Six-minute walk test distance at time of hospital discharge is strongly and independently associated with all-cause mortality following cardiac surgery.

We investigated the impact of distance covered in the six-minute walk test (6mWT) before being discharged from the hospital after cardiac surgery on the risk of all-cause mortality. Our study included 1127 patients who underwent cardiac surgery and then took part in a standardised physiotherapist-supervised inpatient rehabilitation programme during 2007-2017. The percentage of the predicted 6mWT distance, and the lower limit of normal distance was calculated based on individual patients' age, sex, and body mass index. We used Cox regression with adjustment for confounders to determine multivariable-adjusted hazard ratios (HRs) for mortality. Over a median follow-up period of 6.4 (IQR: 3.5-9.2) years, 15% (n = 169) patients died. We observed a strong and independent inverse association between 6mWT distance and mortality, with every 10 m increase in distance associated to a 4% reduction in mortality (HR: 0.96, 95% CI 0.94-0.98, P < 0.001). Those in the top tertile for predicted 6mWT performance had a 49% reduced risk of mortality (HR: 0.51, 95% CI 0.33-0.79) compared to those in the bottom tertile. Patients who met or exceeded the minimum normal 6mWT distance had 36% lower mortality risk (HR: 0.64, 95% CI 0.45-0.92) compared to those who did not meet this benchmark. Subgroup analysis showed that combined CABG and valve surgery patients walked less in the 6mWT compared to those undergoing isolated CABG or valve surgeries, with a significant association between 6mWT and mortality observed in the isolated procedure groups only. In conclusion, the longer the distance covered in the 6mWT before leaving the hospital, the lower the risk of mortality.

Targeting 14-3-3ε activates apoptotic signaling to prevent cutaneous squamous cell carcinoma.

More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.

Effects of Oxytocin for Induction and Augmentation of Labor on Pelvic Floor Symptoms and Support in the Postpartum Period.

OBJECTIVE: The aim of the study was to determine whether oxytocin for induction or augmentation of labor impacts the incidence or persistence of pelvic floor symptoms and support 5 to 10 weeks after first vaginal delivery. METHODS: Participants in this prospective cohort study were nulliparous women 18 years or older that delivered vaginally at 37 weeks gestation or more and completed the Epidemiology of Prolapse and Incontinence Questionnaire (EPIQ) and the Pelvic Organ Prolapse Quantification examination in third trimester and 5 to 10 weeks postpartum. We compared the incidence and persistence of symptomatic EPIQ domains and worse vaginal support (maximal vaginal descent ≥0 cm) between women who received oxytocin with those that did not (with or without prostaglandin or mechanical methods in both groups). We performed modified binomial regression to calculate adjusted relative risks of each outcome with 95% confidence intervals. RESULTS: The mean (SD) age of the 722 participants was 28.3 (5.2) years; 20% were Hispanic. There were no significant differences according to oxytocin exposure in either incidence or persistence of symptomatic EPIQ domains or worse vaginal support. We found similar results in sensitivity analyses comparing women who received oxytocin as the sole pharmacologic agent to women who received no pharmacologic agent. After adjusting for demographic and obstetric factors associated with incidence and persistence of symptoms and support, oxytocin exposure continued to have no effect. CONCLUSIONS: Oxytocin during labor does not significantly increase the risks for the incidence or persistence of pelvic floor symptoms or worse vaginal support in the early postpartum period, although power for less frequent outcomes was limited.

Targeting 14-3-3ε-CDC25A interactions to trigger apoptotic cell death in skin cancer.

Non-melanoma skin cancer is the most common form of cancer worldwide. We previously documented an anti-apoptotic role for CDC25A in cutaneous squamous cell carcinoma (SCC), an activity dependent on its association with 14-3-3 proteins. We hypothesized that targeting CDC25A-14-3-3ε interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3ε, 14-3-3γ and 14-3-3ζ in SCC cells but not normal keratinocytes. 14-3-3ε and CDC25A activated Akt/BAD/Survivin pro-survival signaling. To target the interaction of 14-3-3ε with CDC25A for cancer therapy, we developed two novel phospho-peptides, pS and pT, corresponding to each of the 14-3-3 binding sites of CDC25A, to specifically interfere with 14-3-3ε binding to CDC25A. Peptides pT (IC50 = 22.1 µM), and pS (IC50 = 29 µM) induced SCC cell death and blocked 14-3-3ε binding to CDC25A. pS or pT treatment of SCC xenografts increased apoptotic cell death and decreased pro-survival P-Akt (S473) and Survivin, demonstrating the effectiveness of the peptides in vivo. These findings lay a framework for the further development of peptides to target 14-3-3ε-CDC25A interactions for skin cancer treatment.