutaneous electrical nerve stimulation (TENS) and extracorporeal shockwave therapy (ESWT) with no active treatment. Methods: MEDLINE, Embase, and Cochrane were searched through till September 20, 2021. All English-language randomized trials comparing passive electrophysiotherapy treatments compared with no active treatment/placebo of patients >18 years of age with lateral epicondylitis with minimum 6-month follow-up were included. Results: In the pooled analysis of 2 trials, ESWT provided no benefit compared to no active treatment for pain (-7.063, 95% confidence interval [CI]: -19.16 to 3.89) or function (standardized mean difference [SMD]: 0.03, 95% CI: -0.31 to 0.38, I 2 = 0%). TENS showed no improvement in function compared with control with a mean difference in PRTEE scores of 2.93 points (95% CI -8.30 to 2.43) at 12 months, nor were differences seen in pain scores at 12 months (P = .139). Discussion: The available evidence does not support the use of passive electrophysiotherapy modalities, TENS or ESWT in the treatment of lateral epicondylitis.
ABSTRACT
Purpose: This study compared the responsiveness of a generic (Short Form-36 [SF-36]), an upper extremity-specific (Disabilities of the Arm, Shoulder, and Hand [DASH]) and a wrist-specific (Patient-Rated Wrist Evaluation [PRWE]) outcome score when evaluating distal radius fractures over time. Methods: We observed 235 patients who met the inclusion criteria of an isolated distal radius fracture treated surgically or nonsurgically and greater than age 50 years for 12 months in this prospective study. Standardized assessments were performed at baseline and at 6 and 12 months. Exclusion criteria included subjects with concomitant injuries in the ipsilateral limb and follow-up of less than 1 year. Responsiveness was evaluated through the standardized response mean and the proportion who met a minimal clinically important difference. Floor and ceiling effects were also calculated. Results: The standardized response mean was significantly greatest for the DASH between baseline and 6 months (P < .001), and the PRWE between both baseline and 6 months (P < .01) and 6 and 12 months (P < .01) compared with the SF-36. The proportion of patients who met a minimal clinically important difference between baseline and 6 months was greater in the PRWE, but it did not meet statistical significance (P = .12). The PRWE demonstrated a high ceiling effect at baseline (76.6%) but less so at 12 months (16.9%). The DASH demonstrated similar ceiling effects at baseline (62.9%) and 12 months (18.6%). The SF-36 had no ceiling effect. Conclusions: In the first 6 months, both the DASH and PRWE have greater responsiveness in assessing change over the SF-36 in distal radius fractures. From 6 to 12 months, the wrist-specific PRWE has greater responsiveness over both the DASH and SF-36. This supports the use of the anatomy- and injury-specific outcome measures over the generic outcome measure in detecting change over a patient's early recovery. However, as the time from injury increases, the absence of a ceiling effect from the generic outcome measure may become more useful. Clinical relevance: This study demonstrates the responsiveness of the DASH, PRWE, and SF36 in assessing distal radius fractures treated in patients greater than age 50 in the first year. In establishing the most responsive measure, respondent burden can be decreased in future research.
ABSTRACT
Triple-negative breast cancers (TNBC) are notoriously difficult to treat because they lack hormone receptors and have limited targeted therapies. Recently, we demonstrated that p90 ribosomal S6 kinase (RSK) is essential for TNBC growth and survival indicating it as a target for therapeutic development. RSK phosphorylates Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, highly expressed in TNBC (~70% of cases) and associated with poor prognosis, drug resistance and tumor initiation. YB-1 regulates the tumor-initiating cell markers, CD44 and CD49f however its role in Notch signaling has not been explored. We sought to identify novel chemical entities with RSK inhibitory activity. The Prestwick Chemical Library of 1120 off-patent drugs was screened for RSK inhibitors using both in vitro kinase assays and molecular docking. The lead candidate, luteolin, inhibited RSK1 and RSK2 kinase activity and suppressed growth in TNBC, including TIC-enriched populations. Combining luteolin with paclitaxel increased cell death and unlike chemotherapy alone, did not enrich for CD44(+) cells. Luteolin's efficacy against drug-resistant cells was further indicated in the primary x43 cell line, where it suppressed monolayer growth and mammosphere formation. We next endeavored to understand how the inhibition of RSK/YB-1 signaling by luteolin elicited an effect on TIC-enriched populations. ChIP-on-ChIP experiments in SUM149 cells revealed a 12-fold enrichment of YB-1 binding to the Notch4 promoter. We chose to pursue this because there are several reports indicating that Notch4 maintains cells in an undifferentiated, TIC state. Herein we report that silencing YB-1 with siRNA decreased Notch4 mRNA. Conversely, transient expression of Flag:YB-1(WT) or the constitutively active mutant Flag:YB-1(D102) increased Notch4 mRNA. The levels of Notch4 transcript and the abundance of the Notch4 intracellular domain (N4ICD) correlated with activation of P-RSK(S221/7) and P-YB-1(S102) in a panel of TNBC cell lines. Silencing YB-1 or RSK reduced Notch4 mRNA and this corresponded with loss of N4ICD. Likewise, the RSK inhibitors, luteolin and BI-D1870, suppressed P-YB-1(S102) and thereby reduced Notch4. In conclusion, inhibiting the RSK/YB-1 pathway with luteolin is a novel approach to blocking Notch4 signaling and as such provides a means of inhibiting TICs.
