Citations

Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism.

Key Points Survival of chronic GVHD patients was predicted by clinician-assessed response and changes in patient-reported outcomes. FFS was predicted by clinician-assessed response, changes in patient-reported outcomes, and the 2014 NIH response criteria.

AbstractAimPatent foramen ovale (PFO) is a common atrial septal defect that is largely asymptomatic and often undiagnosed. The impact of aPFOin patients undergoing liver transplantation (LT) is unknown.ObjectiveAssess the impact ofPFOand physiologic intrapulmonary shunt (IPS) on the perioperative outcomes of patients who underwentLT.MethodsWe performed a retrospective, intention‐to‐treat analysis of patients withPFOand controls withoutPFOwho underwentLTat Mayo Clinic in Florida between 2008 and 2013. Patients with physiologicIPSwere also analyzed. The cohorts were compared for baseline characteristics, length of stay in the intensive care unit (ICU), postoperative oxygen requirements, 30‐d cerebrovascular accidents, and mortality.ResultsOf the 935 patients who underwentLT, 10.4% had provenPFOby pre‐LTechocardiogram. Control patients (n = 101) were statistically older thanPFOandIPS(n = 56) patients, but similar in sex,BMI, Model for End‐stage Liver Disease score, American Society of Anesthesiologist score, and left ventricular ejection fraction.PFOandIPSpatients had similar length of stay in theICU, mechanical ventilation times, post‐LToxygen requirements, and 30‐d mortality compared to controls. Subgroup analysis showed similar outcomes for largePFOandIPSpatients to controls.ConclusionsThe presence ofPFOdid not have a negative impact on perioperativeLToutcomes.

Abstract Purpose: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. Experimental design: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. Results: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%–43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%–44%) randomized to rituximab. Six (17%; 95% CI, 7%–34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%–29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. Conclusions: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab. Clin Cancer Res; 22(2); 319–27. ©2015 AACR.

Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications.

SummaryObjectiveInfantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome.MethodsPatients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30‐and 60‐month follow‐ups using the Autism Diagnostic Observation Schedule—Generic (ADOS‐G).ResultsOf the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009).SignificanceASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non‐white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long‐term outcome.

Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. Conclusion: The presence of VI is not an independent predictor of outcome in WDTC.