Citations

Abstract Signaling through fibroblast growth factor receptor one (FGFR1) is a known inducer of proliferation in both embryonic and human adult mesenchymal stem cells (hMSCs) and positively regulates maintenance of stem cell viability. Leveraging the mitogenic potential of FGF2/FGFR1 signaling in stem cells for therapeutic applications necessitates a mechanistic understanding of how this receptor stimulates cell cycle progression. Using small interfering RNA (siRNA) depletion, antibody-inhibition, and small molecule inhibition, we establish that FGFR1 activity is rate limiting for self-renewal of hMSCs. We show that FGFR1 promotes stem cell proliferation through multiple mechanisms that unite to antagonize cyclin-dependent kinase (CDK) inhibitors. FGFR1 not only stimulates c-Myc to suppress transcription of the CDK inhibitors p21Waf1 and p27Kip1, thus promoting cell cycle progression but also increases the activity of protein kinase B (AKT) and the level of S-phase kinase-associated protein 2 (Skp2), resulting in the nuclear exclusion and reduction of p21Waf1. The in vivo importance of FGFR1 signaling for the control of proliferation in mesenchymal progenitor populations is underscored by defects in ventral mesoderm formation during development upon inhibition of its signaling. Collectively, these studies demonstrate that FGFR1 signaling mediates the continuation of MSC growth and establishes a receptor target for enhancing the expansion of mesenchymal progenitors while maintaining their multilineage potential. Stem Cells 2013;31:2724–2736

AbstractTendon‐to‐bone integration is a great challenge for tendon or ligament reconstruction regardless of use of autograft or allograft tendons. We mineralized the tendon, thus transforming the tendon‐to‐bone into a “bone‐to‐bone” interface for healing. Sixty dog flexor digitorum profundus (FDP) tendons were divided randomly into five groups: (1) normal FDP tendon, (2) CaP (non‐extraction and mineralization without fetuin), (3) CaPEXT (Extraction by Na2HPO4 and mineralization without fetuin), (4) CaPFetuin (non‐extraction and mineralization with fetuin), and (5) CaPEXTFetuin (extraction and mineralization with fetuin). The calcium and phosphate content significantly increased in tendons treated with combination of extraction and fetuin compared to the other treatments. Histology also revealed a dense mineral deposition throughout the tendon outer layers and penetrated into the tendon to a depth of 200 µm in a graded manner. Compressive moduli were significantly lower in the four mineralized groups compared with normal control group. No significant differences in maximum failure strength or stiffness were found in the suture pull‐out test among all groups. Mineralization of tendon alters the interface from tendon to bone into mineralized tendon to bone, which may facilitate tendon‐to‐bone junction healing following tendon or ligament reconstruction. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1713–1719, 2013

Background: Currently, patients with type 1 diabetes decide on the amount of insulin to administer based on several factors, including current plasma glucose value, expected meal input, and physical activity (PA). One future therapeutic modality for patients with type 1 diabetes is the artificial endocrine pancreas (AEP). Incorporation of PA could enhance the efficacy of AEP significantly. We compared the main technologies used for PA quantitation. Subjects and Methods: Data were collected during inpatient studies involving healthy control subjects and type 1 diabetes. We report PA quantified from accelerometers (acceleration units [AU]) and heart rate (HR) monitors during a standardized activity protocol performed after a dinner meal at 7 p.m. from nine control subjects (four were males, 37.4±12.7 years old, body mass index of 24.8±3.8 kg/m 2 , and fasting plasma glucose of 4.71±0.63 mmol/L) and eight with type 1 diabetes (six were males, 45.2±13.4 years old, body mass index of 25.1±2.9 kg/m 2 , and fasting plasma glucose of 8.44±2.31 mmol/L). Results: The patient-to-patient variability was considerably less when examining AU compared with HR monitors. Furthermore, the exercise bouts and rest periods were more evident from the data streams when AUs were used to quantify activity. Unlike the AU, the HR measurements provided little insight for active and rest stages, and HR data required patient-specific standardizations to discern any meaningful pattern in the data. Conclusions: Our results indicated that AU provides a reliable signal in response to PA, including low-intensity activity. Correlation of this signal with continuous glucose monitoring data would be the next step before exploring inclusion as input for AEP control.

Objective To evaluate survival in patients after radical cystectomy ( RC ) who presented with non‐muscle‐invasive urothelial carcinoma and progressed to muscle invasion during surveillance. Our secondary objective was to evaluate the association between clinical factors before RC and survival. Patients and Methods In all, 981 consecutive M ayo C linic RC patients without a history of radiation or systemic chemotherapy were reviewed. Of these, 190 had RC after they progressed from non‐muscle invasive disease to muscle invasion (progressed to ≥ pT2 ). These patients were compared to 310 patients who had RC before muscle invasion (≤ pT1 ), and 481 patients who had muscle invasion at initial presentation (presented with ≥ pT2 ). Survival estimates were generated using the K aplan– M eier method and compared using the log‐rank test, while adjusted analyses were performed using C ox proportional hazard regression models. Results Patients who progressed to muscle invasion on surveillance had a higher risk of death than patients who initially presented with muscle invasion (overall survival hazard ratio [ HR ] 1.3; 95% confidence interval [ CI ] 1.0, 1.5). The estimated 5‐year cancer‐specific survival was 85.4% for patients presenting with ≤ pT1 , 52.9% for patients who progressed to ≥ pT2 , and 62.4% for patients who presented with ≥ pT2 ( P < 0.001). The corresponding 5‐year overall survival rates were 70.0%, 42.1%, and 49.5% ( P < 0.001). Of the patients who initially presented with non‐muscle‐invasive disease, progression to muscle invasion was associated with increased risk of cancer‐specific death (adjusted HR 2.38; 95% CI 1.6, 3.5). Lack of information about patients who presented without muscle invasion and never received RC is the major limitation of this study. Conclusions Despite close surveillance, many patients who progress to muscle invasion will die from bladder cancer. Patients who progress to muscle invasion on surveillance seem to have particularly aggressive disease and may benefit from multimodal treatments.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

Object Management of idiopathic normal-pressure hydrocephalus (iNPH) is hard because the diagnosis is difficult and shunt surgery has high complication rates. An important complication is overdrainage, which often can be treated with adjustable–shunt valve manipulations but also may result in the need for subdural hematoma evacuation. The authors evaluated shunt surgery overdrainage complications in iNPH and their relationship to lumbar puncture opening pressure (LPOP). Methods The authors reviewed the charts of 164 consecutive patients with iNPH who underwent shunt surgery at their institution from 2005 to 2011. They noted age, sex, presenting symptoms, symptom duration, hypertension, body mass index (BMI), imaging findings of atrophy, white matter changes, entrapped sulci, LPOP, valve opening pressure (VOP) setting, number of valve adjustments, serious overdrainage (subdural hematoma requiring surgery), radiological overdrainage (subdural hematomas or hygroma seen on postoperative imaging), clinical overdrainage (sustained or postural headache), other complications, and improvements in gait, urine control, and memory. Results Eight patients (5%) developed subdural hematomas requiring surgery. All had an LPOP of greater than 160 mm H2O and an LPOP-VOP of greater than 40 mm H2O. Radiological overdrainage was more common in those with an LPOP of greater than 160 mm H2O than in those with an LPOP of less than 160 mm H2O (38% vs 21%, respectively; p = 0.024). The BMI was also significantly higher in those with an LPOP of greater than 160 mm H2O (median 30.2 vs 27.0, respectively; p = 0.005). Conclusions Serious overdrainage that caused subdural hematomas and also required surgery after shunting was related to LPOP and LPOP-VOP, which in turn were related to BMI. If this can be replicated, individuals with a high LPOP should have their VOP set close to the LPOP, or even higher. In doing this, perhaps overdrainage complications can be reduced.